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Glaucoma is the leading cause of acquired blindness in Japan. One reason that it often leads to blindness is that it can continue to worsen even after effective medical reduction of intraocular pressure (IOP), the only evidence-based treatment. The limitations of current treatments make it critical to identify IOP-independent factors that can cause glaucoma and develop new drugs to target these factors. This is a challenging task, as the pathology of glaucoma is thought to be very complex, with different combinations of factors underlying its development and progression in different patients. Additionally, there is a deficiency in methods to efficiently perform clinical evaluations and reliably probe the state of the disease over relatively short periods. In addition, newly developed drugs need to be evaluated with clinical trials, for which human and financial resources are limited, before they can be widely used for treatment. Taking all these issues into consideration, it is evident that there are two urgent issues to consider: the development of methods to classify glaucoma in detail based on its pathology, and the improvement of clinical evaluation methods. In this review, we discuss some of our efforts to develop new neuroprotective agents for glaucoma, with a focus on the following three areas: 1. Clinical research and development of methods to classify glaucoma in detail based on IOP-independent factors, and the exploration of possibilities for the improvement of clinical evaluation of glaucoma. 2. Pathology-based research and development of new drugs for glaucoma, focusing on comprehensive gene expression analysis and the development of molecule-targeting drugs, using murine optic nerve crush as a disease model. 3. Development of next generation in vivo imaging modalities and the establishment of infrastructure enabling "big-data" analysis. First, we discuss our clinical research and the development of methods to classify glaucoma in detail based on IOP-independent factors, as well as our investigation of ways to improve the clinical evaluation of the disease. Our research was prompted by the multifactorial nature of glaucoma. There is a high degree of variability in the pattern and speed of the progression of visual field defects in individual patients, presenting a major obstacle for successful clinical trials. To overcome this, we classified the eyes of glaucoma patients into 4 types, corresponding to the 4 patterns of glaucomatous optic nerve head morphology described: by Nicolela et al. and then tested the validity of this method by assessing the uniformity of clinical features in each group. We found that in normal tension glaucoma (NTG) eyes, each disc morphology group had a characteristic location in which the loss of circumpapillary retinal nerve fiber layer thickness (cpRNFLT; measured with optical coherence tomography: OCT) was most likely to occur. Furthermore, the incidence of reductions in visual acuity differed between the groups, as did the speed of visual field loss, the distribution of defective visual field test points, and the location of test points that were most susceptible to progressive damage, measured by Humphrey static perimetry. These results indicate that Nicolela's method of classifying eyes with glaucoma was able to overcome the difficulties caused by the diverse nature of the disease, at least to a certain extent. Building on these findings, we then set out to identify sectors of the visual field that correspond to the distribution of retinal nerve fibers, with the aim of detecting glaucoma progression with improved sensitivity. We first mapped the statistical correlation between visual field test points and cpRNFLT in each temporal clock-hour sector (from 6 to 12 o'clock), using OCT data from NTG patients. The resulting series of maps allowed us to identify areas containing visual field test points that were prone to be affected together as a group. We also used a similar method to identify visual field sectors within a 10 x 10 grid displayed by an OCT map of the macula. By analyzing both the visual field and the macular map sectors, we anticipate that a more accurate and sensitive detection of glaucoma progression can become possible. We also used laser speckle flowgraphy (LSFG) to assess optic nerve blood flow. We found that compared to healthy eyes, eyes with early-stage NTG had decreased blood flow, and the peak of the blood flow wave form of each heartbeat was delayed. Finally, we used a method combining swept source OCT (SS-OCT) and newly developed analysis software to reconstruct the entire lamina cribrosa, a structure situated deep in the optic nerve head. This morphological analysis returned preliminary data suggesting that alterations in the morphology of the lamina cribrosa are already present in the early stages of glaucoma. This result indicates that axonal injury, mediated by morphological abnormalities of the lamina cribrosa, is involved in the pathogenesis of glaucoma. The next topic discussed is the pathology-based drug research and development, focusing on the use of comprehensive gene expression analysis and the development of molecule-targeting drugs in a murine model of optic nerve injury. Learning from clinical data on glaucoma and the lamina cribrosa, we carried out basic research to first determine what factors regulate axonal injury, and then develop drugs targeting these factors. Specifically, we performed a comprehensive gene expression analysis, using a next generation sequencer, and pathway analysis of retinal samples obtained from a murine model of axonal injury. This analysis revealed a characteristic upregulation of genes (such as Chop) that belongs to the endoplasmic reticulum stress pathway. An immunohistological analysis revealed that these changes in gene expression took place in the retinal ganglion cells, suggesting that endoplasmic reticulum stress molecules may be suitable therapeutic targets. Among these molecules, we chose CHOP as our primary target for drug development. Currently, we are in the process of screening a library of 1274 drugs, all of which are already used in human subjects, for CHOP inhibitors. The last topic of our discussion is future possibilities for glaucoma management. First, we discuss the development of next generation in vivo imaging modalities that allow detailed description of pathomechanisms of this multifactorial disease, glaucoma. The purpose of this research was to improve the efficacy of glaucoma diagnosis and to visualize its pathology at a cellular/molecular level and develop molecule-specific therapies. Currently available visual field tests are subjective, since they rely on a determination of the threshold of light perception, and are affected by poor reproducibility. The current dependence on visual field tests to ascertain the progression of glaucoma is thus a serious limitation on an important task of ophthalmologists. We, therefore, turned our focus to the establishment of an in vivo imaging method to detect dying retinal ganglion cells, which would highlight the pathologic state of glaucoma with high sensitivity. To this end, we used confocal scanning ophthalmoscopy to assess the usefulness of SYTOX Orange as a cell death probe. Our results showed that this probe could reveal dying retinal ganglion cells clearly, quickly and with high sensitivity. We, therefore, believe that the clinical application of probes that can sensitively detect dying retinal ganglion cells is a highly promising approach. This also applies to the use of molecular tools that can provide information on the molecular pathology of glaucoma. Finally, we would like to introduce our national collaborative work on the analysis of "big-data". The project aims to collect as wide a range of data as possible at an unprecedented scale. The data to be registered ranges from basic glaucoma data, such as IOP and visual field test results, to data from the most sophisticated comprehensive expression analyses or imaging data. This is an important area of research, since it promises to enable the exploration of targets for drug discovery and the identification of new biomarkers to efficiently detect glaucoma progression by applying new analysis strategies to the complex mass data. The project not only depends on the collaborative efforts of various types of clinical settings including private practices, medical centers and university hospitals, but also contributions of the pharmaceutical and the medical device industries. Thus, uniting a wide range of Japanese interests and resources is the key for success. In summary, in order to aim for ZERO BLINDNESS, a drastic improvement in the quality of our patient care, drug development research for unmet medical demands, and a strategic collaboration of various professionals in the ophthalmic industry are essential. With the deep appreciation we fell towards the selfless support extended during the earthquake disaster, we wish to translate our "gratitude" into "power" from Tohoku. In doing so, we as academicians are determined to keep on contributing to the society by making progress in the medicine.

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Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphocytic leukaemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m(2) intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomised comparison of eight cycles of CHOP plus rituximab 375 mg/m(2) intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse haematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced haematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs. Rituximab is a mouse/human chimaeric IgG(1)-kappa monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B lymphocytes. Although treatment with rituximab induces lymphopenia in most patients, typically lasting about 6 months, a full recovery of B lymphocytes in the peripheral blood is usually seen 9-12 months after therapy, as CD20 is not expressed on haematopoietic stem cells. CD20 is, however, expressed on >90% of B-cell non-Hodgkin's lymphomas (NHL) and to a lesser degree on B-cell chronic lymphocytic leukaemia (CLL) cells. Although not fully elucidated, the cytotoxic effects of rituximab on CD20-positive malignant B cells appears to involve complement-dependent cytotoxicity, complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. In addition, in vitro data indicate that rituximab sensitises tumour cells to the effects of conventional chemotherapeutic drugs. Serum rituximab concentrations increased in proportion to dose across a wide range of single- and multiple-dose intravenous regimens in patients with B-cell NHL. When administll NHL. When administered at a dose of 375 mg/m(2) once weekly for 4 weeks in a pivotal trial in patients with relapsed or refractory indolent B-cell NHL (follicular or small lymphocytic subtypes), peak serum concentrations essentially doubled from the first (239.1 mg/L) to the fourth (460.7 mg/L) infusion, while elimination half-life (t(1/2)) increased from 76.3 to 205.8 hours (3.2 to 8.6 days). The concomitant increase in serum rituximab concentrations and t(1/2) with each successive infusion may be due, at least in part, to the elimination of circulating CD20-positive B cells and reduction or saturation of CD20-binding sites after the initial infusions of rituximab. The pharmacokinetic properties of rituximab are also characterised by wide inter-individual variability, and serum drug concentrations that are correlated with clinical response. Although pharmacokinetic data are limited in patients with aggressive forms of NHL, such as diffuse large B-cell lymphoma, rituximab appears to have a similar pharmacokinetic profile in these patients to that in patients with indolent B-cell NHL. The pharmacokinetics of rituximab are also reported to be similar whether the drug is administered with or without cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. A number of studies have demonstrated efficacy of intravenous rituximab in patients with various lymphoid malignancies of B-cell origin, including indolent (e.g. follicular lymphoma) and aggressive (e.g. diffuse large B-cell lymphoma) forms of NHL, and CLL, but the drug has not yet been approved for use in CLL, and approved indications in NHL vary between countries. In the US, for example, rituximab is available for the treatment of patients with low-grade or follicular, relapsed or refractory, CD20-positive B-cell NHL. In Europe, the drug has similar approval for relapsed or refractory follicular NHL as in the US, but has also been approved for use in combination with CHOP chemotherapy for the most common aggressive form of NHL (CD20-positive, diffuse large B-cell lymphoma). Rituximab was approved for these indications primarily on the basis of results from two pivotal trials. In Japan, rituximab has been approved for indolent B-cell NHL and mantle cell lymphoma (an aggressive form of B-cell NHL), primarily on the basis of results of a Japanese phase II trial. Indolent NHL: Results of several studies evaluating rituximab 375 mg/m(2) once weekly for 4 weeks in patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic lymphomas) showed objective response (OR) rates ranging from approximately 40-60% in those receiving the drug for relapsed or refractory indolent B-cell NHL, and slightly higher (50-70%) for those receiving rituximab as first-line therapy. In a pivotal trial in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL, intent-to-treat (ITT) analysis showed an OR rate of 48%, and a projected median time to progression of 13 months. Encouraging data are also emerging on the use of rituximab in combination with chemotherapeutic agents (e.g. CHOP, fludarabine-containing regimens) or other drugs (e.g. interferon-alpha2a) in previously untreated patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic subtypes). Rates for OR were consistently around 95%, with the majority being complete responses (CRs). Follow-up data from a study in 40 patients with low-grade or follicular B-cell NHL treated with rituximab plus CHOP as first-line therapy showed that responses were durable with a progression-free survival and median duration of response >5 years.Bcl-2 gene rearrangement (t14;18) occurs in malignant cells in up to 85% of patients with follicular lymphoma, and minimal residual disease in peripheral blood and bone marrow can be monitored using polymerase chain reaction (PCR). In several studies assessing blood and/or bone marrow, rituximab has achieved molecular response (conversion from PCR-positive to PCR-negative bcl-2 status) in at least half of the patients. Aggressive NHL: Studies with rituximab as monotherapy in aggressive B-cell NHL, a potentially curable disorder, have generally been restricted to patients with relapsed or recurrent disease, since CHOP has traditionally been the standard first-line treatment regimen. However, promising results from phase II monotherapy studies prompted further clinical investigation of rituximab in conjunction with chemotherapy. Thus, most studies with rituximab in patients with aggressive forms of B-cell NHL have involved combination therapy, including a pivotal randomised trial comparing eight cycles of standard CHOP therapy plus rituximab 375 mg/m(2) (one dose per cycle) versus CHOP alone in 399 previously untreated elderly patients (60-80 years of age) with diffuse large B-cell lymphoma. Results of the pivotal trial showed a clear advantage for rituximab plus CHOP versus CHOP in terms of event-free survival (primary endpoint) at 2 years (57% vs 38%, p < 0.001). Overall survival at 2 years (70% vs 57%, p < 0.01) and CR rate (76% vs 63%, p < 0.01) were also higher with the rituximab-CHOP combination. Other, smaller trials with rituximab in combination with CHOP or other chemotherapeutic regimens, either as first-line therapy or for patients with relapsed or refractory aggressive B-cell NHL, have also shown promising results in terms of clinical response rates.CLL: In relatively small trials (n < 40) conducted primarily in patients with relapsed or refractory B-cell CLL, rituximab monotherapy (various regimens) achieved OR rates of 23-45%, with median duration of response ranging from approximately 3-10 months. (ABSTRACT TRUNCATED)

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Mitoxantrone (Novantrone), a synthetic anthracenedione derivative, is an antineoplastic, immunomodulatory agent. Its presumed mechanism of action in patients with multiple sclerosis (MS) is via immunomodulatory mechanisms, although these remain to be fully elucidated. Intravenous mitoxantrone treatment improved neurological disability and delayed progression of MS in patients with worsening relapsing-remitting (RR) [also termed progressive-relapsing (PR) MS] or secondary-progressive (SP) disease. In a pivotal randomised, double-blind, multicentre trial, mitoxantrone 12 mg/m(2) administered once every 3 months for 2 years provided significant improvements in neurological disability ratings, including Kurtzke Expanded Disability Status Scale (EDSS), Ambulatory Index (AI) and Standardised Neurological Status (SNS) scores, compared with placebo. The drug also significantly reduced the mean number of corticosteroid-treated relapses and prolonged the time to the first treated relapse, with the beneficial effects on disease progression supported by magnetic resonance imaging. Post hoc analyses suggest that the benefits associated with mitoxantrone treatment may be sustained for at least 12 months after cessation of treatment, mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo. Concomitant intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g once every month for 6 months was more effective than intravenous methylprednisolone monotherapy in preventing the development of new gadolinium-enhanced lesions in patients with very active RRMS or SPMS. The drug was generally well tolerated in patients with MS. Adverse events were generally mild to moderate in severity and usually resolved upon discontinuation of treatment or with appropriate pharmacotherapy. At the recommended dosage, mitoxantrone appears to have a low potential to cause cardiotoxicity. In conclusion, intravenous mitoxantrone reduces the relapse rate and slows progression of the disease in patients with worsening RRMS, PRMS or SPMS; thus providing a new option for the management of these patients. The drug was generally well tolerated at the recommended dosage, although potential cardiotoxicity limits the total cumulative dose to 140 mg/m(2). Further studies are warranted to determine which patients with worsening RRMS, PRMS or SPMS are most likely to benefit from mitoxantrone treatment and to more fully define the long-term safety and tolerability of mitoxantrone, including the use of concomitant cardioprotectants to extend the therapeutic lifespan of the drug. Pharmacodynamic Profile. Mitoxantrone, a synthetic anthracenedione derivative, is an established cytotoxic, antineoplastic agent. Its presumed mechanism of action in multiple sclerosis (MS) is immunosuppression. In antineoplastic studies, the drug showed several immunomodulatory effects, inducing macrophage-mediated suppression of B-cell, T-helper and T-cytotoxic lymphocyte function. Currently, the pharmacodynamic properties of mitoxantrone have not been investigated to any extent in patients with MS. In one study, 6 months' treatment with intravenous mitoxantrone generally had no effect on the distribution of cytokine-positive peripheral blood monocyte cells in patients with MS. In an animal model of the disease, mitoxantrone suppressed the development and progression of both actively and passively induced acute experimental allergic encephalomyelitis (EAE). It appeared to be 10-20 times more effective than cyclophosphamide in the suppression of EAE. Moreover, mitoxantrone approximately doubled the mean time to onset of EAE versus control animals (279 vs 148 days after immunisation; p < 0.00005). In vitro, mitoxantrone 10 and 100 micro g/L inhibited myelin degradation by leucocytes and peritoneal macrophages derived from mice with acute EAE by approximately 60% and 100%. Pharmacokinetic Profile. Currently, there are no published pharmacokinetic data for intravenous mitoxantrone in pitoxantrone in patients with MS, paediatric patients or in those with renal impairment. All studies, to date, have been in patients with cancer receiving a single, approximately 30-minute intravenous infusion of mitoxantrone 5-14 mg/m(2). The drug exhibits triexponential pharmacokinetics, with a rapid initial distribution (alpha) phase, an intermediate distribution (beta) phase and a much slower elimination (gamma) phase. The mean half-life of the alpha phase appears to be 6-12 minutes and that of the beta phase 1.1-3.1 hours. Mitoxantrone has a high affinity for tissue, with a volume of distribution of up to 2248 L/m(2). Mitoxantrone persists for prolonged periods in tissues and was detectable in autopsy tissue from patients who last received the drug up to 272 days before death. At concentrations of 10-10000 ng/mL, the drug was 70-80 % bound to plasma proteins in dogs. Elimination of mitoxantrone occurs predominantly through biliary excretion and may be impaired in patients with hepatic dysfunction or third space abnormalities (e.g. ascites). The mean terminal elimination half-life of mitoxantrone ranged from 23 hours to 215 hours. Renal clearance accounts for 10 % of the total clearance of the drug. Total clearance of mitoxantrone ranged from 13 to 34.2 L/h/m(2) and renal clearance from 0.9 to 2.7 L/h/m(2). The drug appears to have a low potential for interaction with other concomitantly administered agents. Therapeutic Efficacy. Intravenous mitoxantrone (infusion of > or = 5 minutes), either as monotherapy or in combination with intravenous methylprednisolone, delayed the progression of the disease in patients with secondary-progressive (SP) or worsening relapsing-remitting (RR) MS (the latter is also termed progressive-relapsing MS) in comparative, randomised, multicentre trials. In a double-blind, monotherapy trial (Mitoxantrone In Multiple Sclerosis [MIMS] trial), mitoxantrone 12 mg/m(2) (n = 60) once every 3 months for 2 years significantly improved neurological disability relative to placebo (n = 64), as assessed by changes in mean Kurtzke Expanded Disability Status Scale (EDSS) score, mean Ambulatory Index (AI) score and mean Standardised Neurological Status (SNS) score. The drug also significantly reduced the mean number of corticosteroid-treated relapses per patient and prolonged the time to the first treated relapse. A Wei-Lachin multivariate analysis of these five efficacy variables indicated that the global difference between the two treatment groups was 0.30 (p < 0.0001). Mitroxantrone was also more effective than placebo according to secondary endpoints in this study, with fewer mitoxantrone recipients experiencing a relapse, a deterioration of > or =1 EDSS point or a confirmed deterioration in EDSS score over a 3-month period. Mitoxantrone recipients also showed less deterioration in quality-of-life ratings and had fewer hospital admissions, whereas more placebo recipients had new gadolinium-enhanced lesions at study end (the latter parameter was assessed using magnetic resonance imaging [MRI] in a subgroup of 110 patients, including 40 patients who received an exploratory 5 mg/m(2) dose). Furthermore, post hoc analyses indicated that the beneficial effects of mitoxantrone treatment on EDSS, SNS and AI scores were sustained for at least 12 months after cessation of treatment, with mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo. Preliminary data from a cost-minimisation analysis based on results from the MIMS trial indicated that approximately half of the cost of mitoxantrone was offset by cost savings in other areas associated with the treatment of MS (direct and indirect major costs), with a total annual incremental cost for mitoxantrone of dollar 1661 per patient. Combination therapy once-monthly with intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g was more effective than intravenous methylprednisolone 1g once every month in preventing the development of gadolinium-enhanced lesions in patients with very active RRMS or SPMS (double-blind assessment using MRI scans). After 6 months, significantly more combination therapy recipients had no new gadolinium-enhanced lesions (90.5% vs 31.3% with monotherapy; p < 0.001) [primary endpoint]. There were also significant reductions in both the mean number of new enhancing lesions and the total number of gadolinium-enhanced lesions in patients receiving combination therapy versus methylprednisolone monotherapy.Tolerability. Mitoxantrone was generally well tolerated in patients with MS. Treatment-emergent adverse events occurring significantly more frequently with mitoxantrone (12 mg/m(2) once every 3 months for 2 years) than placebo were nausea, alopecia, menstrual disorders, urinary tract infection, amenorrhoea, leucopenia and elevated gamma-glutamyltranspeptidase levels. Adverse events were usually mild to moderate in severity and generally resolved with discontinuation of treatment or when treated with appropriate pharmacotherapy. Eight percent of patients discontinued treatment in the mitoxantrone 12 mg/m(2) group due to an adverse event versus 3% of placebo recipients. The incidence of drug-related acute myelogenous leukaemia was very low (0.12%) in a cohort of 802 patients with MS receiving mitoxantrone. Evidence suggests that the risk of cardiotoxicity is low in patients with MS. After 1 year of monotherapy, 3.4% of mitoxantrone recipients had a reduction in left ventricular ejection fraction (LVEF) to < or =50% compared with 0% of placebo recipients; at the end of the second year, respective incidences were 1.9% and 2.9% (total cumulative dose of mitoxantrone per patient was 96 mg/m(2) after 2 years' treatment). (ABSTRACT TRUNCATED)

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The isolation of artemisinin from the traditional medicinal herb qīng hāo (Artemisia annua), its characterization as a peroxide and preparation of the derivatives dihydroartemisinin, artemether and artesunate in the 1970s and 1980s by Chinese scientists under the umbrella of Project 523 collectively represents one of the great events in medicine in the latter third of the 20(th) Century. Artemisinins have become the most important component of chemotherapy of malaria: although used initially in monotherapy, they are now used in combination therapies or ACTs with longer half-life quinolines or arylmethanols. Nevertheless, the recent emergence of artemisinin-tolerant strains of the malaria parasite as reflected in increased clearance times of parasitaemia in patients treated with ACTs represents the greatest threat to control of malaria since resistance to chloroquine was first reported over 55 years ago. Importantly, the event brings into sharp focus the realization that relatively little is precisely understood, as opposed to widely assumed, for the mechanism of drug action of artemisinins and their synthetic peroxide analogues. Thus, we review here their antimalarial activities, the use of artemisinins in combination therapies, drug-drug interactions with the quinolines and arylmethanols, and metabolism of the artemisinins and synthetic peroxides. The mechanism of action of quinolines and arylmethanols, in particular their ability to induce redistribution of heme into the parasite cytosol, is also highlighted. This collective information is then used as a counterpoint to screen the validity of two of the prevailing hypotheses of drug action of artemisinins and synthetic peroxides, namely i. 'the C-radical hypothesis' wherein the peroxide undergoes 'bioactivation' by ferrous iron to generate C-radicals that are held to be the cytotoxic agents and ii. the 'heme hypothesis' wherein ferrous heme may generate either the same type of 'cytotoxic' C-radical, or the peroxide forms heme adducts that apparently inherit the exquisite cytotoxicities of the parent peroxide in one way or another. In a subsequent review, we screen the third and fourth hypotheses: the SERCA hypothesis wherein artemisinins modulate operation of the malaria parasite sarcoendo plasmic reticulum calcium pump SERCA Ca(2+)-ATPase ATP6 and the co-factor hypothesis wherein artemisinins act as oxidant drugs through rapidly oxidizing reduced conjugates of flavin cofactors, or those of flavin cofactor precursors such as riboflavin, and other susceptible endogenous substrates that play a role in maintaining intraparasitic redox homeostasis. For the C-radical hypothesis, details of in vitro chemical studies in the context of established chemistry of C-radicals and their ability to react with radical trapping agents such as nitroso compounds, cyclic nitrones, persistent nitroxyl radicals and atmospheric oxygen (dioxygen) are summarized. Overall, there is no correlation between antimalarial activities and abilities of the derived C-radicals to react with trapping agents in a chemical flask. This applies in particular to the reactions of C-radicals from artemisinins and steroidal tetraoxanes with the trapping agents vis-a-vis those from adamantyl capped systems. In an intraparasitic medium, it is not possible to intercept C-radicals either through use of a vast excess of a nitroxyl radical or dioxygen. The lack of correlation of antimalarial activities also applies to the Fe(2+)-mediated decomposition of artemisinins and synthetic peroxides, where literature data taken as indicating otherwise are critically assessed. The antagonism to antimalarial activities of artemisinins exerted by desferrioxamine (DFO) and related Fe(3+)-chelating agents is due to formation of stable chelates with bioavailable Fe(3+) that shuts down redox cycling through Fe(2+) and the subsequent generation of reactive oxygen species (ROS) via the Fenton reaction. The generation of ROS by Fe(2+) complements the action of artemisinins, to be discussed in Part 2; there is no need to posit a reaction of Fe(2+) with the artemisinins to account for their antimalarial activity. The ability of artemisinins and synthetic peroxides to elicit membrane damage is examined in the light of established processes of autoxidation. The oxidant character of the intraparasitic environment is incompatible with the reducing conditions required for generation of C-radicals, and in contrast to the expectation raised by the C-radical hypothesis, and indeed by the heme hypothesis outlined below, antimalarial activities of artemisinins are enhanced under higher partial pressures of dioxygen. Structure-activity data from a wide variety of artemisinins and synthetic peroxides cannot be accommodated within the bounds of the C-radical hypothesis. Finally, the antimalarial Cradical construct sharply contrasts with that of the potently antitumour-active ene-diyne antibiotics such as neocarzinostatin. In an iron-free process, these compounds generate highly reactive aryl C-radicals that abstract H atoms from deoxyribose units in DNA to generate alkyl C-radicals. The last do react with dioxygen in a normal intracellular environment to initiate DNA strand cleavage. Overall, it must be concluded that the C-radical hypothesis as the basis for antimalarial activities of artemisinins and synthetic peroxides is untenable. Heme has been intensively studied as an 'activator' of artemisinins and other antimalarial peroxides, and indeed the hypothesis seemingly has become firmly embedded in the underlying brickwork of the scientific edifice. The locus of activity of the peroxides interacting with the heme is considered to be the parasite digestive vacuole. The basis for the nanomolar activities of artemisinins and synthetic peroxides is variously ascribed to heme-Fe(2+)-mediated generation of C-radicals from the peroxides, formation of heme-artemisinin adducts that are held either to engage in redox cycling with concomitant generation of ROS or to inhibit formation of hemozoin. In the last case, just like the aminoquinolines and arylmethanols, the peroxides are not the active agents, but exert their parasiticidal effects through allowing the build-up of free heme-Fe(3+), the ultimate cytotoxic entity. We assess the literature relating to generation of heme by hemoglobin digestion, and the stage at which this process becomes significant in the intraerythrocytic parasite. The claims of production of heme and conversion into hemozoin occurring in a lipid environment may have to be put aside based on recent literature data that indicates crystallization of hemozoin must take place an aqueous interface; association of lipids with the heme/hemozoin is likely to be a reflection of attractive van der Waals interactions involving the hydrophobic surface of the heme or hemozoin aggregates. In addition, the observation leading to the claim that hemozoin manufacture commences at the mid-ring stage cannot be independently verified. That the quinoline and arylmethanol antimalarials have essentially no activities on the ring stage parasites and exert greatest efficacy at the trophozoite stage where heme production is maximal is consistent with this. Conversely, artemisinins, and indeed redox active drugs such as methylene blue and others, are highly active against early ring stage parasites. Thus, there is a prominent disconnect between stage specificities of artemisinins vis-a-vis those of 4-aminoquinolines and arylmethanols suggesting that heme is not the target of the former class of drug. Further, the ability of the Fe(3+) chelate DFO to antagonize antimalarial activities of artemisinins, but not the activities of 4-aminoquinolines, cannot be explained by involvement of heme as a target for artemisinins. We critically examine the basis for formation of products obtained from reaction of heme with artemisinins and synthetic peroxides under conditions ranging from biomimetic - reactions employing catalytic reagents under aqueous or semi-aqueous conditions - to those conducted under highly reducing and eminently artificial conditions, usually in the solvent dimethyl sulfoxide (DMSO) that both forms well characterized complexes with heme-Fe(2+) and actually assists in driving single electron transfer processes. It is noted that alkylated products tend to form in high yields under the last conditions, and this aspect is readily explained. Irrespective of product yields obtained under various conditions, an overarching correlation between facility of the reaction of the peroxide with heme and their antimalarial activities does not exist. The is underscored by the reproducible outcomes of reactions conducted under biomimetic conditions indicating adducts cannot form in physiologically meaningful concentrations and that heme is a recalcitrant reaction partner to artemisinins in general. Again, as in the case of the C-radical hypothesis, structure-activity data from a wide variety of artemisinins and synthetic peroxides is difficult to reconcile with the heme hypothesis. This applies in particular to dimeric and trimeric artemisinin derivatives where the ascribing of biological activity to reactions of the derived radicals or to the vastly encumbered artemisinin-heme adducts is physically unrealistic. Finally, the facile metabolism and induction of metabolism of the current clinically used artemisinins by members of the CYP superfamily - heme proteins that require an intimate interaction of the heme with the artemisinin for metabolism to occur - is incompatible with the oft-cited proclivity of the peroxide to associate via complex formation with heme as a prelude to its 'activation' as an antimalarial agent within the malaria parasite. (ABSTRACT TRUNCATED)

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The use of implantable cardiac defibrillators (ICDs) to prevent sudden cardiac death (SCD) in patients resuscitated from cardiac arrest or documented dangerous ventricular arrhythmias (secondary prevention of SCD) is an insured service. In 2003 (before the establishment of the Ontario Health Technology Advisory Committee), the Medical Advisory Secretariat conducted a health technology policy assessment on the prophylactic use (primary prevention of SCD) of ICDs for patients at high risk of SCD. The Medical Advisory Secretariat concluded that ICDs are effective for the primary prevention of SCD. Moreover, it found that a more clearly defined target population at risk for SCD that would be likely to benefit from ICDs is needed, given that the number needed to treat (NNT) from recent studies is 13 to 18, and given that the per-unit cost of ICDs is $32,000, which means that the projected cost to Ontario is $770 million (Cdn). Accordingly, as part of an annual review and publication of more recent articles, the Medical Advisory Secretariat updated its health technology policy assessment of ICDs. SUDDEN CARDIAC DEATH IS CAUSED BY THE SUDDEN ONSET OF FATAL ARRHYTHMIAS, OR ABNORMAL HEART RHYTHMS: ventricular tachycardia (VT), a rhythm abnormality in which the ventricles cause the heart to beat too fast, and ventricular fibrillation (VF), an abnormal, rapid and erratic heart rhythm. About 80% of fatal arrhythmias are associated with ischemic heart disease, which is caused by insufficient blood flow to the heart. Management of VT and VF with antiarrhythmic drugs is not very effective; for this reason, nonpharmacological treatments have been explored. One such treatment is the ICD. An ICD is a battery-powered device that, once implanted, monitors heart rhythm and can deliver an electric shock to restore normal rhythm when potentially fatal arrhythmias are detected. The use of ICDs to prevent SCD in patients resuscitated from cardiac arrest or documented dangerous ventricular arrhythmias (secondary prevention) is an insured service in Ontario. Primary prevention of SCD involves identification of and preventive therapy for patients who are at high risk for SCD. Most of the studies in the literature that have examined the prevention of fatal ventricular arrhythmias have focused on patients with ischemic heart disease, in particular, those with heart failure (HF), which has been shown to increase the risk of SCD. The risk of HF is determined by left ventricular ejection fraction (LVEF); most studies have focused on patients with an LVEF under 0.35 or 0.30. While most studies have found ICDs to reduce significantly the risk for SCD in patients with an LVEF less than 0.35, a more recent study (Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT]) reported that patients with HF with nonischemic heart disease could also benefit from this technology. Based on the generalization of the SCD-HeFT study, the Centers for Medicare and Medicaid in the United States recently announced that it would allocate $10 billion (US) annually toward the primary prevention of SCD for patients with ischemic and nonischemic heart disease and an LVEF under 0.35. The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of ICDs for the primary prevention of SCD. The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from January 2003-May 2005. A modification of the GRADE approach (1) was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study's design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations. Overall, ICDs are effective for the primary prevention of SCD. Three studies - the Multicentre Automatic Defibrillator Implantation Trial I (MADIT I), the Multicentre Automatic Defibrillator Implantation Trial II (MADIT II), and SCD-HeFT - showed there was a statistically significant decrease in total mortality for patients who prophylactically received an ICD compared with those who received conventional therapy (Table 1). Table 1:Results of Key Studies on the Use of Implantable Cardioverter Defibrillators for the Primary Prevention of Sudden Cardiac Death - All-Cause MortalityStudy, * YearPopulationNFollow-up, MonthsMortality, ICD† Group, %Mortality, Control Group, %Hazard Ratio (95% CI)PNNT†MADIT, 1996 (2)Ischemic1962715.838.60.46 (0.26-0.82).0094PriormyocardialinfarctionConventional therapy54% relative reductionEjection fraction ≤ 0.35NSVT†EP† +MADIT II, 2002 (3)Ischemic12322014.219.80.69(0.51-0.93).01618PriormyocardialinfarctionConventional therapy31% relative reductionEjection fraction ≤ 0.30SCD-HeFT, 2005 (4)Ischemic & Nonischemic25216022290.77 (0.62-0.96).00713Optimal therapyEjection fraction < 0.3523% relative reduction*MADIT I: Multicentre Automatic Defibrillator Implantation Trial I; MADIT II: Multicentre Automatic Defibrillator Implantation Trial II; SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial.†EP indicates electrophysiology; ICD, implantable cardioverter defibrillator; NNT, number needed to treat; NSVT, nonsustained ventricular tachycardia. The NNT will appear higher if follow-up is short. For ICDs, the absolute benefit increases over time for at least a 5-year period; the NNT declines, often substantially, in studies with a longer follow-up. When the NNT are equalized for a similar period as the SCD-HeFT duration (5 years), the NNT for MADIT-I is 2.2; for MADIT-II, it is 6.3. Using the GRADE Working Group criteria, the quality of these 3 trials was examined (Table 2). Quality refers to the criteria such as the adequacy of allocation concealment, blinding and follow-up. Consistency refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect, and the significance of the differences guide the decision about whether important inconsistency exists. Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker or have more comorbidity than those in the studies. As stated by the GRADE Working Group, the following definitions were used to grade the quality of the evidence: HIGH: Further research is very unlikely to change our confidence n the estimate of effect.MODERATE: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.LOW: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.VERY LOW: Any estimate of effect is very uncertain.Table 2:Quality of Evidence - MADIT I, MADIT II, and SCD-HeFT*TrialDesignQualityConsistencyDirectness†Quality GradeMADIT IRCTImbalance in β-blocker usage between study arms.The overall number of patients from which the study was drawn was not reported.Selection bias may have occurred since patients were selected for randomization if they did not respond to procainamide, thereby introducing a potential bias into the medication arm.Specific details regarding allocation concealment and blinding procedures were not provided.Single-chamber ICD used in study.Trial started with transthoracic implants, and then switched to nontransthoracic implants.Ischemic cardiomyopathy only.5-year NNT = 2.The overall number of Moderate patients from which the study was drawn was not reported.Selection bias may have occurred since patients were selected for randomization if they did not respond to procainamide, thereby introducing a potential bias into the medication arm.ModerateMADIT IIRCT~ 90% of patients were recruited ≥6 months post-MI; 20% of control group died after mean 20-month follow-up.How and where patients recruited?Specific details regarding allocation concealment/blinding procedures not provided.Subset had MADIT I criteria; post hoc analysis of incomplete data suggested "weak-moderate evidence that ICD effect greater in inducible than noninducible patients in MADIT II." (5;6)First study to assess both single- and dual-chamber ICD devices for primary prevention.Programming of device and medications left to the discretion of the patients' physician.Higher rate of hospitalization for new or worsened heart failure in the group receiving the ICDs compared to conventional therapy (19.9% versus 14.9% respectively).Ischemic cardiomyopathy only.5-year NNT = 6.How and where patients Weak recruited?Subset had MADIT I criteria.WeakSCD-HeFTRCTStatistically significant difference in β-blocker usage between treatment groups at last follow-up.Drug arms double-blinded.Shock-only single-lead device. Antitachycardia pacing not permitted.Ischemic and nonischemic cardiomyopathy.There was a statistically significant difference in terms of the NYHA prespecified subgroups analysis. The NYHA subgroups were prespecified a priori and the results of the interaction tests were significant. Yet, ICD treatment had a significant benefit in patients in NYHA class II but not in those in NYHA class III. (ABSTRACT TRUNCATED)

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Diethylamine is used mainly as a chemical intermediate to produce the corrosion inhibitor N,N-diethylethanolamine and a lesser amount is used to produce pesticides and insect repellants and in rubber processing. Diethylamine was nominated for study by the National Institute of Environmental Health Sciences based upon its high production volume and ubiquitous natural occurrence in trace amounts and because of the lack of chronic toxicity and carcinogenicity data on the chemical. Male and female F344/N rats and B6C3F1 mice were exposed to diethylamine (approximately 99.9% pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in bacterial mutagenicity tester strains and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to diethylamine vapor at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 16 days. All rats survived to the end of the study. The mean body weights of 250 and 500 ppm males and females and 125 ppm males were significantly less than those of the chamber controls. Clinical findings included lethargy, nasal/eye discharge, abnormal breathing, thinness, eye abnormalities, and discolored urine. The thymus weights of males exposed to 125 ppm or greater and females exposed to 500 ppm were significantly less than those of the chamber controls. Focal eye lesions were noted at necropsy in four males and three females exposed to 500 ppm and one male exposed to 250 ppm. Crusty noses were observed in most 500 ppm males and females and in two 250 ppm males. Suppurative inflammation, necrosis of the turbinates (except in one 125 ppm female), and squamous metaplasia of the respiratory epithelium of the nose were present in all rats exposed to 125 ppm or greater. Ulcer of the respiratory epithelium and atrophy of the olfactory epithelium occurred in all rats exposed to 250 or 500 ppm, and ulcer of the nasopharyngeal duct was present in all 500 ppm rats. Suppurative inflammation of the cornea was present in most rats exposed to 500 ppm. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to diethylamine vapor at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 17 days. Two males and three females exposed to 500 ppm died during the first week of the study. The mean body weights of males and females exposed to 125 ppm or greater were significantly less than those of the chamber controls. Males and females exposed to 250 or 500 ppm lost weight during the study. Lethargy, abnormal breathing, and thinness were observed in most mice exposed to 250 or 500 ppm. Eye irritation and discharge, nasal discharge, and low fecal and urine output were noted in 500 ppm mice. Thymus weights of 250 and 500 ppm males and 125 ppm or greater females were significantly less than those of the chamber controls. Suppurative inflammation of the nose occurred in all males exposed to 250 or 500 ppm and all females exposed to 125 ppm or greater, and most males exposed to 125 ppm. Turbinate necrosis occurred in all exposed mice except one 31 ppm female. Squamous metaplasia of the respiratory epithelium and olfactory epithelial atrophy were seen in mice exposed to 125 ppm or greater. In the lung, the incidence of minimal chronic active inflammation of mainstem bronchi was significantly increased in 500 ppm males. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to diethylamine vapor at concentrations of 0, 8, 16, 32, 62, or 125 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All rats survived to the end of the study. Mean body weights of all exposed groups were similar to those of the chamber control groups. There were significant exposure concentration-related decreases in sperm motility in 32, 62, and 125 ppm males; there were no significant differences in the lengths of estrous cycles between chamber control and exposed groups of females. Exposure-related nasal lesions were seen primarily in rats exposed to 62 or 125 ppm. These lesions included turbinate necrosis, suppurative inflammation, respiratory epithelial hyperplasia, squamous metaplasia of the respiratory epithelium, and olfactory epithelial atrophy. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to diethylamine vapor at concentrations of 0, 8, 16, 32, 62, or 125 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All mice survived to the end of the study. The mean body weights of 125 ppm males and females were significantly less than those of the chamber controls. There were significant exposure concentration-related decreases in sperm motility in males exposed to 32, 62, or 125 ppm; the estrous cycle of 125 ppm females was significantly longer than that of the chamber controls but only by half a day. Histopathologic changes were noted primarily in the nasal cavity and involved both the respiratory and olfactory epithelium of males and females principally in the 62 or 125 ppm groups. These lesions included suppurative inflammation, squamous metaplasia of the respiratory epithelium, olfactory epithelial atrophy, and necrosis of the turbinates. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to diethylamine vapor at concentrations of 0, 31, 62.5, or 125 ppm, 6 hours plus T90 (15 minutes) per day, 5 days per week for 105 weeks. Survival of exposed groups of rats was similar to that of the chamber control groups. Mean body weights of males and females exposed to 125 ppm were less than those of the chamber controls after week 57. Increased incidences of eye abnormality occurred in exposed males and females. A spectrum of nonneoplastic lesions was observed in the respiratory and olfactory epithelium of the nose in exposed rats. The lesions included suppurative inflammation, ulceration of the respiratory epithelium, hyaline droplet accumulation in the glands of the respiratory epithelium, necrosis of the turbinates, squamous metaplasia of the respiratory epithelium, hyperplasia of the respiratory epithelium, atrophy of the olfactory epithelium, hyaline droplet accumulation in the respiratory and olfactory epithelium, basal cell hyperplasia of the olfactory epithelium, respiratory metaplasia of the olfactory epithelium, and goblet cell hyperplasia. The incidence of chronic inflammation of the pleura was significantly increased in 125 ppm females. The incidences of histiocytic cellular infiltration of the alveolus of the lung were significantly increased in all exposed groups of females and the incidence of chronic inflammation was significantly increased in 125 ppm females. In 125 ppm males, the incidence of suppurative inflammation of the cornea was significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to diethylamine vapor at concentrations of 0, 16, 31, or 62.5 ppm, 6 hours plus T90 (15 minutes) per day, 5 days per week for 105 weeks. Survival of exposed groups of mice was similar to that of the chamber control groups. Mean body weights of males and females were similar to those of the chamber controls. Eye abnormality was observed in greater incidence in exposed groups of males than in the chamber controls, and torso/ventral ulcer/abscess was observed in six 62.5 ppm males compared to none in the chamber controls. A similar spectrum of nonneoplastic lesions was seen in the nose of exposed mice as was seen in rats. Diethylamine was not mutagenic in either of two independent bacterial mutagenicity assays, each conducted with and without exogenous metabolic activation enzymes. Bacterial strains tested included Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia coli strain WP2 uvrA/pKM101. In addition to the negative results in the two bacterial assays, no significant increases in the frequencies of micronucleated erythrocytes were seen in peripheral blood of male or female B6C3F1 mice from the 3-month study. Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of diethylamine in male or female F344/N rats exposed to 31, 62.5, or 125 ppm. There was no evidence of carcinogenic activity of diethylamine in male or female B6C3F1 mice exposed to 16, 31, or 62.5 ppm. Exposure to diethylamine resulted in increased incidences of nonneoplastic lesions of the nose in male and female rats and mice, of the cornea in male rats, and of the pleura and lung in female rats.

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Recent advances in multidisciplinary treatments for various cancers have extended the survival period of patients with spinal metastases. Radiotherapy has been widely used to treat spinal metastases; nevertheless, long-term survivors sometimes undergo more surgical intervention after radiotherapy because of local tumor relapse. Generally, intradural invasion of a spinal tumor seldom occurs because the dura mater serves as a tissue barrier against tumor infiltration. However, after radiation exposure, some spinal tumors invade the dura mater, resulting in leptomeningeal dissemination, intraoperative dural injury, or postoperative local recurrence. The mechanisms of how radiation might affect the dura have not been well-studied. To investigate how radiation affects the spinal meninges, we asked: (1) What is the effect of irradiation on the meningeal barrier's ability to protect against carcinoma infiltration? (2) What is the effect of irradiation on the meningeal barrier's ability to protect against sarcoma infiltration? (3) What is the effect of irradiation on dural microstructure observed by scanning electron microscopy (SEM)? (4) What is the effect of irradiation on dural microstructure observed by transmission electron microscopy (TEM)? Eighty-four 10-week-old female ddY mice were randomly divided into eight groups: mouse mammary tumor (MMT) implantation 6 weeks after 0-Gy irradiation (nonirradiation) (n = 11), MMT implantation 6 weeks after 20-Gy irradiation (n = 10), MMT implantation 12 weeks after nonirradiation (n = 10), MMT implantation 12 weeks after 20-Gy irradiation (n = 11), mouse osteosarcoma (LM8) implantation 6 weeks after nonirradiation (n = 11), LM8 implantation 6 weeks after 20-Gy irradiation (n = 11), LM8 implantation 12 weeks after nonirradiation (n = 10), and LM8 implantation 12 weeks after 20-Gy irradiation (n = 10); female mice were used for a mammary tumor metastasis model and ddY mice, a closed-colony mice with genetic diversity, were selected to represent interhuman diversity. Mice in each group underwent surgery to generate a tumor-induced spinal cord compression model at either 6 weeks or 12 weeks after irradiation to assess changes in the meningeal barrier's ability to protect against tumor infiltration. During surgery, the mice were implanted with MMT (representative of a carcinoma) or LM8 tumor. When the mice became paraplegic because of spinal cord compression by the growing implanted tumor, they were euthanized and evaluated histologically. Four mice died from anesthesia and 10 mice per group were euthanized (MMT-implanted groups: MMT implantation occurred 6 weeks after nonirradiation [n = 10], 6 weeks after irradiation [n = 10], 12 weeks after nonirradiation [n = 10], and 12 weeks after irradiation [n = 10]; LM8-implanted groups: LM8 implantation performed 6 weeks after nonirradiation [n = 10], 6 weeks after irradiation [n = 10], 12 weeks after nonirradiation [n = 10], and 12 weeks after irradiation [n = 10]); 80 mice were evaluated. The spines of the euthanized mice were harvested; hematoxylin and eosin staining and Masson's trichrome staining slides were prepared for histologic assessment of each specimen. In the histologic assessment, intradural invasion of the implanted tumor was graded in each group by three observers blinded to the type of tumor, presence of irradiation, and the timing of the surgery. Grade 0 was defined as no intradural invasion with intact dura mater, Grade 1 was defined as intradural invasion with linear dural continuity, and Grade 2 was defined as intradural invasion with disruption of the dural continuity. Additionally, we euthanized 12 mice for a microstructural analysis of dura mater changes by two observers blinded to the presence of irradiation. Six mice (three mice in the 12 weeks after nonirradiation group and three mice in the 12 weeks after 20-Gy irradiation group) were quantitatively analyzed for defects on the dural surface with SEM. The other six mice (three mice in the 12 weeks after nonirradiation group and three mice in the 12 weeks after 20-Gy irradiation group) were analyzed for layer structure of collagen fibers constituting dura mater by TEM. In the SEM assessment, the number and size of defects on the dural surface on images (200 μm × 300 μm) at low magnification (× 2680) were evaluated. A total of 12 images (two per mouse) were evaluated for this assessment. The days from surgery to paraplegia were compared between each of the tumor groups using the Kruskal-Wallis test. The scores of intradural tumor invasion grades and the number of defects on dural surface per SEM image were compared between irradiation group and nonirradiation group using the Mann-Whitney U test. Interobserver reliabilities of assessing intradural tumor invasion grades and the number of dural defects on the dural surface were analyzed using Fleiss'κ coefficient. P values < 0.05 were considered statistically significant. There was no difference in the median (range) time to paraplegia among the MMT implantation 6 weeks after nonirradiation group, the 6 weeks after irradiation group, the 12 weeks after nonirradiation group, and the 12 weeks after irradiation group (16 days [14 to 17] versus 14 days [12 to 18] versus 16 days [14 to 17] versus 14 days [12 to 15]; χ2 = 4.7; p = 0.19). There was also no difference in the intradural invasion score between the MMT implantation 6 weeks after irradiation group and the 6 weeks after nonirradiation group (8 of 10 Grade 0 and 2 of 10 Grade 1 versus 10 of 10 Grade 0; p = 0.17). On the other hand, there was a higher intradural invasion score in the MMT implantation 12 weeks after irradiation group than the 12 weeks after nonirradiation group (5 of 10 Grade 0, 3 of 10 Grade 1 and 2 of 10 Grade 2 versus 10 of 10 Grade 0; p = 0.02). Interobserver reliability of assessing intradural tumor invasion grades in the MMT-implanted group was 0.94. There was no difference in the median (range) time to paraplegia among in the LM8 implantation 6 weeks after nonirradiation group, the 6 weeks after irradiation group, the 12 weeks after nonirradiation group, and the 12 weeks after irradiation group (12 days [9 to 13] versus 10 days [8 to 13] versus 11 days [8 to 13] versus 9 days [6 to 12]; χ2 = 2.4; p = 0.50). There was also no difference in the intradural invasion score between the LM8 implantation 6 weeks after irradiation group and the 6 weeks after nonirradiation group (7 of 10 Grade 0, 1 of 10 Grade 1 and 2 of 10 Grade 2 versus 8 of 10 Grade 0 and 2 of 10 Grade 1; p = 0.51), whereas there was a higher intradural invasion score in the LM8 implantation 12 weeks after irradiation group than the 12 weeks after nonirradiation group (3 of 10 Grade 0, 3 of 10 Grade 1 and 4 of 10 Grade 2 versus 8 of 10 Grade 0 and 2 of 10 Grade 1; p = 0.04). Interobserver reliability of assessing intradural tumor invasion grades in the LM8-implanted group was 0.93. In the microstructural analysis of the dura mater using SEM, irradiated mice had small defects on the dural surface at low magnification and degeneration of collagen fibers at high magnification. The median (range) number of defects on the dural surface per image in the irradiated mice was larger than that of nonirradiated mice (2 [1 to 3] versus 0; difference of medians, 2/image; p = 0.002) and the median size of defects was 60 μm (30 to 80). Interobserver reliability of assessing number of defects on the dural surface was 1.00. TEM revealed that nonirradiated mice demonstrated well-organized, multilayer structures, while irradiated mice demonstrated irregularly layered structures at low magnification. At high magnification, well-ordered cross-sections of collagen fibers were observed in the nonirradiated mice. However, disordered alignment of collagen fibers was observed in irradiated mice. Intradural tumor invasion and disruptions of the dural microstructure were observed in the meninges of mice after irradiation, indicating radiation-induced disruption of the meningeal barrier. We conclude that in this form of delivery, radiation is associated with disruption of the dural meningeal barrier, indicating a need to consider methods to avoid or limit Postradiation tumor relapse and spinal cord compression when treating spinal metastases so that patients do not experience intradural tumor invasion. Surgeons should be aware of the potential for intradural tumor invasion when they perform post-irradiation spinal surgery to minimize the risks for intraoperative dural injury and spinal cord injury. Further research in patients with irradiated spinal metastases is necessary to confirm that the same findings are observed in humans and to seek irradiation methods that prevent or minimize the disruption of meningeal barrier function.

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The purpose of this project was to determine the role of corneal implants in the management of corneal thinning disease conditions. An evidence-based review was conducted to determine the safety, effectiveness and durability of corneal implants for the management of corneal thinning disorders. The evolving directions of research in this area were also reviewed. SUBJECT OF THE EVIDENCE-BASED ANALYSIS: The primary treatment objectives for corneal implants are to normalize corneal surface topography, improve contact lens tolerability, and restore visual acuity in order to delay or defer the need for corneal transplant. Implant placement is a minimally invasive procedure that is purported to be safe and effective. The procedure is also claimed to be adjustable, reversible, and both eyes can be treated at the same time. Further, implants do not limit the performance of subsequent surgical approaches or interfere with corneal transplant. The evidence for these claims is the focus of this review. The specific research questions for the evidence review were as follows: SafetyCorneal Surface Topographic Effects:Effects on corneal surface remodellingImpact of these changes on subsequent interventions, particularly corneal transplantation (penetrating keratoplasty [PKP])Visual AcuityRefractive OutcomesVISUAL QUALITY (SYMPTOMS): such as contrast vision or decreased visual symptoms (halos, fluctuating vision)Contact lens toleranceFunctional visual rehabilitation and quality of lifePatient satisfaction:Disease Process:Impact on corneal thinning processEffect on delaying or deferring the need for corneal transplantation TARGET POPULATION AND CONDITION Corneal ectasia (thinning) comprises a range of disorders involving either primary disease conditions such as keratoconus and pellucid marginal corneal degeneration or secondary iatrogenic conditions such as corneal thinning occurring after LASIK refractive surgery. The condition occurs when the normally round dome-shaped cornea progressively thins causing a cone-like bulge or forward protrusion in response to the normal pressure of the eye. Thinning occurs primarily in the stoma layers and is believed to be a breakdown in the collagen network. This bulging can lead to an irregular shape or astigmatism of the cornea and, because the anterior part of the cornea is largely responsible for the focusing of light on the retina, results in loss of visual acuity. This can make even simple daily tasks, such as driving, watching television or reading, difficult to perform. Keratoconus (KC) is the most common form of corneal thinning disorder and is a noninflammatory chronic disease process. Although the specific causes of the biomechanical alterations that occur in KC are unknown, there is a growing body of evidence to suggest that genetic factors may play an important role. KC is a rare condition (<0.05% of the population) and is unique among chronic eye diseases as it has an early age of onset (median age of 25 years). Disease management for this condition follows a step-wise approach depending on disease severity. Contact lenses are the primary treatment of choice when there is irregular astigmatism associated with the disease. When patients can no longer tolerate contact lenses or when lenses no longer provide adequate vision, patients are referred for corneal transplant. Keratoconus is one of the leading indications for corneal transplants and has been so for the last three decades. Yet, despite high graft survival rates of up to 20 years, there are reasons to defer receiving transplants for as long as possible. Patients with keratoconus are generally young and life-long term graft survival would be an important consideration. The surgery itself involves lengthy time off work and there are potential complications from long term steroid use following surgery, as well as the risk of developing secondary cataracts, glaucoma etc. After transplant, recurrent KC is possible with need for subsequent intervention. Residual refractive errors and astigmatism can remain challenging after transplantation and high refractive surgery rates and re-graft rates in KC patients have been reported. Visual rehabilitation or recovery of visual acuity after transplant may be slow and/or unsatisfactory to patients. INTACS® (Addition Technology Inc. Sunnyvale, CA, formerly KeraVision, Inc.) are the only currently licensed corneal implants in Canada. The implants are micro-thin poly methyl methacrylate crescent shaped ring segments with a circumference arc length of 150 degrees, an external diameter of 8.10 mm, an inner diameter of 6.77 mm, and a range of different thicknesses. Implants act as passive spacers and, when placed in the cornea, cause local separation of the corneal lamellae resulting in a shortening of the arc length of the anterior corneal curvature and flattening the central cornea. Increasing segment thickness results in greater lamellar separation with increased flattening of the cornea correcting for myopia by decreasing the optical power of the eye. Corneal implants also improve corneal astigmatism but the mechanism of action for this is less well understood. Treatment with corneal implants is considered for patients who are contact lens intolerant, having adequate corneal thickness particularly around the area of the implant incision site and without central corneal scarring. Those with central corneal scarring would not benefit from implants and those without an adequate corneal thickness, particularly in the region that the implants are being inserted, would be at increased risk for corneal perforation. Patients desiring to have visual rehabilitation that does not include glasses or contact lenses would not be candidates for corneal ring implants. Placement of the implants is an outpatient procedure with topical anesthesia generally performed by either corneal specialists or refractive surgeons. It involves creating tunnels in the corneal stroma to secure the implants either by a diamond knife or laser calibrated to an approximate depth of 70% of the cornea. Variable approaches have been employed by surgeons in selecting ring segment size, number and position. Generally, two segments of equal thickness are placed superiorly and inferiorly to manage symmetrical patterns of corneal thinning whereas one segment may be placed to manage asymmetric thinning patterns. Following implantation, the major safety concerns are for potential adverse events including corneal perforation, infection, corneal infiltrates, corneal neovascularization, ring migration and extrusion and corneal thinning. Technical results can be unsatisfactory for several reasons. Treatment may result in an over or under-correction of refraction and may induce astigmatism or asymmetry of the cornea. Progression of the corneal cone with corneal opacities is also invariably an indication for progression to corneal transplant. Other reasons for treatment failure or patient dissatisfaction include foreign body sensation, unsatisfactory visual quality with symptoms such as double vision, fluctuating vision, poor night vision or visual side effects related to ring edge or induced or unresolved astigmatism. The literature search strategy employed keywords and subject headings to capture the concepts of 1) intrastromal corneal rings and 2) corneal diseases, with a focus on keratoconus, astigmatism, and corneal ectasia. The initial search was run on April 17, 2008, and a final search was run on March 6, 2009 in the following databases: Ovid MEDLINE (1996 to February Week 4 2009), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2009 Week 10), OVID Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2000 and April 17, 2008. The resulting citations were downloaded into Reference Manager, v.11 (ISI Researchsoft, Thomson Scientific, U.S.A), and duplicates were removed. The Web sites of several other health technology agencies were also reviewed including the Canadian Agency for Drugs and Technologies in Health (CADTH), ECRI, and the United Kingdom National Institute for Clinical Excellence (NICE). The bibliographies of relevant articles were scanned. English language reports and human studiesAny corneal thinning disorderReports with corneal implants used alone or in conjunction with other interventionsOriginal reports with defined study methodologyReports including standardized measurements on outcome events such as technical success, safety, effectiveness, durability, vision quality of life or patient satisfactionCase reports or case series for complications and adverse events Non-systematic reviews, letters, comments and editorialsReports not involving outcome events such as safety, effectiveness, durability, vision quality or patient satisfaction following an intervention with corneal implantsReports not involving corneal thinning disorders and an intervention with corneal implants In the MAS evidence review on intrastromal corneal ring implants, 66 reports were identified on the use of implants for management of corneal thinning disorders. Reports varied according to their primary clinical indication, type of corneal implant, and whether or not secondary procedures were used in conjunction with the implants. Implants were reported to manage post LASIK thinning and/or uncorrected refractive error and were also reported as an adjunctive intervention both during and after corneal transplant to manage recurrent thinning and/or uncorrected refractive error. (ABSTRACT TRUNCATED)

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The patterns of complexity of the male and female sexual openings in Brachyura, which have been the source of uncertainties and conflicting opinions, are documented, together with a study of the morphologies of the coxal and sternal gonopores in both sexes, penises, spermathecae, and gonopods. The vulvae, male gonopores and penises are described among selected taxa of Eubrachyura, and their function and evolution examined in the context of a wide variety of mating behaviours. The location of female and male gonopores, the condition of the penis (coxal and sternal openings and modalities of protection), and related configurations of thoracic sternites 7 and 8, which are modified by the intercalation of a wide sternal part (thoracic sternites 7 and 8) during carcinisation, show evidence of deep homology. They represent taxonomic criteria at all ranks of the family-series and may be used to test lineages. Of particular significance are the consequences of the posterior expansion of the thoracic sternum, which influences the condition, shape, and sclerotisation of the penis, and its emergence from coxal (heterotreme) to coxo-sternal, which is actually still coxal (heterotreme), in contrast to a sternal emergence (thoracotreme). The heterotreme-thoracotreme distinction results from two different trajectories of the vas deferens and its ejaculatory duct via the P5 coxa (Heterotremata) or through the thoracic sternum (Thoracotremata). Dissections of males of several families have demonstrated that this major difference not only affects the external surface (perforation of the coxa or the sternum by the ejaculatory duct) but also the internal anatomy. There is no evidence for an ejaculatory duct passing through the articular membrane between the P5 coxa and the thoracic sternum in any Brachyura, even when the sternal male gonopore is very close to the P5 coxa. Trends towards the coxo-sternal condition are exemplified by multistate characters, varying from a shallow depression to a long groove along expanded sternites 7 and 8, and ultimately their complete, extended junction typifying the most derived coxo-sternal condition. The coxo-sternal condition is indicative of a long evolutionary history, as evidenced by the presence of multistate characters (e.g., Dorippidae, Goneplacoidea) or by a single, well-established condition (e.g., Chasmocarcinidae, Ethusidae, Panopeidae Eucratopsinae, Rhizopidae, Scalopidiidae). The penial area proves to be an essential diagnostic feature in Brachyura, with a value comparable to that of the gonopods. Penis protection is ubiquitous in Brachyura irrespective of length, and several modalities of protection prevail, which necessitate different modifications of associated structures. A long penis in a gutter developed from a partial invagination of sternite 8 induces the formation of a new "suture" at the same level as the preceding suture 6/7. Such a "supplementary suture 7/8" exists among unrelated heterotreme families (e.g., Ethusidae, Panopeidae Eucratopsinae, Pseudorhombilidae, Rhizopidae). A fully protected penis, concealed in a groove within a complete invagination of sternite 8 in the form of two contiguous plates, evolved independently (homoplasy) in Palicoidea and Chasmocarcinidae (Goneplacoidea), with sternite 8 present as a single plate in females. In condylar protection, described for the first time and occurring in several heterotreme families, the penis emerges from the extremity of the P5 coxo-sternal condyle or from its anterior border instead of from the coxa itself. A penis precisely lodged in a small excavation on sternite 8, which is lined by a row of stiff setae, is unique to Brachyura, and represents a new synapomorphy of the Homoloidea. Five modalities of penis protection are recognised in Podotremata, eight in Eubrachyura (six in Heterotremata and two in Thoracotremata). Special attention has been paid to Dorippoidea (Dorippidae and Ethusidae), which shows transformation series from coxal to coxo-sternal conditions. The coxo-sternal condition is not an intermediate towards the thoracotreme organisation, and a step in heterotreme evolution is the adoption of the coxo-sternal condition. An extreme carcinisition may also result in the sternal arrangement of male gonopores in the form of a "sternitreme" disposition, as in the case of Hymenosomatoidea, which displays a broad thoracic sternum and true sternal male gonopores (as in thoracotremes) together with several plesiomorphic traits that are assumed to represent an old, deeply-rooted heterotreme clade. A sternitreme condition evolved independently in the most ancestral heterotreme clades (such as Hymenosomatoidea) and in Thoracotremata. The older the lineage of a heterotreme is, the higher the possibility of having evolved carcinisation. Evidence that "derived" traits may be the consequence of a strong carcinisation, rather than being recently acquired, necessitates reconsidering certain character states in Brachyura. Eubrachyurans can only evolve either the heterotreme or the thoracotreme arrangement, the consistency of the inferred ancestral characters states providing a useful criterion for evaluating ancestral trait reconstructions. A widened thoracic sternum together with sternal gonopores may be present in carcinised heterotremes such as hymenosomatoids. The thoracic sternum provides a reliable complex of characters that must be carefully interpreted. The hypothesis of a coxo-sternal disposition in Cryptochiroidea and Pinnotheroidea, generally considered thoracotremes, is rejected, and an alternative interpretation of their status is discussed. A new interpretation of the phylogeny of Cryptochiroidea is outlined, but the origin of Pinnotheroidea remains puzzling. The sella turcica, frequently regarded a synapomorphy of Eubrachyura, is redefined as the structure formed by the endosternal intertagmal phragma that connects the tagma/thorax and the tagma/abdomen to thoracic interosternite 7/8. It is here termed the "brachyuran sella turcica" and is shown to be synapomorphic to all Brachyura. The Eubrachyura synapomorphically shares the fusion of the thoracic interopleurite 7/8 with the brachyuran sella turcica, forming the "eubrachyuran sella turcica". In contrast, some Podotremata (Cyclodorippoidea and Raninoidea) share a connection between the sella turcica and the thoracic interosternite 6/7. Six main patterns of the thoracic sternum in relation to variations in sutures 4/5-7/8 are recognised in Eubrachyura, whereas several subpatterns that include variations in the median line are distinguished. The evolution of the thoracic sternum and axial skeleton is reassessed in Podotremata and Eubrachyura. A posteriormost location of the male gonopore (coxal or sternal) in relation to sternite 8 characterises many brachyurans (Cryptochiroidea, Hymenosomatoidea, Majoidea, Matutidae, Menippidae, Orithyioidea, Parthenopoidea, Ucididae, Grapsoidea--including Percnidae, Plagusiidae, Varunidae), in contrast to a location close to suture 7/8 in other groups. The thoracic sternum/pterygostome junction, which has multistate characters, is shown to be a valuable taxonomic criterion. The shapes of the sterno-abdominal depression and sterno-abdominal cavity provide diagnostic features that are helpful in suprageneric assignments. The monophyly of Brachyura, Eubrachyura, and Thoracotremata is reaffirmed. The monophyly of Brachyura is supported by the interdependence of the two pairs of gonopods and penis. An abdomen permanently flexed and held by the pereopods and/or the homoloid press button (on sternite 4) or typical eubrachyuran press-button (on sternite 5) may be considered a synapomorphy of Brachyura, the absence of this condition considered a loss. The double abdominal-locking system ("double peg") on sternite 5, a device discovered in three families of the extinct Palaeocorystoidea from the Upper Aptian, is similar to the double hook present in living lyreidids, although it is lost in all other raninoid extant members. New evidence shows that the abdominal holding was an early occurrence for a brachyuran crab. The Raninoidea, sister to Palaeocorystoidea, is characterised by gymnopleurity, a condition that results from the lifting of the carapace and thus the exposure of several pleurites. The narrowing of the body and thoracic sternum, almost certainly associated with their burrowing behaviour, is a diagnostic feature of raninoid evolution, in contrast to the widening observed in the remaining Brachyura. The monophyly of Heterotremata is discussed. Although the correct assignment of the coxal male gonopore and sternal female gonopore (vulva) at the base of Decapoda and Eubrachyura, respectively, left no synapomorphies to support the Heterotremata, the group nevertheless should be regarded as the sister group to Thoracotremata. The controversial monophyly of Podotremata is discussed and arguments are presented against the suppression of this taxon. The distinction of Homoloidia from Dromioidia is argued, and a classification of Podotremata, which considers the fossil record whenever possible, is presented. The earliest brachyurans are re-examined, and a new interpretation of the phylogeny of several basal eubrachyuran groups (Dorippoidea, Inachoididae, Palicoidea, Retroplumoidea) is proposed. Stenorhynchus shares a number of characters with the Inachoididae that differentiate them from Inachidae, and also has some distinctive features that warrants its assignment to a separate inachoidid subfamily, Stenorhynchinae, which is resurrected. The concealment strategies among Brachyura are documented and discussed. Podotremes use carrying behaviour, often combined with burying and concealment under substrates, whereas living within a host, burying, and decoration are used by heterotremes, burrowing being essentially a thoracotreme strategy. (ABSTRACT TRUNCATED)

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The anareolate New World subfamily Cladomorphinae Bradley & Galil, 1977 is reviewed and keys to the six tribes currently included are presented; these are: Cladomorphini Bradley & Galil, 1977, Cladoxerini Karny, 1923, Cranidiini Günther, 1953, Pterinoxylini n. trib., Hesperophasmatini Bradley & Galil, 1977 and Haplopodini Günther, 1953 rev. stat.. New diagnoses are presented for all these tribes and possible relationships within Cladomorphinae are discusssed. Morphology of the genitalia and egg-structures indicate Cladomorphinae as presently treated to be polyphyletic. Two subordinate groups are recognized within present Cladomorphinae, which differ considerably in numerous morphological characters of the insects and eggs. The first group and here regarded as Cladomorphinae sensu stricto is formed by the mostly South American Cladomorphini + Cranidiini + Cladoxerini, while the second group is formed by the predominantly Caribbean Hesperophasmatini + Pterinoxylini n. trib. + Haplopodini.        Members of the first group (= Cladomorphini sensu stricto) share the dorsally carinate basitarsus in which the two dorsal carinae are melted with another, increasingly elongated gonapophyses VIII of females which are noticeably longer than gonapophyses IX and lamellate as well as strongly displaced medioventral carina of the profemora. Cranidiini + Cladomorphini share the strongly elongated and filiform gonapophyses VIII and presence of gonoplacs in the females, specialized poculum of males and presence of a median line in the eggs. Cranidiini differs from all other tribes of Cladomorphinae by the entirely unarmed legs of both sexes, distinctly broadened and leaf-like body and prominent longitudinal keel of the mesosternum of females, prominently enlarged poculum and spinulose phallus of males as well as the conspicuous narrowing of the posteromedian gap of the internal micropylar plate of the eggs and noticeably separated median line. Cladomorphini is characteristic for the specialized vomer and poculum of males and distinct opercular structures of the eggs. Certain representatives of Cladomorphini indicate relationships to the "Phanocles-group" of Diapheromerinae: Diapheromerini, hence Cladomorphini as presently treated may be paraphyletic. The exclusively South American Cladoxerini (= Baculini n. syn.) differs from the other two tribes of Cladomorphinae sensu stricto by the distinctly serrate profemora of both sexes and conspicuously shortened antennae of females, which consist of less than 30 segments and are much shorter than the profemora in females. Genital morphology, such as the elongated gonapophyses VIII and presence of gonoplacs in females, as well as the lamellate medioventral carina of the profemora indicate close relation to Cladomorphini. Cranidiini appears to be the sister-taxon of Cladomorphini + Cladoxerini. The tribe Baculini Günther, 1953 is synonymised with Cladoxerini (n. syn.), on the basis that the type-genera of both tribes are congeneric, with Baculum Saussure, 1861 being a junior synonym of Cladoxerus St. Fargeau & Audinet-Serville, 1827 (n. syn.). The genus Tersomia Kirby, 1904 is removed from Hesperophasmatini and transferred to Cladoxerini. Wattenwylia Toledo Piza, 1938 is removed from Pachymorphinae: Gratidiini and transferred to Cladoxerini. A detailed new diagnosis is presented for Cranidiini along with a detailed differentiation and the tribe is shown to be monotypical, only containing its type-genus Cranidium Westwood, 1843. All Caribbean genera subsequently added to Cranidiini are removed and transferred to Haplopodini rev. stat..        The three tribes Hesperophasmatini + Pterinoxylini n. trib. + Haplopodini rev. stat. are closely related and might form a monophyletic clade within Cladomorphinae sensu lato. They differ from Cladomorphinae sensu stricto by the short gonapophyses VIII and reduced gonoplacs of females, unspecialized poculum of males and lack of a micropylar line in the eggs. Haplopodini Günther, 1953 is re-established (rev. stat.) and comprises almost exclusively Caribbean genera previously placed in Hesperophasmatini by Bradley & Galil (1977) or Cranidiini by Zompro, (2004). Aploploides Rehn & Hebard, 1938, Diapherodes Gray, 1835, Haplopus Burmeister, 1838 and Paracranidium Brock, 1998 were misplaced in Cranidiini and are transferred to Haplopodini. On the basis of numerous morphological characters of the insects and eggs Hesperophasmatini is removed from Pseudophasmatidae: Xerosomatinae and re-transferred to its previous position in the subfamily Cladomorphinae sensu lato. A detailed newdiagnosis of Hesperophasmatini is presented, but is only provisional since the true diversity is as yet only fractionally known. The lack of a gula distinguishes Hesperophasmatini from all other tribes. The genus Laciphorus Redtenbacher, 1908 is removed from Hesperophasmatini and transferred to Diapheromeridae: Diapheromerinae: Diapheromerini. The new tribe Pterinoxylini n. trib. is established to contain only the type-genus Pterinoxylus Audinet-Serville, 1838. It is closely related and perhaps the sister taxon of Hesperophasmatini, with which it shares the presence of rough sensory areas on the probasisternum and profurcasternum. It differs from Hesperophasmatini and Haplopodini by the presence of a tympanal region (= stridulatory organ) in the alae of females and the alveolar eggs, which possess peripheral opercular and polar structures. Haplopodini is likely to be the sister group of Pterinoxylini n. trib. + Hesperophasmatini.        The tribe Haplopodini rev. stat. is revised at the species level and comprises eight almost exclusively Caribbean genera, four of which are newly described. All eight genera now contained in Haplopodini are described in detail, differentiated from their closest relatives and their relationships and systematic position within Haplopodini are discussed. Keys and maps showing their distributions are presented along with a discussion of the distributional patterns. Detailed descriptions, differential diagnoses, synonymic listings, illustrations, material listings and measurements are given of all 26 currently known species and subspecies of Haplopodini. Four new genera are described within Haplopodini. The monotypical Apteroplopus n. gen. (type-species: Dyme grosse-tuberculata Brunner v. Wattenwyl, 1907) from Honduras is the only taxon of the tribe represented in Central America. It is only known from the male which differs from all other genera by being entirely apterous. Cephaloplopus n. gen. (type-species: Cephaloplopus pulchellus n. sp.) and Parhaplopus n. gen. (type-species: Haplopus cubensis Saussure, 1868) occur only on Hispaniola and Cuba. Both are closely related to Haplopus Burmeister, 1838 but in addition to having noticeably different eggs, both genera differ from Haplopus in several morphological characters. The monotypical Venupherodes n. gen. (type-species: Platycrana venustula Audinet-Serville, 1838) is endemic to Cuba, and in females being apterous resembles the second exclusively Cuban genus Aploploides Rehn & Hebard, 1938. It however differs from all other members of Haplopodini by the laterally expanded mesonotum of females, which overlaps the mesopleurae, as well as the morphology of the eggs. Two species-groups are recognized within Diapherodes Gray, 1835. The gigantea species-group comprises the species from the Lesser Antilles, which are: D. angulata (Fabricius, 1793), Diapherodes dominicae (Rehn & Hebard, 1938), D. gigantea gigantea (Gmélin, 1789), D. gigantea saintluciae n. ssp. and Diapherodes martinicensis Lelong & Langlois, 2005. The three species of the jamaicensis species-group, which are D. achalus (Rehn, 1904), D. jamaicensis (Drury, 1773) and D. laevicollis Redtenbacher, 1906, are restricted to the two Greater Antillean islands Jamaica and Puerto Rico. Haplopus Burmeister, 1838 is the most widely distributed genus being represented on all islands of the Greater Antilles except Jamaica, and also in the Virgin Islands, Bahamas, Florida Keys, Dry Tortugas and as far southwest as the Cayman Islands and Swan Islands.        Nine new species and one new subspecies are described: Cephaloplopus alope n. sp. and Haplopus sobrinus n. sp. from Cuba, Cephaloplopus euchlorus n. sp., Cephaloplopus laetus n. sp., Cephaloplopus pulchellus n. sp., Haplopus brachypterus n. sp., Haplopus intermedius n. sp. and Parhaplopus navarroi n. sp. from Hispaniola, Haplopus woodruffi n. sp. from Cayman Brac (Cayman Islands) and Diapherodes gigantea saintluciae n. ssp. from Saint Lucia. Seven of these are described from both sexes but Cephaloplopus alope n. sp. and Haplopus sobrinus n. sp. are only known from the females and Cephaloplopus laetus n. sp. only from the males. The previously unknown males of Diapherodes angulata (Fabricius, 1793), Diapherodes laevicollis Redtenbacher, 1908, Haplopus bicuspidatus de Haan, 1842 and Parhaplopus cubensis (Saussure, 1868) as well as the previously unknown female of Parhaplopus evadne (Westwood, 1859) n. comb. are described and illustrated for the first time. Descriptions and illustrations of the eggs of eleven species are presented: Cephaloplopus euchlorus n. sp., Cephaloplopus pulchellus n. sp., Diapherodes achalus (Rehn, 1904), Diapherodes dominicae (Rehn & Hebard, 1938), Diapherodes gigantea gigantea (Gmélin, 1789), Diapherodes martinicensis Lelong & Langlois, 2005, Diapherodes jamaicensis (Drury, 1773), Haplopus bicuspidatus de Haan, 1842, Haplopus micropterus St. Fargeau & Audinet-Serville, 1825, Parhaplopus navarroi n. sp. and Venupherodes venustula (Audinet-Seville, 1838) n. comb.. Type specimens of the newly described taxa are deposited in the collections of ANSP, NHMUK, IIBZ, FSCA, MCZC, MNHN and USNM.        Six species are transferred to other genera (n. comb.): Bacteria grossetuberculata (Brunner v. Wattenwyl, 1907) to Apteroplopus n. gen. (ABSTRACT TRUNCATED)

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The objective of this review is to critically appraise and synthesize evidence on the effectiveness of professional oral health care intervention on the oral health of aged care residents with dementia.More specifically the objectives are to identify the efficacy of professional oral health care interventions on general oral health, the presence of plaque and the number of decayed or missing teeth. Dementia poses a significant challenge for health and social policy in Australia. The quality of life of individuals, their families and friends is impacted by dementia. Older people with dementia often have other health comorbidities resulting in the need for a higher level of care. From 2009 to 2010, 53% of permanent residents in Residential Aged Care Facilities (RACFs) had dementia on admission. Older Australians are retaining more of their natural teeth, therefore residents entering RACFs will have more of their natural teeth and require complex dental work than they did in previous generations. Data from the Australian Institute of Health and Welfare showed that more than half the residents in RACFs are now partially dentate with an average of 12 teeth each. Furthermore, coronal and root caries are significant problems, especially in older Australians who are cognitively impaired.Residents in aged care facilities frequently have poor oral health and hygiene with moderate to high levels of oral disease and overall dental neglect. This is reinforced by aged care staff who acknowledge that the demands of feeding, toileting and behavioral issues amongst residents often take precedence over oral health care regimens. Current literature shows that there is a general reluctance on the part of aged care staff to prioritize oral care due to limited knowledge as well as existing psychological barriers to working on another person's mouth. Although staff routinely deal with residents' urinary and faecal incontinence, deep psychological barriers exist when working on someone's mouth due to their own personal values of oral health or their views that residents should be looking after their own teeth or dentures. Furthermore, residents with behavioral issues associated with dementia frequently have their oral hygiene neglected as they may be resistant and violent towards receiving oral care from aged care staff. Studies have shown that residents with dementia will often refuse to open their mouth or partake in oral hygiene care by aged care staff. The aged care staff in return often do not pursue an oral care regimen for these "difficult" residents, perpetuating the cycle of oral neglect and resultant disease.Dental hygienists are qualified oral health professionals who are specifically trained to develop individualized oral health care plans and preventative programs to reduce oral health disease in the community. Residents with dementia in aged care facilities have the right to live their lives comfortably and free of oral discomfort or pain. A Victorian study conducted by Hopcraft et al. investigated the ability of a dental hygienist to undertake a dental examination/screening for residents in aged care facilities, to develop a preventative and periodontal treatment plan and to refer patients appropriately to a dentist. Results from this study demonstrated that there was an excellent agreement between the dentist and dental hygienist regarding the decision to refer residents to a dentist for treatment, demonstrating high sensitivity (99.6%) and high specificity (82.9%). Residents from 31 Victorian RACFs (n=510) were examined by a single experienced dental epidemiologist and one of four dental hygienists using a simple mouth mirror and probe. Hopcraft et al. concluded that hygienists should be utilized more widely in providing holistic oral health care to residents in aged care facilities.Recently, Lewis et al. discussed the need to develop models of care to improve access to dental care for frail and functionally dependent elderly people in aged care facilities, with the model of care involving dental hygienists/oral health therapists having merit.The concept of professional oral care involves an oral health professional such as a dental hygienist or oral health therapist supervising or assisting residents with their oral care. Oral care involves the mechanical removal of plaque and food debris using a toothbrush, interproximal brush and floss.In 2014, Morino et al. explored the efficacy of short term professional oral care from dental hygienists once a week after breakfast for one month. In this study, the dental hygienists did not perform dental scaling but brushed subjects' teeth using a toothbrush and interdental brush. Dental plaque scores decreased significantly (Fisher's two-tailed tests, p<0.05) in the professional oral health intervention group. Interestingly, the positive effects of this short term intervention were sustained for the following three months (Wilcoxon test, p<0.05).A pilot study in Arkansas was conducted by Amerine et al. and utilized the dental hygienist as the "oral health champion" in the residential aged care facility using the Oral Health Assessment Tool (OHAT) and Geriatric Oral Health Assessment Index (GOHAI) scores to measure oral health. The results from this study showed improvements in three measured areas (tongue health, denture status and oral cleanliness) in the dental hygiene champion group. These findings suggest that the presence of a dental hygiene champion in long term care facilities may positively impact the oral health of residents requiring assistance with their oral care. However, the authors noted further research in this concept is required.Van Der Putten GJ et al. explored the effectiveness of a supervised implementation of an oral health care guideline in care homes. In each ward of the care homes, a nurse who acted as the ward oral health care organiser (WOO) was appointed. The dental hygienist and an investigator would attend the RACFs every six weeks to support them. The dental hygienist would train the WOO, and the WOO would train the ward nurses and nurse assistants. Participants were allocated into an intervention or a control group. The intervention group received supervised oral care. Statistically significant differences in mean dental and denture plaque scores at six months in both groups occurred (student t-test, p < 0.0001). This research study implemented an intervention using the train-the-trainer approach and although improvements in dental and denture plaque scores were seen in the six-month period, the long-term effects of this intervention are unknown. Further studies exploring the long-term effects of staff training on oral health education are needed as well as ongoing staff training in aged care facilities.A systematic review on oral health and aspiration pneumonia conducted by Vander Maarel-Wierink et al. has suggested that, in the frail elderly, the best intervention to reduce the incidence of aspiration pneumonia is brushing of teeth after each meal, cleaning dentures once a day, and receiving professional oral health care once a week.The need to advocate for a new model of geriatric dentistry is critical. A holistic multi-disciplinary approach to health care for residents entering aged care homes is imperative to achieve better oral health and comfort for residents, especially with Australia's ageing dentate population. A dental examination and assessment on admission to a RACF should be conducted by a Registered Nurse (RN), followed by an oral health professional such as a dentist, dental hygienist or oral health therapist. Current practice in the majority of Australian government funded nursing homes is that the RN or the Assistant in Nursing (AIN) conduct the oral health assessment as part of the aged care funding instrument (ACFI). Ongoing oral health care supported by an oral health professional is important throughout the individual's residency and eventual palliation whilst in an aged care facility.No systematic reviews conducted on the impact of professional oral care on the oral health of elderly people living in residential aged care facilities could be located, despite extensive searching of Medline, CINAHL, EMBASE, Web of Science, Cochrane Central Register of Trials and Dentistry & Oral Sciences Source (DOSS) databases. A JBI systematic review was conducted in 2004, titled, "Oral hygiene care for adults with dementia in residential aged care facilities"; however, this review examined the prevalence, incidence and increments of oral diseases; the use of assessment tools to evaluate oral health; preventative oral hygiene care strategies; and the provision of dental treatment and so had a different clinical focus. Twenty studies were included for analysis in the review conducted by Weening-Verbree et al, The studies in this review addressed oral health knowledge of aged care staff and mostly were conducted as an educational session delivered by dental hygienists or dentists.Overall, the current evidence available on interventions to improve oral health for residents living in aged care facilities is inadequate and should be explored further.

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Worldwide, more than 20 million patients undergo groin hernia repair annually. The many different approaches, treatment indications and a significant array of techniques for groin hernia repair warrant guidelines to standardize care, minimize complications, and improve results. The main goal of these guidelines is to improve patient outcomes, specifically to decrease recurrence rates and reduce chronic pain, the most frequent problems following groin hernia repair. They have been endorsed by all five continental hernia societies, the International Endo Hernia Society and the European Association for Endoscopic Surgery. An expert group of international surgeons (the HerniaSurge Group) and one anesthesiologist pain expert was formed. The group consisted of members from all continents with specific experience in hernia-related research. Care was taken to include surgeons who perform different types of repair and had preferably performed research on groin hernia surgery. During the Group's first meeting, evidence-based medicine (EBM) training occurred and 166 key questions (KQ) were formulated. EBM rules were followed in complete literature searches (including a complete search by The Dutch Cochrane database) to January 1, 2015 and to July 1, 2015 for level 1 publications. The articles were scored by teams of two or three according to Oxford, SIGN and Grade methodologies. During five 2-day meetings, results were discussed with the working group members leading to 136 statements and 88 recommendations. Recommendations were graded as "strong" (recommendations) or "weak" (suggestions) and by consensus in some cases upgraded. In the Results and summary section below, the term "should" refers to a recommendation. The AGREE II instrument was used to validate the guidelines. An external review was performed by three international experts. They recommended the guidelines with high scores. The risk factors for inguinal hernia (IH) include: family history, previous contra-lateral hernia, male gender, age, abnormal collagen metabolism, prostatectomy, and low body mass index. Peri-operative risk factors for recurrence include poor surgical techniques, low surgical volumes, surgical inexperience and local anesthesia. These should be considered when treating IH patients. IH diagnosis can be confirmed by physical examination alone in the vast majority of patients with appropriate signs and symptoms. Rarely, ultrasound is necessary. Less commonly still, a dynamic MRI or CT scan or herniography may be needed. The EHS classification system is suggested to stratify IH patients for tailored treatment, research and audit. Symptomatic groin hernias should be treated surgically. Asymptomatic or minimally symptomatic male IH patients may be managed with "watchful waiting" since their risk of hernia-related emergencies is low. The majority of these individuals will eventually require surgery; therefore, surgical risks and the watchful waiting strategy should be discussed with patients. Surgical treatment should be tailored to the surgeon's expertise, patient- and hernia-related characteristics and local/national resources. Furthermore, patient health-related, life style and social factors should all influence the shared decision-making process leading up to hernia management. Mesh repair is recommended as first choice, either by an open procedure or a laparo-endoscopic repair technique. One standard repair technique for all groin hernias does not exist. It is recommended that surgeons/surgical services provide both anterior and posterior approach options. Lichtenstein and laparo-endoscopic repair are best evaluated. Many other techniques need further evaluation. Provided that resources and expertise are available, laparo-endoscopic techniques have faster recovery times, lower chronic pain risk and are cost effective. There is discussion concerning laparo-endoscopic management of potential bilateral hernias (occult hernia issue). After patient consent, during TAPP, the contra-lateral side should be inspected. This is not suggested during unilateral TEP repair. After appropriate discussions with patients concerning results tissue repair (first choice is the Shouldice technique) can be offered. Day surgery is recommended for the majority of groin hernia repair provided aftercare is organized. Surgeons should be aware of the intrinsic characteristics of the meshes they use. Use of so-called low-weight mesh may have slight short-term benefits like reduced postoperative pain and shorter convalescence, but are not associated with better longer-term outcomes like recurrence and chronic pain. Mesh selection on weight alone is not recommended. The incidence of erosion seems higher with plug versus flat mesh. It is suggested not to use plug repair techniques. The use of other implants to replace the standard flat mesh in the Lichtenstein technique is currently not recommended. In almost all cases, mesh fixation in TEP is unnecessary. In both TEP and TAPP it is recommended to fix mesh in M3 hernias (large medial) to reduce recurrence risk. Antibiotic prophylaxis in average-risk patients in low-risk environments is not recommended in open surgery. In laparo-endoscopic repair it is never recommended. Local anesthesia in open repair has many advantages, and its use is recommended provided the surgeon is experienced in this technique. General anesthesia is suggested over regional in patients aged 65 and older as it might be associated with fewer complications like myocardial infarction, pneumonia and thromboembolism. Perioperative field blocks and/or subfascial/subcutaneous infiltrations are recommended in all cases of open repair. Patients are recommended to resume normal activities without restrictions as soon as they feel comfortable. Provided expertise is available, it is suggested that women with groin hernias undergo laparo-endoscopic repair in order to decrease the risk of chronic pain and avoid missing a femoral hernia. Watchful waiting is suggested in pregnant women as groin swelling most often consists of self-limited round ligament varicosities. Timely mesh repair by a laparo-endoscopic approach is suggested for femoral hernias provided expertise is available. All complications of groin hernia management are discussed in an extensive chapter on the topic. Overall, the incidence of clinically significant chronic pain is in the 10-12% range, decreasing over time. Debilitating chronic pain affecting normal daily activities or work ranges from 0.5 to 6%. Chronic postoperative inguinal pain (CPIP) is defined as bothersome moderate pain impacting daily activities lasting at least 3 months postoperatively and decreasing over time. CPIP risk factors include: young age, female gender, high preoperative pain, early high postoperative pain, recurrent hernia and open repair. For CPIP the focus should be on nerve recognition in open surgery and, in selected cases, prophylactic pragmatic nerve resection (planned resection is not suggested). It is suggested that CPIP management be performed by multi-disciplinary teams. It is also suggested that CPIP be managed by a combination of pharmacological and interventional measures and, if this is unsuccessful, followed by, in selected cases (triple) neurectomy and (in selected cases) mesh removal. For recurrent hernia after anterior repair, posterior repair is recommended. If recurrence occurs after a posterior repair, an anterior repair is recommended. After a failed anterior and posterior approach, management by a specialist hernia surgeon is recommended. Risk factors for hernia incarceration/strangulation include: female gender, femoral hernia and a history of hospitalization related to groin hernia. It is suggested that treatment of emergencies be tailored according to patient- and hernia-related factors, local expertise and resources. Learning curves vary between different techniques. Probably about 100 supervised laparo-endoscopic repairs are needed to achieve the same results as open mesh surgery like Lichtenstein. It is suggested that case load per surgeon is more important than center volume. It is recommended that minimum requirements be developed to certify individuals as expert hernia surgeon. The same is true for the designation "Hernia Center". From a cost-effectiveness perspective, day-case laparoscopic IH repair with minimal use of disposables is recommended. The development and implementation of national groin hernia registries in every country (or region, in the case of small country populations) is suggested. They should include patient follow-up data and account for local healthcare structures. A dissemination and implementation plan of the guidelines will be developed by global (HerniaSurge), regional (international societies) and local (national chapters) initiatives through internet websites, social media and smartphone apps. An overarching plan to improve access to safe IH surgery in low-resource settings (LRSs) is needed. It is suggested that this plan contains simple guidelines and a sustainability strategy, independent of international aid. It is suggested that in LRSs the focus be on performing high-volume Lichtenstein repair under local anesthesia using low-cost mesh. Three chapters discuss future research, guidelines for general practitioners and guidelines for patients. The HerniaSurge Group has developed these extensive and inclusive guidelines for the management of adult groin hernia patients. It is hoped that they will lead to better outcomes for groin hernia patients wherever they live. More knowledge, better training, national audit and specialization in groin hernia management will standardize care for these patients, lead to more effective and efficient healthcare and provide direction for future research.

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The comparative genomics of butterflies yields additional insights into their phylogeny and classification that are compiled here. As a result, 3 genera, 5 subgenera, 5 species, and 3 subspecies are proposed as new, i.e., in Hesperiidae: <iAntina</i Grishin, <bgen. n.</b (type species <iAntigonus minor</i O. Mielke, 1980), <iPompe</i Grishin and Lamas, <bgen. n.</b (type species <iLerema postpuncta</i Draudt, 1923), and <iCurva</i Grishin, <bgen. n.</b (type species <iMoeris hyagnis</i Godman, 1900); in Lycaenidae: <iFussia</i Grishin, <bsubgen. n.</b (type species <iPolyommatus standfussi</i Grum-Grshimailo, 1891) and <iPava</i Grishin, <bsubgen. n.</b (type species <iThecla panava</i Westwood, 1852); in Hesperiidae: <iMonoca</i Grishin, <bsubgen. n.</b (type species <iTagiades monophthalma</i Plötz, 1884), <iPutuma</i Grishin, <bsubgen. n.</b (type species <iTisias putumayo</i Constantino and Salazar, 2013), and <iRayia</i Grishin, <bsubgen. n.</b (type species <iMastor perigenes</i Godman, 1900); <iCissia wahala</i Grishin, <bsp. n.</b (Nymphalidae; type locality in Mexico: Oaxaca); in Hesperiidae: <iHedone mira</i Grishin and Lamas, <bsp. n.</b (type locality in Peru: Apurímac), <iVidius pompeoides</i Grishin, <bsp. n.</b (type locality in Brazil: Amazonas), <iParphorus hermieri</i Grishin, <bsp. n.</b (Hesperiidae; type locality in Brazil: Rondônia), and <iZenis par</i Grishin, <bsp. n.</b (Hesperiidae; type locality in Peru: Cuzco); in Pieridae: <iGlutophrissa drusilla noroesta</i Grishin, <bssp. n.</b (type locality in USA: Texas, Cameron Co.) and <iPieris marginalis siblanca</i Grishin, <bssp. n.</b (type locality in USA: New Mexico, Lincoln Co.), and <iArgynnis cybele neomexicana</i Grishin, <bssp. n.</b (Nymphalidae; type locality in USA: New Mexico, Sandoval Co.). <iAcidalia leto valesinoides-alba</i Reuss, [1926] and <iAcidalia nokomis valesinoides-alba</i Reuss, [1926] are unavailable names. <bNeotypes</b are designated for <iMylothris margarita</i Hübner, [1825] (type locality in Brazil) and <iPapilio coras</i Cramer, 1775 (type locality becomes USA: Pennsylvania, Montgomery Co., Flourtown). <iMylothris margarita</i Hübner, [1825] becomes a junior objective synonym of <iPieris ilaire</i Godart, 1819, currently a junior subjective synonym of <iGlutophrissa drusilla</i (Cramer, 1777). <bLectotypes</b are designated for <iHesperia ceramica</i Plötz, 1886 (type locality in Indonesia: Seram Island), <iPamphila trebius</i Mabille, 1891 (type locality Colombia: Bogota), <iMethionopsis modestus</i Godman, 1901 and <iPapias microsema</i Godman, 1900 (type locality in Mexico: Tabasco), <iHesperia fusca</i Grote &amp; Robinson, 1867 (type locality in USA: Georgia), <iGoniloba corusca</i Herrich-Schäffer, 1869, and <iGoniloba devanes</i Herrich-Schäffer, 1869; the type localities of the last two species, together with <iPamphila stigma</i Skinner, 1896 and <iCarystus (Argon) lota</i (Hewitson, 1877), are deduced to be in South America. Type locality of <iJunonia pacoma</i Grishin, 2020 is in Sinaloa, not Sonora (Mexico). Abdomen is excluded from the holotype of <iStaphylus ascalon</i (Staudinger, 1876). Furthermore, a number of taxonomic changes are proposed. <iAlciphronia</i Koçak, 1992 is treated as a subgenus, not a synonym of <iHeodes</i Dalman, 1816. The following genera are treated as subgenera: <iLafron</i Grishin, 2020 of <iLycaena</i [Fabricius], 1807, <iAremfoxia</i Real, 1971 of <iEpityches</i D'Almeida, 1938, <iPlacidina</i D'Almeida, 1928 of <iPagyris</i Boisduval, 1870, and <iMethionopsis</i Godman, 1901 of <iMnasinous</i Godman, 1900. <iPolites (Polites) coras</i (Cramer, 1775) is not a <inomen dubium</i but a valid species. The following are species-level taxa (not subspecies or synonyms of taxa given in parenthesis): <iLycaena pseudophlaeas</i (Lucas, 1866) and <iLycaena hypophlaeas</i (Boisduval, 1852) (not <iLycaena phlaeas</i (Linnaeus, 1761), <iSatyrium dryope</i (W. H. Edwards, 1870) (not <iSatyrium sylvinus</i (Boisduval, 1852)), <iApodemia cleis</i (W. H. Edwards, 1882) (not <iApodemia zela</i (Butler, 1870)), <iEpityches thyridiana</i (Haensch, 1909), <bcomb. nov.</b (not <iEpityches ferra</i Haensch, 1909, <bcomb. nov.</b), <iArgynnis bischoffii</i W. H. Edwards, 1870 (not <iArgynnis mormonia</i Boisduval, 1869), <iArgynnis leto</i Behr, 1862 (not <iArgynnis cybele</i (Fabricius, 1775)), <iBoloria myrina</i (Cramer, 1777) (not <iBoloria selene</i ([Denis &amp; Schiffermüller], 1775)), <iPhyciodes jalapeno</i J. Scott, 1998 (not <iPhyciodes phaon</i (W. H. Edwards, 1864)), <iPhyciodes incognitus</i Gatrelle, 2004 and <iPhyciodes diminutor</i J. Scott, 1998 (not <iPhyciodes cocyta</i (Cramer, 1777)), <iPhyciodes orantain</i J. Scott, 1998 (not <iPhyciodes tharos</i (Drury, 1773)), <iPhyciodes anasazi</i J. Scott, 1994 (not <iPhyciodes batesii</i (Reakirt, [1866])), <iCercyonis silvestris</i (W. H. Edwards, 1861) (not <iCercyonis sthenele</i (Boisduval, 1852)), <iParamacera allyni</i L. Miller, 1972 and <iParamacera rubrosuffusa</i L. Miller, 1972 (not <iParamacera xicaque</i (Reakirt, [1867])), <iCissia cheneyorum</i (R. Chermock, 1949), <iCissia pseudocleophes</i (L. Miller, 1976), and <iCissia anabelae</i (L. Miller, 1976) (not <iCissia rubricata</i (W. H. Edwards, 1871)), <iTarsoctenus gaudialis</i (Hewitson, 1876) (not <iTarsoctenus corytus</i (Cramer, 1777)), <iNisoniades inca</i (Lindsey, 1925) (not <iNisoniades mimas</i (Cramer, 1775), <iXenophanes ruatanensis</i Godman &amp; Salvin, 1895 (not <iXenophanes tryxus</i (Stoll, 1780)), <iLotongus shigeoi</i Treadaway &amp; Nuyda, 1994, <iLotongus balta</i Evans, 1949, <iLotongus zalates</i (Mabille, 1893), and <iLotongus taprobanus</i (Plötz, 1885) (not <iLotongus calathus</i (Hewitson, 1876)), <iOxynthes martius</i (Mabille, 1889) (not <iOxynthes corusca</i (Herrich-Schäffer, 1869)), <iNotamblyscirtes durango</i J. Scott, 2017 (not <iNotamblyscirtes simius</i W. H. Edwards, 1881), <iHedone praeceps</i Scudder, 1872, <iHedone catilina</i (Plötz, 1886), and <iHedone calla</i (Evans, 1955) (not <iHedone vibex</i (Geyer, 1832)), <iAtalopedes huron</i (W. H. Edwards, 1863) (not <iAtalopedes campestris</i (Boisduval, 1852)), <iPapias microsema</i Godman, 1900 (not <iMnasinous phaeomelas</i (Hübner, [1829]), <bcomb. nov.</b), <iPapias unicolor</i (Hayward, 1938) and <iPapias monus</i Bell, 1942 (not <iPapias phainis</i Godman, 1900), <iNastra leuconoides</i (Lindsey, 1925) (not <iNastra leucone</i (Godman, 1900)), <iNastra fusca</i (Grote &amp; Robinson, 1867) (not <iNastra lherminier</i (Latreille, [1824])), <iZenis hemizona</i (Dyar, 1918) and <iZenis janka</i Evans, 1955 (not <iZenis jebus</i (Plötz, 1882)), <iCarystus (Argon) argus</i Möschler, 1879 (not <iCarystus (Argon) lota</i Hewitson, 1877), and <iLycas devanes</i (Herrich-Schäffer, 1869) (not <iLycas argentea</i (Hewitson, 1866)). <iBorbo impar ceramica</i (Plötz, 1886), <bcomb. nov.</b is not a synonym of <iPelopidas agna larika</i (Pagenstecher, 1884) but a valid subspecies. <iParnassius smintheus behrii</i W. H. Edwards, 1870 and <iCercyonis silvestris incognita</i J. Emmel, T. Emmel &amp; Mattoon, 2012 are subspecies, not species. The following are junior subjective synonyms: <iShijimiaeoides</i Beuret, 1958 of <iGlaucopsyche</i Scudder, 1872, <iMicropsyche</i Mattoni, 1981 of <iTuranana</i Bethune-Baker, 1916, <iCyclyrius</i Butler, 1897 of <iLeptotes</i Scudder, 1876, <iMesenopsis</i Godman &amp; Salvin, 1886 of <iXynias</i Hewitson, 1874, <iCarystus tetragraphus</i Mabille, 1891 of <iLotongus calathus parthenope</i (Plötz, 1886), <iParnara bipunctata</i Elwes &amp; J. Edwards, 1897 of <iBorbo impar ceramica</i (Plötz, 1886), <iHesperia peckius</i W. Kirby, 1837 of <iPolites (Polites) coras</i (Cramer, 1775), and <iLerodea neamathla</i Skinner &amp; R. Williams, 1923 of <iNastra fusca</i (Grote &amp; Robinson, 1867). The following transfers are proposed: of species between genera (i.e., revised genus-species combinations): <iNervia niveostriga</i (Trimen, 1864) (not <iKedestes</i Watson, 1893), <iLeona lota</i Evans, 1937 (not <iLennia</i Grishin, 2022), <iLeona pruna</i (Evans, 1937) and <iLeona reali</i (Berger, 1962) (not <iPteroteinon</i Watson, 1893), <iMnasinous phaeomelas</i (Hübner, [1829]) (not <iPapias</i Godman, 1900), <iSaturnus jaguar</i (Steinhauser, 2008) (not <iParphorus</i Godman, 1900), <iParphorus harpe</i (Steinhauser, 2008) (not <iSaturnus</i Evans, 1955), <iParphorus kadeni</i (Evans, 1955) (not <iLento</i Evans, 1955), and <iCalpodes chocoensis</i (Salazar &amp; Constantino, 2013) (not <iMegaleas</i Godman, 1901); of subspecies between species (i.e., revised species-subspecies combinations): <iMelitaea sterope</i W. H. Edwards, 1870 of <iChlosyne palla</i (Boisduval, 1852) (not <iChlosyne acastus</i (W. H. Edwards, 1874)) and <iPanoquina ocola distipuncta</i Johnson &amp; Matusik, 1988 of <iPanoquina lucas</i (Fabricius, 1793); and junior subjective synonym transferred between species: <iRhinthon zaba</i Strand, 1921 of <iConga chydaea</i (A. Butler, 1877), not <iCynea cynea</i (Hewitson, 1876), <iPamphila stigma</i Skinner, 1896 of <iHedone catilina</i (Plötz, 1886), not <iHedone praeceps</i Scudder, 1872, and <iPamphila ortygia</i Möschler, 1883 of <iPanoquina hecebolus</i (Scudder, 1872), not <iPanoquina ocola</i (W. H. Edwards, 1863). Proposed taxonomic changes result in additional revised species-subspecies combinations: <iLycaena pseudophlaeas abbottii</i (Holland, 1892), <iSatyrium dryope putnami</i (Hy. Edwards, 1877), <iSatyrium dryope megapallidum</i Austin, 1998, <iSatyrium dryope itys</i (W. H. Edwards, 1882), <iSatyrium dryope desertorum</i (F. Grinnell, 1917), <iArgynnis bischoffi opis</i W. H. Edwards, 1874, <iArgynnis bischoffi washingtonia</i W. Barnes &amp; McDunnough, 1913, <iArgynnis bischoffi erinna</i W. H. Edwards, 1883, <iArgynnis bischoffi kimimela</i Marrone, Spomer &amp; J. Scott, 2008, <iArgynnis bischoffi eurynome</i W. H. Edwards, 1872, <iArgynnis bischoffi artonis</i W. H. Edwards, 1881, <iArgynnis bischoffi luski</i W. Barnes &amp; McDunnough, 1913, <iArgynnis leto letona</i (dos Passos &amp; Grey, 1945), <iArgynnis leto pugetensis</i (F. Chermock &amp; Frechin, 1947), <iArgynnis leto eileenae</i (J. Emmel, T. Emmel &amp; Mattoon, 1998), <iBoloria myrina nebraskensis</i (W. Holland, 1928), <iBoloria myrina sabulocollis</i Kohler, 1977, <iBoloria myrina tollandensis</i (W. Barnes &amp; Benjamin, 1925), <iBoloria myrina albequina</i (W. Holland, 1928), <iBoloria myrina atrocostalis</i (Huard, 1927), <iBoloria myrina terraenovae</i (W. Holland, 1928), <iPhyciodes anasazi apsaalooke</i J. Scott, 1994, <iPolites coras surllano</i J. Scott, 2006, and <iCurva darienensis</i (Gaviria, Siewert, Mielke &amp; Casagrande, 2018). Specimen curated as the holotype of <iAcidalia leto valesinoides-alba</i Reuss, [1926] is <iArgynnis leto letona</i (dos Passos &amp; Grey, 1945) (not <iA. leto leto</i Behr, 1862) from USA: Utah, Provo. A synonymic list of available genus-group names for Lycaeninae [Leach], [1815] is given. Unless stated otherwise, all subgenera, species, subspecies and synonyms of mentioned genera and species are transferred with their parent taxa, and others remain as previously classified.

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We thank van Tongeren et al for responding to our study on occupational disparities in SARS-CoV-2 infection risks during the first pandemic wave in Germany (1). The authors address the potential for bias resulting from differential testing between occupational groups and propose an alternative analytical strategy for dealing with selective testing. In the following, we want to discuss two aspects of this issue, namely (i) the extent and reasons of differential testing in our cohort and (ii) the advantages and disadvantages of different analytical approaches to study risk factors for SARS-CoV-2 infection. Our study relied on nationwide prospective cohort data including more than 100 000 workers in order to compare the incidence of infections between different occupations and occupational status positions. We found elevated infection risks in personal services and business administration, in essential occupations (including health care) and among people in higher occupational status positions (ie, managers and highly skilled workers) during the first pandemic wave in Germany (2). Van Tongeren's et al main concern is that the correlations found could be affected by a systematic bias because people in healthcare professions get tested more often than employees in other professions. A second argument is that better-off people could be more likely to use testing as they are less affected by direct costs (prices for testing) and the economic hardship associated with a positive test result (eg, loss of earnings in the event of sick leave). We share the authors' view that differential testing must be considered when analysing and interpreting the data. Thus, in our study, we examined the proportion of tests conducted in each occupational group as part of the sensitivity analyses (see supplementary figure S1, accessible at www.sjweh.fi/article/4037). As expected, testing proportions were exceptionally high in medical occupations (due to employer requirements). However, we did not observe systematic differences among non-medical occupations or when categorising by skill-level or managerial responsibility. This might be explained by several reasons. First, SARS-CoV-2 testing was free of charge during the first pandemic wave in Germany, but reporting a risk contact or having symptoms was a necessary condition for testing ( https://www.bundesgesundheitsministerium.de/coronavirus/chronik-coronavirus.html (accessed 5 September 2022). The newspaper article cited by van Tongeren et al is misleading as it refers to a calendar date after our study period. Second, different motivation for testing due to economic hardship in case of a positive test result is an unlikely explanation, because Germany has a universal healthcare system, including paid sick leave and sickness benefits for all workers (3). Self-employed people carry greater financial risks in case of sickness. We therefore included self-employment in the multivariable analyses to address this potential source of bias. While the observed inverse social gradient may be surprising, it actually matches with findings of ecological studies from Germany (4, 5), the United States (6, 7) as well as Spain, Portugal, Sweden, The Netherlands, Israel, and Hong Kong (8), all of which observed higher infection rates in wealthier neighbourhoods during the initial outbreak phase of the pandemic. One possible explanation is the higher mobility of managers and better educated workers, who are more likely to participate in meetings and engage in business travel and holiday trips like skiing. Given the increasing number of studies providing evidence for this hypothesis, we conclude that the inverse social gradient in our study likely reflects different exposure probabilities and is not a result of systematic bias. This also holds true for the elevated infection risks in essential workers, which is actually corroborated by a large body of research (9-11). Regarding differential likelihood of testing, van Tongeren et al state that "[i]t is relatively simple to address this problem by using a test-negative design" (1). As van Tongeren et al describe, this is a case-control approach only including individuals who were tested (without considering those who were not tested). However, the proposed analytical strategy can lead to another (more serious) selection bias if testing proportions and/or testing criteria differ between groups (12). This can be easily illustrated when comparing the results based on a time-incidence design with those obtained by a test-negative design as shown in table 1 (see PDF). Both approaches show similar results in terms of vertical occupational differences. Infection was more common if individuals had a high skill level or had a managerial position, but associations were stronger in the time-incidence design and did not reach statistical significance in the test-negative design (as indicated by the confidence intervals overlapping "1"). Unfortunately, the test-negative approach relies on a strongly reduced sample size and thus results in greater statistical uncertainty and loss of statistical power (13). In contrast, the test-negative design yields a different picture when estimating the association between essential occupation and infection risk: In this analysis, essential workers did not differ from non-essential workers in their chance of being infected with SARS-CoV-2 (the test-negative design even exhibits a lower chance for essential workers). This is rather counter-intuitive and is not in accordance with what we know about the occupational hazards of healthcare workers during the pandemic (14). The main problem is that proportions of positive tests are highly unreliable when testing proportions and/or testing criteria differ between groups. As essential workers were tested more often without being symptomatic (due to employer requirements), a lower proportion of positive tests in this group does not necessarily correspond to a lower risk of infection. Consequently, we are not convinced that the test-negative design should be the 'gold standard' for studying risk factors for SARS-CoV-2 infections (15). Especially problematic is the loss of statistical power (increasing the probability of a type II error) and the low validity of the test-positivity when test criteria and/or test proportions differ between groups. References 1. van Tongeren M, Rhodes S, Pearce N. Occupation and SARS-CoV-2 infection risk among workers during the first pandemic wave in Germany: potential for bias. Scand J Work Environ Health 2022;48(7):586-587. https://doi.org/10.5271/sjweh.4052. 2. Reuter M, Rigó M, Formazin M, Liebers F, Latza U, Castell S, et al. Occupation and SARS-CoV-2 infection risk among 108 960 workers during the first pandemic wave in Germany. Scand J Work Environ Health 2022;48:446-56. https://doi.org/10.5271/sjweh.4037. 3. Busse R, Blümel M, Knieps F, Bärnighausen T. Statutory health insurance in Germany: a health system shaped by 135 years of solidarity, self-governance, and competition. Lancet 2017;390:882-97. https://doi.org/10.1016/S0140-6736(17)31280-1. 4. Wachtler B, Michalski N, Nowossadeck E, Diercke M, Wahrendorf M, Santos-Hövener C, et al. Socioeconomic inequalities in the risk of SARS-CoV-2 infection - First results from an analysis of surveillance data from Germany. J Heal Monit 2020;5:18-29. https://doi.org/10.25646/7057. 5. Plümper T, Neumayer E. The pandemic predominantly hits poor neighbourhoods? SARS-CoV-2 infections and COVID-19 fatalities in German districts. Eur J Public Health 2020;30:1176-80. https://doi.org/10.1093/eurpub/ckaa168. 6. Abedi V, Olulana O, Avula V, Chaudhary D, Khan A, Shahjouei S, et al. Racial, Economic, and Health Inequality and COVID-19 Infection in the United States. J Racial Ethn Heal Disparities 2021;8:732-42. https://doi.org/10.1007/s40615-020-00833-4. 7. Mukherji N. The Social and Economic Factors Underlying the Incidence of COVID-19 Cases and Deaths in US Counties During the Initial Outbreak Phase. Rev Reg Stud 2022;52. https://doi.org/10.52324/001c.35255. 8. Beese F, Waldhauer J, Wollgast L, Pförtner T, Wahrendorf M, Haller S, et al. Temporal Dynamics of Socioeconomic Inequalities in COVID-19 Outcomes Over the Course of the Pandemic-A Scoping Review. Int J Public Health 2022;67:1-14. https://doi.org/10.3389/ijph.2022.1605128. 9. Nguyen LH, Drew DA, Graham MS, Joshi AD, Guo C-G, Ma W, et al. Risk of COVID-19 among front-line health-care workers and the general community: a prospective cohort study. Lancet Public Heal 2020;5:e475-83. https://doi.org/10.1016/S2468-2667(20)30164-X. 10. Chou R, Dana T, Buckley DI, Selph S, Fu R, Totten AM. Epidemiology of and Risk Factors for Coronavirus Infection in Health Care Workers. Ann Intern Med 2020;173:120-36. https://doi.org/10.7326/M20-1632. 11. Stringhini S, Zaballa M-E, Pullen N, de Mestral C, Perez-Saez J, Dumont R, et al. Large variation in anti-SARS-CoV-2 antibody prevalence among essential workers in Geneva, Switzerland. Nat Commun 2021;12:3455. https://doi.org/10.1038/s41467-021-23796-4. 12. Accorsi EK, Qiu X, Rumpler E, Kennedy-Shaffer L, Kahn R, Joshi K, et al. How to detect and reduce potential sources of biases in studies of SARS-CoV-2 and COVID-19. Eur J Epidemiol 2021;36:179-96. https://doi.org/10.1007/s10654-021-00727-7. 13. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd Editio. New York: Routledge; 2013. https://doi.org/10.4324/9780203771587. 14. The Lancet. The plight of essential workers during the COVID-19 pandemic. Lancet 2020;395:1587. https://doi.org/10.1016/S0140-6736(20)31200-9. 15. Vandenbroucke JP, Brickley EB, Pearce N, Vandenbroucke-Grauls CMJE. The Evolving Usefulness of the Test-negative Design in Studying Risk Factors for COVID-19. Epidemiology 2022;33:e7-8. https://doi.org/10.1097/EDE.0000000000001438.

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Chronic uremia is characterized by decreased levels of plasma 1,25(OH)2D3 due to decreased renal 1-hydroxylase activity and by decreased renal phosphate excretion. The consequence is an increased synthesis and secretion of parathyroid hormone--secondary hyperparathyroidism--due to the low levels of plasma calcium, low levels of plasma 1,25(OH)2D3 and high levels of phosphate. The association between renal bone disease and chronic renal failure is well described. Epidemiological studies have indicated that an association also exists between secondary hyperparathyroidism and increased mortality and cardiovascular calcifications in chronic uremic patients. Treatment of secondary hyperparathyroidism in chronic uremia focuses on avoiding hyperphosphatemia by the use of oral phosphate binders, which bind phosphate in the intestine and a concomitant substitution by a 1 alpha-hydroxylated vitamin D analog in order to compensate for the reduced renal hydroxylation. Additional treatment with aluminum containing phosphate binders to overcome phosphate absorption and retention was initiated already in the 1960s and used extensively until aluminum toxicity was disclosed in the mid-1980s. Instead calcium carbonate and calcium acetate were used as phosphate binders. Until recently, the most commonly used active vitamin D drug was either the natural 1,25(OH)2D3, or the 1 alpha-hydroxylated analog, 1alpha(OH)D3 which after 25-hydroxylation in the liver is converted to 1,25(OH)2D3. 1alpha(OH)D3 was produced by LEO Pharma in 1973. The two vitamin D analogs were used in different geographical areas: In Europe 1alpha(OH)D3 was mainly used, while 1,25(OH)2D3 was mainly used in the USA. 1,25(OH)2D3 increases the intestinal absorption of calcium and improves skeletal abnormalities. The combined treatment with calcium containing phosphate binders and active vitamin D induces an increase in plasma Ca 2+ and hypercalcemia became a clinical problem. Subsequently therefore, dialysis fluid with a reduced calcium concentration ("low-calcium") was introduced. In 1981 Madsen et al. [148] demonstrated for the first time a direct suppressive effect of intravenous 1,25(OH)2D3 on plasma PTH in acutely uremic patients. In 1984, Slatopolsky et al. [74] demonstrated that intravenous 1,25(OH)2D3 induces a marked suppression of plasma PTH with no increase in plasma Ca 2+ in chronic uremic patients. In the middle of the 1980s, 1alpha(OH)D3 became available not only as an oral, but also as an intravenous formulation. The main purpose of the present studies was to increase the knowledge of the action and effects of different treatment regimes with 1alpha(OH)D3, and thereby to improve the prophylaxis and treatment of secondary hyperparathyroidism in uremic patients on chronic dialysis. 168 patients on chronic dialysis treatment and six healthy volunteers were included in the seven studies included in this thesis. The first part of the studies, focused on short- (12 weeks) and long-term (103 weeks) effects of intravenous 1alpha(OH)D3 on plasma PTH and plasma Ca 2+ in relation to the doses of 1alpha(OH)D3 given. Further, it was examined whether the marked suppression of plasma PTH induced by 300 days of intermittent intravenous treatment with 1alpha(OH)D3, could be maintained when the administration was changed from intravenous to the oral route for 16 further weeks and then shifted back to intravenous administration for another 16 weeks. The second part focused on long-term effects (88 weeks in hemodialysis patients and 52 weeks in CAPD patients) of a treatment modality combining 1alpha(OH)D3, and CaCO3 as phosphate binders instead of aluminum containing compounds and a decreased calcium concentration in the dialysis fluid to 1.25 mmol/l in an attempt to avoid development of hypercalcemia. The third part focused upon the pharmacokinetic differences between intravenous and oral administration of 1,25(OH)2D3 and 1alpha(OH)D3 and upon the acute effects of different doses of the two compounds on the plasma levels of PTH, Ca 2+ and phosphate. Plasma PTH is a biochemical parameter most often used for the diagnosis and monitoring of bone disease in patients with chronic uremia. The level of plasma PTH measures depends on the assay used. More specific assays measuring only whole PTH 1-84 without co-measuring large C-terminal fragments have been developed. In this thesis, five different assays were used - one "N-terminal", one "C-terminal", two "Intact" and one "Whole" PTH assay. Each sample was analyzed by 1-3 different assays. Based on the results of my studies [1-7], it is concluded that: 1a. Intravenous administration of 1alpha(OH)D3 induces a marked suppression of plasma PTH without causing serious side-effects in patients on chronic hemodialysis. It is possible to prevent hypercalcemia by closely monitoring plasma Ca 2+ levels and by adjusting the dose of 1alpha(OH)D3 accordingly. 1b. Long-term intermittent intravenous treatment with 1alpha(OH)D3 was effective in suppressing plasma levels of Intact PTH. 1c. When plasma intact PTH was suppressed to a stable level by intravenous 1alpha(OH)D3 the suppression could be maintained by intermittent oral 1alpha(OH)D3 therapy. It was not examined whether a similar degree of suppression of severe secondary hyperparathyroidism could be induced by intermittent oral 1alpha(OH)D3 treatment alone. The responses following chronic intravenous or oral administration of 1alpha(OH)D3 on circulating levels of intact PTH and N- and C-terminal PTH fragments did not reveal any significant differences between the two routes of administration on the actions on the parathyroid glands. 2a. The combination of "low-calcium" hemodialysis fluid (1.25 mmol/l), CaCO3 as a phosphate binder, and intermittent intravenous 1alpha(OH)D3 prevented development of secondary hyperparathyroidism in uremic patients with normal PTH at the initiation of the study and induced a long-term suppression of PTH in patients with secondary hyperparathyroidism. No clinical or biochemical indications of development of adynamic bone disease were observed. Intravenous administration of 1alpha(OH)D3 prevented a decrease of BMC in the lumbar spine and femoral neck of hemodialysis patients both with normal and with elevated PTH levels. It was possible to use larger doses of CaCO3 and to reduce, but not exclude, the use of aluminum-containing phosphate binders in combination with intravenous administration of 1alpha(OH)D3. A decrease of plasma Ca 2+ was induced during dialysis, and special care had to be taken on the compliance of the patients as to the use of CaCO3 binders in order not to aggravate secondary hyperparathyroidism. 2b. In patients on CAPD, the use of low-calcium dialysis (1.25 mmol/l) made it possible to use larger doses of CaCO3 phosphate binders and to reduce, but not exclude, the use of aluminium containing phosphate binder in combination with oral pulses of 1alpha(OH)D3. A negative calcium balance was induced, and it is therefore recommended that a reduction of the calcium concentration in the dialysis fluid is only used in patients under strict control. 3a. The metabolic clearance rate of 1,25(OH)2D3 was 57% lower in uremic patients than in normal subjects (p &lt; 0.03). The bioavailability of 1,25(OH)2D3 in both normal subjects and uremic patients was markedly lower following administration of 1alpha(OH)D3 both intravenously and orally than after administration of oral 1,25(OH)2D3. Despite lower plasma 1,25(OH)2D3 levels after administration of 1alpha(OH)D3 than after 1,25(OH)2D3, no significant difference was observed in the PTH suppressive effect in uremic patients of 4 mug intravenously of either of the two vitamin D analogs. 3b. A single intravenous high dose of 10 mug of 1alpha(OH)D3 or 1,25(OH)2D3 significantly suppressed plasma PTH. The acute suppressive effect of 1,25(OH)2D3 was three times greater than that of 1alpha(OH)D3.The increase in plasma Ca 2+ after intravenous administration of 10 mug 1,25(OH)2D3 was significantly higher than that of 1alpha(OH)D3. Due to the simultaneous effect on plasma Ca 2+ observed it was not possible to decide whether 1alpha(OH)D3 has a direct effect per se on the parathyroid glands or not. The study further did not give any further knowledge about the possible therapeutic equivalence of long-term treatment with 1alpha(OH)D3 or 1,25(OH)2D3. The PTH responses to acute administration of the 1alpha(OH)D3 and 1,25(OH)2D3 analogs were in principle the same when measured by one "whole" PTH and two "intact" PTH assays, namely mainly in a parallel shift of the PTH response curve. In this study on chronic uremic patients circulating levels of large C-terminal PTH fragments were not affected by differences in plasma Ca 2+ concentration or by the intravenous administration of 1alpha(OH)D3 or 1,25(OH)2D3. There is now a general agreement on the importance of carefully controlling plasma phosphate, normalize and avoid increases of plasma Ca 2+, and not to oversuppress PTH during treatment. Focus today is on the potential deleterious role of calcium overloading in the development of vascular calcifications in uremic patients. There is an urgent need for a development of an algorithm for the use of phosphate binders and vitamin D supplementation in combination with calcimimetics focusing upon long term morbidity and mortality in uremic patients.

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Exposure to air pollution is a well-established risk factor for cardiovascular morbidity and mortality. Most of the evidence supporting an association between air pollution and adverse cardiovascular effects involves exposure to particulate matter (PM). To date, little attention has been paid to acute cardiovascular responses to ozone, in part due to the notion that ozone causes primarily local effects on lung function, which are the basis for the current ozone National Ambient Air Quality Standards (NAAQS). There is evidence from a few epidemiological studies of adverse health effects of chronic exposure to ambient ozone, including increased risk of mortality from cardiovascular disease. However, in contrast to the well-established association between ambient ozone and various nonfatal adverse respiratory effects, the observational evidence for impacts of acute (previous few days) increases in ambient ozone levels on total cardiovascular mortality and morbidity is mixed. Ozone is a prototypic oxidant gas that reacts with constituents of the respiratory tract lining fluid to generate reactive oxygen species (ROS) that can overwhelm antioxidant defenses and cause local oxidative stress. Pathways by which ozone could cause cardiovascular dysfunction include alterations in autonomic balance, systemic inflammation, and oxidative stress. These initial responses could lead ultimately to arrhythmias, endothelial dysfunction, acute arterial vasoconstriction, and procoagulant activity. Individuals with impaired antioxidant defenses, such as those with the null variant of glutathione S-transferase mu 1 (GSTM1), may be at increased risk for acute health effects. The Multicenter Ozone Study in oldEr Subjects (MOSES) was a controlled human exposure study designed to evaluate whether short-term exposure of older, healthy individuals to ambient levels of ozone induces acute cardiovascular responses. The study was designed to test the a priori hypothesis that short-term exposure to ambient levels of ozone would induce acute cardiovascular responses through the following mechanisms: autonomic imbalance, systemic inflammation, and development of a prothrombotic vascular state. We also postulated a priori the confirmatory hypothesis that exposure to ozone would induce airway inflammation, lung injury, and lung function decrements. Finally, we postulated the secondary hypotheses that ozone-induced acute cardiovascular responses would be associated with: (a) increased systemic oxidative stress and lung effects, and (b) the GSTM1-null genotype. The study was conducted at three clinical centers with a separate Data Coordinating and Analysis Center (DCAC) using a common protocol. All procedures were approved by the institutional review boards (IRBs) of the participating centers. Healthy volunteers 55 to 70 years of age were recruited. Consented participants who successfully completed the screening and training sessions were enrolled in the study. All three clinical centers adhered to common standard operating procedures (SOPs) and used common tracking and data forms. Each subject was scheduled to participate in a total of 11 visits: screening visit, training visit, and three sets of exposure visits, each consisting of the pre-exposure day, the exposure day, and the post-exposure day. The subjects spent the night in a nearby hotel the night of the pre-exposure day. On exposure days, the subjects were exposed for three hours in random order to 0 ppb ozone (clean air), 70 ppb ozone, and 120 ppm ozone, alternating 15 minutes of moderate exercise with 15 minutes of rest. A suite of cardiovascular and pulmonary endpoints was measured on the day before, the day of, and up to 22 hours after, each exposure. The endpoints included: (1) electrocardiographic changes (continuous Holter monitoring: heart rate variability [HRV], repolarization, and arrhythmia); (2) markers of inflammation and oxidative stress (C-reactive protein [CRP], interleukin-6 [IL-6], 8-isoprostane, nitrotyrosine, and P-selectin); (3) vascular function measures (blood pressure [BP], flow-mediated dilatation [FMD] of the brachial artery, and endothelin-1 [ET-1]; (4) venous blood markers of platelet activation, thrombosis, and microparticle-associated tissue factor activity (MP-TFA); (5) pulmonary function (spirometry); (6) markers of airway epithelial cell injury (increases in plasma club cell protein 16 [CC16] and sputum total protein); and (7) markers of lung inflammation in sputum (polymorphonuclear leukocytes [PMN], IL-6, interleukin-8 [IL-8], and tumor necrosis factor-alpha [TNF-α]). Sputum was collected only at 22 hours after exposure. The analyses of the continuous electrocardiographic monitoring, the brachial artery ultrasound (BAU) images, and the blood and sputum samples were carried out by core laboratories. The results of all analyses were submitted directly to the DCAC. The variables analyzed in the statistical models were represented as changes from pre-exposure to post-exposure (post-exposure minus pre-exposure). Mixed-effect linear models were used to evaluate the impact of exposure to ozone on the prespecified primary and secondary continuous outcomes. Site and time (when multiple measurements were taken) were controlled for in the models. Three separate interaction models were constructed for each outcome: ozone concentration by subject sex; ozone concentration by subject age; and ozone concentration by subject GSTM1 status (null or sufficient). Because of the issue of multiple comparisons, the statistical significance threshold was set a priori at <iP</i &lt; 0.01. Subject recruitment started in June 2012, and the first subject was randomized on July 25, 2012. Subject recruitment ended on December 31, 2014, and testing of all subjects was completed by April 30, 2015. A total of 87 subjects completed all three exposures. The mean age was 59.9 ± 4.5 years, 60% of the subjects were female, 88% were white, and 57% were GSTM1 null. Mean baseline body mass index (BMI), BP, cholesterol (total and low-density lipoprotein), and lung function were all within the normal range. We found no significant effects of ozone exposure on any of the primary or secondary endpoints for autonomic function, repolarization, ST segment change, or arrhythmia. Ozone exposure also did not cause significant changes in the primary endpoints for systemic inflammation (CRP) and vascular function (systolic blood pressure [SBP] and FMD) or secondary endpoints for systemic inflammation and oxidative stress (IL-6, P-selectin, and 8-isoprostane). Ozone did cause changes in two secondary endpoints: a significant increase in plasma ET-1 (<iP</i = 0.008) and a marginally significant decrease in nitrotyrosine (<iP</i = 0.017). Lastly, ozone exposure did not affect the primary prothrombotic endpoints (MP-TFA and monocyte-platelet conjugate count) or any secondary markers of prothrombotic vascular status (platelet activation, circulating microparticles [MPs], von Willebrand factor [vWF], or fibrinogen.). Although our hypothesis focused on possible acute cardiovascular effects of exposure to low levels of ozone, we recognized that the initial effects of inhaled ozone involve the lower airways. Therefore, we looked for: (a) changes in lung function, which are known to occur during exposure to ozone and are maximal at the end of exposure; and (b) markers of airway injury and inflammation. We found an increase in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV₁) after exposure to 0 ppb ozone, likely due to the effects of exercise. The FEV₁ increased significantly 15 minutes after 0 ppb exposure (85 mL; 95% confidence interval [CI], 64 to 106; <iP</i &lt; 0.001), and remained significantly increased from pre-exposure at 22 hours (45 mL; 95% CI, 26 to 64; <iP</i &lt; 0.001). The increase in FVC followed a similar pattern. The increase in FEV₁ and FVC were attenuated in a dose-response manner by exposure to 70 and 120 ppb ozone. We also observed a significant ozone-induced increase in the percentage of sputum PMN 22 hours after exposure at 120 ppb compared to 0 ppb exposure (<iP</i = 0.003). Plasma CC16 also increased significantly after exposure to 120 ppb (<iP</i &lt; 0.001). Sputum IL-6, IL-8, and TNF-α concentrations were not significantly different after ozone exposure. We found no significant interactions with sex, age, or GSTM1 status regarding the effect of ozone on lung function, percentage of sputum PMN, or plasma CC16. In this multicenter clinical study of older healthy subjects, ozone exposure caused concentration-related reductions in lung function and presented evidence for airway inflammation and injury. However, there was no convincing evidence for effects on cardiovascular function. Blood levels of the potent vasoconstrictor, ET-1, increased with ozone exposure (with marginal statistical significance), but there were no effects on BP, FMD, or other markers of vascular function. Blood levels of nitrotyrosine decreased with ozone exposure, the opposite of our hypothesis. Our study does not support acute cardiovascular effects of low-level ozone exposure in healthy older subjects. Inclusion of only healthy older individuals is a major limitation, which may affect the generalizability of our findings. We cannot exclude the possibility of effects with higher ozone exposure concentrations or more prolonged exposure, or the possibility that subjects with underlying vascular disease, such as hypertension or diabetes, would show effects under these conditions.

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Isotechnika is developing the immunosuppressive drug ISA 247, a calcineurin inhibitor that is undergoing clinical development for the treatment of psoriasis (phase III) and prevention of organ rejection after transplantation (phase II). Preclinical development for uveitis is also underway. Other autoimmune disease indications that could be explored include arthritis, type I diabetes and Crohn's disease. ISA 247 was being co-developed as R 1524 by Isotechnika and Roche. However, Roche is no longer involved in the development of this compound. Based on analysis of previously collected data, the trans-ISA 247 isomer was found to be more bioavailable and it is expected that this isomer can be administered at a lower dose compared with the previous formulation that consisted of an equivalent mixture of the two geometric isomers (cis and trans). Preclinical observations indicate that ISA 247 has the potential to be more potent and less toxic than other marketed immunosuppressants in its class used for the prevention of transplant rejection. Experiments to date suggest that ISA 247 is about three times as potent as ciclosporin, while genotoxicity studies in animals have shown that the compound has a significantly reduced tendency to cause renal toxicity. The combination of reduced toxicity and improved potency would give ISA 247 a therapeutic benefit over existing calcineurin-based treatments. Isotechnika and Roche entered into a co-development and commercialisation agreement in April 2002, with Roche gaining the exclusive worldwide marketing rights for ISA 247; Isotechnika received milestone payments of $US4 million and $CAN21.9 million in September 2002 and May 2003, respectively. The agreement was restructured in April 2004, under which Isotechnika will now solely manage and fund the clinical development of trans-ISA 247. Upon successful completion of these trials, Isotechnika will conduct at its own expense a phase IIb study in renal transplantation and phase III studies in psoriasis. Roche will have the right to opt-in to the development and commercialisation of trans-ISA 247 for transplant indications up to the end of the phase IIb renal transplantation trial. Isotechnika retains all rights to develop and commercialise the product outside of transplant indications. Under an agreement signed with Cellgate Inc. on 25 April 2006, Isotechnika has the option to obtain an exclusive licence to develop and commercialise conjugates consisting of Cellgate's patented transporter technology, for the topical delivery of ISA 247 in patients with mild-to-moderate psoriasis. Cellgate will perform studies to evaluate the feasibility of using their technology to topically deliver ISA 247. In return, Isotechnika will pay Cellgate Inc. a total of $US500 000, with $US100 000 paid upfront, and the remainder at predetermined time points. Upon successful completion of the studies, Isotechnika has the option to further develop and commercialise conjugates for topical delivery of ISA 247. Isotechnika and Atrium Medical Corporation announced an exclusive worldwide licensing agreement for ISA 247 alone and in combination with TAFA 93 with respect to drug-eluting devices, in September 2005. Atrium's implantable products include those for the local, non-systemic treatment of vascular and cardiovascular disorders, soft tissue repair and other disorders. In May 2006, Isotechnika licensed ISA 247 to Lux Biosciences for ophthalmic indications. Under terms of the agreement, Lux Biosciences obtains the exclusive worldwide marketing rights to ISA 247 for treatment and prophylaxis of all ophthalmic indications. The company will be responsible for development, registration and marketing of the drug for ophthalmic indications and will make upfront and milestone payments to Isotechnika in addition to royalties on any sales. Isotechnika formalised a manufacturing agreement with Swiss-based Lonza Ltd in June 2004. Under the terms of the agreement, Lonza will manufacture sufficient quantities of trans-ISA 247 in a GMP environment for use in the company's upcoming clinical trials. Isotechnika completed the phase III SPIRIT trial of ISA 247 for psoriasis in Canada. The randomised, double-blind trial compared the efficacy of three doses of ISA 247 (0.2 mg/kg [low dose], 0.3 mg/kg [mid dose] and 0.4 mg/kg [high dose] twice daily) with placebo, with equal numbers of patients assigned to each of the four groups. Subsequent to the first 12 weeks, those patients who received placebo moved into the mid-dose group for the remaining 12 weeks of the study. Patients already receiving ISA 247 remained in their respective dosing groups for the final 12 weeks of the trial. Patients completing the 24-week SPIRIT trial were given the opportunity to continue therapy for an addditonal 36 weeks or to discontinue therapy. Those patients who chose to enrol in the extension trial were moved from the 0.2 mg/kg bid (low-dose) or 0.4 mg/kg bid (high-dose) groups into the the 0.3 bid mg/kg bid (mid dose) group. Patients who commenced the SPIRIT trial in the mid-dose group remained on the same dosage regimen for the duration of the extension trial. The goal of the extension trial is to demonstrate continued therapeutic benefit to psoriasis patients while gathering long-term safety data. So far, data has been received on 193 patients receiving treatment for a total of 48 weeks. A phase IIa trial investigating the safety and efficacy of ISA 247 in renal transplantation was completed in the US and Canada in January 2003. The trial compared ISA 247 with ciclosporin (Neoral in approximately 130 stable renal transplant patients who underwent transplantation at least 6 months prior to enrolment; patient recruitment was completed in October 2002. Half of the patients were treated with ciclosporin and the other half received ISA 247 over a 90-day period. An extension trial was then initiated in which another 200 patients were treated with ISA 247 for up to 6 months from the time of transplantation. Results from the trial were reported. All endpoints were achieved in a multiple ascending dose study of trans-ISA 247 in November 2004. The study, initiated in June 2004, was conducted by SFBC Anapharm in Montreal, Canada and involved 43 healthy volunteers. Final dosing recommendations are to be determined in phase III trials in patients with psoriasis. Interim results reported in September 2004, of a double-blind, parallel-group, placebo and moxifloxacin controlled, randomised single-dose QTc trial in healthy volunteers, showed no evidence of QTc prolongation when trans-ISA 247 was administered at therapeutic doses. A single ascending dose (SAD) trial for trans-ISA 247 was completed in July 2004. The SAD trial was conducted among healthy volunteers to assess the appropriate dosage of trans-ISA 247 for further clinical evaluations. The trial commenced in March 2004 with approximately 46 subjects enrolled under the supervision of MDS Pharma Services in Phoenix, Arizona, USA. Isotechnika received US FDA approval for the SAD trial in February 2004. A European patent (No. EP 0 991 660) entitled 'Deuterated and Undeuterated Cyclosporine Analgoues and Their Use as Immunomodulating Agents' was issued to Isotechnika for ISA 247, in October 2006. A US patent entitled 'Novel Cyclosporin Analogue Formulations' was issued to Isotechnika (No. 7 060 672) for ISA 247 in June 2006. The patent claims have been filed in 36 countries, and in the US it is the first patent to be issued in this patent family. Isotechnika was issued a US patent (No. 6 998 385, entitled 'Cyclosporine Analogue Mixtures and their use as Immunomodulating Agents') in February 2006 covering mixtures of cis- and trans- isomers of ISA 257. This patent is the first US patent to be issued in this family of patents. These patent claims have been filed in 36 countries. Three patents relating to this claim were previously issued in the following countries; Morocco (No. 26337 issued 1 October 2004); Pakistan (No. 138338 issued 30 September 2004) and South Africa (No. 2004/2270 issued 25 May 2005). A US patent (No 6 686 454) was issued in February 2004 entitled 'Antibodies to Specific Regions of Cyclosporine Related Compounds'. This patent covers a novel, simple and cost-effective assay used in the use and management of ISA 247. It also received another US patent entitled 'Deuterated Cyclosporine Analogs and their Use as Immunomodulating Agents'. Isotechnika has received patents for chemical composition of ISA 247 in New Zealand (November 2001; New Zealand Patent No. 502362), Canada (December 2001; Canadian Patent No. 2 298 572), South Korea (June 2006; South Korean Patent No. 585348) and Australia (November 2002; Australian Patent No. 750245). In addition, Isotechnika announced in August 2003 that it had been granted US patent No. 6 605 593, entitled 'Deuterated Ciclosporine Analogs and their use as Immunomodulating Agents'. An additional US patent covering ISA 247 was granted in September 2003.

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Beta-myrcene, an acyclic unsubstituted monoterpene, and the essential oils which contain it are used as intermediates in the production of terpene alcohols (geraniol, nerol, and linalool), which, in turn, serve as intermediates in the production of aroma and flavor chemicals. Thus beta-myrcene is used widely in cosmetics, soaps, and detergents and as a flavoring additive in food and beverages. Beta-myrcene is also the major constituent of hop and bay oils, which are used in the manufacture of alcoholic beverages. Beta-myrcene was nominated for study by the National Institute of Environmental Health Sciences based on its high production volume, high level of human exposure, and structural relationship to d-limonene, which induced neoplasms in the kidneys of male rats in association with hyaline droplet nephropathy (NTP, 1990). Male and female F344/N rats and B6C3F1 mice were administered beta-myrcene (greater than 90% pure) by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 0.25, 0.5, 1, 2, or 4 g beta-myrcene/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female special study rats were administered the same doses for 23 days. All core study rats in the 4 g/kg groups died during the first week of the study except one male that died on day 11. One to three rats in the 1 and 2 g/kg groups and one 0.5 g/kg male died by week 10 of the study. One 2 g/kg female died during the last week of the study. Except for lesion incidence data in groups administered 2 g/kg or less, data from rats that died early were excluded from the analysis and summary tables. Mean body weights were significantly decreased in male rats in the 0.5, 1, and 2 g/kg groups. Special study rats in the 4 g/kg groups died by the end of the first week. Dose-related clinical findings in animals that died early included thinness, lethargy, abnormal breathing, and ruffled fur. Right kidney and liver weights of dosed males and females were generally significantly greater than those of the vehicle controls. In special study rats evaluated on day 23, the incidences and severities of chronic progressive nephropathy (CPN) and renal tubule degeneration were increased in 2 g/kg males. At the end of the 3-month study, the incidences of renal tubule necrosis were significantly increased in all dosed groups of males and females. At 3 months, the incidences of olfactory epithelium degeneration in 2 g/kg males and females were significantly increased, and the severities were increased. The incidences of chronic inflammation in 1 and 2 g/kg males and females were significantly increased. All 2 g/kg males and females had splenic atrophy. In the mesenteric lymph node, significantly increased incidences of atrophy occurred in 2 g/kg males and 1 and 2 g/kg females. Acute inflammation of the forestomach occurred in four 2 g/kg females. The incidences of porphyrin pigmentation in the Harderian gland of males administered 0.5 g/kg or greater were significantly increased. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 0.25, 0.5, 1, 2, or 4 g beta-myrcene/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All 4 g/kg male and female mice died during week 1; nine 2 g/kg males and eight 2 g/kg females died by week 4. The mean body weights of 1 g/kg males were significantly less than those of the vehicle controls. Clinical findings in animals that did not survive to the end of the study included thinness, lethargy, and abnormal breathing. The right kidney weights of 1 g/kg females and the liver weights of females administered 0.5 or 1 g/kg were significantly increased. No histopathology changes were observed in mice administered 1 g/kg or less. The 2 and 4 g/kg mice were not evaluated due to early deaths. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 0.25, 0.5, or 1 g beta-myrcene/kg body weight in corn oil by gavage, 5 days per week for 105 weeks. All 1 g/kg male rats died before the end of the study due to renal toxicity. Compared to vehicle controls, the mean body weights of 0.25 and 0.5 g/kg males were slightly greater, and mean body weights of 1 g/kg males and females were at least 8% less than those of vehicle controls after 11 weeks and 13 weeks, respectively. In the standard evaluation of the kidney, the incidence of renal tubule adenoma was significantly increased in 0.5 g/kg male rats, and the combined incidences of renal tubule adenoma or carcinoma were significantly increased in 0.25 and 0.5 g/kg males. In both the extended evaluation and the combined standard and extended evaluations, the incidences of renal tubule adenoma and the combined incidences of renal tubule adenoma or carcinoma were significantly increased in the 0.25 and 0.5 g/kg groups of males. The incidences of renal tubule nephrosis (nephrosis) were markedly increased in all dosed groups of both sexes except in 0.25 g/kg females. The incidences of papillary mineralization in 0.25 and 0.5 g/kg males were significantly increased. Significantly increased incidences of nephropathy occurred in dosed females, and the severity was increased in the 0.5 and 1 g/kg males and females. The incidences of hyperplasia of the transitional epithelium lining the pelvis and overlying the renal papilla were significantly increased in all dosed groups of males and females. In male rats, the incidences of focal suppurative inflammation were significantly increased in the 0.25 and 0.5 g/kg groups. A significantly increased incidence of chronic active inflammation of the nose occurred in 0.5 g/kg males. Also in 0.5 g/kg males, the incidence of chronic active inflammation of the forestomach was increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 0.25, 0.5, or 1 g beta-myrcene/kg body weight in corn oil by gavage, 5 days per week for 104 or 105 weeks. Survival of 1 g/kg mice was significantly less than that of the vehicle controls; the cause of the deaths was uncertain. Mean body weights of 1 g/kg males were at least 8% less than those of the vehicle controls between week 8 and week 56. Mean body weights of 0.5 g/kg females were at least 7% less than those of the vehicle controls after week 17, and those of 1 g/kg females were at least 8% less from week 11 to week 96. The incidences of liver neoplasms were significantly increased in 0.25 and/or 0.5 g/kg males and 0.25 g/kg females. Liver neoplasms included hepatocellular adenoma and hepatocellular carcinoma in males and females and hepatoblastoma in males. The incidences of hepatocellular hypertrophy were significantly increased in 0.5 g/kg males and females, as was the incidence of mixed cell focus in 0.5 g/kg females. The incidences of bone marrow atrophy and lymph node follicle atrophy in the spleen were significantly increased in 0.5 g/kg females. In the forestomach, there were significantly increased incidences of inflammation and epithelial hyperplasia in 0.5 g/kg females. beta-myrcene did not show evidence of genotoxicity in assays conducted by the NTP. No mutagenicity was observed in any of several strains of Salmonella typhimurium or Escherichia coli in two independent Ames assays conducted with and without exogenous metabolic activation. In addition, no significant increase in frequency of micronucleated normochromatic erythrocytes, biomarkers of chromosomal damage, was observed in male or female mice administered beta-myrcene for 3 months by gavage. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of beta-myrcene in male F344/N rats based on increased incidences of renal tubule neoplasms. There was equivocal evidence of carcinogenic activity of beta-myrcene in female F344/N rats based on increased incidences of renal tubule adenoma. There was clear evidence of carcinogenic activity of beta-myrcene in male B6C3F1 mice based on increased incidences of hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma. There was equivocal evidence of carcinogenic activity of beta-myrcene in female B6C3F1 mice based on marginally increased incidences of hepatocellular adenoma and carcinoma. Administration of beta-myrcene induced nonneoplastic lesions in the kidney of male and female rats, nose of male rats, and liver of male and female mice. Synonyms: 2-Methyl-6-methylene-2,7-octadiene; 7-methyl-3-methylene-1,6-octadiene; myrcene.

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Computed tomography (CT) scanning continues to be an important modality for the diagnosis of injury and disease, most notably for indications of the head and abdomen. (1) According to a recent report published by the Canadian Institutes of Health Information, (1) there were about 10.3 scanners per million people in Canada as of January 2004. Ontario had the fewest number of CT scanners per million compared to the other provinces (8 CT scanners per million). The wait time for CT in Ontario of 5 weeks approaches the Canadian median of 6 weeks. This health technology and policy appraisal systematically reviews the published literature on multidetector CT (MDCT) angiography as a diagnostic tool for the newest indication for CT, coronary artery disease (CAD), and will apply the results of the review to current health care practices in Ontario. This review does not evaluate MDCT to detect coronary calcification without contrast medium for CAD screening purposes. Compared with conventional CT scanning, MDCT can provide smaller pieces of information and can cover a larger area faster. (2) Advancing MDCT technology (8, 16, 32, 64 slice systems) is capable of producing more images in less time. For general CT scanning, this faster capability can reduce the time that patients must stay still during the procedure, thereby reducing potential movement artefact. However, the additional clinical utility of images obtained from faster scanners compared to the images obtained from conventional CT scanners for current CT indications (i.e., non-moving body parts) is not known. There are suggestions that the new fast scanners can reduce wait times for general CT. MDCT angiography that utilizes a contrast medium, has been proposed as a minimally invasive replacement to coronary angiography to detect coronary artery disease. MDCT may take between 15 to 45 minutes; coronary angiography may take up to 1 hour. Although 16-slice and 32-slice CT scanners have been available for a few years, 64-slice CT scanners were released only at the end of 2004. There are many proven, evidence-based indications for conventional CT. It is not clear how MDCT will add to the clinical utility and management of patients for established CT indications. Therefore, because cardiac imaging, specifically MDCT angiography, is a new indication for CT, this literature review focused on the safety, effectiveness, and cost-effectiveness of MDCT angiography compared with coronary angiography in the diagnosis and management of people with CAD. This review asked the following questions: Is the most recent MDCT angiography effective in the imaging of the coronary arteries compared with conventional angiography to correctly diagnose of significant (&gt; 50% lumen reduction) CAD?What is the utility of MDCT angiography in the management and treatment of patients with CAD?How does MDCT angiography in the management and treatment of patients with CAD affect longterm outcomes?The published literature from January 2003 to January 31, 2005 was searched for articles that focused on the detection of coronary artery disease using 16-slice CT or faster, compared with coronary angiography. The search yielded 138 articles; however, 125 were excluded because they did not meet the inclusion criteria (comparison with coronary angiography, diagnostic accuracy measures calculated, and a sample size of 20 or more). As screening for CAD is not advised, studies that utilized MDCT for this purpose or studies that utilized MDCT without contrast media were also excluded. Overall, 13 studies were included in this review. The published literature focused on 16-slice CT angiography for the detection of CAD. Two abstracts that were presented at the 2005 European Congress of Radiology meeting in Vienna compared 64-slice CT angiography with coronary angiography. The 13 studies focussing on 16-slice CT angiography were stratified into 2 groups: Group 1 included 9 studies that focused on the detection of CAD in symptomatic patients, and Group 2 included 4 studies that examined the use of 16-slice CT angiography to detect disease progression after cardiac interventions. The 2 abstracts on 64-slice CT angiography were presented separately, but were not critically appraised due to the lack of information provided in the abstracts. 16-SLICE COMPUTED TOMOGRAPHY ANGIOGRAPHY: The STARD initiative to evaluate the reporting quality of studies that focus on diagnostic tests was used. Overall the studies were relatively small (fewer than 100 people), and only about one-half recruited consecutive patients. Most studies reported inclusion criteria, but 5 did not report exclusion criteria. In these 5, the patients were highly selected; therefore, how representative they are of the general population of people with suspicion if CAD or those with disease progression after cardiac intervention is questionable. In most studies, patients were either already taking, or were given, β-blockers to reduce their heart rates to improve image quality sufficiently. Only 6 of the 13 studies reported interobserver reliability quantitatively. The studies typically assessed the quality of the images obtained from 16-slice CT angiography, excluded those of poor quality, and compared the rest with the gold standard, coronary angiography. This practice necessarily inflated the diagnostic accuracy measures. Only 3 studies reported confidence intervals around their measures. Evaluation of the studies in Group 1 reported variable sensitivity, from just over 60% to 96%, but a more stable specificity, at more than 95%. The false positive rate ranged from 5% to 8%, but the false negative rate was at best under 10% and at worst about 30%. This means that up to one-third of patients who have disease may be missed. These patients may therefore progress to a more severe level of disease and require more invasive procedures. The calculated positive and negative likelihood ratios across the studies suggested that 16-slice CT angiography may be useful to detect disease, but it is not useful to rule out disease. The prevalence of disease, measured by conventional coronoary angiography, was from 50% to 80% across the studies in this review. Overall, 16-slice CT angiography may be useful, but there is no conclusive evidence to suggest that it is equivalent to or better than coronary angiography to detect CAD in symptomatic patients. In the 4 studies in Group 2, sensitivity and specificity were both reported at more than 95% (except for 1 that reported sensitivity of about 80%). The positive and negative likelihood ratios suggested that the test might be useful to detect disease progression in patients who had cardiac interventions. However, 2 of the 4 studies recruited patients who had been asymptomatic since their intervention. As many of the patients studied were not symptomatic, the relevance of performing MDCT angiography in the patient population may be in question. 64-SLICE COMPUTED TOMOGRAPHY ANGIOGRAPHY: An analysis from the interim results based on 2 abstracts revealed that 64-slice CT angiography was insufficient compared to coronary angiography and may not be better than 16-slice CT angiography to detect CAD. Cardiac imaging is a relatively new indication for CT. A systematic review of the literature was performed from 2003 to January 2005 to determine the effectiveness of MDCT angiography (16-slice and 64-slice) compared to coronary angiography to detect CAD. At the time of this report, there was no published literature on 64-slice CT for any indications. Based on this review, the Medical Advisory Secretariat concluded that there is insufficient evidence to suggest that 16-slice or 64-slice CT angiography is equal to or better than coronary angiography to diagnose CAD in people with symptoms or to detect disease progression in patients who had previous cardiac interventions. An analysis of the evidence suggested that in investigating suspicion of CAD, a substantial number of patients would be missed. This means that these people would not be appropriately treated. These patients might progress to more severe disease and possibly more adverse events. Overall, the clinical utility of MDCT in patient management and long-term outcomes is unknown. Based on the current evidence, it is unlikely that CT angiography will replace coronary angiography completely, but will probably be used adjunctively with other cardiac diagnostic tests until more definitive evidence is published. If multi-slice CT scanners are used for coronary angiography in Ontario, access to the current compliment of CT scanners will necessarily increase wait times for general CT scanning. It is unlikely that these newer-generation scanners will improve patient throughput, despite the claim that they are faster. Screening for CAD in asymptomatic patients and who have no history of ischemic heart disease using any modality is not advised, based on the World Health Organization criteria for screening. Therefore, this review did not examine the use of multi-slice CT for this purpose.

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In order to assess the effect of Social Security reform on current and future workers, it is essential to accurately characterize the initial situations of representative workers affected by reform. For the purpose of analyzing typical reforms, the most important characteristic of a worker is the level and pattern of his or her preretirement earnings. Under the current system, pensions are determined largely by the level of the workers' earnings averaged over their work life. However, several reform proposals would create individual retirement accounts for which the pension would depend on the investment accumulation within the account. Thus, the pension would also depend on the timing of the contributions into the account and hence on the exact shape of the worker's lifetime earnings profile. Most analysis of the distributional impact of reform has focused, however, on calculating benefit changes among a handful of hypothetical workers whose relative earnings are constant over their work life. The earnings levels are not necessarily chosen to represent the situations of workers who have typical or truly representative earnings patterns. Consequently, the results of such analysis can be misleading, especially if reform involves introducing a fundamentally new kind of pension formula. This article presents two broad approaches to creating representative earnings profiles for policy evaluation. First, we use standard econometric methods to predict future earnings for a representative sample of workers drawn from the Survey of Income and Program Participation (SIPP). Our statistical estimates are based on a simple representation of typical career earnings paths and a fixed-effect statistical specification. Because our estimation file contains information on each worker's annual earnings from 1951 through 1996 as reported in the Social Security Administration's earnings files, we have a record (though an incomplete one) of the actual earnings that will be used to determine future benefit payments. Our estimates of the earnings function permit us to make highly differentiated predictions of future earnings for each member of our sample. By combining the historical information on individual earnings with our prediction of future earnings up through the normal retirement age, our first approach produces tens of thousands of predicted career earnings paths that can be used in microsimulation policy analysis. Our second approach to creating lifetime earnings profiles is similar in some ways to the traditional method. For example, it is based on the creation of only a handful of "stylized" career earnings patterns. An important difference with the traditional method, however, is that we define the career earnings patterns so that they are truly representative of patterns observed in the workforce. We use simple mathematical formulas to characterize each stylized earnings pattern, and we then produce estimates of the average path of annual earnings for workers whose career earning path falls within each of the stylized patterns we have defined. Finally, we calculate the percentage of workers in successive birth-year cohorts who have earnings profiles that match each of the stylized earnings patterns. Although this method may seem simple, it allows the analyst to create stylized earnings patterns that are widely varied but still representative of earnings patterns observed among sizable groups of U.S. workers. The effects of policy reforms can then be calculated for workers with each of the stylized earnings patterns. Our analysis of U.S. lifetime earnings patterns and of the impact of selected policy reforms produces a number of findings about past trends in earnings, typical earnings patterns in the population, and the potential impact of reform. The analysis focuses on men and women born between 1931 and 1960. Along with earlier analysts, we find that men earn substantially higher lifetime wages than women and typically attain their peak career earnings at a somewhat earlier age. However, the difference in career earnings patterns between men and women has narrowed dramatically over time. Workers with greater educational attainment earn substantially higher wages than those with less education, and they attain their peak career earnings later in life. For example, among men with the least education, peak earnings are often attained around or even before age 40, whereas many men with substantial postsecondary schooling do not reach their peak career earnings until after 50. Our tabulations of the lifetime earnings profiles of the oldest cohorts (born around 1930) and projections of the earnings of the youngest profiles (born around 1960) imply that the inequality of lifetime earnings has increased noticeably over time. Women in the top one-fifth of female earners and men in the top one-fifth of male earners are predicted to receive a growing multiple of the economy-wide average wage during their career. Women born between 1931 and 1935 who were in the top fifth of female earners had lifetime average earnings that were approximately equal to the average economy-wide wage. In contrast, women born after 1951 who were in the top fifth of earners are predicted to earn almost 50 percent more, that is, roughly 150 percent of the economy-wide average wage. Women with a lower rank in the female earnings distribution will also see gains in their lifetime average earnings, but their gains are predicted to be proportionately much smaller than those of women with a high rank in the distribution. Men with high earnings are also predicted to enjoy substantial gains in their relative lifetime earnings, while men with a lower rank in the earnings distribution will probably see a significant erosion in their typical wages relative to the economy-wide average wage. That is mainly the result of a sharp decline in the relative earnings of low-wage men born after 1950. In creating stylized earnings profiles that are representative of those of significant minorities of U.S. workers, we emphasized three critical elements of the earnings path: the average level of earnings over a worker's career, the upward or downward trend in earnings from the worker's 30s through his or her early 60s, and the "sagging" or "hump-shaped" profile of earnings over the worker's career. That classification scheme yields 27 characteristic patterns of lifetime earnings. Surprisingly, the differnce between men and women within each of those categories is quite modest. The main difference between men and women is in the proportions of workers who fall in each category. Only 14 percent of men born between 1931 and 1940 fall in earnings categories with the lowest one-third of lifetime earnings, whereas 53 percent of women born in those years have low-average-earnings profiles. On the other hand, women born in those years are more likely to have a rising trend in lifetime earnings, while men are more likely to have a declining trend. We find that the distribution of lifetime earnings contains relatively more workers with below-average earnings and relatively fewer with very high earnings than assumed in the Social Security Administration's traditional policy analysis. For example, the "low earner" traditionally assumed by the Office of the Chief Actuary is assigned a level of average lifetime earnings that we find to be higher than the average earnings of persons in the bottom one-third of the lifetime earnings distribution. The stylized earnings profiles developed here can be used for policy evaluation, and the results can be compared with those from the more traditional analysis. That comparison produces several notable findings. Because earnings profiles that are actually representative of the population tend to have lower average earnings than assumed in the traditional analysis, workers typically accumulate somewhat less Social Security wealth than implied in the traditional analysis. On the other hand, because the basic benefit formula is tilted in favor of lower-income workers, the internal rate of return on Social Security contributions is somewhat higher than detected in the traditional analysis. Moreover, the primary insurance amount measured as a percentage of the worker's average indexed earnings tends to be higher than implied by the traditional analysis. Finally, the stylized earnings patterns can be used to compare benefit levels enjoyed by workers under the traditional Social Security formula and under an alternative plan based on individual investment accounts. That comparison shows, as expected, that the traditional formula favors low-wage workers and one-earner couples, while an investment account favors single, high-wage workers. Comparing two workers with the same lifetime average earnings, the traditional formula favors workers with rising earnings profiles (that is, with lifetime earnings heavily concentrated at the end of their career), while investment account pensions favor workers with declining earnings profiles (that is, with earnings concentrated early in their career).

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Riddelliine is a naturally occurring pyrrolizidine alkaloid, a class of compounds occurring in rangeland plants of the genera Crotalaria, Amsinckia, and Senecio. Two-week and 13-week rodent toxicity studies of riddelliine were conducted because riddelliine can be a contaminant of foodstuffs, such as meat, grains, seeds, milk, herbal tea, and honey. In addition to histopathology, evaluations included clinical pathology and reproductive toxicity. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and of the induction of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Riddelliine was also evaluated in vivo for the induction of micronuclei in mouse bone marrow and in peripheral blood and for the induction of S-phase synthesis and unscheduled DNA synthesis in the liver of rats and mice. In the 2-week studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered riddelliine in 0.1 M phosphate buffer by gavage at dose levels of 0, 0. 33, 1.0, 3.3, 10, or 25 mg/kg body weight five times per week, for a total of 12 doses. Four of five male rats in the 25 mg/kg group died or were killed moribund before the end of the study. Mean body weight gains of male rats in the 10 and 25 mg/kg groups were depressed. No deaths or body weight effects were observed in female rats. Male rats had dose-related hemorrhagic centrilobular hepatic necrosis, hepatocytic karyomegaly and cytologic alterations, pulmonary hemorrhage and/or edema, splenic extramedullary hematopoiesis, and pancreatic edema. Female rats exhibited fewer and less severe lesions than identically treated male rats. Heart weights of treated male and female rats were lower than those of the controls. No deaths or effects on body weight were observed in treated mice. Dose-related increases in absolute and relative liver weights and increased incidences of hepatic cytomegaly were the only treatment-related findings in male and female mice administered riddelliine. In the 13-week studies, groups of 20 male and 20 female F344/N rats and B6C3FI mice were administered riddelliine in 0.1 M phosphate buffer by gavage five times per week for 13 weeks. Rats received 0, 0.1, 0.33, 1.0, 3.3, or 10 mg/kg and mice received 0, 0.33, 1.0, 3.3, 10, or 25 mg/kg. Ten animals from each dose group were killed after 13 weeks of treatment. The remaining 10 animals in each dose group were observed without further treatment for up to 14 weeks; five animals from each dose group were killed after 7 weeks of recovery, and the remaining five animals per dose group were killed at the end of the 14-week recovery period. During the 13-week treatment period, 19 of 20 male rats in the high-dose group died; all others survived. Body weight gains were decreased with increasing dose at Week 13. During the 14-week recovery period, all male rats survived, but five high-dose females died. Mean body weight gains of dosed and control male rats were similar throughout the 1 4-week recovery period; the final mean body weights of the treated males approached the final mean body weight of the controls. Similarly, mean body weight gains among the treated female rats were similar to the control value at the end of the 14- week recovery period. However, the final mean body weight of female rats given 1.0 or 3.3 mg/kg remained lower than that of controls at the end of the 14-week recovery period. In the 13-week study, the most significant treatment-related histopathologic lesions in rats occurred in the liver and included hepatocyte cytomegaly and karyomegaly, cytoplasmic vacuolization, centrilobular necrosis, mixed inflammatory cell infiltration, and bile duct hyperplasia. Vascular lesions in the kidneys and lungs were observed in most high- dose rats after 13 weeks of riddelliine administration. Additional lesions were found in the heart, spleen, kidneys, and pancreas at 13 weeks. At the end of the 14-week recovery period, hepatocyte karyomegaly, cytomegaly, and cytoplasmic vacuolization persisted. In addition, the incidence of bile duct hyperplasia was markedly increased in dosed female rats, and foci of cytologic alteration or hyperplastic hepatocytes were observed in dosed rats that were allowed to recover for up to 14 weeks. Adenomas of the liver occurred in 2 of 10 females in the 10 mg/kg group at 13 weeks and in one of five females in this group after the 14-week recovery period; no adenomas were found in the livers of control females. Serum activities of alkaline phosphatase in male rats and sorbitol dehydrogenase in female rats increased with increasing dose. Reticulocyte counts consistently increased and platelet counts consistently decreased with increasing dose in treated male and female rats. The clinical pathology findings were indicative of liver damage and erythrocyte and platelet sequestration. In mice in the 13-week study, no deaths related to riddelliine treatment occurred. Body weight gains were depressed at the two highest dose levels (10 and 25 mg/kg); the depression in body weight persisted throughout the 14- week recovery period. Dose-related increases in erythrocyte counts in male mice and in reticulocyte counts in female mice were observed. Dose-related decreases in platelet counts were also observed in both males and females. Centrilobular cytomegaly in the liver was noted at 13 weeks in males and females administered 25 mg/kg riddelliine; this lesion persisted through the recovery period in females. At the end of the 14-week recovery period, bile duct hyperplasia was seen in the liver in high-dose female mice. Epithelial hyperplasia of the forestomach was noted in male and female mice in the 10 and 25 mg/kg groups after 13 weeks of treatment, but this lesion became less severe during the recovery period. In male rats administered up to 3.3 mg/kg and in male mice administered up to 25 mg/kg for 13 weeks, riddelliine did not adversely affect any of the reproductive end points evaluated. In female rats given 10 mg/kg and in female mice given 25 mg/kg, the length of the estrous cycle was increased. However, no unequivocal adverse effects were noted on fertility, pup growth and survival, or weight gain of dams during pregnancy during the mating trial in rats, although mean body weights of dams given 0.1 or 1.0 mg/kg were significantly lower than the mean body weight of the controls throughout gestation and lactation. In contrast, riddelliine administered at a dose of 25 mg/kg was toxic to the dams in the mouse mating trial, resulting in lower body weights at the beginning of gestation and throughout lactation. Administration of 25 mg/kg riddelliine to mouse dams also affected fetal growth and survival; the average live litter size was significantly reduced, the number of pups born dead was increased, and the average pup weight was reduced throughout the 21-day postpartum period. Riddelliine was mutagenic in Salmonella typhimurium strain TA100 with, but not without, S9 activation; results of mutagenicity testing were negative in strains TA97, TA98, and TA1535. Riddelliine induced sister chromatid exchanges in Chinese hamster ovary (CHO) cells with and without S9. Chromosomal aberrations were induced in CHO cells only in the presence of S9. The frequency of micronucleated erythrocytes in mouse peripheral blood samples was not elevated after 4 or 13 weeks of daily gavage treatments; however, a weakly positive response was noted in the peripheral blood and bone marrow of male mice administered a single, high dose of riddelliine by gavage. Unscheduled DNA synthesis was detected in cultured hepatocytes from male and female rats and mice following 5 or 30 days of riddelliine treatment by gavage. In addition, an increase in S-phase DNA synthesis was observed in cultured hepatocytes of male and female rats treated for either time period. In summary, the administration of riddelliine to rodents by gavage for up to 13 weeks resulted in a spectrum of neoplastic and nonneoplastic effects similar to those previously described for other pyrrolizidine alkaloids. Rats were found to be somewhat more sensitive than mice, and males more sensitive than females, to the toxic effects of riddelliine. The no-observed-adverse-effect level (NOAEL) for histopathologic changes in the 13-week studies was 3.3 mg/kg body weight for mice and 0.1 mg/kg body weight for rats. The liver was the primary target of riddelliine-induced injury that resulted in lesions characterized by cytomegaly and cytologic alteration in rats and mice and also by marked necrotic and proliferative changes in rats. Riddelliine is carcinogenic to female F344/N rats, based on the occurrence of hepatocellular adenomas. Synonyms: 13,19-didehydro-12,18-dihydroxy senecionan-11,16- dione; trans-15-ethylidine-12b-hydroxy-12a-hydroxymethyl-13-methylenesenec-1-enine; 3-ethylidine-3,4,5,6,9,11,13,14,14a,14b-decahydro-6-hydroxy-6-(hydroxymethyl)-5-methylene (1,6)di-oxacyclododecino(2,3,4-gh)-pyrrolizidine-2,7-dione.

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L'objectif principal du présent document est de clarifier les indications de l'examen pelvien. UTILISATEURS CONCERNéS: Médecins, y compris les gynécologues, obstétriciens, médecins de famille, urgentologues; infirmières, y compris les infirmières autorisées et les infirmières praticiennes; sages-femmes, y compris les sages-femmes en pratique clinique et les apprenties sages-femmes et les apprentis en médecine, y compris les étudiants de médecine, résidents, stagiaires (fellows); et tous les autres fournisseurs de soins de santé qui prodiguent des soins aux femmes. La présente publication fournit des données probantes et des recommandations fondées sur des avis d'experts sur l'examen pelvien chez les femmes adultes (18 ans et plus) avec et sans symptômes gynécologiques. La présente publication clarifie les indications de l'examen pelvien dans le contexte des déclarations de groupes d'étude nationaux récemment publiées sur l'utilité de l'examen pelvien. L'objectif est de veiller à ce que les femmes qui présentent des indications cliniques d'examen fassent rapidement l'objet d'une évaluation clinique adéquate pour diagnostiquer les maladies traitables. Pour la présente opinion de comité, les études pertinentes ont été repérées dans PubMed et Medline à l'aide des termes suivants, seuls ou combinés, et les recherches ont été limitées aux publications en anglais portant sur des humains sans date limite de publication : pelvic examination, bimanual examination, speculum examination, rectovaginal examination, ovarian cancer screening, asymptomatic women, periodic health examination. La recherche a été effectuée en mai et en juin 2018. Les données probantes pertinentes ont été retenues dans l'ordre suivant : méta-analyses, revues systématiques, lignes directrices et déclarations des groupes d'étude nationaux, essais cliniques randomisés, études de cohorte prospective, études observationnelles, revues non systématiques, études de série de cas et rapports. Des articles supplémentaires ont été repérés en consultant les notices bibliographiques des publications sélectionnées. Une revue systématique officielle n'a pas été menée pour tous les sujets discutés en raison du manque de données probantes et du nombre de différents sous-thèmes abordés. Le nombre total de publications examinées dans le cadre de cette revue était de 66. Les auteurs principaux ont rédigé le contenu et les recommandations et ils se sont entendus sur ces derniers. Les conseils d'administration de la Society of Gynecologic Oncology of Canada (GOC), de Collège des médecins de famille du Canada (CMFC) et de la Société des obstétriciens et gynécologues du Canada (SOGC) ont approuvé la version définitive aux fins de publication après que leurs comités représentatifs respectifs l'aient passée en revue. La qualité des données probantes utilisées dans le présent document a été évaluée au moyen des critères du cadre méthodologique GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). (Tableaux 1 et 2) Le résumé des conclusions est disponible sur demande. La présente opinion de comité devrait aider toutes les femmes qui souffrent ou non de symptômes gynécologiques qui se présentent chez le gynécologue et un fournisseur de soins primaires. Elle aidera les praticiens à déterminer les indications d'examen pelvien afin de réduire le nombre d'examens inutiles et susceptibles de porter préjudice tout en augmentant le nombre d'examens indiqués afin de réduire les retards de diagnostic des affections gynécologiques traitables. La présente opinion de comité de la SOGC sera automatiquement passée en revue cinq ans après sa publication pour déterminer si une partie ou l'ensemble de l'opinion de comité devrait être mis à jour. Cependant, cette revue peut être effectuée plus tôt si de nouvelles recherches révolutionnaires sont publiées entre-temps. 1) Les déclarations et les directives nationales et internationales sur l'examen pelvien ne devraient pas être interprétées comme si l'examen pelvien est superflu, qu'il ne contribue pas à l’évaluation physique ou que l'examen pelvien chez les femmes symptomatiques devrait être omis. 2) L'examen pelvien peut comprendre les examens visuels, au spéculum, bimanuel, à un doigt ou rectovaginal selon l'indication d'examen. 3) Aucune étude publiée à ce jour n'a évalué adéquatement quelque composante que ce soit de l'examen pelvien comme méthode de dépistage pour quelconque type de maladie gynécologique maligne, à l'exception de l'examen au spéculum pour le dépistage cytologique du cancer du col de l'utérus. Ainsi, toute recommandation universelle, pour ou contre les examens pelviens pour d'autres indications ne peut qu’être faite selon l'opinion des spécialistes et des données probantes de faible qualité. 4) Chez les femmes asymptomatiques dont le risque de cancer du col de l'utérus est moyen, le dépistage cytologique du cancer du col de l'utérus réduit à la fois son incidence et son taux de mortalité en détectant les lésions préinvasives traitables. 5) Chez les femmes asymptomatiques dont le risque de tumeur ou affection maligne est moyen, un examen visuel et bimanuel au moment d'obtenir des échantillons cytologiques cervicaux peut apporter une valeur ajoutée à cette méthode de dépistage. Les femmes peuvent ne pas soulever certaines inquiétudes sur le plan gynécologique jusqu'au moment de l'examen pelvien; l'examen offre une occasion de sensibiliser les patientes et de maintenir les compétences du praticien; de plus, même si le sujet n'a pas encore été étudié adéquatement, il pourrait comporter des effets positifs sur les tumeurs ou affections malignes ovariennes et vulvaires qui nécessiteraient des analyses plus poussées. Ces avantages potentiels devraient être soupesés par rapport aux préjudices potentiels comme l'inconfort de la patiente et les faux positifs ou négatifs qui pourraient la rassurer à tort ou entraîner des analyses et des interventions non justifiées. Femmes symptomatiques 1) Toute femme qui exprime des plaintes de nature gynécologique, y compris, mais sans s'y limiter, des plaintes concernant la vulve, des pertes vaginales, des saignements préménopausiques anormaux, des saignements postménopausiques, l'infertilité, des symptômes de prolapsus des organes pelviens, l'incontinence urinaire, de nouveaux symptômes gastro-intestinaux inexpliqués (douleur abdominale, distension abdominale ou ballonnement et difficulté à manger ou satiété précoce), la douleur pelvienne ou la dyspareunie, devrait subir des composantes pertinentes de l'examen pelvien afin de détecter les maladies bénignes ou malignes (forte, basse). 2) Les fournisseurs de soins de santé peuvent envisager de discuter des risques et avantages de l'exécution d'un examen pelvien de base qui comprend un examen visuel et un examen bimanuel avant de prescrire une hormonothérapie substitutive ou un traitement hormonal de la ménopause (faible, très basse). Femmes asymptomatiques 3) Les professionnels de la santé devraient faire le dépistage cytologique du cancer du col de l'utérus conformément aux lignes directrices provinciales ou territoriales (forte, forte). 4) Les données sont insuffisantes pour orienter les recommandations sur l'examen pelvien aux fins de dépistage de tumeurs ou affections malignes de nature gynécologique non cervicales ou de toute maladie gynécologique bénigne chez les femmes asymptomatiques en santé dont le risque de tumeur ou affection maligne est moyen. Cependant, les professionnels de la santé peuvent envisager d'effectuer un examen pelvien aux fins de dépistage comprenant les examens visuel, bimanuel et au spéculum conjointement avec le prélèvement d’échantillons cytologiques cervicaux selon les intervalles recommandés dans les lignes directrices provinciales ou territoriales. Cette pratique pourrait permettre de détecter d'importantes maladies bénignes ou malignes non reconnues ou signalées par la patiente (faible, très basse). 5) Chez les femmes âgées de plus de 70 ans qui n'ont plus à subir de dépistage cytologique cervical, les professionnels de la santé devraient envisager de continuer chez les femmes asymptomatiques le dépistage périodique des maladies vulvaires en examinant la vulve, le périnée et l'anus afin de détecter les maladies bénignes ou malignes méconnues de cette population. Les données sont insuffisantes pour déterminer des recommandations sur la fréquence de cet examen (faible, basse). 6) Des examens pelviens de dépistage plus fréquents pour déceler les signes précoces de tumeurs ou affections malignes primitives, récidivantes ou métastatiques en l'absence de symptômes pourraient s'avérer bénéfiques pour les femmes qui ont des antécédents personnels de tumeurs malignes de nature gynécologique, un diagnostic génétique qui augmente le risque de tumeurs ou affections malignes gynécologiques ou des antécédents d'exposition in utero au diéthylstilbestrol. Puisque les données pour déterminer ces intervalles de dépistage sont inadéquates, on devrait les déterminer en fonction des lignes directrices provinciales ou territoriales et de l'opinion des spécialistes (faible, très basse). 7) Les options non effractives et par auto-prélèvement de dépistage de la chlamydia et de la gonorrhée sont acceptables chez les femmes asymptomatiques, mais l'examen pelvien, qui comprend les examens visuel, bimanuel et au spéculum, est requis en présence de symptômes pour écarter la possibilité d'une maladie inflammatoire pelvienne ou d'un abcès tubo-ovarien (forte, basse). 8) Aucun examen pelvien n'est requis avant la prescription de contraception hormonale chez une femme en santé qui ne présente aucun symptôme gynécologique (forte, basse).

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Mood and psychotic syndromes most often emerge during adolescence and young adulthood, a period characterised by major physical and social change. Consequently, the effects of adolescent-onset mood and psychotic syndromes can have long term consequences. A key clinical challenge for youth mental health is to develop and test new systems that align with current evidence for comorbid presentations and underlying neurobiology, and are useful for predicting outcomes and guiding decisions regarding the provision of appropriate and effective care. Our highly personalised and measurement-based care model includes three core concepts: ▶ A multidimensional assessment and outcomes framework that includes: social and occupational function; self-harm, suicidal thoughts and behaviour; alcohol or other substance misuse; physical health; and illness trajectory. ▶ Clinical stage. ▶ Three common illness subtypes (psychosis, anxious depression, bipolar spectrum) based on proposed pathophysiological mechanisms (neurodevelopmental, hyperarousal, circadian). The model explicitly aims to prevent progression to more complex and severe forms of illness and is better aligned to contemporary models of the patterns of emergence of psychopathology. Inherent within this highly personalised approach is the incorporation of other evidence-based processes, including real-time measurement-based care as well as utilisation of multidisciplinary teams of health professionals. Data-driven local system modelling and personalised health information technologies provide crucial infrastructure support to these processes for better access to, and higher quality, mental health care for young people. CHAPTER 1: MULTIDIMENSIONAL OUTCOMES IN YOUTH MENTAL HEALTH CARE: WHAT MATTERS AND WHY?: Mood and psychotic syndromes present one of the most serious public health challenges that we face in the 21st century. Factors including prevalence, age of onset, and chronicity contribute to substantial burden and secondary risks such as alcohol or other substance misuse. Mood and psychotic syndromes most often emerge during adolescence and young adulthood, a period characterised by major physical and social change; thus, effects can have long term consequences. We propose five key domains which make up a multidimensional outcomes framework that aims to address the specific needs of young people presenting to health services with emerging mental illness. These include social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness type, stage and trajectory. Impairment and concurrent morbidity are well established in young people by the time they present for mental health care. Despite this, services and health professionals tend to focus on only one aspect of the presentation - illness type, stage and trajectory - and are often at odds with the preferences of young people and their families. There is a need to address the disconnect between mental health, physical health and social services and interventions, to ensure that youth mental health care focuses on the outcomes that matter to young people. CHAPTER 2: COMBINING CLINICAL STAGE AND PATHOPHYSIOLOGICAL MECHANISMS TO UNDERSTAND ILLNESS TRAJECTORIES IN YOUNG PEOPLE WITH EMERGING MOOD AND PSYCHOTIC SYNDROMES: Traditional diagnostic classification systems for mental disorders map poorly onto the early stages of illness experienced by young people, and purport categorical distinctions that are not readily supported by research into genetic, environmental and neurobiological risk factors. Consequently, a key clinical challenge in youth mental health is to develop and test new classification systems that align with current evidence on comorbid presentations, are consistent with current understanding of underlying neurobiology, and provide utility for predicting outcomes and guiding decisions regarding the provision of appropriate and effective care. This chapter outlines a transdiagnostic framework for classifying common adolescent-onset mood and psychotic syndromes, combining two independent but complementary dimensions: clinical staging, and three proposed pathophysiological mechanisms. Clinical staging reflects the progression of mental disorders and is in line with the concept used in general medicine, where more advanced stages are associated with a poorer prognosis and a need for more intensive interventions with a higher risk-to-benefit ratio. The three proposed pathophysiological mechanisms are neurodevelopmental abnormalities, hyperarousal and circadian dysfunction, which, over time, have illness trajectories (or pathways) to psychosis, anxious depression and bipolar spectrum disorders, respectively. The transdiagnostic framework has been evaluated in young people presenting to youth mental health clinics of the University of Sydney's Brain and Mind Centre, alongside a range of clinical and objective measures. Our research to date provides support for this framework, and we are now exploring its application to the development of more personalised models of care. CHAPTER 3: A COMPREHENSIVE ASSESSMENT FRAMEWORK FOR YOUTH MENTAL HEALTH: GUIDING HIGHLY PERSONALISED AND MEASUREMENT-BASED CARE USING MULTIDIMENSIONAL AND OBJECTIVE MEASURES: There is an urgent need for improved care for young people with mental health problems, in particular those with subthreshold mental disorders that are not sufficiently severe to meet traditional diagnostic criteria. New comprehensive assessment frameworks are needed to capture the biopsychosocial profile of a young person to drive highly personalised and measurement-based mental health care. We present a range of multidimensional measures involving five key domains: social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness type, stage and trajectory. Objective measures include: neuropsychological function; sleep-wake behaviours and circadian rhythms; metabolic and immune markers; and brain structure and function. The recommended multidimensional measures facilitate the development of a comprehensive clinical picture. The objective measures help to further develop informative and novel insights into underlying pathophysiological mechanisms and illness trajectories to guide personalised care plans. A panel of specific multidimensional and objective measures are recommended as standard clinical practice, while others are recommended secondarily to provide deeper insights with the aim of revealing alternative clinical paths for targeted interventions and treatments matched to the clinical stage and proposed pathophysiological mechanisms of the young person. CHAPTER 4: PERSONALISING CARE OPTIONS IN YOUTH MENTAL HEALTH: USING MULTIDIMENSIONAL ASSESSMENT, CLINICAL STAGE, PATHOPHYSIOLOGICAL MECHANISMS, AND INDIVIDUAL ILLNESS TRAJECTORIES TO GUIDE TREATMENT SELECTION: New models of mental health care for young people require that interventions be matched to illness type, clinical stage, underlying pathophysiological mechanisms and individual illness trajectories. Narrow syndrome-focused classifications often direct clinical attention away from other key factors such as functional impairment, self-harm and suicidality, alcohol or other substance misuse, and poor physical health. By contrast, we outline a treatment selection guide for early intervention for adolescent-onset mood and psychotic syndromes (ie, active treatments and indicated and more specific secondary prevention strategies). This guide is based on experiences with the Brain and Mind Centre's highly personalised and measurement-based care model to manage youth mental health. The model incorporates three complementary core concepts: ▶A multidimensional assessment and outcomes framework including: social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness trajectory. ▶Clinical stage. ▶Three common illness subtypes (psychosis, anxious depression, bipolar spectrum) based on three underlying pathophysiological mechanisms (neurodevelopmental, hyperarousal, circadian). These core concepts are not mutually exclusive and together may facilitate improved outcomes through a clinical stage-appropriate and transdiagnostic framework that helps guide decisions regarding the provision of appropriate and effective care options. Given its emphasis on adolescent-onset mood and psychotic syndromes, the Brain and Mind Centre's model of care also respects a fundamental developmental perspective - categorising childhood problems (eg, anxiety and neurodevelopmental difficulties) as risk factors and respecting the fact that young people are in a period of major biological and social transition. Based on these factors, a range of social, psychological and pharmacological interventions are recommended, with an emphasis on balancing the personal benefit-to-cost ratio. CHAPTER 5: A SERVICE DELIVERY MODEL TO SUPPORT HIGHLY PERSONALISED AND MEASUREMENT-BASED CARE IN YOUTH MENTAL HEALTH: Over the past decade, we have seen a growing focus on creating mental health service delivery models that better meet the unique needs of young Australians. Recent policy directives from the Australian Government recommend the adoption of stepped-care services to improve the appropriateness of care, determined by severity of need. Here, we propose that a highly personalised approach enhances stepped-care models by incorporating clinical staging and a young person's current and multidimensional needs. It explicitly aims to prevent progression to more complex and severe forms of illness and is better aligned to contemporary models of the patterns of emergence of psychopathology. Inherent within a highly personalised approach is the incorporation of other evidence-based processes, including real-time measurement-based care and use of multidisciplinary teams of health professionals. Data-driven local system modelling and personalised health information technologies provide crucial infrastructure support to these processes for better access to, and higher quality of, mental health care for young people.

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<bObjective:</b To explore the effects of enteral immunonutrition support therapy on nutritional metabolism, immune function, and inflammatory response in adult burn patients at nutritional risk as assessed by the modified 2<supnd</sup nutrition risk screening (NRS) 2002. <bMethods:</b A prospective randomized controlled study was conducted. From December 2019 to January 2022, 500 adult patients who were admitted to the Affiliated Huaihai Hospital of Xuzhou Medical University and had nutritional risk assessed by the modified 2<supnd</sup NRS 2002 were recruited into the study. According to burn severity, the patients were divided into common burn patients (<in</i=450) and severe burn patients (<in</i=50). According to the random number table, the patients with common burn were divided into common burn diet nutrition group and common burn diet enteral immunonutrition group, with 225 patients in each group, and the patients with severe burn were divided into severe burn diet enteral non-immunonutrition group and severe burn diet enteral immunonutrition group, with 25 patients in each group. The patients in each group were given the corresponding nutritional support therapies on the basis of routine burn treatment. On post injury day (PID) 1, 3, 7, 14, and 21, the total energy intake and total protein intake of the patients in 4 groups were recorded, the plasma prealbumin, albumin, transferrin, serum immunoglobulin A (IgA), IgG, IgM, peripheral blood CD3 positive T cell percentage, CD4 positive T cell count, CD8 positive T cell count, the ratio of CD4 positive T cells to CD8 positive T cells, natural killer cell percentage, plasma interleukin-6 (IL-6), free mitochondrial DNA (mtDNA) copy number, and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) of the patients in 4 groups were detected, and the nitrogen balance of the patients in 4 groups on the day was calculated. On PID 7, 14, and 21, the modified 2<supnd</sup NRS 2002 scores of the patients in 4 groups were reassessed. The sepsis incidence during treatment and the length of hospital stay of the patients in 4 groups and the length of intensive care unit (ICU) stay of the patients in the 2 severe burn groups were recorded. Data were statistically analyzed with chi-square test, Fisher's exact probability test, Mann-Whitney <iU</i test, independent sample <it</i test, analysis of variance for repeated measurement, and Bonferroni correction. <bResults:</b A total of 476 patients completed the trial, with 213 patients in common burn diet nutrition group (112 males and 101 females, aged (37±19) years), 218 patients in common burn diet enteral immunonutrition group (115 males and 103 females, aged (42±16) years), 22 patients in severe burn diet enteral non-immunonutrition group (11 males and 11 females, aged (35±8) years), and 23 patients in severe burn diet enteral immunonutrition group (12 males and 11 females, aged (35±8) years). Compared with those in common burn diet nutrition group, the patients in common burn diet enteral immunonutrition group had significantly higher total energy intake on PID 1 (<it</i=6.06, <iP</i&lt;0.01), significantly lower total energy intake on PID 7 and significantly lower total protein intake on PID 1 (with <it</i values of 6.17 and 4.59, respectively,<iP</i&lt;0.01). On PID 21, the total energy intake of patients in severe burn diet enteral immunonutrition group was significantly lower than that in severe burn diet enteral non-immunonutrition group (<it</i=2.70, <iP</i&lt;0.01). The total protein intake of patients in severe burn diet enteral immunonutrition group and severe burn diet enteral non-immunonutrition group were similar at each time point post injury (<iP</i&gt;0.05). Compared with those in common burn diet nutrition group, the patients in common burn diet enteral immunonutrition group had significantly higher level of prealbumin on PID 3, 7, 14, and 21 (with <it</i values of 2.05, 2.33, 2.45, and 2.11, respectively, <iP</i&lt;0.05), significantly higher level of albumin on PID 7, 14, and 21 (with <it</i values of 2.30, 2.56, and 2.15, respectively, <iP</i&lt;0.05), significantly higher level of transferrin on PID 7 and 14 (with <it</i values of 1.99 and 2.27, respectively, <iP</i&lt;0.05), significantly higher nitrogen balance on PID 14 and 21 (with <it</i values of 2.51 and 2.07, respectively, <iP</i&lt;0.05), and significantly lower modified 2<supnd</sup NRS 2002 score on PID 21 (<it</i=1.99, <iP</i&lt;0.05). Compared with those in severe burn diet enteral non-immunonutrition group, the patients in severe burn diet enteral immunonutrition group had significantly higher level of prealbumin on PID 3, 7, 14, and 21 (with <it</i values of 2.50, 2.64, 2.18, and 2.39, respectively, <iP</i&lt;0.05), significantly higher level of albumin​on PID 7, 14, and 21 (with <it</i values of 2.27, 2.39, and 2.69, respectively, <iP</i&lt;0.05), significantly higher level of transferrin and nitrogen balance but significantly lower modified 2<supnd</sup NRS 2002 score on PID 14 and 21 (with <it</i values of 2.30, 2.35, 2.41, 2.16, 2.31, and 2.73, respectively, <iP</i&lt;0.05). Compared with those in common burn diet nutrition group, patients in common burn diet enteral immunonutrition group had significantly higher level of IgA and IgG on PID 7, 14, and 21 (with <it</i values of 2.19, 2.36, 2.17, 2.49, 1.97, and 2.24, respectively, <iP</i&lt;0.05), significantly higher level of IgM on PID 21 (<it</i=2.06, <iP</i&lt;0.05), significantly higher percentage of CD3 positive T cells and ratio of CD4 positive T cells to CD8 positive T cells on PID 3, 7, 14, and 21 (with <it</i values of 2.49, 2.25, 2.33, 2.41, 2.39, 2.24, 2.46, and 2.18, respectively, <iP</i&lt;0.05), significantly higher CD4 positive T cell count (with <it</i values of 2.15 and 2.27, respectively, <iP</i&lt;0.05) but significantly lower CD8 positive T cell count on PID 14 and 21 (with <it</i values of 2.58 and 2.35, <iP</i&lt;0.05), and significantly higher percentage of natural killer cells on PID 7, 14, and 21 (with <it</i values of 2.53, 2.21, and 2.36, respectively, <iP</i&lt;0.05). Compared with those in severe burn diet enteral non-immunonutrition group, patients in severe burn diet immunonutrition group had significantly higher level of IgA on PID 7 and 14 (with <it</i values of 2.15 and 2.03, respectively, <iP</i&lt;0.05), significantly higher level of IgG on PID 7, 14, and 21 (with <it</i values of 2.09, 2.56, and 2.15, respectively, <iP</i&lt;0.05), significantly higher level of IgM on PID 21 (<it</i=2.08, <iP</i&lt;0.05), significantly higher percentage of CD3 positive T cells, CD4 positive T cell count, and percentage of natural killer cells on PID 14 and 21 (with <it</i values of 2.52, 2.14, 2.14, 2.39, 2.56, and 2.19, respectively, <iP</i&lt;0.05), significantly lower CD8 positive T cell count but significantly higher ratio of CD4 positive T cells to CD8 positive T cells on PID 7, 14, and 21 (with <it</i values of 2.27, 2.81, 2.01, 2.11, 2.69, and 2.05, respectively, <iP</i&lt;0.05). Compared with those in common burn diet nutrition group, patients in common burn diet enteral immunonutrition group had significantly lower level of IL-6 (with <it</i values of 2.34 and 2.32, respectively, <iP</i&lt;0.05) and significantly lower free mtDNA copy number on PID 14 and 21 (with <iZ</i values of -2.28 and -2.34,respectively, <iP</i&lt;0.05), significantly lower level of sTREM-1 on PID 7, 14, and 21 (with <it</i values of 2.02, 2.94, and 3.72, respectively, <iP</i&lt;0.05). Compared with those in severe burn diet enteral non-immunonutrition group, patients in severe burn diet enteral immunonutrition group had significantly lower level of IL-6 and sTREM-1 on PID 7, 14, and 21 (with <it</i values of 2.15, 2.29, 2.47, 2.43, 2.07, and 2.32, respectively, <iP</i&lt;0.05), and significantly lower free mtDNA copy number on PID 14 and 21 (with <iZ</i values of -2.49 and -2.21, respectively, <iP</i&lt;0.05). During treatment, the sepsis incidences of patients in 2 common burn groups were similar (<iP</i&gt;0.05), the sepsis incidences of patients in 2 severe burn groups were similar (<iP</i&gt;0.05). The length of ICU stay of patients in severe burn diet enteral immunonutrition group was (11±3) d, which was significantly shorter than (14±3) d in severe burn diet enteral non-immunonutrition group (<it</i=3.12, <iP</i&lt;0.01). The length of hospital stay of patients in common burn diet enteral immunonutrition group was significantly shorter than that in common burn diet nutrition group (<it</i=3.11, <iP</i&lt;0.01). The length of hospital stay of patients in severe burn diet enteral non-immunonutrition group was similar to that in severe burn diet enteral immunonutrition group (<iP</i&gt;0.05). <bConclusions:</b Enteral immunonutrition support therapy for adult burn patients at nutritional risk assessed by the modified 2<supnd</sup NRS 2002 can better improve the nutritional status and the immune function of patients, reduce inflammatory response of the body, and shorten the length of hospital stay in common burn patients and the length of ICU stay in severe burn patients.

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An Undergraduate Nurse Employment Demonstration Project (UNDP) was implemented in four Health Service Areas in British Columbia with a concurrent evaluation study. This demonstration project comprised the development and implementation of a new position in the BC healthcare system. The position enabled third- and fourth-year nursing students to be employed at their level of education. The purposes of the evaluation were to explore the feasibility and outcomes of this type of paid undergraduate student nurse employment. The three-year project and evaluation included both implementation and outcome analysis. The implementation evaluation design was descriptive and prospective, involving multiple data sources. The outcome evaluation design was quasi-experimental, with intervention and comparison groups. Learning outcomes for undergraduate nurses were increased confidence, organizational ability, competency and ability to work with a team. Workplace outcomes were increased unit morale, help with workload and improved patient care. New graduates with undergraduate nurse experience reported less time required for orientation and transition than other graduates who did not have this experience, and workplace nurses viewed these new graduates as more job-ready than other new graduates. After 21 months, new graduates with undergraduate nurse experience were less likely to move to other employment than other new graduates. Results from the four Health Service Areas indicated that the paid undergraduate nurse position was feasible and that outcomes benefited students, new graduates and workplaces. The undergraduate nurse position is now being implemented throughout all Health Service Areas in British Columbia.By 2000, concerns in British Columbia about the nursing workforce, workplace and patient safety had escalated to the point where diverse stakeholder groups were prepared to work together in new ways to prepare nursing graduates to be more job-ready, to recruit and retain new graduates and to retain existing nurses. Stakeholder groups were administrators, labour organizations, professional associations, educators and government. One idea to support job readiness and retention focussed on the feasibility of implementing cooperative education for nursing students. The effort was unsuccessful owing to lack of funding, but resulted in a review of the literature on cooperative education and other work-study programs. Cooperative education connects classroom learning with paid work experience for the purpose of enhancing students' education (Fitt and Heverly 1990; Heinemann and De Falco 1992; Ryder 1987). Reported benefits for students were improved job preparation and graduate retention (Ishida et al. 1998), additional staffing and reduction in orientation time (Cusack 1990; Ishida et al. 1998), increased practice judgment (Cusack 1990; Siedenberg 1989) and better workload management (Ross and Marriner 1985). A work-study model reported in the literature offered benefits similar to those of cooperative education, with greater flexibility in design. An example was the University of Texas Health Science Center at Houston's collaborative work-study scholarship program with local hospitals (Kee and Ryser 2001). Students in second clinical semesters were employed as unlicensed personnel by hospitals. The students, as unlicensed personnel, worked to the level of their nursing preparation. Reported benefits for students were academic credit, financial assistance, interaction with multidisciplinary teams, opportunity to refine clinical skills, understanding of nurses' roles and guaranteed interview for positions on graduation (Kee and Ryser 2001). Benefits for practice organizations were skilled help, the opportunity to recruit new nurses and increased interaction with a university nursing program. While nurse education stakeholders in British Columbia were exploring options, the concept of undergraduate student nurse employment was initiated by a group of fourth-year students at the University of Victoria who were completing the course "Nurses Influencing Change." The students were concerned about having enough practice experience to meet increasing nursing competency requirements and their survival as new graduates given workplace realities. Debt load also was a concern because extensive student practicum time limited opportunities for paid employment during the nursing education program. Students found that the idea of paid undergraduate nurse positions, based on the student employment model in Alberta, was supported by nurse leaders, many practising nurses and nursing faculty who also were concerned about meeting patient care standards and adequately preparing nursing students. In 2000, the BC Ministry of Health Services funded an Undergraduate Nurse Demonstration Project (UNDP) - one type of paid employment for undergraduate student nurses - in four Health Service Areas linked with four schools of nursing. A concurrent three-year evaluation study examined the feasibility and outcomes of the UNDP (Gamroth et al. 2004). This paper summarizes the findings of the evaluation. Evaluation Research An Undergraduate Nurse Employment Demonstration Project (UNDP) was implemented in four Health Service Areas in British Columbia with a concurrent evaluation study. This demonstration project comprised the development and implementation of a new position in the BC healthcare system. The position enabled third- and fourth-year nursing students to be employed at their level of education. The purposes of the evaluation were to explore the feasibility and outcomes of this type of paid undergraduate student nurse employment. The three-year project and evaluation included both implementation and outcome analysis. The implementation evaluation design was descriptive and prospective, involving multiple data sources. The outcome evaluation design was quasi-experimental, with intervention and comparison groups. Learning outcomes for undergraduate nurses were increased confidence, organizational ability, competency and ability to work with a team. Workplace outcomes were increased unit morale, help with workload and improved patient care. New graduates with undergraduate nurse experience reported less time required for orientation and transition than other graduates who did not have this experience, and workplace nurses viewed these new graduates as more job-ready than other new graduates. After 21 months, new graduates with undergraduate nurse experience were less likely to move to other employment than other new graduates. Results from the four Health Service Areas indicated that the paid undergraduate nurse position was feasible and that outcomes benefited students, new graduates and workplaces. The undergraduate nurse position is now being implemented throughout all Health Service Areas in British Columbia. By 2000, concerns in British Columbia about the nursing workforce, workplace and patient safety had escalated to the point where diverse stakeholder groups were prepared to work together in new ways to prepare nursing graduates to be more job-ready, to recruit and retain new graduates and to retain existing nurses. Stakeholder groups were administrators, labour organizations, professional associations, educators and government. One idea to support job readiness and retention focussed on the feasibility of implementing cooperative education for nursing students. The effort was unsuccessful owing to lack of funding, but resulted in a review of the literature on cooperative education and other work-study programs. Cooperative education connects classroom learning with paid work experience for the purpose of enhancing students' education (Fitt and Heverly 1990; Heinemann and De Falco 1992; Ryder 1987). Reported benefits for students were improved job preparation and graduate retention (Ishida et al. 1998), additional staffing and reduction in orientation time (Cusack 1990; Ishida et al. 1998), increased practice judgment (Cusack 1990; Siedenberg 1989) and better workload management (Ross and Marriner 1985). A work-study model reported in the literature offered benefits similar to those of cooperative education, with greater flexibility in design. An example was the University of Texas Health Science Center at Houston's collaborative work-study scholarship program with local hospitals (Kee and Ryser 2001). Students in second clinical semesters were employed as unlicensed personnel by hospitals. The students, as unlicensed personnel, worked to the level of their nursing preparation. Reported benefits for students were academic credit, financial assistance, interaction with multidisciplinary teams, opportunity to refine clinical skills, understanding of nurses' roles and guaranteed interview for positions on graduation (Kee and Ryser 2001). Benefits for practice organizations were skilled help, the opportunity to recruit new nurses and increased interaction with a university nursing program. While nurse education stakeholders in British Columbia were exploring options, the concept of undergraduate student nurse employment was initiated by a group of fourth-year students at the University of Victoria who were completing the course "Nurses Influencing Change." The students were concerned about having enough practice experience to meet increasing nursing competency requirements and their survival as new graduates given workplace realities. Debt load also was a concern because extensive student practicum time limited opportunities for paid employment during the nursing education program. Students found that the idea of paid undergraduate nurse positions, based on the student employment model in Alberta, was supported by nurse leaders, many practising nurses and nursing faculty who also were concerned about meeting patient care standards and adequately preparing nursing students.

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SUBJECT OF THE EVIDENCE-BASED ANALYSIS: The purpose of this evidence based analysis report is to examine the safety and effectiveness of point-of-care (POC) international normalized ratio (INR) monitoring devices for patients on long-term oral anticoagulation therapy (OAT). TARGET POPULATION AND CONDITION Long-term OAT is typically required by patients with mechanical heart valves, chronic atrial fibrillation, venous thromboembolism, myocardial infarction, stroke, and/or peripheral arterial occlusion. It is estimated that approximately 1% of the population receives anticoagulation treatment and, by applying this value to Ontario, there are an estimated 132,000 patients on OAT in the province, a figure that is expected to increase with the aging population. Patients on OAT are regularly monitored and their medications adjusted to ensure that their INR scores remain in the therapeutic range. This can be challenging due to the narrow therapeutic window of warfarin and variation in individual responses. Optimal INR scores depend on the underlying indication for treatment and patient level characteristics, but for most patients the therapeutic range is an INR score of between 2.0 and 3.0. The current standard of care in Ontario for patients on long-term OAT is laboratory-based INR determination with management carried out by primary care physicians or anticoagulation clinics (ACCs). Patients also regularly visit a hospital or community-based facility to provide a venous blood samples (venipuncture) that are then sent to a laboratory for INR analysis. Experts, however, have commented that there may be under-utilization of OAT due to patient factors, physician factors, or regional practice variations and that sub-optimal patient management may also occur. There is currently no population-based Ontario data to permit the assessment of patient care, but recent systematic reviews have estimated that less that 50% of patients receive OAT on a routine basis and that patients are in the therapeutic range only 64% of the time. POC INR devices offer an alternative to laboratory-based testing and venipuncture, enabling INR determination from a fingerstick sample of whole blood. Independent evaluations have shown POC devices to have an acceptable level of precision. They permit INR results to be determined immediately, allowing for more rapid medication adjustments. POC devices can be used in a variety of settings including physician offices, ACCs, long-term care facilities, pharmacies, or by the patients themselves through self-testing (PST) or self-management (PSM) techniques. With PST, patients measure their INR values and then contact their physician for instructions on dose adjustment, whereas with PSM, patients adjust the medication themselves based on pre-set algorithms. These models are not suitable for all patients and require the identification and education of suitable candidates. Potential advantages of POC devices include improved convenience to patients, better treatment compliance and satisfaction, more frequent monitoring and fewer thromboembolic and hemorrhagic complications. Potential disadvantages of the device include the tendency to underestimate high INR values and overestimate low INR values, low thromboplastin sensitivity, inability to calculate a mean normal PT, and errors in INR determination in patients with antiphospholipid antibodies with certain instruments. Although treatment satisfaction and quality of life (QoL) may improve with POC INR monitoring, some patients may experience increased anxiety or preoccupation with their disease with these strategies. 1. EffectivenessDoes POC INR monitoring improve clinical outcomes in various settings compared to standard laboratory-based testing?Does POC INR monitoring impact patient satisfaction, QoL, compliance, acceptability, convenience compared to standard laboratory-based INR determination?Settings include primary care settings with use of POC INR devices by general practitioners or nurses, ACCs, pharmacies, long-term care homes, and use by the patient either for PST or PSM. 2. Cost-effectivenessWhat is the cost-effectiveness of POC INR monitoring devices in various settings compared to standard laboratory-based INR determination? English-language RCTs, systematic reviews, and meta-analysesPUBLICATION DATES: 1996 to November 25, 2008POPULATION: patients on OATINTERVENTION: anticoagulation monitoring by POC INR device in any setting including anticoagulation clinic, primary care (general practitioner or nurse), pharmacy, long-term care facility, PST, PSM or any other POC INR strategyMINIMUM SAMPLE SIZE: 50 patients Minimum follow-up period: 3 monthsCOMPARATOR: usual care defined as venipuncture blood draw for an INR laboratory test and management provided by an ACC or individual practitioner Hemorrhagic events, thromboembolic events, all-cause mortality, anticoagulation control as assessed by proportion of time or values in the therapeutic range, patient reported outcomes including satisfaction, QoL, compliance, acceptability, convenience Non-RCTs, before-after studies, quasi-experimental studies, observational studies, case reports, case series, editorials, letters, non-systematic reviews, conference proceedings, abstracts, non-English articles, duplicate publicationsStudies where POC INR devices were compared to laboratory testing to assess test accuracyStudies where the POC INR results were not used to guide patient management A search of electronic databases (OVID MEDLINE, MEDLINE In-Process &amp; Other Non-Indexed Citations, EMBASE, The Cochrane Library, and the International Agency for Health Technology Assessment [INAHTA] database) was undertaken to identify evidence published from January 1, 1998 to November 25, 2008. Studies meeting the inclusion criteria were selected from the search results. Reference lists of selected articles were also checked for relevant studies. Five existing reviews and 22 articles describing 17 unique RCTs met the inclusion criteria. Three RCTs examined POC INR monitoring devices with PST strategies, 11 RCTs examined PSM strategies, one RCT included both PST and PSM strategies and two RCTs examined the use of POC INR monitoring devices by health care professionals. Anticoagulation control is measured by the percentage of time INR is within the therapeutic range or by the percentage of INR values in the therapeutic range. Due to the differing methodologies and reporting structures used, it was deemed inappropriate to combine the data and estimate whether the difference between groups would be significant. Instead, the results of individual studies were weighted by the number of person-years of observation and then pooled to calculate a summary measure. Across most studies, patients in the intervention groups tended to have a higher percentage of time and values in the therapeutic target range in comparison to control patients. When the percentage of time in the therapeutic range was pooled across studies and weighted by the number of person-years of observation, the difference between the intervention and control groups was 4.2% for PSM, 7.2% for PST and 6.1% for POC use by health care practitioners. Overall, intervention patients were in the target range 69% of the time and control patients were in the therapeutic target range 64% of the time leading to an overall difference between groups of roughly 5%. There was no statistically significant difference in the number of major hemorrhagic events between patients managed with POC INR monitoring devices and patients managed with standard laboratory testing (OR =0.74; 95% CI: 0.52- 1.04). This difference was non-significant for all POC strategies (PSM, PST, health care practitioner). Patients managed with POC INR monitoring devices had significantly fewer thromboembolic events than usual care patients (OR =0.52; 95% CI: 0.37 - 0.74). When divided by POC strategy, PSM resulted in significantly fewer thromboembolic events than usual care (OR =0.46.; 95% CI: 0.29 - 0.72). The observed difference in thromboembolic events for PSM remained significant when the analysis was limited to major thromboembolic events (OR =0.40; 95% CI: 0.17 - 0.93), but was non-significant when the analysis was limited to minor thromboembolic events (OR =0.73; 95% CI: 0.08 - 7.01). PST and GP/Nurse strategies did not result in significant differences in thromboembolic events, however there were only a limited number of studies examining these interventions. No statistically significant difference was observed in the number of deaths between POC intervention and usual care control groups (OR =0.67; 95% CI: 0.41 - 1.10). This difference was non-significant for all POC strategies. Only one study reported on survival with 10-year survival rate of 76.1% in the usual care control group compared to 84.5% in the PSM group (P=0.05). ES Table 1:Summary Results of Meta-Analyses of Major Complications and Deaths in POC INR Monitoring StudiesEventNo. of trials(patients)OR(M-H, Random Effects)95% CIMajor Haemorrhages16 (5057)0.740.52 to 1.04Thromboembolic events16 (5057)0.520.37 to 0.74Deaths11 (2906)0.670.41 to 1.10 PATIENT SATISFACTION AND QUALITY OF LIFE: Quality of life measures were reported in eight studies comparing POC INR monitoring to standard laboratory testing using a variety of measurement tools. It was thus not possible to calculate a quantitative summary measure. The majority of studies reported favourable impacts of POC INR monitoring on QoL and found better treatment satisfaction with POC monitoring. Results from a pre-analysis patient and caregiver focus group conducted in Ontario also indicated improved patient QoL with POC monitoring. (ABSTRACT TRUNCATED)

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The main question to ask himself when preparing to write an article is "why publish a scientific paper?" First of all to publish an own article qualifies his author - or authors - as "scientist". Because the surgery is a mixture of art and knowledge, which coexist and interreact mutually increasing each other, scientific publications are the world where ideas are shared. Secondly, to an academic career is essential to be Author of scientific publications; but also for those who follow an hospital career or simply exercise the surgical profession in other contexts it represents the opportunity to communicate their experience and give a personal contribution to the knowledge of the art. The commitment of the academic world in particular must also stimulate new generations to pursue not only technical skills but at the same time updating their knowledge, and its members must also take on the role of researchers. The dissemination of ideas in the scientific community is a milestone for progress, because if they are not shared their concrete value is fleeting, and professional surgical activity value is itself transient and ephemeral, while the written documentation very often goes beyond the time, but certainly beyond space, stably transmitting ideas: "scripta manent". To write a "paper" - as a scientific publication is conventionally and internationally named - requires compliance with specific rules, which make it suitable to diffusion and well used by the readers. These appropriate rules are stated in the similar although variable "Guidelines for the Authors" set by the editors of most scientific journals - as also of Annali Italiani di Chirurgia - on the common purpose of making clear, comprehensive and concise the exposure of the study that is the motivation of the publication. The printed papers - as well the more recent on-line publications in digital format - use a very different language from that spoken in conferences and in verbal communications. Exemplary is the form of presentation used in the best "papers" of British tradition, where every effort is aimed at the clarity and brevity, for definite, consequential and well understood conclusions. Beyond any residual national pride, in the scientific world that has been globalized well earlier than other sectors of civil life, it is not a surrendering to a foreign tradition to conform oneself to the British model when writing a paper - and not simply adopting the English language - with the certainty to better achieve the brevity, clarity and concreteness of an exhaustive communication. "Be brief and you'll be good" - this is a suggestion always of great value to overcome the congestion and convulsions of our times. Furthermore in following the rules suggested by the "Guidelines for Authors" in writing a paper gives the Author the adjunctive advantage of a preventive and autonomous checking the validity and interest of the article as for premises, objectivity and reality of conclusions, and therefore vehicle of at least of one clear element of knowledge and progress, although possibly and despite of a "niche" argument. A paper is much more effective as more focused on a well-defined theme and as such more easily understood and its conclusions more easily assimilated. Therefore in the formal preparation of a paper, the critical sense must develop itself and grow, added to the vocation of following and attain the curiosity of knowledge typical of surgery, but following the typical procedure of the medical profession in the approaching march to the diagnosis, and then to the identification of the correct therapeutic indications which must take into account individual patient characteristics. As the very technical skill in performing the therapy chosen and agreed with the patient, completion of the professional duties, must not leave aside a constant exercise of criticism and self-criticism at every stage of the profession, similarly this same critical sense is also necessary in the preparation of a scientific paper to transmit a concrete, valid and original scientific contribution. It is useful to keep in mind that, as any student knows and does perhaps unconsciously, those who read an article do not follow the order in which it is printed, but having considered the catchy title go directly to review the conclusions. If still interested, they go on to the Abstract or to Summary, and only at this point if intrigued they read the Introduction, and then the material and method of study with their results, and finally the discussion, and to the end they read anew the Conclusions. However, in the formal drafting of a paper one has to remember this very likely sequence in reading an article and adapt accordingly: first put into focus the conclusions, which in fact are the reason of the publication. Therefore this must lead us to give up writing an article such as a report or a conference, and to conform attentively to the Anglo-Saxon model of presentation of a paper. A last point concerns the language of the presentation of a paper. Using own native language, in our case Italian, it is easy to the precise in language and is facilitated the communication of concepts, but that restricts the communication to own linguistics environment, whereas all scientific knowledge and the surgical one in particular, in accordance as stated by the motto of the International Society of Surgery "La Science n'a pas de Patrie", needs no linguistic boundaries. We should not feel therefore humiliated and colonized in adopting the English language in publishing our papers, because it has become the language of science globally adopted, indeed we must consider positively this choice for formal and substantial reasons. Formally the use of English forces ourselves to conform to a language traditionally pragmatic, schematic and synthetic typical of the Anglo-Saxon world, so renouncing to the usual subordinate phrases of Italian language, that may result contrary to its ingenuous purpose, making instead less clear and more foggy the concepts. This achieves in the meantime the advantage of a better and more schematic final clarity. We must take in mind from the very beginning the final concept you want to express with every sentence, and take it in the highest account. From a substantial point of view the adoption of English opens at the best the entire scientific world to all cultural contributions, no longer limited to the national linguistic areas, that now, in the globalized world of knowledge remains provincial even though vector of undisputed professional value and experience of Italian surgery. Any possible inadequacies of the used English language - that should be carefully avoided in terms of syntactic and orthographic rules, with the eventual help of a native language fellow - can anyways be accepted within certain limits as the price of a globalization of the diffusing knowledge, become even more evident by the introduction of digital editions. A special case is given by the publication of experiences derived from individual case reports. Clearly it is evident the impulse to disclose one's own individual experience, or because of its rare occurrence, or on the enthusiastic wave of a diagnosis successfully completed or because of the own satisfaction in choosing and performing an effective treatment successfully achieved thank to a surgical technique exceptional or of particularly difficulty. One can, however, make the mistake of aiming to publish "a case report" simply to show off one's skills and personal professional value. It is a short-sighted goal that gives the author an ephemeral satisfaction, but it will almost inevitably penalizated in the judgment of colleagues who read it. For psychological reasons it is difficult for someone to cheer the professional success of a not related fellow, and therefore it is advisable to refrain from this type of publication, which is a waste of time not very profitable, both to the one's reputation and for the likely rejection by the most accredited scientific journals. The publication of a case report must follow the same rules set for a "genuine article", with the difference that in the introduction has to be immediately highlighted the particularity of the experience, possibly framing it in common knowledge. The presentation of the clinical and strategic aspects is the result of a careful reflection on the surgical experience lived, because its exposure has to be very different from an extemporaneous oral presentation, which is by nature open to a free immediate confrontation in oral discussions that follow.

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In Section 1, spreading of small liquid drops over thin dry porous layers is investigated from both theoretical and experimental points of view [V.M. Starov, S.R. Kosvintsev, V.D. Sobolev, M.G. Velarde, S.A. Zhdanov, J. Colloid Interface Sci. 252 (2002) 397]. Drop motion over a porous layer is caused by an interplay of two processes: (a) the spreading of the drop over already saturated parts of the porous layer, which results in an expanding of the drop base, and (b) the imbibition of the liquid from the drop into the porous substrate, which results in a shrinkage of the drop base and an expanding of the wetted region inside the porous layer. As a result of these two competing processes, the radius of the drop goes through a maximum value over time. A system of two differential equations has been derived to describe the evolution with time of radii of both the drop base and the wetted region inside the porous layer. This system includes two parameters, one accounts for the effective lubrication coefficient of the liquid over the wetted porous substrate, and the other is a combination of permeability and effective capillary pressure inside the porous layer. Two additional experiments were used for an independent determination of these two parameters. The system of differential equations does not include any fitting parameter after these two parameters are determined. Experiments were carried out on the spreading of silicone oil drops over various dry microfiltration membranes (permeable in both normal and tangential directions). The time evolution of the radii of both the drop base and the wetted region inside the porous layer were monitored. All experimental data fell on two universal curves if appropriate scales are used with a plot of the dimensionless radii of the drop base and of the wetted region inside the porous layer on dimensionless time. The predicted theoretical relationships are two universal curves accounting quite satisfactory for the experimental data. According to theory predictions [1]: (i) the dynamic contact angle dependence on the same dimensionless time as before should be a universal function, and (ii) the dynamic contact angle should change rapidly over an initial short stage of spreading and should remain a constant value over the duration of the rest of the spreading process. The constancy of the contact angle on this stage has nothing to do with hysteresis of the contact angle: there is no hysteresis in the system under investigation. These conclusions again are in good agreement with experimental observations [V.M. Starov, S.R. Kosvintsev, V.D. Sobolev, M.G. Velarde, S.A. Zhdanov, J. Colloid Interface Sci. 252 (2002) 397]. In Section 2, experimental investigations are reviewed on the spreading of small drops of aqueous SDS solutions over dry thin porous substrates (nitrocellulose membranes) in the case of partial wetting [S. Zhdanov, V. Starov, V. Sobolev, M. Velarde, Spreading of aqueous SDS solutions over nitrocellulose membranes. J. Colloid Interface Sci. 264 (2003) 481-489]. The time evolution was monitored of the radii of both the drop base and the wetted area inside the porous substrate. The total duration of the spreading process was subdivided into three stages-the first stage: the drop base expands until the maximum value of the drop base is reached; the contact angle rapidly decreases during this stage; the second stage: the radius of the drop base remains constant and the contact angle decreases linearly with time; the third stage: the drop base shrinks and the contact angle remains constant. The wetted area inside the porous substrate expends during the whole spreading process. Appropriate scales were used with a plot of the dimensionless radii of the drop base, of the wetted area inside the porous substrate, and the dynamic contact angle on the dimensionless time. Experimental data showed [S. Zhdanov, V. Starov, V. Sobolev, M. Velarde, Spreading of aqueous SDS solutions over nitrocellulose membranes. J. Colloid Interface Sci. 264 (2003) 481-489]: the overall time of the spreading of drops of SDS solution over dry thin porous substrates decreases with the increase of surfactant concentration; the difference between advancing and hydrodynamic receding contact angles decreases with the surfactant concentration increase; the constancy of the contact angle during the third stage of spreading has nothing to do with the hysteresis of contact angle, but determined by the hydrodynamic reasons. It is shown using independent spreading experiments of the same drops on nonporous nitrocellulose substrate that the static receding contact angle is equal to zero, which supports the conclusion on the hydrodynamic nature of the hydrodynamic receding contact angle on porous substrates. In Section 3, a theory is developed to describe a spontaneous imbibition of surfactant solutions into hydrophobic capillaries, which takes into account the micelle disintegration and the concentration decreasing close to the moving meniscus as a result of adsorption, as well as the surface diffusion of surfactant molecules [N.V. Churaev, G.A. Martynov, V.M. Starov, Z.M. Zorin, Colloid Polym. Sci. 259 (1981) 747]. The theory predictions are in good agreement with the experimental investigations on the spontaneous imbibition of the nonionic aqueous surfactant solution, Syntamide-5, into hydrophobized quartz capillaries. A theory of the spontaneous capillary rise of surfactant solutions in hydrophobic capillaries is presented, which connects the experimental observations with the adsorption of surfactant molecules in front of the moving meniscus on the bare hydrophobic interface [V.J. Starov, Colloid Interface Sci. 270 (2003)]. In Section 4, capillary imbibition of aqueous surfactant solutions into dry porous substrates is investigated from both theoretical and experimental points of view in the case of partial wetting [V. Straov, S. Zhdanov, M. Velarde, J. Colloid Interface Sci. 273 (2004) 589]. Cylindrical capillaries are used as a model of porous media for theoretical treatment of the problem. It is shown that if an averaged pore size of the porous medium is below a critical value, then the permeability of the porous medium is not influenced by the presence of surfactants at any concentration: the imbibition front moves exactly in the same way as in the case of the imbibition of the pure water. The critical radius is determined by the adsorption of the surfactant molecules on the inner surface of the pores. If an averaged pore size is bigger than the critical value, then the permeability increases with surfactant concentration. These theoretical conclusions are in agreement with experimental observations. In Section 5, the spreading of surfactant solutions over hydrophobic surfaces is considered from both theoretical and experimental points of view [V.M. Starov, S.R. Kosvintsev, M.G. Velarde, J. Colloid Interface Sci. 227 (2000) 185]. Water droplets do not wet a virgin solid hydrophobic substrate. It is shown that the transfer of surfactant molecules from the water droplet onto the hydrophobic surface changes the wetting characteristics in front of the drop on the three-phase contact line. The surfactant molecules increase the solid-vapor interfacial tension and hydrophilise the initially hydrophobic solid substrate just in front of the spreading drop. This process causes water drops to spread over time. The time of evolution of the spreading of a water droplet is predicted and compared with experimental observations. The assumption that surfactant transfer from the drop surface onto the solid hydrophobic substrate controls the rate of spreading is confirmed by experimental observations. In Section 6, the process of the spontaneous spreading of a droplet of a polar liquid over solid substrate is analyzed in the case when amphiphilic molecules (or their amphiphilic fragments) of the substrate surface layer are capable of overturning, resulting in a partial hydrophilisation of the surface [V.M. Starov, V.M. Rudoy, V.I. Ivanov, Colloid J. (Russian Academy of Sciences English Transaction) 61 (3) (1999) 374]. Such a situation may take place, for example, during contact of an aqueous droplet with the surface of a polymer whose macromolecules have hydrophilic side groups capable of rotating around the backbone and during the wetting of polymers containing surface-active additives or Langmuir-Blodgett films composed of amphiphilic molecules. It was shown that droplet spreading is possible only if the lateral interaction between neighbouring amphiphilic molecules (or groups) takes place. This interaction results in the tangential transfer of "the overturning state" to some distance in front of the advancing three-phase contact line making it partially hydrophilic. The quantitative theory describing the kinetics of droplet spreading is developed with allowance for this mechanism of self-organization of the surface layer of a substrate in the contact with a droplet.

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In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of noninvasive cardiac imaging modalities.After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlPOSITRON EMISSION TOMOGRAPHY FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY: An Evidence-Based AnalysisMAGNETIC RESONANCE IMAGING FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY: An Evidence-Based Analysis The objective of this analysis is to assess the effectiveness and cost-effectiveness of cardiovascular magnetic resonance imaging (cardiac MRI) for the assessment of myocardial viability. To evaluate the effectiveness of cardiac MRI viability imaging, the following outcomes were examined: the diagnostic accuracy in predicting functional recovery and the impact of cardiac MRI viability imaging on prognosis (mortality and other patient outcomes). CONDITION AND TARGET POPULATION LEFT VENTRICULAR SYSTOLIC DYSFUNCTION AND HEART FAILURE: Heart failure is a complex syndrome characterized by the heart's inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality. In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD) () is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997. IN GENERAL, THERE ARE THREE OPTIONS FOR THE TREATMENT OF HEART FAILURE: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or, in some cases, through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure. Left ventricular dysfunction may be permanent, due to the formation of myocardial scar, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically: dobutamine echocardiography (echo),stress echo with contrast,SPECT using either technetium or thallium,cardiac magnetic resonance imaging (cardiac MRI), andpositron emission tomography (PET). Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 - 10 µg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability. Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium. SPECT: SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (&gt; 10% increase in tracer uptake) on the re-injection images. The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (&gt; 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%. There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%. Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG). During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. This collision results in annihilation where the combined mass of the positron and electron is converted into energy in the form of two 511 keV gamma rays, which are then emitted in opposite directions (180 degrees) and captured by an external array of detector elements in the PET gantry. Computer software is then used to convert the radiation emission into images. The system is set up so that it only detects coincident gamma rays that arrive at the detectors within a predefined temporal window, while single photons arriving without a pair or outside the temporal window do not active the detector. This allows for increased spatial and contrast resolution. Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. (ABSTRACT TRUNCATED)

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Dr. Ibrahim Fawzy Hassan Local Host and QCCC 2019 Conference Chair Dear Friends and Colleagues, It is an honour to welcome everyone to the first Qatar Critical Care Conference (QCCC). It has been a long journey to make it happen, but this event has been much awaited by the local critical care community. Over the last few years, we have hosted a number of related events of various scales, ranging from Critical Care Grand Rounds targeting Hamad Medical Corporation (HMC) critical care clinicians, ran specialised courses, through to organising an international medical conference on extracorporeal life support in 2017.<sup1</sup This inaugural QCCC event is the fruit of much planning and collaboration. The programme spans from 28<supth</sup to 31<supst</sup October 2019 and consists of two days of pre-conference workshops and two days for the main conference. The vast majority of the pre-conference workshops will be held in the state-of-the-art ITQAN Clinical Simulation and Innovation Centre located within Hamad bin Khalifa Medical City. Although the facility is yet to be offically inaugurated and opened, we have the privilege to have been granted access to it as a way of showcasing our forthcoming continuing professional development capability. "Itqan" in Arabic means <iquality and striving for perfection</i, which is very much in line with the mission of our established Critical Care Network (CCNW).<sup2</sup Simulation-based education is an area in which we have started to be very active through various immersive courses as well as innovative technological developments to train our extracorporeal membrane oxygenation (ECMO) specialists.<sup3,4</sup The scientific part of the conference will be hosted in the iconic Sheraton Grand Doha Resort &amp; Convention Hotel in the West Bay area. It includes a varied selection of topics presented by many renowned experts in their respective domain. This comprehensive programme with a line-up of lectures and workshops addressing e-CPR, ECMO simulation, ECMO cannulation, hemodynamics and so much more will facilitate the exchange of knowledge and experiences to improve patient care in Qatar and beyond. We anticipate that the programme will appeal to a broad audience and hence will bring together clinicians from all professions involved with caring for acutely ill patients. It is QCCC's aim to connect and explore new insights and expertise at a national and international level through networking with other professionals in a multidisciplinary setting. We hope that during this event many fruitful discussions will take place and that it will enhance opportunities for collaboration to develop everyone's practice in critical care. The HMC Critical Care family has a capacity of 163 and 109 intensive care unit (UCI) beds, respectively for adult and paediatric patients, across 7 hospitals spread throughout Qatar. These numbers are complemented by another 52 adult and paediatric beds from non-HMC hospitals. This gives us a national ICU bed capacity of 11.8 per 100,000 inhabitants considering a current population of nearly 2,750,000 inhabitants.<sup5</sup Although this number remains below the international benchmark which can be considered to be around 15/100,000 population,<sup6</sup this quota in Qatar has more than quadrupled over the last ten years, which represents a very significant improvement in the care that can be provided to acutely ill patients. Within HMC only, it is supported by a workforce of 159 intensive care physicians, 1122 intensive care nurses, and many other clinical staff, all of whom undergo a well regulated programme of continuing professional development and are licensed to practise by the Qatar Council for Healthcare Practitioners (QCHP).<sup7</sup The work they do across the various sites is coordinated and monitored by the CCNW<sup2</sup who ensures the best level of care, up-to-date technology, and evidence-based practices are consistently adopted for the wellbeing of our patients. Once again, on behalf of the Scientific and Organizing Committees, it is my pleasure to welcome you all to Doha and we hope that you enjoy and gain meaningful insights during the conference regarding our local critical care setting and practices, but also learn from the experiences and best practices shared by our international guest speakers. Prof. Guillaume Alinier Guest Managing Editor, Qatar Medical Journal QCCC Special Issue and Abstracts Chair of the QCCC Scientific Committee. Dear Contributors and Conferences Delegates, Welcome to this special issue of the Qatar Medical Journal (QMJ) which has been dedicated to the inaugural conference of the Hamad Medical Corporation (HMC) Qatar Critical Care Network (QCCN) which celebrates its fifth anniversary in 2019. I would like to start by thanking everyone who has supported this arduous publication endeavour through their extended abstract submission(s) and the reviewers for the valuable feedback they have provided to the authors to ensure this publication is a representative legacy of the calibre of this conference which includes many local and international experts in their respective field of practice or interest. All the accepted abstracts are being published Open Access thanks to the support of the conference sponsors and this contributes greatly to the sharing of experiences and best practices worldwide, but also showcases the good work that is being done in Qatar in the domain of critical care thanks to the work of dedicated clinicians and the leadership of the CCNW.<sup2</sup Being the Guest Managing Editor of the special issue of a journal is an honour but also an arduous task, especially when a large number of submissions from international authors needs to be handled. It is the second time that I have accepted to take on that role for Qatar Medical Journal as the previous time was in 2017 on the occasion of hosting the South West Asia and African Chapter (SWAAC) of the Extracorporeal Life Support Organisation (ELSO) in Doha.<sup1</sup This was only a couple of years after HMC had established its Extracorporeal Membrane Oxygenation (ECMO) programme, and it was a very successful event with many of its associated open access publications having been downloaded hundreds of times from the QScience.com publishing platform. Working on this new Special Issue really made me reflect on how the domain of critical care is vast and encompasses so many aspects of patient care and so many professions and specialties. The topics of the abstracts published in this special issue of QMJ cover dietetics,<sup8</sup sepsis,<sup9</sup delirium,<sup10,11</sup physical therapy,<sup12</sup end of life care and organ donation,<sup13,14</sup dealing with families,<sup15</sup as well as education and training of clinicians,<sup16,17</sup to only highlight a few. Critical care is fast moving as new clinical practices and technological innovations are adopted and contribute to continuously improving patient care. This is especially true in Qatar where significant investments are constantly made to develop and support healthcare in a strategic way.<sup18</sup At HMC, the critical care phase that some patients have to go through so their medical needs can be met is well integrated across all stakeholder departments that can possibly be involved.<sup2</sup The patient's journey through the healthcare system can be seen as a continuum of care facilitated by the fact that all parties involved belong to the same overarching organisation, HMC, which is the government funded main provider of secondary and tertiary healthcare in Qatar. This means that from initial contact with the Ambulance Service bringing a patient to the Emergency Department for example, right through to rehabilitation and even possible access upon discharge to a mobile healthcare service supported by family physicians, nurses, and paramedics, patients can expect the same high standards of care.<sup19</sup Critical care provision relies on multidisciplinary communication during transition of care as well as during any acute episode. This needs to be underpinned by medical knowledge and understanding of the potential contributions of other professions as nothing can be left to chance when a patient's life is hanging by a thread. The present collection of editorials and abstracts brings different perspectives on a broad range of topics which should be highly relevant to all clinicians involved with critical care and contribute to improving patient outcome and satisfaction, and hence that of the multidisciplinary team members also involved in caring for them. We hope that the Qatar Medical Journal Special Issue publications on critical care meets your needs and expectations. The complete record of QCCC publications including additional open access abstracts and editorials relating to this conference will be made available in Qatar Medical Journal at the following link: https://www.qscience.com/content/journals/qmj. Thanks again to everyone for your contributions, and beyond our email communications, I now hope to meet you in person during the conference!

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<bObjective:</b To analyze the effects of transient receptor potential vanilloid type 4 (TRPV4) activation on the function and endothelial-to-mesenchymal transition (EndMT) of human umbilical vein endothelial cells (HUVECs), as well as to explore the effects of TRPV4 activation on blood perfusion and survival of rat perforator flap and the mechanism. <bMethods:</b The experimental research methods were used. The 3<suprd</sup to 6<supth</sup passages of HUVECs were used for experiments and divided into 0.5 μmol/L 4α-phorbol 12, 13-didecanoate (4αPDD) group, 1.0 μmol/L 4αPDD group, 3.0 μmol/L 4αPDD group, 10.0 μmol/L 4αPDD group, and phosphate buffer solution (PBS) group, which were cultivated in corresponding final molarity of 4αPDD and PBS, respectively. The cell proliferation activity at 6 and 12 h of culture was detected using cell counting kit-8 (CCK-8). Another batch of cells was acquired and divided into PBS group, 1 μmol/L 4αPDD group, and 3 μmol/L 4αPDD group, which were treated similarly as described before and then detected for cell proliferation activity at 6, 12, 24, and 48 h of culture. The residual scratch area of cells at post scratch hour (PSH) 12, 24, and 48 was detected by scratch test, and the percentage of the residual scratch area was calculated. The number of migrated cells at 24 and 48 h of culture was detected by Transwell experiment. The tube-formation assay was used to measure the number of tubular structures at 4 and 8 h of culture. The protein expressions of E-cadherin, N-cadherin, Slug, and Snail at 24 h of culture were detected by Western blotting. All the sample numbers in each group at each time point in vitro experiments were 3. A total of 36 male Sprague-Dawley rats aged 8 to 10 weeks were divided into delayed flap group, 4αPDD group, and normal saline group according to the random number table, with 12 rats in each group, and iliolumbar artery perforator flap models on the back were constructed. The flap surgical delay procedure was only performed in the rats in delayed flap group one week before the flap transfer surgery. Neither rats in 4αPDD group nor normal saline group had flap surgical delay; instead, they were intraperitoneally injected with 4αPDD and an equivalent mass of normal saline, respectively, at 10 min before, 24 h after, and 48 h after the surgery. The general state of flap was observed on post surgery day (PSD) 0 (immediately), 1, 4, and 7. The flap survival rates were assessed on PSD 7. The flap blood perfusion was detected by laser speckle contrast imaging technique on PSD 1, 4, and 7. The microvascular density in the flap's choke vessel zone was detected by immunohistochemical staining. All the sample numbers in each group at each time point in vivo experiments were 12. Data were statistically analyzed with analysis of variance for factorial design, analysis of variance for repeated measurement, one-way analysis of variance, least significant difference <it</i test, and Bonferroni correction. <bResults:</b At 6 and 12 h of culture, there were no statistically significant differences in cell proliferation activity in the overall comparison among PBS group, 0.5 μmol/L 4αPDD group, 1.0 μmol/L 4αPDD group, 3.0 μmol/L 4αPDD group, and 10.0 μmol/L 4αPDD group (<iP</i&gt;0.05). At 6, 12, 24, and 48 h of culture, there were no statistically significant differences in cell proliferation activity in the overall comparison among PBS group, 1 μmol/L 4αPDD group, and 3 μmol/L 4αPDD group (<iP</i&gt;0.05). At PSH 12, the percentages of the residual scratch area of cells in 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD group were close to that in PBS group (<iP</i&gt;0.05). At PSH 24 and 48, compared with those in PBS group, the percentages of the residual scratch area of cells in 3 μmol/L 4αPDD group were significantly decreased (with <it</i values of 2.83 and 2.79, respectively, <iP</i&lt;0.05), while the percentages of the residual scratch area of cells in 1 μmol/L 4αPDD group showed no significant differences (<iP</i&gt;0.05). At 24 h of culture, the number of migrated cells in 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD group were close to that in PBS group (<iP</i&gt;0.05). At 48 h of culture, the number of migrated cells in 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD groups were significantly greater than that in PBS group (with <it</i values of 6.20 and 9.59, respectively, <iP</i&lt;0.01). At 4 h of culture, the numbers of tubular structures of cells in 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD group were significantly greater than that in PBS group (with <it</i values of 4.68 and 4.95, respectively, <iP</i&lt;0.05 or &lt;0.01). At 8 h of culture, the numbers of tubular structures of cells in 1 μmol/L 4αPDD and 3 μmol/L 4αPDD groups were similar to that in PBS group (<iP</i&gt;0.05). At 24 h of culture, compared with those in PBS group, the protein expression level of E-cadherin of cells in 3 μmol/L 4αPDD group was significantly decreased (<it</i=5.13, <iP</i&lt;0.01), whereas there was no statistically significant difference in the protein expression level of E-cadherin of cells in 1 μmol/L 4αPDD group (<iP</i&gt;0.05); the protein expression level of N-cadherin of cells in 3 μmol/L 4αPDD group was significantly increased (<it</i=4.93, <iP</i&lt;0.01), whereas there was no statistically significant difference in the protein expression level of N-cadherin of cells in 1 μmol/L 4αPDD group (<iP</i&gt;0.05); the protein expression levels of Slug of cells in 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD group were significantly increased (with <it</i values of 3.85 and 6.52, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01); and the protein expression level of Snail of cells in 3 μmol/L 4αPDD group was significantly increased (<it</i=4.08, <iP</i&lt;0.05), whereas there was no statistically significant difference in the protein expression level of Snail of cells in 1 μmol/L 4αPDD group (<iP</i&gt;0.05). There were no statistically significant differences in the protein expression levels of E-cadherin, N-cadherin, Slug, or Snail of cells between 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD group (<iP</i&gt;0.05). The general condition of flaps of rats in the three groups was good on PSD 0. On PSD 1, the flaps of rats in the three groups were basically similar, with bruising and swelling at the distal end. On PSD 4, the swelling of flaps of rats in the three groups subsided, and the distal end turned dark brown and necrosis occurred, with the area of necrosis in flaps of rats in normal saline group being larger than the areas in 4αPDD group and delayed flap group. On PSD 7, the necrotic areas of flaps of rats in the 3 groups were fairly stable, with the area of necrosis at the distal end of flap of rats in delayed flap group being the smallest. On PSD 7, the flap survival rates of rats in 4αPDD group ((80±13)%) and delayed flap group ((87±9)%) were similar (<iP</i&gt;0.05), and both were significantly higher than (70±11)% in normal saline group (with <it</i values of 2.24 and 3.65, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01). On PSD 1, the overall blood perfusion signals of rats in the 3 groups were basically the same, and the blood perfusion signals in the choke vessel zone were relatively strong, with a certain degree of underperfusion at the distal end. On PSD 4, the boundary between the surviving and necrotic areas of flaps of rats in the 3 groups became evident, and the blood perfusion signals in the choke vessel zone were improved, with the normal saline group's distal hypoperfused area of flap being larger than the areas in delayed flap group and 4αPDD group. On PSD 7, the blood perfusion signals of overall flap of rats had generally stabilized in the 3 groups, with the intensity of blood perfusion signal in the choke vessel zone and overall flap of rats in delayed flap group and 4αPDD group being significantly greater than that in normal saline group. On PSD 7, the microvascular density in the choke vessel zone of flap of rats in 4αPDD group and delayed flap group were similar (<iP</i&gt;0.05), and both were significantly higher than that in normal saline group (with <it</i values of 4.11 and 5.38, respectively, <iP</i&lt;0.01). <bConclusions:</b After activation, TRPV4 may promote the migration and tubular formation of human vascular endothelial cells via the EndMT pathway, leading to the enhanced blood perfusion of perforator flap and microvascular density in the choke vessel zone, and therefore increase the flap survival rate.

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Methapyrilene hydrochloride is a histamine H(1)-receptor antagonist that was an active ingredient in many over-the-counter cold and allergy medications. In the mid- to late 1970s, studies in rats suggested that methapyrilene hydrochloride was a hepatocarcinogen, and the drug was removed from these preparations. In most cases, methapyrilene hydrochloride was replaced by pyrilamine maleate, a structurally similar analogue. As part of a program to investigate mechanisms of toxicity whereby structurally similar chemicals produce different toxicities, these chemicals were studied for induction of cell proliferation and protein alterations by two-dimensional gel electrophoresis in the liver of F344/N rats. A complete toxicologic evaluation was not needed for this research-oriented study. Rather, the goal of the present study was to provide retrospective data from subchronic toxicity studies with the known rat carcinogen methapyriline hydrochloride that could then be used to predict the potential carcinogenicity of unknown chemical agents and that could also be compared with similar data on the structural analogue pyrilamine maleate. Pyrilamine maleate differs from methapyrilene hydrochloride in the substitution of the thienyl ring with a paramethoxyphenyl ring. Pyrilamine maleate has been shown to produce an equivocal increase in the incidences of liver neoplasms in rats in 2-year feed studies, but only at 2,000 ppm, indicating that its potency, if any, to produce neoplasms is much less than that of methapyriline hydrochloride. The hepatocarcinogenic peroxisome proliferator Wy-14,643 was included in this study as a positive control that is known to induce cell proliferation, as well as protein alterations, in the liver. In the 14-week study of methapyrilene hydrochloride, groups of 40 male F344/N rats were given 0, 50, 100, 250, or 1,000 ppm methapyrilene hydrochloride, 1,000 ppm pyrilamine maleate (negative control), or 50 ppm Wy-14,643 ( positive control) in feed. Rats in all groups were administered bromodeoxyuridine (BrdU) by osmotic minipump for the assessment of hepatocyte proliferation. Ten rats from each group were evaluated on days 15, 29, and 43 and at 14 weeks. At these times, samples of liver tissue were analyzed for evidence of cell proliferation via BrdU labeling and proliferating cell nuclear antigen (PCNA) labeling. There were no exposure-related deaths. Low mean body weights were generally observed in the 1,000 ppm methapyriline hydrochloride group and in the positive control group. Final mean body weights and mean body weight gains of rats exposed to 1,000 ppm methapyrilene hydrochloride were significantly less than those of the untreated control group at all time points. The final mean body weights of rats in the positive control group were significantly less than those of the untreated control group for rats evaluated on days 29 and 43 and at week 14; the mean body weight gains of rats in the positive control group were significantly less than those of the untreated control group on day 29 and at week 14. Feed consumption by rats exposed to 1,000 ppm methapyrilene hydrochloride was significantly less than that by the untreated control group throughout the study. The predominant clinical observation related to methapyrilene hydrochloride exposure was thinness in rats exposed to 1,000 ppm; this finding was first observed on day 29. On days 29 and 43 and at 14 weeks, the absolute liver weights of rats exposed to 1,000 ppm methapyrilene hydrochloride were significantly less than those of the untreated control group. At all time points, the relative liver weights of rats exposed to 1,000 ppm methapyrilene hydrochloride and the absolute and relative liver weights of positive control rats were significantly greater than those of the untreated control group. No significant differences in liver weights were observed between the negative and untreated control groups at any time point. Hepatic lesions were observed predominantly in the 250 and 1,000 ppm methapyrilene hydrochloride groups and in the positive control group. The incidences of bile duct hyperplasia, hepatocyte necrosis, hepatocyte mitosis, and hepatocyte hypertrophy in rats in the 1,000 ppm group were significantly greater than those in the untreated control group at all time points. The severities of hepatocyte hypertrophy and hepatocyte mitosis in 1,000 ppm rats were generally mild to moderate; the lesions occurring in 250 ppm animals were less severe. At each time point, the incidence of bile duct hyperplasia in 250 ppm rats was significantly greater than that in the untreated control group. The incidences of hepatocyte mitosis on days 15 and 29 and the incidences of hepatocyte necrosis on days 29 and 43 in rats in the 250 ppm group were significantly greater than those in the untreated control group. Incidences of pigmentation in the 250 and 1,000 ppm methapyrilene hydrochloride groups were significantly greater than those in the untreated control group on days 29 and 43 and at 14 weeks. In the positive control group, the incidences of granulomatous inflammation were significantly greater than those in the untreated control group on days 15, 29, and 43. The incidences of hepatocyte hypertrophy and hepatocyte mitosis in the positive control group were significantly greater than those in the untreated control group on days 15, 29, and 43. The incidence of hepatocyte hypertrophy was also significantly increased in the positive control group at 14 weeks. The severity of hepatocyte hypertrophy in the 1,000 ppm methapyrilene hydrochloride group was generally greater than that in the positive control group at each time point. In general, methapyriline hydrochloride produced a dramatic and sustained increase in hepatic cell proliferation over 14 weeks, whereas pyrilamine maleate at the same concentration produced few if any effects. Wy-14,643 also induced a large increase in cell proliferation which declined over time, as has been observed in previous studies. The mean BrdU labeling indexes of the 250 and 1,000 ppm methapyrilene hydrochloride groups were generally significantly greater than those of the untreated controls at all time points. In the negative control group, the BrdU labeling index was significantly less than that of the untreated control group on day 29. The BrdU labeling index in the positive control group was significantly greater than that of the untreated control group at all time points. On day 43 and at week 14, the mean PCNA labeling indexes of the 1,000 ppm methapyrilene hydrochloride group were significantly greater than those of the untreated control group. The mean PCNA labeling indexes of the negative control group were significantly less than those of the untreated control group on days 29 and 43. On day 29, the mean PCNA labeling index of the positive control group was significantly greater than that of the untreated control group. The mitotic indexes of the 1,000 ppm methapyrilene hydrochloride group were significantly greater than those of the untreated control group at all time points. The mitotic indexes of the 250 ppm group were significantly greater than those of the untreated control group on day 43 and at week 14. At least 32 proteins underwent significant abundance changes at the highest exposure concentration of methapyrilene hydrochloride, and 39 protein changes were observed in the positive control group. Many, but not all, of the protein changes in the methapyrilene hydrochloride-exposed animals also occurred in the positive control group. Treatment with pyrilamine maleate produced no significant quantitative protein changes, as judged by the same criteria used for methapyrilene hydrochloride and Wy-14,643. Methapyrilene hydrochloride produced covalent modification of mitochondrial proteins as measured by the charge modification index. PCNA abundance in liver samples from the 250 and 1,000 ppm methapyrilene hydrochloride exposure groups on day 43 was significantly greater than that of the untreated control group. Results of tests for induction of mutagenicity by methapyrilene hydrochloride were negative in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and in L5178Y mouse lymphoma cells, with and without S9 metabolic activation. However, positive responses were obtained in cytogenetic tests with cultured Chinese hamster ovary cells, in which methapyrilene hydrochloride induced sister chromatid exchanges and chromosomal aberrations. The increases in sister chromosome exchanges were obtained with and without S9, but chromosomal aberrations were increased only in the presence of S9. In summary, the significance of the increased hepatic cell proliferation and the protein alterations observed in this study is not definite, but may be of predictive value for assessing the toxicity and carcinogenicity of chemicals in preclinical assays. A chemical which does not produce an increase in cell proliferation or a large number of protein changes may be considered safer than a similar chemical that produces many such changes.

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Sudden hearing loss is a frightening symptom that often prompts an urgent or emergent visit to a health care provider. It is frequently, but not universally, accompanied by tinnitus and/or vertigo. Sudden sensorineural hearing loss affects 5 to 27 per 100,000 people annually, with about 66,000 new cases per year in the United States. This guideline update provides evidence-based recommendations for the diagnosis, management, and follow-up of patients who present with sudden hearing loss. It focuses on sudden sensorineural hearing loss in adult patients aged 18 and over and primarily on those with idiopathic sudden sensorineural hearing loss. Prompt recognition and management of sudden sensorineural hearing loss may improve hearing recovery and patient quality of life. The guideline update is intended for all clinicians who diagnose or manage adult patients who present with sudden hearing loss. The purpose of this guideline update is to provide clinicians with evidence-based recommendations in evaluating patients with sudden hearing loss and sudden sensorineural hearing loss, with particular emphasis on managing idiopathic sudden sensorineural hearing loss. The guideline update group recognized that patients enter the health care system with sudden hearing loss as a nonspecific primary complaint. Therefore, the initial recommendations of this guideline update address distinguishing sensorineural hearing loss from conductive hearing loss at the time of presentation with hearing loss. They also clarify the need to identify rare, nonidiopathic sudden sensorineural hearing loss to help separate those patients from those with idiopathic sudden sensorineural hearing loss, who are the target population for the therapeutic interventions that make up the bulk of the guideline update. By focusing on opportunities for quality improvement, this guideline should improve diagnostic accuracy, facilitate prompt intervention, decrease variations in management, reduce unnecessary tests and imaging procedures, and improve hearing and rehabilitative outcomes for affected patients. Consistent with the American Academy of Otolaryngology-Head and Neck Surgery Foundation's <iClinical Practice Guideline Development Manual, Third Edition</i, the guideline update group was convened with representation from the disciplines of otolaryngology-head and neck surgery, otology, neurotology, family medicine, audiology, emergency medicine, neurology, radiology, advanced practice nursing, and consumer advocacy. A systematic review of the literature was performed, and the prior clinical practice guideline on sudden hearing loss was reviewed in detail. Key action statements (KASs) were updated with new literature, and evidence profiles were brought up to the current standard. Research needs identified in the original clinical practice guideline and data addressing them were reviewed. Current research needs were identified and delineated. The guideline update group made strong recommendations for the following: clinicians should distinguish sensorineural hearing loss from conductive hearing loss when a patient first presents with sudden hearing loss (KAS 1); clinicians should educate patients with sudden sensorineural hearing loss about the natural history of the condition, the benefits and risks of medical interventions, and the limitations of existing evidence regarding efficacy (KAS 7); and clinicians should counsel patients with sudden sensorineural hearing loss who have residual hearing loss and/or tinnitus about the possible benefits of audiological rehabilitation and other supportive measures (KAS 13). These strong recommendations were modified from the initial clinical practice guideline for clarity and timing of intervention. The guideline update group made strong recommendation against the following: clinicians should <inot</i order routine computed tomography of the head in the initial evaluation of a patient with presumptive sudden sensorineural hearing loss (KAS 3); clinicians should <inot</i obtain routine laboratory tests in patients with sudden sensorineural hearing loss (KAS 5); and clinicians should <inot</i routinely prescribe antivirals, thrombolytics, vasodilators, or vasoactive substances to patients with sudden sensorineural hearing loss (KAS 11). The guideline update group made recommendations for the following: clinicians should assess patients with presumptive sudden sensorineural hearing loss through history and physical examination for bilateral sudden hearing loss, recurrent episodes of sudden hearing loss, and/or focal neurologic findings (KAS 2); in patients with sudden hearing loss, clinicians should obtain, or refer to a clinician who can obtain, audiometry as soon as possible (within 14 days of symptom onset) to confirm the diagnosis of sudden sensorineural hearing loss (KAS 4); clinicians should evaluate patients with sudden sensorineural hearing loss for retrocochlear pathology by obtaining a magnetic resonance imaging or auditory brainstem response (KAS 6); clinicians should offer, or refer to a clinician who can offer, intratympanic steroid therapy when patients have incomplete recovery from sudden sensorineural hearing loss 2 to 6 weeks after onset of symptoms (KAS 10); and clinicians should obtain follow-up audiometric evaluation for patients with sudden sensorineural hearing loss at the conclusion of treatment and within 6 months of completion of treatment (KAS 12). These recommendations were clarified in terms of timing of intervention and audiometry, as well as method of retrocochlear workup. The guideline update group offered the following KASs as options: clinicians may offer corticosteroids as initial therapy to patients with sudden sensorineural hearing loss within 2 weeks of symptom onset (KAS 8); clinicians may offer, or refer to a clinician who can offer, hyperbaric oxygen therapy combined with steroid therapy within 2 weeks of onset of sudden sensorineural hearing loss (KAS 9a); and clinicians may offer, or refer to a clinician who can offer, hyperbaric oxygen therapy combined with steroid therapy as salvage therapy within 1 month of onset of sudden sensorineural hearing loss (KAS 9b). Incorporation of new evidence profiles to include quality improvement opportunities, confidence in the evidence, and differences of opinion Included 10 clinical practice guidelines, 29 new systematic reviews, and 36 new randomized controlled trials Highlights the urgency of evaluation and initiation of treatment, if treatment is offered, by emphasizing the time from symptom occurrence Clarification of terminology by changing potentially unclear statements; use of the term <isudden sensorineural hearing loss</i to mean idiopathic sudden sensorineural hearing loss to emphasize that over 90% of sudden sensorineural hearing loss is idiopathic sudden sensorineural hearing loss and to avoid confusion in nomenclature for the reader Changes to the key action statements (KASs) from the original guideline: KAS 1: When a patient first presents with sudden hearing loss, conductive hearing loss should be distinguished from sensorineural. KAS 2: The utility of history and physical examination when assessing for modifying factors is emphasized. KAS 3: The word <iroutine</i is added to clarify that this statement addresses a nontargeted head computed tomography scan that is often ordered in the emergency room setting for patients presenting with sudden hearing loss. It does not refer to targeted scans such as a temporal bone computed tomography scan to assess for temporal bone pathology. KAS 4: The importance of audiometric confirmation of hearing status as soon as possible and within 14 days of symptom onset is emphasized. KAS 5: New studies were added to confirm the lack of benefit of nontargeted laboratory testing in sudden sensorineural hearing loss. KAS 6: Audiometric follow-up is excluded as a reasonable workup for retrocochlear pathology. Magnetic resonance imaging, computed tomography scan if magnetic resonance imaging cannot be done, or, secondarily, auditory brainstem response evaluation are the modalities recommended. A time frame for such testing is not specified, nor is it specified which clinician should be ordering this workup; however, it is implied that it would be the general or subspecialty otolaryngologist. KAS 7: The importance of shared decision making is highlighted, and salient points are emphasized. KAS 8: The option for corticosteroid intervention within 2 weeks of symptom onset is emphasized. KAS 9: Changed to KAS 9a and 9b; hyperbaric oxygen therapy remains an option but only when combined with steroid therapy for either initial treatment (9a) or for salvage therapy (9b). The timing is within 2 weeks of onset for initial therapy and within 1 month of onset of sudden sensorineural hearing loss for salvage therapy. KAS 10: Intratympanic steroid therapy for salvage is recommended within 2 to 6 weeks following onset of sudden sensorineural hearing loss. The time to treatment is defined and emphasized. KAS 11: Antioxidants were removed from the list of interventions that the clinical practice guideline recommends against using. KAS 12: Follow-up audiometry at conclusion of treatment and also within 6 months posttreatment is added. KAS 13: This statement on audiologic rehabilitation includes patients who have residual hearing loss and/or tinnitus who may benefit from treatment. Addition of an algorithm outlining KASs Enhanced emphasis on patient education and shared decision making with tools provided to assist in the same.

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The aim of this review was to determine the effectiveness of screening mammography in women aged 40 to 49 years at average risk for breast cancer. The effectiveness of screening mammography in women aged over 50 years has been established, yet the issue of screening in women aged 40 to 49 years is still unsettled. The Canadian Task Force of Preventive Services, which sets guidelines for screening mammography for all provinces, supports neither the inclusion nor the exclusion of this screening procedure for 40- to 49-year-old women from the periodic health examination. In addition to this, 2 separate reviews, one conducted in Quebec in 2005 and the other in Alberta in 2000, each concluded that there is an absence of convincing evidence on the effectiveness of screening mammography for women in this age group who are at average risk for breast cancer. In the United States, there is disagreement among organizations on whether population-based mammography should begin at the age of 40 or 50 years. The National Institutes of Health, the American Association for Cancer Research, and the American Academy of Family Physicians recommend against screening women in their 40s, whereas the United States Preventive Services Task Force, the National Cancer Institute, the American Cancer Society, the American College of Radiology, and the American College of Obstetricians and Gynecologists recommend screening mammograms for women aged 40 to 49 years. Furthermore, in comparing screening guidelines between Canada and the United States, it is also important to recognize that "standard care" within a socialized medical system such as Canada's differs from that of the United States. The National Breast Screening Study (NBSS-1), a randomized screening trial conducted in multiple centres across Canada, has shown there is no benefit in mortality from breast cancer from annual mammograms in women randomized between the ages of 40 and 49, relative to standard care (i.e. physical exam and teaching of breast-self examination on entry to the study, with usual community care thereafter). At present, organized screening programs in Canada systematically screen women starting at 50 years of age, although with a physician's referral, a screening mammogram is an insured service in Ontario for women under 50 years of age. International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined, whereas mortality is decreasing, though at a slower rate. These decreasing mortality rates may be attributed to screening and advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the SEER cancer registry in the United States indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20-year period (from 2.7 to 25 per 100,000). The incidence of breast cancer is lower in women aged 40 to 49 years than in women aged 50 to 69 years (about 140 per 100,000 versus 500 per 100,000 women, respectively), as is the sensitivity (about 75% versus 85% for women aged under and over 50, respectively) and specificity of mammography (about 80% versus 90% for women aged under and over 50, respectively). The increased density of breast tissue in younger women is mainly responsible for the lower accuracy of this procedure in this age group. In addition, as the proportion of breast cancers that occur before the age of 50 are more likely to be associated with genetic predisposition as compared with those diagnosed in women after the age of 50, mammography may not be an optimal screening method for younger women. Treatment options vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy, and/or radiotherapy. Surgery is the first-line intervention for biopsy confirmed tumours. The subsequent use of radiation, chemotherapy, or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is noninvasive. With such controversy as to the effectiveness of mammography and the potential risk associated with women being overtreated or actual cancers being missed, and the increased risk of breast cancer associated with exposure to annual mammograms over a 10-year period, the Ontario Health Technology Advisory Committee requested this review of screening mammography in women aged 40 to 49 years at average risk for breast cancer. This review is the first of 2 parts and concentrates on the effectiveness of screening mammography (i.e., film mammography, FM) for women at average risk aged 40 to 49 years. The second part will be an evaluation of screening by either magnetic resonance imaging or digital mammography, with the objective of determining the optimal screening modality in these younger women. The following questions were asked: Does screening mammography for women aged 40 to 49 years who are at average risk for breast cancer reduce breast cancer mortality?What is the sensitivity and specificity of mammography for this age group?What are the risks associated with annual screening from ages 40 to 49?What are the risks associated with false positive and false negative mammography results?What are the economic considerations if evidence for effectiveness is established?THE MEDICAL ADVISORY SECRETARIAT FOLLOWED ITS STANDARD PROCEDURES AND SEARCHED THESE ELECTRONIC DATABASES: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and the International Network of Agencies for Health Technology Assessment. Keywords used in the search were breast cancer, breast neoplasms, mass screening, and mammography. In total, the search yielded 6,359 articles specific to breast cancer screening and mammography. This did not include reports on diagnostic mammograms. The search was further restricted to English-language randomized controlled trials (RCTs), systematic reviews, and meta-analyses published between 1995 and 2005. Excluded were case reports, comments, editorials, and letters, which narrowed the results to 516 articles and previous health technology policy assessments. These were examined against the criteria outlined below. This resulted in the inclusion of 5 health technology assessments, the Canadian Preventive Services Task Force report, the United States Preventive Services Task Force report, 1 Cochrane review, and 8 RCTs. English-language articles, and English and French-language health technology policy assessments, conducted by other organizations, from 1995 to 2005Articles specific to RCTs of screening mammography of women at average risk for breast cancer that included results for women randomized to studies between the ages of 40 and 49 yearsStudies in which women were randomized to screening with or without mammography, although women may have had clinical breast examinations and/or may have been conducting breast self-examination.UK Age Trial results published in December 2006. Observational studies, including those nested within RCTsRCTs that do not include results on women between the ages of 40 and 49 at randomizationStudies in which mammography was compared with other radiologic screening modalities, for example, digital mammography, magnetic resonance imaging or ultrasound.Studies in which women randomized had a personal history of breast cancer. Film mammography Within RCTs, the comparison group would have been women randomized to not undergo screening mammography, although they may have had clinical breast examinations and/or have been conducting breast self-examination. Breast cancer mortality There is Level 1 Canadian evidence that screening women between the ages of 40 and 49 years who are at average risk for breast cancer is not effective, and that the absence of a benefit is sustained over a maximum follow-up period of 16 years. All remaining studies that reported on women aged under 50 years were based on subset analyses. They provide additional evidence that, when all these RCTs are taken into account, there is no significant reduction in breast cancer mortality associated with screening mammography in women aged 40 to 49 years. There is Level 1 evidence that screening mammography in women aged 40 to 49 years at average risk for breast cancer is not effective in reducing mortality. Moreover, risks associated with exposure to mammographic radiation, the increased risk of missed cancers due to lower mammographic sensitivity, and the psychological impact of false positives, are not inconsequential. The UK Age Trial results published in December 2006 did not change these conclusions.

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In this cluster-randomised controlled study (CoV-Surv Study), four different "active" SARS-CoV-2 testing strategies for general population surveillance are evaluated for their effectiveness in determining and predicting the prevalence of SARS-CoV-2 infections in a given population. In addition, the costs and cost-effectiveness of the four surveillance strategies will be assessed. Further, this trial is supplemented by a qualitative component to determine the acceptability of each strategy. Findings will inform the choice of the most effective, acceptable and affordable strategy for SARS-CoV-2 surveillance, with the most effective and cost-effective strategy becoming part of the local public health department's current routine health surveillance activities. Investigating its everyday performance will allow us to examine the strategy's applicability to real time prevalence prediction and the usefulness of the resulting information for local policy makers to implement countermeasures that effectively prevent future nationwide lockdowns. The authors would like to emphasize the importance and relevance of this study and its expected findings in the context of population-based disease surveillance, especially in respect to the current SARS-CoV-2 pandemic. In Germany, but also in many other countries, COVID-19 surveillance has so far largely relied on passive surveillance strategies that identify individuals with clinical symptoms, monitor those cases who then tested positive for the virus, followed by tracing of individuals in close contact to those positive cases. To achieve higher effectiveness in population surveillance and to reliably predict the course of an outbreak, screening and monitoring of infected individuals without major symptoms (about 40% of the population) will be necessary. While current testing capacities are also used to identify such asymptomatic cases, this rather passive approach is not suitable in generating reliable population-based estimates of the prevalence of asymptomatic carriers to allow any dependable predictions on the course of the pandemic. To better control and manage the SARS-CoV-2 pandemic, current strategies therefore need to be complemented by an active surveillance of the wider population, i.e. routinely conducted testing and monitoring activities to identify and isolate infected individuals regardless of their clinical symptoms. Such active surveillance strategies will enable more effective prevention of the spread of the virus as they can generate more precise population-based parameters during a pandemic. This essential information will be required in order to determine the best strategic and targeted short-term countermeasures to limit infection spread locally. This trial implements a cluster-randomised, two-factorial controlled, prospective, interventional, single-blinded design with four study arms, each representing a different SARS-CoV-2 testing and surveillance strategy. Eligible are individuals age 7 years or older living in Germany's Rhein-Neckar Region who consent to provide a saliva sample (all four arms) after completion of a brief questionnaire (two arms only). For the qualitative component, different samples of study participants and non-participants (i.e. eligible for study, but refuse to participate) will be identified for additional interviews. For these interviews, only individuals age 18 years or older are eligible. Of the four surveillance strategies to be assessed and compared, Strategy A1 is considered the gold standard for prevalence estimation and used to determine bias in other arms. To determine the cost-effectiveness, each strategy is compared to status quo, defined as the currently practiced passive surveillance approach. Strategy A1: Individuals (one per household) receive information and study material by mail with instructions on how to produce a saliva sample and how to return the sample by mail. Once received by the laboratory, the sample is tested for SARS-CoV-2 using Reverse Transcription Loop-mediated Isothermal Amplification (RT-LAMP). Strategy A2: Individuals (one per household) receive information and study material by mail with instructions on how to produce their own as well as saliva samples from each household member and how to return these samples by mail. Once received by the laboratory, the samples are tested for SARS-CoV-2 using RT-LAMP. Strategy B1: Individuals (one per household) receive information by mail on how to complete a brief pre-screening questionnaire which asks about COVID-19 related clinical symptoms and risk exposures. Only individuals whose pre-screening score crosses a defined threshold, will then receive additional study material by mail with instructions on how to produce a saliva sample and how to return the sample by mail. Once received by the laboratory, the saliva sample is tested for SARS-CoV-2 using RT-LAMP. Strategy B2: Individuals (one per household) receive information by mail on how to complete a brief pre-screening questionnaire which asks about COVID-19 related clinical symptoms. Only individuals whose pre-screening score crosses a defined threshold, will then receive additional study material by mail with instructions how to produce their own as well as saliva samples from each household member and how to return these samples by mail. Once received by the laboratory, the samples are tested for SARS-CoV-2 using RT-LAMP. In each strategy, RT-LAMP positive samples are additionally analyzed with qPCR in order to minimize the number of false positives. The identification of the one best strategy will be determined by a set of parameters. Primary outcomes include costs per correctly screened person, costs per positive case, positive detection rate, and precision of positive detection rate. Secondary outcomes include participation rate, costs per asymptomatic case, prevalence estimates, number of asymptomatic cases per study arm, ratio of symptomatic to asymptomatic cases per study arm, participant satisfaction. Additional study components (not part of the trial) include cost effectiveness of each of the four surveillance strategies compared to passive monitoring (i.e. status quo), development of a prognostic model to predict hospital utilization caused by SARS-CoV-2, time from test shipment to test application and time from test shipment to test result, and perception and preferences of the persons to be tested with regard to test strategies. Samples are drawn in three batches of three continuous weeks. Randomisation follows a two-stage process. First, a total of 220 sampling points have been allocated to the three different batches. To obtain an integer solution, the Cox-algorithm for controlled rounding has been used. Afterwards, sample points have been drawn separately per batch, following a probability proportional to size (PPS) random sample. Second, for each cluster the same number of residential addresses is randomly sampled from the municipal registries (self-weighted sample of individuals). The 28,125 addresses drawn per municipality are then randomly allocated to the four study arms A1, A2, B1, and B2 in the ratio 5 to 2.5 to 14 to 7 based on the expected response rates in each arm and the sensitivity and specificity of the pre-screening tool as applied in strategy B1 and B2. Based on the assumptions, this allocation should yield 2500 saliva samples in each strategy. Although a municipality can be sampled by multiple batches and the overall number of addresses per municipality might vary, the number of addresses contacted in each arm is kept constant. The design is single-blinded, meaning the staff conducting the SARS-CoV-2 tests are unaware of the study arm assignment of each single participant and test sample. Total sample size for the trial is 10,000 saliva samples equally allocated to the four study arms (i.e. 2,500 participants per arm). For the qualitative component, up to 60 in-depth interviews will be conducted with about 30 study participants (up to 15 in each arm A and B) and 30 participation refusers (up to 15 in each arm A and B) purposefully selected from the quantitative study sample to represent a variety of gender and ages to explore experiences with admission or rejection of study participation. Up to 25 asymptomatic SARS-CoV-2 positive study participants will be purposefully selected to explore the way in which asymptomatic men and women diagnosed with SARS-CoV-2 give meaning to their diagnosis and to the dialectic between feeling concurrently healthy and yet also being at risk for transmitting COVID-19. In addition, 100 randomly selected study participants will be included to explore participants' perspective on testing processes and implementation. Final protocol version is "Surveillance_Studienprotokoll_03Nov2020_v1_2" from November 3, 2020. Recruitment started November 18, 2020 and is expected to end by or before December 31, 2020. The trial is currently being registered with the German Clinical Trials Register (Deutsches Register Klinischer Studien), DRKS00023271 ( https://www.drks.de/drks_web/navigate.do?navigationId=trial . HTML&amp;TRIAL_ID=DRKS00023271). Retrospectively registered 30 November 2020. The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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4-Vinyl-1-cyclohexene diepoxide is used a chemical intermediate and as a reactive diluent for diepoxides and epoxy resins. Toxicology and carcinogenesis studies were conducted by administering 4-vinyl-1-cyclohexene diepoxide (97% pure) in acetone by dermal application to individually housed F344/N rats and B6C3F1 mice for 14 days, 13 weeks, 15 months, and 2 years. Additional studies included evaluation of immune function after a 5-day dermal exposure and evaluation of the oral toxicity of 4-vinyl-1-cyclohexene diepoxide in 16-day and 13-week corn oil gavage studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day Dermal Studies: In the 14-day studies, all rats that received 924 mg/kg or higher (equivalent to 139 mg/rat or higher for males and 112 mg/rat of higher for females) died before the end of the studies. Final mean body weights were lower than those of vehicle controls in males receiving 68 mg/rat and in females receiving 57 mg/rat. Excoriations on the skin at the application site were observed in the groups receiving 57 mg/rat or more. Males receiving 139 mg/rat and females receiving 112 mg/rat had congestion and/or hypoplasia of the bone marrow; most had acute nephrosis. Skin lesions, including epidermal necrosis and ulceration, epidermal hyperplasia, and hyperkeratosis, were found in the 139 and 112 mg/rat group; similar lesions of lesser severity were seen in the two lowest dose groups of each sex. All mice that received 1,787 mg/kg (equivalent to 43/mouse for males and 37 mg/mouse for females) and 3/5 male mice and 5/5 female mice that received 889 mg/kg (equivalent to 19-21 mg/mouse) died before the end of the 14-day dermal studies. Final mean body weights of exposed and vehicle control mice were generally similar. Lesions of the skin at the site of application were seen in 4/5 males and 4/5 females receiving 5 mg/mouse and all mice receiving 10 and 21 (males) or 19 (females) mg/mouse and included epidermal and sebaceous gland hyperplasia, hyperkeratosis, and ulceration. Thirteen-Week Studies: In the 13-week dermal studies, all rats survived to the end of the studies (doses up to 60 mg/rat). The final mean body weights of the 60 mg/rat groups were 9%-14% lower than those of the vehicle controls. Compound-related clinical signs in the 60 mg/rat groups observed during the second half of the studies included redness, scabs, and ulceration at the application site and burrowing behavior after dermal application. Hyperplasia of the sebaceous glands and acanthosis (hyperplasia) and hyperkeratosis of the squamous epithelium were seen at the site of application. In mice, no compound-related deaths occurred after applications of up to 10 mg/mouse in 13-week dermal studies, and final mean body weights of exposed and vehicle control mice were similar. Relative liver and kidney weights increased with dose. Compound-related lesions of the skin included sebaceous gland hyperplasia and acanthosis (hyperplasia) and hyperkeratosis of the stratified squamous epithelium at the site of application; ovarian atrophy was also considered to be compound related. In the 13-week oral studies, the major target organ of toxicity in rats and mice was the forestomach, as indicated by hyperkeratosis and hyperplasia of the stratified squamous epithelium. In female mice, ovarian atrophy was seen in 4-vinyl-1-cyclohexene diepoxide-dosed groups. Two-year studies were conducted by administering 4-vinyl-1-cyclohexene diepoxide in acetone by dermal application, 5 days per week for 105 weeks to groups of 60 rats of each sex at 0, 15, or 30 mg/animal. Groups of 60 mice of each sex were administered 0, 2.5, 5, or 10 mg/animal on the same schedule for 103 weeks. None of the doses selected had produced ulceration of skin in 13-week studies. Ten animals from each group were killed and examined during month 15 for toxicologic evaluation. Immune Function Studies: The immunotoxic effects of 4-vinyl-1-cyclohexene diepoxide were studied in male B6C3F1 mice in male B6C3F1 mice after a 5-day dermal exposure at doses ranging from 2.5 to 10 mg/mouse per day. 4-Vinyl-1-cyclohexene diepoxide was immunosuppressive at 10 mg/mouse and, to a lesser extent, at 5 mg/mouse, as indicated by a decrease in peripheral lymphocytes and the in vitro lymphoproliferative response to phytohemagglutinin and concanavalin A in the high dose group and suppression of the antibody plaque-forming-cell response in the 5 and 10 mg/mouse groups. Fifteen-Month Evaluation: Two of 10 male rats that received 30 mg had a squamous cell carcinoma of the skin at or adjacent to the site of application. Acanthosis was seen in exposed rats (mild severity at 30 mg/rat and minimal severity at 15 mg/rat); hyperkeratosis was observed for rats in the 30 mg/rat groups. Compound-related nonneoplastic skin lesions in mice included acanthosis, hyperkeratosis, and sebaceous gland hyperplasia/hypertrophy. Squamous cell papillomas and carcinomas were seen in mice that received 5 or 10 mg/mouse; none was seen in vehicle control or low dose groups (papillomas--male: mid dose, 1/10; high dose, 2/10; female: 1/10; 1/10; carcinomas-- male: 2/10; 8/10; female: 2/10; 5/10). One vehicle control and all exposed female mice had atrophy of the ovary. Hyperplasia of the ovarian surface epithelium was seen in 8/10 females receiving 5 mg/mouse and 9/9 females receiving 10 mg/mouse. Two of nine females receiving 10 mg/mouse had granulosa cell tumors of the ovary, and 1/9 females receiving 10 mg/mouse had an ovarian papillary cystadenoma. Body Weights and Survival in the Two-Year Studies: In general, the body weights and survival were lower in mid and high dose groups than in vehicle controls. The survival was lower in exposed groups, primarily because of neoplasms (survival at week 105--male rats: vehicle control, 7/50; low dose, 8/50; high dose, 4/50; female rats: 27/50; 23/50; 15/50; male mice: vehicle control, 38/50; low dose, 35/50; mid dose, 4/50; high dose, 0/50; female mice: 30/50; 31/50; 15/50; 0/50). All high dose male mice died by week 83; the 10 surviving high dose female mice were killed during week 85. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Acanthosis and sebaceous gland hypertrophy of skin from the scapula or back were observed at substantially increased incidences in exposed male and female rats. Squamous cell papillomas in male rats and squamous cell carcinomas in male and female rats were observed only in exposed rats (squamous cell carcinomas--male: vehicle control, 0/50; low dose, 33/50; high dose, 36/50; female: 0/50; 16/50; 34/50). The incidences of basal cell adenomas or carcinomas (combined) were increased (male: 0/50; 1/50; 6/50; female: 0/50; 3/50; 4/50). For exposed mice, acanthosis, hyperkeratosis, and necrotizing inflammation of the skin were observed over the scapula or back. Squamous cell carcinomas were found only in exposed mice (male: vehicle control, 0/50; low dose, 14/50; mid dose, 39/50; high dose, 42/50; female: 0/50; 6/50; 37/50; 41/50). Follicular atrophy and tubular hyperplasia of the ovary in female mice were increased (atrophy: 12/50; 43/49; 47/50; tubular hyperplasia: 5/50; 35/49; 38/49; 34/50). Mid and high dose females had benign or malignant granulosa cell tumors (0/50; 0/49; 7/49; 12/50) and benign mixed tumors (0/50; 0/49; 11/49; 6/50). The combined incidences of luteomas, granulosa cell tumors, benign mixed tumors, or malignant granulosa cell tumors in mid and high dose female mice were increased (1/50; 0/49; 17/49; 18/50). The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in exposed female mice were marginally increased (4/50; 9/50; 11/50; 7/50). Genetic Toxicology: 4-Vinyl-1-cyclohexene diepoxide was mutagenic in S. typhimurium strains TA98, TA100, and TA1535 with and without exogenous metabolic activation; the compound was equivocally mutagenic in strain TA1537 without S9 but gave a positive response in the presence of activation. 4-Vinyl-1-cyclohexene diepoxide induced resistance to trifluorothymidine in mouse L5178Y/TK cells without exogenous metabolic activation; it was not tested with activation. 4-Vinyl-1-cyclohexene diepoxide induced sister chromatid exchanges and chromosomal aberrations in CHO cells in the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year dermal studies, there was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female F344/N rats, as shown by squamous cell and basal cell neoplasms of the skin. There was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female B6C3F1 mice, as shown by squamous cell carcinomas of the skin in males and squamous cell carcinomas of the skin and ovarian neoplasms in females; increased incidences of lung neoplasms in females may also have been related to chemical application. Synonyms: 4-vinylcyclohexene diepoxide; 4-vinyl-1,2-cyclohexene diepoxide; 1-vinyl-3-cyclohexene diepoxide; 4-vinylcyclohexene dioxide; 1,2-epoxy-4-(epoxyethyl) cyclohexane; 1-epoxyethyl-3,4-epoxycyclohexane

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2-Amino-5-nitrophenol is used as a colorant in semipermanent hair dyes and in the manufacture of C.I. Solvent Red 8, an azo dye for synthetic resins, lacquers, and wood stains. 2-Amino-5-nitrophenol was nominated for toxicology and carcinogenesis studies by the National Cancer Institute because of widespread human exposure associated with its use in hair dyes. Toxicology and carcinogenesis studies were conducted by administering 2-amino-5-nitrophenol (98% pure) by gavage in corn oil 5 days per week to groups of F344/N rats and B6C3F1 mice of each sex in 16-day, 13-week, and 2-year studies. In the 2-year studies, male and female rats were given doses of 0, 100, or 200 mg/kg and male and female mice were given doses of 0, 400, or 800 mg/kg. Sixteen-Day and Thirteen-Week Studies: During the 16-day studies, F344/N rats of each sex received 0, 156, 313, 625, 1,250, or 2,500 mg/kg 2-amino-5-nitrophenol by gavage in corn oil vehicle. One of the five males that received 2,500 mg/kg, 1/5 females that received 1,250 mg/kg, and 2/5 females that received 313 mg/kg died before the end of the studies. Final mean body weights of rats that received 1,250 or 2,500 mg/kg were 11% and 30% lower than that of vehicle controls for males and 9% and 13% lower for females. B6C3F1 mice of each sex received doses of 0, 313, 625, 1,250, 2,500, or 5,000 mg/kg 2-amino-5-nitrophenol. Two of five males and 5/5 females that received 5,000 mg/kg, 3/5 males and 3/5 females that received 2,500 mg/kg, 3/5 females that received 1,250 mg/kg, 1/5 females that received 625 mg/kg, and 2/5 male vehicle controls died before the end of the studies. Final mean body weights of chemically exposed mice were not different from those of the vehicle controls. Rats that received 625, 1,250, or 2,500 mg/kg and male mice that received 5,000 mg/kg had loose stools. In 13-week studies, F344/N rats and B6C3F1 mice of both sexes received 0, 100, 200, 400, 800, or 1,600 mg/kg 2-amino-5-nitrophenol by gavage in corn oil. Five of 10 male and 2/10 female rats that received 1,600 mg/kg, 1/10 male and 3/10 female rats that received 800 mg/kg, and 1/10 male rats that received 400 mg/kg died before the end of the studies. Final mean body weights of males that received 400, 800, or 1,600 mg/kg were 10%, 25%, and 43% lower than that of vehicle controls. The final mean body weight of females that received 1,600 mg/kg was 16% lower that of vehicle controls. Four of 10 male and 3/10 female mice that received 1,600 mg/kg died before the end of the 13-week studies. The final mean body weight of male mice that received 1,600 mg/kg was 11% lower than that of vehicle controls; male and female mice that received 1,600 mg/kg appeared lethargic. During the 13-week studies, acute/chronic perivasculitis of vessels of the cecum and colon was observed in rats that received 400, 800, or 1,600 mg/kg and in mice that received 1,600 mg/kg. Body Weight and Survival in the Two-Year Studies: Mean body weights of rats receiving 200 mg/kg were 5%-10% lower than those of vehicle controls after week 33 for males and 4%-5% lower than those of vehicle controls after week 93 for females. Survival of male rats was significantly lower than that of vehicle controls after week 99 for the 100 mg/kg dose group and after week 75 for the 200 mg/kg dose group (final survival: vehicle control, 33/50; 100 mg/kg group, 16/50; 200 mg/kg group, 4/50). Survival of female rats was comparable to that of vehicle controls (30/50; 32/50; 29/50). Loose or poorly formed stools were observed for male rats and occasionally for females that received 200 mg/kg. Mean body weights of mice that received 800 mg/kg were 8%-11% lower than those of vehicle controls between weeks 29 and 74 for males and 8%-13% lower than those of vehicle controls after week 69 for females; mean body weights of mice that received 400 mg/kg were greater than those of vehicle controls after week 69 for males and 5%-9% lower than those of vehicle controls after week 69 for females. Survival of mice that received 800 mg/kg was significantly reduced compared with that of ose of vehicle controls after week 69 for females. Survival of mice that received 800 mg/kg was significantly reduced compared with that of vehicle controls after week 20 for males and week 22 for females and was not considered adequate to evaluate a carcinogenic response (final survival--male: vehicle control, 31/50; 400 mg/kg group, 36/50; 800 mg/kg group, 12/50; female: 37/50; 36/50; 10/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Pigmentation was present at increased incidences in all groups of chemically exposed animals and was characterized by varying amounts of an orange, granular pigment present in the fibrous connective tissue of the lamina propria, in the submucosa, and around vessels in the submucosa of the cecum and colon. Pigmentation of the rectum was observed at increased incidences in male rats that received 100 mg/kg, male and female rats that received 200 mg/kg, and both groups of chemically exposed mice. No pigmentation was found in the intestines of vehicle control rats or mice. Associated with pigmentation was an increased incidence of acute/chronic inflammation in the cecum and colon of all groups chemically exposed rats and mice; this inflammation was similar to that observed in the 13-week studies but was of greater severity. Acute/chronic inflammation was also present in the rectum of male rats that received 100 mg/kg, male and female rats that received 200 mg/kg, and male mice that received 800 mg/kg. The incidence of pancreatic acinar cell adenomas was significantly increased (P&amp;le;0.002) in male rats that received 100 mg/kg 2-amino-5-nitrophenol (vehicle control, 1/50; 100 mg/kg, 10/50; 200 mg/kg, 3/49); the increase was considered to be associated with chemical exposure. The reduced survival of male rats that received 200 mg/kg markedly reduced the sensitivity of this group for detecting the presence of neoplasms. The incidences of adenomas or carcinomas (combined) of the preputial or clitoral glands were marginally increased in male or female rats that received 200 mg/kg 2-amino-5-nitrophenol (preputial gland: 3/50; 2/50; 5/50; clitoral gland: 3/50; 3/50; 7/50). Neoplasms found in the intestinal tract of 3/50 male rats that received 100 mg/kg (one leiomyoma of the small intestine, one adenocarcinoma of the jejunum, one leiomyoma of the cecum), 2/50 male rats that received 200 mg/kg (one lipoma and one osteosarcoma of the cecum), and 1/50 female rats that received 200 mg/kg (one leiomyoma of the cecum) were not considered to be the result of chemical exposure. No compound-related neoplasms were found in mice exposed to 2-amino-5-nitrophenol in the 2-year studies. Genetic Toxicology: 2-Amino-5-nitrophenol was mutagenic in Salmonella typhimurium strains TA98, TA100, and TA1537 when tested in a preincubation protocol with and without exogenous metabolic activation, and it exhibited equivocal mutagenic activity in strain TA1535 in the presence of induced liver S9. 2-Amino-5-nitrophenol induced forward mutations in mouse L5178Y lymphoma cells in the absence of metabolic activation; it was not tested with S9. An increase in chromosomal aberrations and sister chromatid exchanges was observed in cultured Chinese hamster ovary (CHO) cells following incubation with 2-amino-5-nitrophenol both in the presence and absence of exogenous metabolic activation. Data Audit: The data, documents, and pathology materials from the 2-year studies of 2-amino-5-nitrophenol were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity for male F344/N rats that received 100 mg/kg 2-amino-5-nitrophenol, as shown by the increased incidence of acinar cell adenomas of the pancreas. Reduced survival of male F344/N rats that received 200 mg/kg decreased the sensitivity of this group for detecting a carcinogenic response. There was no evidence of carcinogenic activity for female rats that received 100 or 200 mg/kg per day. Marginally increased incidences of preputial or clitoral gland adenomas or carcinomas (combined) occurred in male and female F344/N rats administered 200 mg/kg 2-amino-5-nitrophenol. There was no evidence of carcinogenic activity for B6C3F1 mice that received 400 mg/kg 2-amino-5-nitrophenol; reduced survival of B6C3F1 mice that received 800 mg/kg caused this group to be considered inadequate for detecting a carcinogenic response.

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To assess the effectiveness, cost-effectiveness, and demand in Ontario for catheter ablation of complex arrhythmias guided by advanced nonfluoroscopy mapping systems. Particular attention was paid to ablation for atrial fibrillation (AF). Tachycardia Tachycardia refers to a diverse group of arrhythmias characterized by heart rates that are greater than 100 beats per minute. It results from abnormal firing of electrical impulses from heart tissues or abnormal electrical pathways in the heart because of scars. Tachycardia may be asymptomatic, or it may adversely affect quality of life owing to symptoms such as palpitations, headaches, shortness of breath, weakness, dizziness, and syncope. Atrial fibrillation, the most common sustained arrhythmia, affects about 99,000 people in Ontario. It is associated with higher morbidity and mortality because of increased risk of stroke, embolism, and congestive heart failure. In atrial fibrillation, most of the abnormal arrhythmogenic foci are located inside the pulmonary veins, although the atrium may also be responsible for triggering or perpetuating atrial fibrillation. Ventricular tachycardia, often found in patients with ischemic heart disease and a history of myocardial infarction, is often life-threatening; it accounts for about 50% of sudden deaths. Treatment of Tachycardia The first line of treatment for tachycardia is antiarrhythmic drugs; for atrial fibrillation, anticoagulation drugs are also used to prevent stroke. For patients refractory to or unable to tolerate antiarrhythmic drugs, ablation of the arrhythmogenic heart tissues is the only option. Surgical ablation such as the Cox-Maze procedure is more invasive. Catheter ablation, involving the delivery of energy (most commonly radiofrequency) via a percutaneous catheter system guided by X-ray fluoroscopy, has been used in place of surgical ablation for many patients. However, this conventional approach in catheter ablation has not been found to be effective for the treatment of complex arrhythmias such as chronic atrial fibrillation or ventricular tachycardia. Advanced nonfluoroscopic mapping systems have been developed for guiding the ablation of these complex arrhythmias. Four nonfluoroscopic advanced mapping systems have been licensed by Health Canada: CARTO EP mapping System (manufactured by Biosense Webster, CA) uses weak magnetic fields and a special mapping/ablation catheter with a magnetic sensor to locate the catheter and reconstruct a 3-dimensional geometry of the heart superimposed with colour-coded electric potential maps to guide ablation. EnSite System (manufactured by Endocardial Solutions Inc., MN) includes a multi-electrode non-contact catheter that conducts simultaneous mapping. A processing unit uses the electrical data to computes more than 3,000 isopotential electrograms that are displayed on a reconstructed 3-dimensional geometry of the heart chamber. The navigational system, EnSite NavX, can be used separately with most mapping catheters. The LocaLisa Intracardiac System (manufactured by Medtronics Inc, MN) is a navigational system that uses an electrical field to locate the mapping catheter. It reconstructs the location of the electrodes on the mapping catheter in 3-dimensional virtual space, thereby enabling an ablation catheter to be directed to the electrode that identifies abnormal electric potential. Polar Constellation Advanced Mapping Catheter System (manufactured by Boston Scientific, MA) is a multielectrode basket catheter with 64 electrodes on 8 splines. Once deployed, each electrode is automatically traced. The information enables a 3-dimensional model of the basket catheter to be computed. Colour-coded activation maps are reconstructed online and displayed on a monitor. By using this catheter, a precise electrical map of the atrium can be obtained in several heartbeats. A systematic search of Cochrane, MEDLINE and EMBASE was conducted to identify studies that compared ablation guided by any of the advanced systems to fluoroscopy-guided ablation of tachycardia. English-language studies with sample sizes greater than or equal to 20 that were published between 2000 and 2005 were included. Observational studies on safety of advanced mapping systems and fluoroscopy were also included. Outcomes of interest were acute success, defined as termination of arrhythmia immediately following ablation; long-term success, defined as being arrhythmia free at follow-up; total procedure time; fluoroscopy time; radiation dose; number of radiofrequency pulses; complications; cost; and the cost-effectiveness ratio. Quality of the individual studies was assessed using established criteria. Quality of the overall evidence was determined by applying the GRADE evaluation system. (3) Qualitative synthesis of the data was performed. Quantitative analysis using Revman 4.2 was performed when appropriate. Quality of the Studies Thirty-four studies met the inclusion criteria. These comprised 18 studies on CARTO (4 randomized controlled trials [RCTs] and 14 non-RCTs), 3 RCTs on EnSite NavX, 4 studies on LocaLisa Navigational System (1 RCT and 3 non-RCTs), 2 studies on EnSite and CARTO, 1 on Polar Constellation basket catheter, and 7 studies on radiation safety. The quality of the studies ranged from moderate to low. Most of the studies had small sample sizes with selection bias, and there was no blinding of patients or care providers in any of the studies. Duration of follow-up ranged from 6 weeks to 29 months, with most having at least 6 months of follow-up. There was heterogeneity with respect to the approach to ablation, definition of success, and drug management before and after the ablation procedure. Evidence is based on a small number of small RCTS and non-RCTS with methodological flaws.Advanced nonfluoroscopy mapping/navigation systems provided real time 3-dimensional images with integration of anatomic and electrical potential information that enable better visualization of areas of interest for ablationAdvanced nonfluoroscopy mapping/navigation systems appear to be safe; they consistently shortened the fluoroscopy duration and radiation exposure.Evidence suggests that nonfluoroscopy mapping and navigation systems may be used as adjuncts to rather than replacements for fluoroscopy in guiding the ablation of complex arrhythmias.Most studies showed a nonsignificant trend toward lower overall failure rate for advanced mapping-guided ablation compared with fluoroscopy-guided mapping.Pooled analyses of small RCTs and non-RCTs that compared fluoroscopy- with nonfluoroscopy-guided ablation of atrial fibrillation and atrial flutter showed that advanced nonfluoroscopy mapping and navigational systems:Yielded acute success rates of 69% to 100%, not significantly different from fluoroscopy ablation.Had overall failure rates at 3 months to 19 months of 1% to 40% (median 25%).Resulted in a 10% relative reduction in overall failure rate for advanced mapping guided-ablation compared to fluoroscopy guided ablation for the treatment of atrial fibrillation.Yielded added benefit over fluoroscopy in guiding the ablation of complex arrhythmia. The advanced systems were shown to reduce the arrhythmia burden and the need for antiarrhythmic drugs in patients with complex arrhythmia who had failed fluoroscopy-guided ablationBased on predominantly observational studies, circumferential PV ablation guided by a nonfluoroscopy system was shown to do the following:Result in freedom from atrial fibrillation (with or without antiarrhythmic drug) in 75% to 95% of patients (median 79%). This effect was maintained up to 28 months.Result in freedom from atrial fibrillation without antiarrhythmic drugs in 47% to 95% of patients (median 63%).Improve patient survival at 28 months after the procedure as compared with drug therapy.Require special skills; patient outcomes are operator dependent, and there is a significant learning curve effect.Complication rates of pulmonary vein ablation guided by an advanced mapping/navigation system ranged from 0% to 10% with a median of 6% during a follow-up period of 6 months to 29 months.The complication rate of the study with the longest follow-up was 8%.The most common complications of advanced catheter-guided ablation were stroke, transient ischemic attack, cardiac tamponade, myocardial infarction, atrial flutter, congestive heart failure, and pulmonary vein stenosis. A small number of cases with fatal atrial-esophageal fistula had been reported and were attributed to the high radiofrequency energy used rather than to the advanced mapping systems. An Ontario-based economic analysis suggests that the cumulative incremental upfront costs of catheter ablation of atrial fibrillation guided by advanced nonfluoroscopy mapping could be recouped in 4.7 years through cost avoidance arising from less need for antiarrhythmic drugs and fewer hospitalization for stroke and heart failure. Expert Opinion Expert consultants to the Medical Advisory Secretariat noted the following: Nonfluoroscopy mapping is not necessary for simple ablation procedures (e.g., typical flutter). However, it is essential in the ablation of complex arrhythmias including these:Symptomatic, drug-refractory atrial fibrillationArrhythmias in people who have had surgery for congenital heart disease (e.g., macro re-entrant tachycardia in people who have had surgery for congenital heart disease).Ventricular tachycardia due to myocardial infarctionAtypical atrial flutterAdvanced mapping systems represent an enabling technology in the ablation of complex arrhythmias. The ablation of these complex cases would not have been feasible or advisable with fluoroscopy-guided ablation and, therefore, comparative studies would not be feasible or ethical in such cases. (ABSTRACT TRUNCATED)

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Endovascular repair of abdominal aortic aneurysm (AAA) allows the exclusion of the dilated aneurismal segment of the aorta from the systematic circulation. The procedure requires, however, that the endograft extends to the healthy parts of the aorta above and below the aneurysm, yet the neck of a juxtarenal aortic aneurysm (JRA) is too short for a standard endovascular repair. Fenestrated endovascular aortic repair (f-EVAR) provides a solution to overcome this problem by enabling the continuation of blood flow to the renal and visceral arteries through holes or 'fenestrations' in the graft. These fenestrations are designed to match the ostial diameter of the renal and visceral arteries.There are three varieties fenestration, small, large, and scallop, and their location needs to be customized to fit the anatomy of the patient. If the device is not properly designed, if the alignment is inaccurate, or if the catheterization of the visceral arteries is not possible, the procedure may fail. In such cases, conversion to open surgery may become the only option as fenestrated endografts are not retrievable.It is recommended that a stent be placed within each small fenestration to the target artery to prevent shuttering of the artery or occlusion. Many authors have noted an increased risk of vessel occlusion in unstented fenestrations and scallops.Once placed in a patient, life-long follow-up at regular intervals is necessary to ensure the graft remains in its intended location, and that the components have adequate overlap. Should the need arise, routine follow-up allows the performance of timely and appropriate intervention through detection of events that could impact the long-term outcomes. The technique of fenestrated endovascular grafting is still in evolution and few studies have been with published mid-term outcome data. As the technique become more common in vascular surgery practices, it will be important to determine if it can provide better outcomes than open surgical repair (OSR). In an OSR approach, aortic clamping above one or both renal arteries, or above the visceral arteries, is required. The higher the level of aortic clamping, the greater the risk of cardiac stress and renal or visceral ischemia. During suprarenal or supraceliac aortic clamping, strain-induced myocardial ischemia may also occur due to concomitant rise in cardiac afterload and a decrease in cardiac output. Reports indicate that 6% of patients undergoing surgical repair develop myocardial infarction. The ideal level of clamp location remains controversial with conflicting views having been reported. A search of electronic databases (OVID MEDLINE, MEDLINE In-Process &amp; Other Non-Indexed Citations, EMBASE, The Cochrane Library, and the International Agency for Health Technology Assessment [INAHTA] database was undertaken to identify evidence published from January 1, 2004 to December 19, 2008. The search was limited to English-language articles and human studies. The automatic search alerts were received and reviewed up to March 23, 2009. The literature search and automatic search update identified 320 citations, of which 13 met inclusion/exclusion criteria. One comparative study presented at an international seminar, five single-arm studies on f-EVAR, and 7 studies on OSR (one prospective and six retrospective) were considered for this analysis. To grade the strength of the body of evidence, the grading system formulated by the GRADE working group and adopted by MAS, was applied. The GRADE system classifies evidence quality as high (Grade A), moderate (Grade B), or low (Grade C) according to four key elements: study design, study quality, consistency across studies, and directness. A summary of the characteristics of the f-EVAR and OSR studies found through the literature search is shown in Table ES-1. ES-1. f-EVAR Studies versus OSR StudiesTechniqueNumber ofPatientsMean Age(Range), YearsAneurysm Diameter(Range),mmMean Duration ofFollow-up, Yearsf-EVAR(5 studies)27474 (72-75)63 (59-68)9.4-25.8OSR(7 studies)856:JRA: 675SRA: 136TAA: 4572 (67-78)62 (50-70)1-48JRA, Juxtarenal aortic aneurysm; SRA, Suprarenal aortic aneurysm; TAA, Thoracic aortic aneurysm MORTALITY OUTCOMES: The pooled estimate for 30-day mortality was 1.8% among the f-EVAR studies and 3.1% among the OSR studies that reported data for the repair of JRA separately. The pooled estimate for late mortality was 12.8% among the f-EVAR studies and 23.7% among the OSR studies that reported data for JRA separately. VISCERAL ARTERY EVENTS REPORTED IN F#ENTITYSTARTX02014;EVAR STUDIES: RENAL EVENTS DURING F-EVAR: A total of three main renal arteries and two accessory renal arteries became occluded during the procedure. These were all due to technical issues, except one accessory renal artery in which the artery was intentionally covered. One patient required open surgery following the procedure. RENAL EVENTS DURING THE FOLLOW-UP: A total of 12 renal arteries (12 patients) were found to be occluded during follow-up. In two patients, the same side accessory renal artery was also occluded. Four (1.5%) patients lost one kidney and five (2.3%) patients underwent dialysis, three (1.4%) of which became permanent. A total of 16 cases of renal artery stenosis (16 patients) occurred during follow-up. Eight of these were treated and eight were observed. Segmental renal infarcts were found in six patients but renal function was not impaired. MESENTERIC EVENTS DURING F-EVAR: Three mesenteric events occurred during the f-EVAR procedures resulting in two deaths. One patient developed bowel ischemia due to embolization of the superior mesenteric artery (SMA); this patient died 13 days after the procedure from multiorgan failure. One patient died eights days after the procedure from mesenteric ischemia and bowel perforation. The third SMA event occurred during surgery with subsequent occlusion in early follow-up. MESENTERIC EVENTS DURING FOLLOW-UP: During follow-up, five (1.8%) SMA occlusions/partial occlusions and one SMA stenosis were noted. Three of the five patients with SMA occlusion/partial occlusion remained asymptomatic and no further intervention was necessary. One patient underwent SMA bypass surgery and in two patients, the problem solved by SMA stenting. A summary of the outcomes reported in the f-EVAR and OSR studies is shown in Table ES-2. ES-2.Summary of Outcomes: Fenestrated Endovascular Graft Versus Open Surgical Repair for Treatment of Juxtarenal Aortic AneurysmOutcomef-EVAROSRPooled Estimate (Rate)30-day mortality1.83.1Late mortality12.823.7Permanent dialysis0-2.50-3.5Loss of kidney1.5No report of kidney loss Incidence of post-op renal insufficiency: 14.4%Mesentric ischemia3.32.9Aortic rupture00Post-op cardiac complications1.510.7Post-op pulmonary complications0.713.4Post-op GI complications0.75.9Aneurysm expansion1.40Secondary intervention (Non-endoleak)8.87.8EndoleakType I: 4Type 2: 16.8Type III: 1.8N/AEndoleak required treatmentType I: 2.9Type 2: 3.3Type III: 1.1Graft migration1.5N/AGraft separation0.7Duration (Mean)Operation time (min)240287Hospital stay (days)613 SUMMARY: Short- and medium-term results (up to 2 years) of f-EVAR for the repair of JRA showed that outcomes in f-EVAR series compare favourably with the figures for the OSR series; however, uncertainty remains regarding the long-term results. The following observations are based on low quality evidence. F-EVAR has lower 30-day mortality than OSR (1.8% vs. 3.1%) and a lower late-mortality over the period of time that patients have been followed (12.8% vs. 23.7%).There is a potential for the loss of target vessels during or after f-EVAR procedures. Loss of a target vessel may lead to loss of its respective end organ. The risk associated with this technique is mainly due to branch vessel ischemia or occlusion (primarily among the renal arteries and SMA). Ischemia or occlusion of these arteries can occur during surgery due to technical failure and/or embolization or it may occur during follow-up due to graft complications such as graft migration, component separation, or arterial thrombosis. The risk of kidney loss in this series of f-EVAR studies was 1.5% and the risk of mesenteric ischemia was 3.3%. In the OSR studies, the risk of developing renal insufficiency was 14.4% and the risk of mesenteric ischemia was 2.9%.F-EVAR has a lower rate of postoperative cardiac and pulmonary complications.Endoleak occurs in 22.5% of patients undergoing f-EVAR (all types) and about 8% of these require treatment. Most of the interventions performed to treat such endoleaks conducted using a minimally invasive approach.Due to the complexity of the technique, patients must be appropriately selected for f-EVAR, the procedure performed by highly experienced operators, and in centers with advanced, high-resolution imaging systems to minimize the risk of complications.Graft fenestrations have to be custom designed for each patient to fit and match the anatomy of their visceral arteries. Planning and sizing thus requires scrutiny of the target vessels with a high degree precision. This is important not only to prevent end organ ischemia and infarction, but to avoid prolonging procedures and subsequent adverse outcomes.Assuming the average cost range of FEVAR procedure is $24,395-$30,070 as per hospital data and assuming the maximum number of annual cases in Ontario is 116, the average estimated cost impact range to the province for FEVAR procedures is $2.83M-$3.49M annually.

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The objective of this systematic review is to identify, appraise and synthesize the best available evidence for the effectiveness of internet-based e-learning programs on health care professional behavior and patient outcomes. Technological innovation has not only impacted social change in recent years but has been the prime driver of educational transformation.The newest consumers of post-secondary education, the so-called 'digital natives', have come to expect education to be delivered in a way that offers increased usability and convenience. Health care professionals (HCPs) in the clinical setting, particularly those in rural and remote communities, are no different. Today's health workforce has a professional responsibility to maintain competency in practice through achieving a minimum number of hours of continuing professional development. Consequently, HCPs seeking professional development opportunities are reliant on sourcing these independently according to individual learning needs. However, difficulties exist in some health professionals' access to ongoing professional development opportunities, particularly those with limited access face-to-face educationdue to geographical isolation or for those not enrolled in a formal program of study.These issues challenge traditional methods of teaching delivery; electronic learning (e-learning) is at the nexus of overcoming these challenges.The term e-learning originated in the mid-1990s as the internet began to gather momentum.Electronic learning can be broadly defined as any type of educational media that is delivered in an electronic form.Terms such as computer-assisted learning, online learning, web-based learning and e-learning are often used synonymously but all reflect knowledge transfer via an electronic device. This broad definition allows for a gamut of multimedia to be used for the purpose of constructing and assessing knowledge. Multimedia typically used in e-learning range from the now archaic Compact Disc Read-Only Memory (CD-ROMs), to the simple Microsoft PowerPoint, or the more advanced and complex virtual worlds such a second life. Electronic learning can be delivered in asynchronous or synchronous formats, with the latter (for example interactive online lectures via platforms such as BlackboardCollaborate or WebEx) more commonly used in formal educational settings according to set timetables of study.Person-to-person interactivity is an important enabler of knowledge generation and while functionalities such as web 1.0 (discussion board and email) and more recently web 2.0 (Wikis and blogs) allow for this to occur both synchronously and asynchronously, it is usually utilized in formal educational contexts only. However, the economy of formal education does not allow for free access to courses which proves challenging for HCPs seeking quality educational opportunities who choose not to undergo a formal program of study or are just looking to meet a specific learning need. Alternatively, asynchronous e-learning is a more learner-centred approach that affords the opportunity to engage in learning at a time and location that is convenient and enables the learner to balance professional development with personal and work commitments.These learning opportunities are self-directed and do not require a human to facilitate learning, rather, technology officiates/facilitates the learning process and, in the asynchronous e-learning context, the learner negotiates meaning independently.Health-related e-learning research has focused on several domains including media comparative designs, self-efficacy, user satisfaction, instructional design, knowledge outcomes, clinical skills development, and facilitators/barriers to its use.The benefits of e-learning are well documented in terms of increased accessibility to education, efficacy, cost effectiveness, learner flexibility and interactivity.However, some fundamental methodological and philosophical flaws exist in e-learning research, not least the use of comparative design studies. Comparison between e-learning and traditional teaching methods are illogical and methodologically flawed because comparison groups are heterogeneous, lack uniformity and have multiple confounders that cannot be adjusted for.As early as 1994, researchersin computer-assisted learning were citing these limitations and called for a fresh research agenda in this area. Cookrepeated this call in 2005 and again in 2009 and noted a paucity of research related to patient or clinical practice outcomes. Electronic learning is not an educational panacea and research needs to progress from pre- and post-interventional and comparative designs that evaluate knowledge increases and user satisfaction. It is time to move towards determining whether improved self-efficacy or knowledge gained through e-learning improves patient outcomes or influences clinical behavior change and whether these changes are sustained. In order to develop the empirical evidence base in e-learning, research needs to be guided by established theoretical frameworks and use validated instruments to move from assessing knowledge generation towards improving our understanding of whether e-learning improves HCP behavior and more importantly, patient outcomes.One suitable framework that is congruent with e-learning research is Kirkpatrick'sfour levels of evaluation. Kirkpatrick's model is hierarchically based with level one relating to student reaction and how well the learner is satisfied with the education program. Level two pertains to learning and the evaluation of knowledge, level three expands on this and considers whether the education has influenced behavior. In the context of this review, behavior change is any practice that is intrinsically linked with the outcomes of the e-learning program undertaken. Finally, level four evaluates the impact on outcomes such as cost benefit or quality improvements.The majority of e-learning research has focused on participant experience and knowledge acquisition, outcomes that correspond with the first two levels of Kirkpatrick's model.To date, few studies have examined the effectiveness of internet-based e-learning programs on HCP behavior, which aligns with Level 3 of Kirkpatrick's model.Studies exist that use self-reported measures of intention to change behavior, however self-reported intention to change does not necessarily translate into actual behavior change. Studies that have not used self-reported measures of behavior change have used objectively measured evaluation criteria including objective structured assessment of technical skills (OSATS) using various methods including simulation task trainers and clinical simulations using standardized patients scored by a panel of experts using standardized assessment tools. Carney et al. used a national reporting and data system to measure the impact of a single one hour e-learning program undertaken by radiologists (n=31) aimed at reducing unnecessary recall during mammography screening. Carney et al. reported a null effect and attributed this to the complexities of behavior change, suggesting that longer term reinforcement of principles relating to mammography recall was required to effect behavior change. These findings also suggest that a multi-modal intervention may be required in order to reduce excessive recall rates in this area, rather than a single intervention. Contrary to Carney et al., Pape-Koehler et al. and Smeekins et al. reported positive findings using randomized controlled designs to test the efficacy of e-learning interventions on individual's surgical performance and the detection of child abuse, respectively. Pape-Koehler et al. used a 2x2 factorial design to demonstrate that an e-learning intervention significantly improved novice surgeon (n=70) surgical performance of a laparoscopic cholecystectomy (change between pre-post test OSATS p 0.001) when used in isolation or in combination with a practical training session compared to practical training alone. Smeekins et al. demonstrated that a 2 hour e-learning program improved nurses' (n=25) ability to detect child abuse in an emergency department. The nurses in the intervention (n=13) group demonstrated significantly better (p=0.022) questioning techniques and consequently, higher quality history taking, to determine children at risk of child abuse when compared with the control group who received no training at all.These three exemplar studies demonstrate the broad range of applications e-learning has in HCP education, as each study used different designs, had different subject areas and target health care professionals. This reflects the conceptual and practical challenges of the area of research that addresses levels three of Kirkpatrick's model. For this reason, the e-learning research agenda in health should focus on whether knowledge generated through e-learning is able to be re-contextualized into clinical practice, and influence sustained clinical behavior change and patient outcomes.A preliminary search of PubMed, CINAHL, The Cochrane Library, The JBI Database of Systematic Reviews and Implementation Reports, ERIC and PROSPERO was conducted to determine if a systematic review on the topic of interest already existed. This search identified four systematic reviews that specifically reviewed outcome measures of knowledge and skill improvement in the domain of e-learning. Two examined research conducted in nursing, with the other two in orthodontics. Lahti et al. systematic review examined the impact of e-learning on nurses' and nursing students' knowledge, skills and satisfaction. Lahti et al. were unable to demonstrate a statistical difference between cohorts undertaking e-learning compared to conventional teaching methods, findings that were not replicated by Du et al. This may be due to the decision by Lahti et al. (ABSTRACT TRUNCATED)

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In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenetics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT: http://www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST CANCER: An Evidence-Based AnalysisEpidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based AnalysisK-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based Analysis The Medical Advisory Secretariat undertook a systematic review of the evidence on the clinical effectiveness and cost-effectiveness of epidermal growth factor receptor (EGFR) mutation testing compared with no EGFR mutation testing to predict response to tyrosine kinase inhibitors (TKIs), gefitinib (Iressa(®)) or erlotinib (Tarceva(®)) in patients with advanced non-small cell lung cancer (NSCLC). TARGET POPULATION AND CONDITION With an estimated 7,800 new cases and 7,000 deaths last year, lung cancer is the leading cause of cancer deaths in Ontario. Those with unresectable or advanced disease are commonly treated with concurrent chemoradiation or platinum-based combination chemotherapy. Although response rates to cytotoxic chemotherapy for advanced NSCLC are approximately 30 to 40%, all patients eventually develop resistance and have a median survival of only 8 to 10 months. Treatment for refractory or relapsed disease includes single-agent treatment with docetaxel, pemetrexed or EGFR-targeting TKIs (gefitinib, erlotinib). TKIs disrupt EGFR signaling by competing with adenosine triphosphate (ATP) for the binding sites at the tyrosine kinase (TK) domain, thus inhibiting the phosphorylation and activation of EGFRs and the downstream signaling network. Gefitinib and erlotinib have been shown to be either non-inferior or superior to chemotherapy in the first- or second-line setting (gefitinib), or superior to placebo in the second- or third-line setting (erlotinib). Certain patient characteristics (adenocarcinoma, non-smoking history, Asian ethnicity, female gender) predict for better survival benefit and response to therapy with TKIs. In addition, the current body of evidence shows that somatic mutations in the EGFR gene are the most robust biomarkers for EGFR-targeting therapy selection. Drugs used in this therapy, however, can be costly, up to C$ 2000 to C$ 3000 per month, and they have only approximately a 10% chance of benefiting unselected patients. For these reasons, the predictive value of EGFR mutation testing for TKIs in patients with advanced NSCLC needs to be determined. EGFR MUTATION TESTING The EGFR gene sequencing by polymerase chain reaction (PCR) assays is the most widely used method for EGFR mutation testing. PCR assays can be performed at pathology laboratories across Ontario. According to experts in the province, sequencing is not currently done in Ontario due to lack of adequate measurement sensitivity. A variety of new methods have been introduced to increase the measurement sensitivity of the mutation assay. Some technologies such as single-stranded conformational polymorphism, denaturing high-performance liquid chromatography, and high-resolution melting analysis have the advantage of facilitating rapid mutation screening of large numbers of samples with high measurement sensitivity but require direct sequencing to confirm the identity of the detected mutations. Other techniques have been developed for the simple, but highly sensitive detection of specific EGFR mutations, such as the amplification refractory mutations system (ARMS) and the peptide nucleic acid-locked PCR clamping. Others selectively digest wild-type DNA templates with restriction endonucleases to enrich mutant alleles by PCR. Experts in the province of Ontario have commented that currently PCR fragment analysis for deletion and point mutation conducts in Ontario, with measurement sensitivity of 1% to 5%. In patients with locally-advanced or metastatic NSCLC, what is the clinical effectiveness of EGFR mutation testing for prediction of response to treatment with TKIs (gefitinib, erlotinib) in terms of progression-free survival (PFS), objective response rates (ORR), overall survival (OS), and quality of life (QoL)?What is the impact of EGFR mutation testing on overall clinical decision-making for patients with advanced or metastatic NSCLC?What is the cost-effectiveness of EGFR mutation testing in selecting patients with advanced NSCLC for treatment with gefitinib or erlotinib in the first-line setting?What is the budget impact of EGFR mutation testing in selecting patients with advanced NSCLC for treatment with gefitinib or erlotinib in the second- or third-line setting? A literature search was performed on March 9, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, CINAHL, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment for studies published from January 1, 2004 until February 28, 2010 using the following terms: Non-Small-Cell Lung CarcinomaEpidermal Growth Factor ReceptorAn automatic literature update program also extracted all papers published from February 2010 until August 2010. Abstracts were reviewed by a single reviewer and for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, and then a group of epidemiologists, until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology. The inclusion criteria were as follows: patients with locally advanced or metastatic NSCLC (stage IIIB or IV)PROCEDURE: EGFR mutation testing before treatment with gefitinib or erlotinibLANGUAGE: publication in EnglishPublished health technology assessments, guidelines, and peer-reviewed literature (abstracts, full text, conference abstract) progression-free survival (PFS), Objective response rate (ORR), overall survival (OS), quality of life (QoL).The exclusion criteria were as follows: Studies lacking outcomes specific to those of interestStudies focused on erlotinib maintenance therapyStudies focused on gefitinib or erlotinib use in combination with cytotoxic agents or any other drugGrey literature, where relevant, was also reviewed. PFSORR determined by means of the Response Evaluation Criteria in Solid Tumours (RECIST)OSQoL QUALITY OF EVIDENCE: The quality of the Phase II trials and observational studies was based on the method of subject recruitment and sampling, possibility of selection bias, and generalizability to the source population. The overall quality of evidence was assessed as high, moderate, low or very low according to the GRADE Working Group criteria. Since the last published health technology assessment by Blue Cross Blue Shield Association in 2007 there have been a number of phase III trials which provide evidence of predictive value of EGFR mutation testing in patients who were treated with gefitinib compared to chemotherapy in the first- or second-line setting. The Iressa Pan Asian Study (IPASS) trial showed the superiority of gefitinib in terms of PFS in patients with EGFR mutations versus patients with wild-type EGFR (Hazard ratio [HR], 0.48, 95%CI; 0.36-0.64 versus HR, 2.85; 95%CI, 2.05-3.98). Moreover, there was a statistically significant increased ORR in patients who received gefitinib and had EGFR mutations compared to patients with wild-type EGFR (71% versus 1%). The First-SIGNAL trial in patients with similar clinical characteristics as IPASS as well as the NEJ002 and WJTOG3405 trials that included only patients with EGFR mutations, provide confirmation that gefitinib is superior to chemotherapy in terms of improved PFS or higher ORR in patients with EGFR mutations. The INTEREST trial further indicated that patients with EGFR mutations had prolonged PFS and higher ORR when treated with gefitinib compared with docetaxel. In contrast, there is still a paucity of strong evidence regarding the predictive value of EGFR mutation testing for response to erlotinib in the second- or third-line setting. The BR.21 trial randomized 731 patients with NSCLC who were refractory or intolerant to prior first- or second-line chemotherapy to receive erlotinib or placebo. While the HR of 0.61 (95%CI, 0.51-0.74) favored erlotinib in the overall population, this was not a significant in the subsequent retrospective subgroup analysis. A retrospective evaluation of 116 of the BR.21 tumor samples demonstrated that patients with EGFR mutations had significantly higher ORRs when treated with erlotinib compared with placebo (27% versus 7%; P=0.03). (ABSTRACT TRUNCATED)

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Divinylbenzene-HP is used for producing vinyl polymers. Divinylbenzene-HP was nominated for study by the National Cancer Institute because of the potential for worker exposure and the structural similarity of divinylbenzene to styrene, a potential human carcinogen. Male and female F344/N rats and B6C3F1 mice were exposed to divinylbenzene-HP (80%) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed by whole body inhalation to divinylbenzene-HP at target concentrations of 0, 25, 50, 100, 200, or 400 ppm 6 hours plus T90 (12 minutes) per day, 5 days per week for 16 days. All rats survived to the end of the study. Significant decreases in mean body weights occurred in both male and female rats in the 400 ppm groups. Relative kidney weights of 50 ppm or greater males and relative liver weights of 200 and 400 ppm males were significantly greater than those of the chamber controls. A clear serous nasal/eye discharge was observed in groups of males exposed to 100 ppm or greater and females exposed to 50 ppm or greater. Minimal or mild rhinitis occurred in 400 ppm rats of both sexes. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed by whole body inhalation to divinylbenzene-HP at target concentrations of 0, 25, 50, 100, 200, or 400 ppm for 6 hours plus T90 (12 minutes) per day, 5 days per week for 17 days. All 400 ppm males and females died on or before the second day of the study, and two male and two female 200 ppm mice died early. Mean body weights of 100 and 200 ppm males were significantly less than those of the chamber controls. Thymus weights of exposed groups of males were significantly less than those of the chamber controls, and relative liver weights of 100 and 200 ppm males were significantly increased. Kidney and liver weights of exposed groups of females were significantly greater than those of the chamber controls. Mice exposed to 200 and 400 ppm had liver lesions including degeneration, necrosis, hemorrhage or cytomegaly. Renal tubule necrosis and regeneration occurred at 200 ppm. Necrosis or metaplasia of nasal epithelium and glands occurred in the nose in all exposure groups. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to divinylbenzene-HP at concentrations of 0, 25, 50, 100, 200, or 400 ppm for 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All rats survived to the end of the study. There were no biologically significant changes in body weight in either sex. Nasal/eye discharge was noted in 400 ppm males and 100 ppm females. Kidney and liver weights of exposed groups of males and of 400 ppm females were generally greater than those of the chamber controls. In addition, the relative weights of the heart and testis were significantly increased in 200 and 400 ppm males. Incidences of degeneration of the olfactory epithelium in 200 and 400 ppm rats and basal cell hyperplasia of the olfactory epithelium in rats exposed to 100 ppm or greater were significantly increased. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to divinylbenzene-HP at concentrations of 0, 12.5, 25, 50, 100, or 200 ppm for 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All 200 ppm males and nine 200 ppm females died early. Final mean body weights were significantly lower in males and females exposed to 25, 50, or 100 ppm when compared with chamber controls. Lethargy or hypoactivity was observed in the higher exposure concentration groups. Exposure to divinylbenzene was associated with necrosis of the liver and kidney in 200 ppm males and females dying early. In all exposed groups of male and female mice, there was necrosis of nasal cavity lateral walls, olfactory epithelium, and glands with resultant atrophy of olfactory epithelium and glands in females. A lower number of animals had necrotic or degenerative changes of the upper respiratory tract. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to divinylbenzene-HP at concentrations of 0, 100, 200, or 400 ppm for 6 hours plus T90 (12 minutes) per day, 5 days per week for up to 105 weeks. Survival of 400 ppm females was significantly less than that of the chamber control group. Survival of all exposed groups of males was similar to that of the chamber control group. Mean body weights of 400 ppm males and females were significantly less than those of the controls during the second half of the study. Renal tubule carcinomas occurred in two of 50 males exposed to 400 ppm in the original kidney sections, an incidence that exceeded the historical control range. In 400 ppm males, the incidence of renal tubule hyperplasia was increased, and the incidence of nephropathy was significantly increased. Following combined analysis of single and step-section data, the incidences of renal tubule adenoma and adenoma or carcinoma (combined) were marginally higher in 200 and 400 ppm males, and the incidence of renal tubule hyperplasia was significantly increased in 400 ppm males. The incidences of malignant glial cell tumors (malignant astrocytoma and oligodendroglioma) in the brain were slightly increased in 100 and 200 ppm males, and the incidence in the 200 ppm group exceeded the historical range for chamber controls. There were increased incidences of degenerative and regenerative changes in the olfactory epithelium in the nose of all exposed groups of rats. The incidence of focal chronic inflammation in the lung of 400 ppm males was significantly greater than in the chamber control group. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to divinylbenzene-HP at concentrations of 0, 10, 30, or 100 ppm for 6 hours plus T90 (12 minutes) per day, 5 days per week for up to 105 weeks. Survival of all exposed groups of male and female mice was similar to that of the chamber controls. Mean body weights were lower relative to chamber controls in 100 ppm males and in 30 and 100 ppm females. The incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) in 100 ppm males were greater than chamber control incidences, but the incidences of adenoma or carcinoma (combined) were within the historical control range. The incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) in all exposed groups of females were generally greater than those of the chamber controls; the incidences were at the upper end or exceeded the historical control ranges. There was a greater incidence and severity of alveolar epithelial hyperplasia in 100 ppm females and a greater severity of this lesion in 30 ppm females, when compared to chamber controls. The incidences and/or severities of atypical bronchiole hyperplasia were significantly increased in all exposed groups of mice. Nonneoplastic nasal lesions occurred in most exposed mice. Divinylbenzene-HP was not mutagenic in any of three independent gene mutation assays using Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537 or Escherichia coli tester strain WP2 uvrA with or without induced hamster or rat liver enzymes. No increases in the frequencies of micronucleated normochromatic erythrocytes or alterations in the percentages of polychromatic erythrocytes were seen in peripheral blood of male or female B6C3F1 mice exposed to divinylbenzene-HP by inhalation for 3 months. Under the conditions of this 2-year inhalation study, there was equivocal evidence of carcinogenic activity of divinylbenzene-HP in male F344/N rats based upon the occurrence of carcinomas in the kidney and glial tumors in the brain. There was no evidence of carcinogenic activity in female F344/N rats exposed to 100, 200, or 400 ppm divinylbenzene-HP. There was no evidence of carcinogenic activity in male B6C3F1 mice exposed to 10, 30, or 100 ppm divinylbenzene-HP. There was equivocal evidence of carcinogenic activity of divinylbenzene-HP in female B6C3F1 mice based on the incidences of alveolar/bronchiolar adenoma or carcinoma (combined) in the lung. Exposure to divinylbenzene-HP caused nonneoplastic lesions of the nasal cavity in male and female rats and of the lung and nasal cavity in male and female mice.

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Acetonitrile is used primarily as a solvent in extractive distillation and crystallization of pharmaceutical and agricultural products and as a catalyst in chemical reactions. It was nominated for testing by the National Cancer Institute due to its presence in drinking water supplies and the environment, due to lack of information on the carcinogenicity of alkyl cyanides, and because of widespread worker exposure. Male and female F344/N rats and B6C3F1 mice were exposed to acetonitrile (at least 99% pure) by inhalation for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood of B6C3F1 mice exposed to acetonitrile for 13 weeks. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 100, 200, 400, 800, or 1,600 ppm (equivalent to 0, 168, 335, 670, 1,340, or 2,681 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 13 weeks. Six male and three female rats that received 1,600 ppm and one male that received 800 ppm died during the study. At exposure concentrations up to and including 800 ppm, the final mean body weights and body weight gains were generally similar to those of the controls. At 1,600 ppm, body weight gain was lower and the final mean body weights of both males and females were significantly lower than those of the controls. Hypoactivity and ruffled fur were observed during the first week of the study in males receiving 800 ppm and males and females receiving 1,600 ppm. Additional clinical findings in 1,600 ppm males that died during week 1 were ataxia, abnormal posture, and clonic convulsions. Clinical pathology findings included nonresponsive, normocytic, normochromic anemia in 1,600 ppm males and females and in 800 ppm females, and decreased triiodothyronine (T3) concentrations in 1,600 ppm females. Absolute and relative thymus weights were significantly lower than those of the controls in the 800 and 1,600 ppm males and females. Females exposed to 1,600 ppm had significantly greater absolute and relative heart, kidney, and liver weights than those of the controls. There were no clear exposure-related histopathologic effects, although pulmonary congestion and edema and hemorrhage in the lung and brain were seen in some rats that died early. These lesions are consistent with cyanide-induced anoxia. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 100, 200, 400, 800, or 1,600 ppm (equivalent to 0, 168, 335, 670, 1,340, or 2,681 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 13 weeks. All mice exposed to 1,600 ppm died during the first 3 weeks of the study. In addition, one 400 ppm female and one male and four females from the 800 ppm groups also died before the end of the study. Body weight gains were similar to those of controls for all surviving groups of mice except the 800 ppm males, for which the final mean body weight was slightly lower than that of the controls. Clinical findings observed during the first week in 800 and 1,600 ppm mice were hypoactivity and a hunched, rigid posture. In males that received 200 ppm and above, absolute liver weights were greater than that of the controls and relative liver weights were greater in all exposed groups. In 800 ppm females, the absolute liver weight was greater than that of the controls and relative liver weights of females that received 400 ppm and above were greater than that of the controls. Lesions clearly associated with acetonitrile exposure were observed in the stomach, predominantly the forestomach, of males that received 400 ppm and above and of females that received 200 ppm and above. Histologically, these focal or multifocal pale to dark raised lesions consisted of areas of focal epithelial hyperplasia and ulceration, sometimes associated with hemosiderin deposition. An increased incidence of cytoplasmic vacuolation occurred in the liver of males and females exposed to 400 or 800 ppm. A lack of fatty degenerative change was observed inrved in the X-zone of the adrenal cortex of 800 and 1,600 ppm female mice. 2-YEAR STUDY IN RATS: The doses selected for the 2-year study of acetonitrile were based on reduced survival of 800 ppm males and 1,600 ppm males and females in the 13-week study. Groups of up to 56 male and 56 female rats were exposed to 0, 100, 200, or 400 ppm (equivalent to 0, 168, 335, or 670 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 2 years. Eight male and eight female rats from each exposure group were evaluated at 15 months for histopathology and hematology parameters. Survival, Body Weights, Clinical Findings, and Hematology: Two-year survival, mean body weights, organ weights, behavior, general health, and appearance of exposed male and female rats were similar to those of the controls. The hematologic effects observed were minor and of no biological significance. Pathology Findings: The incidences of hepatocellular adenoma (3/48), hepatocellular carcinoma (3/48), and hepatocellular adenoma or carcinoma (combined; 5/48) were greater in male rats exposed to 400 ppm than in the controls (one carcinoma). The incidences of hepatocellular adenoma and hepatocellular carcinoma were within the range of historical controls. However, the incidence of hepatocellular adenoma or carcinoma (combined) slightly exceeded the range of historical controls (2&amp;percnt;-8&amp;percnt;). In addition, the incidences of basophilic, eosinophilic, and mixed cell foci in 400 ppm males were marginally greater than in controls, suggesting hepatotoxicity of acetonitrile. There were no exposure-related liver lesions in female rats. 2-YEAR STUDY IN MICE: The exposure concentrations selected for the 2-year study were based on reduced survival and gross and histopathologic lesions in 400, 800, and 1,600 ppm groups of male and female mice in the 13-week study. Groups of 60 male and 60 female mice were exposed to 0, 50, 100, or 200 ppm (equivalent to 0, 84, 168, or 335 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 2 years. Ten male and 10 female mice from each exposure group were evaluated at 15 months for histopathology. Survival, Body Weights, and Clinical Findings: Two-year survival of exposed male and female mice was similar to that of the controls, except that the survival of male mice in the 200 ppm group was significantly greater than that of the controls. Mean body weights and organ weights of exposed groups of male and female mice were similar to those of the controls, and no clinical observations in any group were clearly related to acetonitrile exposure. Pathology Findings: There were no increases in the incidences of neoplasms that were considered related to acetonitrile exposure in mice. The incidence of squamous hyperplasia of the epithelium of the forestomach was significantly increased at 15 months in 200 ppm females. At 2 years, the increased incidence of this lesion was dose related in all exposed groups of males and females. GENETIC TOXICOLOGY: Acetonitrile was not mutagenic in Salmonella typhimurium strain TA97, TA98, TA100, TA1535, or TA1537, with or without S9 metabolic activation. In cultured Chinese hamster ovary cells, acetonitrile produced a weakly positive response in the sister chromatid exchange test without, but not with, S9. A small increase in chromosomal aberrations was observed in cultured Chinese hamster ovary cells treated with acetonitrile in the presence, but not in the absence, of S9. A significant increase in micronucleated normochromatic erythrocytes was observed in peripheral blood samples from male mice treated with acetonitrile for 13 weeks; the frequency of micronucleated erythrocytes in female mice was not affected by exposure to acetonitrile. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of acetonitrile in male F344/N rats based on marginally increased incidences of hepatocellular adenoma and carcinoma. There was no evidence of carcinogenic activity of acetonitrile in female F344/N rats exposed to 100, 200, or 400 ppm. There was no evidence of carcinogenic activity of acetonitrile in male or female B6C3F1 mice exposed to 50, 100, or 200 ppm. Exposure to acetonitrile by inhalation resulted in increased incidences of hepatic basophilic foci in male rats and of squamous hyperplasia of the forestomach in male and female mice. Synonyms: Cyanomethane, ethanenitrile, ethyl nitrile, methanecarbonitrile, methyl cyanide, nitrile of acetic acid

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On returning from a medical meeting, we learned that sadly a patient, "Mr. B.," had passed away. His death was a completely unexpected surprise. He had been doing well nine months after a course of intensive radiotherapy for a locally advanced head and neck cancer; in his most recent follow-up notes, he was described as a "complete remission." Nonetheless, he apparently died peacefully in his sleep from a cardiac arrest one night and was found the next day by a concerned neighbor. In our absence, after Mr. B. expired, his death certificate was filled out by a physician who didn't know him in detail, but did know why he recently was treated in our department. The cause of death was listed as head and neck cancer. It wasn't long after his death before we began to receive those notorious "requests for additional information," letters from the statistical office of a well-known cooperative group. Mr. B., as it turns out, was on a clinical trial, and it was "vital" to know further details of the circumstances of his passing. Perhaps this very large cancer had been controlled and Mr. B. succumbed to old age (helped along by the tobacco industry). On the other hand, maybe the residual "fibrosis" in his neck was actually packed with active tumor and his left carotid artery was finally 100% pinched off, or maybe he suffered a massive pulmonary embolism from cancer-related hypercoagulability. The forms and requests were completed with a succinct "cause of death uncertain," adding, "please have the Study Chairs call to discuss this difficult case." Often clinical reports of outcomes utilize and emphasize the endpoint "disease specific survival" (DSS). Like overall survival (OS), the DSS can be calculated by actuarial methods, with patients who have incomplete follow-up "censored" at the time of last follow-up pending further information. In the DSS, however, deaths unrelated to the index cancer of interest are censored at the time of death; thus, a death from intercurrent disease is considered a "success" (to the investigator, that is; obviously, not to the patient and his or her family). The DSS rate will always be superior to the OS rate. Obviously, for any OS curve, if one waits long enough it will ultimately come to zero. There is thus a very logical rationale for reporting the DSS separately, particularly in diseases where death from intercurrent disease is expected to be common. Analyzing the DSS allows researchers to better compare the biologic efficacy of two or more cancer treatments, since it does not necessarily come to zero. Unlike some other endpoints, including local-regional control or freedom from progression, it takes into account the possibility of salvage therapy. DSS also focuses on an endpoint of interest to the public-death from cancer. In a recent popular media survey in which people were asked how they would choose to die if they could, 0% selected cancer. However, there are two serious potential problems with heavy dependence on the DSS. First, since patients who die from intercurrent disease are considered "cured," it seriously inflates the apparent effectiveness of a cancer treatment. Given the same biologic disease and the same treatment, the DSS as calculated in an old, sick population at high risk of intercurrent death will be better than the DSS in a younger, healthier population whose major risk is from their cancer. This problem has been discussed with respect to early stage prostate cancer, in which the conservative approach of observation has been criticized. The studies at issue rely heavily on the DSS, suggesting a comparable DSS (90% at 10 years) with "watchful waiting" to other researchers' results with aggressive therapy. The problem is that these series of conservative management focus on a patient population (as opposed to individuals) with a high risk of competing causes of mortality, which is very different from the population of patients generally treated with aggressive therapy (in which some have shown overall survivals superior to age-matched controls). It is fallacious and illogical to compare nonrandomized series of observation to those of aggressive therapy. In addition to the above problem, the use of DSS introduces another potential issue which we will call the bias of cause-of-death-interpretation. All statistical endpoints (e.g., response rates, local-regional control, freedom from brain metastases), except OS, are known to depend heavily on the methods used to define the endpoint and are often subject to significant interobserver variability. There is no reason to believe that this problem does not occasionally occur with respect to defining a death as due to the index cancer or to intercurrent disease, even though this issue has been poorly studied. In many oncologic situations-for example, metastatic lung cancer-this form of bias does not exist. In some situations, such as head and neck cancer, this could be an intermediate problem (Was that lethal chest tumor a second primary or a metastasis?.Would the fatal aspiration pneumonia have occurred if he still had a tongue?.And what about Mr. B. described above?). In some situations, particularly relatively "good prognosis" neoplasms, this could be a substantial problem, particularly if the adjudication of whether or not a death is cancer-related is performed solely by researchers who have an "interest" in demonstrating a good DSS. What we are most concerned about with this form of bias relates to recent series on observation, such as in early prostate cancer. It is interesting to note that although only 10% of the "observed" patients die from prostate cancer, many develop distant metastases by 10 years (approximately 40% among patients with intermediate grade tumors). Thus, it is implied that many prostate cancer metastases are usually not of themselves lethal, which is a misconception to anyone experienced in taking care of prostate cancer patients. This is inconsistent with U.S. studies of metastatic prostate cancer in which the median survival is two to three years. It is possible that many deaths attributed to intercurrent disease in "watchful waiting" series were in fact prostate cancer-related, perhaps related to failure to thrive, urosepsis, or pulmonary emboli. We will not know without an independent review of the medical records of individual patients; in some cases, even the most detailed review, sometimes even an autopsy, will not be conclusive. There are only a few data available describing the problems created by cause-of-death-interpretation bias. One small study, presented only in abstract form, assessed the cause of death in 50 randomly selected prostate cancer patients who died. Five experts in prostate cancer were asked to assign the cause of death as due to or not due to prostate cancer. The DSS varied from 21% to 35% among the five reviewers, a relative difference of 66%. Studies of autopsies, which are now rarely done in the U.S., have shown that fatal malignant tumors were occasionally missed by clinicians and-even more sobering-an occasional patient thought to have died from metastatic cancer is found to have no tumor but to have died from a "benign" cause such as TB. One study suggested an error rate of approximately 8%. Clearly the use of DSS is here to stay and is a useful adjunct to OS in analyzing randomized trials. There needs to be more research on the validity and interobserver reproducibility of the DSS. In the meantime, researchers should not report DSS without reporting OS and the reasons for intercurrent deaths should be described-peer reviewers should enforce this. As with so many other problems with statistics in the medical literature, it is the job of the reader to remain skeptical. The rate of intercurrent deaths in a study should reflect the age and demographics of the study population. If the DSS is far superior to the OS, the population being studied may be unusually sick (and thus unrealistic), or there may be a bias in classifying the causes of death. Similarly, if the DSS and OS are identical (unless a highly virulent malignancy is being studied), it may suggest the researchers have only included an unusually healthy (and thus unrealistic) patient population. Finally, we would also be a bit suspicious of a sizeable series that did not have any deaths that were considered of "uncertain" cause, unless the researchers specifically included them as being due to the cancer. We honestly think that everybody has a few patients like Mr. B.

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[Structure-see text] 2-Methylimidazole and 4-methylimidazole are intermediate/starting materials or components in the manufacture of pharmaceuticals, photographic and photothermographic chemicals, dyes and pigments, agricultural chemicals, and rubber; these chemicals have been identified as undesirable by-products in several foods and have been detected in mainstream and sidestream tobacco smoke. The National Cancer Institute nominated 2- and 4-methylimidazole as candidates for toxicity and carcinogenicity studies. Toxicity studies were carried out in male and female F344/N rats and B6C3F1 mice. Animals were exposed to 2- or 4-methylimidazole in feed for 15 days or 14 weeks; clinical pathology studies were conducted in the 14-week studies on days 8, 29, and 86 and at week 14. Genetic toxicity studies were conducted in Salmonella typhimurium, rat and mouse bone marrow, and mouse peripheral blood. Groups of five male and five female rats and mice were fed diets containing 0, 1,200, 3,300, or 10,000 ppm 2-methylimidazole (equivalent to average daily doses of approximately 115, 290, or 770 mg 2-methylimidazole/ kg body weight to rats; 220, 640, or 2,100 mg/kg to male mice; 300, 800, or 2,400 to female mice) for 15 days. Groups of five male and five female rats and mice were fed diets containing 0, 300, 800, or 2,500 ppm 4-methylimidazole (equivalent to average daily doses of approximately 30, 80, or 220 mg/kg for rats and 65, 170, or 500 mg/kg for mice) for 15 days. In the 15-day 2-methylimidazole studies, all animals survived to the end of the studies. The mean body weights of 10,000 ppm male rats and female mice were significantly less than those of the controls. Feed consumption by 10,000 ppm male and female rats was reduced. Enlarged thyroid glands were observed in 3,300 and 10,000 ppm male and female rats. The incidences of diffuse hyperplasia of follicular cells of the thyroid gland in 3,300 and 10,000 ppm male and female rats and pars distalis hypertrophy of the pituitary gland in 3,300 and 10,000 ppm males and 10,000 ppm females were increased compared to the controls. In all exposed groups of male and female mice, the incidences and severities of follicular cell hypertrophy of the thyroid gland and the severities of hematopoietic cell proliferation of the spleen generally increased with increasing exposure concentration. In the 4-methylimidazole studies, all animals survived to the end of the studies, and there were no significant differences in mean body weights, clinical findings, organ weights, or gross or microscopic lesions between exposed and control groups. Groups of 10 male and 10 female rats and mice were fed diets containing 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm 2- or 4-methylimidazole (equivalent to average daily doses of approximately 40, 80, 160, 300, or 560 mg/kg 2- or 4-methylimidazole to rats; and 100, 165, 360, 780, or 1,740 mg/kg 2-methylimidazole or 100, 240, 440, 915, or 1,840 mg/kg 4-methylimidazole to male mice; and 90, 190, 400, 800, or 1,860 mg/kg 2-methylimidazole or 110, 240, 540, 1,130, or 3,180 mg/kg 4-methylimidazole to females) for 14 weeks. All animals survived to the end of the 14-week 2-methylimidazole studies. Compared to the controls, the mean body weights were significantly decreased in groups of male rats and mice exposed to 2,500 ppm or greater and in 5,000 and 10,000 ppm female rats and mice. In rats, 2-methylimidazole induced a transient erythrocytosis in females and a minimal, exposure concentration-related, microcytic, normochromic, nonresponsive anemia. 2-Methylimidazole increased thyroid-stimulating hormone concentrations and decreased thyroxine and triiodothyronine concentrations of male and female rats in an exposure concentration-related manner. 2-Methylimidazole induced a mild to moderate, exposure concentration-related, macrocytic, hyperchromic, responsive anemia in mice. Triiodothyronine concentrations were increased in exposed male and female mice, and thyroxine concentrations were decreased in exposed females. Relative to the control groups, clinical chemistry evaluations on day 29 and at week 14 identified decreases in alanine aminotransferase concentrations and total protein and albumin concentrations of rats. In the 2-methylimidazole studies, absolute spleen weights were significantly increased in all exposed groups of male rats. The heart and liver weights were increased in all exposed groups of male mice, as were the spleen weights of female mice exposed to 2,500 ppm or greater. Spermatid heads per testis and mean spermatid count were significantly decreased in 10,000 ppm male rats. The estrous cycle of 10,000 ppm female rats was significantly increased. Gross pathology observations included enlarged thyroid glands, small uteri, and mottled spleen in 5,000 and 10,000 ppm mice. The incidences of diffuse follicular cell hyperplasia of the thyroid gland were significantly increased in male rats exposed to 1,250 ppm or greater and female rats exposed to 2,500 ppm or greater. The incidence of testicular degeneration was significantly increased in 10,000 ppm male rats, and two males in the 10,000 ppm group had follicular cell adenoma of the thyroid gland. In mice, there were generally significant increases in the incidences of follicular cell hypertrophy of the thyroid gland, hematopoietic cell proliferation of the spleen, and hemosiderin pigmentation of the renal tubule in males exposed to 1,250 ppm or greater and females exposed to 2,500 ppm or greater. In the 14-week 4-methylimidazole studies, one 10,000 ppm male mouse was found dead during week 4, and seven 10,000 ppm female mice were found dead during weeks 1 and 2. Mean body weights were significantly less than those of the controls for male rats exposed to 2,500 ppm or greater, 5,000 and 10,000 ppm female rats, male mice exposed to 1,250 ppm or greater, and all exposed groups of female mice. Reduced feed consumption was observed in 5,000 and 10,000 ppm male and female rats. Clinical findings included nasal/eye discharge, ruffled fur, thinness, ataxia, and abnormal breathing in rats, and ruffled fur and dull coats in female mice. On days 29 and 82, functional observations in 5,000 and 10,000 ppm rats included labored or increased respiration, mild tremors, walking on tiptoes, hunched posture, piloerection, crouching over, impaired coordination of movement, ataxia, and pupillary constriction. 4-Methylimidazole induced a transient erythrocytosis and a minimal, exposure concentration-related, microcytic, normochromic, nonresponsive anemia in male and female rats. Clinical chemistry evaluations generally showed a cholestatic effect in exposed male and female rats. At week 14, there was a significant decrease in total protein and albumin concentrations of female rats exposed to 5,000 or 10,000 ppm. In mice, 4-methylimidazole induced a macrocytic, hyperchromic, responsive anemia and, particularly in males, increases in triiododthyronine concentrations and transient decreases in thyroxine concentrations. In the 4-methylimidazole studies, the liver weights of male rats exposed to 2,500 ppm or greater were significantly increased; spleen weights of female rats exposed to 2,500 ppm or greater were decreased. The absolute liver weight was decreased in 10,000 ppm male mice, and relative weights were significantly increased in all exposed groups of mice. In female mice, there was a significant decrease in the absolute weights and increase in the relative weights of the heart, right kidney, and liver in groups exposed to 2,500 ppm or greater. The epididymal spermatozoal concentration was significantly increased in 5,000 ppm male rats. Gross pathology observations included pale livers in male rats exposed to 2,500 ppm or greater and small testes and uteri in 10,000 ppm male and female rats. Microscopic analysis identified significantly increased incidences of cytoplasmic hepatocyte vacuolization of the liver of male rats exposed to 2,500 ppm or greater and 10,000 ppm female rats, hypospermia of the epididymis in 10,000 ppm male rats, atrophy and inflammation of the prostate gland in 10,000 ppm male rats, and degeneration of the testes in 5,000 and 10,000 ppm male rats. 2-Methylimidazole and 4-methylimidazole were negative in the S. typhimurium mutation assay when tested in strains TA97, TA98, TA100, and TA1535, with and without S9 activation enzymes. Testing of 2-methylimidazole in vivo for induction of chromosomal damage, as measured by micronucleated erythrocyte frequency, produced mixed results. When administered by intraperitoneal injection three times at 24-hour intervals, 2-methylimidazole produced negative results in bone marrow micronucleus tests in rats and mice. However, in the 14-week study of 2-methylimidazole, a significant exposure-related increase in the frequency of micronucleated normochromatic erythrocytes was noted in peripheral blood of male and female mice. In vivo, 4-methylimidazole produced uniformly negative results in three-injection bone marrow micronucleus tests in rats and mice and in 14-week peripheral blood micronucleus tests in male and female mice.

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Psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. Several randomised controlled trials (RCTs) have compared the efficacy of the different systemic treatments in psoriasis against placebo. However, the relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis. This is the baseline update of a Cochrane Review first published in 2017, in preparation for this Cochrane Review becoming a living systematic review. To compare the efficacy and safety of conventional systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis, and to provide a ranking of these treatments according to their efficacy and safety. We updated our research using the following databases to January 2019: the Cochrane Skin Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and the conference proceedings of a number of dermatology meetings. We also searched five trials registers and the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) reports (until June 2019). We checked the reference lists of included and excluded studies for further references to relevant RCTs. Randomised controlled trials (RCTs) of systemic treatments in adults (over 18 years of age) with moderate-to-severe plaque psoriasis or psoriatic arthritis whose skin had been clinically diagnosed with moderate-to-severe psoriasis, at any stage of treatment, in comparison to placebo or another active agent. The primary outcomes of this review were: the proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90 at induction phase (from 8 to 24 weeks after the randomisation), and the proportion of participants with serious adverse effects (SAEs) at induction phase. We did not evaluate differences in specific adverse effects. Several groups of two review authors independently undertook study selection, data extraction, 'Risk of bias' assessment, and analyses. We synthesised the data using pair-wise and network meta-analysis (NMA) to compare the treatments of interest and rank them according to their effectiveness (as measured by the PASI 90 score) and acceptability (the inverse of serious adverse effects). We assessed the certainty of the body of evidence from the NMA for the two primary outcomes, according to GRADE, as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We included 140 studies (31 new studies for the update) in our review (51,749 randomised participants, 68% men, mainly recruited from hospitals). The overall average age was 45 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo-controlled (59%), 30% were head-to-head studies, and 11% were multi-armed studies with both an active comparator and a placebo. We have assessed a total of 19 treatments. In all, 117 trials were multicentric (two to 231 centres). All but two of the outcomes included in this review were limited to the induction phase (assessment from 8 to 24 weeks after randomisation). We assessed many studies (57/140) as being at high risk of bias; 42 were at an unclear risk, and 41 at low risk. Most studies (107/140) declared funding by a pharmaceutical company, and 22 studies did not report the source of funding. Network meta-analysis at class level showed that all of the interventions (conventional systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in terms of reaching PASI 90. At class level, in terms of reaching PASI 90, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents. At drug level, in terms of reaching PASI 90, infliximab, all of the anti-IL17 drugs (ixekizumab, secukinumab, bimekizumab and brodalumab) and the anti-IL23 drugs (risankizumab and guselkumab, but not tildrakizumab) were significantly more effective in reaching PASI 90 than ustekinumab and 3 anti-TNF alpha agents: adalimumab, certolizumab and etanercept. Adalimumab and ustekinumab were significantly more effective in reaching PASI 90 than certolizumab and etanercept. There was no significant difference between tofacitinib or apremilast and between two conventional drugs: ciclosporin and methotrexate. Network meta-analysis also showed that infliximab, ixekizumab, risankizumab, bimekizumab, guselkumab, secukinumab and brodalumab outperformed other drugs when compared to placebo in reaching PASI 90. The clinical effectiveness for these seven drugs was similar: infliximab (versus placebo): risk ratio (RR) 29.52, 95% confidence interval (CI) 19.94 to 43.70, Surface Under the Cumulative Ranking (SUCRA) = 88.5; moderate-certainty evidence; ixekizumab (versus placebo): RR 28.12, 95% CI 23.17 to 34.12, SUCRA = 88.3, moderate-certainty evidence; risankizumab (versus placebo): RR 27.67, 95% CI 22.86 to 33.49, SUCRA = 87.5, high-certainty evidence; bimekizumab (versus placebo): RR 58.64, 95% CI 3.72 to 923.86, SUCRA = 83.5, low-certainty evidence; guselkumab (versus placebo): RR 25.84, 95% CI 20.90 to 31.95; SUCRA = 81; moderate-certainty evidence; secukinumab (versus placebo): RR 23.97, 95% CI 20.03 to 28.70, SUCRA = 75.4; high-certainty evidence; and brodalumab (versus placebo): RR 21.96, 95% CI 18.17 to 26.53, SUCRA = 68.7; moderate-certainty evidence. Conservative interpretation is warranted for the results for bimekizumab (as well as tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate), as these drugs, in the NMA, have been evaluated in few trials. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. Nevertheless, the SAE analyses were based on a very low number of events with low to very low certainty for just under half of the treatment estimates in total, and moderate for the others. Thus, the results have to be viewed with caution and we cannot be sure of the ranking. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1) the results were very similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions. Our review shows that compared to placebo, the biologics infliximab, ixekizumab, risankizumab, bimekizumab, guselkumab, secukinumab and brodalumab were the best choices for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of moderate- to high-certainty evidence (low-certainty evidence for bimekizumab). This NMA evidence is limited to induction therapy (outcomes were measured from 8 to 24 weeks after randomisation) and is not sufficient for evaluation of longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean age of 45 years) and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice. Another major concern is that short-term trials provide scanty and sometimes poorly-reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. Indeed, we found no significant difference in the assessed interventions and placebo in terms of SAEs, but the evidence for all the interventions was of very low to moderate quality. In order to provide long-term information on the safety of the treatments included in this review, it will also be necessary to evaluate non-randomised studies and postmarketing reports released from regulatory agencies. In terms of future research, randomised trials comparing directly active agents are necessary once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between conventional systemic and small molecules, and between biological agents (anti-IL17 versus anti-IL23, anti-IL23 versus anti-IL12/23, anti-TNF alpha versus anti-IL12/23). Future trials should also undertake systematic subgroup analyses (e.g. assessing biological-naïve participants, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, outcome measure harmonisation is needed in psoriasis trials, and researchers should look at the medium- and long-term benefit and safety of the interventions and the comparative safety of different agents. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

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In August 2008, the Medical Advisory Secretariat (MAS) presented a vignette to the Ontario Health Technology Advisory Committee (OHTAC) on a proposed targeted health care delivery model for chronic care. The proposed model was defined as multidisciplinary, ambulatory, community-based care that bridged the gap between primary and tertiary care, and was intended for individuals with a chronic disease who were at risk of a hospital admission or emergency department visit. The goals of this care model were thought to include: the prevention of emergency department visits, a reduction in hospital admissions and re-admissions, facilitation of earlier hospital discharge, a reduction or delay in long-term care admissions, and an improvement in mortality and other disease-specific patient outcomes.OHTAC approved the development of an evidence-based assessment to determine the effectiveness of specialized community based care for the management of heart failure, Type 2 diabetes and chronic wounds.PLEASE VISIT THE MEDICAL ADVISORY SECRETARIAT WEB SITE AT: www.health.gov.on.ca/ohtas to review the following reports associated with the Specialized Multidisciplinary Community-Based care series.Specialized multidisciplinary community-based care series: a summary of evidence-based analysesCommunity-based care for the specialized management of heart failure: an evidence-based analysisCommunity-based care for chronic wound management: an evidence-based analysisPlease note that the evidence-based analysis of specialized community-based care for the management of diabetes titled: "Community-based care for the management of type 2 diabetes: an evidence-based analysis" has been published as part of the Diabetes Strategy Evidence Platform at this URL: http://www.health.gov.on.ca/english/providers/program/mas/tech/ohtas/tech_diabetes_20091020.htmlPLEASE VISIT THE TORONTO HEALTH ECONOMICS AND TECHNOLOGY ASSESSMENT COLLABORATIVE WEB SITE AT: http://theta.utoronto.ca/papers/MAS_CHF_Clinics_Report.pdf to review the following economic project associated with this series:Community-based Care for the specialized management of heart failure: a cost-effectiveness and budget impact analysis. The objective of this evidence-based analysis was to determine the effectiveness of specialized multidisciplinary care in the management of heart failure (HF). TARGET POPULATION AND CONDITION HF is a progressive, chronic condition in which the heart becomes unable to sufficiently pump blood throughout the body. There are several risk factors for developing the condition including hypertension, diabetes, obesity, previous myocardial infarction, and valvular heart disease.(1) Based on data from a 2005 study of the Canadian Community Health Survey (CCHS), the prevalence of congestive heart failure in Canada is approximately 1% of the population over the age of 12.(2) This figure rises sharply after the age of 45, with prevalence reports ranging from 2.2% to 12%.(3) Extrapolating this to the Ontario population, an estimated 98,000 residents in Ontario are believed to have HF. Disease management programs are multidisciplinary approaches to care for chronic disease that coordinate comprehensive care strategies along the disease continuum and across healthcare delivery systems.(4) Evidence for the effectiveness of disease management programs for HF has been provided by seven systematic reviews completed between 2004 and 2007 (Table 1) with consistency of effect demonstrated across four main outcomes measures: all cause mortality and hospitalization, and heart-failure specific mortality and hospitalization. (4-10) However, while disease management programs are multidisciplinary by definition, the published evidence lacks consistency and clarity as to the exact nature of each program and usual care comparators are generally ill defined. Consequently, the effectiveness of multidisciplinary care for the management of persons with HF is still uncertain. Therefore, MAS has completed a systematic review of specialized, multidisciplinary, community-based care disease management programs compared to a well-defined usual care group for persons with HF. What is the effectiveness of specialized, multidisciplinary, community-based care (SMCCC) compared with usual care for persons with HF? LITERATURE SEARCH STRATEGY: A comprehensive literature search was completed of electronic databases including MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, Cochrane Library and Cumulative Index to Nursing &amp; Allied Health Literature. Bibliographic references of selected studies were also searched. After a review of the title and abstracts, relevant studies were obtained and the full reports evaluated. All studies meeting explicit inclusion and exclusion criteria were retained. Where appropriate, a meta-analysis was undertaken to determine the pooled estimate of effect of specialized multidisciplinary community-based care for explicit outcomes. The quality of the body of evidence, defined as one or more relevant studies was determined using GRADE Working Group criteria. (11) INCLUSION CRITERIA: Randomized controlled trialSystematic review with meta analysisPopulation includes persons with New York Heart Association (NYHA) classification 1-IV HFThe intervention includes a team consisting of a nurse and physician one of which is a specialist in HF management.The control group receives care by a single practitioner (e.g. primary care physician (PCP) or cardiologist)The intervention begins after discharge from the hospitalThe study reports 1-year outcomes The intervention is delivered predominately through home-visitsStudies with mixed populations where discrete data for HF is not reported All cause mortalityAll cause hospitalizationHF specific mortalityHF specific hospitalizationAll cause duration of hospital stayHF specific duration of hospital stayEmergency room visitsQuality of Life One large and seven small randomized controlled trials were obtained from the literature search. A meta-analysis was completed for four of the seven outcomes including: All cause mortalityHF-specific mortalityAll cause hospitalizationHF-specific hospitalization.Where the pooled analysis was associated with significant heterogeneity, subgroup analyses were completed using two primary categories: direct and indirect model of care; andtype of control group (PCP or cardiologist).The direct model of care was a clinic-based multidisciplinary HF program and the indirect model of care was a physician supervised, nurse-led telephonic HF program. All studies, except one, were completed in jurisdictions outside North America. (12-19) Similarly, all but one study had a sample size of less than 250. The mean age in the studies ranged from 65 to 77 years. Six of the studies(12;14-18) included populations with a NYHA classification of II-III. In two studies, the control treatment was a cardiologist (12;15) and two studies reported the inclusion of a dietitian, physiotherapist and psychologist as members of the multidisciplinary team (12;19). ALL CAUSE MORTALITY: Eight studies reported all cause mortality (number of persons) at 1 year follow-up. (12-19) When the results of all eight studies were pooled, there was a statistically significant RRR of 29% with moderate heterogeneity (I(2) of 38%). The results of the subgroup analyses indicated a significant RRR of 40% in all cause mortality when SMCCC is delivered through a direct team model (clinic) and a 35% RRR when SMCCC was compared with a primary care practitioner. HF-SPECIFIC MORTALITY: Three studies reported HF-specific mortality (number of persons) at 1 year follow-up. (15;18;19) When the results of these were pooled, there was an insignificant RRR of 42% with high statistical heterogeneity (I(2) of 60%). The GRADE quality of evidence is moderate for the pooled analysis of all studies. ALL CAUSE HOSPITALIZATION: Seven studies reported all cause hospitalization at 1-year follow-up (13-15;17-19). When pooled, their results showed a statistically insignificant 12% increase in hospitalizations in the SMCCC group with high statistical heterogeneity (I(2) of 81%). A significant RRR of 12% in all cause hospitalization in favour of the SMCCC care group was achieved when SMCCC was delivered using an indirect model (telephonic) with an associated (I(2) of 0%). The Grade quality of evidence was found to be low for the pooled analysis of all studies and moderate for the subgroup analysis of the indirect team care model. HF-SPECIFIC HOSPITALIZATION: Six studies reported HF-specific hospitalization at 1-year follow-up. (13-15;17;19) When pooled, the results of these studies showed an insignificant RRR of 14% with high statistical heterogeneity (I(2) of 60%); however, the quality of evidence for the pooled analysis of was low. DURATION OF HOSPITAL STAY: Seven studies reported duration of hospital stay, four in terms of mean duration of stay in days (14;16;17;19) and three in terms of total hospital bed days (12;13;18). Most studies reported all cause duration of hospital stay while two also reported HF-specific duration of hospital stay. These data were not amenable to meta-analyses as standard deviations were not provided in the reports. However, in general (and in all but one study) it appears that persons receiving SMCCC had shorter hospital stays, whether measured as mean days in hospital or total hospital bed days. EMERGENCY ROOM VISITS: Only one study reported emergency room visits. (14) This was presented as a composite of readmissions and ER visits, where the authors reported that 77% (59/76) of the SMCCC group and 84% (63/75) of the usual care group were either readmitted or had an ER visit within the 1 year of follow-up (P=0.029). (ABSTRACT TRUNCATED)

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a-Methyldopa sesquihydrate is used in the treatment of hypertension; over 20 million prescriptions are written annually for a -methyldopa or a-methyldopa sesquihydrate in the United States. a-Methyldopa sesquihydrate (USP grade, greater than 99% pure) was selected for study because of widespread human exposure and the lack of carcinogenicity studies on this compound. Fourteen-day, 13-week, and 2-year studies were conducted in F344/N rats and B6C3F1 mice. The chemical was administered in feed because human exposure is primarily by the oral route. Short-term studies were performed in bacteria and mammalian cells to evaluate the potential for genetic damage. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, the chemical was administered at dietary concentrations of 0 and 6,250-100,000 ppm. All rats receiving 100,000 ppm and 2/5 female rats receiving 50,000 ppm died. All mice lived until the end of the studies. Final mean body weights of dosed male rats were 14%-43% lower than that of controls, and those of dosed female rats were 9%-24% lower. Feed consumption by dosed male and female rats was reduced. Final mean body weights of dosed mice were generally within 10% of those of controls; feed consumption by dosed groups was lower than that by controls during the first week of the studies. In the 13-week studies, the chemical was administered at dietary concentrations of 0 and 3,100-50,000 ppm. Deaths occurred in 4/10 male rats, 7/10 female rats, and 2/10 female mice at 50,000 ppm and in 1/10 female rats at 25,000 ppm. Final mean body weights of dosed rats were 6%-46% lower than those of controls. Feed consumption by dosed rat groups was lower than that by controls. Final mean body weights of male mice at 25,000 and 50,000 ppm and female mice at 50,000 ppm were reduced 12%-19%. Feed consumption by dosed and control mice was comparable. Rats and mice receiving 25,000 and 50,000 ppm exhibited clinical signs of toxicity including lethargy, hyperexcitability, ocular discharge, and rough hair coats. Clinical signs of toxicity were judged to be more severe in dosed male mice than in female mice. Minimal to moderate kidney tubular cell regeneration was seen in male and female rats at 12,500, 25,000, and 50,000 ppm. Bone marrow hypoplasia occurred in male rats at 25,000 and 50,000 ppm and in female rats at 6,300 ppm and higher. Nuclear enlargement (karyomegaly) of the renal corticaltubular epithelium was observed in male and female mice administered 12,500-50,000 ppm; these kidney lesions were judged to be more severe and occurred more frequently at concentrations of 25,000 ppm and higher. Because of kidney lesions, bone marrow responses, and body weight effects at 12,500 ppm and higher and increased deaths and clinical signs at 25,000 and 50,000 ppm, dietary concentrations selected for male and female rats in the 2-year studies were 0, 3,100, and 6,300 ppm. Based on clinical signs, kidney effects, and body weight decreases at 25,000 and 50,000 ppm, dietary concentrations selected for male and female mice in the 2-year studies were 0, 6,300, and 12,500 ppm. Diets containing the chemical at these concentrations were fed to groups of 50 male and 50 female rats and 50 male and 50 female mice for 103 weeks. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally 8%-17% lower than those of controls, and mean body weights of dosed mice were generally 5%-22% lower than those of controls throughout the studies. The average amount of a-methyldopa sesquihydrate consumed per day was approximately 110-120 or 230-240 mg/kg per day by low and high dose rats and 830-890 or 1,760-1,800 mg/kg by low and high dose mice. Survival was comparable among dosed and control groups (male rats: control, 28/50; low dose, 26/50; high dose, 27/50; female rats: 35/50; 34/50; 29/50; male mice: 44/50; 42/50; 39/50; female mice: 42/50; 40/50; 38/50). Clinical signs considered to be dose-related included fighting in male rats, irritability in male mice, and rough hair coats in female mice. Nonneoplastic and Neoplasle rats, irritability in male mice, and rough hair coats in female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Several lesions of the forestomach, including edema, chronic inflammation, epithelial hyperplasia, and ulcers, were seen at low incidences in high dose rats. No forestomach neoplasms occurred. No neoplastic lesions were observed in either male or female rats which were considered related to a-methyldopa sesquihydrate exposure. Nephropathy (control, 3/50; low dose, 21/50; high dose, 32/50), karyomegaly (nuclear enlargement) of cells of the tubular epithelium (0/50; 46/50; 44/50, and cysts (2/50; 10/50; 10/50) were observed in the kidney of dosed female mice. Low incidences of tubular cell hyperplasia (0/50; 1/50; 1/50), tubular cell adenomas (0/50; 2/50; 0/50), and tubular cell adenocarcinomas (0/50; 0/50; 1/50) were observed in male mice. Tubular cell adenomas (3/2,029, 0.15&amp;percnt;) and tubular cell adenocarcinomas (3/2,029, 0.15&amp;percnt;)are uncommon in untreated control male B6C3F1 mice. No neoplastic lesions in female mice were considered related to a-methyldopa sesquihydrate exposure. Decreased incidences of several site-specific neoplasms were observed in dosed rats and mice; these decreases might have been due in part to decreased weight gain in dosed groups. The decreases occurred in the adrenal medulla of male rats (pheochromocytomas or malignant pheochromocytomas, combined: 21/49; 3/49; 10/50), uterus of female rats (endometrial stromal polyps: 15/50; 5/49; 1/50), liver of male and female mice (hepatocellular adenomas or carcinomas, combined-- male: 15/50; 5/50; 6/50; female: 4/50; 1/50; 0/50), and anterior pituitary gland of female mice (adenoma: 9/49; 4/40; 2/50). The incidences of malignant tumors (male: 19/50; 9/50; 8/50; female: 21/50; 16/50; 12/50) and benign or malignant tumors (combined) (male: 32/50; 15/50; 17/50; female: 33/50; 22/50; 21/50) were reduced in dosed mice. Reproductive Studies: a-Methyldopa sesquihydrate was administered to male F344/N rats in corn oil by gavage 5 days per week for 65 days at doses of 0, 50, 100, 200, or 400 mg/kg. Decreased body weight was seen in dosed animals. Male rats were mated to untreated female F344/N rats on days 57-61, necropsies were performed on days 65-67, and reproductive toxicity was measured by sperm count, sperm motility, organ weights, hormone levels, and histologic evaluation of the testis. Decreased fertility was observed in males dosed with a-methyldopa sesquihydrate at 200 and 400 mg/kg. Decreases were also seen in sperm count, sperm motility, apparent number of late spermatids, and plasma testosterone levels in males in the 200 and 400 mg/kg groups. This alteration of reproductive function in male rats was found to be reversible after a 13-week recovery period (without dosing). The decreased fertility observed after a-methyldopa sesquihydrate administration was probably due in part to the decreases in plasma testosterone levels. Genetic Toxicity: a-Methyldopa sesquihydrate was not mutagenic when tested with or without exogenous metabolic activation with a preincubation protocol in four strains of Salmonella typhimurium (TA97, TA98, TA100, or TA1535). No increase in chromosomal aberrations or sister chromatid exchanges was observed in Chinese hamsterovary (CHO) cells exposed to a-methyldopa sesquihydrate with or without S9. Audit: The data, documents, and pathology materials from the 2-year studies of a-methyldopa sesquihydrate have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of a-methyldopa sesquihydrate for male or female F344/N rats fed diets containing 3,100 or 6,300 ppm. There was equivocal evidence of carcinogenic activity of a-methyldopa sesquihydrate for male B6C3F1 mice, as shown by three dosed mice having uncommon tubular cell tumors of the kidney. There was no evidence of carcinogenic activity of a -methyldopa sesquihydrate for female B6C3F1 mice fed diets containing 6,300 or 12,500 ppm. Nonneoplastic lesions of the kidney including karyomegaly were observed in dosed female mice. Decreased incidences of several tumor types (in the adrenal gland in male rats, uterus in female rats, liver in male and female mice, and anterior pituitary gland in female mice) were considered related to a-methyldopa sesquihydrate exposure. Synonyms for a-Methyldopa or a-Methyldopa sesquihydrate: 3-hydroxy-a-methyl-L-tyrosine sesquihydrate; L-(a-MD); a-methyl-L-3,4-dihydroxyphenylalanine; L(-)-b-(3,4-dihydroxyphenyl)-a -methylalanine; L-(-)-3-(3,4-dihydroxyphenyl)-2-methylalanine; L-a-methyl-3,4-dihydroxyphenylalanine; a-methyl-b-(3,4-dihydroxyphenyl)-L-alanine; L-(-)-a-methyl-b-(3,4-dihydroxyphenyl)alanine; (-)-methyldopa; L-methyldopa; L-a-methyldopa; a-methyl-L-dopa Trade Names for a-Methyldopa or a-Methyldopa sesquihydrate: Aldomet; Aldometil; Aldomin; a-Medopa; AMD; Bayer 1440 L; Baypresol; Dopamet; Dopatec; Dopegyt; Hyperpax; Medomet; Medopren; Methoplain; MK. B51; MK-351; Presinol; Presolisin; Sedometil; Sembrina

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Pentaerythritol triacrylate is used in the production of ultraviolet-curable inks and coatings, electron beam irradiation- curable coatings, and radiation-cured and photocurable coatings of urethanes and epoxy resins; as a component of photopolymer and flexographic printing inks and plates and photoresists; as an ingredient of acrylic glues, adhesives, and anaerobic sealants; and as a modifier for polyester and fiberglass. It is also used in colloidal dispersions for industrial baked coatings, waterborne and solvent-based alkyds, vinyl/acrylic nonwoven binders, paper and wood impregnates, wire and cable extrusion, polymer-impregnated concrete, and polymer concrete structural composites. Pentaerythritol triacrylate was nominated by the National Cancer Institute for testing based on its high production volume and use, its potential for human exposure, and a lack of adequate testing of the chemical. Male and female F344/N rats and B6C3F(1) mice were administered technical grade pentaerythritol triacrylate (it is reactive and therefore not available as pure pentaerythritol triacrylate) in acetone dermally for 2 weeks or 3 months. Male and female Tg.AC hemizygous mice were administered technical grade pentaerythritol acrylate in acetone for 6 months. Genetic toxicology was evaluated in Salmonella typhimurium and in B6C3F(1) and Tg.AC hemizygous mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female F344/N rats were administered 0, 12.5, 25, 50, 100, or 200 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 17 days. All rats survived to the end of the study; mean body weights of males administered 50 mg/kg or greater and 200 mg/kg females were significantly less than those of the vehicle controls. Irritation at the site of application occurred in all dosed groups except 12.5 mg/kg females. Epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, chronic active inflammation, and suppurative inflammation occurred at the site of application in most dosed groups of rats. 2-WEEK STUDY IN B6C3F(1) MICE: Groups of five male and five female B6C3F(1) mice were administered 0, 12.5, 25, 50, 100, or 200 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 17 days. All mice survived to the end of the study. The final mean body weight and body weight gain of 25 mg/kg males were significantly greater than those of the vehicle controls, as was the mean body weight gain of 50 mg/kg males. All dosed groups had irritation at the site of application. Thymus weights of males administered 50 mg/kg or greater and 200 mg/kg females were significantly less than those of the vehicle controls. Most dosed groups of mice had epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, chronic active inflammation, and suppurative inflammation at the site of application. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 14 weeks. All rats survived to the end of the study. Mean body weights of 12 mg/kg males were significantly less than those of the vehicle controls. Irritation at the site of application occurred in 12 mg/kg rats. Thymus weights of males administered 3 mg/kg or greater were significantly less than those of the vehicle controls. Hematology results indicated that pentaerythritol triacrylate induced a neutrophil count increase that would be consistent with an inflammatory response related to the dermatitis observed histopathologically. Epidermal hyperplasia, hyperkeratosis, epidermal degeneration and necrosis, chronic active inflammation, and sebaceous gland hyperplasia generally occurred at the application site in male and female groups administered 1.5 mg/kg or greater. 3-MONTH STUDY IN B6C3F(1) MICE: Groups of 10 male and 10 female B6C3F(1) mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 14 weeks. One female vehicle control mouse was sacrificed during the first week of the study due to ataxia and one 1.5 mg/kg female died during week 8. Mean body weights of dosed groups were similar to those of the vehicle control groups. Irritation at the site of application occurred in the 6 and 12 mg/kg male groups. Hematology results indicated an increased neutrophil count consistent with an inflammatory response related to the dermatitis observed histopathologically. There also was a minimal decrease in the erythron (hematocrit, hemoglobin concentration, and erythrocyte count) likely secondary to the inflammatory skin process. Males and females administered 1.5 mg/kg or greater generally had increased incidences of epidermal hyperplasia, degeneration, and necrosis; dermal chronic active inflammation, sebaceous gland hyperplasia, and hyperkeratosis at the site of application. 6-MONTH STUDY IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate per kg body weight in acetone 5 days per week for 27 weeks. Additional groups of 15 male and 15 female mice maintained as positive controls received dermal applications of 1.25 mug 12-O-tetradecanoylphorbol-13-acetate per 100 mL acetone 3 days per week for 28 weeks. Survival of all dosed groups of mice was similar to that of the vehicle controls. With the exception of the 3 mg/kg group, body weights of male mice were less than those of the vehicle controls during the last 3 to 6 weeks of the study. Females administered 3 mg/kg had generally reduced body weights during the last month of the study. Treatment-related clinical findings included papillomas at the site of application in males and females receiving 3 mg/kg or more; papillomas were also observed in one 1.5 mg/kg male. Heart and liver weights of 12 mg/kg males were significantly greater than those of the vehicle controls. Lung weights of 6 and 12 mg/kg males and females were significantly decreased, as were thymus weights of 6 and 12 mg/kg females. Squamous cell neoplasms at the site of application were associated with dermal application of pentaerythritol triacrylate. At 6 months, all 3 and 6 mg/kg males had squamous cell papilloma at the site of application, and the incidences of this neoplasm were significantly increased in males and females receiving 3 mg/kg or more. Squamous cell carcinomas at the site of application occurred in two 3 mg/kg males, three 12 mg/kg males, and one 12 mg/kg female. Nonneoplastic lesions noted at the site of application in dosed mice included hyperkeratosis, chronic active inflammation, and epidermal hyperplasia. Incidences of hematopoietic cell proliferation were increased in various organs, including the liver of 12 mg/kg females, the spleen of 6 and 12 mg/kg males and females, and the mandibular lymph node of 12 mg/kg females. A hematopoietic disorder (myelodysplasia) occurred in 12 mg/kg males. Pentaerythritol triacrylate was not mutagenic in several strains of S. typhimurium, with or without hamster or rat liver S9 activation enzymes. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples from B6C3F(1) mice treated with pentaerythritol triacrylate by skin painting for 3 months. In contrast, similar treatment of female Tg.AC hemizygous mice for 6 months induced a significant increase in micronucleated erythrocytes; the increase in micronuclei seen in male Tg.AC hemizygous mice was judged to be equivocal. Studies were conducted with female BALB/c mice to evaluate the potential for pentaerythritol triacrylate to induce contact hypersensitization. In an irritancy study in which formulations of pentaerythritol triacrylate (approximately 10% or 45% pure) in acetone were applied to the ear, the maximal nonirritating concentration was 0.1% and the minimal irritating concentration was 0.25% for both mixtures. A mouse ear swelling test yielded negative results for pentaerythritol triacrylate as a potential contact sensitizer using the 10% mixture and positive results with the 45% mixture. Positive responses were seen in local lymph node assays at concentrations of 0.05%, 0.1%, and 0.25% pentaerythritol triacrylate when the approximately 10% pentaerythritol triacrylate mixture was used and at a concentration of 0.25% pentaerythritol triacrylate when the approximately 45% pentaerythritol triacrylate mixture was used. Male and female Tg.AC hemizygous mice dosed with pentaerythritol triacrylate for 6 months had significantly increased incidences of squamous cell papillomas of the skin at the site of dermal application. Treatment-related squamous cell carcinomas occurred at the site of application in male mice. Nonneoplastic lesions noted at the site of application included hyperkeratosis, chronic active inflammation, and epidermal hyperplasia. A hematopoietic disorder (myelodysplasia) occurred in dosed male mice.

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The objective of this review is to synthesize the best available evidence on palliative care experiences of adult cancer patients from ethnocultural groups.More specifically, this systematic review seeks to answer the following questions:1. What are the palliative care experiences of adult cancer patients from diverse ethnocultural groups?2. What meanings do adult patients with cancer from diverse ethnocultural groups assign to their experiences with palliative care? Globally, over 20.4 million people need palliative care services annually. The majority of these people (19 million) are adults, with 34% of them being patients diagnosed with cancer. With the current increase in the aging population, especially in developed countries, the number of adults requiring palliative care is expected to rise. Furthermore, how palliative care is offered and received continues to be shaped by culture and ethnicity. Likewise, culture and ethnicity influence how palliative care patients experience diseases like cancer, and seek and utilize palliative care services. Also, healthcare providers sometimes find it challenging to address the palliative care needs of patients from different ethnocultural groups. Sometimes these challenges are believed to be due to cultural incompetence of the care provider. When palliative care patients and their providers differ in their perception of care needs and how to address them, negative palliative care experiences are likely to ensue. Therefore, as the demand for palliative care increases, and ethnocultural factors continue to affect palliation, it is important to gain a better understanding of palliative care experiences of patients from different ethnocultural groups.The terms culture and ethnicity have been defined and used differently in literature which sometimes lead to confusion. Ethnicity has been defined as distinctive shared origins or social backgrounds and traditions of a group of people that are maintained between generations and bring about a sense of identity that may encompass a common language and religion. Ethnicity is fluid and should not be confused with nationality or migration or race. In this review, we define ethnicity in relation to the self-identification of participants in studies that will be included in the review.Culture refers to patterns of explanatory models, beliefs, values and customs. These patterns may be informed and expressed in things like diet, clothing or rituals, or in the form of language and social or political systems. Culture may be fluid because of developments in people's lives. In light of the aforementioned definitions, and recognizing the inconsistency in how these terms are sometimes used, the authors of this review define ethnocultural patients, as described in papers to be reviewed, as those who belong to an ethnic group by way of involvement, attachment, self-labelling or attitude towards the group, and who share cultural traditions, ancestry, language, nationality or country of origin.Palliative care in the context of cancer focuses on the improvement of the quality of life of patients by addressing their physical, emotional and spiritual needs, and by supporting their families. Palliative care is often associated with supportive and hospice care. Supportive care emphasizes meeting patients' needs such as physical, mental, social, psychological, emotional and material needs from the period before diagnosis, during diagnosis, treatment to the follow-up period in the cancer trajectory. Hospice care in the context of cancer aims to relieve patients' pain and suffering, and improve their quality of life. Hospice care includes palliative care services and other services such as case management, respite care and bereavement care. Hospice care focuses on patients with terminal illness (i.e. with expected survival of less than six months) and their families. Moreover, hospice care is facilitated by a multidisciplinary team of physicians, nurses, social workers, chaplains, home health aides and volunteers.Palliative care needs for cancer patients are numerous and may include needs related to activities of daily living, communication, sexuality, physical needs, psychological needs, fear, spiritual wellbeing, socioeconomic aspects and insufficiency of information. Cancer patients often report of suffering, pain and being in constant need of support. In dealing with their suffering, some patients seek internal motivation by looking at the disease as a life challenge. Other patients turn to external sources of motivation like religion, or peer and family support groups.Patients from different ethnocultural groups report similar as well as dissimilar palliative care needs and experiences. With respect to similarities, a study from the United States found that African American and Caucasian patients alike valued practical assistance from social groups. Participants from both ethnocultural groups valued friends and families that listened to their cancer-related concerns. Similarly, Turkish and Moroccan patients in a study conducted in Netherlands valued friends and family members that were there for them. Additionally, participants particularly of African American descent treasured positive attitudes from people around them and valued support from religion and faith communities. These sentiments are echoed in a palliative care study conducted in the United Kingdom. In the UK study, Caribbean Blacks and British White patients appreciated the significance of social networks and partner or spousal support in their cancer trajectory.In regards to unsupportive palliative care experiences, authors of the United States study report that African Americans and Caucasians had more similarities than differences. Firstly, both ethnocultural groups shared experiences of losing association with family and close friends after they learnt of the patients' diagnosis. These sentiments were also reported by Danish-born and immigrant patients in a study by Kristiansen and colleagues. Secondly, both African American and Caucasian patients felt responsible for the emotional wellbeing of their loved ones.When it comes to differences in palliative care needs and experiences, Grange and colleagues report that African American and Caucasian participants valued provision of housing which included daily patient care. Participants treasured the opportunity to either move or have family members move in and live with them. However, more African American than Caucasian participants had experiences of moving in with a family member. Important differences in unsupportive palliative care were also reported. Although both African Americans and Caucasians lost friends and family members following knowledge of the cancer diagnoses, more African Americans than Caucasians were likely to report losing friendship. Additionally, African Americans experienced diminished independence mainly because of overprotection from family and friends. Diminishing independence is echoed in the Dutch study involving Turkish and Moroccan patients. However, in the Dutch study, healthcare providers appeared to advocate for patients' independence which contradicted with the value placed by family members in protecting their loved one.In another American study, Latina women desired health-related information more often than their Caucasian American counterparts. The need for information by Latina women was irrespective of their socio-demographic factors, including level of education.The aforementioned similarities and differences in palliative care experiences call for further exploration of ethnocultural palliative care patients' experiences. A better understanding of their experiences will create avenues for finding better ways of providing palliative care, preventing psychological distress and improving quality of life and death.Understanding ethnocultural issues is important because the unique characteristics of ethnocultural groups often inform approaches to palliative care. Ethnocultural meanings of illness, suffering and dying define the theoretical underpinnings that patients and healthcare providers draw upon in their relations. Furthermore, Baker suggests that the provision and receipt of palliative care is more related to culture or ethnicity than to age, education, socioeconomic status or other variables. Moreover, culture affects communication, decision-making, response to symptoms, treatment choices and emotional expression at the end of life.Palliative care patients often regard recommendations from healthcare providers as very useful. Similarly, healthcare providers may find ethnocultural knowledge beneficial in the provision of palliative care. When ethnocultural knowledge is lacking, healthcare providers, especially those with minimal training on ethnocultural issues, may provide unsatisfactory palliative care. Similarly, when ethnocultural differences are overlooked or inadequately addressed, inferior care often occurs. Inferior care which may involve inequality in utilization of and access to palliative care services, pain and symptom management and location of death, is especially disturbing when adequate palliative care resources exist in some health institutions.Although qualitative and quantitative research has been conducted in this area, no systematic review compiling findings on ethnocultural patients' experiences of palliative care has been conducted or is underway as per the Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, Cochrane Database of Systematic Reviews or PROSPERO. The purpose of this systematic review is to summarize findings of qualitative studies that focus on ethnocultural patients' experience of palliative care. (ABSTRACT TRUNCATED)

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The course of HIV infection is accompanied by a wide individual variability. The complex and large interplay between host and viral factors is crucial in the disease's evolution. The lung has been recognised from the beginning of the disease as one of the main targets of infectious and non-infectious complications of AIDS. In this setting both anatomic and immunologic particularities of this organ play an important role. The hallmark of HIV is progressive immune dysfunction. Despite the intensive research into the pathogenesis, several questions remain to be answered on the dynamic effects of HIV on pulmonary cells. Previous studies in which we have participated showed the early presence of lymphocytic alveolitis from the asymptomatic phase of infection. Since then, many collected data has brought new insights into the immune and biochemical mechanisms involving HIV cell entry, as well as target cells, cytokines and other cellular mediators. In this context, the discovery that specific chemokine receptors could act as co-receptors for HIV, allowed a better understanding of the mechanisms underlying viral cellular entry and tropism. On this issue several authors have reported that in addition to the CD4 molecule, most strains of HIV use the chemokine receptor CCR5 for viral attachment and entry into the host cells. This receptor seems to be very important in disease transmission, whereas CXCR4 receptor tends to be used by the viral strains that emerge later in the disease in addition to or instead of the CCR5. To evaluate the pulmonary cellular dynamics in AIDS patients regarding the viral load in bronchoalveolar lavage fluid (LLBA), as well as cellularity and tropism through CCR5 and CXCR4 receptors. 14 AIDS patients were enrolled in this study, with a mean age of 39 +/- 14.3 years (9 males and 5 females) all HIV1, heterosexuals, 6 smokers and 8 non-smokers, none of them drug addicts. These patients were referred to bronchoscopy with BAL, for clinical suspicion of opportunistic lung infections. These patients were later divided into two groups: Group I (recent diagnosis) and Group II (non-recent diagnosis). While all patients had AIDS, group I had also recent diagnosis of opportunistic infections and had not received yet anti-retroviral therapy whilst group II had a long-term disease evolution with several opportunistic episodes and anti-retroviral therapeutic. BAL was performed both in the middle bronchus in diffuse or in other segmentar bronchus, depending on radiographic abnormalities. Plasma viral load was performed through PCR-RT in blood samples with EDTA, centrifuged and frozen (-80 masculine Celsius) in the first 4 hours after being collected. The viral load in BALf was quantified in 9 patients using the automatized Cobas Ampliprep/Cobas Amplicor HIV1 Monitor TM Test, version 1.5 Roche Diagnostic Systems. The results were expressed in a numeric scale, with a dynamic variation of 50-750.000 copies of RNA HIV1/cm3 and later converted into a logarithmic scale. In 10 patients an immunological study was carried out in BALf and blood to quantify the lymphocyte populations and subsets (CD3, CD4, CD8, CD19, CD56 and CD56CD8) as well as the receptors CD3CCR5, CD4CCR5, CD8CCR5, CCR5Mø, CXCR4, CD3CXCR4, CXCR4CD14 and co-stimulatory molecule CD28, CD3CD28, CD4CD28, CD8CD28 through monoclonal antibodies - CD8FITC, CD19FITC, CD3PE, CD56PE, CD4PECY5-Lymphogram Cytognos; CCR5PE, CXCRFITC-R &amp; D Systems; CD8Cy5 and CD3Cy5-DaKo, CD4PE, CD14PE, CD28FITC- Immunotech; CD4FITC-CLB, CD8Percp- Beckton Dickinson and CD3 APC - Beckton Dickinson, by flow cytometry (Facs Calibur-Beckton-Dickinson) with 3 or 4 fluorescences - FL1- -FITC, FL2-PE, FL3-PECY, FL4-APC. In the statistical analysis, we used the Student t-test, and li- near correlation. Presence of HIV1 in BALf (2.95 log +/- 3.08 log), in small levels compared with plasma viral loads (5.89 log +/-5.90 log) (Table IV). There was great variability of viral loads in BALf as there was in blood independent of the time elapsed between diagnosis and the exam. As for the lymphocytic populations and subsets in blood (Table V) determined in 13 patients, there was a significant fall of total lymphocytes as well as of their subsets, although more marked in CD4 cells; 42.9% had CD4 levels &lt; 50 cels/mm3 and only 2 patients (n masculine 12, 13) had CD4&gt; 250 cels/mm3. The CD19 was reduced with an individual distribution similar to the CD4 subset. In most cases, the fall of CD8 accompanied the decrease of CD4 and CD19 (patients-n masculine 7 and 8). The lymphocyte populations and subsets in BALf (10 patients) (Table VI) showed a percentual distribution similar to that observed in blood (Table VII) for CD3, CD19, CD4 and CD8 lymphocytes, although the percentage of T cells was higher than in blood (94.5 +/- 5 /84.1 +/-10.4) as opposed to B cells (2.2 +/-3 /10.4 +/- 9.6). In BALf CD8 T cells were higher than in blood (77.7 +/- 17.6 /67.6 +/- 4.2), which was not observed for the CD4 lymphocytes (8.1 +/- 9.5 BALf vs.10.4 +/- 9.6 in blood). The natural killer activity expressed by CD56 T cells had important individual variations in both biological fluids: higher levels in blood than in BALf (9.1 +/-8 /2.9 +/-1.9). The cytotoxic activity of CD56CD8 was similar in blood and in BALf (2.2 +/- 2 / 1.7+/- 1.2) while the individual distribution seemed more homogeneous in BALf (Table VI) than in blood (Table VII). The double-negative (DN) cells had slightly higher values in BALf (7.6 +/- 4.5 vs 5.6 +/- 5.3). Curiously, in BALf we observed a higher percentage of less differentiated cells (13 +/- 13.6) (Table VI). The analysis of the receptors CCR5 and CXCR4 showed in general terms different behaviour concerning the two biological means (Tables VI and VII). Thus, the CCR5 CD3 was higher in blood (10.9+/- 13.2) than in BALf (8.4 +/- +/- 3.5) while the CCR5 CD4 and CCR5 CD8 had an increased expression in BALf in relation to blood ( 2 +/- 2.3 and 4.9 +/- 3.7 / 0.9 +/- 0.7 and 4.1 +/- 4.0 respectively). Concerning the expression of this receptor on monocyte macrophage lineage a marked higher value was attained in BALft (77.8 +/- +/- 41 in BALf vs. 18.7 +/- 15 in blood). On the contrary the total expression of CXCR4 was higher in BALf (31 +/- 19.9) than in blood (16.4 +/- +/- 8.1). This tendency extended equally to the T lymphocytes (26.6 +/- 19.8 vs. 10.7 +/-7.6) and also to the monocyte-macrophage lineage in an exuberant manner (84.5 +/- 30.2 / 4.8 +/- 4.6). The co- stimulatory activity of CD28 showed higher values in blood (22.8 +/- 16.2) than in BALf (15.9 +/- +/- 10.1) for total T cells, CD4 and CD8 lymphocytes 22.5 +/-16.7; 7.8 +/- 8.3; 13.3 +/- 8.3 / 16.5 +/- +/- 10.5; 2.9 +/- 2.8; 10.8 +/- 8.0 respectively). 1. HIV infection is responsible for important and extensive abnormalities in lung host defences. 2. The complex interaction between host and aggressor as well as the immune response particularly represented by natural killer and cytotoxic activities, apoptosis, and opportunistic diseases or others, therapeutics and other factors may contribute to the difficulty in obtaining homogenous medical samples within research. There are also ethical issues that restrict a purely scientific approach to these patients. 3. These results point to a pulmonary response to HIV in a compartmentalised fashion according to the dynamic cellular elements involved and receptors in which the latter had distinct profiles related to the biological fluids. In this context, the lung compartimental response is particularly dependent on alveolar macrophages activity which is from the beginning the cornerstone of this process and is the last cellular defense mechanism in this territory when all others are profoundly affected. 4. The dynamics of chemokines receptors may be very important in therapeutic approach as the blockage of the CCR5 receptor does not seem to trigger an increased expression of CXCR4 strains. In fact, we found that CXCR4 remained high in monocyte-macrophage cells throughout infection and its expression was increased in T-lymphocytes in Group II patients as opposed to CCR5 behavior in BALf which significantly decreases. However, in blood, CCR5 expression increased, unlike CXCR4. 5. Due to high co-existing opportunistic infections (71.4%) we cannot ignore the hypothesis that this increased expression of CXCR4 was a result of the modulation induced by opportunistic agents. 6. Finally, this striking individual variability undoubtly has clinical implications. This makes a case-by-case management strategy the correct approach.

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In the preceding pages we have presented evidence which we believe furnishes new light on the disease process in avian tuberculosis. From a well known strain of avian tubercle bacillus, A(1), four variants have been dissociated, each manifesting distinct colony topography and physical and chemical characteristics. From these studies we have learned that the variants are sometimes unstable, not only in vitro but also in vivo, and that this characteristic is one of the prominent factors influencing both the advancement and retrogression of the disease. The four variants remain fairly stable in vitro provided they are cultivated on proper culture media. About 80 per cent smooth S and flat smooth F.S. colonies will develop true to type on egg media; and rough R and the chromogenic Ch when cultivated on gycerine agar media, in about the same percentage. An early non-specific eosinophilia followed inoculation, no matter which variant was used. This usually subsided by the 18th hour. The early stages of tubercle formation produced by all the variants appeared similar. First there appeared an aggregation of eosinophiles and their ingested bacilli within the tissues and then followed replacement by large mononuclear cells which wandered in and phagocyted both eosinophiles and bacilli. After the formation of tubercles composed only of large mononuclear cells, certain differences between the virulent and avirulent variants became apparent. There was also a direct relationship between the dosage and the extent of the disease. In our experience from 0.16 to 0.25 mg. gave the most uniform results. If S variant was used, the early non-specific eosinophilia was followed by a second rise which continued to ascend, running parallel with the total leucocyte count. There was a slow increase of monocytes and a corresponding decrease of lymphocytes. The microscopic lesions, 2 weeks after inoculation, were composed of irregularly shaped clumps of necrosing large mononuclear cells. The margins were clear-cut and bordered by few or no lymphocytic cells. By the 3rd and 4th weeks eosinophiles began to migrate into the centers of the tubercles and abscess formation became evident. Death usually occurred after 5 or 6 weeks, although this varied with the dosage. The appearance of the lesions suggested an acute "toxic" nature, as manifested (1) by marked enlargement of the spleen and liver, (2) by the short fatal course of the disease, which never became very extensive, (3) by the presence of few organisms within the tubercles, (4) by destruction of reticulum and (5) by the marked response of the blood leucocytes. After inoculation with F.S. variant the early non-specific eosinophilia disappeared, returning again at the terminal stage, 5 to 6 weeks later. The number of eosinophiles then ascended sharply, accompanied by a marked leucocytosis which continued until death. During this eosinophilia a monocytosis occurred and lymphocytes fell away rapidly. During the 2nd week, clumps of closely packed large mononuclear cells containing masses of phagocyted bacilli were seen. In the 3rd and 4th weeks there appeared a prominent peripheral zone of hyalin, collagenous-like material associated with an increased reticulum formation which apparently walled off the lesion. The bacilli within the tubercle multiplied rapidly, it seemed as though they were more resistant to destruction than the S organisms, perhaps due to their higher lipin content. As a result of their rapid increase, progression of the tubercle continued, with necrosis and abscess formation, accompanied by the dissemination of the organisms both locally and distantly to new uninvolved tissue. Wide extension of the disease followed due to the increase in numbers of bacilli, terminating with death usually during the 5th and 6th weeks. The manifestations of "toxin" damage shown in S disease were not so marked until the approach of the end-stage. We interpret the type of lesion produced by the F.S. variant as a foreign body tubercle to distinguish it from the acute "toxic" nature of the S. A quantitative chemical determination showed that this organism contained 20.14 per cent lipin whereas in the S variant it was only 15.03 per cent. Following inoculation with R variant the initial eosinophilia returned to normal within 24 hours. There was then an increase of both lymphocytes and monocytes, the latter exceeding the former for a time. Later, usually after the 2nd month, the lymphocytes again became predominant over the monocytes, approaching the normal base line. Eosinophiles failed to react. This blood picture indicated a successful resistance against the infecting organisms, and was supported by the pathological findings. None of the chickens of this group died during the period of study (79 days) although infecting doses of 0.25 mg. were used. Necropsies on four chickens revealed no macroscopic evidence of disease approximately 11 weeks after inoculation. Microscopic lesions were present in the spleen and liver of some cases. In chickens inoculated 11 weeks previously these tubercles consisted only of very small, discrete clumps of degenerating mononuclear cells often surrounded by a border of lymphocytes. Necrosis, abscess formation or caseation was not found. Their small size and appearance was evidence of their retrogressive character. Isolated giant cells were rarely seen. It was impossible to find bacilli within these tubercles. In one instance it was possible to show complete innocuousness of this organism in the tissues, as far as producing recognizable tuberculous lesions. Reticulum played little part in the development of the lesion and it was neither increased or destroyed. Following inoculation with the chromogenic Ch variant the initial eosinophilia declined by the 24th or 42nd hour count and from then on remained low. The lymphocytes showed little decrease. A prominent monocytosis of prolonged character usually occurred during the 3rd to 6th weeks and was then displaced by a return of the lymphocytes. By the end of the period of observation the differential count had closely approached the normal values. Again the blood picture was truly representative of the relatively benign character of the lesions. The tubercle formation, even after 93 days' duration of the disease, remained limited to small clumps of two or three large mononuclear cells showing some degeneration. Lymphocytic cells were usually present within and about the lesion. There was never any evidence of abscess formation or actual necrosis. Bacilli could not be found within these tubercles. The reticulum in relation to the lesion showed neither increase nor destruction. None of the chickens died though a dose of 0.5 mg. was used. In three chickens infected with S variant, the blood picture did not follow the pattern set by the others similarly inoculated. Either a high monocytosis replaced the usual eosinophilia, or there was a marked recession of the total leucocyte count followed by a return of lymphocytes towards normal percentage. The blood picture indicated the conversion of an acute process into a subacute or chronic affair. These chickens survived for 78, 79 and 110 days, respectively. An explanation for this occurred to us later when cultures recovered from them, instead of consisting of S colonies, showed the topography of the intermediate type, closely resembling the F.S. type. Evidently this was due to a reversion; i.e., a loss of virulence of the organism occurring within the animal body. At necropsy the spleen and liver were somewhat enlarged and contained prominent, discrete yellow nodules resembling small shot in their size and shape, which, in one case could be lifted from the tissue by the point of the knife. Microscopically, they possessed small centers of caseation surrounded by numerous giant cells and large mononuclear cells with a thick border of lymphocytic cells. This tubercle formation could not be classified in any special group as it was too sharply circumscribed and walled off by lymphocytic cells to be considered as truly malignant in nature as the S type of lesion. Even the younger tubercles in these cases, which consisted of clumped epithelioid cells with prominent lymphocytic cell borders, could not be called acute or "toxic" in character. At present we make only limited deductions from our observations. In the bacterial dissociation phenomenon we have at least a new line of investigation, and different variants of tubercle bacilli must be taken into consideration when planning new tuberculosis studies. With the stabilization of the human type variants, experiments such as reported here may bring about the proper clinical interpretation, of the course of human tuberculosis.

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To assess the safety and efficacy of artificial disc replacement (ADR) technology for degenerative disc disease (DDD). Degenerative disc disease is the term used to describe the deterioration of 1 or more intervertebral discs of the spine. The prevalence of DDD is roughly described in proportion to age such that 40% of people aged 40 years have DDD, increasing to 80% among those aged 80 years or older. Low back pain is a common symptom of lumbar DDD; neck and arm pain are common symptoms of cervical DDD. Nonsurgical treatments can be used to relieve pain and minimize disability associated with DDD. However, it is estimated that about 10% to 20% of people with lumbar DDD and up to 30% with cervical DDD will be unresponsive to nonsurgical treatments. In these cases, surgical treatment is considered. Spinal fusion (arthrodesis) is the process of fusing or joining 2 bones and is considered the surgical gold standard for DDD. Artificial disc replacement is the replacement of the degenerated intervertebral disc with an artificial disc in people with DDD of the lumbar or cervical spine that has been unresponsive to nonsurgical treatments for at least 6 months. Unlike spinal fusion, ADR preserves movement of the spine, which is thought to reduce or prevent the development of adjacent segment degeneration. Additionally, a bone graft is not required for ADR, and this alleviates complications, including bone graft donor site pain and pseudoarthrosis. It is estimated that about 5% of patients who require surgery for DDD will be candidates for ADR. The Medical Advisory Secretariat conducted a computerized search of the literature published between 2003 and September 2005 to answer the following questions: What is the effectiveness of ADR in people with DDD of the lumbar or cervical regions of the spine compared with spinal fusion surgery?Does an artificial disc reduce the incidence of adjacent segment degeneration (ASD) compared with spinal fusion?What is the rate of major complications (device failure, reoperation) with artificial discs compared with surgical spinal fusion?One reviewer evaluated the internal validity of the primary studies using the criteria outlined in the Cochrane Musculoskeletal Injuries Group Quality Assessment Tool. The quality of concealment allocation was rated as: A, clearly yes; B, unclear; or C, clearly no. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the overall quality of the body of evidence (defined as 1 or more studies) supporting the research questions explored in this systematic review. A random effects model meta-analysis was conducted when data were available from 2 or more randomized controlled trials (RCTs) and when there was no statistical and or clinical heterogeneity among studies. Bayesian analyses were undertaken to do the following: Examine the influence of missing data on clinical success rates;Compute the probability that artificial discs were superior to spinal fusion (on the basis of clinical success rates);Examine whether the results were sensitive to the choice of noninferiority margin. The literature search yielded 140 citations. Of these, 1 Cochrane systematic review, 1 RCT, and 10 case series were included in this review. Unpublished data from an RCT reported in the grey literature were obtained from the manufacturer of the device. The search also yielded 8 health technology assessments evaluating ADR that are also included in this review. Six of the 8 health technology assessments concluded that there is insufficient evidence to support the use of either lumbar or cervical ADR. The results of the remaining 2 assessments (one each for lumbar and cervical ADR) led to a National Institute for Clinical Excellence guidance document supporting the safety and effectiveness of lumbar and cervical ADR with the proviso that an ongoing audit of all clinical outcomes be undertaken owing to a lack of long-term outcome data from clinical trials. Regarding lumbar ADR, data were available from 2 noninferiority RCTs to complete a meta-analysis. The following clinical, health systems, and adverse event outcome measures were synthesized: primary outcome of clinical success, Oswestry Disability Index (ODI) scores, pain VAS scores, patient satisfaction, duration of surgery, amount of blood loss, length of hospital stay, rate of device failure, and rate of reoperation. The meta-analysis of overall clinical success supported the noninferiority of lumbar ADR compared with spinal fusion at 24-month follow-up. Of the remaining clinical outcome measures (ODI, pain VAS scores, SF-36 scores [mental and physical components], patient satisfaction, and return to work status), only patient satisfaction and scores on the physical component scale of the SF-36 questionnaire were significantly improved in favour of lumbar ADR compared with spinal fusion at 24 months follow-up. Blood loss and surgical time showed statistical heterogeneity; therefore, meta-analysis results are not interpretable. Length of hospital stay was significantly shorter in patients receiving the ADR compared with controls. Neither the number of device failures nor the number of neurological complications at 24 months was statistically significantly different between the ADR and fusion treatment groups. However, there was a trend towards fewer neurological complications at 24 months in the ADR treatment group compared with the spinal fusion treatment group. Results of the Bayesian analyses indicated that the influence of missing data on the outcome measure of clinical success was minimal. The Bayesian model indicated that the probability for ADR being better than spinal fusion was 79%. The probability of ADR being noninferior to spinal fusion using a -10% noninferiority bound was 92%, and using a -15% noninferiority bound was 94%. The probability of artificial discs being superior to spinal fusion in a future trial was 73%. Six case series were reviewed, mainly to characterize the rate of major complications for lumbar ADR. The Medical Advisory Secretariat defined a major complication as any reoperation; device failure necessitating a revision, removal or reoperation; or life-threatening event. The rates of major complications ranged from 0% to 13% per device implanted. Only 1 study reported the rate of ASD, which was detected in 2 (2%) of the 100 people 11 years after surgery. There were no RCT data available for cervical ADR; therefore, data from 4 case series were reviewed for evidence of effectiveness and safety. Because data were sparse, the effectiveness of cervical ADR compared with spinal fusion cannot be determined at this time. The rate of major complications was assessed up to 2 years after surgery. It was found to range from 0% to 8.1% per device implanted. The rate of ASD is not reported in the clinical trial literature. The total cost of a lumbar ADR procedure is $15,371 (Cdn; including costs related to the device, physician, and procedure). The total cost of a lumbar fusion surgery procedure is $11,311 (Cdn; including physicians' and procedural costs). Lumbar Artificial Disc Replacement Since the 2004 Medical Advisory Secretariat health technology policy assessment, data from 2 RCTs and 6 case series assessing the effectiveness and adverse events profile of lumbar ADR to treat DDD has become available. The GRADE quality of this evidence is moderate for effectiveness and for short-term (2-year follow-up) complications; it is very low for ASD.The effectiveness of lumbar ADR is not inferior to that of spinal fusion for the treatment of lumbar DDD. The rates for device failure and neurological complications 2 years after surgery did not differ between ADR and fusion patients. Based on a Bayesian meta-analysis, lumbar ADR is 79% superior to lumbar spinal fusion.The rate of major complications after lumbar ADR is between 0% and 13% per device implanted. The rate of ASD in 1 case series was 2% over an 11-year follow-up period.Outcome data for lumbar ADR beyond a 2-year follow-up are not yet available.Cervical Artificial Disc Replacement Since the 2004 Medical Advisory Secretariat health technology policy assessment, 4 case series have been added to the body of evidence assessing the effectiveness and adverse events profile of cervical ADR to treat DDD. The GRADE quality of this evidence is very low for effectiveness as well as for the adverse events profile. Sparse outcome data are available.Because data are sparse, the effectiveness of cervical ADR compared with spinal fusion cannot be determined at this time.The rate of major complications was assessed up to 2 years after surgery; it ranged from 0% to 8.1% per device implanted. The rate of ASD is not reported in the clinical trial literature.

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Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P &lt; 0.0001). This represents a reduction in the time to first alleviation of symptoms from 7 to 6.3 days. There was no effect in asthmatic children, but in otherwise healthy children there was (reduction by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001). Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, P &lt; 0.00001), equating to a reduction in the mean duration of symptoms from 6.6 to 6.0 days. The effect in children was not significant. In subgroup analysis we found no evidence of a difference in treatment effect for zanamivir on time to first alleviation of symptoms in adults in the influenza-infected and non-influenza-infected subgroups (P = 0.53). Hospitalisations. Treatment of adults with oseltamivir had no significant effect on hospitalisations: risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no significant effect in children or in prophylaxis. Zanamivir hospitalisation data were unreported. Serious influenza complications or those leading to study withdrawal. In adult treatment trials, oseltamivir did not significantly reduce those complications classified as serious or those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor in child treatment trials; neither did zanamivir in the treatment of adults or in prophylaxis. There were insufficient events to compare this outcome for oseltamivir in prophylaxis or zanamivir in the treatment of children. Pneumonia. Oseltamivir significantly reduced self reported, investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451) in the treated population. The effect was not significant in the five trials that used a more detailed diagnostic form for pneumonia. There were no definitions of pneumonia (or other complications) in any trial. No oseltamivir treatment studies reported effects on radiologically confirmed pneumonia. There was no significant effect on unverified pneumonia in children. There was no significant effect of zanamivir on either self reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir significantly reduced the risk of self reported, investigator-mediated, unverified pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311 (95% CI 244 to 1086), but not oseltamivir. Bronchitis, sinusitis and otitis media. Zanamivir significantly reduced the risk of bronchitis in adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to 155), but not oseltamivir. Neither NI significantly reduced the risk of otitis media and sinusitis in both adults and children. Harms of treatment. Oseltamivir in the treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm (NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I(2) statistic = 0%) (5% absolute difference between arms). Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43 (95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB = 148 (101 to 2509) compared to placebo during the on-treatment period. There was a dose-response effect on psychiatric events in the two oseltamivir "pivotal" treatment trials, WV15670 and WV15671, at 150 mg (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower proportion of children on oseltamivir with a four-fold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00, I(2) = 0%). Prophylaxis. In prophylaxis trials, oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals (oseltamivir: RD 3.05% (95% CI 1.83 to 3.88); NNTB = 33 (26 to 55); zanamivir: RD 1.98% (95% CI 0.98 to 2.54); NNTB = 51 (40 to 103)) and in households (oseltamivir: RD 13.6% (95% CI 9.52 to 15.47); NNTB = 7 (6 to 11); zanamivir: RD 14.84% (95% CI 12.18 to 16.55); NNTB = 7 (7 to 9)). There was no significant effect on asymptomatic influenza (oseltamivir: RR 1.14 (95% CI 0.39 to 3.33); zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-influenza, influenza-like illness could not be assessed due to data not being fully reported. In oseltamivir prophylaxis studies, psychiatric adverse events were increased in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to 2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population. Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%, 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB &gt; 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116). Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.

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Psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. Several randomised controlled trials (RCTs) have compared the efficacy of the different systemic treatments in psoriasis against placebo. However, the relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis. To compare the efficacy and safety of non-biological systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis using a network meta-analysis, and to provide a ranking of these treatments according to their efficacy and safety. For this living systematic review we updated our searches of the following databases monthly to September 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We searched two trials registers to the same date. We checked the reference lists of included studies and relevant systematic reviews for further references to eligible RCTs. Randomised controlled trials (RCTs) of systemic treatments in adults (over 18 years of age) with moderate-to-severe plaque psoriasis or psoriatic arthritis whose skin had been clinically diagnosed with moderate-to-severe psoriasis, at any stage of treatment, in comparison to placebo or another active agent. The primary outcomes of this review were: the proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90 at induction phase (from 8 to 24 weeks after the randomisation), and the proportion of participants with serious adverse events (SAEs) at induction phase. We did not evaluate differences in specific adverse events. Several groups of two review authors independently undertook study selection, data extraction, 'Risk of bias' assessment, and analyses. We synthesised the data using pair-wise and network meta-analysis (NMA) to compare the treatments of interest and rank them according to their effectiveness (as measured by the PASI 90 score) and acceptability (the inverse of serious adverse events). We assessed the certainty of the body of evidence from the NMA for the two primary outcomes and all comparisons, according to CINeMA, as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We used the surface under the cumulative ranking curve (SUCRA) to infer on treatment hierarchy: 0% (treatment is the worst for effectiveness or safety) to 100% (treatment is the best for effectiveness or safety). We included 158 studies (18 new studies for the update) in our review (57,831 randomised participants, 67.2% men, mainly recruited from hospitals). The overall average age was 45 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo-controlled (58%), 30% were head-to-head studies, and 11% were multi-armed studies with both an active comparator and a placebo. We have assessed a total of 20 treatments. In all, 133 trials were multicentric (two to 231 centres). All but two of the outcomes included in this review were limited to the induction phase (assessment from 8 to 24 weeks after randomisation). We assessed many studies (53/158) as being at high risk of bias; 25 were at an unclear risk, and 80 at low risk. Most studies (123/158) declared funding by a pharmaceutical company, and 22 studies did not report their source of funding. Network meta-analysis at class level showed that all of the interventions (non-biological systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in reaching PASI 90. At class level, in reaching PASI 90, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the non-biological systemic agents. At drug level, infliximab, ixekizumab, secukinumab, brodalumab, risankizumab and guselkumab were significantly more effective in reaching PASI 90 than ustekinumab and three anti-TNF alpha agents: adalimumab, certolizumab, and etanercept. Ustekinumab and adalimumab were significantly more effective in reaching PASI 90 than etanercept; ustekinumab was more effective than certolizumab, and the clinical effectiveness of ustekinumab and adalimumab was similar. There was no significant difference between tofacitinib or apremilast and three non-biological drugs: fumaric acid esters (FAEs), ciclosporin and methotrexate. Network meta-analysis also showed that infliximab, ixekizumab, risankizumab, bimekizumab, secukinumab, guselkumab, and brodalumab outperformed other drugs when compared to placebo in reaching PASI 90. The clinical effectiveness of these drugs was similar, except for ixekizumab which had a better chance of reaching PASI 90 compared with secukinumab, guselkumab and brodalumab. The clinical effectiveness of these seven drugs was: infliximab (versus placebo): risk ratio (RR) 50.29, 95% confidence interval (CI) 20.96 to 120.67, SUCRA = 93.6; high-certainty evidence; ixekizumab (versus placebo): RR 32.48, 95% CI 27.13 to 38.87; SUCRA = 90.5; high-certainty evidence; risankizumab (versus placebo): RR 28.76, 95% CI 23.96 to 34.54; SUCRA = 84.6; high-certainty evidence; bimekizumab (versus placebo): RR 58.64, 95% CI 3.72 to 923.86; SUCRA = 81.4; high-certainty evidence; secukinumab (versus placebo): RR 25.79, 95% CI 21.61 to 30.78; SUCRA = 76.2; high-certainty evidence; guselkumab (versus placebo): RR 25.52, 95% CI 21.25 to 30.64; SUCRA = 75; high-certainty evidence; and brodalumab (versus placebo): RR 23.55, 95% CI 19.48 to 28.48; SUCRA = 68.4; moderate-certainty evidence. Conservative interpretation is warranted for the results for bimekizumab (as well as mirikizumab, tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate), as these drugs, in the NMA, have been evaluated in few trials. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. Nevertheless, the SAE analyses were based on a very low number of events with low to moderate certainty for all the comparisons. Thus, the results have to be viewed with caution and we cannot be sure of the ranking. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1) the results were similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions. Our review shows that compared to placebo, the biologics infliximab, ixekizumab, risankizumab, bimekizumab, secukinumab, guselkumab and brodalumab were the most effective treatments for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of moderate- to high-certainty evidence. This NMA evidence is limited to induction therapy (outcomes were measured from 8 to 24 weeks after randomisation) and is not sufficient for evaluation of longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean age of 45 years) and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice. Another major concern is that short-term trials provide scanty and sometimes poorly-reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the evidence for all the interventions was of low to moderate quality. In order to provide long-term information on the safety of the treatments included in this review, it will also be necessary to evaluate non-randomised studies and postmarketing reports released from regulatory agencies. In terms of future research, randomised trials directly comparing active agents are necessary once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between non-biological systemic agents and small molecules, and between biological agents (anti-IL17 versus anti-IL23, anti-IL23 versus anti-IL12/23, anti-TNF alpha versus anti-IL12/23). Future trials should also undertake systematic subgroup analyses (e.g. assessing biological-naïve participants, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, outcome measure harmonisation is needed in psoriasis trials, and researchers should look at the medium- and long-term benefit and safety of the interventions and the comparative safety of different agents. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

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The objective of this evidence-based analysis was to evaluate the clinical utility of serologic testing for celiac disease in asymptomatic individuals presenting with one of the non-gastrointestinal conditions evaluated in this report. The clinical utility was based on the effects of a gluten-free diet (GFD) on outcomes specific to each of these conditions. The prevalence of celiac disease in asymptomatic individuals and one of these non-gastrointestinal conditions was also evaluated. CELIAC DISEASE: Celiac disease is an autoimmune disease characterized by a chronic inflammatory state of the proximal small bowel mucosa accompanied by structural and functional changes. TECHNOLOGY UNDER EVALUATION: SEROLOGIC TESTS FOR CELIAC DISEASE: There are a number of serologic tests for celiac disease available. Serologic tests are automated with the exception of the anti-endomysial antibody test, which is more time-consuming and operator-dependent than the other tests. What is the prevalence of asymptomatic celiac disease in patients presenting with one of the non-gastrointestinal conditions evaluated?What is the effect of the gluten-free diet on condition-specific outcomes in patients with asymptomatic celiac disease presenting with one of the non-gastrointestinal conditions evaluated?What is the clinical utility of serologic testing for celiac disease in asymptomatic patients presenting with one of the non-gastrointestinal conditions evaluated? The clinical utility was defined as the impact of the GFD on disease specific outcomes.What is the risk of all-cause mortality and lymphoma in individuals with asymptomatic celiac disease?What is the budget impact of serologic testing for celiac disease in asymptomatic subjects presenting with one of the non-gastrointestinal conditions evaluated? The study population consisted of individuals with newly diagnosed celiac disease without any symptoms consistent with the disease presenting with one of the non-gastrointestinal conditions evaluated. When evaluating the risk of lymphoma and all-cause mortality, the study population consisted of asymptomatic individuals with a positive celiac disease serologic test and/or small bowel biopsy. Literature searches were performed for each disease/condition evaluated between December 2010 and March 2011 using OVID MEDLINE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA). No restrictions for start date of search were used. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Studies, systematic reviews, and meta-analyses that assessed the effects of a GFD in patients with newly diagnosed asymptomatic celiac disease presenting with one of the non-gastrointestinal conditions evaluated. If symptoms were not reported in the study but subjects were identified through screening for celiac disease the study was included.Studies, systematic reviews, and meta-analyses that assessed the prevalence of newly diagnosed asymptomatic celiac disease in patients with one of the non-gastrointestinal conditions evaluated. If symptoms were not reported in the study but subjects were identified through screening for celiac disease the study was included.Studies, systematic reviews, and meta-analyses that evaluated the risk of all-cause mortality or lymphoma in individuals with asymptomatic celiac disease.Sample size ≥ 10.Publications in English. Studies that retrospectively assessed the prevalence of asymptomatic celiac disease.Studies that reported the prevalence of one of the non-gastrointestinal conditions evaluated in subjects already diagnosed with celiac disease.Studies in individuals with one of the non-gastrointestinal conditions evaluated if the condition could be explained by other causes.Studies in subjects with celiac disease and symptoms consistent with the disease. If the study included individuals with and without symptoms consistent with celiac disease and their results were analysed separately, the results in individuals without symptoms were included in the analysis.Studies in which individuals did not report any symptoms consistent with celiac disease at study start but that either retrospectively reported the presence of such symptoms after following a GFD, or that previously presented with symptoms consistent with celiac disease.Study results published in letters to the editor or comments about other studies.Studies with a sample size ≥ 10, however, in which less than 10 patients were included in the analysis. The effects of a GFD on disease-specific outcomes for each condition evaluated in patients with asymptomatic celiac disease was assessed. The prevalence of asymptomatic celiac disease in patients presenting with one of the conditions evaluated was also assessed. RESULTS OF EVIDENCE-BASED ANALYSIS: Three eligible observational studies evaluated the effects of GFD on growth parameters in subjects with asymptomatic celiac disease and idiopathic short stature. Four eligible observational studies evaluated the effects of GFD on metabolic control in subjects with asymptomatic celiac disease and type 1 diabetes. Five eligible observational studies evaluated the risk of all-cause mortality and five eligible observational studies evaluated the risk of lymphoma in subjects with asymptomatic celiac disease. No eligible studies on the effects of the GFD for the other conditions evaluated were identified. Twenty-three eligible studies measured the prevalence of asymptomatic celiac disease in subjects presenting with one of the conditions evaluated. PREVALENCE OF CELIAC DISEASE IN ASYMPTOMATIC PATIENTS: The prevalence of celiac disease in asymptomatic patients presenting with one of the conditions evaluated was analysed. Most studies also included a control group that generally consisted of individuals randomly selected from the general population. Although there was a trend to a higher prevalence of asymptomatic celiac disease in individuals with the conditions evaluated compared to the controls, it only reached statistical significance in type 1 diabetes. No eligible prevalence studies were identified in patients with amenorrhea, delayed puberty, alopecia, and depression. THE EFFECTS OF A GLUTEN-FREE DIET ON DISEASE-SPECIFIC OUTCOMES IN PATIENTS WITH ASYMPTOMATIC CELIAC DISEASE: THE EFFECTS OF GFD ON METABOLIC CONTROL IN PATIENTS WITH ASYMPTOMATIC CELIAC DISEASE AND TYPE 1 DIABETES: The effects of a GFD on metabolic control (HbA1c, number of hypoglycemic episodes, and changes in insulin dosage) in subjects with asymptomatic celiac disease and type 1 diabetes were evaluated. One prospective case-control study reported an increase in HbA1c levels in cases with type 1 diabetes and asymptomatic celiac disease after the introduction of a GFD, however, the clinical significance of this change is unclear. Only one eligible retrospective case-control study evaluated the effects of a GFD on hypoglycemia episodes and since there were inadequate details in the study about both the ascertainment and severity of hypoglycemia episodes in both cases and controls, it is not possible to draw conclusions regarding the effects of a GFD on hypoglycemia episodes based on this study. One prospective case-control study did not show a statistically significant change in insulin dosage between cases with type 1 diabetes and asymptomatic celiac disease and controls with type 1 diabetes either before or after the introduction of a GFD. No eligible studies that evaluated the effects of a GFD on the long-term outcomes of type 1 diabetes such as cardiovascular or renal events in patients with asymptomatic celiac disease were identified. THE EFFECTS OF A GLUTEN-FREE DIET IN PATIENTS WITH IDIOPATHIC SHORT STATURE AND ASYMPTOMATIC CELIAC DISEASE: A total of 3 eligible studies were identified. All studies consisted of case series that compared growth parameters in subjects with asymptomatic celiac disease and idiopathic short stature before and after the celiac disease was diagnosed and the GFD was instituted. Most subjects included in the studies demonstrated an improvement in growth parameters. Compliance with the GFD was not reported in the studies. The results of the studies suggest an increase in growth velocity in pediatric patients with asymptomatic celiac disease and idiopathic short stature once a GFD is introduced. RISK OF LYMPHOMA IN PATIENTS WITH ASYMPTOMATIC CELIAC DISEASE: One retrospective cohort study evaluated the risk of lymphoma in patients with asymptomatic celiac disease. The authors concluded that the number of events identified was low during the long follow-up period and that the risk of overall malignancies was not increased among patients with asymptomatic celiac disease. RISK OF ASYMPTOMATIC CELIAC DISEASE IN PATIENTS WITH LYMPHOMA: Four case-control studies, one of which retrospective, evaluated the risk of asymptomatic celiac disease in patients newly diagnosed with lymphoma. One retrospective cohort study did not show an increase in the risk of lymphoma among subjects with asymptomatic celiac disease. Three prospective case-control studies did not find a statistically significant risk of asymptomatic celiac disease in patients with newly diagnosed lymphoma. (ABSTRACT TRUNCATED)

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The Tachinidae (Diptera) of Chile are catalogued and information is given on distributions, name-bearing types, synonyms, nomenclatural issues, and pertinent literature. The history of tachinid collectors in Chile and authors who have contributed to the systematic knowledge of Chilean tachinids is extensively reviewed. The classification has been updated and 122 genera and 264 species are recognised in Chile. There is a significant amount of endemism with 28 genera and 100 species known only from Chile. There are also 113 species with distributions shared only between Chile and Argentina, particularly in the southern portions of these countries comprising Patagonia. The catalogue is based on examination of the original descriptions of all nominal species and all other references known to us containing relevant taxonomic and distributional information, for a total of approximately 450 references. Many of the name-bearing types and other Chilean specimens housed in collections were examined. Taxa are arranged hierarchically and alphabetically under the categories of subfamily, tribe, genus, subgenus (where recognised), and species. Nomenclatural information is provided for genus-group and species-group names, including lists of synonyms (mostly restricted to Neotropical taxa) and name-bearing type data. Species distributions are recorded by country within the New World and by larger geographical divisions in the Old World. Additional information is given in the form of notes and references under valid names at the level of tribe, genus, and species. Two genera are newly recorded from Chile: <iChaetoepalpus</i Vimmer &amp; Soukup, 1940 (Tachinini) (also newly recorded from Argentina) and <iPatelloa</i Townsend, 1916 (Goniini). Four species are newly recorded from Chile or other countries: <iLyphaornata</i Aldrich, 1934 (Chile); <iChaetoepalpuscoquilleti</i Vimmer &amp; Soukup, 1940 (Argentina and Chile); <iPhytomypteraevanescens</i (Cortés, 1967) (Argentina); and <iXanthobasisunicolor</i Aldrich, 1934 (Chile). Eight species previously recorded from Chile are deemed to have been misidentified or misrecorded from Chile (known distributions in parentheses): <iArchytasincertus</i (Macquart, 1851) (Argentina, Brazil, Paraguay, Uruguay); <iArchytasseminiger</i (Wiedemann, 1830) (Brazil, Colombia); <iGoniacrassicornis</i (Fabricius, 1794) (Brazil, Peru, Venezuela, Middle America, West Indies, Nearctic); <iLespesiaandina</i (Bigot, 1888) (Cuba); <iLespesiaarchippivora</i (Riley, 1871) (widespread Nearctic and most of Neotropical); <iNeoethillaignobilis</i (van der Wulp, 1890) (Mexico, United States); Siphona (Siphona) geniculata (De Geer, 1776) (Palaearctic, Nearctic [introduced]); and <iWinthemiaquadripustulata</i (Fabricius, 1794) (Palaearctic, Nearctic, Oriental]. As First Reviser we fix <iParatheresiarufiventris</i Townsend, 1929 as the senior homonym and <iSarcoprosenarufiventris</i Townsend, 1929 as the junior homonym when the two are placed together in <iBillaea</i Robineau-Desvoidy, 1830; and we fix <iMayophoriniaangusta</i Townsend, 1927 as the senior homonym and <iMetarrhinomyiaangusta</i Townsend, 1927 as the junior homonym when the two are placed together in <iMyiopharus</i Brauer &amp; Bergenstamm, 1889. New replacement names are proposed for eight preoccupied names of Neotropical species (country of type locality in parentheses): <iBillaearufescens</i O'Hara &amp; Wood for <iSarcoprosenarufiventris</i Townsend, 1929, preoccupied in the genus <iBillaea</i Robineau-Desvoidy, 1830 by <iParatheresiarufiventris</i Townsend, 1929 (Peru), <bnom. nov.</b; <iBillaeatriquetrus</i O'Hara &amp; Wood for <iSarcoprosenatriangulifera</i Townsend, 1927, preoccupied in the genus <iBillaea</i Robineau-Desvoidy, 1830 by <iDexiatriangulifera</i Zetterstedt, 1844 (Peru), <bnom. nov.</b; <iEucelatorianudioculata</i O'Hara &amp; Wood for <iEucelatorioideanigripalpis</i Thompson, 1968, preoccupied in the genus <iEucelatoria</i Townsend, 1909 by <iChetolyganigripalpis</i Bigot, 1889 (Trinidad), <bnom. nov.</b; <iEucelatoriaoblonga</i O'Hara &amp; Wood for <iUrodexodeselongatum</i Cortés &amp; Campos, 1974, preoccupied in the genus <iEucelatoria</i Townsend, 1909 by <iExoristaelongata</i van der Wulp, 1890 (Chile), <bnom. nov.</b; <iLespesiathompsoni</i O'Hara &amp; Wood for <iSturmiopsoideaobscura</i Thompson, 1966, preoccupied in the genus <iLespesia</i Robineau-Desvoidy, 1863 by <iEurigasterobscurus</i Bigot, 1857 (Cuba), <bnom. nov.</b; <iMyiopharuscharapensis</i O'Hara &amp; Wood for <iMetarrhinomyiaangusta</i Townsend, 1927, preoccupied in the genus <iMyiopharus</i Brauer &amp; Bergenstamm, 1889 by <iMayophoriniaangusta</i Townsend, 1927 (Peru), <bnom. nov.</b; <iMyiopharusincognitus</i O'Hara &amp; Wood for <iStenochaetaclaripalpis</i Thompson, 1968, preoccupied in the genus <iMyiopharus</i Brauer &amp; Bergenstamm, 1889 by <iNeoxynopsoideaclaripalpis</i Thompson, 1968 (Trinidad), <bnom. nov.</b; and <iMyiopharusrufopalpus</i O'Hara &amp; Wood for <iParalispepalpalis</i Townsend, 1929, preoccupied in the genus <iMyiopharus</i Brauer &amp; Bergenstamm, 1889 by <iMyioxynopspalpalis</i Townsend, 1927 (Peru), <bnom. nov.</b New type species fixations are made under the provisions of Article 70.3.2 of the ICZN<iCode</i for three genus-group names: <iParafabricia</i Brauer &amp; Bergenstamm, 1894 (synonym of <iArchytas</i Jaennicke, 1867), type species newly fixed as <iParafabriciaperplexa</i Townsend, 1931; <iTachinodes</i Brauer &amp; Bergenstamm, 1889 (synonym of <iArchytas</i Jaennicke, 1867), type species newly fixed as <iJuriniametallica</i Robineau-Desvoidy, 1830; and <iWillistonia</i Brauer &amp; Bergenstamm, 1889 (synonym of <iBelvosia</i Robineau-Desvoidy, 1830), type species newly fixed as <iWillistoniaaldrichi</i Townsend, 1931. Lectotypes are designated for the following four nominal species, all described or possibly described from Chile: <iEchinomyiapygmaea</i Macquart, 1851 (a valid name in the genus <iPeleteria</i Robineau-Desvoidy, 1830); <iGoniachilensis</i Macquart, 1844 (a junior synonym of <iGoniapallens</i Wiedemann, 1830); <iMasiceraauriceps</i Macquart, 1844 (a valid name in the genus <iLespesia</i Robineau-Desvoidy, 1863); and <iProsopochoetanitidiventris</i Macquart, 1851 (a valid name in the genus <iProsopochaeta</i Macquart, 1851). The following 27 new or revived combinations are proposed (distributions in parentheses): <iBlepharipezaandina</i Bigot, 1888 is moved to <iLespesia</i Robineau-Desvoidy, 1863 as <iL.andina</i, <inomen dubium</i (Cuba), <bcomb. nov.</b; <iCamposodesevanescens</i Cortés, 1967 is moved to <iPhytomyptera</i Rondani, 1845 as <iP.evanescens</i (Argentina, Chile), <bcomb. nov.</b; <iEctophasiopsisypiranga</i Dios &amp; Nihei, 2017 is moved to Trichopoda Berthold, 1827 and assigned to subgenus Galactomyia Townsend, 1908 as T. (G.) ypiranga (Argentina, Brazil), <bcomb. nov.</b; <iEmbiomyiaaustralis</i Aldrich, 1934 is moved to <iSteleoneura</i Stein, 1924 as <iS.australis</i (Argentina, Chile), <bcomb. nov.</b; <iEurigastermodestus</i Bigot, 1857 is moved to <iLespesia</i as <iL.modesta</i (Cuba), <bcomb. nov.</b; <iEurigasterobscurus</i Bigot, 1857 is moved to <iLespesia</i as <iL.obscura</i (Cuba), <bcomb. nov.</b; <iMacropatelloatanumeana</i Townsend, 1931 is moved to <iPatelloa</i Townsend, 1916 as <iP.tanumeana</i (Argentina, Chile), <bcomb. nov.</b; <iMasicerainsignis</i van der Wulp, 1882 is moved to <iDrino</i Robineau-Desvoidy, 1863 as <iD.insignis</i (Argentina, Chile), <bcomb. nov.</b; <iParasetigenahichinsi</i Cortés, 1967 is moved to <iChetogena</i Rondani, 1856 as <iC.hichinsi</i (Chile), <bcomb. nov.</b; <iParasetigenaporteri</i Brèthes, 1920 and junior synonym <iStomatotachinasplendida</i Townsend, 1931 are moved to <iChetogena</i as <iC.porteri</i (Chile), both <bcomb. nov.</b; <iPhoroceracalyptrata</i Aldrich, 1934 is moved to <iAdmontia</i Brauer &amp; Bergenstamm, 1889 as <iA.calyptrata</i (Argentina, Chile), <bcomb. nov.</b; <iPoliopsauratus</i Campos, 1953 is moved to <iAdmontia</i Brauer &amp; Bergenstamm, 1889 as <iA.aurata</i (Chile), <bcomb. nov.</b; <iPoliopsstriatus</i Aldrich, 1934 is moved to <iAdmontia</i as <iA.striata</i (Argentina, Chile), <bcomb. nov.</b; <iRuiziellafrontosa</i Cortés, 1951 is moved to <iChaetoepalpus</i Vimmer &amp; Soukup, 1940 and placed in synonymy with <iC.coquilleti</i Vimmer &amp; Soukup, 1940 (Argentina, Chile, Peru), <bcomb. nov.</b; <iRuiziellaluctuosa</i Cortés, 1951 is moved to <iChaetoepalpus</i as <iC.luctuosus</i (Argentina, Chile), <bcomb. nov.</b; <iSarcoprosenaluteola</i Cortés &amp; Campos, 1974 is moved to <iBillaea</i Robineau-Desvoidy, 1830 as <iB.luteola</i (Chile), <bcomb. nov.</b; <iSarcoprosenarufiventris</i Townsend, 1929 is moved to <iBillaea</i where it is a junior secondary homonym and is renamed <iB.rufescens</i O'Hara &amp; Wood (Peru), <bcomb. nov.</b; <iSarcoprosenatriangulifera</i Townsend, 1927 is moved to <iBillaea</i where it is a junior secondary homonym and is renamed <iB.triquetrus</i O'Hara &amp; Wood (Peru),<bcomb. nov.</b; <iSaundersiaaurea</i Giglio-Tos, 1893 is moved to "Unplaced species of Tachinini" (Mexico), <bcomb. nov.</b; <iSchistostephanaaurifrons</i Townsend, 1919 is moved to <iBillaea</i as <iB.aurifrons</i (Peru), <bcomb. nov.</b; <iSiphoactiacharapensis</i Townsend, 1927 is moved to <iClausicella</i Rondani, 1856 as <iC.charapensis</i (Peru), <bcomb. nov.</b; <iSiphoactiaperegrina</i Cortés &amp; Campos, 1971 is moved to <iClausicella</i as C. <iperegrina</i (Chile), <bcomb. nov.</b; <iSturmiafestiva</i Cortés, 1944 is moved to <iDrino</i as <iD.festiva</i (Argentina, Chile), <bcomb. nov.</b; <iSturmiopsoideaobscura</i Thompson, 1966 is moved to <iLespesia</i Robineau-Desvoidy, 1863, where it is a junior secondary homonym and is renamed <iL.thompsoni</i O'Hara &amp; Wood (Trinidad), <bcomb. nov.</b; <iTrichopodaarcuata</i Bigot, 1876 is returned to <iTrichopoda</i from Ectophasiopsis Townsend, 1915 and assigned to subgenus Galactomyia (Argentina, Chile), <bcomb. revived</b; and <iTrichopodagradata</i Wiedemann, 1830 is returned to <iTrichopoda</i from <iEctophasiopsis</i and assigned to subgenus Galactomyia (Argentina, Brazil, Uruguay), <bcomb. revived.</b New or revived generic and specific synonymies are proposed for the following 14 names: <iCamposodes</i Cortés, 1967 with <iPhytomyptera</i Rondani, 1845, <bsyn. nov.</b; <iEctophasiopsis</i Townsend, 1915 with Trichopoda Berthold, 1827, subgenus Galactomyia Townsend, 1908, <bsyn. nov.</b; <iEmbiomyia</i Aldrich, 1934 with <iSteleoneura</i Stein, 1924, <bsyn. nov.</b; <iFabriciaandicola</i Bigot, 1888 with <iPeleteriarobusta</i (Wiedemann, 1830), <bsyn. revived</b; <iMacropatelloa</i Townsend, 1931 with <iPatelloa</i Townsend, 1916, <bsyn. nov.</b; <iPeleteriainca</i Curran, 1925 with <iPeleteriarobusta</i (Wiedemann, 1830), <bsyn. revived</b; <iPoliops</i Aldrich, 1934 with <iAdmontia</i Brauer &amp; Bergenstamm, 1889, <bsyn. nov.</b; <iRuiziella</i Cortés, 1951 with <iChaetoepalpus</i Vimmer &amp; Soukup, 1940, <bsyn. nov.</b; <iRuiziellafrontosa</i Cortés, 1951 with <iChaetoepalpuscoquilleti</i Vimmer &amp; Soukup, 1940, <bsyn. nov.</b; <iSarcoprosena</i Townsend, 1927 with <iBillaea</i Robineau-Desvoidy, 1830, <bsyn. nov.</b; <iSchistostephana</i Townsend, 1919 with <iBillaea</i, <bsyn. nov.</b; <iSiphoactia</i Townsend, 1927 with <iClausicella</i Rondani, 1856, <bsyn. nov.</b; <iStomatotachina</i Townsend, 1931 with <iChetogena</i Rondani, 1856, <bsyn. nov.</b; and <iSturmiopsoidea</i Thompson, 1966 with <iLespesia</i Robineau-Desvoidy, 1863, <bsyn. nov.</b

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Breast cancer is the most common cancer and the second leading cause of cancer death in American women. It was the second most common cancer in the world in 2002, with more than 1 million new cases. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. To offer more effective and less toxic treatment, selecting therapies requires considering the patient and the clinical and molecular characteristics of the tumor. Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, after a variable period of time, progression occurs. At that point, resistance to therapy is not only common but expected. Herein we review general mechanisms of drug resistance, including multidrug resistance by P-glycoprotein and the multidrug resistance protein family in association with specific agents and their metabolism, emergence of refractory tumors associated with multiple resistance mechanisms, and resistance factors unique to host-tumor-drug interactions. Important anticancer agents specific to breast cancer are described. Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. In 2002, 209,995 new cases of breast cancer were registered, and 42,913 patients died of it. In 5 years, the annual prevalence of breast cancer will reach 968,731 cases in the United States. World wide, the problem is just as significant, as breast cancer is the most frequent cancer after nonmelanoma skin cancer, with more than 1 million new cases in 2002 and an expected annual prevalence of more than 4.4 million in 5 years. Breast cancer treatment currently requires the joint efforts of a multidisciplinary team. The alternatives for treatment are constantly expanding. With the use of new effective chemotherapy, hormone therapy, and biological agents and with information regarding more effective ways to integrate systemic therapy, surgery, and radiation therapy, elaborating an appropriate treatment plan is becoming more complex. Developing such a plan should be based on knowledge of the benefits and potential acute and late toxic effects of each of the therapy regimens. Despite advances in early detection and understanding of the molecular bases of breast cancer biology, approximately 30% of all patients with early-stage breast cancer have recurrent disease, which is metastatic in most cases. The rates of local and systemic recurrence vary within different series, but in general, distant recurrences are dominant, strengthening the hypothesis that breast cancer is a systemic disease from presentation. On the other hand, local recurrence may signal a posterior systemic relapse in a considerable number of patients within 2 to 5 years after completion of treatment. To offer better treatment with increased efficacy and low toxicity, selecting therapies based on the patient and the clinical and molecular characteristics of the tumor is necessary. Consideration of these factors should be incorporated in clinical practice after appropriate validation studies are performed to avoid confounding results, making them true prognostic and predictive factors. A prognostic factor is a measurable clinical or biological characteristic associated with a disease-free or overall survival period in the absence of adjuvant therapy, whereas a predictive factor is any measurable characteristic associated with a response or lack of a response to a specific treatment. The main prognostic factors associated with breast cancer are the number of lymph nodes involved, tumor size, histological grade, and hormone receptor status, the first two of which are the basis for the AJCC staging system. The sixth edition of the American Joint Committee on Cancer staging system allows better prediction of prognosis by stage. However, after determining the stage, histological grade, and hormone receptor status, the tumor can behave in an unexpected manner, and the prognosis can vary. Other prognostic and predictive factors have been studied in an effort to explain this phenomenon, some of which are more relevant than others: HER-2/neu gene amplification and protein expression, expression of other members of the epithelial growth factor receptor family, S phase fraction, DNA ploidy, p53 gene mutations, cyclin E, p27 dysregulation, the presence of tumor cells in the circulation or bone marrow, and perineural and lymphovascular space invasion. Systemic treatment of breast cancer includes the use of cytotoxic, hormonal, and immunotherapeutic agents. All of these agents are used in the adjuvant, neoadjuvant, and metastatic setting. Adjuvant systemic therapy is used in patients after they undergo primary surgical resection of their breast tumor and axillary nodes and who have a significant risk of systemic recurrence. Multiple studies have demonstrated that adjuvant therapy for early-stage breast cancer produces a 23% or greater improvement in disease-free survival and a 15% or greater increase in overall survival rates. Recommendations for the use of adjuvant therapy are based on the individual patient's risk and the balance between absolute benefit and toxicity. Anthracycline-based regimens are preferred, and the addition of taxanes increases the survival rate in patients with lymph node-positive disease. Adjuvant hormone therapy accounts for almost two thirds of the benefit of adjuvant therapy overall in patients with hormone-receptor-positive breast cancer. Tamoxifen is considered the standard of care in premenopausal patients. In comparison, the aromatase inhibitor anastrozole has been proven to be superior to tamoxifen in postmenopausal patients with early-stage breast cancer. The adjuvant use of monoclonal antibodies and targeted therapies other than hormone therapy is being studied. Interestingly, some patients have an early recurrence even though they have a tumor with good prognostic features and at a favorable stage. These recurrences have been explained by the existence of certain cellular characteristics at the molecular level that make the tumor cells resistant to therapy. Selection of resistant cell clones of micrometastatic disease has also been proposed as an explanation for these events. Neoadjuvant systemic therapy, which is the standard of care for patients with locally advanced and inflammatory breast cancer, is becoming more popular. It reduces the tumor volume, thus increasing the possibility of breast conservation, and at the same time allows identification of in vivo tumor sensitivity to different agents. The pathological response to neoadj uvant systemic therapy in the breast and lymph nodes correlates with patient survival. Use of this treatment modality produces survival rates identical to those obtained with the standard adjuvant approach. The rates of pathological complete response (pCR) to neoadjuvant systemic therapy vary according to the regimen used, ranging from 6% to 15% with anthracycline-based regimens to almost 30% with the addition of a noncross-resistant agent such as a taxane. In one study, the addition of neoadjuvant trastuzumab in patients with HER-2-positive breast tumors increased the pCR rate to 65%. Primary hormone therapy has also been used in the neoadjuvant systemic setting. Although the pCR rates with this therapy are low, it significantly increases breast conservation. Currently, neoadjuvant systemic therapy is an important tool in not only assessing tumor response to an agent but also studying the mechanisms of action of the agent and its effects at the cellular level. However, no tumor response is observed in some cases despite the use of appropriate therapy. The tumor continues growing during treatment in such cases, a phenomenon called primary resistance to therapy. The use of palliative systemic therapy for metastatic breast cancer is challenging. Five percent of newly diagnosed cases of breast cancer are metastatic, and 30% of treated patients have a systemic recurrence. Once metastatic disease develops, the possibility of a cure is very limited or practically nonexistent. In this heterogeneous group of patients, the 5-year survival rate is 20%, and the median survival duration varies from 12 to 24 months. In this setting, breast cancer has multiple clinical presentations, and the therapy for it should be chosen according to the patient's tumor characteristics, previous treatment, and performance status with the goal of improving survival without compromising quality of life. Treatment resistance is most commonly seen in such patients. They initially may have a response to different agents, but the responses are not sustained, and, in general, the rates of response to subsequent agents are lower. Table 1 summarizes metastatic breast cancer response rates to single-agent systemic therapy.

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alpha-Methylstyrene is used in the production of acrylonitrile-butadiene-styrene resins and copolymers, which improve the impact and heat-resistant properties of polymers, specialty grades of plastics, rubber, and protective coatings. alpha-Methylstyrene also moderates polymerization rates and improves product clarity in coatings and resins. Low molecular weight liquid polymers are used as plasticizers in paints, waxes, adhesives, and plastics. alpha-Methylstyrene was nominated by the U.S. Environmental Protection Agency for toxicologic evaluation and genotoxicity studies based on its high production volume and limited information available on its toxicity. Male and female F344/N rats and B6C3F1 mice were exposed to alpha-methylstyrene (99.5% pure) by inhalation for 3 months or 2 years. Inhalation studies were conducted because the primary route of human exposure is via inhalation. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed by whole-body inhalation to alpha-methylstyrene at concentrations of 0, 75, 150, 300, 600, or 1,000 ppm for 6 hours per day, 5 days per week for 14 weeks. Additional clinical pathology groups of 10 male and 10 female rats were exposed to the same concentrations for 23 days. All rats survived to the end of the study, and mean body weights of all exposed groups were similar to those of the chamber controls. Kidney weights were significantly increased in 1,000 ppm males and 600 and 1,000 ppm females. Statistically significant increases in liver weights occurred in 150 ppm or greater males and 600 and 1,000 ppm females. The incidences of renal hyaline droplet accumulation were similar between exposed groups and chamber control groups, but the severity of hyaline droplet accumulation in 600 and 1,000 ppm males was greater than in chamber controls. Consistent with the hyaline droplet accumulation, an exposure-related increase in alpha2μ-globulin was detected in the kidneys of males exposed to alpha-methylstyrene. Morphologic changes were not detected in the liver. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed by whole-body inhalation to alpha-methylstyrene at concentrations of 0, 75, 150, 300, 600, or 1,000 ppm for 6 hours per day, 5 days per week for 14 weeks. Two female mice in the 1,000 ppm group died before exposure on day 3. Final mean body weights of 600 and 1,000 ppm males and 75, 300, and 1,000 ppm females were significantly less than those of the chamber controls; final mean body weight gains of mice exposed to 300 ppm or greater were also significantly less. Moderate to severe sedation (males only) and ataxia were observed in 1,000 ppm mice. The absolute liver weights of 600 and 1,000 ppm females and the relative liver weights of 300, 600, and 1,000 ppm males and females were significantly increased. The estrous cycle lengths of 600 and 1,000 ppm female mice were significantly longer than that of the chamber controls. Minimal to mild centrilobular hypertrophy was present in the livers of male and female mice exposed to 600 or 1,000 ppm alpha-methylstyrene. The incidences of exposure-related nasal lesions, including atrophy and hyperplasia of Bowman's glands and atrophy and metaplasia of the olfactory epithelium, were significantly increased in all exposed groups of males and females. The incidences of hyaline degeneration, characterized by the accumulation of eosinophilic globules in the cytoplasm of the respiratory epithelium, were significantly increased in females exposed to 150 ppm or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed by whole body inhalation to alpha-methylstyrene at concentrations of 0, 100, 300, or 1,000 ppm for 6 hours per day, 5 days per week, except holidays, for 105 weeks. Survival rates of exposed male and female rats were similar to those of the chamber controls. The mean body weights of 1,000 ppm males and females were less than those of the chamber control groups during year 2 of the study. Two 1,000 ppm males and one 300 ppm male had renal tubule carcinomas, and one 300 ppm male had a renal tubule adenoma. Because of the neoplasms observed in 300 and 1,000 ppm males at the end of the 2-year study and the finding of alpha2μ-globulin accumulation in the kidneys at 3 months, which is often associated with kidney neoplasms, additional step sections of kidney were prepared; additional males with focal hyperplasia or adenoma were identified. The incidences of renal tubule adenoma and carcinoma (combined) in the 1,000 ppm males were significantly greater than those in the chamber controls when the single and step sections were combined. The incidence of mineralization of the renal papilla was significantly increased in 1,000 ppm males. The incidence of mononuclear cell leukemia in 1,000 ppm males was significantly increased compared to the chamber controls. In the nose, the incidences of basal cell hyperplasia were significantly increased in all exposed groups of males and females, and the incidences of degeneration of the olfactory epithelium were increased in 1,000 ppm males and females and 300 ppm females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed by whole body inhalation to alpha-methylstyrene at concentrations of 0, 100, 300, or 600 ppm for 6 hours per day, 5 days per week, except holidays, for 105 weeks. Survival of all exposed male and female mice was similar to that of the chamber control groups. Mean body weights of 600 ppm males were less than those of the chamber control group throughout the study, and those of 600 ppm females were less after week 13. The mean body weights of 300 ppm males and females were less than those of the chamber controls during much of the study, but these groups recovered by the end of the study. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in the 100 and 600 ppm males and in all exposed groups of females. The incidences of hepatocellular adenoma were significantly increased in all exposed groups of females, and the incidences in all exposed groups of males and females exceeded the historical range for chamber controls. The incidences of hepatocellular carcinoma and eosinophilic foci of the liver were significantly increased in 600 ppm females. The incidences of olfactory epithelial metaplasia and hyperplasia of the glands overlying the olfactory epithelium were significantly increased in all exposed groups of males and females. In addition, atrophy of the olfactory epithelium was significantly increased in 300 and 600 ppm males. The incidence and severity of nephropathy were increased in 600 ppm females compared to chamber controls. Epithelial hyperplasia of the forestomach also was present in male mice. alpha-Methylstyrene was not mutagenic in four strains of Salmonella typhimurium, with or without rat or hamster liver metabolic activation enzymes (S9). alpha-Methylstyrene did not induce chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9 activation, but did significantly increase the frequency of sister chromatid exchanges in cultures exposed in the presence of S9. In vivo, no significant increases in the frequencies of micronucleated erythrocytes were seen in blood samples of male mice obtained at the conclusion of the 3-month study. However, in female mice from the 3-month study, a significant increase in micronucleated erythrocytes was observed in the 1,000 ppm group. Under the conditions of this 2-year inhalation study, there was some evidence of carcinogenic activity of alpha-methylstyrene in male F344/N rats based on increased incidences of renal tubule adenomas and carcinomas (combined). The increased incidence of mononuclear cell leukemia in 1,000 ppm male F344/N rats may have been related to alpha-methylstyrene exposure. There was no evidence of carcinogenic activity of alpha-methylstyrene in female F344/N rats exposed to 100, 300, or 1,000 ppm. There was equivocal evidence of carcinogenic activity of alpha-methylstyrene in male B6C3F1 mice based on marginally increased incidences of hepatocellular adenoma or carcinoma (combined). There was clear evidence of carcinogenic activity of alpha-methylstyrene in female B6C3F1 mice based on increased incidences of hepatocellular adenomas and carcinomas. Exposure of rats to alpha-methylstyrene resulted in kidney toxicity, which in males exhibited some features of alpha2μ-globulin nephropathy. Exposure to alpha-methylstyrene resulted in nonneoplastic lesions of the nose in male and female rats and mice and of the liver and kidney in female mice.

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An application was received to review the evidence on the 'The Da Vinci Surgical System' for the treatment of gynecologic malignancies (e.g. endometrial and cervical cancers). Limitations to the current standard of care include the lack of trained physicians on minimally invasive surgery and limited access to minimally invasive surgery for patients. The potential benefits of 'The Da Vinci Surgical System' include improved technical manipulation and physician uptake leading to increased surgeries, and treatment and management of these cancers. The demand for robotic surgery for the treatment and management of prostate cancer has been increasing due to its alleged benefits of recovery of erectile function and urinary continence, two important factors of men's health. The potential technical benefits of robotic surgery leading to improved patient functional outcomes are surgical precision and vision. Uterine and cervical cancers represent 5.4% (4,400 of 81,700) and 1.6% (1,300 of 81,700), respectively, of incident cases of cancer among female cancers in Canada. Uterine cancer, otherwise referred to as endometrial cancer is cancer of the lining of the uterus. The most common treatment option for endometrial cancer is removing the cancer through surgery. A surgical option is the removal of the uterus and cervix through a small incision in the abdomen using a laparoscope which is referred to as total laparoscopic hysterectomy. Risk factors that increase the risk of endometrial cancer include taking estrogen replacement therapy after menopause, being obese, early age at menarche, late age at menopause, being nulliparous, having had high-dose radiation to the pelvis, and use of tamoxifen. Cervical cancer occurs at the lower narrow end of the uterus. There are more treatment options for cervical cancer compared to endometrial cancer, however total laparoscopic hysterectomy is also a treatment option. Risk factors that increase the risk for cervical cancer are multiple sexual partners, early sexual activity, infection with the human papillomavirus, and cigarette smoking, whereas barrier-type of contraception as a risk factor decreases the risk of cervical cancer. Prostate cancer is ranked first in men in Canada in terms of the number of new cases among all male cancers (25,500 of 89,300 or 28.6%). The impact on men who develop prostate cancer is substantial given the potential for erectile dysfunction and urinary incontinence. Prostate cancer arises within the prostate gland, which resides in the male reproductive system and near the bladder. Radical retropubic prostatectomy is the gold standard treatment for localized prostate cancer. Prostate cancer affects men above 60 years of age. Other risk factors include a family history of prostate cancer, being of African descent, being obese, consuming a diet high in fat, physical inactivity, and working with cadium. THE DA VINCI SURGICAL SYSTEM: The Da Vinci Surgical System is a robotic device. There are four main components to the system: 1) the surgeon's console, where the surgeon sits and views a magnified three-dimensional image of the surgical field; 2) patient side-cart, which sits beside the patient and consists of three instrument arms and one endoscope arm; 3) detachable instruments (endowrist instruments and intuitive masters), which simulate fine motor human movements. The hand movements of the surgeon's hands at the surgeon's console are translated into smaller ones by the robotic device and are acted out by the attached instruments; 4) three-dimensional vision system: the camera unit or endoscope arm. The main advantages of use of the robotic device are: 1) the precision of the instrument and improved dexterity due to the use of "wristed" instruments; 2) three-dimensional imaging, with improved ability to locate blood vessels, nerves and tissues; 3) the surgeon's console, which reduces fatigue accompanied with conventional laparoscopy surgery and allows for tremor-free manipulation. The main disadvantages of use of the robotic device are the costs including instrument costs ($2.6 million in US dollars), cost per use ($200 per use), the costs associated with training surgeons and operating room personnel, and the lack of tactile feedback, with the trade-off being increased visual feedback. For endometrial and cervical cancers, 1. What is the effectiveness of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?2. What are the incremental costs of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?For prostate cancer, 3. What is the effectiveness of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?4. What are the incremental costs of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer? A literature search was performed on May 12, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, CINAHL, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment for studies published from January 1, 2000 until May 12, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology. English language articles (January 1, 2000-May 12, 2010)Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a primary data source (e.g. obtained in a clinical setting)Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a secondary data source (e.g. hospital- or population-based registries)Study design and methods must be clearly describedHealth technology assessments, systematic reviews, randomized controlled trials, non-randomized controlled trials and/or cohort studies, case-case studies, regardless of sample size, cost-effectiveness studies Duplicate publications (with the more recent publication on the same study population included)Non-English papersAnimal or in-vitro studiesCase reports or case series without a referent or comparison groupStudies on long-term survival which may be affected by treatmentStudies that do not examine the cancers (e.g. advanced disease) or outcomes of interest For endometrial and cervical cancers, Primary outcomes: Morbidity factors- Length of hospitalization- Number of complicationsPeri-operative factors- Operation time- Amount of blood loss- Number of conversions to laparotomyNumber of lymph nodes recoveredFor prostate cancer, Primary outcomes: Morbidity factors- Length of hospitalization- Amount of morphine use/painPeri-operative factors- Operation time- Amount of blood loss- Number of transfusions- Duration of catheterization- Number of complications- Number of anastomotic stricturesNumber of lymph nodes recoveredOncologic factors- Proportion of positive surgical marginsLong-term outcomes- Urinary continence- Erectile function Robotic use for gynecologic oncology compared to:LAPAROTOMY: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations.The beneficial effect of robotic surgery was shown in pooled analysis for complications, owing to increased sample size.More work is needed to clarify the role of complications in terms of safety, including improved study designs, analysis and measurement.LAPAROSCOPY: benefits of robotic surgery in terms of shorter length of hospitalization, less blood loss and fewer conversions to laparotomy likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.Clinical significance of significant findings for length of hospitalizations and blood loss is low.Fewer conversions to laparotomy indicate clinical effectiveness in terms of reduced morbidity.Robotic use for urologic oncology, specifically prostate cancer, compared to:RETROPUBIC SURGERY: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss/fewer individuals requiring transfusions. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations. There was a beneficial effect in terms of decreased positive surgical margins and erectile dysfunction. These results indicate clinical effectiveness in terms of improved cancer control and functional outcomes, respectively, in the context of study design limitations.Surgeon skill had an impact on cancer control and functional outcomes.The results for complications were inconsistent when measured as either total number of complications, pain management or anastomosis. (ABSTRACT TRUNCATED)

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Sudden hearing loss is a frightening symptom that often prompts an urgent or emergent visit to a health care provider. It is frequently but not universally accompanied by tinnitus and/or vertigo. Sudden sensorineural hearing loss affects 5 to 27 per 100,000 people annually, with about 66,000 new cases per year in the United States. This guideline update provides evidence-based recommendations for the diagnosis, management, and follow-up of patients who present with sudden hearing loss. It focuses on sudden sensorineural hearing loss in adult patients aged ≥18 years and primarily on those with idiopathic sudden sensorineural hearing loss. Prompt recognition and management of sudden sensorineural hearing loss may improve hearing recovery and patient quality of life. The guideline update is intended for all clinicians who diagnose or manage adult patients who present with sudden hearing loss. The purpose of this guideline update is to provide clinicians with evidence-based recommendations in evaluating patients with sudden hearing loss and sudden sensorineural hearing loss, with particular emphasis on managing idiopathic sudden sensorineural hearing loss. The guideline update group recognized that patients enter the health care system with sudden hearing loss as a nonspecific primary complaint. Therefore, the initial recommendations of this guideline update address distinguishing sensorineural hearing loss from conductive hearing loss at the time of presentation with hearing loss. They also clarify the need to identify rare, nonidiopathic sudden sensorineural hearing loss to help separate those patients from those with idiopathic sudden sensorineural hearing loss, who are the target population for the therapeutic interventions that make up the bulk of the guideline update. By focusing on opportunities for quality improvement, this guideline should improve diagnostic accuracy, facilitate prompt intervention, decrease variations in management, reduce unnecessary tests and imaging procedures, and improve hearing and rehabilitative outcomes for affected patients. Consistent with the American Academy of Otolaryngology-Head and Neck Surgery Foundation's "Clinical Practice Guideline Development Manual, Third Edition" (Rosenfeld et al. <iOtolaryngol Head Neck Surg</i. 2013;148[1]:S1-S55), the guideline update group was convened with representation from the disciplines of otolaryngology-head and neck surgery, otology, neurotology, family medicine, audiology, emergency medicine, neurology, radiology, advanced practice nursing, and consumer advocacy. A systematic review of the literature was performed, and the prior clinical practice guideline on sudden hearing loss was reviewed in detail. Key Action Statements (KASs) were updated with new literature, and evidence profiles were brought up to the current standard. Research needs identified in the original clinical practice guideline and data addressing them were reviewed. Current research needs were identified and delineated. The guideline update group made <istrong recommendations for</i the following: (KAS 1) Clinicians should distinguish sensorineural hearing loss from conductive hearing loss when a patient first presents with sudden hearing loss. (KAS 7) Clinicians should educate patients with sudden sensorineural hearing loss about the natural history of the condition, the benefits and risks of medical interventions, and the limitations of existing evidence regarding efficacy. (KAS 13) Clinicians should counsel patients with sudden sensorineural hearing loss who have residual hearing loss and/or tinnitus about the possible benefits of audiologic rehabilitation and other supportive measures. These strong recommendations were modified from the initial clinical practice guideline for clarity and timing of intervention. The guideline update group made <istrong recommendations against the</i following: (KAS 3) Clinicians should <unot</u order routine computed tomography of the head in the initial evaluation of a patient with presumptive sudden sensorineural hearing loss. (KAS 5) Clinicians should <unot</u obtain routine laboratory tests in patients with sudden sensorineural hearing loss. (KAS 11) Clinicians should <unot</u routinely prescribe antivirals, thrombolytics, vasodilators, or vasoactive substances to patients with sudden sensorineural hearing loss. The guideline update group made <irecommendations for</i the following: (KAS 2) Clinicians should assess patients with presumptive sudden sensorineural hearing loss through history and physical examination for bilateral sudden hearing loss, recurrent episodes of sudden hearing loss, and/or focal neurologic findings. (KAS 4) In patients with sudden hearing loss, clinicians should obtain, or refer to a clinician who can obtain, audiometry as soon as possible (within 14 days of symptom onset) to confirm the diagnosis of sudden sensorineural hearing loss. (KAS 6) Clinicians should evaluate patients with sudden sensorineural hearing loss for retrocochlear pathology by obtaining magnetic resonance imaging or auditory brainstem response. (KAS 10) Clinicians should offer, or refer to a clinician who can offer, intratympanic steroid therapy when patients have incomplete recovery from sudden sensorineural hearing loss 2 to 6 weeks after onset of symptoms. (KAS 12) Clinicians should obtain follow-up audiometric evaluation for patients with sudden sensorineural hearing loss at the conclusion of treatment and within 6 months of completion of treatment. These recommendations were clarified in terms of timing of intervention and audiometry and method of retrocochlear workup. The guideline update group offered the following KASs as <ioptions</i: (KAS 8) Clinicians may offer corticosteroids as initial therapy to patients with sudden sensorineural hearing loss within 2 weeks of symptom onset. (KAS 9a) Clinicians may offer, or refer to a clinician who can offer, hyperbaric oxygen therapy combined with steroid therapy within 2 weeks of onset of sudden sensorineural hearing loss. (KAS 9b) Clinicians may offer, or refer to a clinician who can offer, hyperbaric oxygen therapy combined with steroid therapy as salvage therapy within 1 month of onset of sudden sensorineural hearing loss. Incorporation of new evidence profiles to include quality improvement opportunities, confidence in the evidence, and differences of opinion Included 10 clinical practice guidelines, 29 new systematic reviews, and 36 new randomized controlled trials Highlights the urgency of evaluation and initiation of treatment, if treatment is offered, by emphasizing the time from symptom occurrence Clarification of terminology by changing potentially unclear statements; use of the term <isudden sensorineural hearing loss</i to mean idiopathic sudden sensorineural hearing loss to emphasize that &gt;90% of sudden sensorineural hearing loss is idiopathic sudden sensorineural hearing loss and to avoid confusion in nomenclature for the reader Changes to the KASs from the original guideline: KAS 1-When a patient first presents with sudden hearing loss, conductive hearing loss should be distinguished from sensorineural. KAS 2-The utility of history and physical examination when assessing for modifying factors is emphasized. KAS 3-The word "routine" is added to clarify that this statement addresses nontargeted head computerized tomography scan that is often ordered in the emergency room setting for patients presenting with sudden hearing loss. It does not refer to targeted scans, such as temporal bone computerized tomography scan, to assess for temporal bone pathology. KAS 4-The importance of audiometric confirmation of hearing status as soon as possible and within 14 days of symptom onset is emphasized. KAS 5-New studies were added to confirm the lack of benefit of nontargeted laboratory testing in sudden sensorineural hearing loss. KAS 6-Audiometric follow-up is excluded as a reasonable workup for retrocochlear pathology. Magnetic resonance imaging, computerized tomography scan if magnetic resonance imaging cannot be done, and, secondarily, auditory brainstem response evaluation are the modalities recommended. A time frame for such testing is not specified, nor is it specified which clinician should be ordering this workup; however, it is implied that it would be the general or subspecialty otolaryngologist. KAS 7-The importance of shared decision making is highlighted, and salient points are emphasized. KAS 8-The option for corticosteroid intervention within 2 weeks of symptom onset is emphasized. KAS 9-Changed to KAS 9A and 9B. Hyperbaric oxygen therapy remains an option but only when combined with steroid therapy for either initial treatment (9A) or salvage therapy (9B). The timing of initial therapy is within 2 weeks of onset, and that of salvage therapy is within 1 month of onset of sudden sensorineural hearing loss. KAS 10-Intratympanic steroid therapy for salvage is recommended within 2 to 6 weeks following onset of sudden sensorineural hearing loss. The time to treatment is defined and emphasized. KAS 11-Antioxidants were removed from the list of interventions that the clinical practice guideline recommends against using. KAS 12-Follow-up audiometry at conclusion of treatment and also within 6 months posttreatment is added. KAS 13-This statement on audiologic rehabilitation includes patients who have residual hearing loss and/or tinnitus who may benefit from treatment. Addition of an algorithm outlining KASs Enhanced emphasis on patient education and shared decision making with tools provided to assist in same.

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To assess the effectiveness, and cost effectiveness of EECP in patients with severe anginal symptoms, secondary to chronic coronary disease, who are unresponsive to exhaustive pharmacotherapy and not candidates for surgical/percutaneous revascularization procedures (e.g., angioplasty, coronary bypass surgery). To assess the effectiveness, and cost effectiveness of EECP in patients with heart failure. ANGINA: Angina is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back or arm. Angina usually occurs in patients with coronary artery disease (CAD) involving ≥1 large epicardial artery. However it can also occur in people with valvular heart disease, hypertrophic cardiomyopathy, and uncontrolled hypertension. CONVENTIONAL APPROACHES TO RESTORING THE BALANCE BETWEEN OXYGEN SUPPLY AND DEMAND FOCUS ON THE DISRUPTION OF THE UNDERLYING DISEASE THROUGH: drug therapy (β blockers, calcium channel blockers, nitrates, antiplatelet agents, ACE inhibitors, statins); life-style modifications (smoking cessation, weight loss); or revascularization techniques such as coronary artery bypass graft surgery (CABG) or percutaneous coronary interventions (PCI). (1) Limitations of each of these approaches include: adverse drug effects, procedure-related mortality and morbidity, restenosis after PCI, and time dependent graft attrition after CABG. Furthermore, an increasing number of patients are not appropriate candidates for standard revascularization options, due to co-morbid conditions (HF, peripheral vascular disease), poor distal coronary artery targets, and patient preference. The morbidity and mortality associated with repeat surgical revascularization procedures are significantly higher, and often excludes these patients from consideration for further revascularizations. (2) Patients with CAD who have chronic ischemic symptoms that are unresponsive to both conventional medical therapy and revascularization techniques have refractory angina pectoris. It has been estimated that greater than 100,000 patients each year in the US may be diagnosed as having this condition. (3) Patients with refractory angina have marked limitation of ordinary physical activity or are unable to perform any ordinary physical activity without discomfort (CCS functional class III/IV). Also, there must be some objective evidence of ischemia as demonstrated by exercise treadmill testing, stress imaging studies or coronary physiologic studies. (1) Dejongste et al. (4)estimated that the prevalence of chronic refractory angina is about 100,000 patients in the United States. This would correspond to approximately 3,800 (100,000 x 3.8% [Ontario is approximately 3.8% of the population of the United States]) patients in Ontario having chronic refractory angina. Heart failure results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump. A recent study (5) revealed 28,702 patients were hospitalized for first-time HF in Ontario between April 1994 and March 1997. Women comprised 51% of the cohort. Eighty-five percent were aged 65 years or older, and 58% were aged 75 years or older. Patients with chronic HF experience shortness of breath, a limited capacity for exercise, high rates of hospitalization and rehospitalization, and die prematurely. (6) The New York Heart Association (NYHA) has provided a commonly used functional classification for the severity of HF (7): CLASS I: No limitation of physical activity. No symptoms with ordinary exertion.CLASS II: Slight limitations of physical activity. Ordinary activity causes symptoms.CLASS III: Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest.CLASS IV: Inability to carry out any physical activity without discomfort. Symptoms at rest.The National Heart, Lung, and Blood Institute (7) estimates that 35% of patients with HF are in functional NYHA class I; 35% are in class II; 25%, class III; and 5%, class IV. Surveys (8) suggest that from 5% to 15% of patients with HF have persistent severe symptoms, and that the remainder of patients with HF is evenly divided between those with mild and moderately severe symptoms. To date, the diagnosis and management of chronic HF has concentrated on patients with the clinical syndrome of HF accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of HF and the results of large clinical trials. Treatment for chronic HF includes lifestyle management, drugs, cardiac surgery, or implantable pacemakers and defibrillators. Despite pharmacologic advances, which include diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone, and digoxin, many patients remain symptomatic on maximally tolerated doses. (6) THE TECHNOLOGY: Patients are typically treated by a trained technician in a medically supervised environment for 1 hour daily for a total of 35 hours over 7 weeks. The procedure involves sequential inflation and deflation of compressible cuffs wrapped around the patient's calves, lower thighs and upper thighs. In addition to 3 sets of cuffs, the patient has finger plethysmogram and electrocardiogram (ECG) attachments that are connected to a control and display console. External counterpulsation was used in the United States to treat cardiogenic shock after acute myocardial infarction. (9;10) More recently, an enhanced version namely "enhanced external counterpulsation" (EECP) was introduced as a noninvasive procedure for outpatient treatment of patients with severe, uncontrollable cardiac ischemia. EECP is said to increase coronary perfusion pressure and reduce the myocardial oxygen demand. Currently, EECP is not applicable for all patients with refractory angina pectoris. For example, many patients are considered ineligible for therapy due to co-morbidities, including those with severe pulmonary vascular disease, deep vein thrombosis, phlebitis and irregular heart rhythms, and heart failure. (1) Very recently, investigation began into EECP as an adjunctive treatment for patients with HF. Anecdotal reports suggested that EECP may benefit patients with coronary disease and left ventricular dysfunction. The safety and effectiveness of EECP in patients with symptomatic heart failure and coronary disease and its role in patients with nonischemic heart failure secondary to LV dysfunction is unclear. Furthermore, the safety and effectiveness of EECP in the different stages of HF and whether it is only for patients who are refractive to pharmacotherapy is unknown. 2003 HEALTH TECHNOLOGY ASSESSMENT BY THE MEDICAL ADVISORY SECRETARIAT: The Medical Advisory Secretariat health technology assessment (originally published in February 2003) reported on the effectiveness of EECP for patients with angina and HF. The report concluded that there was insufficient evidence to support the use of EECP in patients with refractory stable CCS III/IV angina as well as insufficient evidence to support the use of EECP in patients with HF. The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of EECP for the treatment of refractory stable CCS III/IV angina or HF. The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from December 2002 to March 2006. A modification of the GRADE approach (11) was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study's design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations. The Cochrane and INAHTA databases yielded 3 HTAs or systematic reviews on EECP treatment (Blue Cross Blue Shield Technology Evaluation Center [BCBS TEC], ECRI, and the Centers for Medicare and Medicaid Services [CMS]). A search of Medline and Embase December 2005 - March 2006 (after the literature search cutoff from the most recent HTA) was conducted using key words enhanced external counterpulsation, EECP, angina, myocardial ischemia, congestive heart failure. This search produced 1 study which met the inclusion criteria. This level 4a study was inferior in quality to the RCT which formed the basis of the 2003 Medical Advisory Secretariat recommendation. BCBS reviewed the evidence through November 2005 to determine if EECP improves health outcomes for refractory chronic stable angina pectoris or chronic stable HF. (12) BCBS concluded that the available evidence is not sufficient to permit conclusions of the effect of EECP on health outcomes. Both controlled trials had methodologic flaws (MUST EECP and MUST EECP quality of life studies). The case series and observational studies for both indications while suggestive of a treatment benefit from EECP have shortcomings as well. On March 20 2006, CMS posted their proposed coverage decision memorandum for external counterpulsation therapy. (ABSTRACT TRUNCATED)

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In up to 30% of patients undergoing lumbar disc surgery for herniated or protruded discs outcomes are judged unfavourable. Over the last decades this problem has stimulated the development of a number of minimally-invasive operative procedures. The aim is to relieve pressure from compromised nerve roots by mechanically removing, dissolving or evaporating disc material while leaving bony structures and surrounding tissues as intact as possible. In Germany, there is hardly any utilisation data for these new procedures - data files from the statutory health insurances demonstrate that about 5% of all lumbar disc surgeries are performed using minimally-invasive techniques. Their real proportion is thought to be much higher because many procedures are offered by private hospitals and surgeries and are paid by private health insurers or patients themselves. So far no comprehensive assessment comparing efficacy, safety, effectiveness and cost-effectiveness of minimally-invasive lumbar disc surgery to standard procedures (microdiscectomy, open discectomy) which could serve as a basis for coverage decisions, has been published in Germany. Against this background the aim of the following assessment is: Based on published scientific literature assess safety, efficacy and effectiveness of minimally-invasive lumbar disc surgery compared to standard procedures. To identify and critically appraise studies comparing costs and cost-effectiveness of minimally-invasive procedures to that of standard procedures. If necessary identify research and evaluation needs and point out regulative needs within the German health care system. The assessment focusses on procedures that are used in elective lumbar disc surgery as alternative treatment options to microdiscectomy or open discectomy. Chemonucleolysis, percutaneous manual discectomy, automated percutaneous lumbar discectomy, laserdiscectomy and endoscopic procedures accessing the disc by a posterolateral or posterior approach are included. In order to assess safety, efficacy and effectiveness of minimally-invasive procedures as well as their economic implications systematic reviews of the literature are performed. A comprehensive search strategy is composed to search 23 electronic databases, among them MEDLINE, EMBASE and the Cochrane Library. Methodological quality of systematic reviews, HTA reports and primary research is assessed using checklists of the German Scientific Working Group for Health Technology Assessment. Quality and transparency of cost analyses are documented using the quality and transparency catalogues of the working group. Study results are summarised in a qualitative manner. Due to the limited number and the low methodological quality of the studies it is not possible to conduct metaanalyses. In addition to the results of controlled trials results of recent case series are introduced and discussed. The evidence-base to assess safety, efficacy and effectiveness of minimally-invasive lumbar disc surgery procedures is rather limited: PERCUTANEOUS MANUAL DISCECTOMY: Six case series (four after 1998)AUTOMATED PERCUTANEOUS LUMBAR DISCECTOMY: Two RCT (one discontinued), twelve case series (one after 1998)CHEMONUCLEOLYSIS: Five RCT, five non-randomised controlled trials, eleven case seriesPERCUTANEOUS LASERDISCECTOMY: One non-randomised controlled trial, 13 case series (eight after 1998)ENDOSCOPIC PROCEDURES: Three RCT, 21 case series (17 after 1998) There are two economic analyses each retrieved for chemonucleolysis and automated percutaneous discectomy as well as one cost-minimisation analysis comparing costs of an endoscopic procedure to costs for open discectomy. Among all minimally-invasive procedures chemonucleolysis is the only of which efficacy may be judged on the basis of results from high quality randomised controlled trials (RCT). Study results suggest that the procedure maybe (cost)effectively used as an intermediate therapeutical option between conservative and operative management of small lumbar disc herniations or protrusions causing sciatica. Two RCT comparing transforaminal endoscopic procedures with microdiscectomy in patients with sciatica and small non-sequestered disc herniations show comparable short and medium term overall success rates. Concerning speed of recovery and return to work a trend towards more favourable results for the endoscopic procedures is noted. It is doubtful though, whether these results from the eleven and five years old studies are still valid for the more advanced procedures used today. The only RCT comparing the results of automated percutaneous lumbar discectomy to those of microdiscectomy showed clearly superior results of microdiscectomy. Furthermore, success rates of automated percutaneous lumbar discectomy reported in the RCT (29%) differ extremely from success rates reported in case series (between 56% and 92%). The literature search retrieves no controlled trials to assess efficacy and/or effectiveness of laser-discectomy, percutaneous manual discectomy or endoscopic procedures using a posterior approach in comparison to the standard procedures. Results from recent case series permit no assessment of efficacy, especially not in comparison to standard procedures. Due to highly selected patients, modi-fications of operative procedures, highly specialised surgical units and poorly standardised outcome assessment results of case series are highly variable, their generalisability is low. The results of the five economical analyses are, due to conceptual and methodological problems, of no value for decision-making in the context of the German health care system. Aside from low methodological study quality three conceptual problems complicate the interpretation of results. Continuous further development of technologies leads to a diversity of procedures in use which prohibits generalisation of study results. However, diversity is noted not only for minimally-invasive procedures but also for the standard techniques against which the new developments are to be compared. The second problem refers to the heterogeneity of study populations. For most studies one common inclusion criterion was "persisting sciatica after a course of conservative treatment of variable duration". Differences among study populations are noted concerning results of imaging studies. Even within every group of minimally-invasive procedure, studies define their own in- and exclusion criteria which differ concerning degree of dislocation and sequestration of disc material. There is the non-standardised assessment of outcomes which are performed postoperatively after variable periods of time. Most studies report results in a dichotomous way as success or failure while the classification of a result is performed using a variety of different assessment instruments or procedures. Very often the global subjective judgement of results by patients or surgeons is reported. There are no scientific discussions whether these judgements are generalisable or comparable, especially among studies that are conducted under differing socio-cultural conditions. Taking into account the weak evidence-base for efficacy and effectiveness of minimally-invasive procedures it is not surprising that so far there are no dependable economic analyses. Conclusions that can be drawn from the results of the present assessment refer in detail to the specified minimally-invasive procedures of lumbar disc surgery but they may also be considered exemplary for other fields where optimisation of results is attempted by technological development and widening of indications (e.g. total hip replacement). Compared to standard technologies (open discectomy, microdiscectomy) and with the exception of chemonucleolysis, the developmental status of all other minimally-invasive procedures assessed must be termed experimental. To date there is no dependable evidence-base to recommend their use in routine clinical practice. To create such a dependable evidence-base further research in two directions is needed: a) The studies need to include adequate patient populations, use realistic controls (e.g. standard operative procedures or continued conservative care) and use standardised measurements of meaningful outcomes after adequate periods of time. b) Studies that are able to report effectiveness of the procedures under everyday practice conditions and furthermore have the potential to detect rare adverse effects are needed. In Sweden this type of data is yielded by national quality registries. On the one hand their data are used for quality improvement measures and on the other hand they allow comprehensive scientific evaluations. Since the year of 2000 a continuous rise in utilisation of minimally-invasive lumbar disc surgery is observed among statutory health insurers. Examples from other areas of innovative surgical technologies (e.g. robot assisted total hip replacement) indicate that the rise will probably continue - especially because there are no legal barriers to hinder introduction of innovative treatments into routine hospital care. Upon request by payers or providers the "Gemeinsamer Bundesausschuss" may assess a treatments benefit, its necessity and cost-effectiveness as a prerequisite for coverage by the statutory health insurance. In the case of minimally-invasive disc surgery it would be advisable to examine the legal framework for covering procedures only if they are provided under evaluation conditions. While in Germany coverage under evaluation conditions is established practice in ambulatory health care only ("Modellvorhaben") examples from other European countries (Great Britain, Switzerland) demonstrate that it is also feasible for hospital based interventions. (ABSTRACT TRUNCATED)

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Diagnostic nerve blocks: The popularity of neural blockade as a diagnostic tool in painful conditions, especially in the spine, is due to features like the unspecific character of spinal pain, the irrelevance of radiological findings and the purely subjective character of pain. It is said that apart from specific causes of pain and clear radicular involvement with obvious neurological deficits and corresponding findings of a prolapsed disc in MRI or CT pictures, a diagnosis of the anatomical cause of the pain can only be established if invasive tests are used [5]. These include zygapophyseal joint blocks, sacroiliacal joint blocks, disc stimulation and nerve root blocks. Under controlled conditions, it has been shown that among patients with chronic nonradicular low back pain, some 10-15% have zygapophyseal joint pain [58], some 15-20% have sacroiliacal joint pain [36, 59] and 40% have pain from internal disc disruption [60]. The diagnostic use of neural blockade rests on three premises. First, pathology causing pain is located in an exact peripheral location, and impulses from this site travel via a unique and consistent neural root. Second, injection of local aneasthetic totally abolishes sensory function of intended nerves and does not affect other nerves. Third, relief of pain after local anaesthetic block is attributable solely to block of the target afferent neural pathway. The validity of these assumptions is limited by complexities of anatomy, physiology, and psychology of pain perception and the effect of local anaesthetics on impulse conduction [28]. Facet joints: The prevalence of zygapophyseal joint pain among patients with low back pain seems to be between 15% and 40% [62], but apparently only 7% of patients have pure facet pain [8, 29]. Facet blockade is achieved either by injection of local anaesthetic into the joint space or around the medial branches of the posterior medial rami of the spinal nerves that innervate the joint. There are several problems with intraarticular facet injections, mainly failure to enter the joint capsule and rupture of the capsule during the injection [11]. There is no physiological means to test the adaequacy of medial nerve block, because the lower branches have no cutaneous innervation. Medial ramus blocks (for one joint two nerves have to be infiltrated) are as effective as intraarticular joint blocks [37]. Reproducibility of the test is not high, the specifity is only 65% [61]. For diagnosis of facet pain fluoroscopic control is always necessary as in the other diagnostic blocks. Sacroiliacal joint: Definitely the sacroiliacal joint can be the source of low back pain. Stimulation of the joint by injection in subjects without pain produces pain in the buttock, in the posterior thigh and the knee. There are many clinical tests which confirm the diagnosis, but the interrater reliability is moderate [53]. Intraarticular injection can be achieved in the lower part of the joint with fluoroscopic guidance only, but an accurate intraarticular injection, which is confirmed by contrast medium, even at this place is often difficult. It is not clear whether intraarticular spread is necessary to achieve efficacy. Discography: Two primary syndromes concerning the ventral compartment have been described: anular fissures of the disc and instability of the motion segment. In the syndrome of anular tear, leakage of nucleus pulposus material into the anulus fibrosus is considered to be the source of pain. The studies of Vaharanta [71] and Moneta [41] show a clear and significant correlation between disc pain and grade 3 fissures of the anulus fibrosus. intervertebral discs are difficult to anaesthetize. Intradiskal injections of local anaesthetics may succeed in relieving the patient's pain, but such injections are liable to yield false negative results if the injected agent fails to adequately infiltrate the nerve endings in the outer anulus fibrosus that mediate the patient's pain. In the majority of cases MRI provide adaequate information, but discography may be superior in early stages of anular tear and in clarifying the relation between imaging data and pain [71]. Selective spinal nerve injection: In patients with complicated radiculopathy, the contribution of root inflammation to pain may not be certain, or the level of pathology may be unclear. Diagnostic root blocks are indicated in the following situations: atypical topography of radicular pain, disc prolapses or central spinal stenosis at more than one level and monoradicular pain, lateral spinal stenosis, postnucleotomysyndrome. Injection of individual spinal nerves by paravertebral approach has to be used to elucidate the mechanism and source of pain in this unclear situations. The premise is that needle contact will identify the nerve that produces the patient's characteristic pain and that local anaesthetic delivered to the pathogenic nerve will be uniquely analgesic. Often, this method is used for surgical planning, such as determining the site of foraminotomy. All diagnostic nerve root blocks have to be done under fluoroscopic guidance. Pain relief with blockade of a spinal nerve cannot distinguish between pathology of the proximal nerve in the intervertebral foramen or pain transmitted from distal sites by that nerve. Besides, the tissue injury in the nerve's distribution and neuropathic pain (for instance as a result of root injury) likewise would be relieved by a proximal block of the nerve. Satisfactory needle placement could not be achieved in 10% of patient's at L4, 15% at L5 and 30% at S1 [28]. The positive predictive value of indicated radiculopathy confirmed by surgery ranged between 87-100% [14, 22]. The negative predictive value is poorly studied, because few patients in the negative test group had surgery. Negative predictive values were 27% and 38% of the small number of patients operated on despite a negative test. Only one prospective study was published, which showed a positive predictive value of 95% and an untested negative predictive value [66]. Some studies repeatedly demonstrated that pain relief by nerve root block does not predict success by neuroablative procedures, neither by dorsal rhyzotomy nor by dorsal gangliectomy [46]. Therapeutic nerve blocks - facet joints: Intraarticular injection of steroids offer no greater benefit than injections of normal saline [8, 15] and long lasting success is lacking. In this case, a denervation of the medial branches can be considered. To date three randomized controlled studies of radiofrequency facet denervation have been published. One study [20] reported only modest outcomes and its results remained inconclusive, another study [72] with a double blind controlled design showed some effects in a small selected group of patients (adjusted odds ratio 4.8) 3, 6 and 12 months after treatment, concerning not only reduction of pain but alleviating functional disability also. The third study (34a) showed no effect 3 months after treatment. Discogenic pain: Intradiscal radiofrequency lesions, intradiscal injections of steroids and phenol have been advocated, but there are no well controlled studies. Just recently, intradiscal lesion and denervation of the anulus has been described with promising results, but a randomized controlled study is lacking up to now [31, 55]. Epidural Steroids: Steroids relieve pain by reducing inflammation and by blocking transmission of nociceptive C-fiber input. Koes et al. [33] reviewed the randomized trials of epidural steroids: To date, 15 trials have been performed to evaluate the efficacy, 11 of which showed method scores of 50 points (from 100) ore more. The trials showed inconsistent results of epidural injections. Of the 15 trials, 8 reported positive results and 7 others reported negative results. Consequently the efficacy of epidural steroid injections has not yet been established. The benefits of epidural steroid injections seem to be of short duration only. Future efficacy studies, which are clearly needed, should take into account the apparent methological shortcomings. Furthermore, it is unclear which patients benefit from these injections. In our hands the injection technique can be much improved by fluoroscopic guidance of the needle, with a prone position of the patient, and lateral injection at the relevant level and with a small volume (1-2 ml) and low dose of corticosteroid (20 mg triamcinolone in the case of a monoradicular pain, for example). In the case of epidural adhesions in postoperative radicular pain [50], the study of Heafner showed that the additional effect of hyaloronidase and hypertonic saline to steroids was minimal. In our hands there was no effect in chronic radicular pain 3 months after the injection.

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After the implementation of a regulation restricting sulfur to 0.5% by weight in fuel on July 1, 1990, in Hong Kong, sulfur dioxide (SO2*) levels fell by 45% on average and as much as 80% in the most polluted districts (Hedley et al. 2002). In addition, a reduction of respiratory symptoms and an improvement in bronchial hyperresponsiveness in children were observed (Peters et al. 1996; Wong et al. 1998). A recent time-series study (Hedley et al. 2002) found an immediate reduction in mortality during the cool season at six months after the intervention, followed by an increase in cool-season mortality in the second and third years, suggesting that the reduction in pollution was associated with a delay in mortality. Proportional changes in mortality trends between the 5-year periods before and after the intervention were measured as relative risks and used to assess gains in life expectancy using the life table method (Hedley et al. 2002). To further explore the relation between changes in pollution-related mortality before and after the intervention, our study had three objectives: (1) to evaluate the short-term effects on mortality of changes in the pollutant mix after the Hong Kong sulfur intervention, particularly with changes in the particulate matter (PM) chemical species; (2) to improve the methodology for assessment of the health impact in terms of changes in life expectancy using linear regression models; and (3) to develop an approach for analyzing changes in life expectancy from Poisson regression models. A fourth overarching objective was to determine the relation between short- and long-term benefits due to an improvement in air quality. For an assessment of the short-term effects on mortality due to changes in the pollutant mix, we developed Poisson regression Core Models with natural spline smoothers to control for long-term and seasonal confounding variations in the mortality counts and with covariates to adjust for temperature (T) and relative humidity (RH). We assessed the adequacy of the Core Models by evaluating the results against the Akaike Information Criterion, which stipulates that, at a minimum, partial autocorrelation plots should be between -0.1 and 0.1, and by examining the residual plots to make sure they were free from patterns. We assessed the effects for gaseous pollutants (NO2, SO2, and O3), PM with an aerodynamic diameter &lt; or = 10 microm (PM10), and its chemical species (aluminum [Al], iron [Fe], manganese [Mn], nickel [Ni], vanadium [V], lead [Pb], and zinc [Zn]) using the Core Models, which were developed for the periods 5 years (or 2 years in the case of the sensitivity analysis) before and 5 years after the intervention, as well as in the10-year (or 7-year in the case of the sensitivity analysis) period pre- and post-intervention. We also included an indicator to separate the pre- and post-intervention periods, as well as the product of the indicator with an air pollution concentration variable. The health outcomes were mortality for all natural causes and for cardiovascular and respiratory causes, at all ages and in the 65 years or older age group. To assess the short- and long-term effects, we developed two methods: one using linear regression models reflecting the age-standardized mortality rate D(j) at day j, divided by a reference D(ref); and the other using Poisson regression models with daily mortality counts as the outcome variables. We also used both models to evaluate the relation between outcome variables and daily air pollution concentrations in the current day up to all previous days in the past 3 to 4 years. In the linear regression approach, we adjusted the data for temperature and relative humidity. We then removed season as a potential confounder, or deseasonalized them, by calculating a standard seasonal mortality rate profile, normalized to an annual average of unity, and dividing the mortality rates by this profile. Finally, to correct for long-term trends, we calculated a reference mortality rate D(ref)(j) as a moving average of the corrected and deseasonalized D(j) over the observation window. Then we regressed the outcome variable D(j)/D(ref) on an entire exposure sequence {c(i)} with lags up to 4 years in order to obtain impact coefficient f(i) from the regression model shown below: deltaD(j)/D (ref) = i(max)sigma f(i) c(j - i)(i = 0). The change in life expectancy (LE) for a change of units (deltac) in the concentration of pollutants on T(day)--representing the short interval (i.e., a day)--was calculated from the following equation (deltaL(pop) = average loss in life expectancy of an entire population): deltaL(pop) = -deltac T(day) infinity sigma (j = 0) infinity sigma f(i) (i = 0). In the Poisson regression approach, we fitted a distributed-lag model for exposure to previous days of up to 4 years in order to obtain the cumulative lag effect sigma beta(i). We fit the linear regression model of log(LE*/LE) = gamma(SMR - 1) + alpha to estimate the parameter gamma by gamma, where LE* and LE are life expectancy for an exposed and an unexposed population, respectively, and SMR represents the standardized mortality ratio. The life expectancy change per Ac increase in concentration is LE {exp[gamma delta c(sigma beta(i))]-1}. In our assessment of the changes in pollutant levels, the mean levels of SO2, Ni, and V showed a statistically significant decline, particularly in industrial areas. Ni and V showed the greatest impact on mortality, especially for respiratory diseases in the 5-year pre-intervention period for both the all-ages and 65+ groups among all chemical species. There were decreases in excess risks associated with Ni and V after the intervention, but they were nonsignificant. Using the linear regression approach, with a window of 1095 days (3 years), the losses in life expectancy with a 10-microg/m3 increase in concentrations, using two methods of estimation (one with adjustment for temperature and RH before the regression against pollutants, the other with adjustment for temperature and RH within the regression against pollutants), were 19.2 days (95% CI, 12.5 to 25.9) and 31.4 days (95% CI, 25.6 to 37.2) for PM10; and 19.7 days (95% CI, 15.2 to 24.2) and 12.8 days (95% CI, 8.9 to 16.8) for SO2. The losses in life expectancy in the current study were smaller than the ones implied by Elliott and colleagues (2007) and Pope and colleagues (2002) as expected since the observation window in our study was only 3 years whereas these other studies had windows of 16 years. In particular, the coefficients used by Elliott and colleagues (2007) for windows of 12 and 16 years were non-zero, which suggests that our window of at most 3 years cannot capture the full life expectancy loss and the effects were most likely underestimated. Using the Poisson regression approach, with a window of 1461 days (4 years), we found that a 10-microg/m3 increase in concentration of PM10 was associated with a change in life expectancy of -69 days (95% CI, -140 to 1) and a change of -133 days (95% CI, -172 to -94) for the same increase in SO2. The effect estimates varied as expected according to most variations in the sensitivity analysis model, specifically in terms of the Core Model definition, exposure windows, constraint of the lag effect pattern, and adjustment for smoking prevalence or socioeconomic status. Our results on the excess risks of mortality showed exposure to chemical species to be a health hazard. However, the statistical power was not sufficient to detect the differences between the pre- and post-intervention periods in Hong Kong due to the data limitations (specifically, the chemical species data were available only once every 6 days, and data were not available from some monitoring stations). Further work is needed to develop methods for maximizing the information from the data in order to assess any changes in effects due to the intervention. With complete daily air pollution and mortality data over a long period, time-series analysis methods can be applied to assess the short- and long-term effects of air pollution, in terms of changes in life expectancy. Further work is warranted to assess the duration and pattern of the health effects from an air pollution pulse (i.e., an episode of a rapid rise in air pollution) so as to determine an appropriate length and constraint on the distributed-lag assessment model.

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This catalogue includes all valid family-group (8 subfamilies, 52 tribes, 14 subtribes), genus-group (349 genera, 86 subgenera), and species-group names (2825 species, 215 subspecies) of darkling beetles (Coleoptera: Tenebrionidae) known to occur in North America and their available synonyms. Data on extant, subfossil and fossil taxa are given. For each name the author and year and page number of the description are provided, with additional information (e.g., type species for genus-group names, author of synonymies for invalid taxa) depending on the taxon rank. Several new nomenclatural acts are included. One new genus, <iLepidocnemeplatia</i Bousquet and Bouchard, is described. <iSpelaebiosis</i Bousquet and Bouchard [for <iArdoinia</i Özdikmen, 2004], <iBlapstinus marcuzzii</i Aalbu [for <iBlapstinus kulzeri</i Marcuzzi, 1977], and <iHymenorus campbelli</i Bouchard [for <iHymenorus oculatus</i Doyen and Poinar, 1994] are proposed as new replacement names. Supporting evidence is provided for the conservation of usage of <iTarpela micans</i (Fabricius, 1798) <inomen protectum</i over <iTarpela vittata</i (Olivier, 1793) <inomen oblitum</i. The generic names <iPsilomera</i Motschulsky, 1870 [= <iStenomorpha</i Solier, 1836], <iSteneleodes</i Blaisdell, 1909 [= <iXysta</i Eschscholtz, 1829], <iOoconibius</i Casey, 1895 and <iEuconibius</i Casey, 1895 [= <iConibius</i LeConte, 1851] are new synonyms (valid names in square brackets). The following 127 new synonymies of species-group names, listed in their original combination, are proposed (valid names, in their current combination, placed in square brackets): <iBothrasida mucorea</i Wilke, 1922 [= <iPelecyphorus guanajuatensis</i (Champion, 1884)]; <iParasida zacualpanicola</i Wilke, 1922 [= <iPelecyphorus asidoides</i Solier, 1836]; <iStenosides kulzeri</i Pallister, 1954, <iStenosides bisinuatus</i Pallister, 1954, and <iParasida trisinuata</i Pallister, 1954 [= <iPelecyphorus dispar</i (Champion, 1892)]; <iAsida favosa</i Champion, 1884 and <iAsida similata</i Champion, 1884 [= <iPelecyphorus fallax</i (Champion, 1884)]; <iOloglyptus bicarinatus</i Champion, 1884 [= <iPelecyphorus indutus</i (Champion, 1884)]; <iParasida laciniata</i Casey, 1912 and <iParasida cristata</i Pallister, 1954 [= <iPelecyphorus liratus</i (LeConte, 1854)]; <iParasida esperanzae</i Wilke, 1922 and <iParasida mixtecae</i Wilke, 1922 [= <iPelecyphorus longipennis</i (Champion, 1884)]; <iParasida tolucana</i Casey, 1912 [= <iPelecyphorus scutellaris</i (Champion, 1884)]; <iParasida purpusi</i Wilke, 1922 [= <iPelecyphorus tristis</i (Champion, 1884)]; <iAstrotus nosodermoides</i Champion, 1892 [= <iPelecyphorus erosus</i (Champion, 1892)]; Astrotus seticornis var. humeralis Champion, 1884 [= <iPelecyphorus seticornis</i (Champion, 1884)]; <iPactostoma breviuscula</i Casey, 1912, <iPactostoma exoleta</i Casey, 1912, <iPactostoma luteotecta</i Casey, 1912, <iPactostoma monticola</i Casey, 1912, <iPactostoma obtecta</i Casey, 1912, and <iPactostoma sigillata</i Casey, 1912 [=<iPelecyphorus anastomosis</i (Say, 1824)]; <iOloglyptus canus</i Champion, 1884 and <iOloglyptus sinuaticollis</i Champion, 1884 [= <iPelecyphorus graciliformis</i (Solier, 1836)]; <iGonasida elata reducta</i Casey, 1912, <iGonasida elata prolixa</i Casey, 1912, and <iGonasida aucta</i Casey, 1912 [= <iPhilolithus elatus compar</i (Casey, 1912)]; <iGonasida alaticollis</i Casey, 1912 [= <iPhilolithus elatus difformis</i (LeConte, 1854)]; <iGonasida gravida</i Casey, 1912 [= <iPhilolithus elatus elatus</i (LeConte, 1853)]; <iPelecyphorus aegrotus limbatus</i Casey, 1912 [= <iPhilolithus aegrotus aegrotus</i (LeConte, 1861)]; <iPelecyphorus corporalis</i Casey, 1912, <iPelecyphorus reptans</i Casey, 1912, <iPelecyphorus socer</i Casey, 1912, <iPelecyphorus abscissus</i Casey, 1912, <iPelecyphorus fumosus</i Casey, 1912, <iPelecyphorus parvus</i Casey, 1912, <iPelecyphorus morbillosus pacatus</i Casey, 1912, <iPelecyphorus morbillosus sobrius</i Casey, 1912, <iPelecyphorus piceus</i Casey, 1912, <iPelecyphorus piceus crudelis</i Casey, 1912, <iPelecyphorus snowi</i Casey, 1912, and <iPelecyphorus subtenuis</i Casey, 1912 [= <iPhilolithus morbillosus</i (LeConte, 1858)]; <iBothrasida sanctae-agnae</i Wilke, 1922 [= <iStenomorpha funesta</i (Champion, 1884)]; <iAsida flaccida</i Horn, 1896 [= <iStenomorpha embaphionides</i (Horn, 1894)]; <iAsida angustula</i Casey, 1890, <iStethasida stricta</i Casey, 1912, <iStethasida muricatula languida</i Casey, 1912, <iStethasida pertinax</i Casey, 1912, <iStethasida socors</i Casey, 1912, <iStethasida angustula inepta</i Casey, 1912, <iStethasida tenax</i Casey, 1912, and <iStethasida vegrandis</i Casey, 1912 [= <iStenomorpha muricatula</i (LeConte, 1851)]; <iStethasida obsoleta expansa</i Casey, 1912, <iStethasida obsoleta opacella</i Casey, 1912, <iStethasida brevipes</i Casey, 1912, <iStethasida torpida</i Casey, 1912, <iStethasida convergens</i Casey, 1912, <iStethasida discreta</i Casey, 1912, <iStethasida longula</i Casey, 1912, <iStethasida adumbrata</i Casey, 1912, <iStethasida occulta</i Casey, 1912, <iStethasida tarsalis</i Casey, 1912, <iStethasida unica</i Casey, 1912, and <iPelecyphorus laevigatus</i Papp, 1961 [= <iStenomorpha obsoleta</i (LeConte, 1851)]; <iTrichiasida eremica</i Wilke, 1922 [= <iStenomorpha difficilis</i (Champion, 1884)]; <iTrichiasida lineatopilosa</i Casey, 1912 [= <iStenomorpha hirsuta</i (LeConte, 1851)]; <iTrichiasida tenella</i Casey, 1912 [= <iStenomorpha hispidula</i (LeConte, 1851)]; <iTrichiasida duplex</i Casey, 1912 [= <iStenomorpha villosa</i (Champion, 1884)]; <iAlaudes squamosa</i Blaisdell, 1919, <iAlaudes testacea</i Blaisdell, 1919, and <iAlaudes fallax</i Fall, 1928 [= <iAlaudes singularis</i Horn, 1870]; <iEdrotes barrowsi</i Dajoz, 1999 [=<iEdrotes ventricosus</i LeConte, 1851]; <iNyctoporis tetrica</i Casey, 1907 and <iNyctoporis maura</i Casey, 1907 [= <iNyctoporis aequicollis</i Eschscholtz, 1831]; <iNyctoporis pullata</i Casey, 1907 [= <iNyctoporis sponsa</i Casey, 1907]; Eleodes tibialis forma oblonga Blaisdell, 1909 [= <iEleodes tibialis</i Blaisdell, 1909]; <iEleodes</i (<imanni</i var.) <ivariolosa</i Blaisdell, 1917 [= <iEleodes constrictus</i LeConte, 1858]; Eleodes cordata forma sublaevis Blaisdell, 1909, Eleodes cordata forma intermedia Blaisdell, 1909, Eleodes cordata forma oblonga Blaisdell, 1909, Eleodes cordata forma elongata Blaisdell, 1909, and <iEleodes</i (<icordata</i var.) <iadulterina</i Blaisdell, 1917 [= <iEleodes cordata</i Eschscholtz, 1829]; Eleodes hornii var. monticula Blaisdell, 1918 and <iEleodes manni sierra</i Blaisdell, 1925 [= <iEleodes fuchsii</i Blaisdell, 1909]; Eleodes parvicollis var. squalida Blaisdell, 1918 [= <iEleodes parvicollis</i Eschscholtz, 1829]; <iEleodes reflexicollis</i Mannerheim, 1843 and Eleodes parvicollis forma farallonica Blaisdell, 1909 [= <iEleodes planata</i Eschscholtz, 1829]; <iEleodes indentata</i Blaisdell, 1935 [= <iEleodes rotundipennis</i LeConte, 1857]; <iEleodes intricata</i Mannerheim, 1843 [= <iEleodes scabrosa</i Eschscholtz, 1829]; <iEleodes horni fenyesi</i Blaisdell, 1925 [= <iEleodes tenebrosa</i Horn, 1870]; Eleodes cordata var. horrida Blaisdell, 1918 [= <iEleodes tuberculata</i Eschscholtz, 1829]; <iEleodes oblonga</i Blaisdell, 1933 [= <iEleodes versatilis</i Blaisdell, 1921]; <iEleodes dentipes marinae</i Blaisdell, 1921 [= <iEleodes dentipes</i Eschscholtz, 1829]; Eleodes carbonaria forma glabra Blaisdell, 1909 [= <iEleodes carbonaria carbonaria</i (Say, 1824)]; Eleodes granosa forma fortis Blaisdell, 1909 [= <iEleodes granosa</i LeConte, 1866]; Eleodes pilosa forma ordinata Blaisdell, 1909 [= <iEleodes pilosa</i Horn, 1870]; <iTrogloderus costatus pappi</i Kulzer, 1960 [= <iTrogloderus tuberculatus</i Blaisdell, 1909]; <iTrogloderus costatus mayhewi</i Papp, 1961 [= <iTrogloderus vandykei</i La Rivers, 1946]; <iBolitophagus cristatus</i Gosse, 1840 [= <iBolitotherus cornutus</i (Fabricius, 1801)]; <iEleates explanatus</i Casey, 1890 [= <iEleates depressus</i (Randall, 1838)]; <iBlapstinus sonorae</i Casey, 1890 [= <iBlapstinus brevicollis</i LeConte, 1851]; <iBlapstinus falli</i Blaisdell, 1929 [= <iBlapstinus castaneus</i Casey, 1890]; <iBlapstinus brunneus</i Casey, 1890 and <iBlapstinus coronadensis</i Blaisdell, 1892 [=<iBlapstinus histricus</i Casey, 1890]; <iBlapstinus hesperius</i Casey, 1890 [=<iBlapstinus intermixtus</i Casey, 1890]; <iBlapstinus cinerascens</i Fall, 1929 [= <iBlapstinus lecontei</i Mulsant and Rey, 1859]; <iBlapstinus niger</i Casey, 1890 and <iBlapstinus cribricollis</i Casey, 1890 [= <iBlapstinus pimalis</i Casey, 1885]; <iBlapstinus arenarius</i Casey, 1890 [= <iBlapstinus pratensis</i LeConte, 1859]; <iBlapstinus gregalis</i Casey, 1890 [= <iBlapstinus substriatus</i Champion, 1885]; <iBlapstinus hydropicus</i Casey, 1890 [= <iBlapstinus sulcatus</i LeConte, 1851]; <iBlapstinus hospes</i Casey, 1890 [= <iBlapstinus vestitus</i LeConte, 1859]; <iNotibius reflexus</i Horn, 1894 [= <iConibius opacus</i (LeConte, 1866)]; <iNotibius affinis</i Champion, 1885 [=<iConibius rugipes</i (Champion, 1885)]; <iConibius parallelus</i LeConte, 1851 [= <iConibius seriatus</i LeConte, 1851]; <iNocibiotes rubripes</i Casey, 1895 [=<iNocibiotes caudatus</i Casey, 1895]; <iNocibiotes gracilis</i Casey, 1895 and <iNocibiotes acutus</i Casey, 1895 [=<iNocibiotes granulatus</i (LeConte, 1851)]; <iConibius alternatus</i Casey, 1890 [= <iTonibius sulcatus</i (LeConte, 1851)]; <iPedinus suturalis</i Say, 1824 [= <iAlaetrinus minimus</i (Palisot de Beauvois, 1817)]; <iMenedrio longipennis</i Motschulsky, 1872 [= <iTenebrio obscurus</i Fabricius, 1792]; <iHymenophorus megops</i Hatch, 1965 and <iTelesicles magnus</i Hatch, 1965 [= <iHymenorus sinuatus</i Fall, 1931]; <iAndrimus concolor</i Casey, 1891 and <iAndrimus convergens</i Casey, 1891 [= <iAndrimus murrayi</i (LeConte, 1866)]; <iMycetochara marshalli</i Campbell, 1978 [= <iMycetochara perplexata</i Marshall, 1970]; <iPhaleria globosa</i LeConte, 1857 [= <iPhaleria picta</i Mannerheim, 1843]. The following subspecies of <iTrogloderus costatus</i LeConte, 1879 are given species rank: <iTrogloderus nevadus</i La Rivers, 1943, <iTrogloderus tuberculatus</i Blaisdell, 1909, and <iTrogloderus vandykei</i La Rivers, 1946. The following taxa, previously thought to be junior synonyms, are considered valid: <iAmphidora</i Eschscholtz, 1829; <iXysta</i Eschscholtz, 1829; <iHelops confluens</i (Casey, 1924). Two new combinations are proposed: <iStenomorpha spinimana</i (Champion, 1892) and <iStenomorpha tenebrosa</i (Champion, 1892) [from the genus <iParasida</i Casey, 1912]. The type species [placed in square brackets] of the following 12 genus-group taxa are designated for the first time: <iLagriola</i Kirsch, 1874 [<iLagriola operosa</i Kirsch, 1874]; <iLocrodes</i Casey, 1907 [<iEmmenastus piceus</i Casey, 1890]; <iFalacer</i Laporte, 1840 [<iAcanthopus cupreus</i Laporte, 1840 (= <iHelops contractus</i Palisot de Beauvois, 1812)]; <iBlapylis</i Horn, 1870 [<iEleodes cordata</i Eschscholtz, 1829]; <iDiscogenia</i LeConte, 1866 [<iEleodes scabricula</i LeConte, 1858]; <iMetablapylis</i Blaisdell, 1909 [<iEleodes nigrina</i LeConte, 1858]; <iSteneleodes</i Blaisdell, 1909 [<iEleodes longicollis</i LeConte, 1851]; <iScaptes</i Champion, 1886 [<iScaptes squamulatus</i Champion, 1886 (= <iAsida tropica</i Kirsch, 1866)]; <iAspidius</i Mulsant and Rey, 1859 [<iBlaps punctata</i Fabricius, 1792]; <iCryptozoon</i Schaufuss, 1882 [<iCryptozoon civile</i Schaufuss, 1882]; <iHalophalerus</i Crotch, 1874 [<iPhaleria rotundata</i LeConte, 1851]; <iDignamptus</i LeConte, 1878 [<iDignamptus stenochinus</i LeConte, 1878]. Two species previously known from South America [<iNilio lebasi</i J. Thomson and <iPlatydema erotyloides</i Chevrolat] are reported for the first time from North America.

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Paroxetine is the first selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) to be approved for the treatment of patients with panic disorder with or without agoraphobia. It is a highly selective inhibitor of presynaptic serotonin reuptake and does not interact with adrenergic, dopaminergic, histaminergic or serotonergic receptors to any significant extent. Oral paroxetine 10 to 60 mg/day is significantly more effective than placebo in reducing the frequency of panic attacks and improving associated symptoms, as shown in short term trials in patients with panic disorder with or without agoraphobia. The efficacy of the drug was maintained during up to 6 months'; treatment, and continued therapy reduced the risk of relapse. Oral paroxetine 10 to 60 mg/day was at least as effective as clomipramine 10 to 150 mg/day, but appeared to have a more rapid onset of effect, in a placebo-controlled trial. The tolerability profile of paroxetine is similar to that established for other SSRIs and is characterised by adverse events such as nausea, headache, somnolence, dry mouth, tremor, insomnia, asthenia, sweating, constipation, dizziness and sexual dysfunction. Paroxetine was better tolerated overall than clomipramine and was associated with a lower incidence of certain anticholinergic events (such as dry mouth and constipation) in a comparative trial. It is not associated with the type of dependence seen with benzodiazepines, and it appears to be safer in overdose than the tricyclic antidepressants. Paroxetine 20 or 30mg does not significantly impair psychomotor function or interact with alcohol (ethanol). In conclusion, the good tolerability profile of paroxetine, including lack of dependence potential and relative safety in overdose, makes it attractive for the treatment of patients with panic disorder. It appears to be at least as effective as clomipramine in reducing panic attacks and associated symptoms. Although further trials to compare the efficacy and tolerability of paroxetine with that of other tricyclic agents (especially Imipramine), high-potency benzodiazepines and monoamine oxidase inhibitors are needed, the drug appears to have the potential to become a first-line treatment for panic disorder. Paroxetine increases serotonergic neurotransmission by inhibiting presynaptic reuptake of serotonin (5-hydroxytryptamine; 5-HT) and thereby increasing the level of the neurotransmitter at the synaptic cleft. In vitro, it is a more potent inhibitor of serotonin uptake than the selective serotonin reuptake inhibitors (SSRIs) Citalopram, fluvoxamine and fluoxetine. Paroxetine was more potent than sertraline in one study that compared mean inhibition constants for serotonin uptake, but not in another study that compared the concentrations required to inhibit serotonin uptake by 50%. In contrast to the tricyclic antidepressants, paroxetine has little effect on the uptake of dopamine or noradrenaline (norepinephrine) in vitro. It has negligible affinity for αr(1-), αr(2-) and βr-adrenoceptors, dopamine D(1) and D(2) receptors, hi starnine H(1) receptors and serotonin 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors. However, paroxetine does have weak affinity for muscarinic cholinergic receptors. As shown in rats, paroxetine appears to indirectly activate somatodendritic 5-HT(1A) autoreceptors when initially administered, thereby inhibiting firing of 5-HT neurons and release of serotonin. This may explain why the onset of therapeutic effect of paroxetine is delayed. However, repeated administration of paroxetine causes adaptive changes in synaptic serotonergic receptors, including a decrease in the responsiveness of somatodendritic and terminal serotonin autoreceptors. Central βr-adrenoceptors are not down-regulated by administration of paroxetine to rats. Various studies in healthy volunteers without sleep disorders or volunteers reporting poor sleep have indicated that paroxetine disturbs normal sleep patterns by reducing rapid eye movement (REM) sleep time and lengthening REM latency. The effect of paroxetine on sleep in patients with panic disorder has not been determined, but in patients with depression the drug improves subjective quality of sleep. In electroencephalographic studies in healthy volunteers, administration of a single dose of paroxetine 30mg produced changes indicative of a sedative profile, whereas administration of 70mg produced changes indicative of activating properties. No significant impairment of psychomotor function was observed after administration of single or multiple doses of paroxetine 20 or 30mg to healthy volunteers or patients with depression. The sedation and impairment of psychomotor function caused by haloperidol, amobarbital, oxazepam or alcohol (ethanol) were not potentiated by the administration of paroxetine 30mg. In contrast to amitriptyline 150 mg/day or doxepin 150 mg/day, 2 to 6 weeks' treatment with paroxetine 20 or 30 mg/day did not produce clinically significant haemodynamic or electrophysiological effects on cardiac function in healthy volunteers or patients with depression. Fewer adverse cardiac effects were reported by paroxetine than nortriptyline recipients in a study in patients with depression and ischaemic heart disease. The anxiolytic activity of paroxetine has been demonstrated after 7 or 21 days' administration in several rodent models. Paroxetine is well absorbed after oral administration. It undergoes extensive first-pass metabolism and is rapidly distributed into tissue. Only about 1% of the paroxetine dose remains in the systemic circulation. Approximately 95% of paroxetine is protein bound in the plasma. Steady-state concentrations are reached after 7 to 14 days of oral administration and the terminal elimination half-life (t1/2βr) is approximately 24 hours. However, there is a great deal of interindividual variation in the pharmacokinetics of paroxetine. Paroxetine is metabolised by at least 2 enzymes of the cytochrome P450 (CYP) system, one of which is CYP2D6. This enzyme is subject to genetic polymorphism, and thus the pharmacokinetics of paroxetine differ between individuals who have the enzyme (extensive metabolisers) and those who do not (poor metabolisers). The metabolites of paroxetine are essentially inactive. Metabolism of paroxetine by CYP2D6 is saturable. Consequently, with repeated administration, bioavailability of paroxetine increases and pharmacokinetics may become nonlinear in some patients, especially when the dosage of paroxetine is increased. Approximately two-thirds of a paroxetine dose is eliminated in the urine and the remainder is excreted in faeces. Almost all of the dose is eliminated as metabolites; lt3% is excreted as unchanged drug. The plasma concentration and area under the plasma concentration-time curve of paroxetine are greater, and the t1/2βr prolonged, in elderly patients and those with hepatic or severe renal impairment compared with the general population. Paroxetine distributes into breast milk to produce concentrations similar to those in plasma. As shown in 3 short term placebo-controlled trials in patients with panic disorder with or without agoraphobia, oral paroxetine 10 to 60 mg/day is significantly more effective than placebo for most variables measuring reduction in panic attack frequency. The drug also produced significantly greater improvements in various anxiety and depression scales than placebo. An extension phase of one of the placebo-controlled studies showed that the efficacy of paroxetine in reducing panic attack frequency is maintained during up to 6 months' treatment and that the drug reduces the risk of relapse. Oral paroxetine 10 to 60 mg/day was at least as effective as clomipramine 10 to 150 mg/day in a comparative study. During weeks 7 to 9 of treatment, 51% of paroxetine recipients had no full panic attacks, compared with 37% of clomipramine recipients. The onset of action appeared to be more rapid for paroxetine than for clomipramine. The 2 drugs were equally effective in improving generalised anxiety, phobic avoidance and social, family and work interactions. In patients who elected to continue treatment for a further 36 weeks in an extension phase of the above study, response rates increased further in all groups, including the placebo group. During weeks 34 to 36 of extended treatment, 85% of paroxetine recipients, 72% of clomipramine recipients and 59% of placebo recipients had no panic attacks. The difference between paroxetine and placebo was statistically significant at this time point; however, there was no significant difference between groups at the primary efficacy endpoint (weeks 22 to 24). Paroxetine is generally well tolerated by both younger and older individuals and its adverse event profile is consistent with that expected for an SSRI. The tolerability profile of paroxetine in patients with panic disorder appears to resemble that in patients with depression. Headache, nausea, somnolence, dry mouth and insomnia were the most common adverse events among 469 patients with panic disorder who received paroxetine 10 to 60 mg/day in short term clinical trials. The individual incidences for these events ranged from 18 to 25%; however, the incidence of headache in paroxetine-treated patients was the same as that in placebo recipients. (ABSTRACT TRUNCATED)

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To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality. Guidance for Canadian practitioners on overall effectiveness, mechanism of action, indications, contraindications, non-contraceptive benefits, side effects and risks, and initiation of cited contraceptive methods; family planning in the context of sexual health and general well-being; contraceptive counselling methods; and access to, and availability of, cited contraceptive methods in Canada. Published literature was retrieved through searches of Medline and The Cochrane Database from January 1994 to January 2015 using appropriate controlled vocabulary (e.g., contraception, sexuality, sexual health) and key words (e.g., contraception, family planning, hormonal contraception, emergency contraception). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from January 1994 to January 2015. Searches were updated on a regular basis and incorporated in the guideline to June 2015. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of the evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Chapter 1: Contraception in Canada Summary Statements 1. Canadian women spend a significant portion of their lives at risk of an unintended pregnancy. (II-2) 2. Effective contraceptive methods are underutilized in Canada, particularly among vulnerable populations. (II-2) 3. Long-acting reversible contraceptive methods, including contraceptive implants and intrauterine contraception (copper-releasing and levonorgestrel-releasing devices/systems), are the most effective reversible contraceptive methods and have the highest continuation rates. (II-1) 4. Canada currently does not collect reliable data to determine the use of contraceptive methods, abortion rates, and the prevalence of unintended pregnancy among reproductive-age women. (II-2) 5. A universal subsidy for contraceptive methods as provided by many of Canada's peer nations and a few Canadian provinces may produce health system cost-savings. (II-2) 6. Health Canada approval processes for contraceptives have been less efficient than those of other drug approval agencies and Health Canada processes for other classes of pharmaceuticals. (II-2) 7. It is feasible and safe for contraceptives and family planning services to be provided by appropriately trained allied health professionals such as midwives, registered nurses, nurse practitioners, and pharmacists. (II-2) Recommendations 1. Contraceptive counselling should include a discussion of typical use failure rates and the importance of using the contraceptive method consistently and correctly in order to avoid pregnancy. (II-2A) 2. Women seeking contraception should be counselled on the wide range of effective methods of contraception available, including long-acting reversible contraceptive methods (LARCs). LARCs are the most effective methods of reversible contraception, have high continuation rates, and should be considered when presenting contraceptive options to any woman of reproductive age. (II-2A) 3. Family planning counselling should include counselling on the decline of fertility associated with increasing female age. (III-A) 4. Health policy supporting a universal contraception subsidy and strategies to promote the uptake of highly effective methods as cost-saving measures that improve health and health equity should be considered by Canadian health decision makers. (III-B) 5. Canadian health jurisdictions should consider expanding the scope of practice of other trained professionals such as nurses, nurse practitioners, midwives, and pharmacists and promoting task-sharing in family planning. (II-2B) 6. The Canadian Community Health Survey should include adequate reproductive health indicators in order for health care providers and policy makers to make appropriate decisions regarding reproductive health policies and services in Canada. (III-B) 7. Health Canada processes and policies should be reviewed to ensure a wide range of modern contraceptive methods are available to Canadian women. (III-B) Chapter 2: Contraceptive Care and Access Summary Statements 8. Although there are many contraceptive options in Canada, only a narrow range of contraceptive methods are commonly used by those of reproductive age. (II-3) 9. Condom use decreases with longer relationship tenure and when the sexual partner is considered to be the main partner, likely due to a lower perceived risk of sexually transmitted infection in that relationship. Condom use may also decrease markedly as an unintended consequence when an effective non-barrier method, such as hormonal contraception or intrauterine contraception, is initiated. (II-3) 10. Family planning counselling provides a natural segue into screening for concerns about sexual function or intimate partner violence. (III) 11. Well-informed and well-motivated individuals who have developed skills to practise safer sex behaviours are more likely to use contraceptive and safer sex methods effectively and consistently. (II-2) Recommendations 8. Comprehensive family planning services, including abortion services, should be accessible to all Canadians regardless of geographic location. These services should be confidential, non-judgemental, and respectful of individuals' privacy and cultural contexts. (III-A) 9. A contraceptive visit should include history taking, screening for contraindications, dispensing or prescribing a method of contraception, and exploring contraceptive choice and adherence in the broader context of the individual's sexual behaviour, reproductive health risk, social circumstances, and relevant belief systems. (III-B) 10. Health care providers should provide practical information on the wide range of contraceptive options and their potential non-contraceptive benefits and assist women and their partners in determining the best user-method fit. (III-B) 11. Health care providers should assist women and men in developing the skills necessary to negotiate the use of contraception and the correct and consistent use of a chosen method. (III-B) 12. Contraceptive care should include discussion and management of the risk of sexually transmitted infection, including appropriate recommendations for condom use and dual protection, STI screening, post-exposure prophylaxis, and Hepatitis B and human papillomavirus vaccination. (III-B) 13. Health care providers should emphasize the use of condoms not only for protection against sexually transmitted infection, but also as a back-up method when adherence to a hormonal contraceptive may be suboptimal. (I-A) 14. Health care providers should be aware of current media controversies in reproductive health and acquire relevant evidence-based information that can be briefly and directly communicated to their patients. (III-B) 15. Referral resources for intimate partner violence, sexually transmitted infections, sexual dysfunction, induced abortion services, and child protection services should be available to help clinicians provide contraceptive care in the broader context of women's health. (III-B) Chapter 3: Emergency Contraception Summary Statements 12. The copper intrauterine device is the most effective method of emergency contraception. (II-2) 13. A copper intrauterine device can be used for emergency contraception up to 7 days after unprotected intercourse provided that pregnancy has been ruled out and there are no other contraindications to its insertion. (II-2) 14. Levonorgestrel emergency contraception is effective up to 5 days (120 hours) after intercourse; its effectiveness decreases as the time between unprotected intercourse and ingestion increases. (II-2) 15. Ulipristal acetate for emergency contraception is more effective than levonorgestrel emergency contraception up to 5 days after unprotected intercourse. This difference in effectiveness is more pronounced as the time from unprotected intercourse increases, especially after 72 hours. (I) 16. Hormonal emergency contraception (levonorgestrel emergency contraception and ulipristal acetate for emergency contraception) is not effective if taken on the day of ovulation or after ovulation. (II-2) 17. Levonorgestrel emergency contraception may be less effective in women with a body mass index &gt; 25 kg/m2 and ulipristal acetate for emergency contraception may be less effective in women with a body mass index &gt; 35 kg/m2. However, hormonal emergency contraception may still retain some effectiveness regardless of a woman's body weight or body mass index. (II-2) 18. Hormonal emergency contraception is associated with higher failure rates when women continue to have subsequent unprotected intercourse. (II-2) 19. Hormonal contraception can be initiated the day of or the day following the use of levonorgestrel emergency contraception, with back-up contraception used for the first 7 days. (III) 20. Hormonal contraception can be initiated 5 days following the use of ulipristal acetate for emergency contraception, with back-up contraception used for the first 14 days. (III) Recommendations 16. All emergency contraception should be initiated as soon as possible after unprotected intercourse. (II-2A) 17. Women should be informed that the copper intrauterine device (IUD) is the most effective method of emergency contraception and can be used by any woman with no contraindications to IUD use. (II-3A) 18.

Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.

To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality. Guidance for Canadian practitioners on overall effectiveness, mechanism of action, indications, contraindications, non-contraceptive benefits, side effects and risks, and initiation of cited contraceptive methods; family planning in the context of sexual health and general well-being; contraceptive counselling methods; and access to, and availability of, cited contraceptive methods in Canada. Published literature was retrieved through searches of Medline and The Cochrane Database from January 1994 to January 2015 using appropriate controlled vocabulary (e.g., contraception, sexuality, sexual health) and key words (e.g., contraception, family planning, hormonal contraception, emergency contraception). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from January 1994 to January 2015. Searches were updated on a regular basis and incorporated in the guideline to June 2015. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of the evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Chapter 1: Contraception in Canada Summary Statements  1. Canadian women spend a significant portion of their lives at risk of an unintended pregnancy. (II-2)  2. Effective contraceptive methods are underutilized in Canada, particularly among vulnerable populations. (II-2)  3. Long-acting reversible contraceptive methods, including contraceptive implants and intrauterine contraception (copper-releasing and levonorgestrel-releasing devices/systems), are the most effective reversible contraceptive methods and have the highest continuation rates. (II-1)  4. Canada currently does not collect reliable data to determine the use of contraceptive methods, abortion rates, and the prevalence of unintended pregnancy among reproductive-age women. (II-2)  5. A universal subsidy for contraceptive methods as provided by many of Canada's peer nations and a few Canadian provinces may produce health system cost-savings. (II-2)  6. Health Canada approval processes for contraceptives have been less efficient than those of other drug approval agencies and Health Canada processes for other classes of pharmaceuticals. (II-2)  7. It is feasible and safe for contraceptives and family planning services to be provided by appropriately trained allied health professionals such as midwives, registered nurses, nurse practitioners, and pharmacists. (II-2) Recommendations 1. Contraceptive counselling should include a discussion of typical use failure rates and the importance of using the contraceptive method consistently and correctly in order to avoid pregnancy. (II-2A) 2. Women seeking contraception should be counselled on the wide range of effective methods of contraception available, including long-acting reversible contraceptive methods (LARCs). LARCs are the most effective methods of reversible contraception, have high continuation rates, and should be considered when presenting contraceptive options to any woman of reproductive age. (II-2A) 3. Family planning counselling should include counselling on the decline of fertility associated with increasing female age. (III-A) 4. Health policy supporting a universal contraception subsidy and strategies to promote the uptake of highly effective methods as cost-saving measures that improve health and health equity should be considered by Canadian health decision makers. (III-B) 5. Canadian health jurisdictions should consider expanding the scope of practice of other trained professionals such as nurses, nurse practitioners, midwives, and pharmacists and promoting task-sharing in family planning. (II-2B) 6. The Canadian Community Health Survey should include adequate reproductive health indicators in order for health care providers and policy makers to make appropriate decisions regarding reproductive health policies and services in Canada. (III-B) 7. Health Canada processes and policies should be reviewed to ensure a wide range of modern contraceptive methods are available to Canadian women. (III-B) Chapter 2: Contraceptive Care and Access Summary Statements  8. Although there are many contraceptive options in Canada, only a narrow range of contraceptive methods are commonly used by those of reproductive age. (II-3)  9. Condom use decreases with longer relationship tenure and when the sexual partner is considered to be the main partner, likely due to a lower perceived risk of sexually transmitted infection in that relationship. Condom use may also decrease markedly as an unintended consequence when an effective non-barrier method, such as hormonal contraception or intrauterine contraception, is initiated. (II-3) 10. Family planning counselling provides a natural segue into screening for concerns about sexual function or intimate partner violence. (III) 11. Well-informed and well-motivated individuals who have developed skills to practise safer sex behaviours are more likely to use contraceptive and safer sex methods effectively and consistently. (II-2) Recommendations 8. Comprehensive family planning services, including abortion services, should be accessible to all Canadians regardless of geographic location. These services should be confidential, non-judgemental, and respectful of individuals' privacy and cultural contexts. (III-A) 9. A contraceptive visit should include history taking, screening for contraindications, dispensing or prescribing a method of contraception, and exploring contraceptive choice and adherence in the broader context of the individual's sexual behaviour, reproductive health risk, social circumstances, and relevant belief systems. (III-B) 10. Health care providers should provide practical information on the wide range of contraceptive options and their potential non-contraceptive benefits and assist women and their partners in determining the best user-method fit. (III-B) 11. Health care providers should assist women and men in developing the skills necessary to negotiate the use of contraception and the correct and consistent use of a chosen method. (III-B) 12. Contraceptive care should include discussion and management of the risk of sexually transmitted infection, including appropriate recommendations for condom use and dual protection, STI screening, post-exposure prophylaxis, and Hepatitis B and human papillomavirus vaccination. (III-B) 13. Health care providers should emphasize the use of condoms not only for protection against sexually transmitted infection, but also as a back-up method when adherence to a hormonal contraceptive may be suboptimal. (I-A) 14. Health care providers should be aware of current media controversies in reproductive health and acquire relevant evidence-based information that can be briefly and directly communicated to their patients. (III-B) 15. Referral resources for intimate partner violence, sexually transmitted infections, sexual dysfunction, induced abortion services, and child protection services should be available to help clinicians provide contraceptive care in the broader context of women's health. (III-B) Chapter 3: Emergency Contraception Summary Statements 12. The copper intrauterine device is the most effective method of emergency contraception. (II-2) 13. A copper intrauterine device can be used for emergency contraception up to 7 days after unprotected intercourse provided that pregnancy has been ruled out and there are no other contraindications to its insertion. (II-2) 14. Levonorgestrel emergency contraception is effective up to 5 days (120 hours) after intercourse; its effectiveness decreases as the time between unprotected intercourse and ingestion increases. (II-2) 15. Ulipristal acetate for emergency contraception is more effective than levonorgestrel emergency contraception up to 5 days after unprotected intercourse. This difference in effectiveness is more pronounced as the time from unprotected intercourse increases, especially after 72 hours. (I) 16. Hormonal emergency contraception (levonorgestrel emergency contraception and ulipristal acetate for emergency contraception) is not effective if taken on the day of ovulation or after ovulation. (II-2) 17. Levonorgestrel emergency contraception may be less effective in women with a body mass index &gt; 25 kg/m2 and ulipristal acetate for emergency contraception may be less effective in women with a body mass index &gt; 35 kg/m2. However, hormonal emergency contraception may still retain some effectiveness regardless of a woman's body weight or body mass index. (II-2) 18. Hormonal emergency contraception is associated with higher failure rates when women continue to have subsequent unprotected intercourse. (II-2) 19. Hormonal contraception can be initiated the day of or the day following the use of levonorgestrel emergency contraception, with back-up contraception used for the first 7 days. (III) 20. Hormonal contraception can be initiated 5 days following the use of ulipristal acetate for emergency contraception, with back-up contraception used for the first 14 days. (III) Recommendations 16. All emergency contraception should be initiated as soon as possible after unprotected intercourse. (II-2A) 17. Women should be informed that the copper intrauterine device (IUD) is the most effective method of emergency contraception and can be used by any woman with no contraindications to IUD use. (II-3A) 18.

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Repaglinide (Prandin), NovoNorm, GlucoNorm, an oral insulin secretagogue, was the first meglitinide analogue to become available for use in patients with type 2 diabetes mellitus. The drug lowers postprandial glucose excursions by targeting early-phase insulin release, an effect thought to be important in reducing long-term cardiovascular complications of diabetes. Repaglinide provided similar overall glycaemic control to that achieved with glibenclamide (glyburide), as assessed by glycosylated haemoglobin (HbA(1c)) and fasting blood glucose levels, and was generally well tolerated in well designed clinical trials. Its rapid onset and relatively short duration of action allow for flexible meal schedules. Two modelled US cost-effectiveness analyses projected lifetime costs and outcomes for a hypothetical cohort of patients with type 2 diabetes. Both analyses projected long-term complications using data on HbA(1c) level changes from short-term clinical trials. Repaglinide plus rosiglitazone was dominant over rosiglitazone in one analysis, and repaglinide plus metformin was dominant over nateglinide plus metformin in the other. A similar Canadian analysis showed a favourable incremental cost-effectiveness ratio (&lt;dollars US 1000 per QALY gained; 2001 values) for patients who switched from a sulphonylurea to repaglinide versus those who remained on sulphonylurea therapy. Long-term outcomes were projected using short-term clinical trial data on postprandial blood glucose level changes in the Canadian study. All three cost-effectiveness analyses are available as abstracts/posters. Two US cost analyses (both published in full) have also been conducted comparing the short-term costs (&lt;or=3 years) of repaglinide, with or without metformin, versus other oral antidiabetic regimens. Results of these analyses are somewhat equivocal because of study design issues and/or a lack of statistically significant differences between treatment groups. In conclusion, repaglinide as monotherapy or in combination with other antidiabetic agents, such as metformin or rosiglitazone, achieves good metabolic control, similar to that achieved with comparable glibenclamide regimens. Severe hypoglycaemic episodes are less common with repaglinide than some sulphonylureas, including glibenclamide. Modelled cost-effectiveness analyses conducted in North America showed favourable results for repaglinide-containing regimens versus comparators, largely attributed to projected reductions in long-term cardiovascular complications using short-term data on changes in glycaemic parameters from clinical trials. Results of these cost-effectiveness analyses (all of which have been published as abstracts/posters) should be interpreted with caution since various assumptions regarding long-term costs and outcomes were necessarily incorporated into the economic models. While repaglinide is a useful addition to the available treatment options in type 2 diabetes, potential long-term advantages versus other agents, such as reducing cardiovascular complications, require confirmation. The prevalence of diabetes mellitus is projected to increase to over 3% of the world's population ( approximate, equals 220 million people) by the year 2010. Globally, 97% of patients with diabetes have type 2 disease, although in industrialised countries the proportion of type 2 disease is about 90%. In 2010, an estimated 14.85 million individuals in the US and 2.88 million in the UK will be diagnosed with type 2 diabetes. In addition, approximately one-third to one-half of individuals with diabetes are unaware that they have the disease, and are therefore undiagnosed. Diabetes is associated with significant morbidity, mortality and economic consequences. For the year 2002 in the US, direct medical costs associated with diabetes (type 1 and 2) were estimated at dollars US 91.8 billion (70% of total costs) and indirect costs at dollars US 39.8 billion (30%), for a total of dollars US 132 billion. Data from more than 7000 patients in eight European countries indicate tha the mean cost per patient with diabetes was dollars US 2928 annually (1999 values), and the proportion of total healthcare expenditure directed toward diabetes ranged from 1.6% to 6.6% depending on the country. Several analyses focusing specifically on type 2 disease showed, not surprisingly, that costs were higher among patients with diabetic complications than in those without complications. Repaglinide, a meglitinide analogue, is an oral insulin secretagogue that reduces postprandial glucose excursions by targeting postprandial insulin release. In clinical trials in patients with type 2 diabetes, repaglinide was usually administered at a dosage of 0.5-4 mg three times daily before meals as monotherapy or in combination with other agents. In placebo-controlled trials of up to 24 weeks' duration in patients with type 2 diabetes, repaglinide achieved statistically significant improvements in glycaemic control, as assessed by glycosylated haemoglobin (HbA(1c)), fasting blood glucose (FBG) and/or postprandial blood glucose (PPBG) levels compared with placebo. Preprandial administration of repaglinide achieved similar glycaemic control to glibenclamide (glyburide) 1.75-15 mg/day and better glycaemic control than glipizide 5-15 mg/day in 1-year, double-blind, randomised trials in patients with type 2 disease, the vast majority of whom had previously received oral antidiabetic therapy. Several randomised, open-label studies have evaluated repaglinide as part of combination therapy over 3-6 months in patients with type 2 diabetes who had inadequate glycaemic control with previous drug therapy. In general, results showed statistically significant improvements in glycaemic control when repaglinide was used in combination with metformin, various thiazolidinediones, or metformin plus bedtime insulin compared with monotherapy with either comparator drug in each study (or metformin plus bedtime insulin in one trial). Other studies in this patient population indicate that metformin plus repaglinide is associated with significantly better glycaemic control than metformin plus nateglinide 60-120 mg three times daily over 16 weeks, and similar glycaemic control to that achieved with metformin in combination with either glibenclamide or glimepiride for up to 1 year. Good glycaemic control has also been achieved with preprandial administration of repaglinide in flexible meal schedules. This was demonstrated in a placebo-controlled trial and in a large, prospective survey of patients receiving repaglinide in a clinical setting. The tolerability profile of repaglinide is characterised by adverse events of mild-to-moderate intensity similar to those associated with sulphonylureas. The most frequently reported adverse events with repaglinide include hypoglycaemia, upper respiratory infection, headache, other respiratory events, musculoskeletal events and gastrointestinal events. Severe episodes of hypoglycaemia are rare with repaglinide and occur approximately 2-2.5 times less frequently than with sulphonylureas. In addition, available data indicate that repaglinide may be less likely to increase bodyweight than various commonly used sulphonylurea agents. In general, repaglinide is also well tolerated when used as part of combination therapy. Repaglinide is metabolised by the cytochrome P450 (CYP) 3A4 enzyme system and therefore has the potential to interact with other CYP3A4 substrates when administered concurrently. A number of studies in healthy volunteers have shown no clinically significant pharmacokinetic drug interactions when repaglinide was administered concomitantly with digoxin, theophylline, warfarin, cimetidine, ketoconazole, rifampicin (rifampin), ethinylestradiol, simvastatin or nifedipine. However, a clinically significant increase in systemic exposure to repaglinide occurs when clarithromycin and repaglinide are administered concurrently, which may necessitate a reduction in repaglinide dosage. Moreover, a potentially hazardous interaction occurs when gemfibrozil (alone or with itraconazole) is used concomitantly with repaglinide. In view of the marked increase in systemic exposure to repaglinide, the combination of repaglinide and gemfibrozil should be avoided if possible. Pharmacoeconomic Analyses of RepaglinideTwo US cost analyses have been conducted with repaglinide in patients with type 2 diabetes (both published in full). One was a retrospective analysis of pharmacy and medical claims data from a large managed care organisation in which costs were adjusted for age, gender and comorbidities. Total adjusted (year 2000) cost per patient over a 9-month period was numerically lower for those treated with a combination of repaglinide plus metformin (dollars US 8924) than for patients who received metformin only (dollars US 9448), metformin plus glibenclamide (dollars US 9576) or repaglinide only (dollars US 11910), although there were no statistically significant differences between treatment groups. The other study, a literature-based decision-tree analysis, projected the proportion of patients achieving a target HbA(1c) level (&lt;7%) and the associated direct medical costs over a 3-year period from the time of diagnosis. Among six different treatment regimens evaluated, costs ranged from dollars US 6106 with glipizide gastrointestinal therapeutic system (GITS) to dollars US 9298 with repaglinide monotherapy (2001/2002 values). Probabilistic sensitivity analysis indicated that first-line therapy with glipizide GITS or metformin would be associated with lower total medical costs than rosiglitazone or repaglinide monotherapy. Three cost-effectiveness analyses, all of which are modelled studies published as abstracts and/or posters, have been conducted with repaglinide in patients with type 2 diabetes. (ABSTRACT TRUNCATED)

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Seventy one surgical procedures on abdominal aorta in patients with horseshoe kidney have been reported in literature until 1980. Bergan reviewed 30 operations of abdominal aortic aneurysms (AAA) in these patients until 1974. Of them 3 AAA were ruptured. Gutowitz noticed 57 surgically treated AAA in patients with horseshoe kidney until 1984. Over the period from 1991 to 1996 thirty nine new cases were reported , including 2 ruptured AAA. The surgery of the abdominal aorta in patients with horseshoe kidney is associated with the following major problems: -reservation of anomalous (aberrant) renal arteries; reservation of the kidney excretory system; approach to the abdominal aorta (especially in patients with AAA) and graft placement The aim of the paper is the presentation of 5 new patients operated for abdominal aorta with horseshoe kidney. Over the last 12 years (January 1, 1984 to December 31, 1996) at the Centre of Vascular Surgery of the Institute of Cardiovascular Diseases of the Clinical Centre of Serbia, 5 patients with horseshoe kidney underwent surgery of the abdominal aorta. There were 4 male and one female patients whose average age was 57.8 years (50-70). Patient 1. A 50-year-old male patient was admitted to the hospital for disabling claudication discomforts (Fontan stadium IlI) and with significantly decreased Ankle-Brachial indexes (ABI). The translumbal aortography showed aorto-iliac occlusive disease and horseshoe kidney with two normal and one anomalous renal artery originating from infrarenal aorta (Crawford type II). Intravenous pyelography and retrograde urography showed two separated ureters. The aorto-bifemoral (AFF) bypass with Dacron graft was done with end-to-end (TT) proximal anastomosis just under the anomalous renal artery. The graft was placed behind the isthmus. During a 12-year follow-up renal failure, renovascular hypertension and graft occlusion were not observed. Patient 2. A 53-year-old male patient was admitted to the hospital for symptomatic AAA. Two years before admission the patient underwent coronary artery bypass grafting. The Duplex scan ultrasonography and translumbal aortography showed an infrarenal AAA, aneurysm of the right iliac artery and horseshoe kidney with two normal and one anomalous renal artery originating from the left iliac artery (Crawford type III). Intravenous pyelography and retrograde urography showed two separated ureters. After partial aneurysmectomy, the flow was restaured using bifurcated Dacron graft placed behind the isthmus. The right limb of the bifurcated graft was anastomosed with the common femoral artery and the left limb with left iliac artery just above the origin of the anomalous renal artery. The first day after operation thrombosis of the left common femoral artery with leg ischaemia was observed. (That artery was cannulated for ECC during coronary artery bypass grafting 2 years ago). The revascularisation of the left leg was done with femoro-femoral cross over bypass. During a 11-year follow-up period, the graft was patent and renal failure or revascular hypertension were not observed. Patient 3. A 66-year-old male patient was admitted to the hospital for rest pain (Fontan stadium III) and significantly decreased ABI. The patient had diabetes mellitus and myocardial infarction two months before admission. Translumbar aortography showed an aorto-iliac occlusive disease associated with horseshoe kidney with 5 anomalous renal arteries. (Crawford type III). Due to high risk, the axillo-bifemoral (AxFF) extra-anatomic bypass graft was performed. Five years after the operation the patient died due to new myocardial infarction. During the follow-up period the graft was patent and there were no signs of renal failure and renovascular hypertension. Patient 4. A 50-year old male patient was admitted to the hospital for high asymptomatic AAA. The diagnosis was established by Duplex scan and translumbal aortography. The large infrarenal AAA (transverse diameter 7 cm) associated with horseshoe kidney with two normal renal arteries (Crawford type I) were found. Intravenous pyelography and retrograde urogrpahy showed two separated ureters. After partial aneurysmectomy the tubular Dacron graft was placed behind the isthmus. During a 15-month follow-up the graft was patent and there were no signs of renal failure and renovascular hypertension. Patient 5. A 70-year-old female patient was admitted to the hospital for large asymptomatic AAA. The Duplex ultrasonography, CT scan, NMR and translumbal aortography showed an infrarenal AAA, aneurysms of the both common iliac arteries, aneurysm of the left hypergastric artery and horseshoe kidney with two normal and two anomalous renal arteries. One of the anomalous renal arteries originated from AAA, and the other from the left common iliac artery (Crawford type II). Intravenous pyelography and retrograde urography showed two separated ureters. After partial aneurysmectomy the flow was restaured using bifurcated Dacron graft placed behind the isthmus. The right limb of the graft was anastomosed (TT) with bifurcation of the common iliac artery and the left limb with the distal part of the common iliac artery (end-to-side) just above the origin of the second anomalous renal artery. The first anomalous renal artery that originated from AAA was removed from the aneurysm wall and anastomosed with graft using Carrel patch technique. During a 9-month follow-up the graft was patent and there were no signs of renovascular hypertension and renal failure. The horseshoe kidney is a rare anomaly of the urinary system. The incidence of this anomaly is from 1:1600 to 1:400 In 95% of cases the kidneys are connected with the lower poles, while in 5% with the upper poles In most cases, the isthmus structure is parenchimatous structure, and rarely it consists of the connective tissue. Usually the isthmus is located in front of the abdominal aorta and inferior vena cava, and very rarely behind them In two thirds of patients anomalous vascularization is present There are two classifications of anomalous vascularization: Papin's and Crawford's. According to Papin's classification, based on the number of renal arteries, there are three types of horseshoe kidney vascularization: Papin I (20%): There are two normal renal arteries only. (One of our 5 patients); Papin II (66%): There are 3-5 renal arteries. (Four of our 5 patients); Papin III (14%): There are more than 5 renal arteries. The Crawford's classification based on the origin of renal arteries, is of greater surgical importance than Papin's. According to it there are also three types of vascularization: Crawford I: There are two renal arteries with normal origin. (One of our 5 patients); Crawford II: Besides two normal, there are 1-3 anomalous renal arteries originating from the infrarenal aorta or iliac arteries (Three of our 5 patients); Crawford III: All renal arteries have an anomalous origin. (One of our 5 patients). The patients with horseshoe kidney can also have two separated, or one connected excretory urinary systems. All our 5 patients had two separated ureters. There is no specific clinical manifestation of the horseshoe kidney. Urinary infection or calculosis are very frequent as are in other urinary anomalies. The diagnosis of horseshoe kidney is established by Dupplex ultrasonography, CT scan, NMR, radionuclide scintigraphy and angiography. Very often the diagnosis is established occasionally during the examination of aneurysmal and occlusive diseases of the abdominal aorta. In cases of AAA or AIO associated with horseshoe kidney preoperative vascularization and condition of the excretory system should be established. Besides standard translumbar aortography selective renovasography is often neccessary. In some cases the intraoperative angiography or arterial identification, with metallic probe must be done. All renal arteries are "terminal" without significant anastomosis on the side of the kidney. Therefor its preservation is neccessary. There are three ways. The first is the location of anastomosis (3 of our patients). The second is an AxFF bypass, but only in patients with AIO (One of our patients and in the third reimplantation of the renal artery using Carrel patch technique was performed (One of our patients). The Isthmus of the kidney aggravates aortic preparation especially in patients with AAA. Sometimes isthmectomy is neccessary. In such cases there is danger of urinary fistula. Therefor many authors suggest the left extraperitoneal approach to abdominal aorta. In our patients, the transperitoneal approach was used, isthmectomy was not neccessary and graft was placed behind the isthmus. The operation of the abdominal aorta in patients with horseshoe kidney can be difficult due to anomalous renal arteries, anomalous excretory urinary system and is Ehmus. In these patients a more precise preoperative diagnosis is neccessary.

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Toxicology and carcinogenesis studies of iodinated glycerol (Organidin(R)., a complex mixture prepared by the reaction of iodine with glycerol and found to contain 33% 3-iodo-1,2-propanediol as the major component) were conducted because of human exposure to iodinated glycerol as an expectorant and its possible relationship to the formation of alkyl iodides, e.g., methyl iodide, a suspected animal carcinogen. These studies were conducted by giving iodinated glycerol in water by gavage (5 days per week) to groups of F344/N rats and B6C3F1 mice for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted with iodinated glycerol in Salmonella typhimurium, mouse L5178Y lymphoma cells, Chinese hamster ovary (CHO) cells, and B6C3F1 mice (in vivo bone marrow micronucleus test). Also, 3-iodo-1,2-propanediol was tested in S. typhimurium and B6C3F1 mice (in vivo micronucleus assay). Sixteen-Day and Thirteen-Week Studies: Sixteen-day studies were conducted by giving iodinated glycerol at doses up to 1,000 mg/kg to rats and up to 500 mg/kg to mice. All female rats and 4/5 male mice in the highest dose group died before the end of the studies; there were no dose-related effects on body weights of male or female rats or male mice at the end of the studies. The forestomach of 2/5 female mice that received 500 mg/kg was thickened and granular. Thirteen-week studies were conducted by administering iodinated glycerol at doses up to 500 mg/kg to rats and mice. During these studies, 3/10 female rats and 1/10 female mice that received 500 mg/kg died. Final mean body weights of rats and mice that received 500 mg/kg were 4% lower than those of vehicle controls for males and 6%-7% lower for females. Kidney tubular cell lesions, including cortical necrosis, regeneration, and calcification, were observed at increased incidences in the highest dose group of female rats. Lymphoid hyperplasia of the stomach was observed in dosed male and female rats. Kidney tubular cell regeneration was also observed in dosed female mice. Inflammation or abscesses of mild-to-moderate severity and hyperplasia, acanthosis, and/or hyperkeratosis of mild-to-moderate severity were observed in the forestomach of the highest dosed group of female mice. Body Weight and Survival in the Two-Year Studies: Two-year studies were conducted by administering 0, 125, or 250 mg/kg iodinated glycerol in deionized water by gavage, 5 days per week for 103 weeks, to groups of 50 male F344/N rats and 50 male B6C3F1 mice. Groups of 50 female F344/N rats and 50 female B6C3F1 mice were administered iodinated glycerol on the same schedule at lower doses of 0, 62, or 125 mg/kg because of the increased severity of kidney and stomach lesions in the 13-week studies. Mean body weights of high dose male rats were 5%-10% lower than those of vehicle controls from week 43 to week 68 and 10%-13% lower from week 72 to the end of the studies. Mean body weights of low dose male rats and high dose female rats were 4%-9% lower than those of vehicle controls from week 88 to the end of the studies. The survival of the high dose group of male rats was considerably lower than that of the vehicle controls after week 86. No other significant differences in survival were observed between any groups of rats of either sex (male: vehicle control, 28/50; low dose, 20/50, high dose, 2/50; female: 31/50; 30/50; 27/50). Mean body weights of dosed and vehicle control male mice were similar. Mean body weights of high dose female mice were 6%-8% lower than those of vehicle controls from week 40 to week 64 and were 9%-13% lower thereafter. No significant differences in survival were observed between any groups of mice of either sex (male: 36/50; 40/50; 32/50; female: 40/50; 33/50; 38/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The incidence of mononuclear cell leukemia were increased in dosed male rats (vehicle control, 14/50; low dose, 29/50; high dose, 24/50). Follicular cell carcinomas of the thyroid gland in male rats occurred at an increased incidence in low dose male rats (0/49; s of the thyroid gland in male rats occurred at an increased incidence in low dose male rats (0/49; 5/49; 1/49). Reduced survival of high dose male rats may have been responsible for the decreased tumor incidence in this group relative to that in the low dose group. Follicular cell carcinomas were observed in one low dose and one high dose female rat. Follicular cell carcinomas of the thyroid gland have been observed in 3/293 water gavage vehicle control male F344/N rats and in 10/1,904 untreated control male F344/N rats. Adenomas of the nasal cavity were observed in two high dose male rats. Adenomas of the nasal cavity have not been observed in 300 water gavage vehicle control male F344/N rats or in 1,936 untreated control male F344/N rats. Squamous metaplasia and focal atrophy of the salivary glands were observed at increased incidences in dosed rats (squamous metaplasia--male: 0/48; 47/50; 48/49; female:1/49; 48/50; 49/50; focal atrophy--male: 1/48; 10/50; 30/49; female: 0/49; 4/50; 11/50). In dosed female mice, adenomas of the anterior pituitary gland were increased (10/47; 15/45; 24/46). The incidences of adenomas of the harderian gland in dosed female mice were increased (6/50; 8/40; 13/50). A carcinoma of the harderian gland was observed in another high dose female mouse. Dilatation of the thyroid gland follicle and follicular cell hyperplasia were observed at increased incidences in dosed mice (dilatation--male: 0/48; 28/50; 32/50; female: 4/48; 11/48; 10/48; hyperplasia--male: 3/48; 46/50; 34/50; female: 2/48; 25/48; 35/48). The incidences of follicular cell adenomas were 3/48, 6/50, and 0/50 for males and 2/48, 3/48, and 4/48 for females. Hyperkeratosis and acanthosis of the forestomach were observed at increased incidences in high dose male mice (hyperkeratosis: 0/49; 0/49; 5/50; acanthosis: 0/49; 1/49; 5/50). Squamous cell papillomas were observed in female mice (1/49; 2/50; 5/49). The historical incidence of forestomach squamous cell neoplasms is 4/339 (1.2&amp;percnt;) in water gavage vehicle control female B6C3F1 mice and is 18/1,994 (0.9&amp;percnt;) in untreated control female B6C3F1 mice. Squamous cell neoplasms were not observed in male mice. Genetic Toxicology: Treatment of the base-substitution mutant S. typhimurium strains TA100 and TA1535 with iodinated glycerol in a preincubational protocol with and without S9 resulted in a dose-related increase in the number of revertant colonies; no increase in revertants was observed with the frame-shift mutant strains TA98 or TA1537. 3-Iodo-1,2-propanediol was also mutagenic in TA100 with or without S9; it was not mutagenic in TA98. Iodinated glycerol increased the number of trifluorothymidine-resistant cells in mouse lymphoma L5178Y/TK&amp;plusmn; assay in the absence of exogenous metabolic activation; it was not tested with activation. Iodinated glycerol induced sister chromatid exchanges (SCEs) and chromosomal aberrations in CHO cells without S9; with S9, the frequency of SCEs was increased more than without S9 but no chromosomal aberrations were induced. No increase in micronucleated polychromatic erythrocytes was observed in the bone marrow of B6C3F1 mice after injection with either iodinated glycerol or 3-iodo-1,2-propanediol. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity for male F344/N rats administered iodinated glycerol, as indicated by increased incidences of mononuclear cell leukemia and follicular cell carcinomas of the thyroid gland. Adenomas of the nasal cavity in two high dose male rats may have been related to the administration of iodinated glycerol. There was no evidence of carcinogenic activity for female F344/N rats administered 62 or 125 mg/kg iodinated glycerol by gavage for 103 weeks. There was no evidence of carcinogenic activity for male B6C3F1 mice administered 125 or 250 mg/kg iodinated glycerol by gavage for 103 weeks. There was some evidence of carcinogenic activity for female B6C3F1 mice administered iodinated glycerol, as indicated by increased incidences of adenomas of the anterior pituitary gland and neoplasms of the harderian gland. Squamous cell papillomas of the forestomach may have been related to the administration of iodinated glycerol. Significant nonneoplastic lesions considered related to exposure of iodinated glycerol were squamous metaplasia and focal atrophy of the salivary gland in male and female rats. Dilatation of the thyroid gland follicle and follicular cell hyperplasia were observed in male and female mice. Synonyms or Trade Names: Organidin&amp;reg;.; iodopropylidene glycerol

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In April 2008, the Medical Advisory Secretariat began an evidence-based review of the literature concerning pressure ulcers.Please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/tech/tech_mn.html to review these titles that are currently available within the Pressure Ulcers series.PRESSURE ULCER PREVENTION: an evidence based analysisThe cost-effectiveness of prevention strategies for pressure ulcers in long-term care homes in Ontario: projections of the Ontario Pressure Ulcer Model (field evaluation)MANAGEMENT OF CHRONIC PRESSURE ULCERS: an evidence-based analysis The Medical Advisory Secretariat (MAS) conducted a systematic review on interventions used to treat pressure ulcers in order to answer the following questions: Do currently available interventions for the treatment of pressure ulcers increase the healing rate of pressure ulcers compared with standard care, a placebo, or other similar interventions?Within each category of intervention, which one is most effective in promoting the healing of existing pressure ulcers? A pressure ulcer is a localized injury to the skin and/or underlying tissue usually over a bony prominence, as a result of pressure, or pressure in conjunction with shear and/or friction. Many areas of the body, especially the sacrum and the heel, are prone to the development of pressure ulcers. People with impaired mobility (e.g., stroke or spinal cord injury patients) are most vulnerable to pressure ulcers. Other factors that predispose people to pressure ulcer formation are poor nutrition, poor sensation, urinary and fecal incontinence, and poor overall physical and mental health. The prevalence of pressure ulcers in Ontario has been estimated to range from a median of 22.1% in community settings to a median of 29.9% in nonacute care facilities. Pressure ulcers have been shown to increase the risk of mortality among geriatric patients by as much as 400%, to increase the frequency and duration of hospitalization, and to decrease the quality of life of affected patients. The cost of treating pressure ulcers has been estimated at approximately $9,000 (Cdn) per patient per month in the community setting. Considering the high prevalence of pressure ulcers in the Ontario health care system, the total cost of treating pressure ulcers is substantial. Wounds normally heal in 3 phases (inflammatory phase, a proliferative phase of new tissue and matrix formation, and a remodelling phase). However, pressure ulcers often fail to progress past the inflammatory stage. Current practice for treating pressure ulcers includes treating the underlying causes, debridement to remove necrotic tissues and contaminated tissues, dressings to provide a moist wound environment and to manage exudates, devices and frequent turning of patients to provide pressure relief, topical applications of biologic agents, and nutritional support to correct nutritional deficiencies. A variety of adjunctive physical therapies are also in use. Health technology assessment databases and medical databases were searched from 1996 (Medline), 1980 (EMBASE), and 1982 (CINAHL) systematically up to March 2008 to identify randomized controlled trials (RCTs) on the following treatments of pressure ulcers: cleansing, debridement, dressings, biological therapies, pressure-relieving devices, physical therapies, nutritional therapies, and multidisciplinary wound care teams. Full literature search strategies are reported in appendix 1. English-language studies in previous systematic reviews and studies published since the last systematic review were included if they had more than 10 subjects, were randomized, and provided objective outcome measures on the healing of pressure ulcers. In the absence of RCTs, studies of the highest level of evidence available were included. Studies on wounds other than pressure ulcers and on surgical treatment of pressure ulcers were excluded. A total of 18 systematic reviews, 104 RCTs, and 4 observational studies were included in this review. Data were extracted from studies using standardized forms. The quality of individual studies was assessed based on adequacy of randomization, concealment of treatment allocation, comparability of groups, blinded assessment, and intention-to-treat analysis. Meta-analysis to estimate the relative risk (RR) or weighted mean difference (WMD) for measures of healing was performed when appropriate. A descriptive synthesis was provided where pooled analysis was not appropriate or not feasible. The quality of the overall evidence on each intervention was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) criteria. Findings from the analysis of the included studies are summarized below: CLEANSING: There is no good trial evidence to support the use of any particular wound cleansing solution or technique for pressure ulcers. DEBRIDEMENT: There was no evidence that debridement using collagenase, dextranomer, cadexomer iodine, or maggots significantly improved complete healing compared with placebo.There were no statistically significant differences between enzymatic or mechanical debridement agents with the following exceptions:Papain urea resulted in better debridement than collagenase.Calcium alginate resulted in a greater reduction in ulcer size compared to dextranomer.Adding streptokinase/streptodornase to hydrogel resulted in faster debridement.Maggot debridement resulted in more complete debridement than conventional treatment.There is limited evidence on the healing effects of debridement devices. DRESSINGS: Hydrocolloid dressing was associated with almost three-times more complete healing compared with saline gauze. There is evidence that hydrogel and hydropolymer may be associated with 50% to 70% more complete healing of pressure ulcers than hydrocolloid dressing.No statistically significant differences in complete healing were detected among other modern dressings.There is evidence that polyurethane foam dressings and hydrocellular dressings are more absorbent and easier to remove than hydrocolloid dressings in ulcers with moderate to high exudates.In deeper ulcers (stage III and IV), the use of alginate with hydrocolloid resulted in significantly greater reduction in the size of the ulcers compared to hydrocolloid alone.Studies on sustained silver-releasing dressing demonstrated a tendency for reducing the risk of infection and promoting faster healing, but the sample sizes were too small for statistical analysis or for drawing conclusions. BIOLOGICAL THERAPIES: The efficacy of platelet-derived growth factors (PDGFs), fibroblast growth factor, and granulocyte-macrophage colony stimulating factor in improving complete healing of chronic pressure ulcers has not been established.Presently only Regranex, a recombinant PDGF, has been approved by Health Canada and only for treatment of diabetic ulcers in the lower extremities.A March 2008 US Food and Drug Administration (FDA) communication reported increased deaths from cancers in people given three or more prescriptions for Regranex.Limited low-quality evidence on skin matrix and engineered skin equivalent suggests a potential role for these products in healing refractory advanced chronic pressure ulcers, but the evidence is insufficient to draw a conclusion. ADJUNCTIVE PHYSICAL THERAPY: There is evidence that electrical stimulation may result in a significantly greater reduction in the surface area and more complete healing of stage II to IV ulcers compared with sham therapy. No conclusion on the efficacy of electrotherapy can be drawn because of significant statistical heterogeneity, small sample sizes, and methodological flaws.The efficacy of other adjunctive physical therapies [electromagnetic therapy, low-level laser (LLL) therapy, ultrasound therapy, ultraviolet light therapy, and negative pressure therapy] in improving complete closure of pressure ulcers has not been established. NUTRITION THERAPY: Supplementation with 15 grams of hydrolyzed protein 3 times daily did not affect complete healing but resulted in a 2-fold improvement in Pressure Ulcer Scale for Healing (PUSH) score compared with placebo.Supplementation with 200 mg of zinc three times per day did not have any significant impact on the healing of pressure ulcers compared with a placebo.Supplementation of 500 mg ascorbic acid twice daily was associated with a significantly greater decrease in the size of the ulcer compared with a placebo but did not have any significant impact on healing when compared with supplementation of 10 mg ascorbic acid three times daily.A very high protein tube feeding (25% of energy as protein) resulted in a greater reduction in ulcer area in institutionalized tube-fed patients compared with a high protein tube feeding (16% of energy as protein).Multinutrient supplements that contain zinc, arginine, and vitamin C were associated with a greater reduction in the area of the ulcers compared with standard hospital diet or to a standard supplement without zinc, arginine, or vitamin C.Firm conclusions cannot be drawn because of methodological flaws and small sample sizes. MULTIDISCIPLINARY WOUND CARE TEAMS: The only RCT suggests that multidisciplinary wound care teams may significantly improve healing in the acute care setting in 8 weeks and may significantly shorten the length of hospitalization. However, since only an abstract is available, study biases cannot be assessed and no conclusions can be drawn on the quality of this evidence.

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<bObjective:</b To establish a high glucose senescent model of human dermal fibroblasts (HDFs), and to investigate the effects of exosomes derived from human decidua mesenchymal stem cells (dMSCs) on the proliferation, migration, and apoptosis of senescent HDFs and possible mechanism. <bMethods:</b The experimental research method was used. From January to March 2021, discarded foreskin tissue was collected for isolation and culture of primary HDFs from 4 male phimosis patients (aged 18-22 years) admitted for circumcision in the Fourth Medical Center of the PLA General Hospital. The 6th passage of HDFs were taken and divided into low glucose group and high glucose group according to the random number table, and subsequently cultured in low-glucose complete medium and high-glucose complete medium, respectively, with medium changed every 72 h without subculturing. After 10 days of culture, the cells were taken and measured for cellular senescence using the β-galactosidase kit at 24 h after seeding; the expression of senescence-related proteins p16 and p53 was assessed by Western blotting at 48 h after seeding; cell proliferation was detected at 24, 48, and 72 h after seeding using the cell counting kit 8 (CCK-8) method; the cell proliferation was evaluated by 5-ethynyl-2'-deoxyuridine (EdU) staining method, cell cycle and apoptosis were measured by flow cytometry after 48 h of seeding; Transwell experiment was used for the calculation of cell migration rate at 24 h after seeding. The human dMSCs were taken and cultured for 48-72 h from which the exosomes were extracted by differential high speed centrifugal method. The morphology of dMSC exosomes was observed by transmission electron microscopy, the particle size distribution of dMSC exosomes was measured by nanoparticle tracking analysis, and the expression of dMSC-exosomes marker proteins CD9 and tumor susceptibility gene101 (TSG101) were detected by Western blotting. The dMSC exosomes and high-glucose complete medium-induced senescent HDFs were co-cultured for 24 hours, then PKH67 kit was used to detect the uptake of exosomes by HDFs. High-glucose complete medium-induced senescent HDFs were taken and divided into high glucose alone group, high glucose+low concentration of exosomes group, and high glucose+high concentration of exosomes group according to the same method above. The high-glucose complete medium with equal volume of phosphate buffered saline, dMSC exosomes with final concentration of 50 μg/mL, and dMSC exosomes with final concentration of 100 μg/mL were added to the corresponding groups for conventional cell culture, respectively. After grouped, the cell proliferation, cell cycle and apoptosis as well as cell migration were detected by CCK-8 method and EdU staining method, flow cytometry, and Transwell experiment at the corresponding time points as before, respectively. Based on the previous results, high-glucose complete medium-induced senescent HDFs were taken and divided into high glucose alone group and high glucose+high concentration of exosomes group for the same treatment. After being grouped and cultured for 48 h, real-time fluorescent quantitative polymerase chain reaction was used to evaluate the mRNA expression of senescent-related microRNA (miR)-145-5p, miR-498, miR-503-5p, calcium/calmodulin dependent protein kinase 1D (CAMK1D), phosphates and tensin homologue deleted on chromosome ten (<iPTEN</i) gene, and Cyclin D1 in high glucose alone group and high glucose+high concentration of exosomes group. Data were statistically analyzed with analysis of variance for factorial design, one-way analysis of variance, least significant difference <it</i test, and independent sample <it</i test. <bResults:</b At 24 h after seeding, the rate of β-galactosidase-positive staining of HDF in high glucose group was (38.4±4.2)%, which was significantly higher than (16.5±2.2)% of low glucose group (<it</i=4.65, <iP</i&lt;0.01). At 48 h after seeding, the expression levels of senescence-related proteins p16 and p53 both were significantly higher in HDFs of high glucose group than those in low glucose group (with <it</i values of 11.85 and 3.02, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01). At 0, 24, 48, and 72 h after seeding, the cell proliferation viability of HDFs in high glucose group was all significantly lower than in low glucose group (with <it</i values of 4.13, 9.90, and 15.12, respectively, <iP</i&lt;0.01). At 48 h after seeding, the rate of EdU-positive staining of HDFs in high glucose group was obviously lower than that of low glucose group (<it</i=3.83, <iP</i&lt;0.05). At 48 h after seeding, the percentage of G2/M+S subpopulations in three subpopulations (G0/G1, S, and G2/M) of HDF cycle was significantly lower in high glucose group than that in low glucose group (<it</i=8.74, <iP</i&lt;0.01). At 24 h after seeding, the number of HDFs migrated through the filter membrane to the lower chamber was 37±6 in high glucose group, which was significantly less than 74±7 in low glucose group (<it</i=8.42, <iP</i&lt;0.01). At 48 h after seeding, the HDF apoptosis rate was significantly higher in high glucose group than in low glucose group (<it</i=8.48, <iP</i&lt;0.01). The dMSC exosomes were cup-shaped or round vesicles with well-defined edges and uniform size distribution. The size of dMSC exosomes was basically in the range of 80-200 nm. Exosomal markers including CD9 and TSG101 were positively presented on the dMSC exosomes. After being co-cultured for 24 hours, the dMSC exosomes were taken up intracellularly by HDFs and mainly distributed around the nucleus of HDFs. After being grouped and cultured for 24, 48, and 72 h, the HDF proliferation viabilities in high glucose+low concentration of exosomes group and high glucose+high concentration of exosomes group were both significantly higher than in high glucose alone group (with <it</i values of 6.36, 6.10, 7.76, 8.92, 12.17, and 10.74, respectively, <iP</i&lt;0.01), the HDF proliferation viability in high glucose+high concentration of exosomes group was significantly higher than in high glucose+low concentration of exosomes group (with <it</i values of 7.92, 4.82, and 4.72, respectively, <iP</i&lt;0.01). After being grouped and cultured for 48 h, the percentages of EdU-positive HDFs in high glucose+low concentration of exosomes group and high glucose+high concentration of exosomes group were both significantly higher than in high glucose alone group (with <it</i values of 5.32 and 9.88, respectively, <iP</i&lt;0.01), the percentage of EdU-positive HDFs in high glucose+high concentration of exosomes group was notably higher than in high glucose+low concentration of exosomes group (<it</i=5.27, <iP</i&lt;0.01). After being grouped and cultured for 48 h, the proportion of G0/G1 subpopulation in both high glucose+low concentration of exosomes group and high glucose+high concentration of exosomes group was distinctly lower (with <it</i values of 3.81 and 4.31, respectively, <iP</i&lt;0.05), while the proportion of G2/M+S subpopulation was markedly higher (with <it</i values of 3.81, 4.31, respectively, <iP</i&lt;0.05) than in high glucose alone group. After being grouped and cultured for 24 h, the number of HDFs migrated through the filter membrane in both high glucose+low concentration of exosomes group and high glucose+high concentration of exosomes group was significantly higher than in high glucose alone group (with <it</i values of 10.14 and 13.39, respectively, <iP</i&lt;0.01), the number of HDFs migrated through the filter membrane in high glucose+high concentration of exosomes group was significantly increased than in high glucose+low concentration of exosomes group (<it</i=6.27, <iP</i&lt;0.01). After being grouped and cultured for 48 h, the HDF apoptosis rates in high glucose+low concentration of exosomes group and high glucose+high concentration of exosomes group were both significantly lower than in high glucose alone group (with <it</i values of 3.72 and 5.53, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01). After being grouped and cultured for 48 h, compared with those in high glucose alone group, the mRNA expression levels of miR-145-5p and miR-498 were both obviously higher (with <it</i values of 13.03 and 8.90, respectively, <iP</i&lt;0.01), while the mRNA expression level of miR-503-5p was significantly lower (<it</i=3.85, <iP</i&lt;0.05) in high glucose+high concentration of exosomes group. After being grouped and cultured for 48 h, compared with those in high glucose alone group, the mRNA expression levels of CAMK1D and PTEN gene were both significantly lower (with <it</i values of 8.83 and 5.97, respectively, <iP</i&lt;0.01), while the mRNA expression level of Cyclin D1 was significantly higher in high glucose+high concentration of exosomes group (<it</i=4.03, <iP</i&lt;0.05). <bConclusions:</b The dMSC exosomes are capable of improving cell proliferation and migration, and inhibiting cell apoptosis of high-glucose senescent HDFs. This may be related to the mechanism by which the increased expressions of intracellular miR-145-5p and miR-498 inhibit the expression of CAMK1D and <iPTEN</i gene, and the decreased expression of miR-503-5p promote the expression of Cyclin D1.

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The areolate Oriental family Heteropterygidae Kirby, 1893 is critically reviewed and the results of the present study contradict the arrangement suggested by Zompro (2004), but in most aspects agree with a molecular study presented by Whiting et al (2003) and a phylogenetic study presented by Bradler (2009). The family is critically discussed and new hypotheses are presented for the phylogeny and intra-familiar relationships, placing the subfamily Dataminae Rehn &amp; Rehn, 1939 as the basalmost clade of Heteropterygidae. The subfamilies Obriminae Brunner v. Wattenwyl, 1893 and Heteropteryginae Kirby, 1893 together represent the sister-group of Dataminae. Arguments and a tree are presented to support this hypothesis. New diagnoses and lists of genera are provided for all three subfamilies contained in Heteropterygidae, along with keys to distinguish between them.        The subfamily Obriminae is critically reviewed and the distinction between the three tribes Obrimini Brunner v. Wattenwyl, 1893, Eubulidini Zompro, 2004 and Miroceramiini Zompro, 2004 introduced by Zompro (2004) is shown to be poorly supported. While Obrimini sensu Zompro, 2004 is generally accepted (but now also contains genera that were placed in Eubulidini or Miroceramiini by Zompro (2004)), the tribes Eubulidini and Miroceramiini are not supported. A new arrangement is introduced, which is based on morphological characters neglected or overlooked by Zompro (2004) but were partly discussed by Bradler (2009). The genus Mearnsiana Rehn &amp; Rehn, 1939 is removed from Miroceramiini and transferred to Obrimini. The genera Eubulides Stål, 1877, Heterocopus Redtenbacher, 1906, Theramenes Stål, 1875 and Stenobrimus Redtenbacher, 1906 are removed from Eubulidini and also transferred to Obrimini. Consequently, Eubulidini is synonymised with Obrimini (n. syn.). Miroceramiini is a monotypical tribe and only includes the Wallacean genus Miroceramia Günther, 1934. The new tribe Tisamenini n. trib. is established for the three basal genera Tisamenus Stål, 1875, Ilocano Rehn &amp; Rehn, 1939 and Hoploclonia Stål, 1875 all of which were placed in Eubulidini by Zompro (2004). The latter genus differs from the other two genera by the morphology of the female genitalia, which is unique amongst the entire family. Three generic groups are recognized within Obrimini, the Obrimus-group, Stenobrimus-group and Theramenes-group. Keys are presented to distinguish between the three tribes now contained in the Obriminae, i.e. Obrimini, Tisamenini n. trib. and Miroceramiini. The genus Hennobrimus Conle, 2006 is synonymised with Mearnsiana Rehn &amp; Rehn, 1939, based on the fact that the type-species of both genera are conspecific (n. syn.). Hennobrimus hennemanni Conle, 2006, the type-species of Hennobrimus, and Trachyaretaon manobo Lit &amp; Eusebio, 2005 are synonymised with Mearnsiana bullosa Rehn &amp; Rehn, 1939, the type-species of Mearnsiana (n. syn.). Theramenes dromedarius Stål, 1877 from the Philippines is removed from synonymy with the Wallacean Theramenes olivaceus (Westwood, 1859) and re-established as a valid species (rev. stat.).        The subfamily Heteropteryginae Kirby, 1896 is revised at the species-level and a new diagnosis is presented. Keys to the two genera and all 16 known species are provided along with new descriptions, differential diagnoses, lists of examined material, detailed information on the known distributions, measurements and illustrations of the insects and eggs. The intra-subfamiliar and intra-generic relationships are discussed and a cladogram is presented. Heteropteryginae contains two genera: Heteropteryx Gray, 1835 (Type-species: Phasma dilatatum Parkinson, 1798) and Haaniella Kirby, 1896 (Type-species: Phasma (Heteropteryx) muelleri de Haan, 1842). The distribution of this subfamily is restricted to Sundaland with the exception of a single species that is found in Vietnam. All other species are distributed in Borneo, Sumatra, the Mentawai Islands, Singapore, Peninsular Malaysia and Thailand. Heteropteryginae contains the largest and most striking members of the entire family Heteropteryginae, some of which are amongst the heaviest insects known. The subfamily is characterized by apomorphies such as the presence of wings, having a tympanal area (= stridulatory organ) in the basal portion of the alae, straight profemora, strongly shortened tarsi, lack of rough sensory-areas on the prosternum and typically X-shaped micropylar plate of the eggs. The sister-group of Heteropteryginae is represented by the Obriminae, with which it shares a beak-like secondary ovipositor in the females and presence of a medio-apical spine on the area apicalis. Both features are synapomorphies of Heteropteryginae + Obriminae.        The genus Haaniella Kirby, 1904 contains 16 known species, five of which are newly described herein. The genus Miniopteryx Zompro, 2004 (Type-species: Haaniella parva Günther, 1944) is synonymised with Haaniella on the basis that the distinguishing feature mentioned in the original description is a character that is frequently found throughout the genus (n. syn.). The type-species H. parva Günther, 1944 is automatically retransferred to Haaniella (rev. stat.). Haaniella aculeata n. sp. from western Sumatra is described from the male. Haaniella macroptera n. sp. from Singapore and the Johor state in southern Peninsular Malaysia is described from both sexes and the eggs. Haaniella gintingi n. sp. from Central Sumatra is described from both sexes and the eggs and Haaniella kerincia n. sp. from Western Sumatra is described from the insects only, the eggs being still unknown. One new species, Haaniella gorochovi n. sp., is the only representative of the genus and subfamily Heteropteryginae known from Vietnam and both sexes as well as the eggs are described. Haaniella erringtoniae (Redtenbacher, 1906) is endemic in Peninsular Malaysia, here removed from synonymy with H. muelleri (de Haan, 1842) and re-established as a valid species (rev. stat.). The Sumatran Haaniella glaber (Redtenbacher, 1906) is removed from synonymy with H. muelleri (Haan, 1842) and re-established as a valid species (rev. stat.). Leocrates glaber Redtenbacher, 1906 and Haaniella muelleri simplex Günther, 1944 are removed from synonymy with H. muelleri (Haan, 1842) (rev. stat.) and synonymised with H. glaber. Haaniella mecheli (Redtenbacher, 1906) and H. rosenbergii (Kaup, 1871) are removed from synonymy with H. muelleri (Haan, 1842) and re-established as valid species (rev. stat.). Haaniella erringtoniae novaeguineae Günther, 1934 and Haaniella muelleri var. b. (Haan, 1842) are synonymized with H. rosenbergii (Kaup, 1871) (n. syn.). The type-species Haaniella muelleri (Haan, 1842) is shown to be a fairly rare species that is restricted to Sumatra. All subsequent records of H. muelleri from outside Sumatra and references to captive breeding of stock originating from Peninsular Malaysia in Europe relate to H. erringtoniae (Redtenbacher, 1906). The previously unknown males and eggs of H. rosenbergii (Kaup, 1871) as well as the previously unknown females and eggs of H. parva Günther, 1944 are described and illustrated for the first time. Based on morphological characters of the insects and eggs three distinct species-groups are recognized within Haaniella. The muelleri species-group contains nine species that are distributed throughout Sumatra, the Mentawei Islands, Singapore and Peninsular Malaysia. These are characterized by the smooth ventral surface of the meso- and metafemora and lemon-shaped eggs which entirely lack the setae seen in the two other species-groups. The grayii species-group comprises four species, two of which are endemic in Borneo, one endemic in Sumatra and the fourth species being the only known representative of the subfamily in Vietnam. These species are characteristic for the prominent pair of spines on the abdominal tergites II-IV of males and long apically multidentate epiproct of females. The echinata species-group contains three exceptionally Bornean species, which are characterized by the long and apically pointed subgenital plate of females, which clearly projects beyond the epiproct, as well as the sub-basal lateral tooth of the anal segment of males. The muelleri species-group is sister to the remainder two species-groups.        Heteropteryx Gray, 1853 is a monotypical genus and only contains the type-species H. dilatata (Parkinson, 1798), which is found throughout Peninsular Malaysia, Thailand, Sumatra and Northeastern Borneo. This genus differs from Haaniella by the strongly conically elevated head, which posteriorly projects over the anterior margin of the pronotum, females being bright green or yellow in colour with plain and translucent pink alae and having distinct spines on the abdominal tergites, and males having a strongly shortened mesothorax and dull pink alae.        Lectotypes are designated for Haaniella parva Günther, 1944, Heteropteryx echinata Redtenbacher, 1906, Heteropteryx saussurei Redtenbacher, 1906 and Heteropteryx scabra Redtenbacher, 1906 to guarantee stability of these names.        Information on the habitats, host-plants, biology, life cycle, parasitism and captive breeding of the species of Heteropteryginae is presented and a list summarising all taxonomic changes presented herein.

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OBJECTIVE OF ANALYSIS: The objective of this evidence-based evaluation is to assess the accuracy of serologic tests in the diagnosis of celiac disease in subjects with symptoms consistent with this disease. Furthermore the impact of these tests in the diagnostic pathway of the disease and decision making was also evaluated. CELIAC DISEASE: Celiac disease is an autoimmune disease that develops in genetically predisposed individuals. The immunological response is triggered by ingestion of gluten, a protein that is present in wheat, rye, and barley. The treatment consists of strict lifelong adherence to a gluten-free diet (GFD). Patients with celiac disease may present with a myriad of symptoms such as diarrhea, abdominal pain, weight loss, iron deficiency anemia, dermatitis herpetiformis, among others. There are a number of serologic tests used in the diagnosis of celiac disease. Anti-gliadin antibody (AGA)Anti-endomysial antibody (EMA)Anti-tissue transglutaminase antibody (tTG)Anti-deamidated gliadin peptides antibodies (DGP)Serologic tests are automated with the exception of the EMA test, which is more time-consuming and operator-dependent than the other tests. For each serologic test, both immunoglobulin A (IgA) or G (IgG) can be measured, however, IgA measurement is the standard antibody measured in celiac disease. According to celiac disease guidelines, the diagnosis of celiac disease is established by small bowel biopsy. Serologic tests are used to initially detect and to support the diagnosis of celiac disease. A small bowel biopsy is indicated in individuals with a positive serologic test. In some cases an endoscopy and small bowel biopsy may be required even with a negative serologic test. The diagnosis of celiac disease must be performed on a gluten-containing diet since the small intestine abnormalities and the serologic antibody levels may resolve or improve on a GFD. Since IgA measurement is the standard for the serologic celiac disease tests, false negatives may occur in IgA-deficient individuals. The incidence and prevalence of celiac disease in the general population and in subjects with symptoms consistent with or at higher risk of celiac disease based on systematic reviews published in 2004 and 2009 are summarized below. ADULTS OR MIXED POPULATION: 1 to 17/100,000/year 2 to 51/100,000/yearIn one of the studies, a stratified analysis showed that there was a higher incidence of celiac disease in younger children compared to older children, i.e., 51 cases/100,000/year in 0 to 2 year-olds, 33/100,000/year in 2 to 5 year-olds, and 10/100,000/year in children 5 to 15 years old. The prevalence of celiac disease reported in population-based studies identified in the 2004 systematic review varied between 0.14% and 1.87% (median: 0.47%, interquartile range: 0.25%, 0.71%). According to the authors of the review, the prevalence did not vary by age group, i.e., adults and children. Type 1 diabetes (adults and children): 1 to 11%AUTOIMMUNE THYROID DISEASE: 2.9 to 3.3%FIRST DEGREE RELATIVES OF PATIENTS WITH CELIAC DISEASE: 2 to 20% PREVALENCE OF CELIAC DISEASE IN SUBJECTS WITH SYMPTOMS CONSISTENT WITH THE DISEASE: The prevalence of celiac disease in subjects with symptoms consistent with the disease varied widely among studies, i.e., 1.5% to 50% in adult studies, and 1.1% to 17% in pediatric studies. Differences in prevalence may be related to the referral pattern as the authors of a systematic review noted that the prevalence tended to be higher in studies whose population originated from tertiary referral centres compared to general practice. What is the sensitivity and specificity of serologic tests in the diagnosis celiac disease?What is the clinical validity of serologic tests in the diagnosis of celiac disease? The clinical validity was defined as the ability of the test to change diagnosis.What is the clinical utility of serologic tests in the diagnosis of celiac disease? The clinical utility was defined as the impact of the test on decision making.What is the budget impact of serologic tests in the diagnosis of celiac disease?What is the cost-effectiveness of serologic tests in the diagnosis of celiac disease? A literature search was performed on November 13(th), 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing &amp; Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1(st) 2003 and November 13(th) 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology. Inclusion Criteria Inclusion CriteriaExclusion CriteriaStudies that evaluated diagnostic accuracy, i.e., both sensitivity and specificity of serology tests in the diagnosis of celiac disease.Study population consisted of untreated patients with symptoms consistent with celiac disease.Studies in which both serologic celiac disease tests and small bowel biopsy (gold standard) were used in all subjects.Systematic reviews, meta-analyses, randomized controlled trials, prospective observational studies, and retrospective cohort studies.At least 20 subjects included in the celiac disease group.English language.Human studies.Studies published from 2000 on.Clearly defined cut-off value for the serology test. If more than one test was evaluated, only those tests for which a cut-off was provided were included.Description of small bowel biopsy procedure clearly outlined (location, number of biopsies per patient), unless if specified that celiac disease diagnosis guidelines were followed.Patients in the treatment group had untreated CD.Studies on screening of the general asymptomatic population.Studies that evaluated rapid diagnostic kits for use either at home or in physician's offices.Studies that evaluated diagnostic modalities other than serologic tests such as capsule endoscopy, push enteroscopy, or genetic testing.Cut-off for serologic tests defined based on controls included in the study.Study population defined based on positive serology or subjects pre-screened by serology tests.Celiac disease status known before study enrolment.Sensitivity or specificity estimates based on repeated testing for the same subject.Non-peer-reviewed literature such as editorials and letters to the editor. The population consisted of adults and children with untreated, undiagnosed celiac disease with symptoms consistent with the disease. Anti-gliadin antibody (AGA)Anti-endomysial antibody (EMA)Anti-tissue transglutaminase antibody (tTG)Anti-deamidated gliadin peptides antibody (DGP)Combinations of some of the serologic tests listed above were evaluated in some studiesBoth IgA and IgG antibodies were evaluated for the serologic tests listed above. SensitivitySpecificityPositive and negative likelihood ratiosDiagnostic odds ratio (OR)Area under the sROC curve (AUC)Small bowel biopsy was used as the gold standard in order to estimate the sensitivity and specificity of each serologic test. Pooled estimates of sensitivity, specificity and diagnostic odds ratios (DORs) for the different serologic tests were calculated using a bivariate, binomial generalized linear mixed model. Statistical significance for differences in sensitivity and specificity between serologic tests was defined by P values less than 0.05, where "false discovery rate" adjustments were made for multiple hypothesis testing. The bivariate regression analyses were performed using SAS version 9.2 (SAS Institute Inc.; Cary, NC, USA). Using the bivariate model parameters, summary receiver operating characteristic (sROC) curves were produced using Review Manager 5.0.22 (The Nordiac Cochrane Centre, The Cochrane Collaboration, 2008). The area under the sROC curve (AUC) was estimated by bivariate mixed-efects binary regression modeling framework. Model specification, estimation and prediction are carried out with xtmelogit in Stata release 10 (Statacorp, 2007). Statistical tests for the differences in AUC estimates could not be carried out. The study results were stratified according to patient or disease characteristics such as age, severity of Marsh grade abnormalities, among others, if reported in the studies. The literature indicates that the diagnostic accuracy of serologic tests for celiac disease may be affected in patients with chronic liver disease, therefore, the studies identified through the systematic literature review that evaluated the diagnostic accuracy of serologic tests for celiac disease in patients with chronic liver disease were summarized. The effect of the GFD in patiens diagnosed with celiac disease was also summarized if reported in the studies eligible for the analysis. PUBLISHED SYSTEMATIC REVIEWS: Five systematic reviews of studies that evaluated the diagnostic accuracy of serologic celiac disease tests were identified through our literature search. Seventeen individual studies identified in adults and children were eligible for this evaluation. (ABSTRACT TRUNCATED)

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<bObjective:</b To investigate the effects of Modified Sijunzi Decoction on the diversity of intestinal microflora of in severe scald rabbits based on 16S ribosomal RNA (16S rRNA) high-throughput sequencing. <bMethods:</b The experimental research method was adopted. Ninety Japanese big-ear rabbits regardless gender, aged 6 to 8 months, were randomly divided into normal control group, scald alone group, scald+low-dose group, scald+medium-dose group, and scald+high-dose group, with 18 rabbits in each group. The rabbits in normal control group were free to eat and drink, and the rabbits in scald alone group, scald+low-dose group, scald+medium-dose group, and scald+high-dose group were intragastrically administered normal saline, 0.2 g/mL Modified Sijunzi Decoction, 1.0 g/mL Modified Sijunzi Decoction, and 5.0 g/mL Modified Sijunzi Decoction, respectively for 7 days after sustaining full-thickness scalding of 30% total body surface area. On the 1<supst</sup, 3<suprd</sup, and 7<supth</sup day after grouping, the levels of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-10 in ileal mucosa tissue of rabbits in each group were determined by enzyme-linked immunosorbent assay, and the number of samples in each group at each time point was 6. According to the above experimental results, another 9 rabbits were selected and divided into normal control group, scald alone group and scald+medium-dose group, with 3 rabbits in each group. The grouping and treatment methods of rabbits in each group were the same as before. On the 7<supth</sup day after grouping, the V3, V4 region of 16S rRNA of ileum mucosa of rabbits in three groups were sequenced by high-throughput sequencing technology. The number of quality bacteria was counted by QIME software. The classifications of phylum, class, order, family and genus of microflora were analyzed by RDP Classifier software. The α diversity (Ace, Chao1, Simpson, and Shannon indexes) and β diversity were analyzed by Illumina MiSeq sequencing technology, and the number of experiment samples in each group was 3. Data were statistically analyzed with analysis for variance of factorial design, SNK test, and Bonferroni correction. <bResults:</b Compared with that in normal control group, the levels of TNF-α of ileal mucosa tissue of rabbits in scald alone group, scald+low-dose group, and scald+high-dose group on the 1<supst</sup, 3<suprd</sup, and 7<supth</sup day after grouping and scald+medium-dose group on the 1<supst</sup and 3<suprd</sup day after grouping were all significantly increased (<iP</i&lt;0.01), the levels of IL-1β in ileal mucosa tissue of rabbits in scald alone group, scald+low-dose group, scald+medium-dose group and scald+high-dose group on the 1<supst</sup, 3<suprd</sup, and 7<supth</sup day after grouping were all significantly increased (<iP</i&lt;0.05 or <iP</i&lt;0.01), and the levels of IL-10 in ileal mucosa tissue of rabbits in scald alone group, scald+low-dose group, scald+medium-dose group, and scald+high-dose group on the 1<supst</sup, 3<suprd</sup, and 7<supth</sup day after grouping were all significantly decreased (<iP</i&lt;0.01). Compared with that in scald alone group, the levels of TNF-α in ileal mucosa tissue of rabbits in scald+low-dose group, scald+medium-dose group, and scald+high-dose group on the 3<suprd</sup and 7<supth</sup day after grouping, and scald+medium-dose group on the 1<supst</sup day after grouping were all significantly decreased (<iP</i&lt;0.01), and the levels of IL-1β in ileal mucosa tissue of rabbits in scald+low-dose group, scald+medium-dose group, and scald+high-dose group on the 3<suprd</sup and 7<supth</sup day after grouping and scald+medium-dose group on the 1<supst</sup day after grouping were all significantly decreased (<iP</i&lt;0.01), and the levels of IL-10 in ileal mucosa tissue of rabbits in scald+low-dose group on the 7<supth</sup day after grouping and scald+medium-dose group on the 1<supst</sup, 3<suprd</sup, and 7<supth</sup day after grouping and scald+high-dose group on the 3<suprd</sup and 7<supth</sup day after grouping were all significantly increased (<iP</i&lt;0.05 or <iP</i&lt;0.01). Compared with that in scald+low-dose group, the levels of TNF-α in ileal mucosa tissue of rabbits in medium-dose scald alone group on the 1<supst</sup, 3<suprd</sup, and 7<supth</sup day after grouping and in high-dose scald alone group on the 3<suprd</sup and 7<supth</sup day after grouping were significantly decreased (<iP</i&lt;0.01), and the levels of IL-1β in ileal mucosa tissue of rabbits in medium-dose scald alone group on the 1<supst</sup, 3<suprd</sup, and 7<supth</sup day after grouping and in high-dose scald alone group on the 3<suprd</sup and 7<supth</sup day after grouping were all significantly decreased (<iP</i&lt;0.05 or <iP</i&lt;0.01), and the levels of IL-10 in ileal mucosa tissue of rabbits in scald+medium-dose group on the 1<supst</sup, 3<suprd</sup, and 7<supth</sup day after grouping and in scald+high-dose group on the 7<supth</sup day after grouping were all significantly increased (<iP</i&lt;0.05 or <iP</i&lt;0.01). Compared with that in scald medium-dose group, the levels of TNF-α in ileal mucosa tissue of rabbits in scald+high-dose group on the 1<supst</sup, 3<suprd</sup, and 7<supth</sup day after grouping were all significantly increased (<iP</i&lt;0.01), and the levels of IL-10 in ileal mucosa tissue of rabbits in scald+high-dose group on the 1<supst</sup, 3<suprd</sup, and 7<supth</sup day after grouping were all significantly decreased (<iP</i&lt;0.01), and the levels of IL-1β in ileal mucosa tissue of rabbits in scald+high-dose group on the 7<supth</sup day after grouping was significantly decreased (<iP</i&lt;0.01). Compared with that on the 1<supst</sup day after grouping, the levels of TNF-α in ileal mucosa tissue of rabbits in scald alone group on the 3<suprd</sup and 7<supth</sup day after grouping and in normal control group on the 3<suprd</sup day after grouping were all significantly increased (<iP</i&lt;0.05 or <iP</i&lt;0.01), and the levels of IL-1β in ileal mucosa tissue of rabbits in scald alone group both on the 3<suprd</sup and 7<supth</sup day after grouping were significantly increased (<iP</i&lt;0.01), and the levels of IL-10 in ileal mucosa tissue of rabbits in both scald+low-dose group and scald+high-dose group on the 7<supth</sup day after grouping and scald+medium-dose group both on the 3<suprd</sup and 7<supth</sup day after grouping were significantly increased (<iP</i&lt;0.05 or <iP</i&lt;0.01), and the levels of TNF-α in ileal mucosa tissue of rabbits in scald+high-dose group on the 3<suprd</sup and 7<supth</sup day after grouping and in scald+medium-dose group on the 7<supth</sup day after grouping were all significantly decreased (<iP</i&lt;0.05 or <iP</i&lt;0.01), and the level of IL-1β in ileal mucosa tissue of rabbits in scald+medium-dose group on the 7<supth</sup day after grouping was significantly decreased (<iP</i&lt;0.01), and the level of IL-10 in ileal mucosa tissue of rabbits in scald alone group on the 7<supth</sup day after grouping was significantly decreased (<iP</i&lt;0.01). Compared with that on the 3<suprd</sup day after grouping, the levels of TNF-α and IL-1β in ileal mucosa tissue of rabbits in scald alone group and the levels of IL-10 in ileal mucosa tissue of rabbits in normal control group, scald+low-dose group, scald+medium-dose group, and scald+high-dose group on the 7<supth</sup day after grouping were all significantly increased (<iP</i&lt;0.05 or <iP</i&lt;0.01); and the levels of TNF-α in ileal mucosa tissue of rabbits in scald+low-dose group, scald+medium-dose group, and scald+high-dose group on the 7<supth</sup day after grouping were all significantly decreased (<iP</i&lt;0.05), and the levels of IL-1β in ileal mucosa tissue of rabbits both in scald+medium-dose group and scald+high-dose group on the 7<supth</sup day after grouping were significantly decreased (<iP</i&lt;0.05 or <iP</i&lt;0.01), and the levels of IL-10 in ileal mucosa tissue of rabbits in scald alone group on the 7<supth</sup day after grouping was significantly decreased (<iP</i&lt;0.01). On the 7<supth</sup day after grouping, the high-quality sequences obtained from the microflora in ileum mucosa of rabbits in normal control group, scald alone group, and scald+medium-dose group were 96 023, 107 365, and 95 921, respectively. At the classification level of phylum, class, order, family, and genus of the microflora in ileum mucosa of rabbits in three groups were all <iBacteroidetes</i and <iFirmicutes</i, <iClostridium</i and <iBacteroidetes,</i <iClostridium</i and <iBacteroidetes</i, <iRumenobacteriaceae</i and <iClostridium</i and <iBacteroideaceae</i, <iClostridium</i and <iBacteroidetes</i and <irumen bacteria</i mainly, while the percentage of microflora in each group was different. There were no significant differences in Ace, Chao1, Simpson, Shannon indices (<iP</i&gt;0.05), and no obvious difference in β diversity of microflora in ileal mucosa tissue of rabbits among three groups. <bConclusions:</b After severe scalding, the inflammatory response of rabbit ileal mucosa tissue is obvious and increased in a time-dependent manner. Modified Sijunzi Decoction can reduce inflammation with optimal therapeutic concentration of 1.0 g/mL. The technology of high-throughput sequencing can reflect the structural composition of the intestinal microflora accurately. The ileal microflora of the severe scald rabbit can be regulated by the administration of Modified Sijunzi Decoction.

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<bObjective:</b To investigate the effects of deferoxamine on macrophage polarization and wound healing in mice with deep tissue injury (DTI) and its mechanism. <bMethods:</b The experimental research methods were adopted. Fifty-four male C57BL/6J mice of 6-8 weeks old were divided into DTI control group, 2 mg/mL deferoxamine group, and 20 mg/mL deferoxamine group according to random number table, with 18 mice in each group. DTI was established on the back of mice by magnet compression method. From post injury day (PID) 1, mice were injected subcutaneously with 100 µL normal saline or the corresponding mass concentration of deferoxamine solution every other day at the wound edge until the samples were collected. Another 6 mice without any treatment were selected as normal control group. Six mice in each of the three DTI groups were collected on PID 3, 7, and 14 to observe the wound changes and calculate the wound healing rate. Normal skin tissue of mice in normal control group was collected on PID 3 in other groups (the same below) and wound tissue of mice in the other three groups on PID 7 and 14 was collected for hematoxylin-eosin (HE) staining to observe the tissue morphology. Normal skin tissue of mice in normal control group and wound tissue of mice in the other three groups on PID 7 were collected, and the percentages of CD206 and CD11c positive area were observed and measured by immunohistochemical staining, and the mRNA and protein expressions of CD206, CD11c, and inducible nitric oxide synthase (iNOS) were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction and Western blotting, respectively. Normal skin tissue of mice in normal control group and wound tissue of mice in DTI control group and 20 mg/mL deferoxamine group were collected on PID 3, 7, and 14, and the protein expressions of signal transducer and activator of transcription 3 (STAT3) and interleukin-10 (IL-10) were detected by Western blotting. The sample number in each group at each time point in the above experiments. The RAW264.7 cells were divided into 50 μmol/L deferoxamine group, 100 μmol/L deferoxamine group, 200 μmol/L deferoxamine group, and blank control group, which were treated correspondingly, with 3 wells in each group. The positive cell percentages of CD206 and CD86 after 48 h of culture were detected by flow cytometry. Data were statistically analyzed with analysis of variance for repeated measurement, one-way analysis of variance, and least significant difference test. <bResults:</b On PID 7, the wound healing rates of mice in 2 mg/mL and 20 mg/mL deferoamine groups were (17.7±3.7)% and (21.5±5.0)%, respectively, which were significantly higher than (5.1±2.3)% in DTI control group (<iP</i&lt;0.01). On PID 14, the wound healing rates of mice in 2 mg/mL and 20 mg/mL deferoamine groups were (51.1±3.8)% and (57.4±4.4)%, respectively, which were significantly higher than (25.2±3.8)% in DTI control group (<iP</i&lt;0.01). HE staining showed that the normal skin tissue layer of mice in normal control group was clear, the epidermis thickness was uniform, and skin appendages such as hair follicles and sweat glands were visible in the dermis. On PID 7, inflammation in wound tissue was obvious, the epidermis was incomplete, and blood vessels and skin appendages were rare in mice in DTI control group; inflammatory cells in wound tissue were reduced in mice in 2 mg/mL and 20 mg/mL deferoxamine groups, and a few of blood vessels and skin appendages could be seen. On PID 14, inflammation was significantly alleviated and blood vessels and skin appendages were increased in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoxamine groups compared with those in DTI control group. On PID 7, the percentages of CD206 positive area in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoxamine groups were significantly higher than that in DTI control group (<iP</i&lt;0.01), the percentage of CD206 positive area in wound tissue of mice in DTI control group was significantly lower than that in normal skin tissue of mice in normal control group (<iP</i&lt;0.01), the percentage of CD206 positive area in wound tissue of mice in 20 mg/mL deferoxamine group was significantly higher than that in normal skin tissue of mice in normal control group (<iP</i&lt;0.01). The percentages of CD11c positive area in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoxamine groups were significantly lower than those in DTI control group and normal skin tissue in normal control group (<iP</i&lt;0.05 or <iP</i&lt;0.01), and the percentage of CD11c positive area in normal skin tissue of mice in normal control group was significantly higher than that in DTI control group (<iP</i&lt;0.05). On PID 7, the CD206 mRNA expressions in the wound tissue of mice in 2 mg/mL and 20 mg/mL deferoxamine groups were significantly higher than that in DTI control group (<iP</i&lt;0.01), but significantly lower than that in normal skin tissue in normal control group (<iP</i&lt;0.01); the CD206 mRNA expression in wound tissue of mice in DTI control group was significantly lower than that in normal skin tissue in normal control group (<iP</i&lt;0.01). The mRNA expressions of CD11c and iNOS in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoamine groups were significantly lower than those in DTI control group (<iP</i&lt;0.01). The mRNA expressions of CD11c in the wound tissue of mice in DTI control group, 2 mg/mL and 20 mg/mL deferoamine groups were significantly higher than that in normal skin tissue in normal control group (<iP</i&lt;0.01). Compared with that in normal skin tissue in normal control group, the mRNA expressions of iNOS in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoamine groups were significantly decreased (<iP</i&lt;0.01), and the mRNA expression of iNOS in wound tissue of mice in DTI control group was significantly increased (<iP</i&lt;0.01). On PID 7, the protein expressions of CD206 in the wound tissue of mice in 2 mg/mL and 20 mg/mL deferoamine groups were significantly higher than those in DTI control group and normal skin tissue in normal control group (<iP</i&lt;0.01), and the protein expression of CD206 in wound tissue of mice in DTI control group was significantly lower than that in normal skin tissue in normal control group (<iP</i&lt;0.01). The protein expressions of CD11c and iNOS in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoamine groups were significantly lower than those in DTI control group (<iP</i&lt;0.01). The protein expressions of CD11c and iNOS in wound tissue of mice in DTI control group were significantly higher than those in normal skin tissue in normal control group (<iP</i&lt;0.01). The CD11c protein expressions in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoamine groups were significantly higher than those in normal skin tissue in normal control group (<iP</i&lt;0.05 or <iP</i&lt;0.01). The protein expression of iNOS in wound tissue of mice in 2 mg/mL deferoamine group was significantly lower than that in 20 mg/mL deferoamine group and normal skin tissue in normal control group (<iP</i&lt;0.05). On PID 3, 7, and 14, the protein expressions of STAT3 and IL-10 in wound tissue of mice in 20 mg/mL deferoxamine group were significantly higher than those in DTI control group (<iP</i&lt;0.05 or <iP</i&lt;0.01), and the protein expressions of STAT3 were significantly higher than those in normal skin tissue in normal control group (<iP</i&lt;0.05 or <iP</i&lt;0.01). On PID 7 and 14, the protein expressions of IL-10 in wound tissue of mice in 20 mg/mL deferoxamine group were significantly higher than those in normal skin tissue in normal control group (<iP</i&lt;0.01). On PID 3, 7, and 14, the protein expressions of IL-10 in wound tissue of mice in DTI control group were significantly lower than those in normal skin tissue in normal control group (<iP</i&lt;0.05 or <iP</i&lt;0.01). After 48 h of culture, compared with those in blank control group, the CD206 positive cell percentages in 100 μmol/L and 200 μmol/L deferoamine groups were significantly increased (<iP</i&lt;0.01), while the CD86 positive cell percentages in 100 μmol/L and 200 μmol/L deferoamine groups were significantly decreased (<iP</i&lt;0.01). <bConclusions:</b Deferoxamine can promote the polarization of macrophages toward the anti-inflammatory M2 phenotype and improve wound healing by enhancing the STAT3/IL-10 signaling pathway in DTI mice.

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Giardia is the most common intestinal protozoan parasite found in humans and animals worldwide. Although it has been known for three hundred years, the nomenclature, taxonomy, host specificity, and pathogenicity of Giardia still arouse numerous controversies and ambiguities. Giardia is classified into six species, that are characterised by various ranges of hosts. The most dubious species is G. intestinalis, which includes a dozen or so genotypes, and only two of them (genotype A and B) have wide ranges of hosts, including humans. Moreover, in some genotype assemblages of G. intestinalis certain subgenotypes were distinguished and it was proven that in the same host species various subgenotypes of this parasite may occur. Bearing in mind the significant genetic heterogeneity of G. intestinalis and the fact that various genotypes and subgenotypes of this parasite are characterised by the broad or narrow host specificity, the data concerning the frequency of giardiosis occurrence are insufficient. It is necessary to use molecular biology techniques in order to define the genotype and/or the subgenotype of G. intestinalis that are found in humans and in certain animal species. Furthermore, since more and more pieces of evidence connected with a possibility of the sexual recombination of Giardia are gathered, it is unknown if genotypes and subgenotypes of this parasite are stable in time. The aim of this thesis was to define the frequency of Giardia occurrence in humans and animals in Wielkopolska region, to identify species and genotypes of Giardia that occur in humans and animals, as well as to obtain an axenic culture of the chosen isolates of Giardia from animals and to compare the sequence of the beta-giardin gene fragment obtained from the DNA isolated from cysts and trophozoites in order to check if the axenisation of G. intestinalis leads to the selection of genotypes or if Giardia genotypes are stable in time. Altogether, 2183 faecal samples were examined for the presence of Giardia cysts; 447 faecal samples were taken from 232 persons coming from 5 cities situated in Wielkopolska, and 1736 faecal samples were obtained from 123 animal species, including: 266 faecal samples from 113 species of animals kept in the Zoological Garden in Poznań, 1286 samples from 4 species of breeding animals, 118 samples from dogs, and 66 samples from 5 species of wild animals. Faecal samples were taken from animals coming from 25 places in Wielkopolska. Moreover, seven isolates of G. intestinalis were used in the studies, which were obtained from various species of hosts and kept in an axenic in vitro culture. Microscopic, molecular and bio-informative methods were used in the studies. From each faecal sample fresh smears were made in a 0.6% solution of physiological salt and in Lugol's solution, as well as a permanent smear stained with trichrome was made. Moreover, the following molecular techniques were implemented in the studies: DNA extraction and purification, the PCR technique (two molecular markers), electrophoresis and visualisation of PCR products, and sequencing. A fragment of the beta-giardin gene was used as a molecular marker in order to define the genotype and subgenotype of Giardia. Only in the case of genotyping of two Giardia isolates obtained from Peromyscus eremicus another molecular marker (SSU rRNA)was additionally used. Some widely available computer programmes (Chromas, CAP 3, BioEdit, BLASTn, MEGA version 4.0) were utilised in the analysis of the sequence of the beta-giardin gene fragment and in the phylogenetic analysis. The culture of Giardia trophozoites was established to compare the sequence of the partial beta-giardin gene from cysts and trophozoites. Concentration and purification of Giardia cysts in the saccharose gradient, and the excystation technique were applied in the studies to obtaining an axenic in vitro culture. In this study, Giardia cysts were found in 12 faecal samples obtained from 3 persons and 5 animal species. Giardia cysts were found only in faecal samples from humans living in Poznań and the samples obtained from animals coming from Poznań and around Puszczykowo. The highest frequency of infection was stated in domestic animals (2.5%) and in animals kept in the Zoological Garden (2.0%), whereas a slightly lower frequency was noticed in wild animals (1.5%) and in humans (1.3%). No Giardia cysts were found in the faecal samples collected from breeding animals. Two new species of Giardia hosts were identified, namely Rhinella marina and Peromyscus eremicus; however, due to a minimal amount of faecal samples supplied for the study it was impossible to define the species and genotype of this parasite. PCR products (the partial of beta-giardin gene) were obtained in seven faecal samples out of the ten studied, including three samples from people and four faecal samples derived from three animal species (i.e. dog, tamandua, red deer). Moreover, molecular characterization of seven Giardia isolates from three persons and four animal species (red-bellied monkey, silver marmoset, Thomson's gazelle, and sheep) kept in an axenic in vitro culture was performed. Based on the beta-giardin sequence fragment analysis, four assemblages of G. intestinalis genotypes were identified (A, B, C and D). In humans, A and B G. intestinalis genotypes and three subgenotypes, including a cosmopolitan subgenotype A2 and two new subgenotypes A and B were detected. Furthermore, four G. intestinalis genotypes were found in animals, including three genotypes which are non-infectious to humans, namely: genotypes C and D in dogs and a cervids-specific genotype A in red deer (Cervus elaphus), which indicate that these animals do not constitute the source of infection to humans. On the other hand, in a tamandua from the Zoological Garden in Poznań a new subgenotype B of G. intestinalis was identified, which due to a close relationship with Giardia isolates obtained from humans is potentially infectious to man. In none of the studied faecal samples a mixed infection of Giardia was found. To date, nine sequences of the partial beta-giardin gene have been deposited in the National Center for Biotechnology Information (NCBI), including two sequences of Giardia isolates obtained from humans (GenBank accession numbers FJ009207, FJ009208), three sequences of isolate obtained from red deer (GenBank accession numbers EU621373, EU626198, EU216429), two sequences of both Giardia isolates obtained from dogs (GenBank accession numbers FJ009205, FJ009206), and the single sequences obtained from tamandua (GenBank accession number FJ009209) and from Thomson's gazelle (GenBank accession number EU626199). According to the literature, an axenic in vitro culture of G. intestinalis was obtained from a red deer for the first time. Based on the analysis of the sequence of the beta-giardin gene fragment obtained from the DNA isolated from cysts and trophozoites it was proven that the red deer was infected with a single population of Giardia and that during the axenisation of the culture no mutation in the DNA of the parasite's trophozoites took place. Probably the time distance that the DNA was isolated from the trophozoites kept in the culture was too short to cause the mutation. This suggestion is confirmed by the results of the genotyping of seven G. intestinalis isolates obtained from various host species and kept in an axenic in vitro culture for at least a number of years. Based on the molecular characteristics it was stated that all the studied isolates from the axenic culture were identical and belonged to the same assemblage B. The comparision with the sequences from GenBank database revealed that all mentioned isolates were 99% similar to the sequence of Giardia Nij5 isolate obtained from a person from the Netherlands and characterised as genotype B1. Due to the sameness of the molecular marker sequences it seems improbable that the identical G. intestinalis genotype occurred in various time periods (the largest difference was 14 years) in humans and in a number of animal species in diverse areas of Wielkopolska region. Quite opposite, the long-term keeping of these isolates in the homogenous conditions of an axenic in vitro culture leads to the selection of a genotype or proves the instability of genotypes of this parasite. Long-term studies need to be conducted in order to verify these hypothesis. Their results will have a key meaning in explaining the genetic structure of the Giardia population and in understanding the molecular epidemiology of giardiosis.

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In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlPOSITRON EMISSION TOMOGRAPHY FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY: An Evidence-Based AnalysisMAGNETIC RESONANCE IMAGING FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY: An Evidence-Based Analysis The objective of this analysis is to assess the effectiveness and safety of positron emission tomography (PET) imaging using F-18-fluorodeoxyglucose (FDG) for the assessment of myocardial viability. To evaluate the effectiveness of FDG PET viability imaging, the following outcomes are examined: the diagnostic accuracy of FDG PET for predicting functional recovery;the impact of PET viability imaging on prognosis (mortality and other patient outcomes); andthe contribution of PET viability imaging to treatment decision making and subsequent patient outcomes. CONDITION AND TARGET POPULATION LEFT VENTRICULAR SYSTOLIC DYSFUNCTION AND HEART FAILURE: Heart failure is a complex syndrome characterized by the heart's inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality. In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD) is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997. IN GENERAL, THERE ARE THREE OPTIONS FOR THE TREATMENT OF HEART FAILURE: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure. Left ventricular dysfunction may be permanent if a myocardial scar is formed, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically: dobutamine echocardiography (echo),stress echo with contrast,SPECT using either technetium or thallium,cardiac magnetic resonance imaging (cardiac MRI), andpositron emission tomography (PET). Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 - 10 μg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability. Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium. SPECT: SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (&gt; 10% increase in tracer uptake) on the re-injection images. The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (&gt; 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%. There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%. Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. Two types of cardiac MRI are used to assess myocardial viability: dobutamine stress magnetic resonance imaging (DSMR) and delayed contrast-enhanced cardiac MRI (DE-MRI). DE-MRI, the most commonly used technique in Ontario, uses gadolinium-based contrast agents to define the transmural extent of scar, which can be visualized based on the intensity of the image. Hyper-enhanced regions correspond to irreversibly damaged myocardium. As the extent of hyper-enhancement increases, the amount of scar increases, so there is a lower the likelihood of functional recovery. Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG). During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. (ABSTRACT TRUNCATED)

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The objective of this review is to identify effective enteral nutritional regimens targeting protein and calorie delivery for the critically ill obese patient on morbidity and mortality.More specifically, the review question is:In the critically ill obese patient, what is the optimal enteral protein and calorie target that improves mortality and morbidity? The World Health Organization (WHO) defines obesity as abnormal or excessive fat accumulation that may impair health, or, empirically, as a body mass index (BMI) ≥ 30 kg/m. Twenty-eight percent of the Australian population is obese with the prevalence rising to 44% in rural areas, and there is evidence that rates of obesity are increasing. The prevalence of obese patients in intensive care largely mirrors that of the general population. There is concern, however, that this may also be rising. A recently published multi-center nutritional study of critically ill patients reported a mean BMI of 29 in their sample, suggesting that just under 50% of their intensive care population is obese. It is inevitable, therefore, that the intensivist will care for the critically ill obese patient.Managing the critically ill obese patient is challenging, not least due to the co-morbid diseases frequently associated with obesity, including diabetes mellitus, cardiovascular disease, dyslipidaemia, sleep disordered breathing and respiratory insufficiency, hepatic steatohepatitis, chronic kidney disease and hypertension. There is also evidence that metabolic processes differ in the obese patient, particularly those with underlying insulin resistance, itself a marker of the metabolic syndrome, which may predispose to futile cycling, altered fuel utilization and protein catabolism. These issues are compounded by altered drug pharmacokinetics, and the additional logistical issues associated with prophylactic, therapeutic and diagnostic interventions.It is entirely plausible that the altered metabolic processes observed in the obese intensify and compound the metabolic changes that occur during critical illness. The early phases of critical illness are characterized by an increase in energy expenditure, resulting in a catabolic state driven by the stress response. Activation of the stress response involves up-regulation of the sympathetic nervous system and the release of pituitary hormones resulting in altered cortisol metabolism and elevated levels of endogenous catecholamines. These produce a range of metabolic disturbances including stress hyperglycemia, arising from both peripheral resistance to the effects of anabolic factors (predominantly insulin) and increased hepatic gluconeogenesis. Proteolysis is accelerated, releasing amino acids that are thought to be important in supporting tissue repair, immune defense and the synthesis of acute phase reactants. There is also altered mobilization of fuel stores, futile cycling, and evidence of altered lipoprotein metabolism. In the short term this is likely to be an adaptive response, but with time and ongoing inflammation this becomes maladaptive with a concomitant risk of protein-calorie malnutrition, immunosuppression and wasting of functional muscle tissue resulting from protein catabolism, and this is further compounded by disuse atrophy. Muscle atrophy and intensive care unit (ICU) acquired weakness is complex and poorly understood, but it is postulated that the provision of calories and sufficient protein to avoid a negative nitrogen balance mitigates this process. Avoiding lean muscle mass loss in the obese intuitively has substantial implications, given the larger mass that is required to be mobilized during their rehabilitation phase.There is, in addition, evolving evidence that hormones derived from both the gut and adipose tissue are also involved in the response to stress and critical illness, and that adipose tissue in particular is not a benign tissue bed, but rather should be considered an endocrine organ. Some of these hormones are thought to be pro-inflammatory and some anti-inflammatory; however both the net result and clinical significance of these are yet to be fully elucidated.The provision of adequate nutrition has become an integral component of supportive ICU care, but is complex. There is ongoing debate within critical care literature regarding the optimal route of delivery, the target dose, and the macronutrient components (proportion of protein and non-protein calories) of nutritional support. A number of studies have associated caloric deficit with morbidity and mortality, with the resultant assumption that prescribing sufficient calories to match energy expenditure will reduce morbidity and mortality, although the evidence base underpinning this assumption is limited to observational studies and small, randomized trials.There is research available that suggests hyper-caloric feeding or hyper-alimentation, particularly of carbohydrates, may result in increased morbidity including hyperglycemia, liver steatosis, respiratory insufficiency with prolonged duration of mechanical ventilation, re-feeding syndrome and immune suppression. But the results from studies of hypo-caloric and eucaloric feeding regimens in critically ill patients are conflicting, independent of the added metabolic complexities observed in the critically ill obese patient.Notwithstanding the debate regarding the dose and components of nutritional therapy, there is consensus that nutrition should be provided, preferably via the enteral route, and preferably initiated early in the ICU admission. The enteral route is preferred for a variety of reasons, not the least of which is cost. In addition there is evidence to suggest the enteral route is associated with the maintenance of gut integrity, a reduction in bacterial translocation and infection rates, a reduction in the incidence of stress ulceration, attenuation of oxidative stress, release of incretins and other entero-hormones, and modulation of systemic immune responses. Yet there is evidence that the initiation of enteral nutritional support for the obese critically ill patient is delayed, and that when delivered is at sub-optimal levels. The reasons for this remain obscure, but may be associated with the false assumption that every obese patient has nutritional reserves due to their adipose tissues, and can therefore withstand longer periods with no, or reduced nutritional support. In fact obesity does not necessarily protect from malnutrition, particularly protein and micronutrient malnutrition. It has been suggested by some authors that the malnutrition status of critically ill patients is a stronger predictor of mortality than BMI, and that once malnutrition status is controlled for, the apparent protective effects of obesity observed in several epidemiological studies dissipate. This would be consistent with the large body of evidence that associates malnutrition (BMI &lt; 20 kg/m) with increased mortality, and has led some authors to postulate that the weight-mortality relationship is U-shaped. This has proven difficult to demonstrate, however, due to recognized confounding influences such as chronic co-morbidities, baseline nutritional status and the nature of the presenting critical illness.This has led to interest in nutritional regimens targeting alternative calorie and protein goals to protect the obese critically ill patient from complications arising from critical illness, and particularly protein catabolism. However, of the three major nutritional organizations, the American Society of Parenteral and Enteral Nutrition (ASPEN) is the only professional organization to make specific recommendations about providing enteral nutritional support to the critically ill obese patient, recommending a regimen targeting a hypo-caloric, high-protein goal. It is thought that this regimen, in which 60-70% of caloric requirements are provided promotes steady weight loss, while providing sufficient protein to achieve a neutral, or slightly positive, nitrogen balance, mitigating lean muscle mass loss, and allowing for wound healing. Targeting weight loss is proposed to improve insulin sensitivity, improve nursing care and reduce the risk of co-morbidities, although how this occurs and whether it can occur over the relatively short time frame of an intensive care admission (days to weeks) remains unclear. Despite these recommendations observational data of international nutritional practice suggest that ICU patients are fed uniformly low levels of calories and protein across BMI groups.Supporting the critically ill obese patient will become an increasingly important skill in the intensivist's armamentarium, and enteral nutritional therapy forms a cornerstone of this support. Yet, neither the optimal total caloric goal nor the macronutrient components of a feeding regimen for the critically ill obese patient is evident. Although the suggestion that altering the macronutrient goals for this vulnerable group of patients appears to have a sound physiological basis, the level of evidence supporting this remains unclear, and there are no systematic reviews on this topic. The aim of this systematic review is to evaluate existing literature to determine the best available evidence describing a nutritional strategy that targets energy and protein delivery to reduce morbidity and mortality for the obese patient who is critically ill.

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The interferon alpha stands as a reference both in oncology and virology. But its efficiency is limited by frequent somatic as well as neuropsychic side effects. As a matter of fact, the reduction or the ending of a chemotherapy treatment come chiefly from the psychiatric complications caused by the use of interferon. For about 30% of patients, various psychic disorders are noticed: personality disorders, mood disorders, anxiety states, suicidal tendencies, manic and psychotic symptoms. We thus propose a review which shall be completed by a discussion on wether the interferon is responsible or not of the appearance of the described mental disorders. We shall conclude with a synthesis of the proposed practical management when confronted with such disorders. Psychiatric complications under interferon-Alpha. The appearance of psychiatric complications caused by interferon has been the subject of many publications. They have also raised the question of the toxicity mechanism which is still misunderstood today. This toxicity appears to be dose-dependent with variations depending on the daily dose given, the mode of administration, the combination with other chemotherapy treatments, the concomitance with a cerebral radiotherapy or a medical history of psychiatric disorders. Most of these effects occur after three weeks of treatment but non specific neuropsychic symptoms can be observed earlier. Non specific symptoms. They appear early but are difficult to detect, though they bring together a whole lot of clinical signs: asthenia, irritability, psychomotor slowdown, depressive mood or even a real "subsyndromic" depressive syndrome, anorexia, decline of the libido, concentration and attention problems, dizzy spells and headaches. Some authors have described intense and fluctuating of personality, mixing anxiety, irritability and disorder of drive control. Depression. Depression is the most frequently found psychiatric pathology in studies but the real frequency of clear cases of depressive problems is difficult to determine through lack of serious studies. So the incidence of depressive disorders usually varies from 5 to 15%. The depressive syndrome can settle as soon as the first week treatment, with a peak in the frequency during the first and third months. The seriousness and the incidence of this syndrome seem to be dose-dependent. The gravity of this complication lies in the suicidal risk, a risk all the more dreadful since there is not any identified risk factor. Suicides and suicidal behaviours. Serious complications, because they act directly on the vital prognosis. However fortunately, suicidal behaviours only represent a minority within all the side effects attributed to the interferon-alpha. These actions fit into three main clinical dimensions: complication of a severe depressive syndrome, confusional context and disorder of the impulses control. In practical terms, prevention proves to be difficult without identified predictive factors. Nevertheless, some authors point out the importance of aggravating comorbid disorders like alcoholism or the coinfection by the HIV. Manic syndrome. The appearance of a manic state under a chemotherapy treatment seems to be rare, given that there have been only a dozen cases published around the world. But these observations are interesting as far as both the study of imputability and the understanding of the toxicity mechanisms are concerned. Most of the cases deal with patients without a family or personal history of psychiatric disorders, and whose symptomatology disappears with the end of the treatment, which is an argument in favour of the imputation of the interferon in the appearance of manic disorders. In addition, some authors introduce the notion of tertiary mania: the appearance of an autoimmune hypothyroidism in relation with interferon and leading to athymic elation. Eventually, the appearance of manic problems at the end of the treatment makes it possible to speculate about the physiopathological mechanisms that are at issue. Anxiety disorders. These disorders are not much described: they generally are already existing disorders (like phobic or obsessive compulsive disorders), reactivated or aggravated by the interferon-alpha molecule. Adaptation disorders. It deals with adaptation disorders along with anxious temper coming at the beginning of the treatment. These problems are more concerned with the announcement of the diagnosis and its seriousness than with the toxicity of the interferon-alpha molecule. Psychotic states. There are less papers on the prevalence of psychotic disorders during the treatment, or at the end of it. But they can be found in both viral and malignant pathologies. A large retrospective study has shown ten cases of psychotic disorders and that in the absence of history of psychiatry or of a HIV co-infection. In every case the psychiatric aspect is stopped by the ending of the treatment or by an appropriated treatment. Usually, the few cases of paranoïd delusion described in papers seem to appear between one and three months of treatment, with patients having a history of psychiatric disorders. Aggravation of pre-existing mental disorders. Numerous authors have reported the recurrence of addictive behaviours (alcohol or other psychoactive matter) by weaned patients. Imputability to interferon-alpha in psychiatric disorders. It is difficult to draw the relationship between the chemotherapy with the interferon-alpha treatment and neuropsychiatric complications because there is a lack in specific studies. Nevertheless, it seems to be causal relations between the prescription of interferon and the appearance of psychic disorders. As a matter of fact, even if there is neither predictive criterion nor diagnosis of clinical type (set apart a dose effect), it is clear that there are diagnostic criteria of chronological kind: delay of appearance and disappearance of side effects compatible with the kinetics of the molecule and test of positive reintroduction. The imputability is thus most likely towards, given the reported clinical observations and signs of direct cerebral toxicity described for interferon: induction of neurophysiological changes among healthy volunteers, reversible EEG impairments the second week of treatment, direct vascular and neurological toxicity. Eventually, authors have shown that the psychiatric morbidity could be more important among patients under treatment than in a control group. In conclusion, the imputability of interferon appears to be very likely, more particularly in the appearance of mood disorders, mainly depressive ones, of manic syndromes and of certain psychotic episodes. The most numerous therapeutic propositions naturally concern the depressive syndromes, because of their high frequency. In a recent article, the authors have detailed the pharmacological criteria of the ideal molecule: limited hepatic metabolism, low rate of proteinic fixation, long half-life and absence of active metabolite. So they advise not to prescribe imipraminic molecules and recommend the use of some SRI in first intention: citalopram and sertraline mainly, paroxetine to avoid given its pharmacological features that do not seem adapted. Only the minalcipram seems to show all the theoretical advantages described above. If there is an indication in the introduction of an anxiolytic medication, we shall prefer a benzodiazepine with short half-life like loxazepam and alprazolam. Besides, all the publications point out the importance of a specific clinical observation during the treatment as well as in the six months following its end. The agreement must bear full medical costs, above all including psychotherapic and social aspects. The proposed treatments for the other disorders are conventional: haloperidol and lithium for bipolar disorders, fluvoxamine for obsessive compulsive disorders and neuroleptics for psychotic disorders. The appearance of neuropsychiatric side effects during a chemotherapy using the interferon-alpha molecule is a frequent complication, the consequences of which can prove tragic: involvement of the vital prognosis, family and professional relation disturbances, compliance problems, risks of psychiatric morbidity at short and middle terms.... In spite of the absence of rigorous controlled studies, the imputability to the interferon of the appearance of psychological disorders appears very likely. So the role of the psychiatrist seems to be determining in the follow-up care of these patients who must be considered at high risk to develop a psychiatric pathology. The agreement to bear medical costs has to be made in narrow collaboration with clinical practitioners and must be part of a clinical continuity, from the pre-therapeutical evaluation to the remote follow-up care. Finally, it seems important to implement controlled studies, resting on a great diagnostic and methodological rigour, in order to clarify the toxicity mechanisms of interferon and to optimise the agreement to bear medical cost for the patients.

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Why are some individuals more likely than others to develop a posttraumatic stress disorder (PTSD) in the face of similar levels of trauma exposure? Monitoring the traumatic process combining the antecedents, the determinants of the psychic trauma and the acute symptoms can clarify the causes of the final onset of a chronic repetition syndrome. Epidemiologic research has clarified risk factors that increase the likelihood of PTSD after exposure to a potentially traumatic event. PTSD is an interaction between a subject, a traumatogenic factor and a social context. With each epidemiological, psychopathological and more particularly neurogenetic study, we will expand on the impact of these interactions on the therapeutic treatment of psycho-traumatised persons. Most studies have shown that unrelated to the traumatic event, additional risk factors for developing PTSD include younger age at the time of the trauma, female gender, lower social economic statuts, lack of social support, premorbid personality characteristics and preexisting anxiety or depressive disorders increase the risk of PTSD. The psychic trauma is firmly attached to the repetition and the previous traumas are as many risks of developing a subsequent PTSD in the wake of a new trauma: PTSD in adults may represent a prolonged symptomatic reaction to prior traumatic assault, child abuse and childhood adversities. Related to the traumatic event, the organic pain, the traumatic brain injury, but also the sight of blood can lead to a trauma being considered as more serious or more harmful to life. It is useful to recognize the acute reactions of exhaustion stress as they can guide both the pharmacotherapeutic and the psychotherapeutic treatment thanks to debriefings. Even though the majority of people with acute stress disorder subsequently develop PTSD, the current data indicate that too many people can develop PTSD without initially displaying acute stress disorder. Though peritraumatic dissociation and peritraumatic distress have emerged as the strongest predictors for PTSD and have to be treated as soon as possible with the debriefing or the pharmacology; initial evidence suggests the potential benefits of early intervention, shortly after the trauma, and psychological debriefing has received increasing interest from the scientific community. However the Anglo-Saxon techniques (such as Critical Incident Stress Debriefing also known as the Mitchell model) are in total contrast with the French approach. In the first case the emotional response is controlled to ensure the pursuit of the group action, whilst in the second case the debriefing concerns patients with acute symptoms in order to prevent the development of a PTSD structuring of the latter. The facts, emotions and thoughts are not partitioned but inter-linked, thus enabling a fragmentation of the traumatic experience. In the face of the annihilation experienced, speech production by the subject is restored linking the person to the human community, once abandoned. However, debate continues on the efficacy of single session debriefing in the prevention of PTSD. At the time of the acute stress reactions, benzodiazepines are contraindicated at this stage as they promote dissociation and ulterior revivals. On the other hand, treatment with propranolol could be proposed: a two or three week course of propranolol begun in the aftermath of a traumatic event can reduce subsequent PTSD symptoms. A genetic polymorphism is evidently at work in the development of a PTSD via the regulation of the expression of genes of interest to the serotoninergic system and the adrenocorticotropic axis. The 5-HTTLPR (promoter region of SLC6A4 witch encodes the serotonin transporter) constitutes a genetic candidate region that may modulate emotional responses to traumatic events. The interaction between variation at the 5HTTLPR and stressful life events could predict depression and PTSD. Considering the dopaminergic pathway, the A1 allele coding the type 2 dopaminergic receptor is associated with a severe comorbidity of PTSD with the presence of somatic disorders, anxiety, social change and depression. For noradrenergic neuromodulation, an interaction between the polymorphism of gene GABRA2 and the occurrence of PTSD is described whereas an interaction between the number of traumatic events and Val(158)Met polymorphism of the gene coding for catecholamine-o-methyltransferase has also been found. The role of polymorphisms in FKBP5 (a co-chaperone of hsp 90 which binds to the glucocorticoid receptor) in predicting PTSD too, with a gene-by-environment point of view. These gene-by-environment studies are needed to focus more on distinct endophenotypes and influences from environmental factors. If several candidate genes are involved, a weighting of susceptibility to such and such a neurological regulation system will imply various endophenotypes. According to the monoamine predominantly incriminated, PTSD can take on a more hyper-vegetative clinical expression linked with noradrenergic overuse. Differently, avoidance behaviour and the depressive aspect invoke more a modification of the serotoninergic modulation whilst posttraumatic psychotic reactions question the role of dopaminergic pathways. Neuroscientific discoveries interesting the biological support of PTSD can thus modify our view of the conception of the disorder in relation to different therapeutic prospects. Chronic PTSD can manifest itself in different clinical forms. The repetition syndrome can appear a long time after the traumatic event, following a paucisymptomatic latency period, which can last several years or even decades. The absence of complaints from the patient is common, the latter suffering in silence. Often other comorbid disorders and other complaints arise sooner than the clinical picture. Thus a depressive episode characterised as drug-seeking behaviour is frequently encountered. The therapeutic accompaniment traditionally combines a pharmacological and a psychotherapeutic treatment even if recommendations are rare. A posttraumatic stress disorder is never just a coincidence. The different stages of the evolution and the establishment of a PTSD are the expression of an interaction between the outside and the inner self. Despite a known progression of the posttraumatic stress disorder, this deleterious evolution is far from being a foregone conclusion. On the contrary, several levels of prevention are possible at each stage of its structuration to propose treatments to subjects who are vulnerable and/or present symptoms. No neurobiological study has yet found a biological marker, which would apparently and inevitably destine a subject to structure, a posttraumatic stress disorder in reaction to a stress. Conversely, the psychopathological study finds afterwards that a particular subject has necessarily built a traumatic repetition syndrome according to the concordance of significant data relative to his/her history. The event strikes a repression or an anterior biographical deadlock and of which the thematic questions the fundamentals of human culture in its emancipation with nature, like the question of death and its consequences: bereavement, parentality, transgenerational transmission and organicity often linked to the illness. A therapeutic proposal constitutes an environmental factor par excellence which can be either protective or deleterious. If the traumatic repetition syndrome has been known since Antiquity, the birth of PTSD has followed the chronology of the DSM according to the sociopolitical contexts encountered. A PTSD does not occur by chance: the conditions of possibility of the trauma are established by genetic and psychological determinants interactively integrated at the heart of a social context. After the increase in a psychotraumatic interest in international publications since the 1980s, a fight against over-victimisation seems to be setting in. The advances in genetic and neuroimaging techniques are in the process of superseding psychometric studies in terms of reliability and validity; maybe we should see in this social evolution the changes of tomorrow concerning the clinical of PTSD and its treatment. The healing of the psycho-traumatised subject cannot just be established on the passive status of victim, which would be detrimental to reflection and ultimately reconstruction: the rebirth of the subject will require active commitment, which could distract from the deadly repetition. Whilst the confrontation with death resembled nonsense, the subject will question the psychotraumatic determinants of his/her life history to reinstate this tragic event within a search for meaning. Such restructuring is built on the intersubjectivity of the clinical relationship, which occurs within a social context. PTSD is a pathology which interacts with the societal context: on the one hand the trauma is established on the brutal reconsideration of social values which seem immutable and on the other hand, the clinical and nosographical concept of PTSD is changing with the evolution of society.

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With progression of chronic kidney disease (CKD), disorders of mineral metabolism appear. The classic sequence of events begins with a deficit of calcitriol synthesis and retention of phosphorus. As a result of this, serum calcium decreases and parathyroid hormone (PTH) is stimulated, producing in the bone the high turnover (HT) bone disease known as osteitis fibrosa while on the other extreme we find the forms of low turnover (LT) bone disease. Described later and initially associated with aluminum intoxication, these diseases are now seen primarily in older and/or diabetic patients, who in a uremic setting have relatively low levels of PTH to maintain normal bone turnover. Osteomalacia is also included in this group, which after the disappearance of aluminum intoxication is rarely observed. LT forms of hyperparathyroidism facilitate the exit of calcium (Ca) and phosphorus (P) from bone, whereas the adynamic bone limits the incorporation of Ca and P into bone tissue. Therefore, both forms facilitate the availability of Ca and P, which ends up being deposited in soft tissues such as arteries. The link between bone disease and vascular calcifications in CKD is now a well-established phenomenon. 2. Diagnostic strategies Calcium, Phosphorus They have little capacity to predict underlying bone disease, but their regular measurement is decisive for therapeutic management of the patient, especially in the dose titration stages of intestinal phosphorus binders, vitamin D analogs or calcimimetics. Ideally, Ca++ should be used, but total Ca is routinely used. It is recommended to adjust albumin levels in the event of hypoalbuminemia (for each g/dL of decrease in albumin, total serum Ca decreases 0.9 mg/dL). The following formula facilitates rapid calculation of corrected total calcium: Corrected total Ca (mg/dL) = total Ca (mg/dL) + 0.8 [4-albumina (g/dL)]. Parathyroid hormone "Intact" PTH is the biochemical parameter that best correlates with bone histology (levels measured with the Allegro assay from Nichols Institute Diagnostics, no longer available). Various assays are currently available that use antibodies against different fragments of the molecule, but they have significant intermethod variability and have not been validated. A whole PT assay (1-84) is currently unavailable. A consensus to establish uniform criteria for PTH measurement remains to be established. During the dose titration stages of intestinal phosphorus binders, vitamin D analogs or calcimimetics, more frequent measurement may be required based on clinical judgment. Calcifediol (25(OH)D3) It is important to maintain adequate levels of 25(OH)D3 (&gt; 30 ng/mL), since they will be the substrate for production of 1- 25(OH)2 D3, and their deficiency aggravates hyperthyroidism. Determining 25(OH)D3 levels every 6-12 months is a recommended guideline. Other markers of bone turnover (osteocalcin, total and bone alkaline phosphate, free pyridolines in serum, and C-terminal telopeptide of collagen) do not improve the predictive power of PTH and therefore their systematic use is not justified. Radiologic studies Radiologic studies are of little diagnostic utility, because biochemical changes precede radiologic changes. Systematic radiologic evaluation of the skeleton in asymptomatic patients is not justified at present. They are useful as the first step in the study to detect vascular calcifications and amyloidosis due to b2-microglobulin and in symptomatic and at risk patients to detect vertebral fractures. Bone densitometry: Dual energy x-ray absorptiometry (DEXA) is the standard method to determine bone mineral density (usually in the femoral neck and vertebrae). It provides information on changes in bone mineral content, but not on the type of underlying bone disease. It is useful for follow-up of bone mass or for the study of bone mass changes in the same patient. Its value as a predictor of the risk of fracture has not been demonstrated in patients on kidney replacement therapy or with advanced chronic kidney disease. It is indicated in patients with fractures or risk factors for osteoporosis. Bone biopsy: The "gold standard" for diagnosis of bone disease. With improved knowledge of the value of noninvasive parameters, its use is infrequent. Pathological fractures in the presence or absence of minor trauma. Symptomatic patients in the presence of incongruent clinical parameters. A typical case is the presence of unexplained hypercalcemia from systemic disease, with inconclusive serum PTH values (between 120-450 pg/mL as an estimated range). Evaluation and follow-up of cardiovascular calcifications There are no consensuated clinical practice guidelines for the evaluation and follow-up of extraosseal calcifications in CKD. The clinical tools for evaluation and follow-up of cardiovascular disease are used based on clinical judgment. The periodicity of follow-up has not been established . 3. Recommended biochemical values The biochemical values recommended in clinical practice guidelines for the evaluation of bone mineral metabolism are summarized in Figure 3. The recommended PTH values do not fully coincide with the K/DOQI guidelines. The wide variability in PTH values depending on the assays used has led us to expand the recommended PTH range in stage 3 and 4 CKD. 4. Treatment 4.1. Diet. The recommended diet for the patient with CKD is traditionally based on protein restriction and phosphorus restriction for control of mineral metabolism. A favorable circumstance is that there is a close relationship between protein and phosphorus intake. In CKD stages 3, 4 and 5, it is recommended to restrict phosphorus intake to between 0.8-1 g/day when serum levels of phosphorus and PTH are above the recommended range. This is approximately equivalent to a diet of 50-60 g of protein. This reasonable antiproteinuric strategy that also restricts phosphorus intake is nutritionally safe. What should we tell them to eat? In a practical and oversimplified way, we recommend the following daily intake: Animal proteins: 1 serving (100-120 g), dairy products: 1 serving (equivalent to 200-240 mL of milk or 2 yoghourts), bread, cereals, pastas (1 cup of pasta, rice or legumes + some bread or cookies), vegetables and fruits relatively freely, but with moderation. 4.2. Medication Vitamin D supplements should be provided if serum levels are less than 30 ng/mL. In Spain, vitamin D3 (cholecalciferol) is marketed as Vitamin D3 Berenguer 2,000 IU/mL of solution. Combinations of calcium with cholecalciferol are also available. Most of the dosage forms contain approximately 500 mg of Ca+ and 400 IU of cholecalciferol. Alternatively, calcifediol (25(OH)D3), as Hidroferol 100 mcg/mL, has been used, although the dose range is very variable and has not been established. 4.3. Phosphorus binders. Use if hyperphosphatemia occurs. Start with calcium-containing phosphorus binders (calcium carbonate or calcium acetate), which also provide calcium if dietary intake is inadequate. Do not exceed 1.5 g of Ca++ per day. The most used are calcium carbonate and calcium acetate. Calcium acetate shows a similar binding potency to calcium carbonate but with a lesser calcium overload, and thus would have certain advantages as well as its greater effect at different pH ranges. However, gastric intolerance is more frequent with this dosage form. Aluminum hydroxide may sometimes be required to control phosphoremia or the occurrence of hypercalcemia. Serum aluminum values should be maintained below 30 mcg/L. Avoid use for longer than 6 months and daily doses greater than 1.5 g. Sevelamer is associated with an increased risk of acidosis and has not been approved for use in predialysis stages. Lanthanum carbonate has been recently marketed in Spain, although its indication for use in the predialysis stage of CKD is still not approved. 4.4. Vitamin D derivatives. Indicated when PTH levels are elevated. A prerequisite for their use is that Ca and P serum levels are adequately controlled. Vitamin D derivates available in Spain are 1,25(OH)2D3 (Calcitriol)and 1a(OH)D3 (a-Calcidiol). Doses should be titrated until PTH levels are normalized. Phosphate binder doses often need to be increased because these vitamin D derivatives increase intestinal absorption of calcium and phosphorus. Low doses do not cause hypercalcemia or hyperphosphatemia and do not worsen the course of renal function. Recommended doses: Calcitriol 0.25 mcg every 48 hours and alpha-Calcidiol 0.50 mcg every 48 hours. Soon to be available on the Spanish market is the oral dosage form of paricalcitol (recommended initial dose of 1 mcg/24 h), with a lesser hypercalcemic and hyperphosphoremic effect. Clinical use of calcimimetics in the predialysis state is not yet recommended and is currently under investigation.

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Methyl trans-styryl ketone is used as a synthetic flavoring agent and a fragrance additive in food and personal care products. Methyl trans-styryl ketone was nominated for study by the National Cancer Institute due to widespread human exposure as a flavoring and fragrance additive, positive results in the Ames/Salmonella assay and the mouse lymphoma L5178Y/tk+/- assay, and as a representative of the α,β-unsaturated ketone chemical class. Male and female F344/N rats and B6C3F1 mice received methyl trans-styryl ketone (98.6% pure) in feed for 3 months and dermally for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. Two-year studies were conducted to provide data for assessment of possible toxicity due to exposure to methyl trans-styryl ketone. The dermal route was chosen since this is the route for highest human exposure and due to studies demonstrating systemic exposure following dermal application to methyl trans-styryl ketone. 3-MONTH FEED STUDY IN RATS Groups of 10 male and 10 female rats were fed diets containing 0%, 0.025%, 0.05%, 0.1%, 0.2%, or 0.4% methyl trans-styryl ketone (equivalent to average daily doses of approximately 18, 36, 72, 145, or 290 mg methyl trans-styryl ketone/kg body weight to males and 19, 38, 77, 150, or 300 mg/kg to females) for 14 weeks. Groups of 10 male and 10 female clinical pathology rats were fed the same concentrations for 24 days. All core study rats survived to the end of the study. Final mean body weights of males and females receiving 0.4% and mean body weight gains of males receiving 0.4% were significantly less than those of the controls. Feed consumption by exposed groups was similar to that by the controls. Clinical findings included diarrhea and hyperactivity in males and females. Results of sperm motility and vaginal cytology evaluations indicated methyl trans-styryl ketone is unlikely to be a reproductive toxicant in male rats; however, it exhibits potential for reproductive toxicity in female rats based upon an increased probability of extended diestrus at the highest exposure concentration. In all exposed groups of males, there were treatment-related increased incidences of goblet cell hyperplasia of the respiratory epithelium of the nose and nephropathy of the kidney. In females, there was an increased incidence of goblet cell hyperplasia of the respiratory epithelium of the nose in the group receiving 0.4%. 3-MONTH FEED STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0%, 0.025%, 0.05%, 0.1%, 0.2%, or 0.4% methyl trans-styryl ketone (equivalent to average daily doses of approximately 55, 110, 220, 400, or 750 mg/kg to males and 50, 100, 200, 350, or 600 mg/kg to females) for 14 weeks. One male receiving 0.2% and one control female died before the end of the study. Mean body weights of males and females receiving 0.4% were significantly less than those of the controls. Feed consumption by exposed groups was similar to that by the controls. Hyperactivity in both sexes was the only clinical finding. Results of sperm motility and vaginal cytology evaluations indicated methyl trans-styryl ketone is unlikely to be a reproductive toxicant in male mice; however, it exhibits potential for reproductive toxicity in female mice based upon an increased probability of extended diestrus at the lowest and the highest exposure concentrations. There were significantly increased incidences of olfactory epithelial atrophy of the nose in males and females receiving 0.4%. 3-MONTH DERMAL STUDY IN RATS: Groups of 10 male and 10 female rats were dermally administered 0, 22, 44, 87.5, 175, or 350 mg methyl trans-styryl ketone/kg body weight in 95% ethanol, 5 days per week for 14 weeks. Groups of 10 male and 10 female clinical pathology rats were administered the same doses for 23 days. All rats survived to the end of the study. Mean body weights of 175 and 350 mg/kg males were significantly less than that of the vehicle controls. Clinical findings in groups administered 175 or 350 mg/kg included dermal irritation, thickened skin, and ulceration at the site of application. Results of sperm motility and vaginal cytology evaluations indicated methyl trans-styryl ketone is unlikely to be a reproductive toxicant in male or female rats at the doses used in this study. Histologically, there were significantly increased incidences of epidermal hyperplasia, hyperkeratosis, chronic active inflammation, epidermal necrosis, and sebaceous gland hypertrophy in the skin at the site of application in males and/or females. There were significantly increased incidences of goblet cell hyperplasia of the nose in 350 mg/kg males and 22, 175, and 350 mg/kg females. 3-MONTH DERMAL STUDY IN MICE Groups of 10 male and 10 female mice were dermally administered 0, 87.5, 175, 350, 700, or 1,400 mg methyl trans-styryl ketone/kg body weight in 95% ethanol, 5 days per week for 13 weeks. All mice in the 700 and 1,400 mg/kg groups were sacrificed moribund before the end of the study. The final mean body weights of surviving groups of dosed males and females were similar to those of the vehicle controls; however, the mean body weight gains of the 175 mg/kg groups were significantly less than those of the vehicle controls. Clinical findings at the site of application included dermal irritation in 350 mg/kg males and crust formation in all 700 and 1,400 mg/kg mice except one female. Results of sperm motility and vaginal cytology evaluations indicated methyl trans-styryl ketone is unlikely to be a reproductive toxicant in male or female mice at the doses used in this study. There were treatment-related increased incidences of epidermal hyperplasia, hyperkeratosis, chronic active inflammation, epidermal necrosis, sebaceous gland hypertrophy, and hair follicle hyperplasia in the skin at the site of application in males and females. There were increased incidences of olfactory epithelial atrophy of the nose in groups of males and females administered 350 mg/kg or greater. 2-YEAR DERMAL STUDY IN RATS: Groups of 50 male and 50 female rats were dermally administered 0, 10, 30, or 90 mg methyl trans-styryl ketone/kg body weight in 95% ethanol, 5 days per week for 105 weeks. Survival of all dosed groups was similar to that of the vehicle controls. Mean body weights of dosed groups were within 10% of those of the vehicle control groups throughout the study. In the skin at the site of application, there were increased incidences of epidermal hyperplasia and hyperkeratosis in males and females administered 30 or 90 mg/kg. 2-YEAR DERMAL STUDY IN MICE: Groups of 50 male and 50 female mice were dermally administered 0, 10, 30, or 90 mg methyl trans-styryl ketone/kg body weight in 95% ethanol, 5 days per week for 105 weeks. Survival of all dosed groups was similar to that of the vehicle controls. Mean body weights of dosed groups were within 10% of those of the vehicle control groups throughout the study. In the skin at the site of application in males and females, there were treatment-related increased incidences of epidermal hyperplasia, hyperkeratosis, chronic inflammation, and melanocyte hyperplasia. Methyl trans-styryl ketone was mutagenic in Salmonella typhimurium strain TA100 when testing was conducted in the presence of rat liver microsomes (S9). No mutagenic activity was seen with methyl trans-styryl ketone in strain TA98 with or without S9 or in Escherichia coli strain WP2 uvrA/pKM101 in the absence of S9. With S9, inconsistent responses were seen in the E. coli tester strain. No increases in the frequencies of micronucleated normochromatic erythrocytes were seen in peripheral blood samples from male or female mice administered methyl trans-styryl ketone for 3 months via dosed feed or dermal application. Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of methyl trans-styryl ketone in male or female F344/N rats or in male or female B6C3F1 mice administered 10, 30, or 90 mg/kg. Administration of methyl trans-styryl ketone resulted in nonneoplastic lesions of the skin at the site of application in male and female rats and mice. Synonyms: Acetocinnamone; benzalacetone; benzylideneacetone; methyl 2-phenylvinyl ketone; methyl styryl ketone; methyl β-styryl ketone; MSK; 4-phenyl-3-butene-2-one; 4-phenylbutenone; 2-phenylvinyl methyl ketone; styryl methyl ketone Systematic name: (3E)-4-Phenylbut-3-en-2-one.

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Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca2+ buffering, etc. This pivotal role makes mitochondria a potential target to treat a great variety of diseases. Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new pharmacological targets and natural therapies. It contributes to the field by covering and gathering the scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis. There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber's hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh's syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC- 1, Sirtuins, AMPK). Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-PGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10,MitoQ10 and other mitochondria-targeted antioxidants,N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or -lipoic acid. As aforementioned, other diseases do not have exclusively a mitochondrial origin but they might have an important mitochondrial component both on their onset and on their development. This is the case of type 2 diabetes or neurodegenerative diseases. Type 2 diabetes is characterized by a peripheral insulin resistance accompanied by an increased secretion of insulin as a compensatory system. Among the explanations about the origin of insulin resistance Mónica Zamora and Josep A. Villena (Department of Experimental and Health Sciences, Universitat Pompeu Fabra / Laboratory of Metabolism and Obesity, Universitat Autònoma de Barcelona, Spain) [5] consider the hypothesis that mitochondrial dysfunction, e.g. impaired (mitochondrial) oxidative capacity of the cell or tissue, is one of the main underlying causes of insulin resistance and type 2 diabetes. Although this hypothesis is not free of controversy due to the uncertainty on the sequence of events during type 2 diabetes onset, e.g. whether mitochondrial dysfunction is the cause or the consequence of insulin resistance, it has been widely observed that improving mitochondrial function also improves insulin sensitivity and prevents type 2 diabetes. Thus restoring oxidative capacity by increasing mitochondrial mass appears as a suitable strategy to treat insulin resistance. The effort made by researchers trying to understand the signaling pathways mediating mitochondrial biogenesis has uncovered new potential pharmacological targets and opens the perspectives for the design of suitable treatments for insulin resistance. In addition some of the current used strategies could be used to treat insulin resistance such as lifestyle interventions (caloric restriction and endurance exercise) and pharmacological interventions (thiazolidinediones and other PPAR agonists, resveratrol and other calorie restriction mimetics, AMPK activators, ERR activators). Mitochondrial biogenesis is of special importance in modern neurochemistry because of the broad spectrum of human diseases arising from defects in mitochondrial ion and ROS homeostasis, energy production and morphology [1]. Parkinson´s Disease (PD) is a very good example of this important mitochondrial component on neurodegenerative diseases. Anuradha Yadav, Swati Agrawal, Shashi Kant Tiwari, and Rajnish K. Chaturvedi (CSIR-Indian Institute of Toxicology Research / Academy of Scientific and Innovative Research, India) [6] remark in their review the role of mitochondrial dysfunction in PD with special focus on the role of oxidative stress and bioenergetic deficits. These alterations may have their origin on pathogenic gene mutations in important genes such as DJ-1, -syn, parkin, PINK1 or LRRK2. These mutations, in turn, may cause defects in mitochondrial dynamics (key events like fission/fusion, biogenesis, trafficking in retrograde and anterograde directions, and mitophagy). This work reviews different strategies to enhance mitochondrial bioenergetics in order to ameliorate the neurodegenerative process, with an emphasis on clinical trials reports that indicate their potential. Among them creatine, Coenzyme Q10 and mitochondrial targeted antioxidants/peptides are reported to have the most remarkable effects in clinical trials. They highlight a dual effect of PGC-1α expression on PD prognosis. Whereas a modest expression of this transcriptional co-activator results in positive effects, a moderate to substantial overexpession may have deleterious consequences. As strategies to induce PGC-1α activation, these authors remark the possibility to activate Sirt1 with resveratrol, to use PPAR agonists such as pioglitazone, rosiglitazone, fenofibrate and bezafibrate. Other strategies include the triggering of Nrf2/antioxidant response element (ARE) pathway by triterpenoids (derivatives of oleanolic acid) or by Bacopa monniera, the enhancement of ATP production by carnitine and -lipoic acid. Mitochondrial dysfunctions are the prime source of neurodegenerative diseases and neurodevelopmental disorders. In the context of neural differentiation, Martine Uittenbogaard and Anne Chiaramello (Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, USA) [7] thoroughly describe the implication of mitochondrial biogenesis on neuronal differentiation, its timing, its regulation by specific signaling pathways and new potential therapeutic strategies. The maintenance of mitochondrial homeostasis is crucial for neuronal development. A mitochondrial dynamic balance is necessary between mitochondrial fusion, fission and quality control systems and mitochondrial biogenesis. Concerning the signaling pathways leading to mitochondrial biogenesis this review highlights the implication of different regulators such as AMPK, SIRT1, PGC-1α, NRF1, NRF2, Tfam, etc. on the specific case of neuronal development, providing examples of diseases in which these pathways are altered and transgenic mouse models lacking these regulators. A common hallmark of several neurodegenerative diseases (Huntington´s Disease, Alzheimer´s Disease and Parkinson´s Disease) is the impaired function or expression of PGC-1α, the master regulator of mitochondrial biogenesis. Among the promising strategies to ameliorate mitochondrial-based diseases these authors highlight the induction of PGC-1α via activation of PPAR receptors (rosiglitazone, bezafibrate) or modulating its activity by AMPK (AICAR, metformin, resveratrol) or SIRT1 (SRT1720 and several isoflavone-derived compounds). This article also presents a review of the current animal and cellular models useful to study mitochondriogenesis. Although it is known that many neurodegenerative and neurodevelopmental diseases are originated in mitochondria, the regulation of mitochondrial biogenesis has never been extensively studied. (ABSTRACT TRUNCATED)

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Neuroimaging studies of human cognitive, sensory, and motor processes are usually based on noninvasive techniques such as electroencephalography (EEG), magnetoencephalography or functional magnetic-resonance imaging. These techniques have either inherently low temporal or low spatial resolution, and suffer from low signal-to-noise ratio and/or poor high-frequency sensitivity. Thus, they are suboptimal for exploring the short-lived spatio-temporal dynamics of many of the underlying brain processes. In contrast, the invasive technique of electrocorticography (ECoG) provides brain signals that have an exceptionally high signal-to-noise ratio, less susceptibility to artifacts than EEG, and a high spatial and temporal resolution (i.e., &lt;1 cm/&lt;1 millisecond, respectively). ECoG involves measurement of electrical brain signals using electrodes that are implanted subdurally on the surface of the brain. Recent studies have shown that ECoG amplitudes in certain frequency bands carry substantial information about task-related activity, such as motor execution and planning, auditory processing and visual-spatial attention. Most of this information is captured in the high gamma range (around 70-110 Hz). Thus, gamma activity has been proposed as a robust and general indicator of local cortical function. ECoG can also reveal functional connectivity and resolve finer task-related spatial-temporal dynamics, thereby advancing our understanding of large-scale cortical processes. It has especially proven useful for advancing brain-computer interfacing (BCI) technology for decoding a user's intentions to enhance or improve communication and control. Nevertheless, human ECoG data are often hard to obtain because of the risks and limitations of the invasive procedures involved, and the need to record within the constraints of clinical settings. Still, clinical monitoring to localize epileptic foci offers a unique and valuable opportunity to collect human ECoG data. We describe our methods for collecting recording ECoG, and demonstrate how to use these signals for important real-time applications such as clinical mapping and brain-computer interfacing. Our example uses the BCI2000 software platform and the SIGFRIED method, an application for real-time mapping of brain functions. This procedure yields information that clinicians can subsequently use to guide the complex and laborious process of functional mapping by electrical stimulation. PREREQUISITES AND PLANNING: Patients with drug-resistant partial epilepsy may be candidates for resective surgery of an epileptic focus to minimize the frequency of seizures. Prior to resection, the patients undergo monitoring using subdural electrodes for two purposes: first, to localize the epileptic focus, and second, to identify nearby critical brain areas (i.e., eloquent cortex) where resection could result in long-term functional deficits. To implant electrodes, a craniotomy is performed to open the skull. Then, electrode grids and/or strips are placed on the cortex, usually beneath the dura. A typical grid has a set of 8 x 8 platinum-iridium electrodes of 4 mm diameter (2.3 mm exposed surface) embedded in silicon with an inter-electrode distance of 1cm. A strip typically contains 4 or 6 such electrodes in a single line. The locations for these grids/strips are planned by a team of neurologists and neurosurgeons, and are based on previous EEG monitoring, on a structural MRI of the patient's brain, and on relevant factors of the patient's history. Continuous recording over a period of 5-12 days serves to localize epileptic foci, and electrical stimulation via the implanted electrodes allows clinicians to map eloquent cortex. At the end of the monitoring period, explantation of the electrodes and therapeutic resection are performed together in one procedure. In addition to its primary clinical purpose, invasive monitoring also provides a unique opportunity to acquire human ECoG data for neuroscientific research. The decision to include a prospective patient in the research is based on the planned location of their electrodes, on the patient's performance scores on neuropsychological assessments, and on their informed consent, which is predicated on their understanding that participation in research is optional and is not related to their treatment. As with all research involving human subjects, the research protocol must be approved by the hospital's institutional review board. The decision to perform individual experimental tasks is made day-by-day, and is contingent on the patient's endurance and willingness to participate. Some or all of the experiments may be prevented by problems with the clinical state of the patient, such as post-operative facial swelling, temporary aphasia, frequent seizures, post-ictal fatigue and confusion, and more general pain or discomfort. At the Epilepsy Monitoring Unit at Albany Medical Center in Albany, New York, clinical monitoring is implemented around the clock using a 192-channel Nihon-Kohden Neurofax monitoring system. Research recordings are made in collaboration with the Wadsworth Center of the New York State Department of Health in Albany. Signals from the ECoG electrodes are fed simultaneously to the research and the clinical systems via splitter connectors. To ensure that the clinical and research systems do not interfere with each other, the two systems typically use separate grounds. In fact, an epidural strip of electrodes is sometimes implanted to provide a ground for the clinical system. Whether research or clinical recording system, the grounding electrode is chosen to be distant from the predicted epileptic focus and from cortical areas of interest for the research. Our research system consists of eight synchronized 16-channel g.USBamp amplifier/digitizer units (g.tec, Graz, Austria). These were chosen because they are safety-rated and FDA-approved for invasive recordings, they have a very low noise-floor in the high-frequency range in which the signals of interest are found, and they come with an SDK that allows them to be integrated with custom-written research software. In order to capture the high-gamma signal accurately, we acquire signals at 1200Hz sampling rate-considerably higher than that of the typical EEG experiment or that of many clinical monitoring systems. A built-in low-pass filter automatically prevents aliasing of signals higher than the digitizer can capture. The patient's eye gaze is tracked using a monitor with a built-in Tobii T-60 eye-tracking system (Tobii Tech., Stockholm, Sweden). Additional accessories such as joystick, bluetooth Wiimote (Nintendo Co.), data-glove (5(th) Dimension Technologies), keyboard, microphone, headphones, or video camera are connected depending on the requirements of the particular experiment. Data collection, stimulus presentation, synchronization with the different input/output accessories, and real-time analysis and visualization are accomplished using our BCI2000 software. BCI2000 is a freely available general-purpose software system for real-time biosignal data acquisition, processing and feedback. It includes an array of pre-built modules that can be flexibly configured for many different purposes, and that can be extended by researchers' own code in C++, MATLAB or Python. BCI2000 consists of four modules that communicate with each other via a network-capable protocol: a Source module that handles the acquisition of brain signals from one of 19 different hardware systems from different manufacturers; a Signal Processing module that extracts relevant ECoG features and translates them into output signals; an Application module that delivers stimuli and feedback to the subject; and the Operator module that provides a graphical interface to the investigator. A number of different experiments may be conducted with any given patient. The priority of experiments will be determined by the location of the particular patient's electrodes. However, we usually begin our experimentation using the SIGFRIED (SIGnal modeling For Realtime Identification and Event Detection) mapping method, which detects and displays significant task-related activity in real time. The resulting functional map allows us to further tailor subsequent experimental protocols and may also prove as a useful starting point for traditional mapping by electrocortical stimulation (ECS). Although ECS mapping remains the gold standard for predicting the clinical outcome of resection, the process of ECS mapping is time consuming and also has other problems, such as after-discharges or seizures. Thus, a passive functional mapping technique may prove valuable in providing an initial estimate of the locus of eloquent cortex, which may then be confirmed and refined by ECS. The results from our passive SIGFRIED mapping technique have been shown to exhibit substantial concurrence with the results derived using ECS mapping. The protocol described in this paper establishes a general methodology for gathering human ECoG data, before proceeding to illustrate how experiments can be initiated using the BCI2000 software platform. Finally, as a specific example, we describe how to perform passive functional mapping using the BCI2000-based SIGFRIED system.

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The objective of this analysis is to review the effectiveness, safety, and cost-effectiveness of phakic intraocular lenses (pIOLs) for the treatment of myopia, hyperopia, and astigmatism. CONDITION AND TARGET POPULATION REFRACTIVE ERRORS: Refractive errors occur when the eye cannot focus light properly. In myopia (near- or short-sightedness), distant objects appear blurry because the axis of the eye is too long or the cornea is too steep, so light becomes focused in front of the retina. Hyperopia (far sightedness) occurs when light is focused behind the retina causing nearby objects to appear blurry. In astigmatism, blurred or distorted vision occurs when light is focused at two points rather than one due to an irregularly shaped cornea or lens. Refractive errors are common worldwide, but high refractive errors are less common. In the United States, the prevalence of high myopia (≤ -5 D) in people aged 20 to 39, 40 to 59, and 60 years and older is 7.4% (95% confidence interval [CI], 6.5% - 8.3%), 7.8% (95% CI, 6.4% - 8.6%), and 3.1% (95% CI, 2.2% - 3.9%), respectively. The prevalence of high hyperopia (≥ 3 D) is 1.0% (95% CI, .6% - 1.4%), 2.4% (95% CI, 1.7% - 3.0%), and 10.0% (95% CI, 9.1% - 10.9%) for the same age groupings. Finally, the prevalence of astigmatism (≥ 1 D cylinder) is 23.1% (95% CI, 21.6% - 24.5%), 27.6% (95% CI, 25.8% - 29.3%) and 50.1% (48.2% - 52.0%). LOW VISION: According to the Ontario Schedule of Benefits, low visual acuity is defined by a best spectacle corrected visual acuity (BSCVA) of 20/50 (6/15) or less in the better eye and not amenable to further medical and/or surgical treatment. Similarly, the Ontario Assistive Devices Program defines low vision as BSCVA in the better eye in the range of 20/70 or less that cannot be corrected medically, surgically, or with ordinary eyeglasses or contact lenses. Estimates of the prevalence of low vision vary. Using the criteria of BSCVA ranging from 20/70 to 20/160, one study estimated that 35.6 per 10,000 people in Canada have low vision. The 2001 Participation and Activity Limitation Survey (PALS) found that 594,350 (2.5%) Canadians had "difficulty seeing ordinary newsprint or clearly seeing the face of someone from 4 m," and the Canadian National Institute for the Blind (CNIB) registry classified 105,000 (.35%) Canadians as visually disabled. PHAKIC INTRAOCULAR LENSES (PIOL): A phakic intraocular lens (pIOL) is a supplementary lens that is inserted into the anterior or posterior chamber of the eye to correct refractive errors (myopia, hyperopia, and astigmatism). Unlike in cataract surgery, the eye's natural crystalline lens is not removed when the pIOL is inserted, so the eye retains its accommodative ability. In Canada and the United States, iris-fixated (anterior chamber lenses that are anchored to the iris with a claw) and posterior chamber lenses are the only types of pIOLs that are licensed by Health Canada and the Food and Drug Administration, respectively. EVIDENCE-BASED ANALYSIS METHOD: RESEARCH QUESTIONS #ENTITYSTARTX00026; What are the effectiveness, cost-effectiveness, and safety of pIOLs for the treatment of myopia, hyperopia, and astigmatism?Do certain subgroups (e.g. high myopia and low vision) benefit more from pIOLs?How do pIOLs compare with alternative surgical treatment options (LASIK, PRK, and CLE)?Using appropriate keywords, a literature search was conducted up to January 2009. Systematic reviews, meta-analyses, randomized controlled trials, and observational studies with more than 20 eyes receiving pIOLs were eligible for inclusion. The primary outcomes of interest were uncorrected visual acuity (UCVA), predictability of manifest refraction spherical equivalent (MRSE), and adverse events. The GRADE approach was used to systematically and explicitly evaluate the quality of evidence. The search identified 1,131 citations published between January 1, 2003, and January 16, 2009. Including a health technology assessment (HTA) identified in the bibliography review, 30 studies met the inclusion criteria: two HTAs; one systematic review; 20 pre-post observational studies; and seven comparative studies (five pIOL vs. LASIK, one pIOL vs. PRK, and one pIOL vs. CLE). Both HTAs concluded that there was good evidence of the short-term efficacy and safety of pIOLs, however, their conclusions regarding long-term safety differed. The 2006 HTA found convincing evidence of long-term safety, while the 2009 HTA found no long-term evidence about the risks of complications including cataract development, corneal damage, and retinal detachment. The systematic review of adverse events found that cataract development (incidence rate of 9.6% of eyes) is a substantial risk following posterior chamber pIOL implantation, while chronic endothelial cell loss is a safety concern after iris-fixated pIOL implantation. Adverse event rates varied by lens type, but they were more common in eyes that received posterior chamber pIOLs. The evidence of pIOL effectiveness is based on pre-post case series. These studies reported a variety of outcomes and different follow-up time points. It was difficult to combine the data into meaningful summary measures as many time points are based on a single study with a very small sample size. Overall, the efficacy evidence is low to very low quality based on the GRADE Working Group Criteria. For all refractive errors (low to high), most eyes experienced a substantial increase in uncorrected visual acuity (UCVA) with more than 75% of eyes achieving UCVA of 20/40 or better at all postoperative time points. The proportion of eyes that achieved postoperative UCVA 20/20 or better varied substantially according type of lens used and the type of refractive error being corrected, ranging from about 30% of eyes that received iris-fixated lenses for myopia to more than 78% of eyes that received posterior chamber toric lenses for myopic astigmatism. Predictability of manifest refraction spherical equivalent (MRSE) within ± 2.0 D was very high (≥ 90%) for all types of lenses and refractive error. At most time points, more than 50% of eyes achieved a MRSE within ± 0.5 D of emmetropia and at least 85% within ± 1.0 D. Predictability was lower for eyes with more severe preoperative refractive errors. The mean postoperative MRSE was less than 1.0 D in all but two studies. Safety, defined as a loss of two or more Snellen lines of best spectacle corrected visual acuity (BSCVA), was high for all refractive errors and lens types. Losses of two or more lines of BSCVA were uncommon, occurring in fewer than 2% of eyes that had received posterior chamber pIOLs for myopia, and less than 1% of eyes that received iris-fixated lens implantation for myopia. Most eyes did not experience a clinically significant change in BSCVA (i.e. loss of one line, no change, or gain of one line), but 10% to 20% of eyes gained two or more lines of BSCVA. The pIOL outcomes for UCVA, predictability, BSCVA, and adverse events were compared with FDA targets and safety values for refractive surgery and found to meet or exceed these targets at most follow-up time points. The results were then stratified to examine the efficacy of pIOLs for high refractive errors. There was limited data for many outcomes and time points, but overall the results were similar to those for all levels of refractive error severity. The studies that compared pIOLs with LASIK, PRK, and CLE for patients with moderate to high myopia and myopic astigmatism showed that pIOLs performed better than these alternative surgical options for the outcomes of: UCVA,predictability and stability of MRSE,postoperative MRSE,safety (measured as clinically significant loss of BSCVA), andgains in BSCVA.Correction of refractive cylinder (astigmatism) was the only outcome that favoured refractive surgery over pIOLs. This was observed for both toric and non-toric pIOLs (toric pIOLs correct for astigmatism, non-toric pIOLs do not). Common adverse events in the LASIK groups were diffuse lamellar keratitis and striae in the corneal flap. In the pIOL groups, lens repositioning and lens opacities (both asymptomatic and visually significant cataracts) were the most commonly observed adverse events. These studies were determined to be of low to very low evidence quality based on the GRADE Working Group Criteria. Eye, myopia, hyperopia, astigmatism, phakic intraocular lens, LASIK, PRK, uncorrected visual acuity, best corrected visual acuity, refractive errors, clear lens extraction.

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The purpose of this evidence-based analysis is to examine the safety and efficacy of airway clearance devices (ACDs) for cystic fibrosis and attempt to differentiate between devices, where possible, on grounds of clinical efficacy, quality of life, safety and/or patient preference. Cystic fibrosis (CF) is a common, inherited, life-limiting disease that affects multiple systems of the human body. Respiratory dysfunction is the primary complication and leading cause of death due to CF. CF causes abnormal mucus secretion in the airways, leading to airway obstruction and mucus plugging, which in turn can lead to bacterial infection and further mucous production. Over time, this almost cyclical process contributes to severe airway damage and loss of respiratory function. Removal of airway secretions, termed airway clearance, is thus an integral component of the management of CF. A variety of methods are available for airway clearance, some requiring mechanical devices, others physical manipulation of the body (e.g. physiotherapy). Conventional chest physiotherapy (CCPT), through the assistance of a caregiver, is the current standard of care for achieving airway clearance, particularly in young patients up to the ages of six or seven. CF patients are, however, living much longer now than in decades past. The median age of survival in Canada has risen to 37.0 years for the period of 1998-2002 (5-year window), up from 22.8 years for the 5-year window ending in 1977. The prevalence has also risen accordingly, last recorded as 3,453 in Canada in 2002, up from 1,630 in 1977. With individuals living longer, there is a greater need for independent methods of airway clearance. AIRWAY CLEARANCE DEVICES: THERE ARE AT LEAST THREE CLASSES OF AIRWAY CLEARANCE DEVICES: positive expiratory pressure devices (PEP), airway oscillating devices (AOD; either handheld or stationary) and high frequency chest compression (HFCC)/mechanical percussion (MP) devices. Within these classes are numerous different brands of devices from various manufacturers, each with subtle iterations. At least 10 devices are licensed by Health Canada (ranging from Class 1 to Class 3 devices). EVIDENCE-BASED ANALYSIS OF EFFECTIVENESS: Does long-term use of ACDs improve outcomes of interest in comparison to CCPT in patients with CF?Does long-term use of one class of ACD improve outcomes of interest in comparison to another class of ACD in CF patients? A comprehensive literature search was performed on March 7, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing &amp; Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1950 to March 7, 2009. All randomized controlled trials including those of parallel and crossover design,Systematic reviews and/or meta-analyses. Randomized controlled trials (RCTs), systematic reviews and meta-analyses Abstracts were generally excluded because their methods could not be examined; however, abstract data was included in several Cochrane meta-analyses presented in this paper;Studies of less than seven days duration (including single treatment studies);Studies that did not report primary outcomes;Studies in which less than 10 patients completed the study. Primary outcomes under review were percent-predicted forced expiratory volume (FEV-1), forced vital capacity (FVC), and forced expiratory flow between 25%-75% (FEF25-75). Secondary outcomes included number of hospitalizations, adherence, patient preference, quality of life and adverse events. All outcomes were decided a priori. Literature searching and back-searching identified 13 RCTs meeting the inclusion criteria, along with three Cochrane systematic reviews. The Cochrane reviews were identified in preliminary searching and used as the basis for formulating this review. Results were subgrouped by comparison and according to the available literature. For example, results from Cochrane meta-analyses included abstract data and therefore, additional meta-analyses were also performed on trials reported as full publications only (MAS generally excludes abstracted data when full publications are available as the methodological quality of trials reported in abstract cannot be properly assessed). Executive Summary Table 1 summarizes the results across all comparisons and subgroupings for primary outcomes of pulmonary function. Only two comparisons yielded evidence of moderate or high quality according to GRADE criteria-the comparisons of CCPT vs. PEP and handheld AOD vs. PEP-but only the comparison of CCPT vs. PEP noted a significant difference between treatment groups. In comparison to CCPT, there was a significant difference in favour of PEP for % predicted FEV-1 and FVC according to one long-term, parallel RCT. This trial was accepted as the best available evidence for the comparison. The body of evidence for the remaining comparisons was low to very low, according to GRADE criteria, being downgraded most often because of poor methodological quality and low generalizability. Specifically, trials were likely not adequately powered (low sample sizes), did not conduct intention-to-treat analyses, were conducted primarily in children and young adolescents, and outdated (conducted more than 10 years ago). Secondary outcomes were poorly or inconsistently reported, and were generally not of value to decision-making. Of note, there were a significantly higher number of hospitalizations among participants undergoing AOD therapy in comparison to PEP therapy. ES Table 1:Summarization of results for primary outcomes by comparison and subgroupingsOutcome or SubgroupNo. of StudiesEstimate of Effectiveness (95% CI)P-valueHeterogeneity (I(2))GRADECCPT vs. PEP     Cochrane          FEV-1          FVC          FEF(25-75%)6640.08 (-1.45 to 1.62)0.38 (-1.56 to 2.23)-0.44 (-3.38 to 2.50)0.910.700.7746%63%36 N/A      Full publications only          FEV-1          FVC          FEF(25-75%)332-0.50 (-3.93 to 2.92)-0.86 (-4.66 to 2.95)-0.12 (-6.22 to 5.98)0.770.660.9777%74%0%  N/A     Long-term, parallel     RCTs only          FEV-1          FVC          FEF(25-75%)111-8.25 (-15.77 to -0.75)-8.74 (-16.03 to -1.45)-3.56 (-13.30 to 6.18)0.030.020.47N/AN/AN/A 1 TrialMODERATECCPT vs. HFCC/MP     Cochrane          FEV-1          FVC     FEF(25-75%)332-1.76 (-4.67 to 1.16)-1.42 (-5.17 to 2.33)0.49 (-2.54 to 3.52)0.240.460.750%70%0%  N/A     Full publications only          FEV-1          FVC          FEF(25-75%)332-2.10 (-5.49 to 1.29)-3.86 (-8.05 to 0.33)0.49 (-2.54 to 3.52)0.230.070.750%0%0% 3 TrialsLOWCCPT vs. AOD     2 of 3 RCTs/Cochrane          FEV-1          FVC          FEF(25-75%)2220.80 (-5.79 to 7.39)6.06 (-2.42 to 14.55)1.26 (-7.56 to 10.09)0.810.160.780%12%0% 3 TrialsLOWAOD vs. PEP     Long-term, parallel     RCTs only/Cochrane          FEV-1          FVC          FEF(25-75%)2220.29 (-4.17 to 4.75)-0.55 (-4.60 to 3.50)0.10 (-4.86 to 5.06)0.900.790.9773%77%0% 2 TrialsMODERATEAOD vs. HFCC/MP     Long-term, parallel     RCTs only/Cochrane          FEV-1          FVC          FEF(25-75%)111-1.6 (-3.44 to 0.24)-1.80 (-4.32 to 0.72)-1.40 (-3.07 to 0.27)0.090.080.16N/AN/AN/A 1 TrialVERY LOWBolding indicates significant differencePositive summary statistics favour the former intervention AOD, airway oscillating device; CCPT, conventional chest physiotherapy; CI, confidence interval; HFCC, high frequency chest compression; MP, mechanical percussion; N/A: not applicable; PEP, positive expiratory pressure Devices ranged in cost from around $60 for PEP and handheld AODs to upwards of $18,000 for a HFCC vest device. Although the majority of device costs are paid out-of-pocket by the patients themselves, their parents, or covered by third-party medical insurance, Ontario did provide funding assistance through the Assistive Devices Program (ADP) for postural drainage boards and MP devices. These technologies, however, are either obsolete or their clinical efficacy is not supported by evidence. ADP provided roughly $16,000 in funding for the 2008/09 fiscal year. Using device costs and prevalent and incident cases of CF in Ontario, budget impact projections were generated for Ontario. Prevalence of CF in Ontario for patients from ages 6 to 71 was cited as 1,047 cases in 2002 while incidence was estimated at 46 new cases of CF diagnosed per year in 2002. Budget impact projections indicated that PEP and handheld AODs were highly economically feasible costing around $90,000 for the entire prevalent population and less than $3,000 per year to cover new incident cases. HFCC vest devices were by far the most expensive, costing in excess of $19 million to cover the prevalent population alone. There is currently a lack of sufficiently powered, long-term, parallel randomized controlled trials investigating the use of ACDs in comparison to other airway clearance techniques. While much of the current evidence suggests no significant difference between various ACDs and alternative therapies/technologies, at least according to outcomes of pulmonary function, there is a strong possibility that past trials were not sufficiently powered to identify a difference. Unfortunately, it is unlikely that there will be any future trials comparing ACDs to CCPT as withholding therapy using an ACD may be seen as unethical at present. Conclusions of clinical effectiveness are as follows: Moderate quality evidence suggests that PEP is at least as effective as or more effective than CCPT, according to primary outcomes of pulmonary function. (ABSTRACT TRUNCATED)

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The overall aim of this systematic review is to identify the appropriateness and meaningfulness of maternal-child simulation-based learning for undergraduate or pre-registration nursing students in educational settings to inform curriculum decision-making.1. What are the experiences of nursing or health professional students participating in undergraduate or pre-licensure maternal-child simulation-based learning in educational settings?2. What are the experiences of educators participating in undergraduate or pre-licensure maternal-child simulation-based learning in educational settings?3. What teaching and learning practices in maternal-child simulation-based learning are considered appropriate and meaningful by students and educators? Maternal-child care is one of the pillars of primary health care. Health promotion and illness/ injury prevention begin in the preconception period and continue through pregnancy, birth, the postpartum period and the childrearing years. Thus, lifelong wellness is promoted across the continuum of perinatal and pediatric care which influences family health and early child development. Registered nurses (RNs) are expected to have the knowledge and skills needed to provide evidence-based nursing with childbearing and child-rearing families to promote health and address health inequities in many settings, including inner city, rural, northern, indigenous and global communities. The Canadian Maternity Experiences survey and the Report by the Advisor on Healthy Children and Youth provide information on current shortages of perinatal and child health care providers and stress the importance of the role of nurses as providers of rural and remote care. From a global health perspective, continued concern with both perinatal and child health morbidities and mortalities highlight the importance of maintaining and strengthening the presence of maternal and child health learning opportunities within undergraduate nursing curriculum.Despite this importance, educators in many countries have acknowledged difficulties providing nursing students with maternal-child hospital learning experiencesdue to declining birth rates, women's changing expectations about childbirth (i.e. birth as an intimate experience), increased outpatient and community management of early childhood health conditions, and increased competition for clinical placements. Canadian nurse educators and practice leaders have also identified gaps in recent RN graduates' readiness to provide safe, competent and evidence-based care for childbearing and child-rearing families. Newly graduated RNs working in acute care hospitals and in rural/remote community practice settings report feeling unprepared for providing maternity, neonatal and early childhood care.Recent concerns about the clinical reasoning skills of new graduates and the link to poor patient outcomes (e.g. not recognizing deteriorating patients) have led to calls to reform nursing education. In the Carnegie report, Benner, Sutphen, Leonard and Day identified four essential themes needed in the thinking and approach to nursing education, including: (1) a shift in focus from covering decontextualized knowledge to "teaching for a sense of salience, situated cognition, and identifying action in particular clinical situations"; (2) better integration of classroom and clinical teaching; (3) more emphasis on clinical reasoning; and, (4) an emphasis on identity formation rather than socialization. Brown and Hartrick Doane propose that nurses need to draw on a range of knowledge that enhances the nurse's "sensitivity and ability to be responsive in particular moments of practice". Theoretical or decontextualized knowledge becomes a "pragmatic tool" used to improve nursing practice. Simulation has been identified as a promising pragmatic educational tool for practice learning that can be integrated with theoretical knowledge from nursing and other disciplines.Bland, Topping and Wood conducted a concept analysis and defined simulation in nursing education as:They also proposed that "simulated learning is a dynamic concept that deserves empirical evaluation not merely to determine its effects but to uncover its full potential as a learning strategy".Simulation usually involves student(s) providing nursing care to a simulated patient who might be a manikin or actor based on a standardized scenario. Following the experiential learning opportunity the scenario is debriefed and the clinical situation analyzed with opportunities for reflection on performance. In nursing education, simulation is usually used in a way that complements learning in practice settings. However simulation has also been used: to make up some clinical practice hours, to provide opportunities to practice and assess particular clinical skills, and for remedial learning when students encounter difficulties in practice settings. In addition simulation provides the opportunity to focus on quality and safety competencies (QSEN) that have been identified for nurses. New forms of simulation are being developed with multiple patients so that nursing students can learn to prioritize care needs and delegate care to other team members.Nurse educators have identified several advantages for learners using simulation, including: providing a safe environment to improve nursing competence, allowing learners to become more comfortable with receiving feedback about their clinical performance, providing consistent and comparable experiences for all students, and learning a mix of technical and non-technical skills including communication, teamwork and delegation. Within the Canadian context, students and instructors have reported positive learning experiences with simulation, particularly in understanding complex patient care scenarios, multidisciplinary team scenarios, team-based learning, and reflective debriefing. Furthermore, simulation technology has been proposed as a strategy for developing clinical reasoning skills, enhancing nurses' abilities to build upon previous knowledge and past experiences, and manage new or unfamiliar situations.Simulation has previously been integrated into nursing curricula in a "piecemeal" fashion that lacks an integrative pedagogy or theoretical approach. More recently a number of theoretical and pedagogical frameworks and best practice standards have been published. In April 2014 a preliminary search of literature (in CINAHL, Medline, Academic Search Complete and Web of Science) was conducted with guidance from our library specialist to test the search strategy and ensure that there would be enough qualitative findings to include in the systematic review. A preliminary scan of the abstracts from these searches demonstrated that many experiential case reports with qualitative findings were missed with the use of research limiters (including our search strategy specifically constructed to retrieve qualitative research) so the decision was made to err on the side of caution by searching more broadly and review a larger number of abstracts for inclusion in the study. However, a number of reports with qualitative findings were identified. For example, from a review of the abstracts from a CINAHL search dated April 17, qualitative research papers (including two dissertations), 12 evaluation study reports, six mixed methods studies and nine case reports with qualitative findings were identified. It is timely then to review qualitative studies to better understand the meaningfulness and appropriateness of integrating maternal-child simulation-based learning activities in undergraduate nursing education programs.A search of both the Cochrane Library of Systematic Reviews and the Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports has been conducted. No systematic reviews of qualitative studies of maternal-child simulation-based learning for undergraduate or pre-registration nursing students in educational settings are evident in the literature. Although a systematic review of the meaningfulness and appropriateness of using human patient simulation manikins as a teaching and learning strategy in undergraduate nursing education had been planned and a protocol registered in October 2009, we learned from contacting the lead author that this systematic review was not completed. Currently little is known about how nursing students and/or educators have experienced maternal-child simulation or their understandings of the appropriateness and meaningfulness of particular simulation-based learning practices. Our proposed systematic review therefore fulfills all requirements for the PROSPERO database. For this review we will use the definition of "simulation-based learning experience" adopted by the International Nursing Association for Clinical Simulation and Learning (INACSL):We will include any use of simulation in an educational setting (with pre-registration or pre-licensure or undergraduate nursing or health professional students) with a focus relevant for maternal-child nursing.Maternal-child nursing has been variously defined in literature to include maternity care and pediatric nursing. For the purposes of this review, we will include perinatal, neonatal and pediatric contexts of care that focus on families with children under the age of five. We will exclude studies that focus on school age children, adolescents and/or youth.We have adapted an earlier definition of "appropriateness" as the "best conditions under which simulation can be integrated into undergraduate nursing education". In this review "meaningfulness" refers to the experiences and reflections of undergraduate nursing or health professional students and educators as presented in the studies reviewed.

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Chloral hydrate is widely used as a sedative and a hypnotic in pediatric medicine. It is also a byproduct of water chlorination. Chloral hydrate has been shown to be genotoxic in numerous prokaryotic and eukaryotic assay systems including human lymphocytes in vitro. One of its metabolites, trichloroacetic acid, has demonstrated hepatocarcinogenic activity in mice. Trichloroethylene and perchloroethylene, both of which are metabolized to chloral hydrate, have been shown to be carcinogenic in rats and/or mice. Because of this evidence of carcinogenicity and because of the wide-spread use of chloral hydrate, 16- or 17-day range-finding toxicity studies and separate 16- or 17-day metabolism studies were performed in F344/N rats and B6C3F1 mice in preparation for further long-term rodent studies. In addition, in vitro studies of the metabolism and DNA-binding capacity of chloral hydrate and its metabolites were performed. Genetic toxicity studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. For the range-finding studies, groups of eight male and eight female F344/N Nctr BR rats and B6C3F1/Nctr BR (C57BL/6N x C3H/HeN MTV-) mice were administered 0, 50, 100, 200, 400, or 800 mg chloral hydrate per kg body weight in water by gavage 5 days per week for 17 days (rats) or 16 days (mice) for a total of 12 doses. One male rat receiving 800 mg/kg died after five doses. Two 800 mg/kg female rats died after dosing ended but before study termination. One male mouse in each group except the 400 mg/kg group died before the end of the study. Two 800 mg/kg female mice also died before the end of the study. The final mean body weight of 800 mg/kg male rats and the mean body weight gains of 400 and 800 mg/kg males were significantly less than those of the vehicle controls. The mean body weight gains of all groups of dosed male mice were significantly greater than that of the vehicle control group. The only clinical finding in rats and mice attributed to chloral hydrate treatment was light sedation in the 400 mg/kg groups and heavy sedation in the 800 mg/kg groups; sedation subsided within 30 minutes or 3 hours, respectively. The liver weights of 400 mg/kg male mice and 800 mg/kg male and female mice were significantly greater than those of the vehicle control groups. No chemical-related lesions were observed in rats or mice. Male and female rats and mice were administered a single dose of 50 or 200 mg chloral hydrate per kg body weight in water by gavage, or 12 doses of 50 or 200 mg/kg over 17 days (rats) or 16 days (mice). Plasma concentrations of chloral hydrate and its metabolites were determined 15 minutes, 1, 3, 6, and 24 hours, and 2, 4, 8, and 16 days after receiving 1 or 12 doses. Maximum concentrations of chloral hydrate were observed at the initial sampling point of 15 minutes. By 1 hour, the concentrations had dropped substantially, and by 3 hours, chloral hydrate could not be detected in rats or mice. Trichloroacetic acid was the major metabolite detected in the plasma. In rats, the concentrations rose slowly, with the peaks occurring between 1 and 6 hours after treatment. In mice, the peak concentrations were found 1 hour after dosing. The concentrations then slowly decreased such that by 2 days the metabolite could no longer be detected in rats or mice. Trichloroethanol was assayed both as the free alcohol and its glucuronide. In rats, the maximum concentrations of free trichloroethanol occurred at 15 minutes, while the peak concentrations of trichloroethanol glucuronide were found at 1 hour; by 3 hours, concentrations of both metabolites approached background levels. In mice, the maximum concentrations of both metabolites occurred at 15 minutes, and by 1 to 3 hours concentrations approached background levels. The plasma concentrations of chloral hydrate and its metabolites were dose dependent in rats and mice. In mice, plasma concentrations of trichloroacetic acid were significantly higher after a single dose than after 12 doses. None of the metabolic parameters appears to account for species differences that may exist in hepatocarcinogenicity. The data from the study of metabolism and DNA adduct formation indicated that in vitro metabolism of 200 microM to 5 mM chloral hydrate by male B6C3F1 mouse liver microsomes (control microsomes) generated free radical intermediates that resulted in endogenous lipid peroxidation, forming malondialdehyde, formaldehyde, acetaldehyde, acetone, and propionaldehyde. Similar concentrations of trichloroacetic acid and trichloroethanol, the primary metabolites of chloral hydrate, also generated free radicals and induced lipid peroxidation. Lipid peroxidation induced by trichloroacetic acid nearly equaled that induced by chloral hydrate, while that from trichloroethanol was three- to fourfold less. Metabolism of 200 microM to 5 mM chloral hydrate, trichloroacetic acid, and trichloroethanol by liver microsomes of B6C3F1 mice pretreated with pyrazole (pyrazole-induced microsomes) yielded lipid peroxidation products at concentrations two- to threefold greater than those from liver microsomes of untreated mice. Additionally, chloral hydrate-induced lipid peroxidation catalyzed by control and pyrazole-induced microsomes was reduced significantly by 2,4-dichloro-6-phenylphenoxyethylamine, a general cytochrome P450 inhibitor. Human lymphoblastoid transgenic cells expressing cytochrome P(450)2E1 metabolized 200 to 5,000 micrograms/mL chloral hydrate to reactants inducing mutations, whereas the parental cell line was inactive. The malondialdehyde-modified DNA adduct, 3-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2 alpha]purin-10(3H)-one (MDA-MG-1), formed from the metabolism of 1 mM chloral hydrate, trichloroacetic acid, and trichloroethanol by control B6C3F1 mouse liver microsomes, mouse pyrazole-induced microsomes, male F344/N rat liver microsomes, and human liver microsomes in the presence and absence of calf thymus DNA was also determined. When incubated in the absence of calf thymus DNA, the amount of malondialdehyde formed from metabolism by pyrazole-induced mouse microsomes was twice that from rat or human liver microsomes. Amounts of chloral hydrate-induced and trichloroacetic acid-induced lipid peroxidation products formed from metabolism by rat and human liver microsomes were similar, and these quantities were about twice those formed from the metabolism of trichloroethanol. The quantity of MDA-MG-1 formed from the metabolism of chloral hydrate, trichloroacetic acid, and trichloroethanol by mouse, rat, and human liver microsomes exhibited a linear correlation with the quantity of malondialdehyde formed under incubation conditions in the absence of calf thymus DNA. Chloral hydrate was shown to be mutagenic in vitro and in vivo. At doses from 1,000 to 10,000 micrograms/plate, it induced mutations in S. typhimurium strain TA100, with and without S9 activation; an equivocal response was obtained in S. typhimurium strain TA98 in the absence of S9, and no mutagenicity was detected with strain TA1535 or TA1537. Chloral hydrate at doses from 1,700 to 5,000 micrograms/mL induced sister chromatid exchanges; at doses from 1,000 to 3,000 micrograms/mL, chromosomal aberrations were induced in cultured Chinese hamster ovary cells, with and without S9. Results of a sex-linked recessive lethal test in D. melanogaster were unclear; administration of chloral hydrate by feeding produced an inconclusive increase in recessive lethal mutations, results of the injection experiment were negative. An in vivo mouse bone marrow micronucleus test with chloral hydrate at doses from 125 to 500 mg/kg gave a positive dose trend. In summary, due to the absence of chloral hydrate-induced histopathologic lesions in rats and mice, no-observed-adverse-effect levels (NOAELs) were based on body weights of rats and liver weights of mice. The NOAELs for rats and mice were 200 mg/kg. Chloral hydrate was rapidly metabolized by rats and mice, with trichloroacetic acid occurring as the major metabolite. Peak concentrations of trichloroacetic acid occurred more quickly in mice. Plasma concentrations of chloral hydrate were dose dependent, but metabolic rates were unaffected by dose or sex. Chloral hydrate was mutagenic in vitro and in vivo. Metabolism of chloral hydrate and its metabolites produced free radicals that resulted in lipid peroxidation in liver microsomes of mice, rats, and humans. Induction of cytochrome P(450)2E1 by pyrazole increased the concentrations of lipid peroxidation products; inhibition of cytochrome P(450)2E1 by 2,4-dinitrophenylhydrazine reduced these concentrations. Metabolism of chloral hydrate and its metabolites by mouse, rat, and human liver microsomes formed malondialdehyde, and in the presence of calf thymus DNA formed the DNA adduct MDA-MG-1.

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Malonaldehyde occurs as a natural metabolic byproduct of prostaglandin biosynthesis and as an end product of polyunsaturated lipid peroxidation. Toxicology and carcinogenesis studies of malonaldehyde were conducted by administering the chemical as malonaldehyde, sodium salt, a stabilized form of malonaldehyde, in distilled water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and two years. The study material was 63%-79% malonaldehyde, sodium salt, 22%-38% water, and 1% or less other impurities. The water content was taken into account when the dose mixtures were prepared. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, groups of five rats and five mice of each sex were dosed with 250, 500, 750, 1,000, or 1,500 mg/kg malonaldehyde, sodium salt. Controls were untreated. Rats and mice that received 1,500 mg/kg malonaldehyde, sodium salt, did not survive to the end of the 14-day studies. No compound-related gross lesions were seen in the dosed animals. In the 13-week studies, groups of 10 males and 10 females of each species were administered 0, 30, 60, 125, 250, or 500 mg/kg malonaldehyde, sodium salt. Nine of 10 male rats, 10/10 female rats, 3/10 male mice, and 1/10 female mice that received 500 mg/kg malonaldehyde, sodium salt, died before the end of the studies. Body weights were reduced by more than 15% in rats receiving 250 or 500 mg/kg and in mice receiving 500 mg/kg. Compound-related nonneoplastic lesions were present in the stomach, testis, and kidney of rats and in the pancreas, stomach, and testis of mice. Focal and multifocal erosive lesions were observed in the gastric mucosa of the glandular stomach in the 500 mg/kg groups of male and female rats. Dilatation of the gastric glands of the stomach mucosa occurred in the 500 mg/kg male mice. Lesions of the kidney included membranous glomerular nephropathy in the 250 and 500 mg/kg male rats and the 125, 250, and 500 mg/kg female rats and mineralization in the 250 and 500 mg/kg male rats and the 60, 125, 250, and 500 mg/kg female rats. Degeneration of the testicular germinal epithelium was observed in male rats and male mice receiving 250 and 500 mg/kg. Atrophy of the exocrine pancreas was seen in the 125, 250, and 500 mg/kg male and the 250 and 500 mg/kg female mice. Based on these results, 2-year studies of malonaldehyde, sodium salt, were conducted by exposing groups of 50F344/N rats of each sex at doses of 0, 50, or 100 mg/kg, administered 5 days per week for 103 weeks. Doses of 0, 60, or 120 mg/kg were administered in the same schedule to groups of 50 male and 50 female B6C3F1 mice. Body Weight and Survival in the Two-Year Studies: Final mean body weights at the end of the study were reduced by 26% and 36% for high dose male and female rats compared with those for the vehicle controls. The final mean body weight of high dose male mice was 92% that of the vehicle controls. The final mean body weights of low dose male mice, low dose rats, and all groups of female mice were comparable to those of the vehicle controls. The survival of high dose male and female rats was significantly lower than that of the vehicle controls, with survival declining rapidly after week 76 for high dose males and after week 59 for high dose females (survival-- male: vehicle control, 37/50; low dose, 33/50; high dose, 15/50; female: 37/50; 37/50; 14/50). Survival of all groups of male mice was low (male: 24/50; 20/50; 14/50; female: 41/50; 38/50; 30/50). Survival of the high dose groups of male mice was significantly lower than that of the vehicle controls; no other significant differences in survival were observed between any groups of mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The incidences of a variety of nonneoplastic lesions were increased in dosed rats of each sex, primarily in the high dose male and female rat groups. These lesions were ulceration and inflammation of the glandular stomach; epithelial hyperplasia of the forestomach; inflammation of the cornea, retinal atrophy, and cataracts of the crysttion of the cornea, retinal atrophy, and cataracts of the crystalline lens; focal lipoid degeneration of the adrenal cortex; and diffuse pancreatic atrophy. Cytoplasmic vacuolization and cystic degeneration in the liver occurred at increased incidences in the high dose rat groups; in addition, the incidences of bile duct hyperplasia and bile duct fibrosis were increased in the high dose female and male rat groups, respectively. Bone marrow hematopoietic hyperplasia, hematopoiesis of the spleen, and ultimobranchial cysts of thyroid gland occurred with increased incidences in high dose female rats. The incidences of thyroid gland follicular cell adenomas or carcinomas (combined) were significantly increased in high dose male (vehicle control, 4/50; low dose, 8/49; high dose, 13/50) and female (2/50; 1/50; 7/50) rats. Follicular cell hyperplasia of the thyroid gland also occurred at an increased incidence in high dose female rats (10/50; 10/50;26/50) but not in male rats (9/50; 7/49; 7/50). The incidence of pancreatic islet cell adenomas was increased in low dose male rats (0/49; 9/50; 1/49). Adenomas and adenomas or carcinomas (combined) of the anterior pituitary gland occurred at significantly lower incidences in high dose rats than those in vehicle controls (combined incidence--male: 20/47; 14/49; 8/49; female: 18/49; 10/49; 2/48). Nonneoplastic lesions that occurred at increased incidences in dosed mice included atrophy of the pancreatic acinus and dilatation of the uterus. Depigmentation of hair shafts and change of coat color from agouti to gray were observed in high dose mice. No compound-related neoplasms were observed in dosed mice. Genetic Toxicology: Malonaldehyde, sodium salt, was not mutagenic in the Salmonella typhimurium/microsome assay when tested at doses of up to 10,000 ug/plate in a preincubational protocol using the excision-repair deficient strains TA98, TA100, TA1535, and TA1537 with or without S9 metabolic activation. The chemical induced forward mutations in mouse L5178Y lymphoma cells in the absence of S9; it was not tested with S9. Malonaldehyde, sodium salt was not mutagenic in the Drosophila melanogaster sex-linked recessive lethal mutagenicity test in which adult male flies were exposed either by feeding or by abdominal injection. In cytogenetic assays with cultured Chinese hamster ovary (CHO) cells, malonaldehyde, sodium salt, produced a dose-related increase in the frequency of sister-chromatid exchanges both in the presence and absence of rat liver S9; no increase in the number of chromosomal aberrations was observed in CHO cells in the absence or presence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of malonaldehyde, sodium salt, have been audited. The audit found no special circumstances or significant deficiencies in the conduct or documentation of the studies which needed to be taken into consideration for reporting purposes. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats administered malonaldehyde, sodium salt, as shown by the increased incidences of follicular cell adenomas or carcinomas (combined) of the thyroid gland. Pancreatic islet cell adenomas were also observed at an increased incidence in low dose male rats. There was no evidence of carcinogenic activity for B6C3F1 mice administered 60 or 120 mg/kg malonaldehyde, sodium salt, in distilled water by gavage 5 days per week for 2 years. Chemically related increased incidences of nonneoplastic lesions included ulcers and inflammation of the glandular stomach and epithelial hyperplasia of the forestomach; corneal inflammation, retinal atrophy, and cataracts of the crystalline lens; and cystic degeneration of the liver, bile duct fibrosis, and bile duct hyperplasia in rats. Most of these nonneoplastic lesions as well as the thyroid gland follicular cell neoplasms occurred primarily in the high dose rat groups, in which survival and final body weights were reduced in high dose male and female rats. Increased incidences of atrophy of the pancreatic acinus and pigmentation loss in hair shafts were seen in high dose mice. Synonyms: malonaldehyde, enol, sodium salt; propanedial, sodium; 3-hydroxy-2-propenal, sodium salt; sodium b-oxyacrolein

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Constriction of the aorta just above the origin of both main renal arteries invariably resulted in elevation of the carotid systolic and carotid mean pressure. The hypertension was not immediate, but developed in about the same time as after constriction of the main renal arteries (3). Constriction of the aorta just below the origin of both main renal arteries had no significant effect on the carotid systolic or carotid mean pressure. Since these results were first reported (1), Rytand (88, 89) has shown by an indirect method, namely, the demonstration of the development of cardiac hypertrophy, that hypertension in the upper part of the body can be produced in the rat by constriction of the aorta just above the origin of both main renal arteries. The immediate effect of constriction of the aorta either below or above the main renal arteries is a fall of blood pressure (femoral mean pressure) below the site of the clamp, the extent of the fall being directly dependent upon the degree of constriction of the aorta. Of particular interest is the eventual elevation of the femoral mean pressure above the normal in some animals with the aorta constricted or even occluded above the origin of the main renal arteries. This was most pronounced and persistent in those animals in which, in addition, the aorta below the origin of the renal arteries, and, in some animals, the main renal arteries, also were constricted. The most important factors which determined this elevation of blood pressure in the lower part of the body were probably increased flow of blood into the vascular bed below the clamp and peripheral vasoconstriction of renal and humoral origin, as in the case of the hypertension produced by constriction of the main renal arteries alone (2-86). Although elevation of the carotid systolic or carotid mean pressure occurred invariably within 24 to 48 hours after the constriction of the aorta above the site of origin of both main renal arteries, yet there was a tendency, after a variable period, for the elevated blood pressure to become lower or even to drop to the original level. Increased constriction, and finally occlusion of the aorta, above the origin of the main renal arteries, and even constriction or occlusion of the aorta below the renal arteries, in addition, failed to induce hypertension that persisted for a long time at a high level. In order to produce this effect, it was necessary to constrict the main renal arteries as well. The possible explanation of the failure of the hypertension to persist for a long time after constriction of the aorta alone, is that the initial ischemia of the kidneys disappeared due to the improvement of the blood flow through the kidneys as a result of (a) the increase of the natural accessory circulation to the kidneys; (b) the increased blood pressure above the site of the clamp and consequent increased flow of blood into the part of the aorta below the clamp; (c) increased pressure below the site of the clamp due, in great part, to peripheral vasoconstriction, and in part to the increased inflow of blood into the lower part of the body through the aorta and collateral channels. For the dog, this method is not necessary for the production of persistent hypertension. Constriction of the main renal arteries is easily performed and is effective for the production of generalized hypertension (2-11). However, constriction of the aorta in addition to constriction of the renal arteries results in greatly elevated persistent hypertension. Constriction of the aorta alone above the origin of the main renal arteries would be useful in the dog only for the production of relatively short periods of hypertension in the upper part of the body. For small animals it may be a more effective and useful method. In the dog, the only technical difficulty encountered was the erosion of the wall of the aorta by the clamp. This may not occur in small animals. In previous studies (2-11) that have dealt with the constriction of the main renal arteries, this accident rarely occurred. When the constriction of the aorta above the origin of the main renal arteries was of moderate degree, or was gradually made very great, the resultant hypertension was not accompanied by impairment of renal excretory function, as determined by urea clearance or by the quantity of urea, creatinine or non-protein nitrogen in the blood, the benign phase of hypertension (3). When the constriction of the aorta was suddenly made very great, impairment of the renal excretory function usually followed, and the animal developed fatal convulsive uremia and characteristic vascular lesions, the malignant phase of hypertension (9). These facts, are all indicative of the renal origin of the hypertension which results from the constriction of the aorta just above the origin of both main renal arteries. Hypertension did not persist for a sufficiently long time to permit any conclusive comparison between the effect of the high and low pressures on the structure of the vascular system, above and below the site of the clamp, respectively. During the period of survival of these animals, no significant differences were observed between the appearance of the vascular system of the upper part of the body and that of the lower part of the body, and significant cardiac hypertrophy did not develop. In the aorta and large arteries, intimal arteriosclerosis was not observed. In the aorta of one old animal several small plaques of calcification were found in the media, but these were present in the portion of the aorta below, as well as above the clamp, and they were no larger or more abundant than were observed in some old dogs with normal blood pressure. Dogs 3-50 and 3-83, that are still alive, with very high blood pressure above the site of the aortic clamps, and relatively low pressure (though greater than normal) below the site of the aortic clamps, will be valuable for the determination of possible differences between the effects of the two levels of blood pressure in the large and small blood vessels. In these dogs also, it will be possible to determine the effect of the persistently high blood pressure on the myocardium. The possible application of the results of this study to the problem of the pathogenesis of human eclampsia is mentioned here for consideration. Since this condition occurs in pregnancy only at a time when the uterus is greatly enlarged, it is at least possible that the mass may press on the aorta or both main renal arteries sufficiently to produce renal ischemia. The suddenness with which the uremic convulsive phase of eclampsia develops is in keeping with this idea. In the dog, an aggravating effect of pregnancy on an already established hypertension has not been noted. As a matter of fact, most of the hypertensive dogs that have become pregnant, have shown a slight or moderate fall, rather than an increased rise of pressure. Since the dog stands with the body in a horizontal position, and does not lie on its back, pressure of the pregnant uterus on the aorta and blood vessels is less than in human beings who stand erect and frequently lie on their backs. The soundness of this suggestion could be tested by placing pregnant women, in the early stage of eclampsia, in a position which could relieve possible pressure on the aorta and main renal arteries. A possible explanation of the fall of pressure in the pregnant hypertensive dogs is the compensatory effect of the normal kidneys of the pups, as in the case of an animal with one main renal artery constricted and the other kidney normal. As has been shown (3, 31, 72), the presence of one normal kidney in an animal hypertensive due to constriction of the other main renal artery, results, after a variable period, in a return of the blood pressure to normal. How the normal kidney acts to produce this effect is not known.

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The main objectives for this evidence-based analysis were to determine the safety and effectiveness of photochemical corneal collagen cross-linking with riboflavin (vitamin B(2)) and ultraviolet-A radiation, referred to as CXL, for the management of corneal thinning disease conditions. The comparative safety and effectiveness of corneal cross-linking with other minimally invasive treatments such as intrastromal corneal rings was also reviewed. The Medical Advisory Secretariat (MAS) evidence-based analysis was performed to support public financing decisions. SUBJECT OF THE EVIDENCE-BASED ANALYSIS: The primary treatment objective for corneal cross-linking is to increase the strength of the corneal stroma, thereby stabilizing the underlying disease process. At the present time, it is the only procedure that treats the underlying disease condition. The proposed advantages for corneal cross-linking are that the procedure is minimally invasive, safe and effective, and it can potentially delay or defer the need for a corneal transplant. In addition, corneal cross-linking does not adversely affect subsequent surgical approaches, if they are necessary, or interfere with corneal transplants. The evidence for these claims for corneal cross-linking in the management of corneal thinning disorders such as keratoconus will be the focus of this review. The specific research questions for the evidence review were as follows: TECHNICAL: How technically demanding is corneal cross-linking and what are the operative risks? What is known about the broader safety profile of corneal cross-linking?Effectiveness - Corneal Surface Topographic Affects:What are the corneal surface remodeling effects of corneal cross-linking?Do these changes interfere with subsequent interventions, particularly corneal transplant known as penetrating keratoplasty (PKP)?Effectiveness -Visual Acuity:What impacts does the remodeling have on visual acuity?Are these impacts predictable, stable, adjustable and durable?Effectiveness - Refractive Outcomes: What impact does remodeling have on refractive outcomes?Effectiveness - Visual Quality (Symptoms): What impact does corneal cross-linking have on vision quality such as contrast vision, and decreased visual symptoms (halos, fluctuating vision)?Effectiveness - Contact lens tolerance: To what extent does contact lens intolerance improve after corneal cross-linking?Vision-Related QOL: What is the impact of corneal cross-linking on functional visual rehabilitation and quality of life?PATIENT SATISFACTION: Are patients satisfied with their vision following the procedure?Disease Process:What impact does corneal cross-linking have on the underling corneal thinning disease process?Does corneal cross-linking delay or defer the need for a corneal transplant?What is the comparative safety and effectiveness of corneal cross-linking compared with other minimally invasive treatments for corneal ectasia such as intrastromal corneal rings? TARGET POPULATION AND CONDITION Corneal ectasia (thinning) disorders represent a range of disorders involving either primary disease conditions, such as keratoconus (KC) and pellucid marginal corneal degeneration, or secondary iatrogenic conditions, such as corneal thinning occurring after laser in situ keratomileusis (LASIK) refractive surgery. Corneal thinning is a disease that occurs when the normally round dome-shaped cornea progressively thins causing a cone-like bulge or forward protrusion in response to the normal pressure of the eye. The thinning occurs primarily in the stroma layers and is believed to be a breakdown in the collagen process. This bulging can lead to irregular astigmatism or shape of the cornea. Because the anterior part of the cornea is responsible for most of the focusing of the light on the retina, this can then result in loss of visual acuity. The reduced visual acuity can make even simple daily tasks, such as driving, watching television or reading, difficult to perform. Keratoconus is the most common form of corneal thinning disorder and involves a noninflammatory chronic disease process of progressive corneal thinning. Although the specific cause for the biomechanical alterations in the corneal stroma is unknown, there is a growing body of evidence suggesting that genetic factors may play an important role. Keratoconus is a rare disease (&lt; 0.05% of the population) and is unique among chronic eye diseases because it has an early onset, with a median age of 25 years. Disease management for this condition follows a step-wise approach depending on disease severity. Contact lenses are the primary treatment of choice when there is irregular astigmatism associated with the disease. Patients are referred for corneal transplants as a last option when they can no longer tolerate contact lenses or when lenses no longer provide adequate vision. Keratoconus is one of the leading indications for corneal transplants and has been so for the last 3 decades. Despite the high success rate of corneal transplants (up to 20 years) there are reasons to defer it as long as possible. Patients with keratoconus are generally young and a longer-term graft survival of at least 30 or 40 years may be necessary. The surgery itself involves lengthy time off work and postsurgery, while potential complications include long-term steroid use, secondary cataracts, and glaucoma. After a corneal transplant, keratoconus may recur resulting in a need for subsequent interventions. Residual refractive errors and astigmatism can remain challenges after transplantation, and high refractive surgery and regraft rates in KC patients have been reported. Visual rehabilitation or recovery of visual acuity after transplant may be slow and/or unsatisfactory to patients. Corneal cross-linking involves the use of riboflavin (vitamin B(2)) and ultraviolet-A (UVA) radiation. A UVA irradiation device known as the CXL® device (license number 77989) by ACCUTECH Medical Technologies Inc. has been licensed by Health Canada as a Class II device since September 19, 2008. An illumination device that emits homogeneous UVA, in combination with any generic form of riboflavin, is licensed by Health Canada for the indication to slow or stop the progression of corneal thinning caused by progressive keratectasia, iatrogenic keratectasia after laser-assisted in situ keratomileusis (LASIK) and pellucid marginal degeneration. The same device is named the UV-X® device by IROCMedical, with approvals in Argentina, the European Union and Australia. UVA devices all use light emitting diodes to generate UVA at a wavelength of 360-380 microns but vary in the number of diodes (5 to 25), focusing systems, working distance, beam diameter, beam uniformity and extent to which the operator can vary the parameters. In Ontario, CXL is currently offered at over 15 private eye clinics by refractive surgeons and ophthalmologists. The treatment is an outpatient procedure generally performed with topical anesthesia. The treatment consists of several well defined procedures. The epithelial cell layer is first removed, often using a blunt spatula in a 9.0 mm diameter under sterile conditions. This step is followed by the application of topical 0.1% riboflavin (vitamin B(2)) solution every 3 to 5 minutes for 25 minutes to ensure that the corneal stroma is fully penetrated. A solid-state UVA light source with a wavelength of 370 nm (maximum absorption of riboflavin) and an irradiance of 3 mW/cm(2) is used to irradiate the central cornea. Following treatment, a soft bandage lens is applied and prescriptions are given for oral pain medications, preservative-free tears, anti-inflammatory drops (preferably not nonsteroidal anti-inflammatory drugs, or NSAIDs) and antibiotic eye drops. Patients are recalled 1 week following the procedure to evaluate re-epithelialization and they are followed-up subsequently. A literature search was conducted on photochemical corneal collagen cross-linking with riboflavin (vitamin B(2)) and ultraviolet-A for the management of corneal thinning disorders using a search strategy with appropriate keywords and subject headings for CXL for literature published up until April 17, 2011. The literature search for this Health Technology Assessment (HTA) review was performed using the Cochrane Library, the Emergency Care Research Institute (ECRI) and the Centre for Reviews and Dissemination. The websites of several other health technology agencies were also reviewed, including the Canadian Agency for Drugs and Technologies in Health (CADTH) and the United Kingdom's National Institute for Clinical Excellence (NICE). The databases searched included OVID MEDLINE, MEDLINE IN-Process and other Non-Indexed Citations such as EMBASE. As the evidence review included an intervention for a rare condition, case series and case reports, particularly for complications and adverse events, were reviewed. A total of 316 citations were identified and all abstracts were reviewed by a single reviewer for eligibility. For those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. (ABSTRACT TRUNCATED)

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Decalin is used as an industrial solvent for naphthalene, fats, resins, oils, and waxes. It is also used as a substitute for turpentine in lacquers, paints, and varnishes; as a solvent and stabilizer for shoe polishes and floor waxes; and as a constituent of motor fuels and lubricants. Other applications include use as a paint thinner and remover, a patent fuel in stoves, a high-density fuel in submarine-launched cruise missile systems, and in stain removal and cleaning machinery. Decalin was nominated for study by the National Cancer Institute because of its chemical structure, its potential for consumer exposure, and a lack of adequate testing of the chemical. Male and female F344/N rats and B6C3F(1) mice were exposed to decalin (greater than 99% pure) by inhalation for 2 weeks, 3 months, or 2 years. Groups of male NBR rats were exposed to decalin for 2 weeks. Male NBR rats do not produce alpha2u-globulin; the NBR rats were included to study the relationship of alpha2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK STUDIES IN RATS: Groups of five male and five female F344/N rats and five male NBR rats were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber controls. Renal toxicity studies were performed in male F344/N and NBR rats. The numbers of labeled cells and the labeling indices in the left kidney of 200 and 400 ppm F344/N male rats were significantly greater than those in the chamber controls. The alpha2u-globulin/soluble protein ratios were significantly increased in all exposed groups of F344/N rats. Liver weights of male F344/N and NBR rats exposed to 100 ppm or greater were significantly increased, as were those of all exposed groups of females. Kidney weights of male F344/N rats exposed to 50 ppm or greater were significantly increased. Exposure-related hyaline droplet accumulation, degeneration and regeneration of renal cortical tubules, and granular casts occurred in the kidney of exposed F344/N male rats. 2-WEEK STUDIES IN MICE: Groups of five male and five female B6C3F(1) mice were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 17 days. All mice survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber control groups. Liver weights of 200 and 400 ppm males and females and 100 ppm females were significantly increased. 3-MONTH STUDY IN RATS: Groups of 25 male and 20 female F344/N rats were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 2 (five male renal toxicity rats), 6 (10 male and 10 female clinical pathology rats), or 14 (10 core study rats) weeks. All rats survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber control groups. Urinalysis results indicated that decalin exposure caused increases in urine glucose and protein concentrations and enzyme activities that were consistent with the renal lesions observed microscopically. Renal toxicity studies were performed on rats sacrificed at 2 and 6 weeks and at the end of the study. In kidney tissue examined for cell proliferation, the numbers of PCNA-labeled cells and labeling indices were generally significantly greater than those of the chamber controls in exposed groups of rats at all three time points. Concentrations of alpha2u-globulin in the kidney as well as the alpha2u-globulin/soluble protein ratios were significantly increased at week 2 in all exposed groups and in the 200 and 400 ppm groups at week 6 and at the end of the study. Absolute and/or relative kidney and liver weights of male rats exposed to 50 ppm or greater were increased. Incidences of renal tubule regeneration and granular casts in the medulla of the kidney in exposed male rats were increased, and the severities of hyaline droplets generally increased with increasing exposure concentration. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female B6C3F(1) mice were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 14 weeks. All mice survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber control groups. Liver weights of 200 and 400 ppm males and females were significantly increased. There was a significant exposure concentration-related decrease in the absolute spermatid head count and a significant decrease in absolute head count of the 400 ppm group compared to the chamber controls. Incidences of centrilobular cytomegaly of the liver were increased in exposed male mice. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 25, 50 (male rats only), 100, or 400 ppm (female rats only) decalin vapor 6 hours per day, 5 days per week for 105 weeks. A group of 20 male rats was exposed to 400 ppm. Survival of exposed groups was similar to that of the chamber control groups. Mean body weights of 400 ppm males were slightly less than those of the chamber controls during the second year of the study. Incidences of renal tubule adenoma and adenoma or carcinoma (combined) and of benign or malignant pheochromocytoma (combined) of the adrenal medulla in 100 and 400 ppm males were significantly increased. There was a significant association between nephropathy severity and adrenal pheochromocytoma incidence. Nonneoplastic lesions related to decalin exposure occurred in the kidney of male rats. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F(1) mice were exposed to 0, 25, 100, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 105 weeks. Survival of exposed mice was similar to that of the chamber controls. Mean body weights of exposed groups were generally similar to those of the chamber control groups throughout the study. Increased incidences of hepatocellular neoplasms occurred in 25 and 400 ppm female mice, and the incidences of centrilobular hypertrophy, necrosis, syncytial alteration, and erythrophagocytosis of the liver in 400 ppm males were significantly increased. The incidences of uterine stromal polyp and stromal polyp or stromal sarcoma (combined) occurred with positive trends in female mice. The rate of metabolism of decalin was the same for males and females in rats and mice. Also in rats and mice, decalin metabolism was saturated at less than 400 ppm. Increased labeling indices in male rats were likely due to changes related to alpha2u-globulin. Decalin was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535, with or without induced hamster or rat liver S9 enzymes. A small but significant increase in the frequency of micronucleated normochromatic erythrocytes was noted in male mice exposed to decalin for 3 months; however, no induction of micronuclei was observed in female mice. Under the conditions of these studies, there was clear evidence of carcinogenic activity of decalin in male F344/N rats based on increased incidences of renal tubule neoplasms. The increased incidences of benign or malignant pheochromocytoma (combined) of the adrenal medulla in male rats were also considered to be exposure related. There was no evidence of carcinogenic activity of decalin in female F344/N rats exposed to 25, 100, or 400 ppm. There was no evidence of carcinogenic activity of decalin in male B6C3F(1) mice exposed to 25, 100, or 400 ppm. There was equivocal evidence of carcinogenic activity of decalin in female B6C3F(1) mice based on marginally increased incidences of hepatocellular and uterine neoplasms. Exposure of male rats to decalin resulted in nonneoplastic lesions of the kidney characteristic of alpha2u-globulin accumulation. Nonneoplastic lesions of the liver were observed in male mice exposed to decalin.

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In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of published literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenomics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST CANCER: An Evidence-Based and Economic AnalysisEpidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: An Evidence-Based and Ecopnomic AnalysisK-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based and Economic Analysis To review and synthesize the available evidence regarding the laboratory performance, prognostic value, and predictive value of Oncotype-DX for the target population. CONDITION AND TARGET POPULATION The target population of this review is women with newly diagnosed early stage (stage I-IIIa) invasive breast cancer that is estrogen-receptor (ER) positive and/or progesterone-receptor (PR) positive. Much of this review, however, is relevant for women with early stage (I and II) invasive breast cancer that is specifically ER positive, lymph node (LN) negative and human epidermal growth factor receptor 2 (HER-2/neu) negative. This refined population represents an estimated incident population of 3,315 new breast cancers in Ontario (according to 2007 data). Currently it is estimated that only 15% of these women will develop a distant metastasis at 10 years; however, a far great proportion currently receive adjuvant chemotherapy, suggesting that more women are being treated with chemotherapy than can benefit. There is therefore a need to develop better prognostic and predictive tools to improve the selection of women that may benefit from adjuvant chemotherapy. TECHNOLOGY OF CONCERN: The Oncotype-DX Breast Cancer Assay (Genomic Health, Redwood City, CA) quantifies gene expression for 21 genes in breast cancer tissue by performing reverse transcription polymerase chain reaction (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tumour blocks that are obtained during initial surgery (lumpectomy, mastectomy, or core biopsy) of women with early breast cancer that is newly diagnosed. The panel of 21 genes include genes associated with tumour proliferation and invasion, as well as other genes related to HER-2/neu expression, ER expression, and progesterone receptor (PR) expression. What is the laboratory performance of Oncotype-DX?How reliable is Oncotype-DX (i.e., how repeatable and reproducible is Oncotype-DX)?How often does Oncotype-DX fail to give a useable result?What is the prognostic value of Oncotype-DX?Is Oncotype-DX recurrence score associated with the risk of distant recurrence or death due to any cause in women with early breast cancer receiving tamoxifen?What is the predictive value of Oncotype-DX?Does Oncoytpe-DX recurrence score predict significant benefit in terms of improvements in 10-year distant recurrence or death due to any cause for women receiving tamoxifen plus chemotherapy in comparison to women receiving tamoxifen alone?How does Oncotype-DX compare to other known predictors of risk such as Adjuvant! Online?How does Oncotype-DX impact patient quality of life and clinical/patient decision-making? A literature search was performed on March 19(th), 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing &amp; Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1(st), 2006 to March 19(th), 2010. A starting search date of January 1(st), 2006 was because a comprehensive systematic review of Oncotype-DX was identified in preliminary literature searching. This systematic review, by Marchionni et al. (2008), included literature up to January 1(st), 2007. All studies identified in the review by Marchionni et al. as well as those identified in updated literature searching were used to form the evidentiary base of this review. The quality of the overall body of evidence was identified as high, moderate, low or very low according to GRADE methodology. Any observational trial, controlled clinical trial, randomized controlled trial (RCT), meta-analysis or systematic review that reported on the laboratory performance, prognostic value and/or predictive value of Oncotype-DX testing, or other outcome relevant to the Key Questions, specific to the target population was included. Studies that did not report original data or original data analysis,Studies published in a language other than English,Studies reported only in abstract or as poster presentations (such publications were not sought nor included in this review since the MAS does not generally consider evidence that is not subject to peer review nor does the MAS consider evidence that lacks detailed description of methodology). Outcomes of interest varied depending on the Key Question. For the Key Questions of prognostic and predictive value (Key Questions #2 and #3), the prospectively defined primary outcome was risk of 10-year distant recurrence. The prospectively defined secondary outcome was 10-year death due to any cause (i.e., overall survival). All additional outcomes such as risk of locoregional recurrence or disease-free survival (DFS) were not prospectively determined for this review but were reported as presented in included trials; these outcomes are referenced as tertiary outcomes in this review. Outcomes for other Key Questions (i.e., Key Questions #1, #4 and #5) were not prospectively defined due to the variability in endpoints relevant for these questions. A total of 26 studies were included. Of these 26 studies, only five studies were relevant to the primary questions of this review (Key Questions #2 and #3). The following conclusions were drawn from the entire body of evidence: There is a lack of external validation to support the reliability of Oncotype-DX; however, the current available evidence derived from internal industry validation studies suggests that Oncotype-DX is reliable (i.e., Oncotype-DX is repeatable and reproducible).Current available evidence suggests a moderate failure rate of Oncotype-DX testing; however, the failure rate observed across clinical trials included in this review is likely inflated; the current Ontario experience suggests an acceptably lower rate of test failure.In women with newly diagnosed early breast cancer (stage I-II) that is estrogen-receptor positive and/or progesterone-receptor positive and lymph-node negative:There is low quality evidence that Oncotype-DX has prognostic value in women who are being treated with adjuvant tamoxifen or anastrozole (the latter for postmenopausal women only),There is very low quality evidence that Oncotype-DX can predict which women will benefit from adjuvant CMF/MF chemotherapy in women being treated with adjuvant tamoxifen.In postmenopausal women with newly diagnosed early breast cancer that is estrogen-receptor positive and/or progesterone-receptor positive and lymph-node positive:There is low quality evidence that Oncotype-DX has limited prognostic value in women who are being treated with adjuvant tamoxifen or anastrozole,There is very low quality evidence that Oncotype-DX has limited predictive value for predicting which women will benefit from adjuvant CAF chemotherapy in women who are being treated with adjuvant tamoxifen.There are methodological and statistical limitations that affect both the generalizability of the current available evidence, as well as the magnitude and statistical strength of the observed effect sizes; in particular:Of the major predictive trials, Oncotype-DX scores were only produced for a small subset of women (&lt;40% of the original randomized population) potentially disabling the effects of treatment randomization and opening the possibility of selection bias;Data is not specific to HER-2/neu-negative women;There were limitations with multivariate statistical analyses.Additional trials of observational design may provide further validation of the prognostic and predictive value of Oncotype-DX; however, it is unlikely that prospective or randomized data will become available in the near future due to ethical, time and resource considerations.There is currently insufficient evidence investigating how Oncoytpe-DX compares to other known prognostic estimators of risk, such as Adjuvant! Online, and there is insufficient evidence investigating how Oncotype-DX would impact clinician/patient decision-making in a setting generalizable to Ontario.

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Due to continuing advances in the development of structures, devices, and systems with a length of about 1 to 100 nanometres (nm) (1 nm is one billionth of a metre), the Medical Advisory Secretariat conducted a horizon scanning appraisal of nanotechnologies as new and emerging technologies, including an assessment of the possibly disruptive impact of future nanotechnologies. The National Cancer Institute (NCI) in the United States proclaimed a 2015 challenge goal of eliminating suffering and death from cancer. To help meet this goal, the NCI is engaged in a concerted effort to introduce nanotechnology "to radically change the way we diagnose, treat and prevent cancer." It is the NCI's position that "melding nanotechnology and cancer research and development efforts will have a profound, disruptive effect on how we diagnose, treat, and prevent cancer." Thus, this appraisal sought to determine the systemic effects of nanotechnologies that target, image and deliver drugs, for example, with respect to health human resources, training, and new specialties; and to assess the current status of these nanotechnologies and their projected timeline to clinical utilization. TARGET POPULATION AND CONDITION Cancer is a heterogeneous set of many malignant diseases. In each sex, 3 sites account for over one-half of all cancers. In women, these are the breast (28%), colorectum (13%) and lungs (12%). In men, these are the prostate (28%), lungs (15%), and the colorectum (13%). It is estimated that 246,000 people in Ontario (2% of the population) have been diagnosed with cancer within the past 10 years and are still alive. Most were diagnosed with cancer of the breast (21%), prostate (20%), or colon or rectum (13%). The number of new cancer cases diagnosed each year in Ontario is expected to increase from about 53,000 in 2001 to 80,000 in 2015. This represents more than a 50% increase in new cases over this period. An aging population, population growth, and rising cancer risk are thought to be the main factors that will contribute to the projected increase in the number of new cases. THE TECHNOLOGY BEING REVIEWED - MEDICAL ADVISORY SECRETARIAT DEFINITION OF NANOTECHNOLOGY: FIRST-GENERATION NANOTECHNOLOGIES: Early application of nanotechnology-enabled products involved drug reformulation to deliver some otherwise toxic drugs (e.g., antifungal and anticancer agents) in a safer and more effective manner. Examples of first-generation nanodevices include the following: liposomes;albumin bound nanoparticles;gadolinium chelate for magnetic resonance imaging (MRI);iron oxide particles for MRI;silver nanoparticles (antibacterial wound dressing); andnanoparticulate dental restoratives.First-generation nanodevices have been in use for several years; therefore, they are not the focus of this report. SECOND-GENERATION NANOTECHNOLOGIES: Second-generation nanotechnologies are more sophisticated than first- generation nanotechnologies, due to novel molecular engineering that enables the devices to target, image, deliver a therapeutic agent, and monitor therapeutic efficacy in real time. Details and examples of second-generation nanodevices are discussed in the following sections of this report. The questions asked were as follows: What is the status of these multifunctional nanotechnologies? That is, what is the projected timeline to clinical utilization?What are the systemic effects of multifunctional nanodevices with integrated applications that target, image, and deliver drugs? That is, what are the implications of the emergence of nanotechnology on health human resources training, new specialties, etc.?The Medical Advisory Secretariat used its usual search techniques to conduct the literature review by searching relevant databases. Outcomes of interest were improved imaging, improved sensitivity or specificity, improved response rates to therapeutic agents, and decreased toxicity. The search yielded 1 health technology assessment on nanotechnology by The Centre for Technology Assessment TA-Swiss and, in the grey literature, a technology review by RAND. These, in addition to data from the National Cancer Institute (United States) formed the basis for the conclusions of the review. With respect to the question as to how soon until nanotechnology is used in patient care, overall, the use of second-generation nanodevices, (e.g., quantum dots [QDs]), nanoshells, dendrimers) that can potentially target, image, and deliver drugs; and image cell response to therapy in real time are still in the preclinical benchwork stage. Table 1 summarizes the projected timelines to clinical utilization. Table 1:Summary of Timelines to Clinical Use*Organization/YearSecond-Generation NanodeviceEstimate of When Nanodevice Will be in Clinical UseNCI 2001Imaging/detection (e.g., QDs)Therapeutic (e.g., nanoshell)Combined (e.g., dendrimer)~2006-2016~2006-2016~2016-2020NCI 2004Imaging/detectionTherapeuticCombined~2009-2019~2009-2019~2019-2024RAND 2006Combinedunlikely before 2021Swiss 2003ImagingTherapeuticCombined~2005-2010~2008-2013~ 2010-2013*NCI refers to National Cancer Institute; QD, quantum dot.Medical Advisory Secretariat Estimated Timeline for Ontario Upon synthesizing the estimated timelines from the NCI, the Swiss technology assessment and the RAND reports (Figure 1), it appears that: the clinical use of separate imaging and therapeutic nanodevices is estimated to start occurring around 2010;the clinical use of combined imaging and therapeutic nanodevices is estimated to start occurring around 2020;changes in the way disease is diagnosed, treated and monitored are anticipated; andthe full (and realistic) extent of these changes within the next 10 to 20 years is uncertain.Figure 1:Medical Advisory Secretariat Estimated Timeline for the Clinical Use of Second-Generation Nanodevices in OntarioWith respect to the question on potential systemic effects of second-generation nanodevices (i.e., the implications of the emergence of these nanodevices on health human resources training, new specialties etc.), Table 2 summarizes the findings from the review. Table 2:Potential Systemic Effects Caused by Second Generation Nanodevices*ImagingTherapeuticCombined (Detect, Image, Treat, Monitor)Increased sensitivity and specificity of QDs or other nanodevices could lead to the replacement of existing technologies (e.g., PSA testing, mammogram).Sudden demand in use of MRI due to use of nanodevices that are activated in the presence of a magnetic field.Universal demand to detect cancer- how will patients be prioritized for this?Sudden demand in use of MRI due to use of nanodevices that are activated in the presence of a magnetic field.Cost: possibly more expensive than current screening modalities.Possibly more expensive than existing therapies (gold nanoshells)Many functions can be performed on one device → possibly faster, more cost-effective than individual devices.Report of results: possibly faster than existing technologies.Possibly faster determination of therapeutic efficacy (vs. existing technologies)Increase in life expectancy of population? Free-up beds in hospitals?Nanodevices may be able to pinpoint with more accuracy when cancer starts.Ethical question: when does disease start?Increased demand for imaging by people who are asymptomatic and concerned they may get cancer.Nano-radiologist or medical nano-oncologist provides treatment rather than conventional radiologists or medical oncologists.Creation of nano-nursing compared to conventional nursing.Nano-radiologist or medical nano-oncologist provides treatment, rather than conventional radiologists or medical oncologists.Creation of nano-nursing compared to conventional nursing.Uncertainty regarding how many "traditional" cancer radiologists/oncologists should be retained and trained.New branch of (nano) radiology compared to conventional radiology New/longer training in biochemistry and targeting ligands will be required by nanoradiologists.More training required for new nano-treatments Patient education - people may be concerned regarding the use of nanodevices inside their bodies.Longer time to specialize in medicine in order to use nanotechnology clinically?Insufficient number of dendrimer specialists to treat everyone with personalized dendrimersRestricted to specialized centres Possible in-house nanodevice production required to keep up with the demand for use.Will the same specialized centres that offer imaging also offer treatment?How many specialized centres will be required?Only specialized centres can perform this combined imaging/treatmentPossible nano-monitoring from patient home via wireless technology. This may free hospital beds for other patients.After imaging with nanodevices, specifically targeted therapeutic nanodevices may also be required for immediate treatment of the patient. Will both of these nanodevices be commercially available in sufficient quantities?Possible waiting time for preparation of appropriately targeted nanodevice after imaging (will a therapeutic nanodevice be immediately available?)Will a patient receive conventional treatment if there is a waiting period required to prepare the therapeutic nanodevice?Will there be a patient waiting time required for preparation of personalized dendrimers (hours, days, weeks after a patient sees a physician)?*MRI indicates magnetic resonance imaging; PSA, prostate-specific antigen; QD, quantum dot. The United States National Nanotechnology Initiative (NNI) funds a variety of research in the economic, ethical, legal, and cultural implications of the use of nanotechnology, as well as the implications for science, education and quality of life. There are many uncertainties that are sparsely or not addressed at all in the literature regarding second generation nanodevices. (ABSTRACT TRUNCATED)

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The work described in the present report has been requested by the Secretary of Hygiene, Health and Social Welfare of the Sardinia Region (Italy). It has been carried out by the Regional Epidemiological Observatory within the domain of ESA (Epidemiology Development and Environment) and with the support of the European Union. Eighteen areas (for a total of 73 municipalities) were identified a priori as "potentially polluted", accounting for a population of 917,977 in 2001 census (56% of the total population of Sardinia). The areas have been named after the most important town, as listed below (in brackets rounded 2001 population), major activities in industrial areas are briefly described. Portoscuso (59,000). Processing of aluminium and other metals. Foundry. Power plants. Dismissed mines (mainly coal mining, lead, zinc). Plants for storing and treating special wastes. Italian Law 349/1986 classified this area as "at high risk of environmental crisis" and classified some plants as being "at high technological risk" (Norma Seveso Decree 334/1999). The area is part of the Sulcis National Restoration site. San Gavino (24,000). Industrial and commercial activities. Lead and zinc foundry. Dairy factories. Food industry. Sarroch (52,000). Petrochemical and refinery industry. Power plants. Mining. Incinerator. Plants for storing and treating special wastes. Gas and mineral oil deposits. Ottana (15,000). Chemical industry. Production of plastics and synthetic fibres. Denim production. Porto Torres (168,000). Chemical industry: production of basic chemicals (benzene, toluene, ethylene, propylene and others), polyethylene, elastomers and vinyl chloride. Textile industry. First and second category landfills. Some plants have been classified "at high technological risk" (Norma Seveso Decree 334/1999). The area is a National Restoration site. The town of Sassari is included. Tortolì (23,000). Construction of steel structures for offshore facilities of the oil and gas industry. Paper industry. Tempio Pausania (21,000). Cork production. Stone quarries. Macomer (17,000). Textile industry (velvet). First and second category landfills. Incinerator. Arbus (30,000). Extraction of zinc, lead and silver. Iglesias (39,000). Extraction of zinc, lead and silver. Teulada (16,000). La Maddalena (11,000). Naval army shipyards. Salto di Quirra (31,000). Mining area. Cagliari (299,000). Petrochemical plants, port, airport. Nuoro (37,000). Olbia (47,000). Port and airport. Oristano (31,000). Sassari (121,000). THE COMPARISON SARDINIA-ITALY: In 1997-2001, the age-standardized mortality rate (x1,000 person-years) among males was higher than in Italy (84.4 vs 80.8) while the reverse occurred in females (50.9 vs 52.0). Ill defined causes of death were 1.4% in males and 2.5% in females (vs corresponding estimates of 1.1% and 1.4% in Italy). Compared to Italian national data, regional age-standardized estimates were higher in Sardinia for infectious diseases (23% in males and 12% in females), respiratory diseases (22% and 14%: pneumoconiosis was more than 6 times more frequent in Sardinia than in Italy), diseases of the digestive system (26% and 9%: for liver cirrhosis, the excess was 33% in males and 9% in females; corresponding figures for liver cancer were 13% and 16%), breast cancer in females (5%). On the other hand, regional mortality rates were lower than the national rates for cardiovascular diseases (-1.3% and -7.4% in males and females respectively), all cancers considered as a whole (-9% and -7%) and lung cancer (-5% and -32%). Regional and national death rates for non Hodgkin lymphoma in both sexes and for leukaemia in females were almost identical, whereas the latter rate in males was slightly higher in Sardinia than in Italy (9.4 vs 8.4 x100,000 person-years). Particularly in men, the differences in mortality rates from all causes and from cardiovascular, respiratory diseases and lung cancer among the four traditional Provinces (Cagliari, Nuoro, Oristano and Sassari) were greater than the difference between Sardinia and Italy. Remarkably enough, also death rates from lymphohaemopoietic tumours were more heterogeneous within Sardinia. Rates of hospital discharges in Sardinia showed a high variability, which is partly attributable to differences in the availability of both hospital beds and alternative forms of care. This heterogeneity must be taken into account in the interpretation of rates of hospital discharge. These were relatively high in some areas (Cagliari, Iglesias, Portoscuso, Tortolì) and low in others (Olbia, Porto Torres, Sassari). All the reported observed/expected ratios were based on material deprivation adjusted figures. All the estimated statistics were reported with 90% Confidence Interval. In 1997-2001, deaths from respiratory diseases were significantly in excess in males in Portoscuso (obs/exp 205/124.77) and in San Gavino (69/46.77). Deaths from pneumoconiosis were recorded sporadically, with the exception of Portoscuso, where the excess was impressive (obs/exp 112/30.46). SMRs for lung cancer in males ranged between 0.62 in Ottana and 1.22 in San Gavino, with statistically significant departure from expected values in Portoscuso and Sarroch (both with SMR significantly in excess in males: 1.24). In Porto Torres mortality from all causes was in significant excess in both sexes (SMRs 1.04 in males and 1.09 in females), for respiratory diseases (1.08 and 1.28), for diseases of the digestive system (1.13 and 1.21), for all cancers (1.04 and 1.09). Liver cancer deaths were also in excess in both sexes (SMRs 1.18 and 1.21). The latter finding is confirmed by incidence rates from the local cancer registry. Among industrial areas, Porto Torres was also the one with a stronger evidence of an excess of deaths from lymphohaemopoietic cancer in males (obs/exp 99/83.60) and females (73/68.20). These areas are characterized by statistically significant excesses of mortality in males, largely caused by non neoplastic respiratory conditions (obs/exp 119/86.41 in Iglesias and 156/62.55 in Arbus). In recent years, deaths from pneumoconiosis averaged 20 per year in Arbus and 10 per year in Iglesias. Lung cancer in males was also significantly in excess in both areas (obs/exp 72/56.38 in Arbus and 108/72.14 in Iglesias). There is a time trend (1981-2001) towards a decrease of mortality from respiratory conditions, which nevertheless remains largely in excess over the regional average also in the most recent period. Statistically significant excesses of deaths and hospital discharges for non Hodgkin lymphoma were detected in La Maddalena (mortality, 1981-2001, in males 17 observed cases vs 6.13 expected, in females 8/5.64). In Salto di Quirra in 1997-2001 deaths from myeloma (in males 5/2.3) and leukaemias were increased in both sexes (total obs/exp 20/13.3, statistically non significant). Urban areas in Sardinia are relatively well developed with high values of socioeconomic indicators. The health profile in Cagliari and Sassari is typical of towns of the Western world. In Cagliari there is a higher mortality for colorectal, breast, cervical and lung cancer. Environmental (non occupational) pollution might explain some of the observed excesses of disease in the investigated industrial areas of Sardinia, particularly in women, less likely to be exposed to hazards in the work environment, whereas in the mining areas studied the disease pattern suggests a major role of occupational exposures. On the other hand, the causal links between disease occurrence and exposures in the screened military areas remain uncertain. The disease patterns in the cities of Sardinia are likely to be associated with lifestyle and urban pollution. Historically, southern Italian Regions have been characterized by an advantage over the rest of the country in terms of health, but during the last decade such advantage tended to vanish. Sardinia confirms this secular trend. However in the most recent years studied, overall age-standardized mortality rate in Sardinian females still remains lower than Italian average, but this is not the case for males any more. Differences in the health profile between residents in different areas of Sardinia have been found to be far greater than the difference between Sardinia as a whole and Italy. A major contribution to intraregional differences is given by the 18 investigated areas where excesses were registered for: respiratory diseases (including cancer) in the industrial areas of Portoscuso, Sarroch and Porto Torres, and in the mining areas; diseases of the digestive tract, liver cancer and lymphohaemopoietic cancer in the area of Porto Torres; cancer of the lymphohaemopoietic system in some military areas; cancers of the colon and rectum, lung, breast and uterus in some of the major cities of the Region.

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Let us now revisit our original assumptions. First, we note that for the participants in Hacinas Carnival the Tarasca is a figure of fun and joy, but it also exudes a strain of aggressive misogyny that many female residents, not to mention tourists, find somewhat unsettling. In the spirit of feminist currents in Spain, a group of young women protested in 1992 to town officials and, when rebuffed, sought to build their own female monster, which they intended to use to attack boys and men. While their plan was never carried out, and indeed met with stiff opposition from officialdom and, especially, from older women, some of the younger, more modern girls find the Tarasca appalling, and they told me so without compunction. Accordingly, today the festival tends to polarize the sexes as well as the generations. Also, many children are frightened by the gigantic mock-up with its snapping teeth and foul breath, and many of them burst into tears at the roaring of the demons. But despite these negatives--or perhaps because of them--the Tarasca breaks down boundaries between things normally kept separate in the mind: humor and terror, man and beast, order and disorder, old and young, life and death, and so on. In so collapsing opposites, the Tarasca causes people to pause and to think about and question everyday reality in the non-Carnival universe. All these observations of course support the structural arguments of our four theorists above and in particular seem to corroborate Bloch's concept (1992) of the regenerative power of "rebounding violence." However, there are three specific features here that need psychological amplification beyond simply confirming the work of previous theorists. We must first note that like most grotesque fantasies, the Hacinas monster combines disparate organic "realities" into a bizarre and monstrous image that by its very oddness and the resulting "cognitive mismatch" captures people's attention and sparks the imagination, especially that of children (Konner 2002, 222). The Pentecostal beastie combines equine, reptilian, and bird-like features with a giraffe's neck, an elephant's bulk, an impossible number of legs, the usual human malevolence, and the satyr's insatiable lust. The monster also combines cognitive antitheses in a way that reinforces cultural biases while at the same time undermining them--a typical paradox of the Monstrous in ritual and art (Andriano 1999). In the Hacinas festival the integrated themes are those of bodily mutilation, sexual abuse, cannibalism, death, and decay. All these themes come together in certain compelling Iberian traditions: misogyny, costumed parading, religious revitalization, ritual displacement of aggression onto external objects, spontaneous street theatre. All forms of aggression are visually embodied in the image of the mystic beast, as happens every day in the classic Spanish bullfight pitting man against raw nature (Mitchell 1991). Peremptory male sexuality both parodied and glorified, women both raped and rescued, children both terrified and liberated. As Bloch has argued in the aptly titled Prey into Hunter (1992), the narrative of the Tarasca rite, turning victim into victimizer, enables the community to "absorb the vitality" of the external threat and thereby to regenerate itself and to transcend everyday reality. We may make a third, psychoanalytic, observation. As with all such fabulous and scary images, the Tarasca provokes regressive responses that probably go back to the primary organization of the mind before the advent of speech. In this childhood environment, sensations are limited to visions and primary emotions, and the world is experienced largely through the eyes and mouth. Psychoanalysts of childhood have called this the phase of oral/visual primacy. It may explain the locus of aggression in typical monster imagery: the rending teeth, the gnashing jaws, the cavernous belly. It would also help us understand the terror at being devoured by a giant predator during the ritual or, as Bloch puts it (1992, 101), "the horrifying possibility of being consumed" as an essential aspect of ritual process. The snapping mouth as well as other incorporative morphological features of the Hacinas monster, for example, the bulging belly, give an animated shape to primordial fear, with its dynamic mixture of oral, erotic, and self-identity themes. This is exactly what Bloch refers to as the "consuming" threat, the evil that "bites" and "eats" before succumbing to the power of the good. The Tarasca exemplifies both childhood anxieties and the residual fears of adults; and so the festival evokes passionate intensity in all age groups. As Turner might have put it, the "pressure points" that find expression in Hacinas are those between sexual desire and guilt, terror and curiosity, good and evil, purity and corruption; the tensions are those between old and young, death and re-birth (emerging anew from the Tarasca's belly). All of these themes are probably universally encountered and thus constitute the "core" of rituals everywhere by "reenacting the creation ot moral life" (Bloch 1992, 47). Although the Tarasca frightens children and makes them bawl and run away, it also stimulates their cognitive growth and offers ultimately a sense of safety provided by a united and victorious community. Some child psychologists such as Denyse Beaudet (1990) and Jean Piaget (1962, 229) have surmised as much. Piaget says that unconstrained mental operations caused by shock or disorientation provide Spieltaum: an imaginary playground where youngsters experiment with ideas. Bruno Bettelheim says that such creativity permits children to give anxieties tangible form: these can then be distanced and defeated (1976, 120). This projective process, beginning in infancy, of course continues in adulthood, not only in dreams and fantasy but in community rituals, where it reaches apotheosis as Bloch has so persuasively argued. Finally, we must address the misogynist theme that is so marked in the Spanish festival. Many anthroooloeists have noted the theme of the treacherous siren in Spanish folklore, a theme that corresponds to the female models carried aloft on the Tarasca's spine in Granada, Toledo, and other places. One observer, Stanley Brandes, was impressed with the pervasiveness of this specific male anxiety in the Andalusian town of Monteros. In his book on male folklore, Metaphors of Masculinity (1980), Brandes records a number of popular aphorisms that warn men to protect their fragile manhood from duplicitous females or suffer emasculation (one urges men literally to keep their penises in their pants or be castrated). In my own fieldwork in Seville Province, I found the eating/castration theme paramount in male folklore and I have recorded numerous Carnival ditties warning men and boys against the vagina dentata and other forms of female sexual aggression (Gilmore 1987; 1998). Literary scholar Louise Vasvari (1991, 3) refers to the "gastro-genital equivalence" symbolism of Spanish versification, which she identifies in writings dating back to the Middle Ages. Given all this evidence, we may conclude that with its defining misogynist theme and its female/monster imagery, the Spanish Tarasca embodies a dread of feminine sexuality that colors the Spanish male subculture. In particular, in the Hacinas case, the misogynist element combines a devouring theme along with the castration threat in the attack on the boys' genitals and in the liquid thrown onto the crotch, symbolizing, one may conjecture, semen and blood. While these themes are probably universal, their annual apotheosis in visual tropes, public rites, monster effigies, and masques may be specific to Spain. Both appalling in its ferocity and ennobling in its ultimate function as sacrificial object, the Tarasca is one of countless projections of universal human mental shadows as an embodiment, a visual metaphor, as James Fernandez has shown in his classic paper on the role of tropes in culture (1986). Like the other monsters of the world, the Tarascas of Spain are man-eaters and rapists, both lascivious females and priapic males; their toothy (and in Hacinas smelly) oral symbolism is at the same time lurid and hypnotic to the crowds that fight them. As an aspect of local pride, the beast calls forth reverence as well as repugnance. Frightening and also endearing, the Tarasca embodies the human imagination in all its whimsy, grotesqueness, and terror.

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Acitretin (etretin), a second generation monoaromatic retinoid for use in the treatment of severe psoriasis and other dermatoses, is the major active metabolite of etretinate and possesses a similar therapeutic index; i.e. a similar ratio of clinical efficacy to adverse effects. When used alone at a maintenance dosage of 30 to 50mg daily, acitretin is effective in the treatment of psoriasis, causing a reduction in the severity of scaling, erythema and induration. Efficacy appears to be further enhanced by combination with psoralen-ultraviolet A photochemotherapy (PUVA) or ultraviolet B irradiation (UVB). These combinations reduce the time to lesion clearance and reduce the total radiation dose, improving overall safety. Comparative studies have confirmed the equivalence of acitretin and etretinate with regard to efficacy and toxicity. Adverse reactions are dose-related and generally typical of hypervitaminosis A. Alopecia and mucocutaneous symptoms such as cheilitis and drying of the mucous membranes are particularly prevalent. Hypertriglyceridaemia and elevation of cholesterol levels also occur. Examination of the pharmacokinetic profile of acitretin reveals its main advantage over etretinate. Acitretin is less lipophilic than etretinate, and its lack of sequestration into 'deep' fatty storage sites is reflected in a comparatively short terminal elimination half-life of 50 to 60 hours, compared with 120 days for etretinate. Due to its teratogenic potential, acitretin is strictly contraindicated in women of childbearing potential unless effective contraceptive measures are employed. Etretinate has been identified in plasma samples of some patients treated with acitretin. Thus, acetretin has an established place in the treatment of keratinising disorders, although its use in women of child-bearing potential must be accompanied by effective contraceptive measures, with a further 2-year contraceptive period after therapy completion. Investigation of the pharmacodynamic properties of acitretin has been restricted to some extent by the lack of a suitable experimental model. While in vitro results using normal human skin fibroblasts have been conflicting, acitretin generally modulates cell proliferation in cultures from hyperproliferative conditions such as psoriasis or neoplasia, and inhibits epidermal cell growth and differentiation. Acitretin also inhibits chemically induced hyperplasia, and causes regression or inhibits further growth and development of a number of established or transplantable carcinoma cell lines. The mechanism of action of acitretin in hyperproliferative disorders has yet to be fully elucidated; however, there appear to be a number of cellular effects. Target receptor site candidates include the cellular retinoic acid binding protein (CRABP), the epidermal growth factor (EGF) receptor, and retinoic acid nuclear receptors (RARs). Acitretin binds competitively to CRABP, a protein present in high concentrations in psoriatic plaques, and induces a marked elevation of CRABP levels in normal epidermis. However, 13-cis-acitretin does not bind to CRABP and acitretin may act via activation of RARs following conversion to a substance which binds to these receptors. In addition, the EGF receptor may be involved since acitretin has been found to influence its normal modulation of cell growth in both normal fibroblasts and squamous carcinoma cell lines. Cyclic adenosine monophosphate (cAMP)-dependent protein kinases and ornithine decarboxylase are probable mediators of the clinical response. In addition, acitretin demonstrates immunomodulatory and anti-inflammatory effects. It is hypothesised that the mechanisms entail inhibition of polymorphonuclear leucocyte accumulation in the stratum corneum, inhibition of lymphocytic blastogenesis by mitogens and stimulation of T cell-mediated cytotoxicity. Following oral administration of the drug to patients with psoriasis, peak plasma acitretin concentrations range from 98 to 526 µg/L and are reached approximately 1.9 hours after a single 40mg dose. Acitretin is widely distributed in the body and systemic bioavailability is approximately 60%. It is extensively bound to albumin and has a high affinity for CRABP. Less than 5% of acitretin is bound to lipoproteins and this is reflected in its comparative lack of sequestration into fatty 'deep' storage sites and its short terminal elimination half-life relative to etretinate. Multiple dose studies have indicated an elimination half-life of 50 to 60 hours, and neither acitretin nor its isomeric counterpart, 13-cis-acitretin, is detectable in plasma 3 to 4 weeks after cessation of long term therapy. Isomeric interconversion is prevalent following oral administration of acitretin: mean maximum plasma concentrations of the 13-cis-isomeric metabolite are lower and occur slightly later than with acitretin. Plasma trough concentrations of this metabolite following long term administration of acitretin are about 5 times higher than those of the parent drug and the terminal elimination half-life is about 15 times longer. Acitretin is excreted predominantly via the renal and hepatic routes, as glucuronides in bile or as products with shortened side chains in urine. In blood, 13-cis-acitretin and 3 other metabolites have been identified. Liquid chromatography/mass spectroscopy has identified etretinate in plasma samples of some patients treated with acitretin. The results obtained so far are of concern with regard to a potential teratogenic effect in female patients. Therefore, an increase in the post therapy contraception period to 2 years instead of the 2 months previously advocated is appropriate until clarification of these recent results have been obtained. Trials with an initial double-blind phase and a subsequent noncomparative phase of up to 6 months duration have demonstrated the efficacy of orally administered acitretin (generally 25 to 75 mg/day) in the treatment of severe psoriasis. Variants of psoriasis vulgaris are notably susceptible to treatment and acitretin also appears to be effective against severe forms of pustular and erythrodermic psoriasis. Preliminary studies in small patient populations and a number of individual case reports suggest that acitretin, 30 to 50 mg/day, is beneficial in a variety of other cutaneous disorders including Darier's disease, lupus erythematosus and severe recessive x-linked ichthyosis. The rarity of these conditions prevents adequate extensive trials. Double-blinding in placebo-controlled trials is difficult to maintain due to the ubiquitous and distinctive nature of acitretin-induced adverse effects. However, double-blinding strategies have been used effectively in studies in which a dose-finding phase preceded a longer term noncomparative phase. Subjective assessments have revealed good to excellent (⩾ 50%) clearance of severe psoriasis in &gt; 75% of patients: the severity of scaling, erythema and epidermal induration, and the percentage of body surface involvement, are reduced. Comparative studies in patients with psoriasis indicate that acitretin is comparable with etretinate in terms of therapeutic efficacy and adverse effects. When acitretin is combined with psoralen-ultraviolet A photochemotherapy (PUVA), clinical efficacy is improved, as evidenced by a higher complete remission rate and a reduced time to clearance of psoriasis. Total irradiation requirement is also reduced. Similar results are also achieved when acitretin is combined with ultraviolet B irradiation. Acitretin therapy has distinctive adverse effects generally typical of hypervitaminosis A. While the incidence of mucocutaneous clinical adverse effects is high, their severity does not usually necessitate withdrawal of therapy, and they are completely reversed on cessation of treatment. Adverse effects are usually dose-related, although alopecia is also dependent on the duration of therapy. Mucocutaneous reactions are most common - drying of mucous membranes of the eyes, nose and lips, and cheilitis occurs in nearly all patients. Other clinical symptoms include alopecia, desquamation of the skin, pruritus and 'sticky' skin. Changes in the lipid profile are often observed. Hypertriglyceridaemia occurs in 35% of patients treated with acitretin 50 mg/day, but increases in serum cholesterol are less frequently reported. Liver enzyme levels are also adversely affected, hepatitis has been reported and acitretin therapy may have an adverse effect on bone. As with etretinate, acitretin is a potent teratogen. Initial acitretin dosage has usually ranged from 10 to 75 mg/day orally. After a few weeks, the dose should be individually adjusted to obtain optimum therapeutic response with tolerable adverse effects. Maintenance doses in such trials have ranged from 30 to 50 mg/day. Some authorities advocate low-dose therapy initially followed by a progressive dosage increase. Because of its potent teratogenicity and the detection of etretinate in patients treated with acitretin, the drug is contraindicated in women of childbearing potential unless effective contraceptive measures are adopted. It is essential that pregnancy be avoided for a full 2 years after therapy finishes, instead of the 2 months previously advocated.

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