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Pelvic organ prolapse (POP) is common in women and is frequently associated with stress urinary incontinence (SUI). In many cases however, SUI is present only with the prolapse reduced (occult SUI) or may develop after surgical treatment for prolapse (de novo SUI). To determine the impact on postoperative bladder function of surgery for symptomatic pelvic organ prolapse with or without concomitant or delayed two-stage continence procedures to treat or prevent stress urinary incontinence. We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE-In-Process, ClinicalTrials.gov, WHO ICTRP, handsearching journals and conference proceedings (searched 11 November 2017) and reference lists of relevant articles. We also contacted researchers in the field. Randomised controlled trials (RCTs) including surgical operations for POP with or without continence procedures in continent or incontinent women. Our primary outcome was subjective postoperative SUI. Secondary outcomes included recurrent POP on examination, overactive bladder (OAB) symptoms, and voiding dysfunction. We used standard methodological procedures as expected by Cochrane. We included 19 RCTs (2717 women). The quality of the evidence ranged from low to moderate. The main limitations were risk of bias (especially blinding of outcome assessors), indirectness and imprecision associated with low event rates and small samples.POP surgery in women with SUIVaginal repair with vs without concomitant mid-urethral sling (MUS)A concomitant MUS probably improves postoperative rates of subjective SUI, as the evaluated clinical effect appears large (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.19 to 0.48; 319 participants, two studies; I² = 28%; moderate-quality evidence), and probably decreases the need for further continence surgery (RR 0.04, 95% CI 0.00 to 0.74; 134 participants, one study; moderate-quality evidence). This suggests that if the risk of SUI with POP surgery alone is 39%, the risk with an MUS is between 8% and 19%.Rates of recurrent POP on examination, OAB, and voiding dysfunction were not reported.Vaginal repair with concomitant vs delayed MUSEvidence suggested little or no difference between groups in reporting postoperative SUI (RR 0.41, 95% CI 0.12 to 1.37; 140 participants, one study; moderate-quality evidence).Rates of recurrent POP on examination, OAB, and voiding dysfunction and the need for further surgery were not reported.Abdominal sacrocolpopexy with vs without Burch colposuspensionAn additional Burch colposuspension probably has little or no effect on postoperative SUI at one year (RR 1.38, 95% CI 0.74 to 2.60; 47 participants, one study; moderate-quality evidence), OAB symptoms (RR 0.85, 95% CI 0.61 to 1.18; 33 participants, one study; moderate-quality evidence), or voiding dysfunction (RR 0.96, 95% CI 0.06 to 14.43; 47 participants, one study; moderate-quality evidence). Rates of recurrent POP and the need for further surgery were not reported.POP surgery in women with occult SUIVaginal repair with vs without concomitant MUSMUS probably improves rates of subjective postoperative SUI (RR 0.38, 95% CI 0.26 to 0.55; 369 participants, five studies; I² = 44%; moderate-quality evidence). This suggests that if the risk with surgery alone is 34%, the risk with a concomitant MUS is between 10% and 22%. Evidence suggests little or no difference between groups in rates of recurrent POP (RR 0.86, 95% CI 0.34 to 2.19; 50 participants, one study; moderate-quality evidence), OAB symptoms (RR 0.75, 95% CI 0.52 to 1.07; 43 participants, one study; low-quality evidence), or voiding dysfunction (RR 1.00, 95% CI 0.15 to 6.55; 50 participants, one study; low-quality evidence). The need for further surgery was not reported.POP surgery in continent women Vaginal repair with vs without concomitant MUSResearchers provided no conclusive evidence of a difference between groups in rates of subjective postoperative SUI (RR 0.69, 95% CI 0.47 to 1.00; 220 participants, one study; moderate-quality evidence). This suggests that if the risk with surgery alone is 40%, the risk with a concomitant MUS is between 19% and 40%. Rates of recurrent POP, OAB, and voiding dysfunction and the need for further surgery were not reported.Abdominal sacrocolpopexy with vs without Burch colposuspensionWe are uncertain whether there is a difference between groups in rates of subjective postoperative SUI (RR 1.31, 95% CI 0.19 to 9.01; 379 participants, two studies; I² = 90%; low-quality evidence), as RCTs produced results in different directions with a very wide confidence interval. We are also uncertain whether there is a difference between groups in rates of voiding dysfunction (RR 8.49, 95% CI 0.48 to 151.59; 66 participants, one study; low-quality evidence) or recurrent POP (RR 0.98, 95% CI 0.74 to 1.30; 250 participants, one study; moderate-quality evidence. No study reported OAB symptoms and need for further surgery.Vaginal repair with armed anterior vaginal mesh repair vs anterior native tissue Anterior armed mesh repair may slightly increase postoperative de novo SUI (RR 1.58, 95% CI 1.05 to 2.37; 905 participants, seven studies; I² = 0%; low-quality evidence) but may decrease recurrent POP (RR 0.29, 95% CI 0.22 to 0.38; 848 participants, five studies; I² = 0%; low-quality evidence). There may be little or no difference in rates of voiding dysfunction (RR 1.65, 95% CI 0.22 to 12.10; 125 participants, two studies; I² = 0%; low-quality evidence). Rates of OAB and the need for further surgery were not reported.Adverse events were infrequently reported in all studies; cost was not studied in any trial. In women with POP and SUI (symptomatic or occult), a concurrent MUS probably reduces postoperative SUI and should be discussed in counselling. It might be feasible to postpone the MUS and perform a delayed (two-stage) continence procedure, if required.Although an abdominal continence procedure (Burch colposuspension) during abdominal POP surgery in continent women reduced de novo SUI rates in one underpowered trial, another RCT reported conflicting results. Adding an MUS during vaginal POP repair might reduce postoperative development of SUI.An anterior native tissue repair might be better than use of transobturator mesh for preventing postoperative SUI; however, prolapse recurrence is more common with native tissue repair.

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Olanzapine as an antiemetic represents a new use of an antipsychotic drug. People with cancer may experience nausea and vomiting whilst receiving chemotherapy or radiotherapy, or whilst in the palliative phase of illness. To assess the efficacy and safety of olanzapine when used as an antiemetic in the prevention and treatment of nausea and vomiting related to cancer in adults. We searched CENTRAL, MEDLINE and Embase for published data on 20th September 2017, as well as ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform for unpublished trials. We checked reference lists, and contacted experts in the field and study authors. We included randomised controlled trials (RCTs) of olanzapine versus any comparator with or without adjunct therapies for the prevention or treatment, or both, of nausea or vomiting in people with cancer aged 18 years or older, in any setting, of any duration, with at least 10 participants per treatment arm. We used standard Cochrane methodology. We used GRADE to assess quality of evidence for each main outcome. We extracted data for absence of nausea or vomiting and frequency of serious adverse events as primary outcomes. We extracted data for patient perception of treatment, other adverse events, somnolence and fatigue, attrition, nausea or vomiting severity, breakthrough nausea and vomiting, rescue antiemetic use, and nausea and vomiting as secondary outcomes at specified time points. We included 14 RCTs (1917 participants) from high-, middle- and low-income countries, representing over 24 different cancers. Thirteen studies were in chemotherapy-induced nausea and vomiting. Oral olanzapine was administered during highly emetogenic (HEC) or moderately emetogenic (MEC) chemotherapy (12 studies); chemoradiotherapy (one study); or palliation (one study). Eight studies await classification and 13 are ongoing.The main comparison was olanzapine versus placebo/no treatment. Other comparisons were olanzapine versus NK1 antagonist, prokinetic, 5-HT3 antagonist or dexamethasone.We assessed all but one study as having one or more domains that were at high risk of bias. Eight RCTs with fewer than 50 participants per treatment arm, and 10 RCTs with issues related to blinding, were at high risk of bias. We downgraded GRADE assessments due to imprecision, inconsistency and study limitations.Olanzapine versus placebo/no treatmentPrimary outcomesOlanzapine probably doubles the likelihood of no nausea or vomiting during chemotherapy from 25% to 50% (risk ratio (RR) 1.98, 95% confidence interval (CI) 1.59 to 2.47; 561 participants; 3 studies; solid tumours; HEC or MEC therapy; moderate-quality evidence) when added to standard therapy. Number needed to treat for additional beneficial outcome (NNTB) was 5 (95% CI 3.3 - 6.6).It is uncertain if olanzapine increases the risk of serious adverse events (absolute risk difference 0.7% more, 95% CI 0.2 to 5.2) (RR 2.46, 95% CI 0.48 to 12.55; 7 studies, 889 participants, low-quality evidence).Secondary outcomesFour studies reported patient perception of treatment. One study (48 participants) reported no difference in patient preference. Four reported quality of life but data were insufficient for meta-analysis.Olanzapine may increase other adverse events (RR 1.71, 95% CI 0.99 to 2.96; 332 participants; 4 studies; low-quality evidence) and probably increases somnolence and fatigue compared to no treatment or placebo (RR 2.33, 95% CI 1.30 to 4.18; anticipated absolute risk 8.2% more, 95% CI 1.9 to 18.8; 464 participants; 5 studies; moderate-quality evidence). Olanzapine probably does not affect all-cause attrition (RR 0.99, 95% CI 0.57 to 1.73; 943 participants; 8 studies; I² = 0%). We are uncertain if olanzapine increases attrition due to adverse events (RR 3.00, 95% CI 0.13 to 70.16; 422 participants; 6 studies). No participants withdrew due to lack of efficacy.We are uncertain if olanzapine reduces breakthrough nausea and vomiting (RR 0.38, 95% CI 0.10 to 1.47; 501 participants; 2 studies; I² = 54%) compared to placebo or no treatment. No studies reported 50% reduction in severity of nausea or vomiting, use of rescue antiemetics, or attrition.We are uncertain of olanzapine's efficacy in reducing acute nausea or vomiting. Olanzapine probably reduces delayed nausea (RR 1.71, 95% CI 1.40 to 2.09; 585 participants; 3 studies) and vomiting (RR 1.28, 95% CI 1.14 to 1.42; 702 participants; 5 studies).Subgroup analysis: 5 mg versus 10 mgPlanned subgroup analyses found that it is unclear if 5 mg is as effective an antiemetic as 10 mg. There is insufficient evidence to exclude the possibility that 5 mg may confer a lower risk of somnolence and fatigue than 10 mg.Other comparisonsOne study (20 participants) compared olanzapine versus NK1 antagonists. We observed no difference in any reported outcomes.One study (112 participants) compared olanzapine versus a prokinetic (metoclopramide), reporting that olanzapine may increase freedom from overall nausea (RR 2.95, 95% CI 1.73 to 5.02) and overall vomiting (RR 3.03, 95% CI 1.78 to 5.14).One study (62 participants) examined olanzapine versus 5-HT3 antagonists, reporting olanzapine may increase the likelihood of 50% or greater reduction in nausea or vomiting at 48 hours (RR 1.82, 95% CI 1.11 to 2.97) and 24 hours (RR 1.36, 95% CI 0.80 to 2.34).One study (229 participants) compared olanzapine versus dexamethasone, reporting that olanzapine may reduce overall nausea (RR 1.73, 95% CI 1.37 to 2.18), overall vomiting (RR 1.27, 95% CI 1.10 to 1.48), delayed nausea (RR 1.66, 95% CI 1.33 to 2.08) and delayed vomiting (RR 1.25, 95% CI 1.07 to 1.45). There is moderate-quality evidence that oral olanzapine probably increases the likelihood of not being nauseous or vomiting during chemotherapy from 25% to 50% in adults with solid tumours, in addition to standard therapy, compared to placebo or no treatment. There is uncertainty whether it increases serious adverse events. It may increase the likelihood of other adverse events, probably increasing somnolence and fatigue. There is uncertainty about relative benefits and harms of 5 mg versus 10 mg.We identified only RCTs describing oral administration. The findings of this review cannot be extrapolated to provide evidence about the efficacy and safety of any injectable form (intravenous, intramuscular or subcutaneous) of olanzapine.

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Crohn's disease (CD) is a chronic immune-mediated condition of transmural inflammation in the gastrointestinal tract, associated with significant morbidity and decreased quality of life. The endocannabinoid system provides a potential therapeutic target for cannabis and cannabinoids and animal models have shown benefit in decreasing inflammation. However, there is also evidence to suggest transient adverse events such as weakness, dizziness and diarrhea, and an increased risk of surgery in people with CD who use cannabis. The objectives were to assess the efficacy and safety of cannabis and cannabinoids for induction and maintenance of remission in people with CD. We searched MEDLINE, Embase, AMED, PsychINFO, the Cochrane IBD Group Specialized Register, CENTRAL, ClinicalTrials.Gov, and the European Clinical Trials Register up to 17 October 2018. We searched conference abstracts, references and we also contacted researchers in this field for upcoming publications. Randomized controlled trials comparing any form of cannabis or its cannabinoid derivatives (natural or synthetic) to placebo or an active therapy for adults with Crohn's disease were included. Two authors independently screened search results, extracted data and assessed bias using the Cochrane risk of bias tool. The primary outcomes were clinical remission and relapse. Remission is commonly defined as a Crohn's disease activity index (CDAI) of < 150. Relapse is defined as a CDAI > 150. Secondary outcomes included clinical response, endoscopic remission, endoscopic improvement, histological improvement, quality of life, C-reactive protein (CRP) and fecal calprotectin measurements, adverse events (AEs), serious AEs, withdrawal due to AEs, and cannabis dependence and withdrawal effects. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. For continuous outcomes, we calculated the mean difference (MD) and 95% CI. Data were combined for analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). Data were analyzed on an intention-to-treat basis and the overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria. Three studies (93 participants) that assessed cannabis in people with active CD met the inclusion criteria. One ongoing study was also identified. Participants in two of the studies were adults with active Crohn's disease who had failed at least one medical treatment. The inclusion criteria for the third study were unclear. No studies that assessed cannabis therapy in quiescent CD were identified. The studies were not pooled due to differences in the interventional drug.One small study (N = 21) compared eight weeks of treatment with cannabis cigarettes containing 115 mg of D9-tetrahydrocannabinol (THC) to placebo cigarettes containing cannabis with the THC removed in participants with active CD. This study was rated as high risk of bias for blinding and other bias (cannabis participants were older than placebo). The effects of cannabis on clinical remission were unclear. Forty-five per cent (5/11) of the cannabis group achieved clinical remission compared with 10% (1/10) of the placebo group (RR 4.55, 95% CI 0.63 to 32.56; very low certainty evidence). A difference was observed in clinical response (decrease in CDAI score of >100 points) rates. Ninety-one per cent (10/11) of the cannabis group achieved a clinical response compared to 40% (4/10) of the placebo group (RR 2.27, 95% CI 1.04 to 4.97; very low certainty evidence). More AEs were observed in the cannabis cigarette group compared to placebo (RR 4.09, 95% CI 1.15 to 14.57; very low certainty evidence). These AEs were considered to be mild in nature and included sleepiness, nausea, difficulty with concentration, memory loss, confusion and dizziness. This study did not report on serious AEs or withdrawal due to AEs.One small study (N = 22) compared cannabis oil (5% cannabidiol) to placebo oil in people with active CD. This study was rated as high risk of bias for other bias (cannabis participants were more likely than placebo participants to be smokers). There was no difference in clinical remission rates. Forty per cent (4/10) of cannabis oil participants achieved remission at 8 weeks compared to 33% (3/9) of the placebo participants (RR 1.20, 95% CI 0.36 to 3.97; very low certainty evidence). There was no difference in the proportion of participants who had a serious adverse event. Ten per cent (1/10) of participants in the cannabis oil group had a serious adverse event compared to 11% (1/9) of placebo participants (RR 0.90, 95% CI 0.07 to 12.38, very low certainty evidence). Both serious AEs were worsening Crohn's disease that required rescue intervention. This study did not report on clinical response, CRP, quality of life or withdrawal due to AEs.One small study (N= 50) compared cannabis oil (15% cannabidiol and 4% THC) to placebo in participants with active CD. This study was rated as low risk of bias. Differences in CDAI and quality of life scores measured by the SF-36 instrument were observed. The mean quality of life score after 8 weeks of treatment was 96.3 in the cannabis oil group compared to 79.9 in the placebo group (MD 16.40, 95% CI 5.72 to 27.08, low certainty evidence). After 8 weeks of treatment, the mean CDAI score was118.6 in the cannabis oil group compared to 212.6 in the placebo group (MD -94.00, 95%CI -148.86 to -39.14, low certainty evidence). This study did not report on clinical remission, clinical response, CRP or AEs. The effects of cannabis and cannabis oil on Crohn's disease are uncertain. Thus no firm conclusions regarding the efficacy and safety of cannabis and cannabis oil in adults with active Crohn's disease can be drawn. The effects of cannabis or cannabis oil in quiescent Crohn's disease have not been investigated. Further studies with larger numbers of participants are required to assess the potential benefits and harms of cannabis in Crohn's disease. Future studies should assess the effects of cannabis in people with active and quiescent Crohn's disease. Different doses of cannabis and delivery modalities should be investigated.

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Periodontal (gum) disease and dental caries (tooth decay) are the most common causes of tooth loss; dental plaque plays a major role in the development of these diseases. Effective oral hygiene involves removing dental plaque, for example, by regular toothbrushing. People with intellectual disabilities (ID) can have poor oral hygiene and oral health outcomes. To assess the effects (benefits and harms) of oral hygiene interventions, specifically the mechanical removal of plaque, for people with intellectual disabilities (ID). Cochrane Oral Health's Information Specialist searched the following databases to 4 February 2019: Cochrane Oral Health's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane Register of Studies), MEDLINE Ovid, Embase Ovid and PsycINFO Ovid. ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. The Embase search was restricted by date due to the Cochrane Centralised Search Project, which makes available clinical trials indexed in Embase through CENTRAL. We handsearched specialist conference abstracts from the International Association of Disability and Oral Health (2006 to 2016). We included randomised controlled trials (RCTs) and some types of non-randomised studies (NRS) (non-RCTs, controlled before-after studies, interrupted time series studies and repeated measures studies) that evaluated oral hygiene interventions targeted at people with ID or their carers, or both. We used the definition of ID in the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10). We defined oral hygiene as the mechanical removal of plaque. We excluded studies that evaluated chemical removal of plaque, or mechanical and chemical removal of plaque combined. At least two review authors independently screened search records, identified relevant studies, extracted data, assessed risk of bias and judged the certainty of the evidence according to GRADE criteria. We contacted study authors for additional information if required. We reported RCTs and NRSs separately. We included 19 RCTs and 15 NRSs involving 1795 adults and children with ID and 354 carers. Interventions evaluated were: special manual toothbrushes, electric toothbrushes, oral hygiene training, scheduled dental visits plus supervised toothbrushing, discussion of clinical photographs showing plaque, varied frequency of toothbrushing, plaque-disclosing agents and individualised care plans. We categorised results as short (six weeks or less), medium (between six weeks and 12 months) and long term (more than 12 months).Most studies were small; all were at overall high or unclear risk of bias. None of the studies reported quality of life or dental caries. We present below the evidence available from RCTs (or NRS if the comparison had no RCTs) for gingival health (inflammation and plaque) and adverse effects, as well as knowledge and behaviour outcomes for the training studies.Very low-certainty evidence suggested a special manual toothbrush (the Superbrush) reduced gingival inflammation (GI), and possibly plaque, more than a conventional toothbrush in the medium term (GI: mean difference (MD) -12.40, 95% CI -24.31 to -0.49; plaque: MD -0.44, 95% CI -0.93 to 0.05; 1 RCT, 18 participants); brushing was carried out by the carers. In the short term, neither toothbrush showed superiority (GI: MD -0.10, 95% CI -0.77 to 0.57; plaque: MD 0.20, 95% CI -0.45 to 0.85; 1 RCT, 25 participants; low- to very low-certainty evidence).Moderate- and low-certainty evidence found no difference between electric and manual toothbrushes for reducing GI or plaque, respectively, in the medium term (GI: MD 0.02, 95% CI -0.06 to 0.09; plaque: standardised mean difference 0.29, 95% CI -0.07 to 0.65; 2 RCTs, 120 participants). Short-term findings were inconsistent (4 RCTs; low- to very low-certainty evidence).Low-certainty evidence suggested training carers in oral hygiene care had no detectable effect on levels of GI or plaque in the medium term (GI: MD -0.09, 95% CI -0.63 to 0.45; plaque: MD -0.07, 95% CI -0.26 to 0.13; 2 RCTs, 99 participants). Low-certainty evidence suggested oral hygiene knowledge of carers was better in the medium term after training (MD 0.69, 95% CI 0.31 to 1.06; 2 RCTs, 189 participants); this was not found in the short term, and results for changes in behaviour, attitude and self-efficacy were mixed.One RCT (10 participants) found that training people with ID in oral hygiene care reduced plaque but not GI in the short term (GI: MD -0.28, 95% CI -0.90 to 0.34; plaque: MD -0.47, 95% CI -0.92 to -0.02; very low-certainty evidence).One RCT (304 participants) found that scheduled dental recall visits (at 1-, 3- or 6-month intervals) plus supervised daily toothbrushing were more likely than usual care to reduce GI (pocketing but not bleeding) and plaque in the long term (low-certainty evidence).One RCT (29 participants) found that motivating people with ID about oral hygiene by discussing photographs of their teeth with plaque highlighted by a plaque-disclosing agent, did not reduce plaque in the medium term (very low-certainty evidence).One RCT (80 participants) found daily toothbrushing by dental students was more effective for reducing plaque in people with ID than once- or twice-weekly toothbrushing in the short term (low-certainty evidence).A benefit to gingival health was found by one NRS that evaluated toothpaste with a plaque-disclosing agent and one that evaluated individualised oral care plans (very low-certainty evidence).Most studies did not report adverse effects; of those that did, only one study considered them as a formal outcome. Some studies reported participant difficulties using the electric or special manual toothbrushes. Although some oral hygiene interventions for people with ID show benefits, the clinical importance of these benefits is unclear. The evidence is mainly low or very low certainty. Moderate-certainty evidence was available for only one finding: electric and manual toothbrushes were similarly effective for reducing gingival inflammation in people with ID in the medium term. Larger, higher-quality RCTs are recommended to endorse or refute the findings of this review. In the meantime, oral hygiene care and advice should be based on professional expertise and the needs and preferences of the individual with ID and their carers.

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Conventionally used soybean oil-based lipid emulsion (S-LE) have high polyunsaturated fatty acid (PUFA) content and phytosterols that may contribute to adverse effects in preterm infants. The newer lipid emulsions (LE) from different lipid sources are currently available for use in preterm infants. To compare the safety and efficacy of all LE for parenteral nutrition (PN) in preterm infants (less than 37 weeks' gestation) including preterm infants with surgical conditions or parenteral nutrition-associated liver disease (PNALD)/cholestasis using direct comparisons and pair-wise meta-analyses. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE (1946 to 18 June 2018), Embase (1974 to 18 July 2018), CINAHL (1982 to 18 June 2018), MIDRIS (1971 to 31 May 2018), conference proceedings, trial registries (ClinicalTrials.gov and WHO's Trials Registry and Platform), and reference lists of retrieved articles. Randomised or quasi-randomised controlled studies in preterm infants with or without surgical conditions or PNALD within the first six months of life. Data collection and analysis conformed to the methods of Cochrane Neonatal. We used the GRADE approach to assess the quality of evidence for important outcomes in addition to reporting statistical significance of results. We included 29 studies (n = 2037) in this review. LE were classified in three broad groups: 1. all fish oil-containing LE including pure fish oil-LE (F-LE) and multisource LE (e.g. medium-chain triglycerides (MCT)-olive-fish-soybean oil-LE (MOFS-LE), MCT-fish-soybean oil-LE (MFS-LE) and olive-fish-soybean oil-LE (OFS-LE); 2. conventional S-LE; 3. alternative-LE (e.g. MCT-soybean oil-LE (MS-LE), olive-soybean oil-LE and borage oil-based LE).We considered the following broad comparisons: fish oil LE versus non-fish oil LE; fish oil LE versus another fish oil LE; alternative-LE versus S-LE; alternative-LE versus another alternative-LE in preterm infants less than 37 weeks' gestation, preterm infants with surgical conditions and preterm infants with PNALD/cholestasis. Separate subgroup comparisons of each LE preparation were included within these broader groups.Most studies in preterm infants used PN for mean duration of four weeks or less and for longer duration in infants with cholestasis or surgical conditions.We defined the primary outcome of PNALD/cholestasis as conjugated bilirubin (Cbil) 2 mg/dL or greater and resolution of PNALD/cholestasis as Cbil less than 2 mg/dL. There was heterogeneity in definitions used by the included studies with Cbil cut-offs ranging from 17.1 μmol/L (1 mg/dL) up to 50 μmol/L (about 3 mg/dL).In preterm infants, meta-analysis found no evidence of a difference in the incidence of PNALD/cholestasis (Cbil cut-off: 2 mg/dl) between fish oil-LEs and all non-fish oil LEs (typical risk ratio (RR) 0.61, 95% confidence interval (CI) 0.24 to 1.56; typical risk difference (RD) -0.03, 95% CI -0.08 to 0.02; 4 studies; n = 328; low-quality evidence).We also considered an outcome allowing for any definition of PNALD (different Cbil cutoffs). In the meta-analysis for PNALD/cholestasis, using any definition and restricted to low or unclear risk of bias studies, there was no evidence of a difference between fish oil LE and all non-fish oil LE for incidence of cholestasis (typical RR 0.80, 95% CI 0.53 to 1.21; typical RD -0.02, 95% CI -0.05 to 0.02; 10 studies; n = 1024; low-quality evidence). There was no evidence of difference in subgroup meta-analyses of individual LE types in any comparison.In preterm infants with surgical conditions or cholestasis, there was only one small study each reporting no evidence of a difference in incidence or resolution of cholestasis respectively with use of a pure F-LE versus S-LE (using a Cbil cut-off of 2 mg/dL).In preterm infants with PNALD/cholestasis (using any definition), the meta-analysis showed significantly less cholestasis with the use of fish oil-LE compared to S-LE (typical RR 0.54, 95% CI 0.32 to 0.91; typical RD -0.39, 95% CI -0.65 to -0.12; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 9; 2 studies; n = 40; very low-quality evidence). However, this outcome had a very low number of participants from two small studies with methodological differences, one of which was terminated early, increasing the uncertainty about effect estimates.There were no differences between LE types in pair-wise meta-analyses for growth in preterm infants. There was paucity of studies in preterm infants with surgical conditions or cholestasis to perform meta-analyses for growth and most other outcomes.In the secondary outcomes for preterm infants, there was no difference between fish-oil LE and non-fish oil LE in meta-analysis for severe retinopathy of prematurity (ROP) (stage 3 or greater, or requiring surgery: typical RR 0.80, 95% CI 0.55 to 1.16; typical RD -0.03, 95% CI -0.07 to 0.02; 7 studies; n = 731; very low-quality evidence). There were no differences in the LE types in pair-wise meta-analyses for death, bronchopulmonary dysplasia (BPD), ventilation duration, patent ductus arteriosus, sepsis, necrotising enterocolitis, intraventricular haemorrhage, periventricular leukomalacia, jaundice, hyperglycaemia, hypertriglyceridaemia, intrahepatocellular lipid content and conjugated bilirubin levels in any comparison.In surgical infants, one study (n = 19) reported no differences in death, sepsis rates, Cbil and neurodevelopmental outcomes with pure F-LE versus S-LE.In infants with cholestasis, there were no evidence of differences in death or sepsis in meta-analyses between fish oil-LE and S-LE; (2 studies; n = 40; very low-quality evidence). In the current review, we did not find any particular LE with or without fish oil to be better than another LE in preterm infants for prevention of PNALD/cholestasis, growth, mortality, ROP, BPD and other neonatal outcomes.In preterm infants with surgical conditions or cholestasis, there is currently insufficient evidence from randomised studies to determine with any certainty if fish oil LEs offer advantage in prevention or resolution of cholestasis or in any other clinical outcome.Further research, with larger well-designed trials, is warranted to evaluate the ideal composition of LE in preterm infants and the role of fish oil-containing and other LEs in the prevention and resolution of PNALD, ROP and other clinical outcomes.

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Osteoarthritis affecting the knee is common and represents a continuum of disease from early cartilage thinning to full-thickness cartilage loss, bony erosion, and deformity. Many studies do not stratify their results based on the severity of the disease at baseline or recruitment. To assess the benefits and harms of surgical intervention for the management of symptomatic mild to moderate knee osteoarthritis defined as knee pain and radiographic evidence of non-end stage osteoarthritis (Kellgren-Lawrence grade 1, 2, 3 or equivalent on MRI/arthroscopy). Outcomes of interest included pain, function, radiographic progression, quality of life, short-term serious adverse events, re-operation rates and withdrawals due to adverse events. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase up to May 2018. We also conducted searches of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform for ongoing trials. Authors of trials were contacted if some but not all their participants appeared to fit our inclusion criteria. We included randomised controlled trials that compared surgery to non-surgical interventions (including sham and placebo control groups, exercise or physiotherapy, and analgesic or other medication), injectable therapies, and trials that compared one type of surgical intervention to another surgical intervention in people with symptomatic mild to moderate knee osteoarthritis. Two review authors independently selected trials and extracted data using standardised forms. We analysed the quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. A total of five studies involving 566 participants were identified as eligible for this review. Single studies compared arthroscopic partial meniscectomy to physical therapy (320 participants), arthroscopic surgery (debridement ± synovectomy ± chondroplasty) to closed needle joint lavage with saline (32 participants) and high tibial osteotomy surgery to knee joint distraction surgery (62 participants). Two studies (152 participants) compared arthroscopic surgery (washout ± debridement; debridement) to a hyaluronic acid injection. Only one study was at low risk of selection bias, and due to the difficulty of blinding participants to their treatment, all studies were at risk of performance and detection bias.Reporting of results in this summary has been restricted to the primary comparison: surgical intervention versus non-surgical intervention.A single study, included 320 participants with symptoms consistent with meniscal tear. All subjects had the meniscal tear confirmed on knee MRI and radiographic evidence of mild to moderate osteoarthritis (osteophytes, cartilage defect or joint space narrowing). Patients with severe osteoarthritis (KL grade 4) were excluded. The study compared arthroscopic partial meniscectomy and physical therapy to physical therapy alone (a six-week individualised progressive home exercise program). This study was at low risk of selection bias and outcome reporting biases, but was susceptible to performance and detection biases. A high rate of cross-over (30.2%) occurred from the physical therapy group to the arthroscopic group.Low-quality evidence suggests there may be little difference in pain and function at 12 months follow-up in people who have arthroscopic partial meniscectomy and those who have physical therapy. Evidence was downgraded to low quality due to risk of bias and imprecision.Mean pain was 19.3 points on a 0 to 100 point KOOS pain scale with physical therapy at 12 months follow-up and was 0.2 points better with surgery (95% confidence interval (CI) 4.05 better to 3.65 points worse with surgery, an absolute improvement of 0.2% (95% CI 4% better to 4% worse) and relative improvement 0.4% (95% CI 9% better to 8% worse) (low quality evidence). Mean function was 14.5 on a 0 to 100 point KOOS function scale with physical therapy at 12 months follow-up and 0.8 points better with surgery (95% CI 4.3 better to 2.7 worse); 0.8% absolute improvement (95% CI 4% better to 3% worse) and 2.1% relative improvement (95% CI 11% better to 7% worse) (low quality evidence).Radiographic structural osteoarthritis progression and quality of life outcomes were not reported.Due to very low quality evidence, we are uncertain if surgery is associated with an increased risk of serious adverse events, incidence of total knee replacement or withdrawal rates. Evidence was downgraded twice due to very low event rates, and once for risk of bias.At 12 months, the surgery group had a total of three serious adverse events including fatal pulmonary embolism, myocardial infarction and hypoxaemia. The physical therapy alone group had two serious adverse events including sudden death and stroke (Peto OR 1.58, 95% CI 0.27 to 9.21); 1% more events with surgery (95% CI 2% less to 3% more) and 58% relative change (95% CI 73% less to 821% more). One participant in each group withdrew due to adverse events.Two of 164 participants (1.2%) in the physical therapy group and three of 156 in the surgery group underwent conversion to total knee replacement within 12 months (Peto OR 1.76, 95% CI 0.43 to 7.13); 1% more events with surgery (95% CI 2% less to 5% more); 76% relative change (95% CI 57% less to 613% more). The review found no placebo-or sham-controlled trials of surgery in participants with symptomatic mild to moderate knee osteoarthritis. There was low quality evidence that there may be no evidence of a difference between arthroscopic partial meniscectomy surgery and a home exercise program for the treatment of this condition. Similarly, low-quality evidence from a few small trials indicates there may not be any benefit of arthroscopic surgery over other non-surgical treatments including saline irrigation and hyaluronic acid injection, or one type of surgery over another. We are uncertain of the risk of adverse events or of progressing to total knee replacement due to very small event rates. Thus, there is uncertainty around the current evidence to support or oppose the use of surgery in mild to moderate knee osteoarthritis. As no benefit has been demonstrated from the low quality trials included in this review, it is possible that future higher quality trials for these surgical interventions may not contradict these results.

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Assisted reproductive technologies (ART) including in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), combine gametes to enhance the probability of fertilisation and pregnancy. Advanced sperm selection techniques are increasingly employed in ART, most commonly in cycles utilising ICSI. Advanced sperm selection techniques are proposed to improve the chance that structurally intact and mature sperm with high DNA integrity are selected for fertilisation. Strategies include selection according to surface charge; sperm apoptosis; sperm birefringence; ability to bind to hyaluronic acid; and sperm morphology under ultra-high magnification. These techniques are intended to improve ART outcomes. To evaluate the effectiveness and safety of advanced sperm selection techniques on ART outcomes. We conducted a systematic search of electronic databases (Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL via the Cochrane Register of Studies Online, MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL); trials registers (ClinicalTrials.gov, Current Controlled Trials, and the World Health Organization International Clinical Trials Registry Platform); conference abstracts (Web of Knowledge); and grey literature (OpenGrey) for relevant randomised controlled trials (RCTs). We handsearched the reference lists of included studies and similar reviews. The search was conducted in June 2018. We included RCTs comparing advanced sperm selection techniques versus standard IVF, ICSI, or another technique. We excluded studies of intracytoplasmic morphologically selected sperm injection (IMSI), as they are subject to a separate Cochrane Review. Primary outcomes measured were live birth and miscarriage per woman randomly assigned. Secondary outcome measures included clinical pregnancy per woman randomly assigned. Secondary adverse events measured included miscarriage per clinical pregnancy and foetal abnormality. Two review authors independently assessed study eligibility and risk of bias and extracted data. Any disagreements were resolved by consultation with a third review author. We consulted study investigators to resolve queries. Risk ratios (RRs) were calculated with 95% confidence intervals (CIs). We combined studies using a fixed-effect model. We evaluated the quality of the evidence using GRADE methods. We included eight RCTs (4147 women). The quality of evidence ranged from very low to low. The main limitations were imprecision, performance bias, and attrition bias.Hyaluronic acid selected sperm-intracytoplasmic sperm injection (HA-ICSI) compared to ICSITwo RCTs compared the effects of HA-ICSI versus ICSI on live birth. The quality of the evidence was low. There may be little or no difference between groups: 25% chance of live birth with ICSI versus 24.5% to 31% with HA-ICSI (RR 1.09, 95% CI 0.97 to 1.23, 2903 women, I<sup2</sup = 0%, low-quality evidence). Three RCTs reported on miscarriage. HA-ICSI may decrease miscarriage per woman randomly assigned: 7% chance of miscarriage with ICSI versus 3% to 6% chance with HA-ICSI (RR 0.61, 95% CI 0.45 to 0.83, 3005 women, I<sup2</sup = 0%, low-quality evidence) and per clinical pregnancy: 20% chance of miscarriage with ICSI compared to 9% to 16% chance with HA-ICSI (RR 0.62, 95% CI 0.46 to 0.82, 1065 women, I<sup2</sup = 0%, low-quality evidence). Four RCTs reported on clinical pregnancy. There may be little or no difference between groups: 37% chance of pregnancy with ICSI versus 34% to 40% chance with HA-ICSI (RR 1.00, 95% CI 0.92 to 1.09, 3492 women, I<sup2</sup = 0%, low-quality evidence).HA-ICSI compared to SpermSlowOne RCT compared HA-ICSI to SpermSlow. The quality of the evidence was very low. We are uncertain whether HA-ICSI improves live birth compared to SpermSlow (RR 1.13, 95% CI 0.64 to 2.01, 100 women) or clinical pregnancy (RR 1.05, 95% CI 0.66 to 1.68, 100 women). We are uncertain whether HA-ICSI reduces miscarriage per woman (RR 0.80, 95% CI 0.23 to 2.81, 100 women) or per clinical pregnancy (RR 0.76, 95% CI 0.24 to 2.44, 41 women).Magnetic-activated cell sorting (MACS) compared to ICSIOne RCT compared MACS to ICSI for live birth; three reported clinical pregnancy; and two reported miscarriage. The quality of the evidence was very low. We are uncertain whether MACS improves live birth (RR 1.95, 95% CI 0.89 to 4.29, 62 women) or clinical pregnancy (RR 1.05, 95% CI 0.84 to 1.31, 413 women, I<sup2</sup = 81%). We are also uncertain if MACS reduces miscarriage per woman (RR 0.95, 95% CI 0.16 to 5.63, 150 women, I<sup2</sup = 0%) or per clinical pregnancy (RR 0.51, 95%CI 0.09 to 2.82, 53 women, I<sup2</sup=0)Zeta sperm selection compared to ICSIOne RCT evaluated Zeta sperm selection. The quality of the evidence was very low. We are uncertain of the effect of Zeta sperm selection on live birth (RR 2.48, 95% CI 1.34 to 4.56, 203 women) or clinical pregnancy (RR 1.82, 95% CI 1.20 to 2.75, 203 women). We are also uncertain if Zeta sperm selection reduces miscarriage per woman (RR 0.73, 95% CI 0.16 to 3.37, 203 women) or per clinical pregnancy (RR 0.41, 95% CI 0.10 to 1.68, 1 RCT, 62 women).MACS compared to HA-ICSIOne RCT compared MACS to HA-ICSI. This study did not report on live birth. The quality of the evidence was very low. We are uncertain of the effect on miscarriage per woman (RR 1.52, 95% CI 0.10 to 23.35, 78 women) or per clinical pregnancy (RR 1.06, 95% CI 0.07 to 15.64, 37 women). We are also uncertain of the effect on clinical pregnancy (RR 1.44, 95% CI 0.91 to 2.27, 78 women). The evidence suggests that sperm selected by hyaluronic acid binding may have little or no effect on live birth or clinical pregnancy but may reduce miscarriage. We are uncertain of the effect of Zeta sperm selection on live birth, clinical pregnancy, and miscarriage due principally to the very low quality of the evidence for this intervention. We are uncertain of the effect of the other selection techniques on live birth, miscarriage, or pregnancy.Further high-quality studies, including the awaited data from the identified ongoing studies, are required to evaluate whether any of these advanced sperm selection techniques can be recommended for use in routine practice.

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Infants born preterm (before 37 weeks' gestation) have poorer outcomes than infants at term, particularly if born before 32 weeks. Early cord clamping has been standard practice over many years, and enables quick transfer of the infant to neonatal care. Delayed clamping allows blood flow between the placenta, umbilical cord and baby to continue, and may aid transition. Keeping baby at the mother's side enables neonatal care with the cord intact and this, along with delayed clamping, may improve outcomes. Umbilical cord milking (UCM) is proposed for increasing placental transfusion when immediate care for the preterm baby is needed. This Cochrane Review is a further update of a review first published in 2004 and updated in 2012. To assess the effects on infants born at less than 37 weeks' gestation, and their mothers of: 1) delayed cord clamping (DCC) compared with early cord clamping (ECC) both with immediate neonatal care after cord clamping; 2) DCC with immediate neonatal care with cord intact compared with ECC with immediate neonatal care after cord clamping; 3) DCC with immediate neonatal care after cord clamping compared with UCM; 4) UCM compared with ECC with immediate neonatal care after cord clamping. We searched the Cochrane Pregnancy and Childbirth Group Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 November 2017), and reference lists of retrieved studies. We updated the search in November 2018 and added nine new trial reports to the awaiting classification section to be assessed at the next update. Randomised controlled trials (RCTs) comparing delayed with early clamping of the umbilical cord (with immediate neonatal care after cord clamping or with cord intact) and UCM for births before 37 weeks' gestation. Quasi-RCTs were excluded. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Random-effects are used in all meta-analyses. Review authors assessed the certainty of the evidence using the GRADE approach. This update includes forty-eight studies, involving 5721 babies and their mothers, with data available from 40 studies involving 4884 babies and their mothers. Babies were between 24 and 36<sup+6</sup weeks' gestation at birth and multiple births were included. The data are mostly from high-income countries. Delayed clamping ranged between 30 to 180 seconds, with most studies delaying for 30 to 60 seconds. Early clamping was less than 30 seconds and often immediate. UCM was mostly before cord clamping but some were milked after cord clamping. We undertook subgroup analysis by gestation and type of intervention, and sensitivity analyses by low risk of selection and attrition bias.All studies were high risk for performance bias and many were unclear for other aspects of risk of bias. Certainty of the evidence using GRADE was mostly low, mainly due to imprecision and unclear risk of bias.Delayed cord clamping (DCC) versus early cord clamping (ECC) both with immediate neonatal care after cord clamping (25 studies, 3100 babies and their mothers)DCC probably reduces the number of babies who die before discharge compared with ECC (average risk ratio (aRR) 0.73, 95% confidence interval (CI) 0.54 to 0.98, 20 studies, 2680 babies (moderate certainty)).No studies reported on 'Death or neurodevelopmental impairment' in the early years'.DCC may make little or no difference to the number of babies with severe intraventricular haemorrhage (IVH grades 3 and 4) (aRR 0.94, 95% CI 0.63 to 1.39, 10 studies, 2058 babies, low certainty) but slightly reduces the number of babies with any grade IVH (aRR 0.83, 95% CI 0.70 to 0.99, 15 studies, 2333 babies, high certainty).DCC has little or no effect on chronic lung disease (CLD) (aRR 1.04, 95% CI 0.94 to 1.14, 6 studies, 1644 babies, high certainty).Due to insufficient data, we were unable to form conclusions regarding periventricular leukomalacia (PVL) (aRR 0.58, 95% CI 0.26 to 1.30, 4 studies, 1544 babies, low certainty) or maternal blood loss of 500 mL or greater (aRR 1.14, 95% CI 0.07 to 17.63, 2 studies, 180 women, very low certainty).We identified no important heterogeneity in subgroup or sensitivity analyses.Delayed cord clamping (DCC) with immediate neonatal care with cord intact versus early cord clamping (ECC) (one study, 276 babies and their mothers)There are insufficient data to be confident in our findings, but DCC with immediate neonatal care with cord intact may reduce the number of babies who die before discharge, although the data are also compatible with a slight increase in mortality, compared with ECC (aRR 0.47, 95% CI 0.20 to 1.11, 1 study, 270 babies, low certainty). DCC may also reduce the number of babies who die or have neurodevelopmental impairment in early years (aRR 0.61, 95% CI 0.39 to 0.96, 1 study, 218 babies, low certainty). There may be little or no difference in: severe IVH; all grades IVH; PVL; CLD; maternal blood loss ≥ 500 mL, assessed as low certainty mainly due to serious imprecision.Delayed cord clamping (DCC) with immediate neonatal care after cord clamping versus umbilical cord milking (UCM) (three studies, 322 babies and their mothers) and UCM versus early cord clamping (ECC) (11 studies, 1183 babies and their mothers)There are insufficient data for reliable conclusions about the comparative effects of UCM compared with delayed or early clamping (mostly low or very low certainty). Delayed, rather than early, cord clamping may reduce the risk of death before discharge for babies born preterm. There is insufficient evidence to show what duration of delay is best, one or several minutes, and therefore the optimum time to clamp the umbilical cord remains unclear. Whilst the current evidence supports not clamping the cord before 30 seconds at preterm births, future trials could compare different lengths of delay. Immediate neonatal care with the cord intact requires further study, and there are insufficient data on UCM.The nine new reports awaiting further classification may alter the conclusions of the review once assessed.

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A statement from the Editor in Chief about this review and its planned update is available here: https://www.cochrane.org/news/cfs Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is a serious disorder characterised by persistent postexertional fatigue and substantial symptoms related to cognitive, immune and autonomous dysfunction. There is no specific diagnostic test, therefore diagnostic criteria are used to diagnose CFS. The prevalence of CFS varies by type of diagnostic criteria used. Existing treatment strategies primarily aim to relieve symptoms and improve function. One treatment option is exercise therapy. The objective of this review was to determine the effects of exercise therapy for adults with CFS compared with any other intervention or control on fatigue, adverse outcomes, pain, physical functioning, quality of life, mood disorders, sleep, self-perceived changes in overall health, health service resources use and dropout. We searched the Cochrane Common Mental Disorders Group controlled trials register, CENTRAL, and SPORTDiscus up to May 2014, using a comprehensive list of free-text terms for CFS and exercise. We located unpublished and ongoing studies through the World Health Organization International Clinical Trials Registry Platform up to May 2014. We screened reference lists of retrieved articles and contacted experts in the field for additional studies. We included randomised controlled trials (RCTs) about adults with a primary diagnosis of CFS, from all diagnostic criteria, who were able to participate in exercise therapy. Two review authors independently performed study selection, 'Risk of bias' assessments and data extraction. We combined continuous measures of outcomes using mean differences (MDs) or standardised mean differences (SMDs). To facilitate interpretation of SMDs, we re-expressed SMD estimates as MDs on more common measurement scales. We combined dichotomous outcomes using risk ratios (RRs). We assessed the certainty of evidence using GRADE. We included eight RCTs with data from 1518 participants.Exercise therapy lasted from 12 weeks to 26 weeks. The studies measured effect at the end of the treatment and at long-term follow-up, after 50 weeks or 72 weeks.Seven studies used aerobic exercise therapies such as walking, swimming, cycling or dancing, provided at mixed levels in terms of intensity of the aerobic exercise from very low to quite rigorous, and one study used anaerobic exercise. Control groups consisted of passive control, including treatment as usual, relaxation or flexibility (eight studies); cognitive behavioural therapy (CBT) (two studies); cognitive therapy (one study); supportive listening (one study); pacing (one study); pharmacological treatment (one study) and combination treatment (one study).Most studies had a low risk of selection bias. All had a high risk of performance and detection bias.Exercise therapy compared with 'passive' controlExercise therapy probably reduces fatigue at end of treatment (SMD -0.66, 95% CI -1.01 to -0.31; 7 studies, 840 participants; moderate-certainty evidence; re-expressed MD -3.4, 95% CI -5.3 to -1.6; scale 0 to 33). We are uncertain if fatigue is reduced in the long term because the certainty of the evidence is very low (SMD -0.62, 95 % CI -1.32 to 0.07; 4 studies, 670 participants; re-expressed MD -3.2, 95% CI -6.9 to 0.4; scale 0 to 33).We are uncertain about the risk of serious adverse reactions because the certainty of the evidence is very low (RR 0.99, 95% CI 0.14 to 6.97; 1 study, 319 participants).Exercise therapy may moderately improve physical functioning at end of treatment, but the long-term effect is uncertain because the certainty of the evidence is very low. Exercise therapy may also slightly improve sleep at end of treatment and at long term. The effect of exercise therapy on pain, quality of life and depression is uncertain because evidence is missing or of very low certainty.Exercise therapy compared with CBTExercise therapy may make little or no difference to fatigue at end of treatment (MD 0.20, 95% CI -1.49 to 1.89; 1 study, 298 participants; low-certainty evidence), or at long-term follow-up (SMD 0.07, 95% CI -0.13 to 0.28; 2 studies, 351 participants; moderate-certainty evidence).We are uncertain about the risk of serious adverse reactions because the certainty of the evidence is very low (RR 0.67, 95% CI 0.11 to 3.96; 1 study, 321 participants).The available evidence suggests that there may be little or no difference between exercise therapy and CBT in physical functioning or sleep (low-certainty evidence) and probably little or no difference in the effect on depression (moderate-certainty evidence). We are uncertain if exercise therapy compared to CBT improves quality of life or reduces pain because the evidence is of very low certainty.Exercise therapy compared with adaptive pacingExercise therapy may slightly reduce fatigue at end of treatment (MD -2.00, 95% CI -3.57 to -0.43; scale 0 to 33; 1 study, 305 participants; low-certainty evidence) and at long-term follow-up (MD -2.50, 95% CI -4.16 to -0.84; scale 0 to 33; 1 study, 307 participants; low-certainty evidence).We are uncertain about the risk of serious adverse reactions (RR 0.99, 95% CI 0.14 to 6.97; 1 study, 319 participants; very low-certainty evidence).The available evidence suggests that exercise therapy may slightly improve physical functioning, depression and sleep compared to adaptive pacing (low-certainty evidence). No studies reported quality of life or pain.Exercise therapy compared with antidepressantsWe are uncertain if exercise therapy, alone or in combination with antidepressants, reduces fatigue and depression more than antidepressant alone, as the certainty of the evidence is very low. The one included study did not report on adverse reactions, pain, physical functioning, quality of life, sleep or long-term results. Exercise therapy probably has a positive effect on fatigue in adults with CFS compared to usual care or passive therapies. The evidence regarding adverse effects is uncertain. Due to limited evidence it is difficult to draw conclusions about the comparative effectiveness of CBT, adaptive pacing or other interventions. All studies were conducted with outpatients diagnosed with 1994 criteria of the Centers for Disease Control and Prevention or the Oxford criteria, or both. Patients diagnosed using other criteria may experience different effects.

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Cerebral palsy (CP) is the most common cause of physical disabilities in children in high-income countries. Spasticity is the most common motor disturbance in CP. Botulinum toxin type A (BoNT-A) is considered the first-line treatment for focal spasticity in people with CP. To evaluate the effectiveness and safety of BoNT-A compared to other treatments used in the management of lower limb spasticity in children with CP. We searched CENTRAL, PubMed, four other databases, and two trial registers in October 2018. We also searched the reference lists of relevant studies and reviews and contacted experts in the field. We did not apply any date or language restrictions. Randomised controlled trials of children with CP, aged between birth and 19 years, treated with BoNT-A injections in the lower limb muscles compared to other interventions. The primary outcomes were gait analysis and function. The secondary outcomes were joint range of motion, quality of life, satisfaction, spasticity, and adverse events. Two review authors independently selected studies, extracted data, assessed risk of bias, and rated the quality of the evidence using GRADE. A third review author arbitrated in case of disagreements. We conducted meta-analyses of available data whenever possible, analysing dichotomous data with risk ratios (RR), and continuous data with mean differences (MD) or standardised mean differences (SMD), with 95% confidence intervals (CI). We considered a 5% significance level for all analyses.Whenever possible, we analysed outcomes at the time points at which they were assessed: short term (2 to 8 weeks); medium term (12 to 16 weeks); and long term (&gt; 24 weeks). We included 31 randomised controlled trials assessing 1508 participants. Most studies included ambulatory patients with more than one motor type of CP, and with a mean age of between three and seven years. There was a slight predominance of males.Studies compared BoNT-A in the lower limb muscles to usual care or physiotherapy (14 studies), placebo or sham (12 studies), serial casting (4 studies), or orthoses (1 study).We rated studies as at high or unclear risk of bias mainly due to random sequence generation, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment.BoNT-A versus usual care or physiotherapyBoNT-A might improve overall gait scores at medium-term follow-up (MD 2.80, 95% CI 1.55 to 4.05; 1 study, 40 children; very low-quality evidence) and is moderately effective at improving function at short-term (SMD 0.59, 95% CI 0.23 to 0.95; 2 studies, 123 children) and medium-term (SMD 1.04, 95% CI 0.16 to 1.91; 4 studies, 191 children) follow-up (all very low-quality evidence).BoNT-A improves ankle range of motion, satisfaction, and ankle plantarflexors spasticity at one or more time points (very low-quality evidence).The proportion of adverse events in the BoNT-A group was 0.37 (95% CI 0.08 to 0.66; I<sup2</sup = 95%; very low-quality evidence). No adverse events were reported in the control group.BoNT-A versus placebo or shamBoNT-A improves overall gait scores at short-term (RR 1.66, 95% CI 1.16 to 2.37, P = 0.006; 4 studies, 261 assessments) and medium-term (RR 1.90, 95% CI 1.32 to 2.74, P &lt; 0.001; 3 studies, 248 assessments) follow-up, and may improve peak ankle dorsiflexion in stance (MD 15.90 degrees, 95% CI 4.87 to 26.93, P = 0.005; 1 study, 19 children) and in swing (MD 10.20 degrees, 95% CI 4.01 to 16.39, P = 0.001; 1 study, 19 children) at short-term follow-up (all moderate-quality evidence).BoNT-A is not more effective than placebo or sham at improving function at short-term (SMD 0.24, 95% CI -0.35 to 0.83, P = 0.42; 4 studies, 305 children) or long-term (SMD -0.07, 95% CI -0.48 to 0.35, P = 0.76; 2 studies, 91 children) follow-up, but has a small positive effect at medium-term follow-up (SMD 0.28, 95% CI 0.06 to 0.49, P = 0.01; 5 studies, 327 children) (all moderate-quality evidence).BoNT-A improves passive ankle range of motion, satisfaction, and ankle plantarflexors spasticity at one or more time points (moderate-quality evidence).There was no difference between groups in the rate of adverse events at short-term follow-up (RR 1.29, 95% CI 0.87 to 1.93, P = 0.21; 12 studies, 918 children; moderate-quality evidence).BoNT-A versus serial castingThere was no difference between groups for overall gait scores at short-term (MD 0.00, 95% CI -1.66 to 1.66); medium-term (MD 0.65, 95% CI -1.21 to 2.51); or long-term (MD 0.46, 95% CI -1.33 to 2.25) follow-up in one study with 18 children (moderate-quality evidence).BoNT-A improved instrumented gait analysis only in terms of ankle dorsiflexion at initial contact (MD 6.59 degrees, 95% CI 1.39 to 11.78, P = 0.01; 2 studies, 47 children). There was no difference between groups for peak ankle dorsiflexion in stance and swing, and gait speed at any time point (moderate- and low-quality evidence).BoNT-A is not more effective than serial casting at improving function, ankle range of motion, and spasticity at any time point (moderate- and low-quality evidence).BoNT-A is not associated with a higher risk of adverse events than serial casting (RR 0.59, 95% CI 0.03 to 11.03; 3 studies, 64 children; low-quality evidence).BoNT-A versus orthosesThere was no difference between groups for function at medium-term follow-up (MD 11.14, 95% CI -0.05 to 22.33; 1 study, 43 children), but BoNT-A is more effective than orthoses at improving hip range of motion and hip adductors spasticity (all very low-quality evidence). The quality of the evidence was low or very low for most of the outcomes analysed. We found limited evidence that BoNT-A is more effective than placebo or a non-placebo control at improving gait, joint range of motion, satisfaction, and lower limb spasticity in children with CP, whereas the results for function were contradictory. The rate of adverse events with BoNT-A is similar to placebo. BoNT-A is not more effective than ankle serial casting to treat ankle contractures for any of the assessed outcomes, but is more effective than orthotics at improving range of motion and spasticity.

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Ulcerative colitis is an inflammatory condition affecting the colon, with an annual incidence of approximately 10 to 20 per 100,000 people. The majority of people with ulcerative colitis can be put into remission, leaving a group who do not respond to first- or second-line therapies. There is a significant proportion of people who experience adverse effects with current therapies. Consequently, new alternatives for the treatment of ulcerative colitis are constantly being sought. Probiotics are live microbial feed supplements that may beneficially affect the host by improving intestinal microbial balance, enhancing gut barrier function and improving local immune response. To assess the efficacy of probiotics compared with placebo or standard medical treatment (5-aminosalicylates, sulphasalazine or corticosteroids) for the induction of remission in people with active ulcerative colitis. We searched CENTRAL, MEDLINE, Embase, and two other databases on 31 October 2019. We contacted authors of relevant studies and manufacturers of probiotics regarding ongoing or unpublished trials that may be relevant to the review, and we searched ClinicalTrials.gov. We also searched references of trials for any additional trials. Randomised controlled trials (RCTs) investigating the effectiveness of probiotics compared to standard treatments or placebo in the induction of remission of active ulcerative colitis. We considered both adults and children, with studies reporting outcomes of clinical, endoscopic, histologic or surgical remission as defined by study authors DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We analysed data using Review Manager 5. We expressed dichotomous and continuous outcomes as risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE methodology. In this review, we included 14 studies (865 randomised participants) that met the inclusion criteria. Twelve of the studies looked at adult participants and two studies looked at paediatric participants with mild to moderate ulcerative colitis, the average age was between 12.5 and 47.7 years. The studies compared probiotics to placebo, probiotics to 5-ASA and a combination of probiotics plus 5-ASA compared to 5-ASA alone. Seven studies used a single probiotic strain and seven used a mixture of strains. The studies ranged from two weeks to 52 weeks. The risk of bias was high for all except two studies due to allocation concealment, blinding of participants, incomplete reports of outcome data and selective reporting. This led to GRADE ratings of the evidence ranging from moderate to very low. Probiotics versus placebo Probiotics may induce clinical remission when compared to placebo (RR 1.73, 95% CI 1.19 to 2.54; 9 studies, 594 participants; low-certainty evidence; downgraded due to imprecision and risk of bias, number needed to treat for an additional beneficial outcome (NNTB) 5). Probiotics may lead to an improvement in clinical disease scores (RR 2.29, 95% CI 1.13 to 4.63; 2 studies, 54 participants; downgraded due to risk of bias and imprecision). There may be little or no difference in minor adverse events, but the evidence is of very low certainty (RR 1.04, 95% CI 0.42 to 2.59; 7 studies, 520 participants). Reported adverse events included abdominal bloating and discomfort. Probiotics did not lead to any serious adverse events in any of the seven studies that reported on it, however five adverse events were reported in the placebo arm of one study (RR 0.09, CI 0.01 to 1.66; 1 study, 526 participants; very low-certainty evidence; downgraded due to high risk of bias and imprecision). Probiotics may make little or no difference to withdrawals due to adverse events (RR 0.85, 95% CI 0.42 to 1.72; 4 studies, 401 participants; low-certainty evidence). Probiotics versus 5-ASA There may be little or no difference in the induction of remission with probiotics when compared to 5-ASA (RR 0.92, 95% CI 0.73 to 1.16; 1 study, 116 participants; low-certainty evidence; downgraded due to risk of bias and imprecision). There may be little or no difference in minor adverse events, but the evidence is of very low certainty (RR 1.33, 95% CI 0.53 to 3.33; 1 study, 116 participants). Reported adverse events included abdominal pain, nausea, headache and mouth ulcers. There were no serious adverse events with probiotics, however perforated sigmoid diverticulum and respiratory failure in a patient with severe emphysema were reported in the 5-ASA arm (RR 0.21, 95% CI 0.01 to 4.22; 1 study, 116 participants; very low-certainty evidence). Probiotics combined with 5-ASA versus 5-ASA alone Low-certainty evidence from a single study shows that when combined with 5-ASA, probiotics may slightly improve the induction of remission (based on the Sunderland disease activity index) compared to 5-ASA alone (RR 1.22 CI 1.01 to 1.47; 1 study, 84 participants; low-certainty evidence; downgraded due to unclear risk of bias and imprecision). No information about adverse events was reported. Time to remission, histological and biochemical outcomes were sparsely reported in the studies. None of the other secondary outcomes (progression to surgery, need for additional therapy, quality of life scores, or steroid withdrawal) were reported in any of the studies. Low-certainty evidence suggests that probiotics may induce clinical remission in active ulcerative colitis when compared to placebo. There may be little or no difference in clinical remission with probiotics alone compared to 5-ASA. There is limited evidence from a single study which failed to provide a definition of remission, that probiotics may slightly improve the induction of remission when used in combination with 5-ASA. There was no evidence to assess whether probiotics are effective in people with severe and more extensive disease, or if specific preparations are superior to others. Further targeted and appropriately designed RCTs are needed to address the gaps in the evidence base. In particular, appropriate powering of studies and the use of standardised participant groups and outcome measures in line with the wider field are needed, as well as reporting to minimise risk of bias.

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Anaemia is a condition where the number of red blood cells (and consequently their oxygen-carrying capacity) is insufficient to meet the body's physiologic needs. Fortification of wheat flour is deemed a useful strategy to reduce anaemia in populations. To determine the benefits and harms of wheat flour fortification with iron alone or with other vitamins and minerals on anaemia, iron status and health-related outcomes in populations over two years of age. We searched CENTRAL, MEDLINE, Embase, CINAHL, and other databases up to 4 September 2019. We included cluster- or individually randomised controlled trials (RCT) carried out among the general population from any country aged two years and above. The interventions were fortification of wheat flour with iron alone or in combination with other micronutrients. Trials comparing any type of food item prepared from flour fortified with iron of any variety of wheat were included. Two review authors independently screened the search results and assessed the eligibility of studies for inclusion, extracted data from included studies and assessed risk of bias. We followed Cochrane methods in this review. Our search identified 3048 records, after removing duplicates. We included nine trials, involving 3166 participants, carried out in Bangladesh, Brazil, India, Kuwait, Phillipines, Sri Lanka and South Africa. The duration of interventions varied from 3 to 24 months. One study was carried out among adult women and one trial among both children and nonpregnant women. Most of the included trials were assessed as low or unclear risk of bias for key elements of selection, performance or reporting bias. Three trials used 41 mg to 60 mg iron/kg flour, two trials used less than 40 mg iron/kg and three trials used more than 60 mg iron/kg flour. One trial employed various iron levels based on type of iron used: 80 mg/kg for electrolytic and reduced iron and 40 mg/kg for ferrous fumarate. All included studies contributed data for the meta-analyses. Seven studies compared wheat flour fortified with iron alone versus unfortified wheat flour, three studies compared wheat flour fortified with iron in combination with other micronutrients versus unfortified wheat flour and two studies compared wheat flour fortified with iron in combination with other micronutrients versus fortified wheat flour with the same micronutrients (but not iron). No studies included a 'no intervention' comparison arm. None of the included trials reported any other adverse side effects (including constipation, nausea, vomiting, heartburn or diarrhoea). Wheat flour fortified with iron alone versus unfortified wheat flour (no micronutrients added) Wheat flour fortification with iron alone may have little or no effect on anaemia (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.61 to 1.07; 5 studies; 2200 participants; low-certainty evidence). It probably makes little or no difference on iron deficiency (RR 0.43, 95% CI 0.17 to 1.07; 3 studies; 633 participants; moderate-certainty evidence) and we are uncertain about whether wheat flour fortified with iron increases haemoglobin concentrations by an average 3.30 (g/L) (95% CI 0.86 to 5.74; 7 studies; 2355 participants; very low-certainty evidence). No trials reported data on adverse effects in children, except for risk of infection or inflammation at the individual level. The intervention probably makes little or no difference to risk of Infection or inflammation at individual level as measured by C-reactive protein (CRP) (moderate-certainty evidence). Wheat flour fortified with iron in combination with other micronutrients versus unfortified wheat flour (no micronutrients added) Wheat flour fortified with iron, in combination with other micronutrients, may or may not decrease anaemia (RR 0.95, 95% CI 0.69 to 1.31; 2 studies; 322 participants; low-certainty evidence). It makes little or no difference to average risk of iron deficiency (RR 0.74, 95% CI 0.54 to 1.00; 3 studies; 387 participants; moderate-certainty evidence) and may or may not increase average haemoglobin concentrations (mean difference (MD) 3.29, 95% CI -0.78 to 7.36; 3 studies; 384 participants; low-certainty evidence). No trials reported data on adverse effects in children. Wheat flour fortified with iron in combination with other micronutrients versus fortified wheat flour with same micronutrients (but not iron) Given the very low certainty of the evidence, the review authors are uncertain about the effects of wheat flour fortified with iron in combination with other micronutrients versus fortified wheat flour with same micronutrients (but not iron) in reducing anaemia (RR 0.24, 95% CI 0.08 to 0.71; 1 study; 127 participants; very low-certainty evidence) and in reducing iron deficiency (RR 0.42, 95% CI 0.18 to 0.97; 1 study; 127 participants; very low-certainty evidence). The intervention may make little or no difference to the average haemoglobin concentration (MD 0.81, 95% CI -1.28 to 2.89; 2 studies; 488 participants; low-certainty evidence). No trials reported data on the adverse effects in children. Eight out of nine trials reported source of funding with most having multiple sources. Funding source does not appear to have distorted the results in any of the assessed trials. Eating food items containing wheat flour fortified with iron alone may have little or no effect on anaemia and probably makes little or no difference in iron deficiency. We are uncertain on whether the intervention with wheat flour fortified with iron increases haemoglobin concentrations improve blood haemoglobin concentrations. Consuming food items prepared from wheat flour fortified with iron, in combination with other micronutrients, has little or no effect on anaemia, makes little or no difference to iron deficiency and may or may not improve haemoglobin concentrations. In comparison to fortified flour with micronutrients but no iron, wheat flour fortified with iron with other micronutrients, the effects on anaemia and iron deficiency are uncertain as certainty of the evidence has been assessed as very low. The intervention may make little or no difference to the average haemoglobin concentrations in the population. None of the included trials reported any other adverse side effects. The effects of this intervention on other health outcomes are unclear.

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This is an update of the review published on the Cochrane Library in 2016, Issue 8. Having cancer may result in extensive emotional, physical and social suffering. Music interventions have been used to alleviate symptoms and treatment side effects in people with cancer. This review includes music interventions defined as music therapy offered by trained music therapists, as well as music medicine, which was defined as listening to pre-recorded music offered by medical staff. To assess and compare the effects of music therapy and music medicine interventions for psychological and physical outcomes in people with cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 3) in the Cochrane Library, MEDLINE via Ovid, Embase via Ovid, CINAHL, PsycINFO, LILACS, Science Citation Index, CancerLit, CAIRSS, Proquest Digital Dissertations, ClinicalTrials.gov, Current Controlled Trials, the RILM Abstracts of Music Literature, http://www.wfmt.info/Musictherapyworld/ and the National Research Register. We searched all databases, except for the last two, from their inception to April 2020; the other two are no longer functional, so we searched them until their termination date. We handsearched music therapy journals, reviewed reference lists and contacted experts. There was no language restriction. We included all randomized and quasi-randomized controlled trials of music interventions for improving psychological and physical outcomes in adults and pediatric patients with cancer. We excluded patients undergoing biopsy and aspiration for diagnostic purposes. Two review authors independently extracted the data and assessed the risk of bias. Where possible, we presented results in meta-analyses using mean differences and standardized mean differences. We used post-test scores. In cases of significant baseline difference, we used change scores. We conducted separate meta-analyses for studies with adult participants and those with pediatric participants. Primary outcomes of interest included psychological outcomes and physical symptoms and secondary outcomes included physiological responses, physical functioning, anesthetic and analgesic intake, length of hospitalization, social and spiritual support, communication, and quality of life (QoL) . We used GRADE to assess the certainty of the evidence. We identified 29 new trials for inclusion in this update. In total, the evidence of this review rests on 81 trials with a total of 5576 participants. Of the 81 trials, 74 trials included adult (N = 5306) and seven trials included pediatric (N = 270) oncology patients. We categorized 38 trials as music therapy trials and 43 as music medicine trials. The interventions were compared to standard care. Psychological outcomes The results suggest that music interventions may have a large anxiety-reducing effect in adults with cancer, with a reported average anxiety reduction of 7.73 units (17 studies, 1381 participants; 95% confidence interval (CI) -10.02 to -5.44; very low-certainty evidence) on the Spielberger State Anxiety Inventory scale (range 20 to 80; lower values reflect lower anxiety). Results also suggested a moderately strong, positive impact of music interventions on depression in adults (12 studies, 1021 participants; standardized mean difference (SMD): -0.41, 95% CI -0.67 to -0.15; very low-certainty evidence). We found no support for an effect of music interventions on mood (SMD 0.47, 95% CI -0.02 to 0.97; 5 studies, 236 participants; very low-certainty evidence). Music interventions may increase hope in adults with cancer, with a reported average increase of 3.19 units (95% CI 0.12 to 6.25) on the Herth Hope Index (range 12 to 48; higher scores reflect greater hope), but this finding was based on only two studies (N = 53 participants; very low-certainty evidence). Physical outcomes We found a moderate pain-reducing effect of music interventions (SMD -0.67, 95% CI -1.07 to -0.26; 12 studies, 632 adult participants; very low-certainty evidence). In addition, music interventions had a small treatment effect on fatigue (SMD -0.28, 95% CI -0.46 to -0.10; 10 studies, 498 adult participants; low-certainty evidence). The results suggest a large effect of music interventions on adult participants' QoL, but the results were highly inconsistent across studies, and the pooled effect size was accompanied by a large confidence interval (SMD 0.88, 95% CI -0.31 to 2.08; 7 studies, 573 participants; evidence is very uncertain). Removal of studies that used improper randomization methods resulted in a moderate effect size that was less heterogeneous (SMD 0.47, 95% CI 0.06 to 0.88, P = 0.02, I<sup2</sup = 56%). A small number of trials included pediatric oncology participants. The findings suggest that music interventions may reduce anxiety but this finding was based on only two studies (SMD -0.94, 95% CI -1.9 to 0.03; very low-certainty evidence). Due to the small number of studies, we could not draw conclusions regarding the effects of music interventions on mood, depression, QoL, fatigue or pain in pediatric participants with cancer. The majority of studies included in this review update presented a high risk of bias, and therefore the overall certainty of the evidence is low. For several outcomes (i.e. anxiety, depression, pain, fatigue, and QoL) the beneficial treatment effects were consistent across studies for music therapy interventions delivered by music therapists. In contrast, music medicine interventions resulted in inconsistent treatment effects across studies for these outcomes. This systematic review indicates that music interventions compared to standard care may have beneficial effects on anxiety, depression, hope, pain, and fatigue in adults with cancer. The results of two trials suggest that music interventions may have a beneficial effect on anxiety in children with cancer. Too few trials with pediatric participants were included to draw conclusions about the treatment benefits of music for other outcomes. For several outcomes, music therapy interventions delivered by a trained music therapist led to consistent results across studies and this was not the case for music medicine interventions. Moreover, evidence of effect was found for music therapy interventions for QoL and fatigue but not for music medicine interventions. Most trials were at high risk of bias and low or very low certainty of evidence; therefore, these results need to be interpreted with caution.

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Hip fracture is a major cause of morbidity and mortality in older people, and its impact on society is substantial. After surgery, people require rehabilitation to help them recover. Multidisciplinary rehabilitation is where rehabilitation is delivered by a multidisciplinary team, supervised by a geriatrician, rehabilitation physician or other appropriate physician. This is an update of a Cochrane Review first published in 2009. To assess the effects of multidisciplinary rehabilitation, in either inpatient or ambulatory care settings, for older people with hip fracture. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, CENTRAL, MEDLINE and Embase (October 2020), and two trials registers (November 2019). We included randomised and quasi-randomised trials of post-surgical care using multidisciplinary rehabilitation of older people (aged 65 years or over) with hip fracture. The primary outcome - 'poor outcome' - was a composite of mortality and decline in residential status at long-term (generally one year) follow-up. The other 'critical' outcomes were health-related quality of life, mortality, dependency in activities of daily living, mobility, and related pain. Pairs of review authors independently performed study selection, assessed risk of bias and extracted data. We pooled data where appropriate and used GRADE for assessing the certainty of evidence for each outcome. The 28 included trials involved 5351 older (mean ages ranged from 76.5 to 87 years), usually female, participants who had undergone hip fracture surgery. There was substantial clinical heterogeneity in the trial interventions and populations. Most trials had unclear or high risk of bias for one or more items, such as blinding-related performance and detection biases. We summarise the findings for three comparisons below. Inpatient rehabilitation: multidisciplinary rehabilitation versus 'usual care' Multidisciplinary rehabilitation was provided primarily in an inpatient setting in 20 trials. Multidisciplinary rehabilitation probably results in fewer cases of 'poor outcome' (death or deterioration in residential status, generally requiring institutional care) at 6 to 12 months' follow-up (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.80 to 0.98; 13 studies, 3036 participants; moderate-certainty evidence). Based on an illustrative risk of 347 people with hip fracture with poor outcome in 1000 people followed up between 6 and 12 months, this equates to 41 (95% CI 7 to 69) fewer people with poor outcome after multidisciplinary rehabilitation. Expressed in terms of numbers needed to treat for an additional harmful outcome (NNTH), 25 patients (95% CI 15 to 100) would need to be treated to avoid one 'poor outcome'. Subgroup analysis by type of multidisciplinary rehabilitation intervention showed no evidence of subgroup differences. Multidisciplinary rehabilitation may result in fewer deaths in hospital but the confidence interval does not exclude a small increase in the number of deaths (RR 0.77, 95% CI 0.58 to 1.04; 11 studies, 2455 participants; low-certainty evidence). A similar finding applies at 4 to 12 months' follow-up (RR 0.91, 95% CI 0.80 to 1.05; 18 studies, 3973 participants; low-certainty evidence). Multidisciplinary rehabilitation may result in fewer people with poorer mobility at 6 to 12 months' follow-up (RR 0.83, 95% CI 0.71 to 0.98; 5 studies, 1085 participants; low-certainty evidence). Due to very low-certainty evidence, we have little confidence in the findings for marginally better quality of life after multidisciplinary rehabilitation (1 study). The same applies to the mixed findings of some or no difference from multidisciplinary rehabilitation on dependence in activities of daily living at 1 to 4 months' follow-up (measured in various ways by 11 studies), or at 6 to 12 months' follow-up (13 studies). Long-term hip-related pain was not reported. Ambulatory setting: supported discharge and multidisciplinary home rehabilitation versus 'usual care' Three trials tested this comparison in 377 people mainly living at home. Due to very low-certainty evidence, we have very little confidence in the findings of little to no between-group difference in poor outcome (death or move to a higher level of care or inability to walk) at one year (3 studies); quality of life at one year (1 study); in mortality at 4 or 12 months (2 studies); in independence in personal activities of daily living (1 study); in moving permanently to a higher level of care (2 studies) or being unable to walk (2 studies). Long-term hip-related pain was not reported. One trial tested this comparison in 240 nursing home residents. There is low-certainty evidence that there may be no or minimal between-group differences at 12 months in 'poor outcome' defined as dead or unable to walk; or in mortality at 4 months or 12 months. Due to very low-certainty evidence, we have very little confidence in the findings of no between-group differences in dependency at 4 weeks or at 12 months, or in quality of life, inability to walk or pain at 12 months. In a hospital inpatient setting, there is moderate-certainty evidence that rehabilitation after hip fracture surgery, when delivered by a multidisciplinary team and supervised by an appropriate medical specialist, results in fewer cases of 'poor outcome' (death or deterioration in residential status). There is low-certainty evidence that multidisciplinary rehabilitation may result in fewer deaths in hospital and at 4 to 12 months; however, it may also result in slightly more. There is low-certainty evidence that multidisciplinary rehabilitation may reduce the numbers of people with poorer mobility at 12 months. No conclusions can be drawn on other outcomes, for which the evidence is of very low certainty. The generally very low-certainty evidence available for supported discharge and multidisciplinary home rehabilitation means that we are very uncertain whether the findings of little or no difference for all outcomes between the intervention and usual care is true. Given the prevalent clinical emphasis on early discharge, we suggest that research is best orientated towards early supported discharge and identifying the components of multidisciplinary inpatient rehabilitation to optimise patient recovery within hospital and the components of multidisciplinary rehabilitation, including social care, subsequent to hospital discharge.

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Psoriasis is an immune-mediated disease with either skin or joints manifestations, 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. 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 update of the living systematic review, we updated our searches of the following databases monthly to October 2021: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. Randomised controlled trials (RCTs) of systemic treatments in adults over 18 years with moderate-to-severe plaque psoriasis, at any stage of treatment, compared to placebo or another active agent. The primary outcomes were: proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90; proportion of participants with serious adverse events (SAEs) at induction phase (8 to 24 weeks after randomisation). We conducted duplicate study selection, data extraction, risk of bias assessment and analyses. We synthesised data using pairwise and network meta-analysis (NMA) to compare treatments and rank them according to effectiveness (PASI 90 score) and acceptability (inverse of SAEs). We assessed the certainty of NMA evidence for the two primary outcomes and all comparisons using CINeMA, as 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 treatment hierarchy, from 0% (worst for effectiveness or safety) to 100% (best for effectiveness or safety). This update includes an additional 19 studies, taking the total number of included studies to 167, and randomised participants to 58,912, 67.2% men, mainly recruited from hospitals. Average age was 44.5 years, mean PASI score at baseline was 20.4 (range: 9.5 to 39). Most studies were placebo-controlled (57%). We assessed a total of 20 treatments. Most (140) trials were multicentric (two to 231 centres). One-third of the studies (57/167) had high risk of bias; 23 unclear risk, and most (87) low risk. Most studies (127/167) declared funding by a pharmaceutical company, and 24 studies did not report a funding source. Network meta-analysis at class level showed that all interventions (non-biological systemic agents, small molecules, and biological treatments) showed a higher proportion of patients reaching PASI 90 than placebo. Anti-IL17 treatment showed a higher proportion of patients reaching PASI 90 compared to all the interventions, except anti-IL23. Biologic treatments anti-IL17, anti-IL12/23, anti-IL23 and anti-TNF alpha showed a higher proportion of patients reaching PASI 90 than the non-biological systemic agents. For reaching PASI 90, the most effective drugs when compared to placebo were (SUCRA rank order, all high-certainty evidence): infliximab (risk ratio (RR) 50.19, 95% CI 20.92 to 120.45), bimekizumab (RR 30.27, 95% CI 25.45 to 36.01), ixekizumab (RR 30.19, 95% CI 25.38 to 35.93), risankizumab (RR 28.75, 95% CI 24.03 to 34.39). Clinical effectiveness of these drugs was similar when compared against each other. Bimekizumab, ixekizumab and risankizumab showed a higher proportion of patients reaching PASI 90 than other anti-IL17 drugs (secukinumab and brodalumab) and guselkumab. Infliximab, anti-IL17 drugs (bimekizumab, ixekizumab, secukinumab and brodalumab) and anti-IL23 drugs (risankizumab and guselkumab) except tildrakizumab showed a higher proportion of patients reaching PASI 90 than ustekinumab and three anti-TNF alpha agents (adalimumab, certolizumab and etanercept). Ustekinumab was superior to certolizumab; adalimumab and ustekinumab were superior to etanercept. No significant difference was shown between apremilast and two non-biological drugs: ciclosporin and methotrexate. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. The risk of SAEs was significantly lower for participants on methotrexate compared with most of the interventions. Nevertheless, the SAE analyses were based on a very low number of events with low- to moderate-certainty for all the comparisons (except methotrexate versus placebo, which was high-certainty). The findings therefore have to be viewed with caution. 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, bimekizumab, ixekizumab, and risankizumab were the most effective treatments for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of high-certainty evidence. This NMA evidence is limited to induction therapy (outcomes measured from 8 to 24 weeks after randomisation), and is not sufficient for evaluating longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean 44.5 years) and high level of disease severity (PASI 20.4 at baseline) may not be typical of patients seen in daily clinical practice. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the safety evidence for most interventions was low to moderate quality. More randomised trials directly comparing active agents are needed, and these should include systematic subgroup analyses (sex, age, ethnicity, comorbidities, psoriatic arthritis). To provide long-term information on the safety of treatments included in this review, an evaluation of non-randomised studies and postmarketing reports from regulatory agencies is needed. 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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Ovulation induction may impact endometrial receptivity due to insufficient progesterone secretion. Low progesterone is associated with poor pregnancy outcomes. To assess the effectiveness and safety of luteal phase support (LPS) in infertile women trying to conceive by intrauterine insemination or by sexual intercourse. We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trial registries for ongoing trials, and reference lists of articles (from inception to 25 August 2021). Randomised controlled trials (RCTs) of LPS using progestogen, human chorionic gonadotropin (hCG), or gonadotropin-releasing hormone (GnRH) agonist supplementation in IUI or natural cycle. We used standard methodological procedures expected by Cochrane. Our primary outcomes were live birth rate/ongoing pregnancy rate (LBR/OPR) and miscarriage.  MAIN RESULTS: We included 25 RCTs (5111 participants). Most studies were at unclear or high risk of bias. We graded the certainty of evidence as very low to low. The main limitations of the evidence were poor reporting and imprecision. 1. Progesterone supplement versus placebo or no treatment  We are uncertain if vaginal progesterone increases LBR/OPR (risk ratio (RR) 1.10, 95% confidence interval (CI) 0.81 to 1.48; 7 RCTs; 1792 participants; low-certainty evidence) or decreases miscarriage per pregnancy compared to placebo or no treatment (RR 0.70, 95% CI 0.40 to 1.25; 5 RCTs; 261 participants). There were no data on LBR or miscarriage with oral stimulation. We are uncertain if progesterone increases LBR/OPR in women with gonadotropin stimulation (RR 1.24, 95% CI 0.80 to 1.92; 4 RCTs; 1054 participants; low-certainty evidence) and oral stimulation (clomiphene citrate or letrozole) (RR 0.97, 95% CI 0.58 to 1.64; 2 RCTs; 485 participants; low-certainty evidence). One study reported on OPR in women with gonadotropin plus oral stimulation; the evidence from this study was uncertain (RR 0.73, 95% CI 0.37 to 1.42; 1 RCT; 253 participants; low-certainty evidence). Given the low certainty of the evidence, it is unclear if progesterone reduces miscarriage per clinical pregnancy in any stimulation protocol (RR 0.68, 95% CI 0.24 to 1.91; 2 RCTs; 102 participants, with gonadotropin; RR 0.67, 95% CI 0.30 to 1.50; 2 RCTs; 123 participants, with gonadotropin plus oral stimulation; and RR 0.53, 95% CI 0.25 to 1.14; 2 RCTs; 119 participants, with oral stimulation). Low-certainty evidence suggests that progesterone in all types of ovarian stimulation may increase clinical pregnancy compared to placebo (RR 1.38, 95% CI 1.10 to 1.74; 7 RCTs; 1437 participants, with gonadotropin; RR 1.40, 95% CI 1.03 to 1.90; 4 RCTs; 733 participants, with gonadotropin plus oral stimulation (clomiphene citrate or letrozole); and RR 1.44, 95% CI 1.04 to 1.98; 6 RCTs; 1073 participants, with oral stimulation). 2. Progesterone supplementation regimen  We are uncertain if there is any difference between 300 mg and 600 mg of vaginal progesterone for OPR and multiple pregnancy (RR 1.58, 95% CI 0.81 to 3.09; 1 RCT; 200 participants; very low-certainty evidence; and RR 0.50, 95% CI 0.05 to 5.43; 1 RCT; 200 participants, very low-certainty evidence, respectively). No other outcomes were reported for this comparison. There were three different comparisons between progesterone regimens. For OPR, the evidence is very uncertain for intramuscular (IM) versus vaginal progesterone (RR 0.59, 95% CI 0.34 to 1.02; 1 RCT; 225 participants; very low-certainty evidence); we are uncertain if there is any difference between oral and vaginal progesterone (RR 1.25, 95% CI 0.70 to 2.22; 1 RCT; 150 participants; very low-certainty evidence) or between subcutaneous and vaginal progesterone (RR 1.05, 95% CI 0.54 to 2.05; 1 RCT; 246 participants; very low-certainty evidence). We are uncertain if IM or oral progesterone reduces miscarriage per clinical pregnancy compared to vaginal progesterone (RR 0.75, 95% CI 0.43 to 1.32; 1 RCT; 81 participants and RR 0.58, 95% CI 0.11 to 3.09; 1 RCT; 41 participants, respectively). Clinical pregnancy and multiple pregnancy were reported for all comparisons; the evidence for these outcomes was very uncertain. Only one RCT reported adverse effects. We are uncertain if IM route increases the risk of adverse effects when compared with the vaginal route (RR 9.25, 95% CI 2.21 to 38.78; 1 RCT; 225 participants; very low-certainty evidence). 3. GnRH agonist versus placebo or no treatment  No trials reported live birth. The evidence is very uncertain about the effect of GnRH agonist in ongoing pregnancy (RR 1.10, 95% CI 0.70 to 1.74; 1 RCT; 291 participants, very low-certainty evidence), miscarriage per clinical pregnancy (RR 0.73, 95% CI 0.26 to 2.10; 2 RCTs; 79 participants, very low-certainty evidence) and clinical pregnancy (RR 1.00, 95% CI 0.68 to 1.47; 2 RCTs; 340 participants; very low-certainty evidence), and multiple pregnancy (RR 0.28, 95% CI 0.11 to 0.70; 2 RCTs; 126 participants). 4. GnRH agonist versus vaginal progesterone  The evidence for the effect of GnRH agonist injection on clinical pregnancy is very uncertain (RR 1.00, 95% CI 0.51 to 1.95; 1 RCT; 242 participants). 5. HCG injection versus no treatment  The evidence for the effect of hCG injection on clinical pregnancy (RR 0.93, 95% CI 0.40 to 2.13; 1 RCT; 130 participants) and multiple pregnancy rates (RR 1.03, 95% CI 0.22 to 4.92; 1 RCT; 130 participants) is very uncertain. 6. Luteal support in natural cycle No study evaluated the effect of LPS in natural cycle. We could not perform sensitivity analyses, as there were no studies at low risk of selection bias and not at high risk in other domains. We are uncertain if vaginal progesterone supplementation during luteal phase is associated with a higher live birth/ongoing pregnancy rate. Vaginal progesterone may increase clinical pregnancy rate; however, its effect on miscarriage rate and multiple pregnancy rate is uncertain. We are uncertain if IM progesterone improves ongoing pregnancy rates or decreases miscarriage rate when compared to vaginal progesterone. Regarding the other reported comparisons, neither oral progesterone nor any other medication appears to be associated with an improvement in pregnancy outcomes (very low-certainty evidence).

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<bObjective:</b To investigate the effect of P62 on the migration and motility of human epidermal cell line HaCaT in high glucose microenvironment and its possible molecular mechanism, so as to explore the mechanism of refractory diabetic foot wound healing. <bMethods:</b The method of experimental research was used. HaCaT cells in logarithmic growth phase was taken for experiment. The cells were collected and divided into normal control group (culture solution containing glucose with final molarity of 5.5 mmol/L) and high glucose (culture solution containing glucose with final molarity of 30.0 mmol/L) 24 h group, high glucose 48 h group, and high glucose 72 h group according to the random number table (the same grouping method below). The cells in normal control group were routinely cultured for 72 h, cells in high glucose 72 h group were cultured with high glucose for 72 h, cells in high glucose 48 h group were routinely cultured for 24 h then cultured with high glucose for 48 h, cells in high glucose 24 h group were routinely cultured for 48 h then cultured with high glucose for 24 h. Then the protein expression of P62 was detected by Western blotting. The cells were collected and divided into normal control group and high glucose group. After being correspondingly cultured for 48 h as before, the protein expression of P62 was detected by immunofluorescence method (indicated as green fluorescence). The cells were collected and divided into negative control small interfering RNA (siRNA) group, P62-siRNA-1 group, P62-siRNA-2 group, and P62-siRNA-3 group, and transfected with the corresponding reagents. At post transfection hour (PTH) 72, the protein expression of P62 was detected by Western blotting. The cells were collected and divided into normal glucose+negative control siRNA group, normal glucose+P62-siRNA group, high glucose+negative control siRNA group, and high glucose+P62-siRNA group. After the corresponding treatment, the protein expression of P62 was detected by Western blotting at PTH 72 h, the cell migration rate was detected and calculated at 24 h after scratching by scratch test, with the number of samples being 9; and the range of cell movement was observed and the trajectory velocity was calculated within 3 h under the living cell workstation, with the number of samples being 76, 75, 80, and 79 in normal glucose+negative control siRNA group, normal glucose+P62-siRNA group, high glucose+negative control siRNA group, and high glucose+P62-siRNA group, respectively. The cells were collected and divided into normal glucose+phosphate buffered solution (PBS) group, high glucose+PBS group, and high glucose+N-acetylcysteine (NAC) group. After the corresponding treatment, the protein expression of P62 at 48 h of culture was detected by Western blotting and immunofluorescence method, respectively. Except for scratch test and cell motility experiment, the number of samples was all 3 in the rest experiments. Data were statistically analyzed with one-way analysis of variance and least significant difference test. <bResults:</b Compared with the protein expression in normal control group, the protein expressions of P62 of cells in high glucose 24 h group, high glucose 48 h group, and high glucose 72 h group were significantly increased (<iP</i&lt;0.01). At 48 h of culture, the green fluorescence of P62 of cells in high glucose group was stronger than that in normal control group. At PTH 72, compared with the protein expression in negative control siRNA group, the protein expressions of P62 of cells in P62-siRNA-1 group, P62-siRNA-2 group, and P62-siRNA-3 group were significantly decreased (<iP</i&lt;0.01). At PTH 72, compared with the protein expression in normal glucose+negative control siRNA group, the protein expression of P62 of cells in normal glucose+P62-siRNA group was significantly decreased (<iP</i&lt;0.01), while the protein expression of P62 of cells in high glucose+negative control siRNA group was significantly increased (<iP</i&lt;0.01); compared with the protein expression in high glucose+negative control siRNA group, the protein expression of P62 of cells in high glucose+P62-siRNA group was significantly decreased (<iP</i&lt;0.01). At 24 h after scratching, compared with (55±7)% in normal glucose+negative control siRNA group, the cell migration rate in normal glucose+P62-siRNA group was significantly increased ((72±14)%, <iP</i&lt;0.01), while the cell migration rate in high glucose+negative control siRNA group was significantly decreased ((37±7)%, <iP</i&lt;0.01); compared with that in high glucose+negative control siRNA group, the cell migration rate in high glucose+P62-siRNA group was significantly increased ((54±10)%, <iP</i&lt;0.01). Within 3 h of observation, the cell movement range in high glucose+negative control siRNA group was smaller than that in normal glucose+negative control siRNA group, while the cell movement range in normal glucose+P62-siRNA group was larger than that in normal glucose+negative control siRNA group, and the cell movement range in high glucose+P62-siRNA group was larger than that in high glucose+negative control siRNA group. Compared with that in normal glucose+negative control siRNA group, the cell trajectory speed in normal glucose+P62-siRNA group was significantly increased (<iP</i&lt;0.01), while the cell trajectory speed in high glucose+negative control siRNA group was significantly decreased (<iP</i&lt;0.01); compared with that in high glucose+negative control siRNA group, the cell trajectory speed in high glucose+P62-siRNA group was significantly increased (<iP</i&lt;0.01). At 48 h of culture, compared with that in normal glucose+PBS group, the protein expression of P62 of cells in high glucose+PBS group was significantly increased (<iP</i&lt;0.01); compared with that in high glucose+PBS group, the protein expression of P62 of cells in high glucose+NAC group was significantly decreased (<iP</i&lt;0.01). At 48 h of culture, the green fluorescence of P62 of cells in high glucose+PBS group was stronger than that in normal glucose+PBS group, while the green fluorescence of P62 of cells in high glucose+NAC group was weaker than that in high glucose+PBS group. <bConclusions:</b In HaCaT cells, high glucose microenvironment can promote the protein expression of P62; knockdown of P62 protein can promote the migration and increase the mobility of HaCaT cells; and the increase of reactive oxygen species in high glucose microenvironment may be the underlying mechanism for the increase of P62 expression.

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Type 2 diabetes mellitus (T2DM) is a growing health problem worldwide. Whether sulphonylureas show better, equal or worse therapeutic effects in comparison with other antidiabetic interventions for patients with T2DM remains controversial. To assess the effects of sulphonylurea monotherapy versus placebo, no intervention or other antidiabetic interventions for patients with T2DM. We searched publications in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS and CINAHL (all until August 2011) to obtain trials fulfilling the inclusion criteria for our review. We included clinical trials that randomised patients 18 years old or more with T2DM to sulphonylurea monotherapy with a duration of 24 weeks or more. Two authors independently assessed the risk of bias. The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes were other patient-important outcomes and metabolic variables. Where possible, we used risk ratios (RR) with 95% confidence intervals (95% CI) to analyse the treatment effect of dichotomous outcomes. We used mean differences with 95% CI to analyse the treatment effect of continuous outcomes. We evaluated the risk of bias. We conducted trial sequential analyses to assess whether firm evidence could be established for a 10% relative risk reduction (RRR) between intervention groups. We included 72 randomised controlled trials (RCTs) with 22,589 participants; 9707 participants randomised to sulphonylureas versus 12,805 participants randomised to control interventions. The duration of the interventions varied from 24 weeks to 10.7 years. We judged none of the included trials as low risk of bias for all bias domains. Patient-important outcomes were seldom reported.First-generation sulphonylureas (FGS) versus placebo or insulin did not show statistical significance for all-cause mortality (versus placebo: RR 1.46, 95% CI 0.87 to 2.45; P = 0.15; 2 trials; 553 participants; high risk of bias (HRB); versus insulin: RR 1.18, 95% CI 0.88 to 1.59; P = 0.26; 2 trials; 1944 participants; HRB). FGS versus placebo showed statistical significance for cardiovascular mortality in favour of placebo (RR 2.63, 95% CI 1.32 to 5.22; P = 0.006; 2 trials; 553 participants; HRB). FGS versus insulin did not show statistical significance for cardiovascular mortality (RR 1.36, 95% CI 0.68 to 2.71; P = 0.39; 2 trials; 1944 participants; HRB). FGS versus alpha-glucosidase inhibitors showed statistical significance in favour of FGS for adverse events (RR 0.63, 95% CI 0.52 to 0.76; P = 0.01; 2 trials; 246 participants; HRB) and for drop-outs due to adverse events (RR 0.28, 95% CI 0.12 to 0.67; P = 0.004; 2 trials; 246 participants; HRB).Second-generation sulphonylureas (SGS) versus metformin (RR 0.98, 95% CI 0.61 to 1.58; P = 0.68; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 0.92, 95% CI 0.60 to 1.41; P = 0.70; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.79 to 1.18; P = 0.72; 4 trials; 1642 participants; HRB), meglitinides (RR 1.44, 95% CI 0.47 to 4.42; P = 0.52; 7 trials; 2038 participants; HRB), or incretin-based interventions (RR 1.39, 95% CI 0.52 to 3.68; P = 0.51; 2 trials; 1503 participants; HRB) showed no statistically significant effects regarding all-cause mortality in a random-effects model. SGS versus metformin (RR 1.47; 95% CI 0.54 to 4.01; P = 0.45; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 1.30, 95% CI 0.55 to 3.07; P = 0.55; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.73 to 1.28; P = 0.80; 4 trials; 1642 participants; HRB) or meglitinide (RR 0.97, 95% CI 0.27 to 3.53; P = 0.97; 7 trials, 2038 participants, HRB) showed no statistically significant effects regarding cardiovascular mortality. Mortality data for the SGS versus placebo were sparse. SGS versus thiazolidinediones and meglitinides did not show statistically significant differences for a composite of non-fatal macrovascular outcomes. SGS versus metformin showed statistical significance in favour of SGS for a composite of non-fatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93; P = 0.02; 3018 participants; 3 trials; HRB). The definition of non-fatal macrovascular outcomes varied among the trials. SGS versus metformin, thiazolidinediones and meglitinides showed no statistical significance for non-fatal myocardial infarction. No meta-analyses could be performed for microvascular outcomes. SGS versus placebo, metformin, thiazolidinediones, alpha-glucosidase inhibitors or meglitinides showed no statistical significance for adverse events. SGS versus alpha-glucosidase inhibitors showed statistical significance in favour of SGS for drop-outs due to adverse events (RR 0.48, 95% CI 0.24 to 0.96; P = 0.04; 9 trials; 870 participants; HRB). SGS versus meglitinides showed no statistical significance for the risk of severe hypoglycaemia. SGS versus metformin and thiazolidinediones showed statistical significance in favour of metformin (RR 5.64, 95% CI 1.22 to 26.00; P = 0.03; 4 trials; 3637 participants; HRB) and thiazolidinediones (RR 6.11, 95% CI 1.57 to 23.79; P = 0.009; 6 trials; 5660 participants; HRB) for severe hypoglycaemia.Third-generation sulphonylureas (TGS) could not be included in any meta-analysis of all-cause mortality, cardiovascular mortality or non-fatal macro- or microvascular outcomes. TGS versus thiazolidinediones showed statistical significance regarding adverse events in favour of TGS (RR 0.88, 95% CI 0.78 to 0.99; P = 0.03; 3 trials; 510 participants; HRB). TGS versus thiazolidinediones did not show any statistical significance for drop-outs due to adverse events. TGS versus other comparators could not be performed due to lack of data.For the comparison of SGS versus FGS no meta-analyses of all-cause mortality, cardiovascular mortality, non-fatal macro- or microvascular outcomes, or adverse events could be performed.Health-related quality of life and costs of intervention could not be meta-analysed due to lack of data.In trial sequential analysis, none of the analyses of mortality outcomes, vascular outcomes or severe hypoglycaemia met the criteria for firm evidence of a RRR of 10% between interventions. There is insufficient evidence from RCTs to support the decision as to whether to initiate sulphonylurea monotherapy. Data on patient-important outcomes are lacking. Therefore, large-scale and long-term randomised clinical trials with low risk of bias, focusing on patient-important outcomes are required.

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Many women experience perineal pain after childbirth, especially after having sustained perineal trauma. Perineal pain-management strategies are thus an important part of postnatal care. Non-steroidal anti-inflammatory drugs (NSAIDs) are a commonly used type of medication in the management of postpartum pain and their effectiveness and safety should be assessed. To determine the effectiveness of a single dose of an oral NSAID for relief of acute perineal pain in the early postpartum period. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2016), OpenSIGLE, ProQuest Dissertations and Theses, the ISRCTN Registry and ClinicalTrials.gov (31 March 2016). We also reviewed reference lists of retrieved papers and contacted experts in the field. Randomised controlled trials (RCTs) assessing a single dose of a NSAID versus a single dose of placebo, paracetamol or another NSAID for women with perineal pain in the early postpartum period. Quasi-RCTs and cross-over trials were excluded. Two review authors (FW and VS) independently assessed all identified papers for inclusion and risk of bias. Any discrepancies were resolved through discussion and consensus. Data extraction, including calculations of pain relief scores, was also conducted independently by two review authors and checked for accuracy. We included 28 studies that examined 13 different NSAIDs and involved 4181 women (none of whom were breastfeeding). Studies were published between 1967 and 2013, with the majority published in the 1980s. Of the 4181 women involved in the studies, 2642 received a NSAID and 1539 received placebo or paracetamol. Risk of bias was generally unclear due to poor reporting, but in most studies the participants and personnel were blinded, outcome data were complete and the outcomes that were specified in the methods section were reported.None of the included studies reported on any of this review's secondary outcomes: prolonged hospitalisation or re-hospitalisation due to perineal pain; breastfeeding (fully or mixed) at discharge; breastfeeding (fully or mixed) at six weeks; perineal pain at six weeks; maternal views; postpartum depression; instrumental measures of disability due to perineal pain. NSAID versus placeboCompared to women who received a placebo, more women who received a single dose NSAID achieved adequate pain relief at four hours (risk ratio (RR) 1.91, 95% confidence interval (CI) 1.64 to 2.23, 10 studies, 1573 participants (low-quality evidence)) and adequate pain relief at six hours (RR 1.92, 95% CI 1.69 to 2.17, 17 studies, 2079 participants (very low-quality evidence)). Women who received a NSAID were also less likely to need additional analgesia compared to women who received placebo at four hours (RR 0.39, 95% CI 0.26 to 0.58, four studies, 486 participants (low-quality evidence)) and at six hours after initial administration (RR 0.32, 95% CI 0.26 to 0.40, 10 studies, 1012 participants (low-quality evidence)). Fourteen maternal adverse effects were reported in the NSAID group (drowsiness (5), abdominal discomfort (2), weakness (1), dizziness (2), headache (2), moderate epigastralgia (1), not specified (1)) and eight in the placebo group (drowsiness (2), light headed (1), nausea (1), backache (1), dizziness (1), epigastric pain (1), not specified (1)), although not all studies assessed adverse effects. There was no difference in overall maternal adverse effects between NSAIDs and placebo at six hours post-administration (RR 1.38, 95% CI 0.71 to 2.70, 13 studies, 1388 participants (very low-quality evidence)). One small study (with two treatment arms) assessed maternal adverse effects at four hours post-administration, but there were no maternal adverse effects observed (one study, 90 participants (low-quality evidence)). Neonatal adverse effects were not assessed in any of the included studies. NSAID versus paracetamolNSAIDs versus paracetamol were also more effective for adequate pain relief at four hours (RR 1.54, 95% CI 1.07 to 2.22, three studies, 342 participants) but not at six hours post-administration. There was no difference in the need for additional analgesia between the two groups at four hours (RR 0.55, 95% CI 0.27 to 1.13, one study, 73 participants), but women in the NSAID group were less likely to need any additional analgesia at six hours (RR 0.28, 95% CI 0.12 to 0.67, one study, 59 participants). No maternal adverse effects were reported four hours after drug administration (one study). Six hours post-administration, there was no difference between the groups in the number of maternal adverse effects (RR 0.74, 95% CI 0.27 to 2.08, three studies, 300 participants), with one case of pruritis in the NSAID group and one case of sleepiness in the paracetamol group. Neonatal adverse effects were not assessed in any of the included studies.Comparisons of different NSAIDs and different doses of the same NSAID did not demonstrate any differences in their effectiveness on any of the primary outcome measures; however, few data were available on some NSAIDs. In women who are not breastfeeding and who sustained perineal trauma, NSAIDs (compared to placebo) provide greater pain relief for acute postpartum perineal pain and fewer women need additional analgesia when treated with a NSAID. However, the risk of bias was unclear for many of the included studies, adverse effects were often not assessed and breastfeeding women were not included in the studies. The overall quality of the evidence (GRADE) was low with the evidence for all outcomes rated as low or very low. The main reasons for downgrading were inclusion of studies with high risk of bias and inconsistency of findings of individual studies.NSAIDs also appear to be more effective in providing relief for perineal pain than paracetamol, but few studies were included in this analysis.Future studies should examine NSAIDs' adverse effects profile including neonatal adverse effects and the compatibility of NSAIDs with breastfeeding, and assess other important secondary outcomes of this review. Moreover, studies mostly included women who had episiotomies. Future research should consider women with and without perineal trauma, including perineal tears. High-quality studies should be conducted to further assess the efficacy of NSAIDs versus paracetamol and the efficacy of multimodal treatments.

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Various hormone therapies (HT) are available to treat menopausal vasomotor symptoms. Bioidentical hormones are chemically identical to those produced by the human body, and several types are well-tested and available on prescription. Many women have opted for bioidentical hormone therapy (BHT) on the assumption that it is safer than other forms of HT. We evaluated the evidence. To determine the effectiveness and safety of bioidentical hormones compared to placebo or non-bioidentical hormones for the relief of vasomotor symptoms. In July 2015 we searched the Cochrane Central Register of Controlled Trials, PubMed, Embase, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), registers of ongoing trials and the reference lists of articles retrieved. Randomised controlled trials (RCTs) comparing bioidentical hormone therapy (BHT) versus placebo or non-bioidentical hormones. We used standard methodological procedures expected by the Cochrane Collaboration. Our primary outcome was vasomotor symptoms (hot flushes and night sweats). We evaluated the overall quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation criteria (GRADE). We included 23 RCTs (5779 participants). Most studies (20/23) included only women with moderate to severe hot flushes. All studies compared unopposed 17 beta-estradiol (beta-estradiol) versus placebo or conjugated equine estrogens (CEE). None of the studies reported night sweats as a separate outcome. BHT patch versus placebo Frequency of hot flushesFour RCTs reported data suitable for analysis. There were fewer hot flushes in the BHT group, with a moderate to large effect size (SMD -0.68, 95% CI -0.83 to -0.53, four RCTs, 793 women, I(2) = 67%, low quality evidence). There was moderate heterogeneity, but a consistent direction of effect. Seven RCTs reported data unsuitable for analysis; all reported a benefit in the intervention group. Symptom intensityTwo RCTs reported analysable data. Measured on a 0-100 visual analogue scale (VAS), hot flush intensity was lower in the BHT group (MD -19.94 points, 95% CI -24.86 to -15.02, two RCTs, 393 women, I(2) = 54%, low quality evidence). There was moderate heterogeneity, but a consistent direction of effect. Adverse effectsAdverse events (such as headache, vaginal bleeding, breast tenderness and skin reactions) were more common in the intervention group (odds ratio (OR) 2.14, 95% CI 1.29 to 3.54, 9 RCTs, 1822 women, I(2) = 73%, low quality evidence). There was moderate heterogeneity, but a consistent direction of effect. In one study, five women in the intervention group developed endometrial hyperplasia. BHT gel versus placebo Hot flush frequencyThree RCTs reported this outcome, but the data were unsuitable for analysis. All reported a benefit in the BHT group. Adverse effectsAdverse events were more common in the BHT group (OR 1.41, 95% CI 1.09 to 1.83, 3 RCTs, 1086 women, I(2) = 0%, moderate quality evidence). Oral BHT versus placebo Hot flush frequencyTwo studies reported analysable data. There were fewer hot flushes in the BHT group, with a moderate to large effect size (SMD -0.80, 95% CI -1.03 to -0.57, two RCTs, 356 women, I(2) = 14%, low quality evidence). Adverse effectsThere was no evidence of a difference between the groups (OR 1.28, 95% CI 0.84 to 1.96, 3 RCTs, 433 women, I(2) = 0%, low quality evidence). Topical BHT emulsion versus placebo Hot flush frequencyOne study with data unsuitable for analysis reported a benefit in the intervention group. Adverse effectsThere was no evidence of a difference between the groups (OR 1.46, 95% CI 0.80 to 2.66, one RCT, 200 women, low quality evidence). Intranasal BHT versus placebo Hot flush frequencyOnly one study reported analysable data. There were fewer hot flushes per day in the BHT group (MD -3.04 95% CI -4.05 to -2.03, one study, 458 women, moderate quality evidence) Adverse effectsAdverse events (such as headache, breast tenderness, arthralgia and nausea) were more common in the intervention group (OR 1.96, 95% CI 1.26 to 3.03, one RCT, 458 women, moderate quality evidence). Subgroup analysesSubgroup analyses by dose of BHT suggested that higher doses of BHT may be associated with more effectiveness but also higher risk of adverse effects. BHT patch versus 0.625 mg CEETwo RCTs reported this comparison, but the data were unsuitable for analysis. Hot flush frequencyBoth RCTs reported no evidence of a difference between the groups. Adverse effectsFindings were inconsistent. In one comparison (0.1 mg BHT versus CEE), breast pain and vaginal bleeding were more frequent in the BHT group. Oral BHT versus 0.625 mg CEE Hot flush frequencyOne study with data unsuitable for analysis reported no evidence of a difference between the groups. Adverse effectsThere was no evidence of a difference between the groups (OR 1.20, 95% CI 0.50 to 2.87, one RCT, 103 women, very low quality evidence). There was low to moderate quality evidence that BHT in various forms and doses is more effective than placebo for treating moderate to severe menopausal hot flushes. There was low to moderate quality evidence of higher rates of adverse effects such as headache, vaginal bleeding, breast tenderness and skin reactions in the BHT group. There was some evidence to suggest that higher doses of BHT are associated with greater effectiveness but also with higher risk of adverse effects. Although all the included studies used unopposed estrogen, it is recommended best practice to use progestogen therapy in women with a uterus taking estrogen in order to avoid endometrial hyperplasia, regardless of the source of the estrogen. No data are yet available about the safety of BHT with regard to long-term outcomes such as heart attack, stroke and breast cancer.There was no good evidence of a difference in effectiveness between BHT and CEE, and findings with regard to adverse effects were inconsistent. The quality of the evidence was too low to reach any firm conclusions.The main limitations in the quality of the evidence were study risk of bias (mainly due to poor reporting of methods), imprecision and lack of data suitable for analysis.

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Sickle cell disease is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. Sickle cell disease can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Stroke affects around 10% of children with sickle cell anaemia (HbSS). Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation.This is an update of a Cochrane Review first published in 2002, and last updated in 2013. To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention (excluding silent cerebral infarcts). We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 04 April 2016.We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 25 April 2016. Randomised controlled trials comparing red blood cell transfusions as prophylaxis for stroke in people with sickle cell disease to alternative or standard treatment. There were no restrictions by outcomes examined, language or publication status. Two authors independently assessed trial eligibility and the risk of bias and extracted data. We included five trials (660 participants) published between 1998 and 2016. Four of these trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of sickle cell disease.Three trials compared regular red cell transfusions to standard care in primary prevention of stroke: two in children with no previous long-term transfusions; and one in children and adolescents on long-term transfusion.Two trials compared the drug hydroxyurea (hydroxycarbamide) and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children); and one in secondary prevention (children and adolescents).The quality of the evidence was very low to moderate across different outcomes according to GRADE methodology. This was due to the trials being at a high risk of bias due to lack of blinding, indirectness and imprecise outcome estimates. Red cell transfusions versus standard care Children with no previous long-term transfusionsLong-term transfusions probably reduce the incidence of clinical stroke in children with a higher risk of stroke (abnormal transcranial doppler velocities or previous history of silent cerebral infarct), risk ratio 0.12 (95% confidence interval 0.03 to 0.49) (two trials, 326 participants), moderate quality evidence.Long-term transfusions may: reduce the incidence of other sickle cell disease-related complications (acute chest syndrome, risk ratio 0.24 (95% confidence interval 0.12 to 0.48)) (two trials, 326 participants); increase quality of life (difference estimate -0.54, 95% confidence interval -0.92 to -0.17) (one trial, 166 participants); but make little or no difference to IQ scores (least square mean: 1.7, standard error 95% confidence interval -1.1 to 4.4) (one trial, 166 participants), low quality evidence.We are very uncertain whether long-term transfusions: reduce the risk of transient ischaemic attacks, Peto odds ratio 0.13 (95% confidence interval 0.01 to 2.11) (two trials, 323 participants); have any effect on all-cause mortality, no deaths reported (two trials, 326 participants); or increase the risk of alloimmunisation, risk ratio 3.16 (95% confidence interval 0.18 to 57.17) (one trial, 121 participants), very low quality evidence. Children and adolescents with previous long-term transfusions (one trial, 79 participants)We are very uncertain whether continuing long-term transfusions reduces the incidence of: stroke, risk ratio 0.22 (95% confidence interval 0.01 to 4.35); or all-cause mortality, Peto odds ratio 8.00 (95% confidence interval 0.16 to 404.12), very low quality evidence.Several review outcomes were only reported in one trial arm (sickle cell disease-related complications, alloimmunisation, transient ischaemic attacks).The trial did not report neurological impairment, or quality of life. Hydroxyurea and phlebotomy versus red cell transfusions and chelationNeither trial reported on neurological impairment, alloimmunisation, or quality of life. Primary prevention, children (one trial, 121 participants)Switching to hydroxyurea and phlebotomy may have little or no effect on liver iron concentrations, mean difference -1.80 mg Fe/g dry-weight liver (95% confidence interval -5.16 to 1.56), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: risk of stroke (no strokes); all-cause mortality (no deaths); transient ischaemic attacks, risk ratio 1.02 (95% confidence interval 0.21 to 4.84); or other sickle cell disease-related complications (acute chest syndrome, risk ratio 2.03 (95% confidence interval 0.39 to 10.69)), very low quality evidence. Secondary prevention, children and adolescents (one trial, 133 participants)Switching to hydroxyurea and phlebotomy may: increase the risk of sickle cell disease-related serious adverse events, risk ratio 3.10 (95% confidence interval 1.42 to 6.75); but have little or no effect on median liver iron concentrations (hydroxyurea, 17.3 mg Fe/g dry-weight liver (interquartile range 10.0 to 30.6)); transfusion 17.3 mg Fe/g dry-weight liver (interquartile range 8.8 to 30.7), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy: increases the risk of stroke, risk ratio 14.78 (95% confidence interval 0.86 to 253.66); or has any effect on all-cause mortality, Peto odds ratio 0.98 (95% confidence interval 0.06 to 15.92); or transient ischaemic attacks, risk ratio 0.66 (95% confidence interval 0.25 to 1.74), very low quality evidence. There is no evidence for managing adults, or children who do not have HbSS sickle cell disease.In children who are at higher risk of stroke and have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke, and low quality evidence they also reduce the risk of other sickle cell disease-related complications.In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration.In secondary prevention of stroke there is low-quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events.All other evidence in this review is of very low quality.

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Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action is unknown. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed and it is now available in Australia and some countries in Europe. This is an update of a previous review. To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences.Date of last search: 28 September 2017. All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment. Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies. The quality of the evidence was assessed using GRADE. Six studies (reported in 50 publications) were included with a total of 784 participants.Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population.Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole.While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies.Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non-respirable mannitol groups; however, we judged this evidence to be of low to very low quality.For the comparisons of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF.For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low-quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations.In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa). There is moderate-quality evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa.The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.

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A large number of people are employed in sedentary occupations. Physical inactivity and excessive sitting at workplaces have been linked to increased risk of cardiovascular disease, obesity, and all-cause mortality. To evaluate the effectiveness of workplace interventions to reduce sitting at work compared to no intervention or alternative interventions. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, OSH UPDATE, PsycINFO, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal up to 9 August 2017. We also screened reference lists of articles and contacted authors to find more studies. We included randomised controlled trials (RCTs), cross-over RCTs, cluster-randomised controlled trials (cluster-RCTs), and quasi-RCTs of interventions to reduce sitting at work. For changes of workplace arrangements, we also included controlled before-and-after studies. The primary outcome was time spent sitting at work per day, either self-reported or measured using devices such as an accelerometer-inclinometer and duration and number of sitting bouts lasting 30 minutes or more. We considered energy expenditure, total time spent sitting (including sitting at and outside work), time spent standing at work, work productivity and adverse events as secondary outcomes. Two review authors independently screened titles, abstracts and full-text articles for study eligibility. Two review authors independently extracted data and assessed risk of bias. We contacted authors for additional data where required. We found 34 studies - including two cross-over RCTs, 17 RCTs, seven cluster-RCTs, and eight controlled before-and-after studies - with a total of 3,397 participants, all from high-income countries. The studies evaluated physical workplace changes (16 studies), workplace policy changes (four studies), information and counselling (11 studies), and multi-component interventions (four studies). One study included both physical workplace changes and information and counselling components. We did not find any studies that specifically investigated the effects of standing meetings or walking meetings on sitting time.Physical workplace changesInterventions using sit-stand desks, either alone or in combination with information and counselling, reduced sitting time at work on average by 100 minutes per workday at short-term follow-up (up to three months) compared to sit-desks (95% confidence interval (CI) -116 to -84, 10 studies, low-quality evidence). The pooled effect of two studies showed sit-stand desks reduced sitting time at medium-term follow-up (3 to 12 months) by an average of 57 minutes per day (95% CI -99 to -15) compared to sit-desks. Total sitting time (including sitting at and outside work) also decreased with sit-stand desks compared to sit-desks (mean difference (MD) -82 minutes/day, 95% CI -124 to -39, two studies) as did the duration of sitting bouts lasting 30 minutes or more (MD -53 minutes/day, 95% CI -79 to -26, two studies, very low-quality evidence).We found no significant difference between the effects of standing desks and sit-stand desks on reducing sitting at work. Active workstations, such as treadmill desks or cycling desks, had unclear or inconsistent effects on sitting time.Workplace policy changesWe found no significant effects for implementing walking strategies on workplace sitting time at short-term (MD -15 minutes per day, 95% CI -50 to 19, low-quality evidence, one study) and medium-term (MD -17 minutes/day, 95% CI -61 to 28, one study) follow-up. Short breaks (one to two minutes every half hour) reduced time spent sitting at work on average by 40 minutes per day (95% CI -66 to -15, one study, low-quality evidence) compared to long breaks (two 15-minute breaks per workday) at short-term follow-up.Information and counsellingProviding information, feedback, counselling, or all of these resulted in no significant change in time spent sitting at work at short-term follow-up (MD -19 minutes per day, 95% CI -57 to 19, two studies, low-quality evidence). However, the reduction was significant at medium-term follow-up (MD -28 minutes per day, 95% CI -51 to -5, two studies, low-quality evidence).Computer prompts combined with information resulted in no significant change in sitting time at work at short-term follow-up (MD -10 minutes per day, 95% CI -45 to 24, two studies, low-quality evidence), but at medium-term follow-up they produced a significant reduction (MD -55 minutes per day, 95% CI -96 to -14, one study). Furthermore, computer prompting resulted in a significant decrease in the average number (MD -1.1, 95% CI -1.9 to -0.3, one study) and duration (MD -74 minutes per day, 95% CI -124 to -24, one study) of sitting bouts lasting 30 minutes or more.Computer prompts with instruction to stand reduced sitting at work on average by 14 minutes per day (95% CI 10 to 19, one study) more than computer prompts with instruction to walk at least 100 steps at short-term follow-up.We found no significant reduction in workplace sitting time at medium-term follow-up following mindfulness training (MD -23 minutes per day, 95% CI -63 to 17, one study, low-quality evidence). Similarly a single study reported no change in sitting time at work following provision of highly personalised or contextualised information and less personalised or contextualised information. One study found no significant effects of activity trackers on sitting time at work.Multi-component interventions Combining multiple interventions had significant but heterogeneous effects on sitting time at work (573 participants, three studies, very low-quality evidence) and on time spent in prolonged sitting bouts (two studies, very low-quality evidence) at short-term follow-up. At present there is low-quality evidence that the use of sit-stand desks reduce workplace sitting at short-term and medium-term follow-ups. However, there is no evidence on their effects on sitting over longer follow-up periods. Effects of other types of interventions, including workplace policy changes, provision of information and counselling, and multi-component interventions, are mostly inconsistent. The quality of evidence is low to very low for most interventions, mainly because of limitations in study protocols and small sample sizes. There is a need for larger cluster-RCTs with longer-term follow-ups to determine the effectiveness of different types of interventions to reduce sitting time at work.

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The risk of maternal mortality and morbidity (particularly postoperative infection) is higher for caesarean section (CS) than for vaginal birth. With the increasing rate of CS, it is important to minimise the risks to the mother as much as possible. This review focused on different forms and methods of preoperative skin preparation to prevent infection. This review is an update of a review that was first published in 2012, and updated in 2014. To compare the effects of different antiseptic agents, different methods of application, or different forms of antiseptic used for preoperative skin preparation for preventing postcaesarean infection. For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (27 November 2017), and reference lists of retrieved studies. Randomised and quasi-randomised trials, evaluating any type of preoperative skin preparation agents, forms, and methods of application for caesarean section.Comparisons of interest in this review were between different antiseptic agents used for CS skin preparation (e.g. alcohol, povidone iodine), different methods of antiseptic application (e.g. scrub, paint, drape), different forms of antiseptic (e.g. powder, liquid), and also between different skin preparations, such as a plastic incisional drape, which may or may not be impregnated with antiseptic agents.Only studies involving the preparation of the incision area were included. This review did not cover studies of preoperative handwashing by the surgical team or preoperative bathing. Three review authors independently assessed all potential studies for inclusion, assessed risk of bias, and extracted the data using a predesigned form. We checked data for accuracy. We assessed the quality of the evidence using the GRADE approach. For this update, we included 11 randomised controlled trials (RCTs), with a total of 6237 women who were undergoing CS. Ten trials (6215 women) contributed data to this review. All included studies were individual RCTs. We did not identify any quasi- or cluster-RCTs. The trial dates ranged from 1983 to 2016. Six trials were conducted in the USA, and the remainder in Nigeria, South Africa, France, Denmark, and Indonesia.The included studies were broadly methodologically sound, but raised some specific concerns regarding risk of bias in a number of cases.Drape versus no drapeThis comparison investigated the use of a non-impregnated drape versus no drape, following preparation of the skin with antiseptics. For women undergoing CS, low-quality evidence suggested that using a drape before surgery compared with no drape, may make little or no difference to the incidence of surgical site infection (risk ratio (RR) 1.29, 95% confidence interval (CI) 0.97 to 1.71; 2 trials, 1294 women), or length of stay in the hospital (mean difference (MD) 0.10 day, 95% CI -0.27 to 0.46 1 trial, 603 women).One-minute alcohol scrub with iodophor drape versus five-minute iodophor scrub without drapeOne trial compared an alcohol scrub and iodophor drape with a five-minute iodophor scrub only, and reported no surgical site infection in either group (79 women, very-low quality evidence). We were uncertain whether the combination of a one-minute alcohol scrub and a drape reduced the incidence of endomyometritis when compared with a five-minute scrub, because the quality of the evidence was very low (RR 1.62, 95% CI 0.29 to 9.16; 1 trial, 79 women).Parachlorometaxylenol with iodine versus iodine aloneWe were uncertain whether parachlorometaxylenol with iodine before CS made any difference to the incidence of surgical site infection (RR 0.33, 95% CI 0.04 to 2.99; 1 trial, 50 women), or endometritis (RR 0.88, 95% CI 0.56 to 1.38; 1 trial, 50 women) when compared with iodine alone, because the quality of the evidence was very low.Chlorhexidine gluconate versus povidone iodineLow-quality evidence suggested that chlorhexidine gluconate before CS, when compared with povidone iodine, may make little or no difference to the incidence of surgical site infection (RR 0.80, 95% CI 0.62 to 1.02; 6 trials, 3607 women). However, surgical site infection appeared to be slightly reduced for women for whom chlorhexidine gluconate was used compared with povidone iodine after we removed four trials at high risk of bias for outcome assessment, in a sensitivity analysis (RR 0.59, 95% CI 0.37 to 0.95; 2 trials, 1321 women).Low-quality evidence indicated that chlorhexidine gluconate before CS, when compared with povidone iodine, may make little or no difference to the incidence of endometritis (RR 1.01, 95% CI 0.51 to 2.01; 2 trials, 2079 women), or to reducing maternal skin irritation or allergic skin reaction (RR 0.60, 95% CI 0.22 to 1.63; 2 trials, 1521 women).One small study (60 women) reported reduced bacterial growth at 18 hours after CS for women who had chlorhexidine gluconate preparation compared with women who had povidone iodine preparation (RR 0.23, 95% CI 0.07 to 0.70).None of the included trials reported on maternal mortality or repeat surgery.Chlorhexidine 0.5% versus 70% alcohol plus drapeOne trial, which was only available as an abstract, investigated the effect of skin preparation on neonatal adverse events, and found cord blood iodine concentration to be higher in the iodine group. There was insufficient evidence available from the included RCTs to fully evaluate different agents and methods of skin preparation for preventing infection following caesarean section. Therefore, it is not yet clear what sort of skin preparation may be most effective for preventing postcaesarean surgical site infection, or for reducing other undesirable outcomes for mother and baby.Most of the evidence in this review was deemed to be very low or low quality. This means that for most findings, our confidence in any evidence of an intervention effect is limited, and indicates the need for more high-quality research.This field needs high quality, well designed RCTs, with larger sample sizes. High priority questions include comparing types of antiseptic (especially iodine versus chlorhexidine), and application methods (scrubbing, swabbing, or draping). We found four studies that were ongoing; we will incorporate the results of these studies in future updates of this review.

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Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier stage could avoid the risk of cancer progression and lead to improvements in cancer-related mortality and morbidity. This is an update of a review first published in 2015. To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the lower limb or PE) is effective in reducing cancer or VTE-related mortality and morbidity and to determine which tests for cancer are best at identifying treatable cancers early. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 11 July 2018. We also undertook reference checking to identify additional studies. Randomised and quasi-randomised trials in which people with an unprovoked VTE were allocated to receive specific tests for identifying cancer or clinically indicated tests only were eligible for inclusion. Primary outcomes included all-cause mortality, cancer-related mortality and VTE-related mortality. Two review authors independently selected studies, assessed risk of bias and extracted data. We resolved any disagreements by discussion. No new studies were identified for this 2018 update. In total, four studies with 1644 participants are included. Two studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the physician's discretion, the quality of the evidence, as assessed according to GRADE, was low due to risk of bias (early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing alone, the quality of evidence was moderate due to a risk of detection bias. The quality of the evidence was downgraded further as detection bias was present in one study with a low number of events.When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two studies showed that testing for cancer was consistent with either benefit or no benefit on cancer-related mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; P = 0.26; low-quality evidence). One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control group (OR 5.00, 95% CI 1.05 to 23.76; P = 0.04; low-quality evidence). There was no clear difference in detection of advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; P = 0.22; low-quality evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1 month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95% CI 0.59 to 2.93; 396 participants; 2 studies; P = 0.50; low-quality evidence). Neither study measured all-cause mortality, VTE-related morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life.When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus PET/CT screening was consistent with either benefit or no benefit on all-cause mortality (OR 1.22, 95% CI 0.49 to 3.04; 1248 participants; 2 studies; P = 0.66; moderate-quality evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to 1.52; 1248 participants; 2 studies; P = 0.25; moderate-quality evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to 2.17; 854 participants; 1 study; P = 0.96; moderate-quality evidence). Regarding stage of cancer, there was no clear difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; P = 0.37; low-quality evidence) or advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; P = 1.00; low-quality evidence) stages of cancer. There was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248 participants; 2 studies; P = 0.09; moderate-quality evidence). Time to cancer diagnosis was 4.2 months in the standard testing group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-related mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in reducing cancer- or VTE-related morbidity and mortality. The results could be consistent with either benefit or no benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be made.

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A large number of people are employed in sedentary occupations. Physical inactivity and excessive sitting at workplaces have been linked to increased risk of cardiovascular disease, obesity, and all-cause mortality. To evaluate the effectiveness of workplace interventions to reduce sitting at work compared to no intervention or alternative interventions. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, OSH UPDATE, PsycINFO, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal up to 9 August 2017. We also screened reference lists of articles and contacted authors to find more studies. We included randomised controlled trials (RCTs), cross-over RCTs, cluster-randomised controlled trials (cluster-RCTs), and quasi-RCTs of interventions to reduce sitting at work. For changes of workplace arrangements, we also included controlled before-and-after studies. The primary outcome was time spent sitting at work per day, either self-reported or measured using devices such as an accelerometer-inclinometer and duration and number of sitting bouts lasting 30 minutes or more. We considered energy expenditure, total time spent sitting (including sitting at and outside work), time spent standing at work, work productivity and adverse events as secondary outcomes. Two review authors independently screened titles, abstracts and full-text articles for study eligibility. Two review authors independently extracted data and assessed risk of bias. We contacted authors for additional data where required. We found 34 studies - including two cross-over RCTs, 17 RCTs, seven cluster-RCTs, and eight controlled before-and-after studies - with a total of 3,397 participants, all from high-income countries. The studies evaluated physical workplace changes (16 studies), workplace policy changes (four studies), information and counselling (11 studies), and multi-component interventions (four studies). One study included both physical workplace changes and information and counselling components. We did not find any studies that specifically investigated the effects of standing meetings or walking meetings on sitting time.Physical workplace changesInterventions using sit-stand desks, either alone or in combination with information and counselling, reduced sitting time at work on average by 100 minutes per workday at short-term follow-up (up to three months) compared to sit-desks (95% confidence interval (CI) -116 to -84, 10 studies, low-quality evidence). The pooled effect of two studies showed sit-stand desks reduced sitting time at medium-term follow-up (3 to 12 months) by an average of 57 minutes per day (95% CI -99 to -15) compared to sit-desks. Total sitting time (including sitting at and outside work) also decreased with sit-stand desks compared to sit-desks (mean difference (MD) -82 minutes/day, 95% CI -124 to -39, two studies) as did the duration of sitting bouts lasting 30 minutes or more (MD -53 minutes/day, 95% CI -79 to -26, two studies, very low-quality evidence).We found no significant difference between the effects of standing desks and sit-stand desks on reducing sitting at work. Active workstations, such as treadmill desks or cycling desks, had unclear or inconsistent effects on sitting time.Workplace policy changesWe found no significant effects for implementing walking strategies on workplace sitting time at short-term (MD -15 minutes per day, 95% CI -50 to 19, low-quality evidence, one study) and medium-term (MD -17 minutes/day, 95% CI -61 to 28, one study) follow-up. Short breaks (one to two minutes every half hour) reduced time spent sitting at work on average by 40 minutes per day (95% CI -66 to -15, one study, low-quality evidence) compared to long breaks (two 15-minute breaks per workday) at short-term follow-up.Information and counsellingProviding information, feedback, counselling, or all of these resulted in no significant change in time spent sitting at work at short-term follow-up (MD -19 minutes per day, 95% CI -57 to 19, two studies, low-quality evidence). However, the reduction was significant at medium-term follow-up (MD -28 minutes per day, 95% CI -51 to -5, two studies, low-quality evidence).Computer prompts combined with information resulted in no significant change in sitting time at work at short-term follow-up (MD -14 minutes per day, 95% CI -39 to 10, three studies, low-quality evidence), but at medium-term follow-up they produced a significant reduction (MD -55 minutes per day, 95% CI -96 to -14, one study). Furthermore, computer prompting resulted in a significant decrease in the average number (MD -1.1, 95% CI -1.9 to -0.3, one study) and duration (MD -74 minutes per day, 95% CI -124 to -24, one study) of sitting bouts lasting 30 minutes or more.Computer prompts with instruction to stand reduced sitting at work on average by 14 minutes per day (95% CI 10 to 19, one study) more than computer prompts with instruction to walk at least 100 steps at short-term follow-up.We found no significant reduction in workplace sitting time at medium-term follow-up following mindfulness training (MD -23 minutes per day, 95% CI -63 to 17, one study, low-quality evidence). Similarly a single study reported no change in sitting time at work following provision of highly personalised or contextualised information and less personalised or contextualised information. One study found no significant effects of activity trackers on sitting time at work.Multi-component interventions Combining multiple interventions had significant but heterogeneous effects on sitting time at work (573 participants, three studies, very low-quality evidence) and on time spent in prolonged sitting bouts (two studies, very low-quality evidence) at short-term follow-up. At present there is low-quality evidence that the use of sit-stand desks reduce workplace sitting at short-term and medium-term follow-ups. However, there is no evidence on their effects on sitting over longer follow-up periods. Effects of other types of interventions, including workplace policy changes, provision of information and counselling, and multi-component interventions, are mostly inconsistent. The quality of evidence is low to very low for most interventions, mainly because of limitations in study protocols and small sample sizes. There is a need for larger cluster-RCTs with longer-term follow-ups to determine the effectiveness of different types of interventions to reduce sitting time at work.

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Pouchitis occurs in approximately 50% of patients following ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (UC). The primary objective was to determine the efficacy and safety of medical therapies for prevention or treatment of acute or chronic pouchitis. We searched MEDLINE, Embase and CENTRAL from inception to 25 July 2018. We also searched references, trials registers, and conference proceedings. Randomized controlled trials of prevention or treatment of acute or chronic pouchitis in adults who underwent IPAA for UC were considered for inclusion. Two authors independently screened studies for eligibility, extracted data and assessed the risk of bias. The certainty of the evidence was evaluated using GRADE. The primary outcome was clinical improvement or remission in participants with acute or chronic pouchitis, or the proportion of participants with no episodes of pouchitis after IPAA. Adverse events (AEs) was a secondary outcome. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. Fifteen studies (547 participants) were included. Four studies assessed treatment of acute pouchitis. Five studies assessed treatment of chronic pouchitis. Six studies assessed prevention of pouchitis. Three studies were low risk of bias. Three studies were high risk of bias and the other studies were unclear. Acute pouchitis: All ciprofloxacin participants (7/7) achieved remission at two weeks compared to 33% (3/9) of metronidazole participants (RR 2.68, 95% CI 1.13 to 6.35, very low certainty evidence). No ciprofloxacin participants (0/7) had an AE compared to 33% (3/9) of metronidazole participants (RR 0.18, 95% CI 0.01 to 2.98; very low certainty evidence). AEs included vomiting, dysgeusia or transient peripheral neuropathy. Forty-three per cent (6/14) of metronidazole participants achieved remission at 6 weeks compared to 50% (6/12) of budesonide enema participants (RR 0.86, 95% CI 0.37 to 1.96, very low certainty evidence). Fifty per cent (7/14) of metronidazole participants improved clinically at 6 weeks compared to 58% (7/12) of budesonide enema participants (RR 0.86, 95% CI 0.42 to 1.74, very low certainty evidence). Fifty-seven per cent (8/14) of metronidazole participants had an AE compared to 25% (3/12) of budesonide enema participants (RR 2.29, 95% CI 0.78 to 6.73, very low certainty evidence). AEs included anorexia, nausea, headache, asthenia, metallic taste, vomiting, paraesthesia, and depression. Twenty-five per cent (2/8) of rifaximin participants achieved remission at 4 weeks compared to 0% (0/10) of placebo participants (RR 6.11, 95% CI 0.33 to 111.71, very low certainty evidence). Thirty-eight per cent (3/8) of rifaximin participants improved clinically at 4 weeks compared to 30% (3/10) of placebo participants (RR 1.25, 95% CI 0.34 to 4.60, very low certainty evidence). Seventy-five per cent (6/8) of rifaximin participants had an AE compared to 50% (5/10) of placebo participants (RR 1.50, 95% CI 0.72 to 3.14, very low certainty evidence). AEs included diarrhea, flatulence, nausea, proctalgia, vomiting, thirst, candida, upper respiratory tract infection, increased hepatic enzyme, and cluster headache. Ten per cent (1/10) of Lactobacillus GG participants improved clinically at 12 weeks compared to 0% (0/10) of placebo participants (RR 3.00, 95% CI 0.14 to 65.90, very low certainty evidence). Chronic pouchitis: Eighty-five per cent (34/40) of De Simone Formulation (a probiotic formulation) participants maintained remission at 9 to 12 months compared to 3% (1/36) of placebo participants (RR 20.24, 95% CI 4.28 to 95.81, 2 studies; low certainty evidence). Two per cent (1/40) of De Simone Formulation participants had an AE compared to 0% (0/36) of placebo participants (RR 2.43, 95% CI 0.11 to 55.89; low certainty evidence). AEs included abdominal cramps, vomiting and diarrhea. Fifty per cent (3/6) of adalimumab patients achieved clinical improvement at 4 weeks compared to 43% (3/7) of placebo participants (RR, 1.17, 95% CI 0.36 to 3.76, low certainty evidence). Sixty per cent (6/10) of glutamine participants maintained remission at 3 weeks compared to 33% (3/9) of butyrate participants (RR 1.80, 95% CI 0.63 to 5.16, very low certainty evidence). Forty-five per cent (9/20) of patients treated with bismuth carbomer foam enema improved clinically at 3 weeks compared to 45% (9/20) of placebo participants (RR 1.00, 95% CI 0.50 to 1.98, very low certainty evidence). Twenty-five per cent (5/20) of participants in the bismuth carbomer foam enema group had an AE compared to 35% (7/20) of placebo participants (RR 0.71, 95% CI 0.27 to 1.88, very low certainty evidence). Adverse events included diarrhea, worsening symptoms, cramping, sinusitis, and abdominal pain. At 12 months, 90% (18/20) of De Simone Formulation participants had no episodes of acute pouchitis compared to 60% (12/20) of placebo participants (RR 1.50, 95% CI 1.02 to 2.21, low certainty evidence). Another study found 100% (16/16) of De Simone Formulation participants had no episodes of acute pouchitis at 12 months compared to 92% (11/12) of the no treatment control group (RR 1.10, 95% 0.89 to 1.36, very low certainty evidence). Eighty-six per cent (6/7) of Bifidobacterium longum participants had no episodes of acute pouchitis at 6 months compared to 60% (3/5) of placebo participants (RR 1.43, 95% CI 0.66 to 3.11, very low certainty evidence). Eleven per cent (1/9) of Clostridium butyricum MIYAIRI participants had no episodes of acute pouchitis at 24 months compared to 50% (4/8) of placebo participants (RR 0.22, 95% CI 0.03 to 1.60, very low certainty evidence). Forty-six per cent (43/94) of allopurinol participants had no episodes of pouchitis at 24 months compared to 43% (39/90) of placebo participants (RR 1.06, 95% CI 0.76 to 1.46; low certainty evidence). Eighty-one per cent (21/26) of tinidazole participants had no episodes of pouchitis over 12 months compared to 58% (7/12) of placebo participants (RR 1.38, 95% CI 0.83 to 2.31, very low certainty evidence). The effects of antibiotics, probiotics and other interventions for treating and preventing pouchitis are uncertain. Well designed, adequately powered studies are needed to determine the optimal therapy for the treatment and prevention of pouchitis.

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Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. This is an update of a review published in 2005 and updated in 2012. To assess the effectiveness, safety, and long- and short-term adverse effects associated with the trivalent vaccine, containing measles, rubella, mumps strains (MMR), or concurrent administration of MMR vaccine and varicella vaccine (MMR+V), or tetravalent vaccine containing measles, rubella, mumps, and varicella strains (MMRV), given to children aged up to 15 years. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase (1974 to 2 May 2019), the WHO International Clinical Trials Registry Platform (2 May 2019), and ClinicalTrials.gov (2 May 2019). We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS), interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only ecological method (COEM) studies, self-controlled case series (SCCS) studies, person-time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM) studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any dose, preparation or time schedule compared with no intervention or placebo, on healthy children up to 15 years of age. Two review authors independently extracted data and assessed the methodological quality of the included studies. We grouped studies for quantitative analysis according to study design, vaccine type (MMR, MMRV, MMR+V), virus strain, and study settings. Outcomes of interest were cases of measles, mumps, rubella, and varicella, and harms. Certainty of evidence of was rated using GRADE. We included 138 studies (23,480,668 participants). Fifty-one studies (10,248,159 children) assessed vaccine effectiveness and 87 studies (13,232,509 children) assessed the association between vaccines and a variety of harms. We included 74 new studies to this 2019 version of the review. Effectiveness Vaccine effectiveness in preventing measles was 95% after one dose (relative risk (RR) 0.05, 95% CI 0.02 to 0.13; 7 cohort studies; 12,039 children; moderate certainty evidence) and 96% after two doses (RR 0.04, 95% CI 0.01 to 0.28; 5 cohort studies; 21,604 children; moderate certainty evidence). The effectiveness in preventing cases among household contacts or preventing transmission to others the children were in contact with after one dose was 81% (RR 0.19, 95% CI 0.04 to 0.89; 3 cohort studies; 151 children; low certainty evidence), after two doses 85% (RR 0.15, 95% CI 0.03 to 0.75; 3 cohort studies; 378 children; low certainty evidence), and after three doses was 96% (RR 0.04, 95% CI 0.01 to 0.23; 2 cohort studies; 151 children; low certainty evidence). The effectiveness (at least one dose) in preventing measles after exposure (post-exposure prophylaxis) was 74% (RR 0.26, 95% CI 0.14 to 0.50; 2 cohort studies; 283 children; low certainty evidence). The effectiveness of Jeryl Lynn containing MMR vaccine in preventing mumps was 72% after one dose (RR 0.24, 95% CI 0.08 to 0.76; 6 cohort studies; 9915 children; moderate certainty evidence), 86% after two doses (RR 0.12, 95% CI 0.04 to 0.35; 5 cohort studies; 7792 children; moderate certainty evidence). Effectiveness in preventing cases among household contacts was 74% (RR 0.26, 95% CI 0.13 to 0.49; 3 cohort studies; 1036 children; moderate certainty evidence). Vaccine effectiveness against rubella is 89% (RR 0.11, 95% CI 0.03 to 0.42; 1 cohort study; 1621 children; moderate certainty evidence). Vaccine effectiveness against varicella (any severity) after two doses in children aged 11 to 22 months is 95% in a 10 years follow-up (rate ratio (rr) 0.05, 95% CI 0.03 to 0.08; 1 RCT; 2279 children; high certainty evidence). Safety There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (rr 1.30, 95% CI 0.66 to 2.56; low certainty evidence). The analyses provide evidence supporting an association between MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2% to 4% of healthy children at least once before the age of 5. The attributable risk febrile seizures vaccine-induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. The analyses provide evidence supporting an association between MMR vaccination and idiopathic thrombocytopaenic purpura (ITP). However, the risk of ITP after vaccination is smaller than after natural infection with these viruses. Natural infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The attributable risk is estimated about 1 case of ITP per 40,000 administered MMR doses. There is no evidence of an association between MMR immunisation and encephalitis or encephalopathy (rate ratio 0.90, 95% CI 0.50 to 1.61; 2 observational studies; 1,071,088 children; low certainty evidence), and autistic spectrum disorders (rate ratio 0.93, 95% CI 0.85 to 1.01; 2 observational studies; 1,194,764 children; moderate certainty). There is insufficient evidence to determine the association between MMR immunisation and inflammatory bowel disease (odds ratio 1.42, 95% CI 0.93 to 2.16; 3 observational studies; 409 cases and 1416 controls; moderate certainty evidence). Additionally, there is no evidence supporting an association between MMR immunisation and cognitive delay, type 1 diabetes, asthma, dermatitis/eczema, hay fever, leukaemia, multiple sclerosis, gait disturbance, and bacterial or viral infections. Existing evidence on the safety and effectiveness of MMR/MMRV vaccines support their use for mass immunisation. Campaigns aimed at global eradication should assess epidemiological and socioeconomic situations of the countries as well as the capacity to achieve high vaccination coverage. More evidence is needed to assess whether the protective effect of MMR/MMRV could wane with time since immunisation.

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Non-infectious intermediate, posterior, and panuveitis (NIIPPU) represent a heterogenous collection of autoimmune and inflammatory disorders isolated to or concentrated in the posterior structures of the eye. Because NIIPPU is typically a chronic condition, people with NIIPPU frequently require treatment with steroid-sparing immunosuppressive therapy. Methotrexate, mycophenolate, cyclosporine, azathioprine, and tacrolimus are non-biologic, disease-modifying antirheumatic drugs (DMARDs) which have been used to treat people with NIIPPU. To compare the effectiveness and safety of selected DMARDs (methotrexate, mycophenolate mofetil, tacrolimus, cyclosporine, and azathioprine) in the treatment of NIIPPU in adults. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), MEDLINE, Embase, the Latin American and Caribbean Health Sciences database, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform, most recently on 16 April 2021. We included randomized controlled trials (RCTs) comparing selected DMARDs (methotrexate, mycophenolate, tacrolimus, cyclosporine, and azathioprine) with placebo, standard of care (topical steroids, with or without oral steroids), or with each other. We used standard methodological procedures expected by Cochrane. We included 11 RCTs with a total of 601 participants in this review. DMARDs versus control Two studies compared an experimental DMARD (cyclosporine A or enteric-coated mycophenolate [EC-MPS]) plus oral steroid with steroid monotherapy. We did not pool these results into a meta-analysis because the dose of cyclosporine used was much higher than that used in current clinical practice. The evidence is very uncertain about whether EC-MPS plus low-dose oral steroid results in a higher proportion of participants achieving control of inflammation over steroid monotherapy (risk ratio [RR] 2.81, 95% confidence interval [CI] 1.10 to 7.17; 1 study, 41 participants; very low-certainty evidence). The change in best-corrected visual acuity (BCVA) was reported separately for right and left eyes. The evidence for improvement (lower logarithm of the minimum angle of resolution (logMAR) indicates better vision) between the groups is very uncertain (mean difference [MD] -0.03 and -0.10, 95% CI -0.96 to 0.90 and -0.27 to 0.07 for right and left, respectively; 1 study, 82 eyes; very low-certainty evidence). No data were available for the following outcomes: proportion of participants achieving a 2-line improvement in visual acuity, with confirmed macular edema, or achieving steroid-sparing control. The evidence for the proportion of participants requiring cessation of medication in the DMARD versus control group is very uncertain (RR 2.61, 95% CI 0.11 to 60.51; 1 study, 41 participants; very low-certainty evidence). Methotrexate versus mycophenolate We were able to combine two studies into a meta-analysis comparing methotrexate versus mycophenolate mofetil. Methotrexate probably results in a slight increase in the proportion of participants achieving control of inflammation, including steroid-sparing control, compared to mycophenolate at six months (RR 1.23, 95% CI 1.01 to 1.50; 2 studies, 261 participants; moderate-certainty evidence). Change in BCVA was reported per eye and the treatments likely result in little to no difference in change in vision (MD 0.01 logMAR higher [worse] for methotrexate versus mycophenolate; 2 studies, 490 eyes; moderate-certainty evidence). No data were available for the proportion of participants achieving a 2-line improvement in visual acuity. The evidence is very uncertain regarding the proportion of participants with confirmed macular edema between methotrexate versus mycophenolate (RR 0.49, 95% CI 0.19 to 1.30; 2 studies, 35 eyes; very low-certainty). Methotrexate versus mycophenolate may result in little to no difference in the proportion of participants requiring cessation of medication (RR 0.99, 95% CI 0.43 to 2.27; 2 studies, 296 participants; low-certainty evidence). Steroids with or without azathioprine versus cyclosporine A Four studies compared steroids with or without azathioprine (oral steroids, intravenous [IV] steroids, or azathioprine) to cyclosporine A. We excluded two studies from the meta-analysis because the participants were treated with 8 mg to 15 mg/kg/day of cyclosporine A, a significantly higher dose than is utilized today because of concerns for nephrotoxicity. The remaining two studies were conducted in all Vogt-Koyanagi-Harada disease (VKH) populations and compared cyclosporine A to azathioprine or IV pulse-dose steroids. The evidence is very uncertain for whether the steroids with or without azathioprine or cyclosporine A influenced the proportion of participants achieving control of inflammation (RR 0.84, 95% CI 0.70 to 1.02; 2 studies, 112 participants; very low-certainty evidence), achieving steroid-sparing control (RR 0.64, 95% CI 0.33 to 1.25; 1 study, 21 participants; very low-certainty evidence), or requiring cessation of medication (RR 0.85, 95% 0.21 to 3.45; 2 studies, 91 participants; very low-certainty evidence). The evidence is uncertain for improvement in BCVA (MD 0.04 logMAR lower [better] with the steroids with or without azathioprine versus cyclosporine A; 2 studies, 91 eyes; very low-certainty evidence). There were no data available (with current cyclosporine A dosing) for the proportion of participants achieving a 2-line improvement in visual acuity or with confirmed macular edema. Studies not included in synthesis We were unable to include three studies in any of the comparisons (in addition to the aforementioned studies excluded based on historic doses of cyclosporine A). One was a dose-response study comparing cyclosporine A to cyclosporine G, a formulation which was never licensed and is not clinically available. We excluded another study from meta-analysis because it compared cyclosporine A and tacrolimus, considered to be of the same class (calcineurin inhibitors). We were unable to combine the third study, which examined tacrolimus monotherapy versus tacrolimus plus oral steroid, with any group. There is a paucity of data regarding which DMARD is most effective or safe in NIIPPU. Studies in general were small, heterogenous in terms of their design and outcome measures, and often did not compare different classes of DMARD with each other. Methotrexate is probably slightly more efficacious than mycophenolate in achieving control of inflammation, including steroid-sparing control (moderate-certainty evidence), although there was insufficient evidence to prefer one medication over the other in the VKH subgroup (very low-certainty evidence). Methotrexate may result in little to no difference in safety outcomes compared to mycophenolate.

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Before the availability of high-resolution genotyping tools in 1990s, there was a prevailing dogma of little genomic sequence diversity in Mycobacterium tuberculosis. Due to the low levels of genetic variation, it was assumed that M. tuberculosis exhibit very little phenotypic variation in immunologic and virulence factors. The fingerprinting method based on restriction fragment length polymorphisms (RFLP) of IS6110 insertion sequences had unveiled the underestimation of the sequence variation in M. tuberculosis and the importance of strain-to-strain variation for understanding pathogenesis, immune mechanisms, bacterial evolution, and host adaptation. This method became a gold standard for strain differentiation in the molecular epidemiological study. It had lead to a profusion of studies in molecular epidemiology such as the detection of unsuspected transmission, the estimation of the extent of recent transmission, the identification of laboratory cross-contamination, the identification of outbreaks, and distinction between reinfection and relapse. This, in 1990s, is the opening of the molecular epidemiology of tuberculosis. After the completion of genome project of the M. tuberculosis laboratory strain H37Rv, some of the clinical isolates were completely sequenced. This prompted the in silico genome comparison and identified various genomic markers which can give a unifying framework for both epidemiology and evolutionary analysis of M. tuberculosis population. Of them, variable numbers of tandem repeats (VNTR) was found as the most promising PCR-based method which can provide adequate discrimination of M. tuberculosis strains in many cases, including the estimation of M. tuberculosis transmission and the identification of genetic lineages. PCR-based VNTR analysis is easy, rapid, and highly specific and can generate portable digit-based data, unlike the analog information obtained from IS6110 RFLP which is labor intensive. In this regards, investigators can easily compare the genotypic data of independent studies between different laboratories. With the advantages, VNTR surpassed IS6110 RFLP and became the first line genotyping method in molecular epidemiology. One of the most attractive potentials on this method is its applicability for establishment of the database of M. tuberculosis genotype which covers not only local area but also world wide scale. This would open the door to "in silico epidemiology" which brings a breakthrough on the current TB control program. The optimization and standardization of the combination of VNTR loci for strain genotyping is the only but hard issue for the development of global database system. Road to the global Mtb genotype database is hard, but we believe, "Yes, We Can!". Another attractive potential of VNTR is its use for phylogenetic analysis, although more intensive research on this with using comprehensive marker sets, such as large sequence polymorphisms and single-nucleotide polymorphisms are required. Again, with the advantages of VNTR analysis, i.e., easy, rapid, specific, and digit-based data, VNTR became the first line method in molecular epidemiology. Molecular epidemiology of tuberculosis is expanding its research field from the investigation of TB transmission to more basic science such as evolution and phylogeographic distribution. In this symposium, we have invited four opinion leaders in molecular epidemiology of TB in Japan who are talking about each title as followed. 1. Establishment of the standard VNTR analysis systems for Tuberculosis (TB) and preparation of databases for TB genotyping: Shinji MAEDA and Yoshiro MURASE (Department of Mycobacterium Reference and Research, Research Institute of Tuberculosis, JATA). We have already reported the JATA (12)-VNTR system for TB genotyping in Japan. However, by comparison of cluster formation rate, the discrimination power of JATA (12)-VNTR was lower than that of IS6110 RFLP analysis. Therefore, we improved the JATA (12)-VNTR system for developing discrimination power. By addition of 3 loci (ETR-A, VNTR-1982 and VNTR-2163 a) to JATA (12)-VNTR, we established new JATA (15)-VNTR. We found that the discrimination power of JATA (15)-VNTR was almost the same as that of RFLP analysis. 2. Molecular epidemiology of Mycobacterium tuberculosis reviewed by molecular epidemiology of other pathogenic bacteria: Eiji YOKOYAMA (Division of Bacteriology, Chiba Prefectural Institute of Public Health). Molecular epidemiology of M. tuberculosis should be progressed to two goals. First is the short-term goal that intends to elucidate the unapparent route of transmission of the organism. Second is the long-term goal that intends to ascertain the phylogeny of the organism. The combination of VNTR loci should be changed according to the goals of molecular epidemiology of the organism. 3. Progress of the research in molecular epidemiology of Mycobacterium tuberculosis: Tomotada IWAMOTO (Department of Microbiology, Kobe Institute of Health). In the past decade, molecular epidemiology of tuberculosis brought significant insights into the transmission of tuberculosis, genetic diversity of M. tuberculosis, population structure and geographical distribution of M. tuberculosis, etc. In the advanced stage of the molecular epidemiological study, we expect to change the current geno-typing based molecular epidemiology to whole genome-typing based molecular epidemiology on the basis of the rapid innovation of next-generation sequencing technology. 4. Clinical application of molecular epidemiology of tuberculosis: Tomoshige MATSUMOTO (Department of Clinical Research and Development, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases). The molecular epidemiology can be applied in clinical practice. We showed some examples about usefulness of the clinical application of molecular epidemiology, especially using variable number of tandem repeats (VNTR) analysis. One example we showed: using VNTR, we can know whether two tuberculosis bacilli which developed from the patients, who have close contact, are the same or not in a few days; Especially, when one patient suffers from multidrug-resistant (MDR) strain of or extensively drug resistant (XDR) of tuberculosis, we can easily know whether the other suffers from MDR/XDR tuberculosis or not. The other example we showed: we can know relapse, reinfection, or laboratory contamination by using VNTR in a few days when a patient shows bacteriological relapse during the treatment. By introducing VNTR to clinical practice, we can diminish days of inappropriate hospitalization. Because VNTR data are numerical, we can easily construct VNTR database, compare data, and survey emergence of MDR/XDR-tuberculosis.

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Two different breeds of Andalusian sheep, 'Grazalema Merino' and 'Lebrijan Churro', and two different breeds of Andalusian goats, 'Andalusian White' and 'Andalusian Black', chosen by previous studies (Rodero et al. 1992a) as priority breeds for conservation, were studied. The systems used corresponded to ethnozootechnic characteristics, as well as the different biochemical-polymorphism variables. Farms were differentiated within breeds, or between themselves, and different tests were used of genetic and genotypic frequencies: Wright's indices, medium heterozygosities, Whalund's variances, G test of probability of reason, etc. Also Cavalli-Sforza's genetic distance was obtained. In the Andalusian Black and Grazalema Merino breeds, the Whalund's variances obtained were a result of selection, that has divided the breeds into distinct populations differentiated spatially. Medium heterozygosities of each breed do not differ much within themselves, but when each system is considered alone, discrepancies between ethnic groups are relevant. Wright's F indices demonstrated in the Andalusian White and Grazalema Merino breeds, genetic heterozygosities between populations or studied herds can be deduced, but this is not possible in the Andalusian Black. The F(IS) values indicated, despite the small size of the populations, that inbreeding has been avoided, probably because of the entry of foreign sires. In none of the breeds is there a significant excess of heterozygosis. The genetic distances between flocks within breeds do not differ from those found between breeds. RÉSUMÉ: On a travallé avec, differents troupeau des races de montons de l'Andalusie, Grazalema Merino et Lebrija Churro, et avec les races caprines Andalusian White et Andalusian Black, choisie entre les races Andaluciennes comme prioritaires pour la conservation, dans un etudie avant (Rodero et col. 1992a). Les sistémes utilicés dans cette travaille correspondent á charactérés etnozootechniques et á differents variables de polymorphism biochimique. Lorsque on fait differences entre troupeau, dedans de races, ou entre elles, on a utilicés differents preuves, á partir des fréquences géniques et génotipiques: l'index de Wright, hétérozygotie moyennes, variances de Whalund, preuve G de raison de probabilité, etc. Aussi le distance de Cavalli-Sforza. Comme conclusion, dans les races Andalusian Black et Grazalema Merino les variances de Whalund obtenues sont cosequences de l'action de la selection, donant different populations avec differentiation spaciale. Les hétérozygoties moyennes de chaque race sont parus, mais lorsque on considérent chaque systéme separé, les differences entre groupes ethniques sont importantes. Les indexes F de Wright demonstrent que, dans le races Andalusian White et Grazalema Merino on peuvent déduire d'heterozygoties génétique entre les populations ou troupeau analicées, dans le race Andalusian Black les differences valeurs de FIS indiquent que, malgré les petites dimensions des populations, on a evité la consanguinitée, due, probablement, á l'entrée d'étalons externes. Il n'y a pas, chez auqune race, d'un signifivative accroissement d'hétérizygosis. Les distances génétiques entre troupeau, dedans des races, en different pas des distances obtenues entre races. RESUMEN: Se ha trabajado con diferentes ganaderias de las razas ovinas andaluzas Merino de Grazalema y Churra Lebrijana, y con las caprinas Blanca Serrana y Negra Serrana, elegidas entre el resto de las razas de Andalucia como prioritarias pra la conservación, por estudio previo (Rodero y col., 1992a). Los sistemas utilizados en este trabajo corresponden tanto a caracteres etnozootécnicos como a diferentes variables de polimorfismos bioquimicos. Cuando se han diferenciado las ganaderias dentrde razas, o las ganaderias entre si, se han utilizado diferentes pruebas, a partir de las frecuencias genéticas y genotipicas: indices de Wright, heterocigosidades media, varianzas de Whalund, prueba G de razón de probabilidad, etc. También se obtuvieron las distancia genéticas de Cavalli-Sforza. Se concluye que en las razas Negra Serrana y Merino de Grazalema las varianzas de Whalund obtenidas son consecuencia de la acción de la selección que ha actuado dividiendo las razas en distintas poblaciones con diferenciación espacial. Las heterocigosidades medias de cada raza no difieren mucho entre si, pero cuando se considera cada sistema aisladamente, las discrepancias entre grupos étnicos son acusadas. Los indices F de Wright ponen de manifiesto que, mientras en las razas Blanca Serrana y Merino de Grazalema se pueden deducir heterocigosidades genéticas entre las problaciones o ganaderias estudiadas, no ocurre otro tanto en la raza Negra Serrana. Los valores de F(IS) parecen indicar que, a pesar del tamaño pequeño de las poblaciones, se ha evitado la consanguinidad, probablemente por la entrada de sementales externos. No se produce en ninguna de las razas un exceso significativo de heterocigosis. Las distancias genéticas entre ganaderias dentro de razas no difieren de lashalladas entre razas. ZUSAMMENFASSUNG: Es wurde mit verschiedenen andalusischen Zuchten der Schafrassen 'Grazalema Merino' and 'Lebrijan Churro' und der Ziegenrassen 'Andalusian White' und 'Andalusian Black' gearbeitet, die man von den andalusichen Rassen im Hinblick auf Erhaltung ausgewählt hat. Die benutzten Systeme in dieser Forschungsarbeit entsprechen Merkmalen, die sich sowohl auf ethnisch wie auch auf die verschiedenen Variablen des biochemischen Polimorfismius bezichen. Zur Unterschlidung von Zuchten innerhalb die Rassen oder von zuchten untereinander wurden verschiedene Tests benutzt, die von den genetischen und genotypischen Frequenzen ausgehen: Wright-Index, Durchschnittsheterozygositäten, Wahl und Varianz G-Test der Wahrscheinlichkeit, etc. Außerdem wurden die genetischen Distanzen nach Cavalli-Sforza errechnet. Man Kommt zum Schluß, daß in den Andalusian Black und Grazalema Merino die Wahl und Varianz das Ergebnis einer Selektionsaktivität ist, die die Rassen in Verschiedenen Populationen und unterschiedlichen Räumen aufgeteilt hat. Die durchschnittlichen Heterozygositäten jeder Rasse unterscheiden sich wenig voneinander, aber wenn man jedes System für sich betrachtet, stell man doch erhebliche Diskrepanzen zwischen den ethnischen Gruppen fest. Der Wright-Index offenbart, daß man in den Rassen Andalusian White und Grazalema Merino genetische Heterozygositäten ableiten kann zwischen den Populationen oder den untersuchten Zuchten; dies ist nicht der Fall inder Rasse Andalusian Black. Die F(IS) werte scheinen anzugeben, da trotz der kleinen Größe der Populationen die Blutsverwandschaft vermieden wurde, wahrscheinlich durch von außerhalb kommenden Böcken. In keiner der Rassen existiert übermässige Heterozygotie Die genetischen Distanzen zwischer der Zuchten unterscheiden sich nicht van dener der Rassen.

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Gold and other alloys have long been used for the production of crowns and bridges as replacements for damaged or lost teeth. However, doubts have arisen on the suitability of using these materials for dental restorations, as gold has also shown a capacity to cause side-effects such as allergic reactions. This is especially valid for alloys, which during the last decades have been used as porcelain-fused-to metal restorations. This fact has led to an interest in using titanium instead of these alloys. Trials to use titanium for this purpose were initiated in Japan in the early 1980s. Titanium as an unalloyed metal differs in two aspects from the above named alloys: it has a phase transformation at 882 degrees C, which changes its outer and inner properties, and it has an expansion that lies between that of the porcelain types available on the market at the time. In Japan a technique for casting titanium was developed, where the after-treatment of the casting was elaborate, to re-establish the original properties of titanium. The porcelain developed for veneering had shortcomings as the rendering produced a rough surface and non satisfactory esthetics. In Sweden a new concept was introduced in 1989. Here the processing of titanium was performed by industrial methods such as milling, spark erosion and laser welding. The idea behind this was to avoid phase transformation. During the 1990s a number of porcelain products were launched and a vast number of both laboratory and clinical studies were performed and published, with varying results. In the first study of this thesis a prospective clinical trial was performed at a public dental health clinic in Sweden. Twenty-five patients were provided with 40 copings of pure titanium, which were veneered with porcelain. After 2 years 36 of these crowns were evaluated and the patients were also interviewed regarding problems such as shooting pains or difficulties in cleaning around the teeth that were crowned. This evaluation showed generally unchanged values for color, form, surface and fit. Regarding surfaces, one porcelain fracture was registered (3%). The patient responses were positive and no case of sensitivity was reported after 2 years, but in 3 cases food impaction was reported. The second study is a systematic review of published articles on bond strength between titanium and porcelain. The review made comparisons of bond strength using three-point bending tests between different porcelain bonds to different alloys and to titanium, between different brands of porcelain and titanium, with porcelain following various types of processing of the titanium surface, with different compositions of the porcelain and with different firing conditions. Generally it could be seen that with this type of test (three-point bending) the bond strength between porcelain and titanium was lower than with alloys. It was also seen that there are differences in bond strengths between different brands of porcelain, that processing the titanium surface and composition of the porcelain affected bond strength, and that firing conditions were also important. The third study was performed with the intention of examining the firing accuracy of different types of dental furnaces and to investigate how maintenance and quality control is performed at Swedish dental laboratories. Since titanium porcelain is fired at a temperature which is 200 degrees C below that used for most conventional alloys, there are specific demands on the furnaces used. The optimum firing temperature is judged to be 750 degrees C for porcelain veneering of titanium, according to published studies. In this study the real firing temperature at the holding period of 1 minute was recorded by a thermo-element connected to a digital temperature measurement apparatus. The accuracy of tested furnaces demonstrated a wide variation, and in almost all cases the real temperature was higher than the temperature indicated by the furnace display; in some cases this was very much higher than the temperature displayed. This means a risk for an unwanted augmentation of the oxide layer on the titanium, which could fracture on loading. Regarding maintenance and quality control, interviews performed at 62 laboratories revealed that most of these did not attain the standards expected and claimed. The fourth study was performed with the intention of studying how the bond strength between titanium and porcelain is affected by a temperature increase of 30 degrees C, performed with two firing concepts for titanium porcelain and examined by three-point bending tests. The fractured surfaces were also analyzed with SEM and EDX. These two concepts for titanium porcelain differ in that one has an oxide firing of the titanium metal as the first firing step, while the other is fired with a bonding agent as the first step in the firing procedure. Furthermore, half of the test bodies were aged by thermo-cycling. This study has shown that a moderate elevation in the firing temperature does not affect the bond strength in this case. Comparing bond strengths between the two different firing concepts, three-point bending tests showed that the test bodies that had undergone an oxidation firing had significantly higher bond strengths in all but one situation. These results were contradicted by the SEM and EDX analysis. These showed that with oxidation firing the fractures occurred in the brittle (and probably thickened) oxide layer of the titanium, while the fractures occurred in the well integrated interface with titanium oxide and porcelain components when firing without oxidation. The reasons for these contradictory results might be that oxidation firing changed the ductility of the titanium, creating a higher stiffness which could better withstand the deflection of the specimens created during the three-point bending tests. For the same reason it might also be irrelevant to test bond strength between porcelain and metals with differing properties. Considering these results and the results from other studies, the validity of the current test standard for metal-ceramic bond strengths may be questioned.

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People with central neurological disease or injury have a much higher risk of both faecal incontinence and constipation than the general population. There is often a fine line between the two symptoms, with any management intended to ameliorate one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical, with a limited research base. This is an update of a Cochrane review first published in 2001 and subsequently updated in 2003 and 2006. The review is relevant to individuals with any disease directly and chronically affecting the central nervous system (post-traumatic, degenerative, ischaemic or neoplastic), such as multiple sclerosis, spinal cord injury, cerebrovascular disease, Parkinson's disease and Alzheimer's disease. To determine the effects of management strategies for faecal incontinence and constipation in people with a neurological disease or injury affecting the central nervous system. We searched the Cochrane Incontinence Group Trials Register (searched 8 June 2012), which includes searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE In-Process as well as handsearching of journals and conference proceedings; and all reference lists of relevant articles. Randomised and quasi-randomised trials evaluating any type of conservative or surgical intervention for the management of faecal incontinence and constipation in people with central neurological disease or injury were selected. Specific therapies for the treatment of neurological diseases that indirectly affect bowel dysfunction were also considered. At least two review authors independently assessed the risk of bias of eligible trials and independently extracted data from the included trials using a range of pre-specified outcome measures. Twenty trials involving 902 people were included. Oral medications There was evidence from individual small trials that people with Parkinson's disease had a statistically significant improvement in the number of bowel motions or successful bowel care routines per week when fibre (psyllium) (mean difference (MD) -2.2 bowel motions, 95% confidence interval (CI) -3.3 to -1.4) or oral laxative (isosmotic macrogol electrolyte solution) (MD 2.9 bowel motions per week, 95% CI 1.48 to 4.32) are used compared with placebo. One trial in people with spinal cord injury showed statistically significant improvement in total bowel care time comparing intramuscular neostigmine-glycopyrrolate (anticholinesterase plus an anticholinergic drug) with placebo (MD 23.3 minutes, 95% CI 4.68 to 41.92).Five studies reported the use of cisapride and tegaserod in people with spinal cord injuries or Parkinson's disease. These drugs have since been withdrawn from the market due to adverse effects; as they are no longer available they have been removed from this review. Rectal stimulants One small trial in people with spinal cord injuries compared two bisacodyl suppositories, one polyethylene glycol-based (PGB) and one hydrogenated vegetable oil-based (HVB). The trial found that the PGB bisacodyl suppository significantly reduced the mean defaecation period (PGB 20 minutes versus HVB 36 minutes, P &lt; 0.03) and mean total time for bowel care (PGB 43 minutes versus HVB 74.5 minutes, P &lt; 0.01) compared with the HVB bisacodyl suppository.Physical interventions There was evidence from one small trial with 31 participants that abdominal massage statistically improved the number of bowel motions in people who had a stroke compared with no massage (MD 1.7 bowel motions per week, 95% CI 2.22 to 1.18). A small feasibility trial including 30 individuals with multiple sclerosis also found evidence to support the use of abdominal massage. Constipation scores were statistically better with the abdominal massage during treatment although this was not supported by a change in outcome measures (for example the neurogenic bowel dysfunction score).One small trial in people with spinal cord injury showed statistically significant improvement in total bowel care time using electrical stimulation of abdominal muscles compared with no electrical stimulation (MD 29.3 minutes, 95% CI 7.35 to 51.25).There was evidence from one trial with a low risk of bias that for people with spinal cord injury transanal irrigation, compared against conservative bowel care, statistically improved constipation scores, neurogenic bowel dysfunction score, faecal incontinence score and total time for bowel care (MD 27.4 minutes, 95% CI 7.96 to 46.84). Patients were also more satisfied with this method.Other interventions In one trial in stroke patients, there appeared to be a short term benefit (less than six months) to patients in terms of the number of bowel motions per week with a one-off educational intervention from nurses (a structured nurse assessment leading to targeted education versus routine care), but this did not persist at 12 months. A trial in individuals with spinal cord injury found that a stepwise protocol did not reduce the need for oral laxatives and manual evacuation of stool.Finally, one further trial reported in abstract form showed that oral carbonated water (rather than tap water) improved constipation scores in people who had had a stroke. There is still remarkably little research on this common and, to patients, very significant issue of bowel management. The available evidence is almost uniformly of low methodological quality. The clinical significance of some of the research findings presented here is difficult to interpret, not least because each intervention has only been addressed in individual trials, against control rather than compared against each other, and the interventions are very different from each other.There was very limited evidence from individual trials in favour of a bulk-forming laxative (psyllium), an isosmotic macrogol laxative, abdominal massage, electrical stimulation and an anticholinesterase-anticholinergic drug combination (neostigmine-glycopyrrolate) compared to no treatment or controls. There was also evidence in favour of transanal irrigation (compared to conservative management), oral carbonated (rather than tap) water and abdominal massage with lifestyle advice (compared to lifestyle advice alone). However, these findings need to be confirmed by larger well-designed controlled trials which should include evaluation of the acceptability of the intervention to patients and the effect on their quality of life.

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Peripheral arterial disease (PAD) may cause occlusions (blockages) in the main arteries of lower limbs. One treatment option is bypass surgery using autologous (the patient's own tissue) vein graft or prosthetic (artificial) graft. A number of factors influence occlusion rates in these patients, including the material used. To prevent graft occlusion patients are usually treated with antiplatelet, antithrombotic drugs, or a combination of both. To determine the effects of antiplatelet agents for the prevention of thrombosis in people with lower limb atherosclerosis who were undergoing femoropopliteal or femorodistal bypass grafting. Outcomes included the overall success of therapy (graft patency and limb salvage rates) and complications of treatment. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched June 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 5). We sought additional trials through screening the reference lists of relevant papers. Two review authors, RB and AL, independently reviewed studies found in the search and evaluated them based on the inclusion and exclusion criteria, resolving disagreements through discussion. RB and AL independently extracted details of the selected studies for the update. We compared the treatment and control groups for important prognostic factors and differences described. If any data were unavailable, we sought further information from study authors. We synthesised data by comparing group results. We addressed unit of analysis issues by subgroup analysis. We include 16 studies with 5683 randomised participants. Nine different treatment groups were evaluated: aspirin (ASA) or aspirin and dipyridamole (ASA/DIP) versus placebo or nothing (six studies); ASA or ASA/DIP versus pentoxifylline (two studies); ASA/DIP versus indobufen (one study); ASA or ASA/DIP versus vitamin K antagonists (two studies); ASA/DIP versus low molecular weight heparin (one study); ticlopidine versus placebo (one study); ASA versus prostaglandin E1 (one study); ASA versus naftidrofuryl (one study); and clopidogrel and ASA versus ASA alone (one study). The treatment comparisons were evaluated separately, and, where possible, we performed subgroup analysis for venous grafts and prosthetic grafts and at different follow-up time points. The quality of evidence was low to moderate as many of the treatment comparisons had very few studies to contribute data, several of the included studies had unit of analysis issues, the treatment dosages varied between studies, and data for many outcomes important to this review were not given in any of the studies, or differed greatly between studies. Overall study quality was moderate, with the largest problem being that the majority of studies did not describe their methods of randomisation, allocation concealment or blinding of outcome assessors, leading to risk ratings of 'unclear'. The other main issue with study quality was studies not blinding participants or personnel.The treatment comparison with the most number of included studies, which allowed for robust conclusions, was that of aspirin (ASA) or ASA and dipyridamole (ASA/DIP) versus placebo or nothing, covered by six studies. For this treatment group, there was improved graft patency in the ASA or ASA/DIP treatment group, odds ratio (OR) 0.42 (95% confidence interval (CI) 0.22 to 0.83; P = 0.01; 952 participants). This effect was not seen for venous grafts alone at any of the time points, but was observed for all time points in prosthetic grafts, including the final time point of 12 months (OR 0.19, 95% CI 0.10 to 0.36; P &lt; 0.00001; 222 participants). Only a single study evaluated secondary patency, for which there was no difference between treatment groups. For the comparison ASA or ASA/DIP versus placebo or nothing there was no difference for any of the side effects, including general, gastrointestinal, bleeding and wound/graft infection. Amputations, cardiovascular events and mortality were also similar between the treatment groups. The comparison of ASA or ASA/DIP versus vitamin K antagonists included two studies, one of which was very large, with over 2000 participants. There were no differences between treatment for primary graft patency at three, six, 12 or 24 months, and there was also no evidence of a difference for limb amputation, cardiovascular events or mortality. One large study (851 participants) evaluated clopidogrel and ASA versus ASA alone, and for all grafts there was no evidence of a difference of primary patency at 24 months. There was evidence of increased total bleeding in the clopidogrel and ASA group (OR 2.65, 95% CI 1.69 to 4.15) from an increase in mild (OR 2.34, 95% CI 1.37 to 4.00), and moderate bleeding (OR 4.13, 95% CI 1.37 to 12.45), but no difference in severe or fatal bleeding. There was no difference between the treatment groups for limb amputation or mortality. For the remaining treatment comparisons there is not currently enough evidence to draw any robust conclusions about the efficacy or safety of the treatment on graft patency after peripheral bypass. Antiplatelet therapy with aspirin or with aspirin plus dipyridamole had a beneficial effect on primary patency of peripheral bypass grafts compared to placebo or no treatment. This effect was not evident when evaluating venous grafts alone, but antiplatelet therapy did have a beneficial effect on patency in those who had prosthetic grafts. There was no evidence of differences in side effects (including general, gastrointestinal, bleeding or infection), amputation, cardiovascular events or mortality between the treatment groups. However, the number of participants included in this analysis might be too small to detect a statistically significant effect for side effects, amputation, cardiovascular morbidity or mortality. We found no difference in primary graft patency when aspirin or aspirin with dipyridamole was compared to a vitamin K antagonist or when clopidogrel with aspirin was compared to aspirin alone. However, there was evidence of increase bleeding in the clopidogrel with aspirin group for the latter comparison. The remaining six treatment comparisons did not include enough data to draw any robust conclusions about their efficacy or safety at this time.

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Telemedicine (TM) is the use of telecommunication systems to deliver health care at a distance. It has the potential to improve patient health outcomes, access to health care and reduce healthcare costs. As TM applications continue to evolve it is important to understand the impact TM might have on patients, healthcare professionals and the organisation of care. To assess the effectiveness, acceptability and costs of interactive TM as an alternative to, or in addition to, usual care (i.e. face-to-face care, or telephone consultation). We searched the Effective Practice and Organisation of Care (EPOC) Group's specialised register, CENTRAL, MEDLINE, EMBASE, five other databases and two trials registers to June 2013, together with reference checking, citation searching, handsearching and contact with study authors to identify additional studies. We considered randomised controlled trials of interactive TM that involved direct patient-provider interaction and was delivered in addition to, or substituting for, usual care compared with usual care alone, to participants with any clinical condition. We excluded telephone only interventions and wholly automatic self-management TM interventions. For each condition, we pooled outcome data that were sufficiently homogenous using fixed effect meta-analysis. We reported risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and mean differences (MD) for continuous outcomes. We included 93 eligible trials (N = 22,047 participants), which evaluated the effectiveness of interactive TM delivered in addition to (32% of studies), as an alternative to (57% of studies), or partly substituted for usual care (11%) as compared to usual care alone.The included studies recruited patients with the following clinical conditions: cardiovascular disease (36), diabetes (21), respiratory conditions (9), mental health or substance abuse conditions (7), conditions requiring a specialist consultation (6), co morbidities (3), urogenital conditions (3), neurological injuries and conditions (2), gastrointestinal conditions (2), neonatal conditions requiring specialist care (2), solid organ transplantation (1), and cancer (1).Telemedicine provided remote monitoring (55 studies), or real-time video-conferencing (38 studies), which was used either alone or in combination. The main TM function varied depending on clinical condition, but fell typically into one of the following six categories, with some overlap: i) monitoring of a chronic condition to detect early signs of deterioration and prompt treatment and advice, (41); ii) provision of treatment or rehabilitation (12), for example the delivery of cognitive behavioural therapy, or incontinence training; iii) education and advice for self-management (23), for example nurses delivering education to patients with diabetes or providing support to parents of very low birth weight infants or to patients with home parenteral nutrition; iv) specialist consultations for diagnosis and treatment decisions (8), v) real-time assessment of clinical status, for example post-operative assessment after minor operation or follow-up after solid organ transplantation (8) vi), screening, for angina (1).The type of data transmitted by the patient, the frequency of data transfer, (e.g. telephone, e-mail, SMS) and frequency of interactions between patient and healthcare provider varied across studies, as did the type of healthcare provider/s and healthcare system involved in delivering the intervention.We found no difference between groups for all-cause mortality for patients with heart failure (16 studies; N = 5239; RR:0.89, 95% CI 0.76 to 1.03, P = 0.12; I(2) = 44%) (moderate to high certainty of evidence) at a median of six months follow-up. Admissions to hospital (11 studies; N = 4529) ranged from a decrease of 64% to an increase of 60% at median eight months follow-up (moderate certainty of evidence). We found some evidence of improved quality of life (five studies; N = 482; MD:-4.39, 95% CI -7.94 to -0.83; P &lt; 0.02; I(2) = 0%) (moderate certainty of evidence) for those allocated to TM as compared with usual care at a median three months follow-up. In studies recruiting participants with diabetes (16 studies; N = 2768) we found lower glycated haemoglobin (HbA1c %) levels in those allocated to TM than in controls (MD -0.31, 95% CI -0.37 to -0.24; P &lt; 0.00001; I(2)= 42%, P = 0.04) (high certainty of evidence) at a median of nine months follow-up. We found some evidence for a decrease in LDL (four studies, N = 1692; MD -12.45, 95% CI -14.23 to -10.68; P &lt; 0.00001; I(2 =) 0%) (moderate certainty of evidence), and blood pressure (four studies, N = 1770: MD: SBP:-4.33, 95% CI -5.30 to -3.35, P &lt; 0.00001; I(2) = 17%; DBP: -2.75 95% CI -3.28 to -2.22, P &lt; 0.00001; I(2) = 45% (moderate certainty evidence), in TM as compared with usual care.Seven studies that recruited participants with different mental health and substance abuse problems, reported no differences in the effect of therapy delivered over video-conferencing, as compared to face-to-face delivery. Findings from the other studies were inconsistent; there was some evidence that monitoring via TM improved blood pressure control in participants with hypertension, and a few studies reported improved symptom scores for those with a respiratory condition. Studies recruiting participants requiring mental health services and those requiring specialist consultation for a dermatological condition reported no differences between groups. The findings in our review indicate that the use of TM in the management of heart failure appears to lead to similar health outcomes as face-to-face or telephone delivery of care; there is evidence that TM can improve the control of blood glucose in those with diabetes. The cost to a health service, and acceptability by patients and healthcare professionals, is not clear due to limited data reported for these outcomes. The effectiveness of TM may depend on a number of different factors, including those related to the study population e.g. the severity of the condition and the disease trajectory of the participants, the function of the intervention e.g., if it is used for monitoring a chronic condition, or to provide access to diagnostic services, as well as the healthcare provider and healthcare system involved in delivering the intervention.

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Crowns for primary molars are preformed and come in a variety of sizes and materials to be placed over decayed or developmentally defective teeth. They can be made completely of stainless steel (know as 'preformed metal crowns' or PMCs), or to give better aesthetics, may be made of stainless steel with a white veneer cover or made wholly of a white ceramic material. In most cases, teeth are trimmed for the crowns to be fitted conventionally using a local anaesthetic. However, in the case of the Hall Technique, PMCs are pushed over the tooth with no local anaesthetic, carious tissue removal or tooth preparation. Crowns are recommended for restoring primary molar teeth that have had a pulp treatment, are very decayed or are badly broken down. However, few dental practitioners use them in clinical practice. This review updates the original review published in 2007. Primary objectiveTo evaluate the clinical effectiveness and safety of all types of preformed crowns for restoring primary teeth compared with conventional filling materials (such as amalgam, composite, glass ionomer, resin modified glass ionomer and compomers), other types of crowns or methods of crown placement, non-restorative caries treatment or no treatment. Secondary objectiveTo explore whether the extent of decay has an effect on the clinical outcome of primary teeth restored with all types of preformed crowns compared with those restored with conventional filling materials. We searched the following electronic databases: Cochrane Oral Health Group Trials Register (to 21 January 2015), Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, 2014, Issue 12), MEDLINE via Ovid (1946 to 21 January 2015) and EMBASE via Ovid (1980 to 21 January 2015). We searched the US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials and Open Grey for grey literature (to 21 January 2015). No restrictions were placed on the language or date of publication when searching the databases. Randomised controlled trials (RCTs) that assessed the effectiveness of crowns compared with fillings, other types of crowns, non-restorative approaches or no treatment in children with untreated tooth decay in one or more primary molar teeth. We would also have included trials comparing different methods of fitting crowns.For trials to be considered for this review, the success or failure of the interventions and other clinical outcomes had to be reported at least six months after intervention (with the exception of 'pain/discomfort during treatment and immediately postoperatively'). Two review authors independently assessed the title and abstracts for each article from the search results. and independently assessed the full text for each potentially relevant study. At least two authors assessed risk of bias and extracted data using a piloted data extraction form. We included five studies that evaluated three comparisons. Four studies compared crowns with fillings; two of them compared conventional PMCs with open sandwich restorations, and two compared PMCs fitted using the Hall Technique with fillings. One of these studies included a third arm, which allowed the comparison of PMCs (fitted using the Hall Technique) versus non-restorative caries treatment. In the two studies using crowns fitted using the conventional method, all teeth had undergone pulpotomy prior to the crown being placed. The final study compared two different types of crowns: PMCs versus aesthetic stainless steel crowns with white veneers. No RCT evidence was found that compared different methods of fitting preformed metal crowns (i.e. Hall Technique versus conventional technique).We considered outcomes reported at the dental appointment or within 24 hours of it, and in the short term (less than 12 months) or long term (12 months or more). Some of our outcomes of interest were not measured in the studies: time to restoration failure or retreatment, patient satisfaction and costs. Crowns versus fillingsAll studies in this comparison used PMCs. One study reported outcomes in the short term and found no reports of major failure or pain in either group. There was moderate quality evidence that the risk of major failure was lower in the crowns group in the long term (risk ratio (RR) 0.18, 95% confidence interval (CI) 0.06 to 0.56; 346 teeth in three studies, one conventional and two using Hall Technique). Similarly, there was moderate quality evidence that the risk of pain was lower in the long term for the crown group (RR 0.15, 95% CI 0.04 to 0.67; 312 teeth in two studies).Discomfort associated with the procedure was lower for crowns fitted using the Hall Technique than for fillings (RR 0.56, 95% CI 0.36 to 0.87; 381 teeth) (moderate quality evidence).It is uncertain whether there is a clinically important difference in the risk of gingival bleeding when using crowns rather than fillings, either in the short term (RR 1.69, 95% CI 0.61 to 4.66; 226 teeth) or long term (RR 1.74, 95% CI 0.99 to 3.06; 195 teeth, two studies using PMCs with conventional technique at 12 months) (low quality evidence). Crowns versus non-restorative caries treatmentOnly one study compared PMCs (fitted with the Hall Technique) with non-restorative caries treatment; the evidence quality was very low and we are therefore we are uncertain about the estimates. Metal crowns versus aesthetic crownsOne split-mouth study (11 participants) compared PMCs versus aesthetic crowns (stainless steel with white veneers). It provided very low quality evidence so no conclusions could be drawn. Crowns placed on primary molar teeth with carious lesions, or following pulp treatment, are likely to reduce the risk of major failure or pain in the long term compared to fillings. Crowns fitted using the Hall Technique may reduce discomfort at the time of treatment compared to fillings. The amount and quality of evidence for crowns compared to non-restorative caries, and for metal compared with aesthetic crowns, is very low. There are no RCTs comparing crowns fitted conventionally versus using the Hall Technique.

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Office work has changed considerably over the previous couple of decades and has become sedentary in nature. Physical inactivity at workplaces and particularly increased sitting has been linked to increase in cardiovascular disease, obesity and overall mortality. To evaluate the effects of workplace interventions to reduce sitting at work compared to no intervention or alternative interventions. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, OSH UPDATE, PsycINFO, Clinical trials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal up to 2 June, 2015. We also screened reference lists of articles and contacted authors to find more studies to include. We included randomised controlled trials (RCTs), cluster-randomised controlled trials (cRCTs), and quasi-randomised controlled trials of interventions to reduce sitting at work. For changes of workplace arrangements, we also included controlled before-and-after studies (CBAs) with a concurrent control group. The primary outcome was time spent sitting at work per day, either self-reported or objectively measured by means of an accelerometer-inclinometer. We considered energy expenditure, duration and number of sitting episodes lasting 30 minutes or more, work productivity and adverse events as secondary outcomes. Two review authors independently screened titles, abstracts and full-text articles for study eligibility. Two review authors independently extracted data and assessed risk of bias. We contacted authors for additional data where required. We included 20 studies, two cross-over RCTs, 11 RCTs, three cRCTs and four CBAs, with a total of 2180 participants from high income nations. The studies evaluated physical workplace changes (nine studies), policy changes (two studies), information and counselling (seven studies) and interventions from multiple categories (two studies). One study had both physical workplace changes and information and counselling components. We did not find any studies that had investigated the effect of periodic breaks or standing or walking meetings. Physical workplace changesA sit-stand desk alone compared to no intervention reduced sitting time at work per workday with between thirty minutes to two hours at short term (up to three months) follow-up (six studies, 218 participants, very low quality evidence). In two studies, sit-stand desks with additional counselling reduced sitting time at work in the same range at short-term follow-up (61 participants, very low quality evidence). One study found a reduction at six months' follow-up of -56 minutes (95% CI -101 to -12, very low quality evidence) compared to no intervention. Also total sitting time at work and outside work decreased with sit-stand desks compared to no intervention (MD -78 minutes, 95% CI -125 to -31, one study) as did the duration of sitting episodes lasting 30 minutes or more (MD -52 minutes, 95% CI -79 to -26, two studies). This is considerably less than the two to four hours recommended by experts. Sit-stand desks did not have a considerable effect on work performance, musculoskeletal symptoms or sick leave. It remains unclear if standing can repair the harms of sitting because there is hardly any extra energy expenditure.The effects of active workstations were inconsistent. Treadmill desks combined with counselling reduced sitting time at work (MD -29 minutes, 95% CI -55 to -2, one study) compared to no intervention at 12 weeks' follow-up. Pedalling workstations combined with information did not reduce inactive sitting at work considerably (MD -12 minutes, 95% CI -24 to 1, one study) compared to information alone at 16 weeks' follow-up. The quality of evidence was low for active workstations. Policy changesTwo studies with 443 participants provided low quality evidence that walking strategies did not have a considerable effect on workplace sitting time at 10 weeks' (MD -16 minutes, 95% CI -54 to 23) or 21 weeks' (MD -17 minutes, 95% CI -58 to 25) follow-up respectively. Information and counsellingCounselling reduced sitting time at work (MD -28 minutes, 95% CI -52 to -5, two studies, low quality evidence) at medium term (three months to 12 months) follow-up. Mindfulness training did not considerably reduce workplace sitting time (MD -2 minutes, 95% CI -22 to 18) at six months' follow-up and at 12 months' follow-up (MD -16 minutes, 95% CI -45 to 12, one study, low quality evidence). There was no considerable increase in work engagement with counselling.There was an inconsistent effect of computer prompting on sitting time at work. One study found no considerable effect on sitting at work (MD -17 minutes, 95% CI -48 to 14, low quality evidence) at 10 days' follow-up, while another study reported a significant reduction in sitting at work (MD -55 minutes, 95% CI -96 to -14, low quality evidence) at 13 weeks' follow-up. Computer prompts to stand reduced sitting at work by 14 minutes more (95% CI 10 to 19, one study) compared to computer prompts to step at six days' follow-up. Computer prompts did not change the number of sitting episodes that last 30 minutes or longer. Interventions from multiple categories Interventions combining multiple categories had an inconsistent effect on sitting time at work, with a reduction in sitting time at 12 weeks' (25 participants, very low quality evidence) and six months' (294 participants, low quality evidence) follow-up in two studies but no considerable effect at 12 months' follow-up in one study (MD -47.98, 95% CI -103 to 7, 294 participants, low quality evidence). At present there is very low to low quality evidence that sit-stand desks may decrease workplace sitting between thirty minutes to two hours per day without having adverse effects at the short or medium term. There is no evidence on the effects in the long term. There were no considerable or inconsistent effects of other interventions such as changing work organisation or information and counselling. There is a need for cluster-randomised trials with a sufficient sample size and long term follow-up to determine the effectiveness of different types of interventions to reduce objectively measured sitting time at work.

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Tibolone is a synthetic steroid used for the treatment of menopausal symptoms, on the basis of short-term data suggesting its efficacy. We considered the balance between the benefits and risks of tibolone. To evaluate the effectiveness and safety of tibolone for treatment of postmenopausal and perimenopausal women. In October 2015, we searched the Gynaecology and Fertility Group (CGF) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO (from inception), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinicaltrials.gov. We checked the reference lists in articles retrieved. We included randomised controlled trials (RCTs) comparing tibolone versus placebo, oestrogens and/or combined hormone therapy (HT) in postmenopausal and perimenopausal women. We used standard methodological procedures of The Cochrane Collaboration. Primary outcomes were vasomotor symptoms, unscheduled vaginal bleeding and long-term adverse events. We evaluated safety outcomes and bleeding in studies including women either with or without menopausal symptoms. We included 46 RCTs (19,976 women). Most RCTs evaluated tibolone for treating menopausal vasomotor symptoms. Some had other objectives, such as assessment of bleeding patterns, endometrial safety, bone health, sexuality and safety in women with a history of breast cancer. Two included women with uterine leiomyoma or lupus erythematosus. Tibolone versus placebo Vasomotor symptomsTibolone was more effective than placebo (standard mean difference (SMD) -0.99, 95% confidence interval (CI) -1.10 to -0.89; seven RCTs; 1657 women; moderate-quality evidence), but removing trials at high risk of attrition bias attenuated this effect (SMD -0.61, 95% CI -0.73 to -0.49; odds ratio (OR) 0.33, 85% CI 0.27 to 0.41). This suggests that if 67% of women taking placebo experience vasomotor symptoms, between 35% and 45% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with greater likelihood of bleeding (OR 2.79, 95% CI 2.10 to 3.70; nine RCTs; 7814 women; I<sup2</sup = 43%; moderate-quality evidence). This suggests that if 18% of women taking placebo experience unscheduled bleeding, between 31% and 44% of women taking tibolone will do so. Long-term adverse eventsMost of the studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Breast cancerWe found no evidence of differences between groups among women with no history of breast cancer (OR 0.52, 95% CI 0.21 to 1.25; four RCTs; 5500 women; I<sup2</sup= 17%; very low-quality evidence). Among women with a history of breast cancer, tibolone was associated with increased risk (OR 1.5, 95% CI 1.21 to 1.85; two RCTs; 3165 women; moderate-quality evidence). Cerebrovascular eventsWe found no conclusive evidence of differences between groups in cerebrovascular events (OR 1.74, 95% CI 0.99 to 3.04; four RCTs; 7930 women; I<sup2</sup = 0%; very low-quality evidence). We obtained most data from a single RCT (n = 4506) of osteoporotic women aged 60 to 85 years, which was stopped prematurely for increased risk of stroke. Other outcomesEvidence on other outcomes was of low or very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 2.04, 95% CI 0.79 to 5.24; nine RCTs; 8504 women; I<sup2</sup = 0%.• Cardiovascular events: OR 1.38, 95% CI 0.84 to 2.27; four RCTs; 8401 women; I<sup2</sup = 0%.• Venous thromboembolic events: OR 0.85, 95% CI 0.37 to 1.97; 9176 women; I<sup2</sup = 0%.• Mortality from any cause: OR 1.06, 95% CI 0.79 to 1.41; four RCTs; 8242 women; I<sup2</sup = 0%. Tibolone versus combined HT Vasomotor symptomsCombined HT was more effective than tibolone (SMD 0.17, 95% CI 0.06 to 0.28; OR 1.36, 95% CI 1.11 to 1.66; nine studies; 1336 women; moderate-quality evidence). This result was robust to a sensitivity analysis that excluded trials with high risk of attrition bias, suggesting a slightly greater disadvantage of tibolone (SMD 0.25, 95% CI 0.09 to 0.41; OR 1.57, 95% CI 1.18 to 2.10). This suggests that if 7% of women taking combined HT experience vasomotor symptoms, between 8% and 14% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with a lower rate of bleeding (OR 0.32, 95% CI 0.24 to 0.41; 16 RCTs; 6438 women; I<sup2</sup = 72%; moderate-quality evidence). This suggests that if 47% of women taking combined HT experience unscheduled bleeding, between 18% and 27% of women taking tibolone will do so. Long-term adverse eventsMost studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Evidence was of very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 1.47, 95% CI 0.23 to 9.33; five RCTs; 3689 women; I<sup2</sup = 0%.• Breast cancer: OR 1.69, 95% CI 0.78 to 3.67; five RCTs; 4835 women; I<sup2</sup = 0%.• Venous thromboembolic events: OR 0.44, 95% CI 0.09 to 2.14; four RCTs; 4529 women; I<sup2</sup = 0%.• Cardiovascular events: OR 0.63, 95% CI 0.24 to 1.66; two RCTs; 3794 women; I<sup2</sup = 0%.• Cerebrovascular events: OR 0.76, 95% CI 0.16 to 3.66; four RCTs; 4562 women; I<sup2</sup = 0%.• Mortality from any cause: only one event reported (two RCTs; 970 women). Moderate-quality evidence suggests that tibolone is more effective than placebo but less effective than HT in reducing menopausal vasomotor symptoms, and that tibolone is associated with a higher rate of unscheduled bleeding than placebo but with a lower rate than HT.Compared with placebo, tibolone increases recurrent breast cancer rates in women with a history of breast cancer, and may increase stroke rates in women over 60 years of age. No evidence indicates that tibolone increases the risk of other long-term adverse events, or that it differs from HT with respect to long-term safety.Much of the evidence was of low or very low quality. Limitations included high risk of bias and imprecision. Most studies were financed by drug manufacturers or failed to disclose their funding source.

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Breast cancer continues to be the most commonly diagnosed cancer in women globally. Early detection, diagnosis and treatment of breast cancer are key to better outcomes. Since many women will discover a breast cancer symptom themselves, it is important that they are breast cancer aware i.e. have the knowledge, skills and confidence to detect breast changes and present promptly to a healthcare professional. To assess the effectiveness of interventions for raising breast cancer awareness in women. We searched the Cochrane Breast Cancer Group's Specialised Register (searched 25 January 2016), Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 12) in the Cochrane Library (searched 27 January 2016), MEDLINE OvidSP (2008 to 27 January 2016), Embase (Embase.com, 2008 to 27 January 2016), the World Health Organization's International Clinical Trials Registry Platform (ICTRP) search portal and ClinicalTrials.gov (searched 27 Feburary 2016). We also searched the reference lists of identified articles and reviews and the grey literature for conference proceedings and published abstracts. No language restriction was applied. Randomised controlled trials (RCTs) focusing on interventions for raising women's breast cancer awareness i.e. knowledge of potential breast cancer symptoms/changes and the confidence to look at and feel their breasts, using any means of delivery, i.e. one-to-one/group/mass media campaign(s). Two authors selected studies, independently extracted data and assessed risk of bias. We reported the odds ratio (OR) and 95% confidence intervals (CIs) for dichotomous outcomes and mean difference (MD) and standard deviation (SD) for continuous outcomes. Since it was not possible to combine data from included studies due to their heterogeneity, we present a narrative synthesis. We assessed the quality of evidence using GRADE methods. We included two RCTs involving 997 women: one RCT (867 women) randomised women to receive either a written booklet and usual care (intervention group 1), a written booklet and usual care plus a verbal interaction with a radiographer or research psychologist (intervention group 2) or usual care (control group); and the second RCT (130 women) randomised women to either an educational programme (three sessions of 60 to 90 minutes) or no intervention (control group). Knowledge of breast cancer symptomsIn the first study, knowledge of non-lump symptoms increased in intervention group 1 compared to the control group at two years postintervention, but not significantly (OR 1.1, 95% CI 0.7 to 1.6; P = 0.66; 449 women; moderate-quality evidence). Similarly, at two years postintervention, knowledge of symptoms increased in the intervention group 2 compared to the control group but not significantly (OR 1.4, 95% CI 0.9 to 2.1; P = 0.11; 434 women; moderate-quality evidence). In the second study, women's awareness of breast cancer symptoms had increased one month post intervention in the educational group (MD 3.45, SD 5.11; 65 women; low-quality evidence) compared to the control group (MD -0.68, SD 5.93; 65 women; P &lt; 0.001), where there was a decrease in awareness. Knowledge of age-related riskIn the first study, women's knowledge of age-related risk of breast cancer increased, but not significantly, in intervention group 1 compared to control at two years postintervention (OR 1.8; 95% CI 0.9 to 3.5; P &lt; 0.08; 447 women; moderate-quality evidence). Women's knowledge of risk increased significantly in intervention group 2 compared to control at two years postintervention (OR 4.8, 95% CI 2.6 to 9.0; P &lt; 0.001; 431 women; moderate-quality evidence). In the second study, women's perceived susceptibility (how at risk they considered themselves) to breast cancer had increased significantly one month post intervention in the educational group (MD 1.31, SD 3.57; 65 women; low-quality evidence) compared to the control group (MD -0.55, SD 3.31; 65 women; P = 0.005), where a decrease in perceived susceptibility was noted. Frequency of Breast CheckingIn the first study, no significant change was noted for intervention group 1 compared to control at two years postintervention (OR 1.1, 95% CI 0.8 to 1.6; P = 0.54; 457 women; moderate-quality evidence). Monthly breast checking increased, but not significantly, in intervention group 2 compared to control at two years postintervention (OR 1.3, 95% CI 0.9 to 1.9; P = 0.14; 445 women; moderate-quality evidence). In the second study, women's breast cancer preventive behaviours increased significantly one month post intervention in the educational group (MD 1.21, SD 2.54; 65 women; low-quality evidence) compared to the control group (MD 0.15, SD 2.94; 65 women; P &lt; 0.045). Breast Cancer AwarenessWomen's overall breast cancer awareness did not change in intervention group 1 compared to control at two years postintervention (OR 1.8, 95% CI 0.6 to 5.30; P = 0.32; 435 women; moderate-quality evidence) while overall awareness increased in the intervention group 2 compared to control at two years postintervention (OR 8.1, 95% CI 2.7 to 25.0; P &lt; 0.001; 420 women; moderate-quality evidence). In the second study, there was a significant increase in scores on the Health Belief Model (that included the constructs of awareness and perceived susceptibility) at one month postintervention in the educational group (mean 1.21, SD 2.54; 65 women) compared to the control group (mean 0.15, SD 2.94; 65 women; P = 0.045).Neither study reported outcomes relating to motivation to check their breasts, confidence to seek help, time from breast symptom discovery to presentation to a healthcare professional, intentions to seek help, quality of life, adverse effects of the interventions, stages of breast cancer, survival estimates or breast cancer mortality rates. Based on the results of two RCTs, a brief intervention has the potential to increase women's breast cancer awareness. However, findings of this review should be interpreted with caution, as GRADE assessment identified moderate-quality evidence in only one of the two studies reviewed. In addition, the included trials were heterogeneous in terms of the interventions, population studied and outcomes measured. Therefore, current evidence cannot be generalised to the wider context. Further studies including larger samples, validated outcome measures and longitudinal approaches are warranted.

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When extraembryonic egg material is placed apart from prospective diapause germ anlagen or early germ bands, it will stimulate their development without dormancy via the medium. This method of a bipartial systemin vitro (21° C) helps to analyze the regulatory mechanisms involved in the egg diapause ofBombyx mori. 1. In preliminary experiments, a culture medium free of egg extracts but containing foreign proteins (LYS) proved useful, since 100% of the test germs reached dormancy in the absence of stored egg material. Mitoses decrease and morphogenesis decelerates until the stage of the fully segmented germ-band is reached, which means the end of the prediapausal period. 2. When eggs were opened they developedin vitro without egg diapause. One may assume that the access of free oxygen activates some regulatory mechanisms permitting development without dormancy (nondormancy=Nd). In addition, the separate deposit of chorion, serosa and yolk cells (CDS Depot) will in any case prevent dormancy. Thus, the factors responsible for egg diapause must be sought in the extraembryonic egg system. A direct contact between the extraembryonic action-system and the embryonic reactionsystem is not a prerequisite. TheLYS medium without deposits offers sufficient oxygen to the test germ. Therefore the prospective diapause germ possesses a tendency to dormancy, according to its reaction norm. The potency to stimulateNd was tested with various depotmaterials (C, D, S, CS, DS, CDS) removed from eggs during prediapause (21° C), diapause (3° C) and post-diapause (returned to 21° C for 4 days). Each material produced a specificNd rate.In vitro, the test germs can progress in their organogenesis optimally to the stage of a small larva. The means of a collective effect in development are determined and related to one of the nine possibledegrees of organogenesis. 3. In comparison to serosa and chorion, yolk material has the highest mean both inNd rate (68 %,n=219) and degree of organogenesis. Surprisingly, cell-free chorionic material prevents dormancy development in 55% (n=296). As compared to theD Depot, the combination ofDS elicits a higherNd rate (79%,n=234), which is only surpassed by theCDS combination (100%,n=76). In comparison toS Depot(44%,n=294) theNd rate of aCS Depot reaches only 37% (n=161), presumably due to a restriction of the experiments to young material only. Probes, tested separately according to germ anlage or germ band, showed that there was no influence of the operational age of the test germ on theNd rate. 4. However, theNd-stimulating potency ofC, D, S, CS andDS depends on the operational age of the donator egg. Yolk material starts out having a highNd effect, decreasing with pre-diapausal age and staying relatively high in diapausal age. Similar changes are observed in the combination of yolk and serosa. TheNd rate of chorion starts low, increases steeply with the operational age and remains rather uniform. TheNd rate of serosa increases steeply in the stage critical to the beginning of egg diapause (dish-like germ anlage), decreases after pre-diapause and increases again after the minimal period for diapause (3 months at 3° C). HigherNd rates are observed whenS, D, andDS Depot were returned to 21° C for 4 days.D Depot has the maximal potency favouring organogenesis at the dish-like germ anlage stage. 5. The following subjects are discussed: the results of Chino (1957, 1958) on glycogen metabolismin ovo, the findings of Okada (1971) on the development of de-chorionized eggs under paraffin oil and our ownin ovo observations on the ultrastructural changes in the chorion, the mitotic activity before and after diapause and the distribution of glycogen in germ, yolk cells and serosa. These facts can be utilized to formulate a concept of the physiological phases of egg diapausein ovo: Egg diapause begins during a critical stage of the germ anlage with a reaction between serosa and chorionic material, which reduces the rate of oxygen consumption. Under these conditions, glycogen is metabolized into sorbitol and glyoerol. The physiologicalprophase of egg diapause is terminated, when the germ-band reaches dormancy. Diapause begins (e.g. at 3° C) with themesophase, during which the metabolism of glycogen continues decreasingly. Now glycogen is found only in the germ.Metaphase may begin with the re-uptake of oxygen, which starts the re-synthesis of glycogen from sorbitol and glycerol via oxydation and phosphorylation. However, the exposure to cold (3° C) will inhibit mitosis in the dormant germ band. In thetelophase of egg diapause, after terminated resynthesis, the dormant germ can remain in quiescence. When exposed to 21° C during the embryonic post-diapause period, it consumes the stored glycogen. If the high temperature starts prematurely during the mesophase, no embryo will hatch. However, when high temperatures set in during the metaphase, glycogen resynthesis and glycogen-breakdown in embryogenesis will compete and thus the hatching rate will be low. 6. Assuming that in the depot experimentsin vitro at 21° C and with free access of oxygen, glycogen metabolism can be considered one parameter of theNd rate, a satisfactory explanation of our experiments can be offered. With aCDS Depot,Nd stimulatory mechanism will always work satisfactorily, assuming a considerable resynthesis of glycogen of previously cold-exposed depot material.Nd rate ofD Depot will first follow the glycogen parameterin ovo; when removed from diapause, it may be capable of the resynthesis of glycogen. This will also explain the correspondingNd rates of theDS Depots. There is no correlation between theNd rates ofC Depots and the glycogen parameterin ovo. S Depots acquire a dependency on the glycogen parameter, which is independent of exposure to high temperature and oxygenin vitro. Further investigations on the glycogen metabolim of the depot materialin vitro are necessary to clarify these hypotheses. 7. The observations on the physiological phases inBombyx may also hold true for egg diapause of other insects. Various experiments with eggs of other strains ofBombyx with different reaction norms may substantiate our present conclusions. The enzymatic basis of the regulatory mechanisms with special regard to chorion should receive further clarification.

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Aortic valve disease is a common condition that is easily treatable with cardiac surgery. This is conventionally performed by opening the sternum longitudinally down the centre ("median sternotomy") and replacing the valve under cardiopulmonary bypass. Median sternotomy is generally well tolerated, but as less invasive options have become available, the efficacy of limited incisions has been called into question. In particular, the effects of reducing the visibility and surgical access has raised safety concerns with regards to the placement of cannulae, venting of the heart, epicardial wire placement, and de-airing of the heart at the end of the procedure. These difficulties may increase operating times, affecting outcome. The benefits of smaller incisions are thought to include decreased pain; improved respiratory mechanics; reductions in wound infections, bleeding, and need for transfusion; shorter intensive care stay; better cosmesis; and a quicker return to normal activity. To assess the effects of minimally invasive aortic valve replacement via a limited sternotomy versus conventional aortic valve replacement via median sternotomy in people with aortic valve disease requiring surgical replacement. We performed searches of CENTRAL, MEDLINE, Embase, clinical trials registries, and manufacturers' websites from inception to July 2016, with no language limitations. We reviewed references of identified papers to identify any further studies of relevance. Randomised controlled trials comparing aortic valve replacement via a median sternotomy versus aortic valve replacement via a limited sternotomy. We excluded trials that performed other minimally invasive incisions such as mini-thoracotomies, port access, trans-apical, trans-femoral or robotic procedures. Although some well-conducted prospective and retrospective case-control and cohort studies exist, these were not included in this review. Two review authors independently assessed trial papers to extract data, assess quality, and identify risk of bias. A third review author provided arbitration where required. The quality of evidence was determined using the GRADE methodology and results of patient-relevant outcomes were summarised in a 'Summary of findings' table. The review included seven trials with 511 participants. These included adults from centres in Austria, Spain, Italy, Germany, France, and Egypt. We performed 12 comparisons investigating the effects of minimally invasive limited upper hemi-sternotomy on aortic valve replacement as compared to surgery performed via full median sternotomy.There was no evidence of any effect of upper hemi-sternotomy on mortality versus full median sternotomy (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.36 to 2.82; participants = 511; studies = 7; moderate quality). There was no evidence of an increase in cardiopulmonary bypass time with aortic valve replacement performed via an upper hemi-sternotomy (mean difference (MD) 3.02 minutes, 95% CI -4.10 to 10.14; participants = 311; studies = 5; low quality). There was no evidence of an increase in aortic cross-clamp time (MD 0.95 minutes, 95% CI -3.45 to 5.35; participants = 391; studies = 6; low quality). None of the included studies reported major adverse cardiac and cerebrovascular events as a composite end point.There was no evidence of an effect on length of hospital stay through limited hemi-sternotomy (MD -1.31 days, 95% CI -2.63 to 0.01; participants = 297; studies = 5; I<sup2</sup = 89%; very low quality). Postoperative blood loss was lower in the upper hemi-sternotomy group (MD -158.00 mL, 95% CI -303.24 to -12.76; participants = 297; studies = 5; moderate quality). The evidence did not support a reduction in deep sternal wound infections (RR 0.71, 95% CI 0.22 to 2.30; participants = 511; studies = 7; moderate quality) or re-exploration (RR 1.01, 95% CI 0.48 to 2.13; participants = 511; studies = 7; moderate quality). There was no change in pain scores by upper hemi-sternotomy (standardised mean difference (SMD) -0.33, 95% CI -0.85 to 0.20; participants = 197; studies = 3; I<sup2</sup = 70%; very low quality), but there was a small increase in postoperative pulmonary function tests with minimally invasive limited sternotomy (MD 1.98 % predicted FEV1, 95% CI 0.62 to 3.33; participants = 257; studies = 4; I<sup2</sup = 28%; low quality). There was a small reduction in length of intensive care unit stays as a result of the minimally invasive upper hemi-sternotomy (MD -0.57 days, 95% CI -0.93 to -0.20; participants = 297; studies = 5; low quality). Postoperative atrial fibrillation was not reduced with minimally invasive aortic valve replacement through limited compared to full sternotomy (RR 0.60, 95% CI 0.07 to 4.89; participants = 240; studies = 3; moderate quality), neither were postoperative ventilation times (MD -1.12 hours, 95% CI -3.43 to 1.19; participants = 297; studies = 5; low quality). None of the included studies reported cost analyses. The evidence in this review was assessed as generally low to moderate quality. The study sample sizes were small and underpowered to demonstrate differences in outcomes with low event rates. Clinical heterogeneity both between and within studies is a relatively fixed feature of surgical trials, and this also contributed to the need for caution in interpreting results.Considering these limitations, there was uncertainty of the effect on mortality or extracorporeal support times with upper hemi-sternotomy for aortic valve replacement compared to full median sternotomy. The evidence to support a reduction in total hospital length of stay or intensive care stay was low in quality. There was also uncertainty of any difference in the rates of other, secondary outcome measures or adverse events with minimally invasive limited sternotomy approaches to aortic valve replacement.There appears to be uncertainty between minimally invasive aortic valve replacement via upper hemi-sternotomy and conventional aortic valve replacement via a full median sternotomy. Before widespread adoption of the minimally invasive approach can be recommended, there is a need for a well-designed and adequately powered prospective randomised controlled trial. Such a study would benefit from performing a robust cost analysis. Growing patient preference for minimally invasive techniques merits thorough quality-of-life analyses to be included as end points, as well as quantitative measures of physiological reserve.

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It has been proposed that antioxidants may prevent cellular damage in the retina by reacting with free radicals that are produced in the process of light absorption. Higher dietary levels of antioxidant vitamins and minerals may reduce the risk of progression of age-related macular degeneration (AMD). The objective of this review was to assess the effects of antioxidant vitamin or mineral supplementation on the progression of AMD in people with AMD. We searched CENTRAL (2017, Issue 2), MEDLINE Ovid (1946 to March 2017), Embase Ovid (1947 to March 2017), AMED (1985 to March 2017), OpenGrey (System for Information on Grey Literature in Europe, the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 29 March 2017. We included randomised controlled trials (RCTs) that compared antioxidant vitamin or mineral supplementation (alone or in combination) to placebo or no intervention, in people with AMD. Both review authors independently assessed risk of bias in the included studies and extracted data. One author entered data into RevMan 5; the other author checked the data entry. We graded the certainty of the evidence using GRADE. We included 19 studies conducted in USA, Europe, China, and Australia. We judged the trials that contributed data to the review to be at low or unclear risk of bias.Nine studies compared multivitamins with placebo (7 studies) or no treatment (2 studies) in people with early and moderate AMD. The duration of supplementation and follow-up ranged from nine months to six years; one trial followed up beyond two years. Most evidence came from the Age-Related Eye Disease Study (AREDS) in the USA. People taking antioxidant vitamins were less likely to progress to late AMD (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.58 to 0.90; 2445 participants; 3 RCTs; moderate-certainty evidence). In people with very early signs of AMD, who are at low risk of progression, this would mean that there would be approximately 4 fewer cases of progression to late AMD for every 1000 people taking vitamins (1 fewer to 6 fewer cases). In people at high risk of progression (i.e. people with moderate AMD) this would correspond to approximately 8 fewer cases of progression for every 100 people taking vitamins (3 fewer to 13 fewer). In one study of 1206 people, there was a lower risk of progression for both neovascular AMD (OR 0.62, 95% CI 0.47 to 0.82; moderate-certainty evidence) and geographic atrophy (OR 0.75, 95% CI 0.51 to 1.10; moderate-certainty evidence) and a lower risk of losing 3 or more lines of visual acuity (OR 0.77, 95% CI 0.62 to 0.96; 1791 participants; moderate-certainty evidence). Low-certainty evidence from one study of 110 people suggested higher quality of life scores (National Eye Institute Visual Function Questionnaire) in treated compared with the non-treated people after 24 months (mean difference (MD) 12.30, 95% CI 4.24 to 20.36). Six studies compared lutein (with or without zeaxanthin) with placebo. The duration of supplementation and follow-up ranged from six months to five years. Most evidence came from the AREDS2 study in the USA. People taking lutein or zeaxanthin may have similar or slightly reduced risk of progression to late AMD (RR 0.94, 95% CI 0.87 to 1.01; 6891 eyes; low-certainty evidence), neovascular AMD (RR 0.92, 95% CI 0.84 to 1.02; 6891 eyes; low-certainty evidence), and geographic atrophy (RR 0.92, 95% CI 0.80 to 1.05; 6891 eyes; low-certainty evidence). A similar risk of progression to visual loss of 15 or more letters was seen in the lutein and control groups (RR 0.98, 95% CI 0.91 to 1.05; 6656 eyes; low-certainty evidence). Quality of life (measured with Visual Function Questionnaire) was similar between groups in one study of 108 participants (MD 1.48, 95% -5.53 to 8.49, moderate-certainty evidence). One study, conducted in Australia, compared vitamin E with placebo. This study randomised 1204 people to vitamin E or placebo, and followed up for four years. Participants were enrolled from the general population; 19% had AMD. The number of late AMD events was low (N = 7) and the estimate of effect was uncertain (RR 1.36, 95% CI 0.31 to 6.05, very low-certainty evidence). There were no data on neovascular AMD or geographic atrophy.There was no evidence of any effect of treatment on visual loss (RR 1.04, 95% CI 0.74 to 1.47, low-certainty evidence). There were no data on quality of life. Five studies compared zinc with placebo. The duration of supplementation and follow-up ranged from six months to seven years. People taking zinc supplements may be less likely to progress to late AMD (OR 0.83, 95% CI 0.70 to 0.98; 3790 participants; 3 RCTs; low-certainty evidence), neovascular AMD (OR 0.76, 95% CI 0.62 to 0.93; 2442 participants; 1 RCT; moderate-certainty evidence), geographic atrophy (OR 0.84, 95% CI 0.64 to 1.10; 2442 participants; 1 RCT; moderate-certainty evidence), or visual loss (OR 0.87, 95% CI 0.75 to 1.00; 3791 participants; 2 RCTs; moderate-certainty evidence). There were no data reported on quality of life.Very low-certainty evidence was available on adverse effects because the included studies were underpowered and adverse effects inconsistently reported. People with AMD may experience some delay in progression of the disease with multivitamin antioxidant vitamin and mineral supplementation. This finding was largely drawn from one large trial, conducted in a relatively well-nourished American population. We do not know the generalisability of these findings to other populations. Although generally regarded as safe, vitamin supplements may have harmful effects. A systematic review of the evidence on harms of vitamin supplements is needed. Supplements containing lutein and zeaxanthin are heavily marketed for people with age-related macular degeneration but our review shows they may have little or no effect on the progression of AMD.

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Acetylcholinesterase inhibitors, such as neostigmine, have traditionally been used for reversal of non-depolarizing neuromuscular blocking agents. However, these drugs have significant limitations, such as indirect mechanisms of reversal, limited and unpredictable efficacy, and undesirable autonomic responses. Sugammadex is a selective relaxant-binding agent specifically developed for rapid reversal of non-depolarizing neuromuscular blockade induced by rocuronium. Its potential clinical benefits include fast and predictable reversal of any degree of block, increased patient safety, reduced incidence of residual block on recovery, and more efficient use of healthcare resources. The main objective of this review was to compare the efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade caused by non-depolarizing neuromuscular agents in adults. We searched the following databases on 2 May 2016: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (WebSPIRS Ovid SP), Embase (WebSPIRS Ovid SP), and the clinical trials registries www.controlled-trials.com, clinicaltrials.gov, and www.centerwatch.com. We re-ran the search on 10 May 2017. We included randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status, outcomes published, or language. We included adults, classified as American Society of Anesthesiologists (ASA) I to IV, who received non-depolarizing neuromuscular blocking agents for an elective in-patient or day-case surgical procedure. We included all trials comparing sugammadex versus neostigmine that reported recovery times or adverse events. We included any dose of sugammadex and neostigmine and any time point of study drug administration. Two review authors independently screened titles and abstracts to identify trials for eligibility, examined articles for eligibility, abstracted data, assessed the articles, and excluded obviously irrelevant reports. We resolved disagreements by discussion between review authors and further disagreements through consultation with the last review author. We assessed risk of bias in 10 methodological domains using the Cochrane risk of bias tool and examined risk of random error through trial sequential analysis. We used the principles of the GRADE approach to prepare an overall assessment of the quality of evidence. For our primary outcomes (recovery times to train-of-four ratio (TOFR) &gt; 0.9), we presented data as mean differences (MDs) with 95 % confidence intervals (CIs), and for our secondary outcomes (risk of adverse events and risk of serious adverse events), we calculated risk ratios (RRs) with CIs. We included 41 studies (4206 participants) in this updated review, 38 of which were new studies. Twelve trials were eligible for meta-analysis of primary outcomes (n = 949), 28 trials were eligible for meta-analysis of secondary outcomes (n = 2298), and 10 trials (n = 1647) were ineligible for meta-analysis.We compared sugammadex 2 mg/kg and neostigmine 0.05 mg/kg for reversal of rocuronium-induced moderate neuromuscular blockade (NMB). Sugammadex 2 mg/kg was 10.22 minutes (6.6 times) faster then neostigmine 0.05 mg/kg (1.96 vs 12.87 minutes) in reversing NMB from the second twitch (T2) to TOFR &gt; 0.9 (MD 10.22 minutes, 95% CI 8.48 to 11.96; I<sup2</sup = 84%; 10 studies, n = 835; GRADE: moderate quality).We compared sugammadex 4 mg/kg and neostigmine 0.07 mg/kg for reversal of rocuronium-induced deep NMB. Sugammadex 4 mg/kg was 45.78 minutes (16.8 times) faster then neostigmine 0.07 mg/kg (2.9 vs 48.8 minutes) in reversing NMB from post-tetanic count (PTC) 1 to 5 to TOFR &gt; 0.9 (MD 45.78 minutes, 95% CI 39.41 to 52.15; I<sup2</sup = 0%; two studies, n = 114; GRADE: low quality).For our secondary outcomes, we compared sugammadex, any dose, and neostigmine, any dose, looking at risk of adverse and serious adverse events. We found significantly fewer composite adverse events in the sugammadex group compared with the neostigmine group (RR 0.60, 95% CI 0.49 to 0.74; I<sup2</sup = 40%; 28 studies, n = 2298; GRADE: moderate quality). Risk of adverse events was 28% in the neostigmine group and 16% in the sugammadex group, resulting in a number needed to treat for an additional beneficial outcome (NNTB) of 8. When looking at specific adverse events, we noted significantly less risk of bradycardia (RR 0.16, 95% CI 0.07 to 0.34; I<sup2</sup= 0%; 11 studies, n = 1218; NNTB 14; GRADE: moderate quality), postoperative nausea and vomiting (PONV) (RR 0.52, 95% CI 0.28 to 0.97; I<sup2</sup = 0%; six studies, n = 389; NNTB 16; GRADE: low quality) and overall signs of postoperative residual paralysis (RR 0.40, 95% CI 0.28 to 0.57; I<sup2</sup = 0%; 15 studies, n = 1474; NNTB 13; GRADE: moderate quality) in the sugammadex group when compared with the neostigmine group. Finally, we found no significant differences between sugammadex and neostigmine regarding risk of serious adverse events (RR 0.54, 95% CI 0.13 to 2.25; I<sup2</sup= 0%; 10 studies, n = 959; GRADE: low quality).Application of trial sequential analysis (TSA) indicates superiority of sugammadex for outcomes such as recovery time from T2 to TOFR &gt; 0.9, adverse events, and overall signs of postoperative residual paralysis. Review results suggest that in comparison with neostigmine, sugammadex can more rapidly reverse rocuronium-induced neuromuscular block regardless of the depth of the block. Sugammadex 2 mg/kg is 10.22 minutes (˜ 6.6 times) faster in reversing moderate neuromuscular blockade (T2) than neostigmine 0.05 mg/kg (GRADE: moderate quality), and sugammadex 4 mg/kg is 45.78 minutes (˜ 16.8 times) faster in reversing deep neuromuscular blockade (PTC 1 to 5) than neostigmine 0.07 mg/kg (GRADE: low quality). With an NNTB of 8 to avoid an adverse event, sugammadex appears to have a better safety profile than neostigmine. Patients receiving sugammadex had 40% fewer adverse events compared with those given neostigmine. Specifically, risks of bradycardia (RR 0.16, NNTB 14; GRADE: moderate quality), PONV (RR 0.52, NNTB 16; GRADE: low quality), and overall signs of postoperative residual paralysis (RR 0.40, NNTB 13; GRADE: moderate quality) were reduced. Both sugammadex and neostigmine were associated with serious adverse events in less than 1% of patients, and data showed no differences in risk of serious adverse events between groups (RR 0.54; GRADE: low quality).

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Oral zuclopenthixol dihydrochloride (Clopixol) is an anti-psychotic treatment for people with psychotic symptoms, especially those with schizophrenia. It is associated with neuroleptic malignant syndrome, a prolongation of the QTc interval, extra-pyramidal reactions, venous thromboembolism and may modify insulin and glucose responses. To determine the effects of zuclopenthixol dihydrochloride for treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's Trials Register (latest search 09 June 2015). There were no language, date, document type, or publication status limitations for inclusion of records in the register. All randomised controlled trials (RCTs) focusing on zuclopenthixol dihydrochloride for schizophrenia. We included trials meeting our inclusion criteria and reporting useable data. We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. We included 20 trials, randomising 1850 participants. Data were reported for 12 comparisons, predominantly for the short term (up to 12 weeks) and inpatient populations. Overall risk of bias for included studies was low to unclear.Data were unavailable for many of our pre-stated outcomes of interest. No data were available, across all comparisons, for death, duration of stay in hospital and general functioning.Zuclopenthixol dihydrochloride versus: 1. placeboMovement disorders (EPSEs) were similar between groups (1 RCT, n = 28, RR 6.07 95% CI 0.86 to 43.04 very low-quality evidence). There was no clear difference in numbers leaving the study early (2 RCTs, n = 100, RR 0.29, 95% CI 0.01 to 6.60, very low-quality evidence). 2. chlorpromazineNo clear differences were found for the outcomes of global state (average CGI-SI endpoint score) (1 RCT, n = 60, MD 0.00, 95% CI -0.49 to 0.49) or movement disorders (EPSEs) (3 RCTs, n = 199, RR 0.94, 95% CI 0.61 to 1.45), both very low-quality evidence. More people left the study early for any reason from the zuclopenthixol group (6 RCTs, n = 766, RR 0.54, 95% CI 0.36 to 0.81, low-quality evidence). 3. chlorprothixeneThere was no clear difference in numbers leaving the study early for any reason (1 RCT, n = 20, RR 1.00, 95% CI 0.34 to 2.93, very low-quality evidence). 4. clozapineNo useable data were presented. 5. haloperidolNo clear differences between treatment groups were found for the outcomes global state score (average CGI endpoint score) (1 RCT, n = 49, MD 0.13, 95% CI -0.30 to 0.55) or leaving the study early (2 RCTs, n = 141, RR 0.99, 95% CI 0.72 to 1.35), both very low-quality evidence. 6. perphenazineThose receiving zuclopenthixol were more likely to require medication in the short term for EPSEs than perphenazine (1 RCT, n = 50, RR 1.90, 95% CI 1.12 to 3.22, very low-quality evidence). Similar numbers left the study early (2 RCTs, n = 104, RR 0.63, 95% CI 0.27 to 1.47, very low-quality evidence). 7. risperidoneThose receiving zuclopenthixol were more likely to require medications for EPSEs than risperidone (1 RCT, n = 98,RR 1.92, 95% CI 1.12 to 3.28, very low quality evidence). There was no clear difference in numbers leaving the study early ( 3 RCTs, n = 154, RR 1.30, 95% CI 0.84 to 2.02) or in mental state (average PANSS total endpoint score) (1 RCT, n = 25, MD -3.20, 95% CI -7.71 to 1.31), both very low-quality evidence). 8. sulpirideNo clear differences were found for global state (average CGI endpoint score) ( 1 RCT, n = 61, RR 1.18, 95% CI 0.49 to 2.85, very low-quality evidence), requiring hypnotics/sedatives (1 RCT, n = 61, RR 0.60, 95% CI 0.27 to 1.32, very low-quality evidence) or leaving the study early (1 RCT, n = 61, RR 2.07 95% CI 0.97 to 4.40, very low-quality evidence). 9. thiothixeneNo clear differences were found for the outcomes of 'global state (average CGI endpoint score) (1 RCT, n = 20, RR 0.50, 95% CI 0.17 to 1.46) or leaving the study early (1 RCT, n = 20, RR 0.57, 95% CI 0.24 to 1.35), both very low-quality evidence). 10. trifluoperazineNo useable data were presented. 11. zuclopenthixol depotThere was no clear difference in numbers leaving the study early (1 RCT, n = 46, RR 1.95, 95% CI 0.36 to 10.58, very low-quality evidence). 12. Zuclopenthixol dihydrochloride (cis z isomer) versus zuclopenthixol (cis z/trans e isomer)There were no clear differences in reported side-effects ( 1 RCT, n = 57, RR 1.34, 95% CI 0.82 to 2.18, very low-quality evidence) and in numbers leaving the study early (4 RCTs, n = 140, RR 2.15, 95% CI 0.49 to 9.41, very low-quality evidence). Zuclopenthixol dihydrochloride appears to cause more EPSEs than clozapine, risperidone or perphenazine, but there was no difference in EPSEs when compared to placebo or chlorpromazine. Similar numbers required hypnotics/sedatives when zuclopenthixol dihydrochloride was compared to sulpiride, and similar numbers of reported side-effects were found when its isomers were compared. The other comparisons did not report adverse-effect data.Reported data indicate zuclopenthixol dihydrochloride demonstrates no difference in mental or global states compared to placebo, chlorpromazine, chlorprothixene, clozapine, haloperidol, perphenazine, sulpiride, thiothixene, trifluoperazine, depot and isomers. Zuclopenthixol dihydrochloride, when compared with risperidone, is favoured when assessed using the PANSS in the short term, but not in the medium term.The data extracted from the included studies are mostly equivocal, and very low to low quality, making it difficult to draw firm conclusions. Prescribing practice is unlikely to change based on this meta-analysis. Recommending any particular course of action about side-effect medication other than monitoring, using rating scales and clinical assessment, and prescriptions on a case-by-case basis, is also not possible.There is a need for further studies covering this topic with more antipsychotic comparisons for currently relevant outcomes.

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Depression is recognised as a major public health problem that has a substantial impact on individuals and on society. People with depression may consider using complementary therapies such as acupuncture, and an increasing body of research has been undertaken to assess the effectiveness of acupuncture for treatment of individuals with depression. This is the second update of this review. To examine the effectiveness and adverse effects of acupuncture for treatment of individuals with depression.To determine:• Whether acupuncture is more effective than treatment as usual/no treatment/wait list control for treating and improving quality of life for individuals with depression.• Whether acupuncture is more effective than control acupuncture for treating and improving quality of life for individuals with depression.• Whether acupuncture is more effective than pharmacological therapies for treating and improving quality of life for individuals with depression.• Whether acupuncture plus pharmacological therapy is more effective than pharmacological therapy alone for treating and improving quality of life for individuals with depression.• Whether acupuncture is more effective than psychological therapies for treating and improving quality of life for individuals with depression.• Adverse effects of acupuncture compared with treatment as usual/no treatment/wait list control, control acupuncture, pharmacological therapies, and psychological therapies for treatment of individuals with depression. We searched the following databases to June 2016: Cochrane Common Mental Disorders Group Controlled Trials Register (CCMD-CTR), Korean Studies Information Service System (KISS), DBPIA (Korean article database website), Korea Institute of Science and Technology Information, Research Information Service System (RISS), Korea Med, Korean Medical Database (KM base), and Oriental Medicine Advanced Searching Integrated System (OASIS), as well as several Korean medical journals. Review criteria called for inclusion of all published and unpublished randomised controlled trials comparing acupuncture versus control acupuncture, no treatment, medication, other structured psychotherapies (cognitive-behavioural therapy, psychotherapy, or counselling), or standard care. Modes of treatment included acupuncture, electro-acupuncture, and laser acupuncture. Participants included adult men and women with depression diagnosed by Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV), Research Diagnostic Criteria (RDC), International Statistical Classification of Diseases and Related Health Problems (ICD), or Chinese Classification of Mental Disorders Third Edition Revised (CCMD-3-R). If necessary, we used trial authors' definitions of depressive disorder. We performed meta-analyses using risk ratios (RRs) for dichotomous outcomes and standardised mean differences (SMDs) for continuous outcomes, with 95% confidence intervals (CIs). Primary outcomes were reduction in the severity of depression, measured by self-rating scales or by clinician-rated scales, and improvement in depression, defined as remission versus no remission. We assessed evidence quality using the GRADE method. This review is an update of previous versions and includes 64 studies (7104 participants). Most studies were at high risk of performance bias, at high or unclear risk of detection bias, and at low or unclear risk of selection bias, attrition bias, reporting bias, and other bias.Acupuncture versus no treatment/wait list/treatment as usualWe found low-quality evidence suggesting that acupuncture (manual and electro-) may moderately reduce the severity of depression by end of treatment (SMD -0.66, 95% CI -1.06 to -0.25, five trials, 488 participants). It is unclear whether data show differences between groups in the risk of adverse events (RR 0.89, 95% CI 0.35 to 2.24, one trial, 302 participants; low-quality evidence).Acupuncture versus control acupuncture (invasive, non-invasive sham controls)Acupuncture may be associated with a small reduction in the severity of depression of 1.69 points on the Hamilton Depression Rating Scale (HAMD) by end of treatment (95% CI -3.33 to -0.05, 14 trials, 841 participants; low-quality evidence). It is unclear whether data show differences between groups in the risk of adverse events (RR 1.63, 95% CI 0.93 to 2.86, five trials, 300 participants; moderate-quality evidence).Acupuncture versus medicationWe found very low-quality evidence suggesting that acupuncture may confer small benefit in reducing the severity of depression by end of treatment (SMD -0.23, 95% CI -0.40 to -0.05, 31 trials, 3127 participants). Studies show substantial variation resulting from use of different classes of medications and different modes of acupuncture stimulation. Very low-quality evidence suggests lower ratings of adverse events following acupuncture compared with medication alone, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) (mean difference (MD) -4.32, 95% CI -7.41 to -1.23, three trials, 481 participants).Acupuncture plus medication versus medication aloneWe found very low-quality evidence suggesting that acupuncture is highly beneficial in reducing the severity of depression by end of treatment (SMD -1.15, 95% CI -1.63 to -0.66, 11 trials, 775 participants). Studies show substantial variation resulting from use of different modes of acupuncture stimulation. It is unclear whether differences in adverse events are associated with different modes of acupuncture (SMD -1.32, 95% CI -2.86 to 0.23, three trials, 200 participants; very low-quality evidence).Acupuncture versus psychological therapyIt is unclear whether data show differences between acupuncture and psychological therapy in the severity of depression by end of treatment (SMD -0.5, 95% CI -1.33 to 0.33, two trials, 497 participants; low-quality evidence). Low-quality evidence suggests no differences between groups in rates of adverse events (RR 0.62, 95% CI 0.29 to 1.33, one trial, 452 participants). The reduction in severity of depression was less when acupuncture was compared with control acupuncture than when acupuncture was compared with no treatment control, although in both cases, results were rated as providing low-quality evidence. The reduction in severity of depression with acupuncture given alone or in conjunction with medication versus medication alone is uncertain owing to the very low quality of evidence. The effect of acupuncture compared with psychological therapy is unclear. The risk of adverse events with acupuncture is also unclear, as most trials did not report adverse events adequately. Few studies included follow-up periods or assessed important outcomes such as quality of life. High-quality randomised controlled trials are urgently needed to examine the clinical efficacy and acceptability of acupuncture, as well as its effectiveness, compared with acupuncture controls, medication, or psychological therapies.

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Vitamins and minerals play multiple functions within the central nervous system which may help to maintain brain health and optimal cognitive functioning. Supplementation of the diet with various vitamins and minerals has been suggested as a means of maintaining cognitive function, or even of preventing dementia, in later life. To evaluate the effects of vitamin and mineral supplementation on cognitive function in cognitively healthy people aged 40 years or more. We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov and the WHO Portal/ICTRP from inception to 26th January 2018. We included randomised controlled trials that evaluated the cognitive effects on people aged 40 years or more of any vitamin or mineral supplements taken by mouth for at least three months. Study selection, data extraction, and quality assessments were done in duplicate. Vitamins were considered broadly in the categories of B vitamins, antioxidant vitamins, and combinations of both. Minerals were considered separately, where possible. If interventions and outcomes were considered sufficiently similar, then data were pooled. In order to separate short-term cognitive effects from possible longer-term effects on the trajectory of cognitive decline, data were pooled for various treatment durations from 3 months to 12 months and up to 10 years or more. In total, we included 28 studies with more than 83,000 participants. There were some general limitations of the evidence. Most participants were enrolled in studies which were not designed primarily to assess cognition. These studies often had no baseline cognitive assessment and used only brief cognitive assessments at follow-up. Very few studies assessed the incidence of dementia. Most study reports did not mention adverse events or made only very general statements about them. Only 10 studies had a mean follow-up &gt; 5 years. Only two studies had participants whose mean age was &lt; 60 years at baseline. The risk of bias in the included studies was generally low, other than a risk of attrition bias for longer-term outcomes. We considered the certainty of the evidence behind almost all results to be moderate or low.We included 14 studies with 27,882 participants which compared folic acid, vitamin B12, vitamin B6, or a combination of these to placebo. The majority of participants were aged over 60 years and had a history of cardio- or cerebrovascular disease. We found that giving B vitamin supplements to cognitively healthy adults, mainly in their 60s and 70s, probably has little or no effect on global cognitive function at any time point up to 5 years (SMD values from -0.03 to 0.06) and may also have no effect at 5-10 years (SMD -0.01). There were very sparse data on adverse effects or on incidence of cognitive impairment or dementia.We included 8 studies with 47,840 participants in which the active intervention was one or more of the antioxidant vitamins: ß-carotene, vitamin C or vitamin E. Results were mixed. For overall cognitive function, there was low-certainty evidence of benefit associated with ß-carotene after a mean of 18 years of treatment (MD 0.18 TICS points, 95% CI 0.01 to 0.35) and of vitamin C after 5 years to 10 years (MD 0.46 TICS points, 95% CI 0.14 to 0.78), but not at earlier time points. From two studies which reported on dementia incidence, there was low-certainty evidence of no effect of an antioxidant vitamin combination or of vitamin E, either alone or combined with selenium. One of the included studies had been designed to look for effects on the incidence of prostate cancer; it found a statistically significant increase in prostate cancer diagnoses among men taking vitamin E.One trial with 4143 participants compared vitamin D3 (400 IU/day) and calcium supplements to placebo. We found low- to moderate-certainty evidence of no effect of vitamin D3 and calcium supplements at any time-point up to 10 years on overall cognitive function (MD after a mean of 7.8 years -0.1 MMSE points, 95% CI -0.81 to 0.61) or the incidence of dementia (HR 0.94, 95% CI 0.72 to 1.24). A pilot study with 60 participants used a higher dose of vitamin D3 (4000 IU on alternate days) and found preliminary evidence that this dose probably has no effect on cognitive function over six months.We included data from one trial of zinc and copper supplementation with 1072 participants. There was moderate-certainty evidence of little or no effect on overall cognitive function (MD 0.6 MMSE points, 95% CI -0.19 to 1.39) or on the incidence of cognitive impairment after 5 years to 10 years. A second smaller trial provided no usable data, but reported no cognitive effects of six months of supplementation with zinc gluconate.From one study with 3711 participants, there was low-certainty evidence of no effect of approximately five years of selenium supplementation on the incidence of dementia (HR 0.83, 95% CI 0.61 to 1.13).Finally, we included three trials of complex supplements (combinations of B vitamins, antioxidant vitamins, and minerals) with 6306 participants. From the one trial which assessed overall cognitive function, there was low-certainty evidence of little or no effect on the TICS (MD after a mean of 8.5 years 0.12, 95% CI -0.14 to 0.38). We did not find evidence that any vitamin or mineral supplementation strategy for cognitively healthy adults in mid or late life has a meaningful effect on cognitive decline or dementia, although the evidence does not permit definitive conclusions. There were very few data on supplementation starting in midlife (&lt; 60 years); studies designed to assess cognitive outcomes tended to be too short to assess maintenance of cognitive function; longer studies often had other primary outcomes and used cognitive measures which may have lacked sensitivity. The only positive signals of effect came from studies of long-term supplementation with antioxidant vitamins. These may be the most promising for further research.

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At least one-third of community-dwelling people over 65 years of age fall each year. Exercises that target balance, gait and muscle strength have been found to prevent falls in these people. An up-to-date synthesis of the evidence is important given the major long-term consequences associated with falls and fall-related injuries OBJECTIVES: To assess the effects (benefits and harms) of exercise interventions for preventing falls in older people living in the community. We searched CENTRAL, MEDLINE, Embase, three other databases and two trial registers up to 2 May 2018, together with reference checking and contact with study authors to identify additional studies. We included randomised controlled trials (RCTs) evaluating the effects of any form of exercise as a single intervention on falls in people aged 60+ years living in the community. We excluded trials focused on particular conditions, such as stroke. We used standard methodological procedures expected by Cochrane. Our primary outcome was rate of falls. We included 108 RCTs with 23,407 participants living in the community in 25 countries. There were nine cluster-RCTs. On average, participants were 76 years old and 77% were women. Most trials had unclear or high risk of bias for one or more items. Results from four trials focusing on people who had been recently discharged from hospital and from comparisons of different exercises are not described here.Exercise (all types) versus control Eighty-one trials (19,684 participants) compared exercise (all types) with control intervention (one not thought to reduce falls). Exercise reduces the rate of falls by 23% (rate ratio (RaR) 0.77, 95% confidence interval (CI) 0.71 to 0.83; 12,981 participants, 59 studies; high-certainty evidence). Based on an illustrative risk of 850 falls in 1000 people followed over one year (data based on control group risk data from the 59 studies), this equates to 195 (95% CI 144 to 246) fewer falls in the exercise group. Exercise also reduces the number of people experiencing one or more falls by 15% (risk ratio (RR) 0.85, 95% CI 0.81 to 0.89; 13,518 participants, 63 studies; high-certainty evidence). Based on an illustrative risk of 480 fallers in 1000 people followed over one year (data based on control group risk data from the 63 studies), this equates to 72 (95% CI 52 to 91) fewer fallers in the exercise group. Subgroup analyses showed no evidence of a difference in effect on both falls outcomes according to whether trials selected participants at increased risk of falling or not.The findings for other outcomes are less certain, reflecting in part the relatively low number of studies and participants. Exercise may reduce the number of people experiencing one or more fall-related fractures (RR 0.73, 95% CI 0.56 to 0.95; 4047 participants, 10 studies; low-certainty evidence) and the number of people experiencing one or more falls requiring medical attention (RR 0.61, 95% CI 0.47 to 0.79; 1019 participants, 5 studies; low-certainty evidence). The effect of exercise on the number of people who experience one or more falls requiring hospital admission is unclear (RR 0.78, 95% CI 0.51 to 1.18; 1705 participants, 2 studies, very low-certainty evidence). Exercise may make little important difference to health-related quality of life: conversion of the pooled result (standardised mean difference (SMD) -0.03, 95% CI -0.10 to 0.04; 3172 participants, 15 studies; low-certainty evidence) to the EQ-5D and SF-36 scores showed the respective 95% CIs were much smaller than minimally important differences for both scales.Adverse events were reported to some degree in 27 trials (6019 participants) but were monitored closely in both exercise and control groups in only one trial. Fourteen trials reported no adverse events. Aside from two serious adverse events (one pelvic stress fracture and one inguinal hernia surgery) reported in one trial, the remainder were non-serious adverse events, primarily of a musculoskeletal nature. There was a median of three events (range 1 to 26) in the exercise groups.Different exercise types versus controlDifferent forms of exercise had different impacts on falls (test for subgroup differences, rate of falls: P = 0.004, I² = 71%). Compared with control, balance and functional exercises reduce the rate of falls by 24% (RaR 0.76, 95% CI 0.70 to 0.81; 7920 participants, 39 studies; high-certainty evidence) and the number of people experiencing one or more falls by 13% (RR 0.87, 95% CI 0.82 to 0.91; 8288 participants, 37 studies; high-certainty evidence). Multiple types of exercise (most commonly balance and functional exercises plus resistance exercises) probably reduce the rate of falls by 34% (RaR 0.66, 95% CI 0.50 to 0.88; 1374 participants, 11 studies; moderate-certainty evidence) and the number of people experiencing one or more falls by 22% (RR 0.78, 95% CI 0.64 to 0.96; 1623 participants, 17 studies; moderate-certainty evidence). Tai Chi may reduce the rate of falls by 19% (RaR 0.81, 95% CI 0.67 to 0.99; 2655 participants, 7 studies; low-certainty evidence) as well as reducing the number of people who experience falls by 20% (RR 0.80, 95% CI 0.70 to 0.91; 2677 participants, 8 studies; high-certainty evidence). We are uncertain of the effects of programmes that are primarily resistance training, or dance or walking programmes on the rate of falls and the number of people who experience falls. No trials compared flexibility or endurance exercise versus control. Exercise programmes reduce the rate of falls and the number of people experiencing falls in older people living in the community (high-certainty evidence). The effects of such exercise programmes are uncertain for other non-falls outcomes. Where reported, adverse events were predominantly non-serious.Exercise programmes that reduce falls primarily involve balance and functional exercises, while programmes that probably reduce falls include multiple exercise categories (typically balance and functional exercises plus resistance exercises). Tai Chi may also prevent falls but we are uncertain of the effect of resistance exercise (without balance and functional exercises), dance, or walking on the rate of falls.

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Cyclodestructive procedures are often used in patients with refractory glaucoma who have failed to achieve lower intraocular pressure (IOP) from filtration procedures and maximal medical therapy. Destruction of the ciliary body helps to lower IOP by reducing aqueous humor formation. Of the many types of cyclodestructive procedures, laser cyclophotocoagulation (CPC) has become the most common surgical method for reducing aqueous inflow. Options for CPC are wide-ranging: they can be performed using a neodymium:yttrium-aluminum-garnet (Nd:YAG) or diode laser and laser energy can be delivered by either the contact or non-contact method. Another cyclodestructive procedure is endoscopic cyclophotocoagulation (ECP), which the ophthalmologist can use selectively to target the ciliary epithelium and ablate ciliary body tissue. There is debate regarding which cyclodestructive method is best and how they compare to other glaucoma surgeries. To assess the relative effectiveness and safety of cyclodestructive procedures compared with other procedures in people with refractory glaucoma of any type and to assess the relative effectiveness and safety of individual cyclodestructive procedures compared with each other. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 9); Ovid MEDLINE; Embase.com; PubMed; LILACS BIREME; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 21 September 2018. We included randomized controlled trials or quasi-randomized trials in which participants underwent a secondary procedure for refractory glaucoma. We included trials with any laser type, route of administration, and laser settings. The primary comparison was any cyclodestructive procedure versus another glaucoma treatment, and the secondary comparisons were individual cyclodestructive procedures versus another cyclodestructive procedure. Two review authors independently reviewed the titles and abstracts from the database searches, and after retrieving the full-text reports of those that were potentially relevant, classified the full-text articles as included or excluded. Two review authors independently extracted data from the included studies and assessed the risk of bias. Discrepancies were resolved by discussion or by consultation with a third review author when necessary. We included five trials reporting data for 330 eyes (326 participants). One study to had a low risk of bias for most domains and the other studies had an overall unclear risk of bias. This review includes four different comparisons: 1) ECP versus Ahmed implant, 2) micropulse CPC versus continuous-wave CPC; 3) CPC with a diode versus Nd:YAG laser; and 4) CPC with an Nd:YAG laser emitting 8J versus 4J.No study reported data for our primary outcome, change from baseline in pain severity as reported by the participant or change in number of pain medications.For our primary comparison, we included one trial that compared ECP with the Ahmed implant. At 12-month follow-up, the mean difference (MD) in IOPs between groups was -1.14 mmHg (95% confidence interval (CI) -4.21 to 1.93; 58 participants; low-certainty evidence (LCE)). At 24 months postintervention, we found very LCE suggesting that visual acuity may be better among participants in the ECP group than in the Ahmed implant group (MD -0.24 logMAR, 95% CI -0.52 to 0.04; 54 participants), and the difference in the mean number of glaucoma medications used by participants in each group was unclear (MD -0.50, 95% CI -1.17 to 0.17; 54 participants; very LCE). Reported adverse events in the ECP group (34 participants) were one case each of hypotony, phthisis bulbi, retinal detachment, and choroidal detachment; in the Ahmed implant group (34 participants) there was one case of endophthalmitis, two cases of retinal detachment, and six cases of choroidal detachment.Three types of comparisons from four included studies provided data for our secondary comparisons. In the study that compared micropulse with continuous-wave CPC, median IOP was reported to be similar between the two groups at all time points. At 18 months postintervention, the median number of IOP-lowering medications was reduced from two to one in both groups. One participant in the micropulse and two in the continuous group exhibited worsened visual acuity. One case of prolonged inflammation was seen in the micropulse group (23 participants). Seven cases of prolonged inflammation, five cases of hypotony, and one case of phthisis bulbi were seen in the continuous group (23 participants).Two studies compared CPC using a semiconductor diode versus an Nd:YAG laser. At 12 months postintervention, the MD in IOP was 1.02 mmHg (95% CI -1.49 to 3.53) in one study (LCE). The second study did not report mean IOP beyond three months of follow-up. Neither study reported the mean change in best-corrected visual acuity or number of glaucoma medications. Both studies reported hypotony as an adverse event in three participants in each study.One study compared different energy settings of the same Nd:YAG laser. At 12-month follow-up, visual acuity was unchanged or improved in 21 of 33 participants in the 8J group and 20 of 27 participants in the 4J group (risk ratio 0.86, 95% CI 0.61 to 1.21; very LCE). More participants in the 8J group reduced the number of medications taken compared with the 4J group (RR 1.49, 95% CI 0.76 to 2.91; 50 participants; very low-certainty evidence). The presence of fibrin or hyphema were seen in five participants who received 8J and none who received 4J. There was a severe anterior chamber reaction in 11 of 26 (42%) participants who received 8J of energy and 2 of 21 (10%) participants who received 4J of energy. Evidence from five studies included in this review was inconclusive as to whether cyclodestructive procedures for refractory glaucoma result in better outcomes and fewer complications than other glaucoma treatments, and whether one type of cyclodestructive procedure is better than another. The most commonly reported adverse events across all five studies were hypotony and phthisis bulbi. Large, well-designed randomized controlled trials are needed. Patient-reported outcomes such as pain and quality of life should be considered as primary outcomes or important secondary outcomes of future trials.

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Vitamin A deficiency is a significant public health problem in many low- and middle-income countries, especially affecting young children, women of reproductive age, and pregnant women. Fortification of staple foods with vitamin A has been used to increase vitamin A consumption among these groups. To assess the effects of fortifying staple foods with vitamin A for reducing vitamin A deficiency and improving health-related outcomes in the general population older than two years of age. We searched the following international databases with no language or date restrictions: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 6) in the Cochrane Library; MEDLINE and MEDLINE In Process OVID; Embase OVID; CINAHL Ebsco; Web of Science (ISI) SCI, SSCI, CPCI-exp and CPCI-SSH; BIOSIS (ISI); POPLINE; Bibliomap; TRoPHI; ASSIA (Proquest); IBECS; SCIELO; Global Index Medicus - AFRO and EMRO; LILACS; PAHO; WHOLIS; WPRO; IMSEAR; IndMED; and Native Health Research Database. We also searched clinicaltrials.gov and the International Clinical Trials Registry Platform to identify ongoing and unpublished studies. The date of the last search was 19 July 2018. We included individually or cluster-randomised controlled trials (RCTs) in this review. The intervention included fortification of staple foods (sugar, edible oils, edible fats, maize flour or corn meal, wheat flour, milk and dairy products, and condiments and seasonings) with vitamin A alone or in combination with other vitamins and minerals. We included the general population older than two years of age (including pregnant and lactating women) from any country. Two authors independently screened and assessed eligibility of studies for inclusion, extracted data from included studies and assessed their risk of bias. We used standard Cochrane methodology to carry out the review. We included 10 randomised controlled trials involving 4455 participants. All the studies were conducted in low- and upper-middle income countries where vitamin A deficiency was a public health issue. One of the included trials did not contribute data to the outcomes of interest.Three trials compared provision of staple foods fortified with vitamin A versus unfortified staple food, five trials compared provision of staple foods fortified with vitamin A plus other micronutrients versus unfortified staple foods, and two trials compared provision of staple foods fortified with vitamin A plus other micronutrients versus no intervention. No studies compared staple foods fortified with vitamin A alone versus no intervention.The duration of interventions ranged from three to nine months. We assessed six studies at high risk of bias overall. Government organisations, non-governmental organisations, the private sector, and academic institutions funded the included studies; funding source does not appear to have distorted the results.Staple food fortified with vitamin A versus unfortified staple food We are uncertain whether fortifying staple foods with vitamin A alone makes little or no difference for serum retinol concentration (mean difference (MD) 0.03 μmol/L, 95% CI -0.06 to 0.12; 3 studies, 1829 participants; I² = 90%, very low-certainty evidence). It is uncertain whether vitamin A alone reduces the risk of subclinical vitamin A deficiency (risk ratio (RR) 0.45, 95% CI 0.19 to 1.05; 2 studies; 993 participants; I² = 33%, very low-certainty evidence). The certainty of the evidence was mainly affected by risk of bias, imprecision and inconsistency.It is uncertain whether vitamin A fortification reduces clinical vitamin A deficiency, defined as night blindness (RR 0.11, 95% CI 0.01 to 1.98; 1 study, 581 participants, very low-certainty evidence). The certainty of the evidence was mainly affected by imprecision, inconsistency, and risk of bias.Staple foods fortified with vitamin A versus no intervention No studies provided data for this comparison.Staple foods fortified with vitamin A plus other micronutrients versus same unfortified staple foods Fortifying staple foods with vitamin A plus other micronutrients may not increase the serum retinol concentration (MD 0.08 μmol/L, 95% CI -0.06 to 0.22; 4 studies; 1009 participants; I² = 95%, low-certainty evidence). The certainty of the evidence was mainly affected by serious inconsistency and risk of bias.In comparison to unfortified staple foods, fortification with vitamin A plus other micronutrients probably reduces the risk of subclinical vitamin A deficiency (RR 0.27, 95% CI 0.16 to 0.49; 3 studies; 923 participants; I² = 0%; moderate-certainty evidence). The certainty of the evidence was mainly affected by serious risk of bias.Staple foods fortified with vitamin A plus other micronutrients versus no interventionFortification of staple foods with vitamin A plus other micronutrients may increase serum retinol concentration (MD 0.22 μmol/L, 95% CI 0.15 to 0.30; 2 studies; 318 participants; I² = 0%; low-certainty evidence). When compared to no intervention, it is uncertain whether the intervention reduces the risk of subclinical vitamin A deficiency (RR 0.71, 95% CI 0.52 to 0.98; 2 studies; 318 participants; I² = 0%; very low-certainty evidence) . The certainty of the evidence was affected mainly by serious imprecision and risk of bias.No trials reported on the outcomes of all-cause morbidity, all-cause mortality, adverse effects, food intake, congenital anomalies (for pregnant women), or breast milk concentration (for lactating women). Fortifying staple foods with vitamin A alone may make little or no difference to serum retinol concentrations or the risk of subclinical vitamin A deficiency. In comparison with provision of unfortified foods, provision of staple foods fortified with vitamin A plus other micronutrients may not increase serum retinol concentration but probably reduces the risk of subclinical vitamin A deficiency.Compared to no intervention, staple foods fortified with vitamin A plus other micronutrients may increase serum retinol concentration, although it is uncertain whether the intervention reduces the risk of subclinical vitamin A deficiency as the certainty of the evidence has been assessed as very low.It was not possible to estimate the effect of staple food fortification on outcomes such as mortality, morbidity, adverse effects, congenital anomalies, or breast milk vitamin A, as no trials included these outcomes.The type of funding source for the studies did not appear to distort the results from the analysis.

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Crohn's disease (CD) is a chronic inflammatory disorder that can involve any part of the gastrointestinal tract. 5-Aminosalicylates (5-ASAs) are locally acting, anti-inflammatory compounds that reduce inflammation of the colonic mucosa with release profiles that vary among various commercially available formulations. This updated Cochrane review summarizes current evidence on the use of 5-ASA formulations for maintenance of surgically-induced remission in CD. To assess the efficacy and safety of 5-ASA agents for the maintenance of surgically-induced remission in CD. We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register from inception to 16 July 2018. We also searched references, conference abstracts, and trials registers. Randomised controlled trials (RCTs) that included participants with CD in remission following surgery and compared 5-ASAs to no treatment, placebo or any other active intervention with duration of at least three months were considered for inclusion. We used standard methodological procedures expected by Cochrane. The primary outcome was clinical relapse. Secondary outcomes included endoscopic recurrence, radiologic and surgical relapse, adverse events, serious adverse events and withdrawal due to adverse events. Fourteen RCTs (1867 participants) were included in the review. Participants (15 to 70 years) were recruited from gastroenterology hospitals and medical clinics in Europe and North America and followed up between 3 and 72 months. The risk of bias was assessed as 'low' in one study, 'unclear' in seven and as 'high' in six.At 12 months, 36% (20/55) of participants in the 5-ASA group experienced clinical relapse compared to 51% (28/55) in the no treatment control group (RR 0.71, 95% CI 0.46 to 1.10; low certainty evidence). Moderate certainty evidence suggests that 5-ASAs are more effective for preventing clinical relapse than placebo. During a follow-up period of 12 to 72 months, 36% (131/361) of 5-ASA participants relapsed compared to 43% (160/369) of placebo participants (RR 0.83, 95% CI 0.72 to 0.96; I² = 0%; moderate certainty evidence). At 12 months, 17% (17/101) of the 4 g/day mesalamine group relapsed compared to 26% (27/105) of the 2.4 g/day group (RR 0.65, 95% CI 0.38 to 1.13; moderate certainty evidence). There was no evidence of a difference in clinical relapse rates when 5-ASA compounds were compared to purine antimetabolites. At 24 months, 61% (103/170) of mesalamine participants relapsed compared to 67% (119/177) of azathioprine participants (RR 0.90, 95% CI 0.76 to 1.07; I² = 28%; low certainty evidence). During 24 months, 50% (9/18) of 5-ASA participants had clinical relapse compared to 13% (2/16) of adalimumab participants (RR 4.0, 95% CI 1.01 to 15.84; low certainty evidence). The effects of sulphasalazine compared to placebo on clinical relapse rate is uncertain. After 18 to 36 months, 66% (95/143) of participants treated with sulphasalazine relapsed compared to 71% (110/155) in the placebo group (RR 0.88, 95% CI 0.56 to 1.38; I² = 38%; low certainty evidence).The effect of 5-ASA drugs on safety was uncertain. During 24 months follow-up, 4% (2/55) of 5-ASA participants experienced adverse events compared to none (0/55) in the no treatment control group (RR 5.00, 95% CI 0.25 to 101.81; very low certainty evidence). An equal proportion of 5-ASA participants (10%; 23/241) and placebo (9%; 20/225) groups experienced an adverse event during a follow-up of 3 to 72 months (RR 1.07, 95% CI 0.60 to 1.91; I² = 0%; low certainty evidence). Adverse event rates were similar in the 5-ASA and purine analogues groups. However, serious adverse events and withdrawals due to adverse events were more common in participants who received purine analogues than 5-ASA. At 52 weeks to 24 months, 52% (107/207) of 5-ASA participants had an adverse event compared to 47% (102/218) of purine analogue participants (RR 1.11, 95% CI 0.97 to 1.27, I² = 0%; low certainty evidence). Four per cent (6/152) of 5-ASA participants had a serious adverse event compared to 17% (27/159) of purine analogue participants (RR 0.30, 95% CI 0.11 to 0.80; very low certainty evidence). Eight per cent (17/207) of 5-ASA participants withdrew due to an adverse event compared to 19% (42/218) of purine analogue participants (RR 0.48, 95% CI 0.28 to 0.83; low certainty evidence). Adverse event rates were similar in high and low dose mesalamine participants. After 12 months, 2% (2/101) of 4 g/day mesalamine participants had an adverse event compared to 2% (2/105) of 2.4 g/day participants (RR 1.04, 95% CI 0.15 to 7.24; low certainty evidence). The proportion of participants who experienced adverse events over a 24 month follow-up in the mesalamine group was 78% (14/18) compared to 69% (11/16) of adalimumab participants (RR 1.13, 95% CI 0.75 to 1.71; very low certainty evidence). None (0/32) of the sulphasalazine participants had an adverse event at 18 months follow-up compared to 3% (1/34) of the placebo group (RR 0.35, 95% CI 0.01 to 8.38; very low certainty evidence). Commonly reported adverse events in the included studies were diarrhoea, nausea, increased liver function tests, pancreatitis, and abdominal pain. 5-ASA preparations are superior to placebo for the maintenance of surgically-induced clinical remission in patients with CD (moderate certainty). The number needed to treat to prevent one relapse was 13 patients. The evidence for endoscopic remission is uncertain. The sulphasalazine class of 5-ASA agents failed to demonstrate superiority against placebo, 5-ASAs failed to demonstrate superiority compared to no treatment (very low and low certainty). The efficacy of two different doses of the same 5-ASA and the efficacy of 5-ASA compared to purine antimetabolites (azathioprine or 6-mercaptopurine) in maintaining surgically-induced remission of CD remains unclear. However, purine analogues lead to more serious adverse events and discontinuation due to adverse events. There is a low certainty that 5-ASA is inferior for maintaining surgically-induced remission of CD compared to biologics (anti TNF-ɑ). 5-ASA formulations appear to be safe with no difference in the occurrence of adverse events or withdrawal when compared with placebo, no treatment or biologics.

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In epidemics of highly infectious diseases, such as Ebola Virus Disease (EVD) or Severe Acute Respiratory Syndrome (SARS), healthcare workers (HCW) are at much greater risk of infection than the general population, due to their contact with patients' contaminated body fluids. Contact precautions by means of personal protective equipment (PPE) can reduce the risk. It is unclear which type of PPE protects best, what is the best way to remove PPE, and how to make sure HCW use PPE as instructed. To evaluate which type of full body PPE and which method of donning or doffing PPE have the least risk of self-contamination or infection for HCW, and which training methods increase compliance with PPE protocols. We searched MEDLINE (PubMed up to 15 July 2018), Cochrane Central Register of Trials (CENTRAL up to 18 June 2019), Scopus (Scopus 18 June 2019), CINAHL (EBSCOhost 31 July 2018), and OSH-Update (up to 31 December 2018). We also screened reference lists of included trials and relevant reviews, and contacted NGOs and manufacturers of PPE. We included all controlled studies that compared the effects of PPE used by HCW exposed to highly infectious diseases with serious consequences, such as Ebola or SARS, on the risk of infection, contamination, or noncompliance with protocols. This included studies that used simulated contamination with fluorescent markers or a non-pathogenic virus.We also included studies that compared the effect of various ways of donning or doffing PPE, and the effects of training in PPE use on the same outcomes. Two authors independently selected studies, extracted data and assessed risk of bias in included trials. We planned to perform meta-analyses but did not find sufficiently similar studies to combine their results. We included 17 studies with 1950 participants evaluating 21 interventions. Ten studies are Randomised Controlled Trials (RCTs), one is a quasi RCT and six have a non-randomised controlled design. Two studies are awaiting assessment.Ten studies compared types of PPE but only six of these reported sufficient data. Six studies compared different types of donning and doffing and three studies evaluated different types of training. Fifteen studies used simulated exposure with fluorescent markers or harmless viruses. In simulation studies, contamination rates varied from 10% to 100% of participants for all types of PPE. In one study HCW were exposed to Ebola and in another to SARS.Evidence for all outcomes is based on single studies and is very low quality.Different types of PPEPPE made of more breathable material may not lead to more contamination spots on the trunk (Mean Difference (MD) 1.60 (95% Confidence Interval (CI) -0.15 to 3.35) than more water repellent material but may have greater user satisfaction (MD -0.46; 95% CI -0.84 to -0.08, scale of 1 to 5).Gowns may protect better against contamination than aprons (MD large patches -1.36 95% CI -1.78 to -0.94).The use of a powered air-purifying respirator may protect better than a simple ensemble of PPE without such respirator (Relative Risk (RR) 0.27; 95% CI 0.17 to 0.43).Five different PPE ensembles (such as gown vs. coverall, boots with or without covers, hood vs. cap, length and number of gloves) were evaluated in one study, but there were no event data available for compared groups.Alterations to PPE design may lead to less contamination such as added tabs to grab masks (RR 0.33; 95% CI 0.14 to 0.80) or gloves (RR 0.22 95% CI 0.15 to 0.31), a sealed gown and glove combination (RR 0.27; 95% CI 0.09 to 0.78), or a better fitting gown around the neck, wrists and hands (RR 0.08; 95% CI 0.01 to 0.55) compared to standard PPE.Different methods of donning and doffing proceduresDouble gloving may lead to less contamination compared to single gloving (RR 0.36; 95% CI 0.16 to 0.78).Following CDC recommendations for doffing may lead to less contamination compared to no guidance (MD small patches -5.44; 95% CI -7.43 to -3.45).Alcohol-based hand rub used during the doffing process may not lead to less contamination than the use of a hypochlorite based solution (MD 4.00; 95% CI 0.47 to 34.24).Additional spoken instruction may lead to fewer errors in doffing (MD -0.9, 95% CI -1.4 to -0.4).Different types of trainingThe use of additional computer simulation may lead to fewer errors in doffing (MD -1.2, 95% CI -1.6 to -0.7).A video lecture on donning PPE may lead to better skills scores (MD 30.70; 95% CI 20.14,41.26) than a traditional lecture.Face to face instruction may reduce noncompliance with doffing guidance more (OR 0.45; 95% CI 0.21 to 0.98) than providing folders or videos only.There were no studies on effects of training in the long term or on resource use.The quality of the evidence is very low for all comparisons because of high risk of bias in all studies, indirectness of evidence, and small numbers of participants. We found very low quality evidence that more breathable types of PPE may not lead to more contamination, but may have greater user satisfaction. Alterations to PPE, such as tabs to grab may decrease contamination. Double gloving, following CDC doffing guidance, and spoken instructions during doffing may reduce contamination and increase compliance. Face-to-face training in PPE use may reduce errors more than video or folder based training. Because data come from single small studies with high risk of bias, we are uncertain about the estimates of effects.We still need randomised controlled trials to find out which training works best in the long term. We need better simulation studies conducted with several dozen participants to find out which PPE protects best, and what is the safest way to remove PPE. Consensus on the best way to conduct simulation of exposure and assessment of outcome is urgently needed. HCW exposed to highly infectious diseases should have their use of PPE registered and should be prospectively followed for their risk of infection in the field.

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This is an update of a Cochrane Review first published in 2002 and last updated in 2017. This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenytoin are commonly-used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for focal onset seizures in the USA and Europe. Phenytoin is no longer considered a first-line treatment, due to concerns over adverse events associated with its use, but the drug is still commonly used in low- to middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin in individual trials; however, the confidence intervals generated by these trials are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy. To review the time to treatment failure, remission and first seizure with carbamazepine compared with phenytoin when used as monotherapy in people with focal onset seizures (simple or complex focal and secondarily generalised), or generalised onset tonic-clonic seizures (with or without other generalised seizure types). For the latest update, we searched the following databases on 13 August 2018: the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy's Specialised Register and CENTRAL; MEDLINE; the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov); and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. Randomised controlled trials comparing monotherapy with either carbamazepine or phenytoin in children or adults with focal onset seizures or generalised onset (tonic-clonic) seizures. This was an individual participant data (IPD) review. Our primary outcome was time to treatment failure. Our secondary outcomes were time to first seizure post-randomisation, time to six-month remission, time to 12-month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs), with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI. IPD were available for 595 participants out of 1102 eligible individuals, from four out of 11 trials (i.e. 54% of the potential data). For remission outcomes, a HR greater than 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes, a HR greater than 1 indicates an advantage for carbamazepine. Most participants included in analysis (78%) were classified as experiencing focal onset seizures at baseline and only 22% were classified as experiencing generalised onset seizures; the results of this review are therefore mainly applicable to individuals with focal onset seizures.Results for the primary outcome of the review were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type for 546 participants: 0.94, 95% CI 0.70 to 1.26, moderate-certainty evidence); time to treatment failure due to lack of efficacy (pooled HR adjusted for seizure type for 546 participants: 0.99, 95% CI 0.69 to 1.41, moderate-certainty evidence); both showing no clear difference between the drugs and time to treatment failure due to adverse events (pooled HR adjusted for seizure type for 546 participants: 1.27, 95% CI 0.87 to 1.86, moderate-certainty evidence), showing that treatment failure due to adverse events may occur earlier on carbamazepine than phenytoin, but we cannot rule out a slight advantage to carbamazepine or no difference between the drugs.For our secondary outcomes (pooled HRs adjusted for seizure type), we did not find any clear differences between carbamazepine and phenytoin: time to first seizure post-randomisation (582 participants): 1.15, 95% CI 0.94 to 1.40, moderate-certainty evidence); time to 12-month remission (551 participants): 1.00, 95% CI 0.79 to 1.26, moderate-certainty evidence); and time to six-month remission (551 participants): 0.90, 95% CI 0.73 to 1.12, moderate-certainty evidence).For all outcomes, results for individuals with focal onset seizures were similar to overall results (moderate-certainty evidence), and results for the small subgroup of individuals with generalised onset seizures were imprecise, so we cannot rule out an advantage to either drug, or no difference between drugs (low-certainty evidence). There was also evidence that misclassification of seizure type may have confounded the results of this review, particularly for the outcome 'time to treatment failure'. Heterogeneity was present in analysis of 'time to first seizure' for individuals with generalised onset seizures, which could not be explained by subgroup analysis or sensitivity analyses.Limited information was available about adverse events in the trials and we could not compare the rates of adverse events between carbamazepine and phenytoin. Some adverse events reported on both drugs were abdominal pain, nausea, and vomiting, drowsiness, motor and cognitive disturbances, dysmorphic side effects (such as rash). Moderate-certainty evidence provided by this systematic review does not show any differences between carbamazepine and phenytoin in terms of effectiveness (retention) or efficacy (seizure recurrence and seizure remission) for individuals with focal onset or generalised onset seizures.However, some of the trials contributing to the analyses had methodological inadequacies and inconsistencies, which may have had an impact on the results of this review. We therefore do not suggest that results of this review alone should form the basis of a treatment choice for a person with newly-onset seizures. We did not find any evidence to support or refute current treatment policies. We implore that future trials be designed to the highest quality possible, with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.

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Laparoscopic colposuspension was one of the first minimal access operations for treating stress urinary incontinence in women, with the presumed advantages of shorter hospital stays and quicker return to normal activities. This Cochrane Review was last updated in 2010. To assess the effects of laparoscopic colposuspension for urinary incontinence in women; and summarise the principal findings of relevant economic evaluations of these interventions. We searched the Cochrane Incontinence Specialised Register (22 May 2019), which contains trials identified from CENTRAL, MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, CINAHL, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings. Randomised controlled trials of women with urinary incontinence that included laparoscopic surgery in at least one arm. We independently extracted data from eligible trials, assessed risk of bias and implemented GRADE. We included 26 trials involving 2271 women. Thirteen trials (1304 women) compared laparoscopic colposuspension to open colposuspension and nine trials (412 women) to midurethral sling procedures. One trial (161 women) compared laparoscopic colposuspension with one suture to laparoscopic colposuspension with two sutures; and three trials (261 women) compared laparoscopic colposuspension with sutures to laparoscopic colposuspension with mesh and staples. The majority of trials did not follow up participants beyond 18 months. Overall, there was unclear risk of selection, performance and detection bias and generally low risk of attrition and reporting bias. There is little difference between laparoscopic colposuspension using sutures and open colposuspension for subjective cure within 18 months (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.99 to 1.08; 6 trials, 755 women; high-quality evidence). We are uncertain whether laparoscopic colposuspension using mesh and staples is better or worse than open colposuspension for subjective cure within 18 months (RR 0.75, 95% CI 0.61 to 0.93; 3 trials, 362 women; very low-quality evidence) or whether there is a greater risk of repeat continence surgery with laparoscopic colposuspension. Laparoscopic colposuspension may have a lower risk of perioperative complications (RR 0.67, 95% CI 0.47 to 0.94; 11 trials, 1369 women; low-quality evidence). There may be similar or higher rates of bladder perforations with laparoscopic colposuspension (RR 1.72, 95% CI 0.90 to 3.29; 10 trials, 1311 women; moderate-quality evidence). Rates for de novo detrusor overactivity (RR 1.29, 95% CI 0.72 to 2.30; 5 trials, 472 women) and voiding dysfunction (RR 0.81, 95% CI 0.50 to 1.31; 5 trials, 507 women) may be similar but we are uncertain due to the wide confidence interval. Five studies reported on quality of life but we could not synthesise the data. There may be little difference between laparoscopic colposuspension using sutures and tension-free vaginal tape (TVT) for subjective cure within 18 months (RR 1.01, 95% CI 0.88 to 1.16; 4 trials, 256 women; low-quality evidence) or between laparoscopic colposuspension using mesh and staples and TVT (RR 0.71, 95% CI 0.55 to 0.91; 1 trial, 121 women; low-quality evidence). For laparoscopic colposuspension compared with midurethral slings, there may be lower rates of repeat continence surgery (RR 0.40, 95% CI 0.04 to 3.62; 1 trial, 70 women; low-quality evidence) and similar risk of perioperative complications (RR 0.99, 95% CI 0.60 to 1.64; 7 trials, 514 women; low-quality evidence) but we are uncertain due to the wide confidence intervals. There may be little difference in terms of de novo detrusor overactivity (RR 0.80, 95% CI 0.34 to 1.88; 4 trials, 326 women; low-quality evidence); and probably little difference in terms of voiding dysfunction (RR 1.06, 95% CI 0.47 to 2.41; 5 trials, 412 women; moderate-quality evidence) although we are uncertain due to the wide confidence interval. Five studies reported on quality of life but we could not synthesise the data. No studies reported on bladder perforations. Low-quality evidence indicates that there may be higher subjective cure rates within 18 months with two sutures compared to one suture (RR 1.37, 95% CI 1.14 to 1.64; 1 trial, 158 women). Comparing one suture and two sutures, one suture may have lower rates of repeat continence surgery (RR 0.35, 95% CI 0.01 to 8.37; 1 trial, 157 women) and similar risk of perioperative complications (RR 0.88, 95% CI 0.45 to 1.70) but we are uncertain due to the wide 95% CIs. There may be higher rates of voiding dysfunction with one suture compared to two sutures (RR 2.82; 95% CI 0.30 to 26.54; 1 trial, 158 women; low-quality evidence), but we are uncertain due to the wide confidence interval. This trial did not report bladder perforations, de novo detrusor overactivity or quality of life. We are uncertain whether laparoscopic colposuspension with sutures is better or worse for subjective cure within 18 months compared to mesh and staples (RR 1.24, 95% CI 0.96 to 1.59; 2 trials, 180 women; very low-quality evidence) or in terms of repeat continence surgery (RR 0.97, 95% CI 0.06 to 14.91; 1 trial, 69 women; very low-quality evidence). Laparoscopic colposuspension with sutures may increase the number of perioperative complications compared to mesh and staples (RR 1.94, 95% CI 1.09 to 3.48; 3 trials, 260 women; low-quality evidence) but rates of de novo detrusor overactivity may be similar (RR 0.72, 95% CI 0.17 to 3.06; 2 trials, 122 women; low-quality evidence), however, we are uncertain due to the wide confidence interval. None of the studies reported bladder perforations, voiding dysfunction or quality of life. The data indicate that, in terms of subjective cure of incontinence within 18 months, there is probably little difference between laparoscopic colposuspension and open colposuspension, or between laparoscopic colposuspension and midurethral sling procedures. Much of the evidence is low quality, meaning that a considerable degree of uncertainty remains about laparoscopic colposuspension. Future trials should recruit adequate numbers, conduct long-term follow-up and measure clinically important outcomes. A brief economic commentary identified three studies. We have not quality-assessed them and they should be interpreted in light of the findings on clinical effectiveness.

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Following surgery, surgical wounds can be closed using a variety of devices including sutures (subcuticular or transdermal), staples and tissue adhesives. Subcuticular sutures are intradermal stitches (placed immediately below the epidermal layer). The increased availability of synthetic absorbable filaments (stitches which are absorbed by the body and do not have to be removed) has led to an increased use of subcuticular sutures. However, in non-obstetric surgery, there is still controversy about whether subcuticular sutures increase the incidence of wound complications. To examine the efficacy and acceptability of subcuticular sutures for skin closure in non-obstetric surgery. In March 2019, we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process &amp; Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. All randomised controlled trials which compared subcuticular sutures with any other methods for skin closure in non-obstetric surgery were included in the review. Two review authors independently identified the trials, extracted data and carried out risk of bias and GRADE assessment of the certainty of the evidence. We included 66 studies (7487 participants); 11 included trials had more than two arms. Most trials had poorly-reported methodology, meaning that it is unclear whether they were at high risk of bias. Most trials compared subcuticular sutures with transdermal sutures, skin staples or tissue adhesives. Most outcomes prespecified in the review protocol were reported. The certainty of evidence varied from high to very low in the comparisons of subcuticular sutures with transdermal sutures or staples and tissue adhesives; the certainty of the evidence for the comparison with surgical tapes and zippers was low to very low. Most evidence was downgraded for imprecision or risk of bias. Although the majority of studies enrolled people who underwent CDC class 1 (clean) surgeries, two-thirds of participants were enrolled in studies which included CDC class 2 to 4 surgeries, such as appendectomies and gastrointestinal surgeries. Most participants were adults in a hospital setting. Subcuticular sutures versus transdermal sutures There may be little difference in the incidence of SSI (risk ratio (RR) 1.10; 95% confidence interval (CI) 0.80 to 1.52; 3107 participants; low-certainty evidence). It is uncertain whether subcuticular sutures reduce wound complications (RR 0.83; 95% CI 0.40 to 1.71; 1489 participants; very low-certainty evidence). Subcuticular sutures probably improve patient satisfaction (score from 1 to 10) (at 30 days; MD 1.60, 95% CI 1.32 to 1.88; 290 participants; moderate-certainty evidence). Wound closure time is probably longer when subcuticular sutures are used (MD 5.81 minutes; 95% CI 5.13 to 6.49 minutes; 585 participants; moderate-certainty evidence). Subcuticular sutures versus skin staples There is moderate-certainty evidence that, when compared with skin staples, subcuticular sutures probably have little effect on SSI (RR 0.81, 95% CI 0.64 to 1.01; 4163 participants); but probably decrease the incidence of wound complications (RR 0.79, 95% CI 0.64 to 0.98; 2973 participants). Subcuticular sutures are associated with slightly higher patient satisfaction (score from 1 to 5) (MD 0.20, 95% CI 0.10 to 0.30; 1232 participants; high-certainty evidence). Wound closure time may also be longer compared with staples (MD 0.30 to 5.50 minutes; 1384 participants; low-certainty evidence). Subcuticular sutures versus tissue adhesives, surgical tapes and zippers There is moderate-certainty evidence showing no clear difference in the incidence of SSI between participants treated with subcuticular sutures and those treated with tissue adhesives (RR 0.77, 95% CI 0.41 to 1.45; 869 participants). There is also no clear difference in the incidence of wound complications (RR 0.62, 95% CI 0.35 to 1.11; 1058 participants; low-certainty evidence). Subcuticular sutures may also achieve lower patient satisfaction ratings (score from 1 to 10) (MD -2.05, 95% CI -3.05 to -1.05; 131 participants) (low-certainty evidence). In terms of SSI incidence, the evidence is uncertain when subcuticular sutures are compared with surgical tapes (RR 1.31, 95% CI 0.40 to 4.27; 354 participants; very low-certainty evidence) or surgical zippers (RR 0.80, 95% CI 0.08 to 8.48; 424 participants; very low-certainty evidence). There may be little difference in the incidence of wound complications between participants treated with subcuticular sutures and those treated with surgical tapes (RR 0.90, 95% CI 0.61 to 1.34; 492 participants; low-certainty evidence). It is uncertain whether subcuticular sutures reduce the risk of wound complications compared with surgical zippers (RR 0.55, 95% CI 0.15 to 2.04; 424 participants; very low-certainty evidence). It is also uncertain whether it takes longer to close a wound with subcuticular sutures compared with tissue adhesives (MD -0.34 to 10.39 minutes; 895 participants), surgical tapes (MD 0.74 to 6.36 minutes; 169 participants) or zippers (MD 4.38 to 8.25 minutes; 424 participants) (very low-certainty evidence). No study reported results for patient satisfaction compared with surgical tapes or zippers. There is no clear difference in the incidence of SSI for subcuticular sutures in comparison with any other skin closure methods. Subcuticular sutures probably reduce wound complications compared with staples, and probably improve patient satisfaction compared with transdermal sutures or staples. However, tissue adhesives may improve patient satisfaction compared with subcuticular sutures, and transdermal sutures and skin staples may be quicker to apply than subcuticular sutures. The quality of the evidence ranged from high to very low; evidence for almost all comparisons was subject to some limitations. There seems to be no need for additional new trials to explore the comparison with staples because there are high-quality studies with large sample sizes and some ongoing studies. However, there is a need for studies exploring the comparisons with transdermal sutures, tissue adhesives, tapes and zippers, with high-quality studies and large sample sizes, including long-term assessments.

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Serious illness is often characterised by physical/psychological problems, family support needs, and high healthcare resource use. Hospital-based specialist palliative care (HSPC) has developed to assist in better meeting the needs of patients and their families and potentially reducing hospital care expenditure. There is a need for clarity on the effectiveness and optimal models of HSPC, given that most people still die in hospital and also to allocate scarce resources judiciously. To assess the effectiveness and cost-effectiveness of HSPC compared to usual care for adults with advanced illness (hereafter patients) and their unpaid caregivers/families. We searched CENTRAL, CDSR, DARE and HTA database via the Cochrane Library; MEDLINE; Embase; CINAHL; PsycINFO; CareSearch; National Health Service Economic Evaluation Database (NHS EED) and two trial registers to August 2019, together with checking of reference lists and relevant systematic reviews, citation searching and contact with experts to identify additional studies. We included randomised controlled trials (RCTs) evaluating the impact of HSPC on outcomes for patients or their unpaid caregivers/families, or both. HSPC was defined as specialist palliative care delivered by a palliative care team that is based in a hospital providing holistic care, co-ordination by a multidisciplinary team, and collaboration between HSPC providers and generalists. HSPC was provided to patients while they were admitted as inpatients to acute care hospitals, outpatients or patients receiving care from hospital outreach teams at home. The comparator was usual care, defined as inpatient or outpatient hospital care without specialist palliative care input at the point of entry into the study, community care or hospice care provided outside of the hospital setting. We used standard methodological procedures expected by Cochrane. We assessed risk of bias and extracted data. To account for use of different scales across studies, we calculated standardised mean differences (SMDs) with 95% confidence intervals (CIs) for continuous data. We used an inverse variance random-effects model. For binary data, we calculated odds ratio (ORs) with 95% CIs. We assessed the evidence using GRADE and created a 'Summary of findings' table. Our primary outcomes were patient health-related quality of life (HRQoL) and symptom burden (a collection of two or more symptoms). Key secondary outcomes were pain, depression, satisfaction with care, achieving preferred place of death, mortality/survival, unpaid caregiver burden, and cost-effectiveness. Qualitative data was analysed where available. We identified 42 RCTs involving 7779 participants (6678 patients and 1101 caregivers/family members). Twenty-one studies were with cancer populations, 14 were with non-cancer populations (of which six were with heart failure patients), and seven with mixed cancer and non-cancer populations (mixed diagnoses). HSPC was offered in different ways and included the following models: ward-based, inpatient consult, outpatient, hospital-at-home or hospital outreach, and service provision across multiple settings which included hospital. For our main analyses, we pooled data from studies reporting adjusted endpoint values. Forty studies had a high risk of bias in at least one domain. Compared with usual care, HSPC improved patient HRQoL with a small effect size of 0.26 SMD over usual care (95% CI 0.15 to 0.37; I<sup2</sup = 3%, 10 studies, 1344 participants, low-quality evidence, higher scores indicate better patient HRQoL). HSPC also improved other person-centred outcomes. It reduced patient symptom burden with a small effect size of -0.26 SMD over usual care (95% CI -0.41 to -0.12; I<sup2</sup = 0%, 6 studies, 761 participants, very low-quality evidence, lower scores indicate lower symptom burden). HSPC improved patient satisfaction with care with a small effect size of 0.36 SMD over usual care (95% CI 0.41 to 0.57; I<sup2</sup = 0%, 2 studies, 337 participants, low-quality evidence, higher scores indicate better patient satisfaction with care). Using home death as a proxy measure for achieving patient's preferred place of death, patients were more likely to die at home with HSPC compared to usual care (OR 1.63, 95% CI 1.23 to 2.16; I<sup2</sup = 0%, 7 studies, 861 participants, low-quality evidence). Data on pain (4 studies, 525 participants) showed no evidence of a difference between HSPC and usual care (SMD -0.16, 95% CI -0.33 to 0.01; I<sup2</sup = 0%, very low-quality evidence). Eight studies (N = 1252 participants) reported on adverse events and very low-quality evidence did not demonstrate an effect of HSPC on serious harms. Two studies (170 participants) presented data on caregiver burden and both found no evidence of effect of HSPC (very low-quality evidence). We included 13 economic studies (2103 participants). Overall, the evidence on cost-effectiveness of HSPC compared to usual care was inconsistent among the four full economic studies. Other studies that used only partial economic analysis and those that presented more limited resource use and cost information also had inconsistent results (very low-quality evidence). Quality of the evidence The quality of the evidence assessed using GRADE was very low to low, downgraded due to a high risk of bias, inconsistency and imprecision. Very low- to low-quality evidence suggests that when compared to usual care, HSPC may offer small benefits for several person-centred outcomes including patient HRQoL, symptom burden and patient satisfaction with care, while also increasing the chances of patients dying in their preferred place (measured by home death). While we found no evidence that HSPC causes serious harms, the evidence was insufficient to draw strong conclusions. Although these are only small effect sizes, they may be clinically relevant at an advanced stage of disease with limited prognosis, and are person-centred outcomes important to many patients and families. More well conducted studies are needed to study populations with non-malignant diseases and mixed diagnoses, ward-based models of HSPC, 24 hours access (out-of-hours care) as part of HSPC, pain, achieving patient preferred place of care, patient satisfaction with care, caregiver outcomes (satisfaction with care, burden, depression, anxiety, grief, quality of life), and cost-effectiveness of HSPC. In addition, research is needed to provide validated person-centred outcomes to be used across studies and populations.

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Endometriosis is associated with pain and infertility. Surgical interventions aim to remove visible areas of endometriosis and restore the anatomy. To assess the effectiveness and safety of laparoscopic surgery in the treatment of pain and infertility associated with endometriosis. This review has drawn on the search strategy developed by the Cochrane Gynaecology and Fertility Group including searching the Cochrane Gynaecology and Fertility Group's specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, reference lists for relevant trials, and trial registries from inception to April 2020. We selected randomised controlled trials (RCTs) that compared the effectiveness and safety of laparoscopic surgery with any other laparoscopic or robotic intervention, holistic or medical treatment, or diagnostic laparoscopy only. Two review authors independently performed selection of studies, assessment of trial quality and extraction of relevant data with disagreements resolved by a third review author. We collected data for the core outcome set for endometriosis. Primary outcomes included overall pain and live birth. We evaluated the quality of evidence using GRADE methods. We included 14 RCTs. The studies randomised 1563 women with endometriosis. Four RCTs compared laparoscopic ablation or excision with diagnostic laparoscopy only. Two RCTs compared laparoscopic excision with diagnostic laparoscopy only. One RCT compared laparoscopic ablation or excision with laparoscopic ablation or excision and uterine suspension. Two RCTs compared laparoscopic ablation and uterine nerve transection with diagnostic laparoscopy only. One RCT compared laparoscopic ablation with diagnostic laparoscopy and gonadotropin-releasing hormone (GnRH) analogues. Two RCTs compared laparoscopic ablation with laparoscopic excision. One RCT compared laparoscopic ablation or excision with helium thermal coagulator with laparoscopic ablation or excision with electrodiathermy. One RCT compared conservative laparoscopic surgery with laparoscopic colorectal resection of deep endometriosis infiltrating the rectum. Common limitations in the primary studies included lack of clearly described blinding, failure to fully describe methods of randomisation and allocation concealment, and poor reporting of outcome data. Laparoscopic treatment versus diagnostic laparoscopy We are uncertain of the effect of laparoscopic treatment on overall pain scores compared to diagnostic laparoscopy only at six months (mean difference (MD) 0.90, 95% confidence interval (CI) 0.31 to 1.49; 1 RCT, 16 participants; very low quality evidence) and at 12 months (MD 1.65, 95% CI 1.11 to 2.19; 1 RCT, 16 participants; very low quality evidence), where a positive value means pain relief (the higher the score, the more pain relief) and a negative value reflects pain increase (the lower the score, the worse the increase in pain). No studies looked at live birth. We are uncertain of the effect of laparoscopic treatment on quality of life compared to diagnostic laparoscopy only: EuroQol-5D index summary at six months (MD 0.03, 95% CI -0.12 to 0.18; 1 RCT, 39 participants; low quality evidence), 12-item Short Form (SF-12) mental health component (MD 2.30, 95% CI -4.50 to 9.10; 1 RCT, 39 participants; low quality evidence) and SF-12 physical health component (MD 2.70, 95% CI -2.90 to 8.30; 1 RCT, 39 participants; low quality evidence). Laparoscopic treatment probably improves viable intrauterine pregnancy rate compared to diagnostic laparoscopy only (odds ratio (OR) 1.89, 95% CI 1.25 to 2.86; 3 RCTs, 528 participants; I<sup2</sup = 0%; moderate quality evidence). We are uncertain of the effect of laparoscopic treatment compared to diagnostic laparoscopy only on ectopic pregnancy (MD 1.18, 95% CI 0.10 to 13.48; 1 RCT, 100 participants; low quality evidence) and miscarriage (MD 0.94, 95% CI 0.35 to 2.54; 2 RCTs, 112 participants; low quality evidence). There was limited reporting of adverse events. No conversions to laparotomy were reported in both groups (1 RCT, 341 participants). Laparoscopic ablation and uterine nerve transection versus diagnostic laparoscopy We are uncertain of the effect of laparoscopic ablation and uterine nerve transection on adverse events (more specifically vascular injury) compared to diagnostic laparoscopy only (OR 0.33, 95% CI 0.01 to 8.32; 1 RCT, 141 participants; low quality evidence). No studies looked at overall pain scores (at six and 12 months), live birth, quality of life, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy and miscarriage. Laparoscopic ablation versus laparoscopic excision There was insufficient evidence to determine whether there was a difference in overall pain, measured at 12 months, for laparoscopic ablation compared with laparoscopic excision (MD 0.00, 95% CI -1.22 to 1.22; 1 RCT, 103 participants; very low quality evidence). No studies looked at overall pain scores at six months, live birth, quality of life, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy, miscarriage and adverse events. Helium thermal coagulator versus electrodiathermy We are uncertain whether helium thermal coagulator compared to electrodiathermy improves quality of life using the 30-item Endometriosis Health Profile (EHP-30) at nine months, when considering the components: pain (MD 6.68, 95% CI -3.07 to 16.43; 1 RCT, 119 participants; very low quality evidence), control and powerlessness (MD 4.79, 95% CI -6.92 to 16.50; 1 RCT, 119 participants; very low quality evidence), emotional well-being (MD 6.17, 95% CI -3.95 to 16.29; 1 RCT, 119 participants; very low quality evidence) and social support (MD 5.62, 95% CI -6.21 to 17.45; 1 RCT, 119 participants; very low quality evidence). Adverse events were not estimable. No studies looked at overall pain scores (at six and 12 months), live birth, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy and miscarriage. Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. No data were reported on live birth. There is moderate quality evidence that laparoscopic surgery increases viable intrauterine pregnancy rates confirmed by ultrasound compared to diagnostic laparoscopy only. No studies were found that looked at live birth for any of the comparisons. Further research is needed considering the management of different subtypes of endometriosis and comparing laparoscopic interventions with lifestyle and medical interventions. There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety.

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It is estimated that the 12-month prevalence of depression in the United States is 8.6%, and for anxiety it is 2.9%. Although prior studies have evaluated depression and anxiety in patients with carcinoma, few have specifically evaluated patients with sarcoma, who often have unique treatment considerations such as mobility changes after surgery. We evaluated patients with sarcoma seen in our orthopaedic oncology clinic to determine (1) the proportion of patients with depression symptoms, symptom severity, how many patients triggered a referral to mental health professionals based upon our prespecified cutoff scores on the nine-item Patient Health Questionnaire (PHQ-9), and if their symptoms varied by disease state; (2) the proportion of patients with anxiety symptoms, symptom severity, how many patients triggered a referral to mental health professionals based upon our prespecified cutoff scores on the seven-item Generalized Anxiety Disorder Scale (GAD-7), and if they symptoms varied by disease state; (3) whether other factors were associated with the proportion and severity of symptoms of anxiety or depression, such as tumor location in the body (axial skeleton, upper extremity, or lower extremity), general type of tumor (bone or soft tissue), specific diagnosis, use of chemotherapy, length of follow-up (less than 1 year or greater than 1 year), and gender; and (4) what proportion of patients accepted referrals to mental health professionals, when offered. This study was a cross-sectional survey study performed at a single urban National Cancer Institute-designated Comprehensive Cancer Center from April 2021 until July 2021. All patients seen in the orthopaedic clinic 18 years of age and older with a diagnosis/presumed diagnosis of sarcoma were provided the PHQ-9 as well as the GAD-7 in our clinic. We did not track those who elected not to complete the surveys. Surveys were scored per survey protocol (each question was scored from 0 to 3 and summed). Specifically, PHQ-9 scores the symptoms of depression as 5 to 9 (mild), 10 to 14 (moderate), 15 to 19 (moderately severe), and 20 to 27 (severe). The GAD-7 scores symptoms of anxiety as 5 to 9 (mild), 10 to 14 (moderate), and 15 to 21 (severe). Patients with PHQ-9 or GAD-7 scores of 10 to 14 were referred to social work and those with scores 15 or higher were referred to psychiatry. Patients with thoughts of self-harm were referred regardless of score. Patients were divided based on disease state: patients during their initial management; patients with active, locally recurrent disease; patients with active metastatic disease; patients with prior recurrence or metastatic lesions who were subsequently treated and now have no evidence of disease (considered to be patients with discontinuous no evidence of disease); patients with no evidence of disease; and patients with an active, noncancerous complication but otherwise no evidence of disease. We additionally looked at the association of gender, chemotherapy administration, and tumor location on survey responses. Data are summarized using descriptive statistics. Differences across categories of disease state were tested for statistical significance using Kruskal-Wallis tests for continuous variables and Fisher exact tests for categorical variables as well as pairwise Wilcoxon rank sum tests. Overall, symptoms of depression were seen in 35% (67 of 190) of patients, at varying levels of severity: 19% (37 of 190) had mild symptoms, 9% (17 of 190) had moderate symptoms, 6% (12 of 190) had moderately severe symptoms, and 1% (1 of 190) had severe symptoms. Depresssion symptoms severe enough to trigger a referral were seen in 17% (32 of 190) of patients overall. Patients scored higher on the PHQ-9 during their initial treatment or when they had recurrent or metastatic disease, and they were more likely to trigger a referral during those timepoints as well. The mean PHQ-9 was 5.7 ± 5.8 during initial treatment, 6.1 ± 4.9 with metastatic disease, and 7.4 ± 5.2 with recurrent disease as compared with 3.2 ± 4.2 if there was no evidence of disease (p = 0.001). Anxiety symptoms were seen in 33% (61 of 185) of patients: 17% (32 of 185) had mild symptoms, 8% (14 of 185) had moderate symptoms, and 8% (15 of 185) had severe symptoms. Anxiety symptoms severe enough to trigger a referral were seen in 16% (29 of 185) of patients overall. Patients scored higher on the GAD-7 during initial treatment and when they had recurrent disease or an active noncancerous complication. The mean GAD-7 was 6.3 ± 3.2 in patients with active noncancerous complications, 6.8 ± 5.8 in patients during initial treatment, and 8.4 ± 8.3 in patients with recurrent disease as compared with 3.1 ± 4.2 in patients with no evidence of disease (p = 0.002). Patients were more likely to trigger a referral during initial treatment (32% [9 of 28]) and with recurrent disease (43% [6 of 14]) compared with those with no evidence of disease (9% [9 of 97]) and those with discontinuous no evidence of disease (6% [1 of 16]; p = 0.004). There was an increase in both PHQ-9 and GAD-7 scores among patients who had chemotherapy. Other factors that were associated with higher PHQ-9 scores were location of tumor (upper extremity versus lower extremity or axial skeleton) and gender. Another factor that was associated with higher GAD-7 scores included general category of diagnosis (bone versus soft tissue sarcoma). Specific diagnosis and length of follow-up had no association with symptoms of depression or anxiety. Overall, 22% (41 of 190) of patients were offered referrals to mental health professionals; 73% (30 of 41) accepted the referral. When treating patients with sarcoma, consideration should be given to potential concomitant psychiatric symptoms. Screening, especially at the highest-risk timepoints such as at the initial diagnosis and the time of recurrence, should be considered. Further work should be done to determine the effect of early psychiatric referral on patient-related outcomes and healthcare costs. Level III, therapeutic study.

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The concept of cardiac surgery on the beating heart is acceptable rationale for the cardiac surgery in the next millenium. Beating heart (off-pump) coronary artery bypass grafting (CABG) techniques have led us to consider the possibility for performing the aortic and mitral valve surgery (mitral valve repairs and replacements - with or without CABG) on the beating heart with the technique of retrograde oxygenated coronary sinus perfusion. We used the technique of retrograde oxygenated blood coronary sinus perfusion in 78 patients (Group All) - (36 patients were with extremely low ejection fraction (Group X) - 62% of whom were in New York Heart Association (NYHA) class 4 and 34% of whom were in NYHA class 3). The procedures for the patients were: aortic, mitral and tricuspid valve surgery, in combination with CABG in ischemic patients. CABG was done in all the cases off-pump. In addition, we performed a case match study for 37 patients with good ejection fraction (51.65 +/- 11.88) (Beating Heart Group) operated on the beating heart with most appropriate group of patients (No. 37) operated in our institutions on arrested heart (ejection fraction 51.07 +/- 12.93) (Arrested Heart Group). The case match selection criteria were: gender, left ventricular ejection fraction, atrial fibrillation, hypertension, pulmonary hypertension, and diabetes. The selected beating heart group and selected arrested heart groups were without statistically significant differences for the mentioned criteria. There were statistically significant differences between Beating Heart Group and Arrested Heart Group in the duration of Cardiopulmonary Bypass Time (69.35 +/- 13.52 min. versus 93.59 +/- 28.54 min.), p&lt;0.001, and statistically significant differences in Aortic Cross Clamp Time (46.5 +/- 8.95 min. versus 61.5 +/- 18.34 min.), p&lt;0.001. The values for Creatinin Kinase (CK) and LDH were not statistically different, however the absolute values for Beating Heart Group were lower. There was no statistical difference in complication rate for both the groups for: sternal infection, bleeding, death, atrial fibrillation, AV block and neurological complications. The total early mortality for all the patients was 5.1% (4 out of 78) - for the group X 8.3 % (3 of 36 patients). Two were in-hospital deaths. One patient with triple-vessel disease and acute mitral insufficiency on intra aortic balloon pump (IABP) had been operated on 6 days after acute myocardial infarction (AMI). The cause of the death was systemic meticillin resistant staphylococus aureus (MRSA) infection - (eight days prior to our operation, arthrodesis of the talocrural joint was performed by an orthopedic surgeon). The other death was a female patient who was operated on after previous multiple cerebrovascular infarctions (CVI) (cause of the death was CVI). In addition, one patient died one month after the operation because of prosthetic valve endocarditis (PVE) on aortic and mitral valves (silver-coated silzone aortic and mitral valves were implanted because of chronic latent asymptomatic tibial osteitis). None of these deaths were cardiac related. We conclude that beating heart valve surgery (any combination) with or without CABG significantly lower the cardiopulmonary bypass and aortic cross clamp time. In addition, the advantages of beating-heart surgery are 1) the perfused myocardial muscle, 2) the heart is not doing any work, 3) no reperfusion injury, 4) the possibility for ablation of atrial fibrillation on the beating heart, and 5) testing of the mitral valve repair is done in real physiologic conditions in the state of left ventricle beating tonus. The procedure could be the procedure of choice for the valve operation or combined operations (valve operation and CABG) in high-risk patients with low ejection fractions. There is no doubt that at present day in cardiac surgery exist at least two major factors for mortality and morbidity after cardiac surgery, which are operation - related, namely cardiopulmonary bypass time and its duration and aortic cross clamp time (ischemic time of myocardium). In the last few years a number of different techniques emerged in the field of cardiac surgery, which were directed toward better results in the selected high risk patients or to minimize the deleterious effects of cardiopulmonary bypass (CPB) on the overall postoperative performance [Calafiore 1996, Tasdemir 1998]. Due to the fact, that the cardiac muscle should be protected at most during the cardiac arrest, retrograde blood cardioplegia was successfully introduced [Buckberg 1990], and more - the warm cardioplegia is being used recently [Kawasuji 1997]. The natural status of the human heart is the beating status, so it is reasonable to try to perform the operations on the beating heart. This has been done recently with the MID - CAB and OP - CAB (off-pump CABG) operations [Tasdemir 1998]. The retrograde warm blood cardioplegia has therefore led us to the premise, that with retrograde oxygenated blood perfusion it would be possible to achieve the operations on the beating heart even in the open heart surgery, such as aortic and/or mitral valve surgery. All will agree that the most damaging effect of the cardioplegia is the reperfusion injury [Allen 1997], and it is obvious that with the technique of retrograde continuous oxygenated blood perfusion this effect will be canceled. In this article, we would like to show the how-to technique for the operations on the beating heart in the case of operations on the aortic valve replacement (AVR) with mitral valve repair (MVR) or replacement MVR and with/without concomitant coronary artery bypass (CABG) surgery. The tricuspid valve repair (PTV) is normally done on the beating heart and there it is realized what problems or technical difficulties may arise during procedures on the mitral valve: the walls of the ventricles are not flattened and the exposure of the mitral valve is challenging task. Furthermore, the free walls of the ventricles with interventricular septum are in the state of the tonus, so every force applied to better expose the aortic or mitral valve is not acceptable

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To examine the comorbidity of borderline personality disorder and other personality disorders in a nonclinical sample of high-school students. 311 high-school students who completed the French version of the CES-D (Center for Epidemiological Studies-Depression Scale), were asked to participate to interviews evaluating personality functioning: 60 subjects (19%) accepted to participate in the study. The mean CES-D score of these 60 subjects (16 boys, 44 girls, mean age=17.7 1.7) was significantly higher than the mean score of the whole sample (23.9 10.4 versus 16.7 9.8). Thus the interviewed sample was not representative of the population of high-school students. Subjects were assessed using the major depressive episode module of the MINI (Mini International Neuropsychiatric Interview) and the SIDP IV (Structured Interview for DSM IV Personality). Inter-rater reliability was determined by comparing the independent ratings of interviewers and an experienced clinician on a random sample of 20 interviews. For DSM IV borderline personality disorder diagnosis, the Cohen's kappa coefficient was 0.85. For personality disorder criteria, kappa ranged from 0.6 to 1.0 (average kappa=0.79). Sixteen of these subjects (26,7%, 4 males, 12 females) received a diagnosis of borderline personality disorder according to DSM IV criteria. The mean CES-D score of borderline subjects (30.6 10.2) was significantly higher than the mean score of nonborderline subjects (21.6 10.5). Of the 16 borderline subjects, 11 (75%) received a diagnosis of major depressive disorder versus 14 (31%) of the non borderline subjects. None of the other personality disorders approached the frequency of borderline personality disorder. The next most frequent diagnoses were depressive and dependent personality disorders which occurred in respectively in 16.6% and 10% of the 60 subjects. All the personality-disorders occurred at higher rates in the group with borderline personality disorder with the exception of obsessive-compulsive personality disorder which was diagnosed only in nonborderline subjects. Of the 16 borderline subjects, 11 (68.7%) met the criteria for another personality disorder which were depressive personality disorder (N=5), paranoid personality disorder (N=4), dependent personality disorder (N=3), antisocial personality disorder (N=2), histrionic personality disorder (N=2), avoidant personality disorder (N=2), negativistic personality disorder (N=2), schizotypal personality disorder (N=1), narcissistic personality disorder (N=1), self-defeating personality disorder (N=1). The optional diagnoses (self-defeating, depressive and negati-vistic personality disorders) accounted for 8 of 23 (34.7%) cases of personality disorders diagnosed among borderline subjects. Among these 11 adolescents, 5 received 2 diagnoses of personality disorders (borderline and paranoid personality disorders, N=1; borderline and dependent personality disorders, N=1; borderline and depressive personality disorders, N=3), 3 received 3 diagnoses (borderline, antisocial and histrionic personality disorders, N=1; borderline, avoidant and negativistic personality disorders, N=1; borderline, depressive and negativistic personality disorders, N=1), 3 received 5 diagnoses (borderline, paranoid, histrionic, narcissistic and dependent personality disorders, N=1; borderline, paranoid, dependent, avoidant and depressive personality disorders, N=1; borderline, paranoid, schizotypal, antisocial and self-defeating personality disorders, N=1). Among the 44 adolescents (12 boys, 32 girls) without borderline personality disorder, 10 (22.7%) (3 boys, 7 girls) met the criteria for another personality disorder which were depressive personality disorder (N=5) or cluster C disorders -obsessive-compulsive personality disorder (N=4), dependent personality disorder (N=2), avoidant personality disorder (N=1) - with the exception of one diagnosis of histrionic personality disorder. Two subjects received 2 diagnoses (obsessive-compulsive and depressive personality disorder). The internal consistency of personality disorders criteria was assessed with Cronbach's alpha coefficient. Borderline personality disorder criteria had high internal consistency (0.82). The factor structure of borderline personality disorder criteria was studied with an exploratory factorial analysis which extracted three factors. The eigenvalues were 3.70, 1.06, and 1.01. Confirmatory factorial analyses were conducted. The correlated two-factor model and the three-factor model fit the data well but the correlation between factors was, however, judged too high, ranging from 0.70 to 0.78. The one-factor model proved to have a good fit (Goodness of Fit Index=0.89, Comparative Fit Index=0.90, Root Mean Square Residual=0.07). As a previous study showed the frequency of two schizotypal personality disorder criteria (odd beliefs/magical thinking experiences and unusual perceptual experiences), an exploratory factorial analysis was performed on the combined set of criteria of borderline and schizotypal personality disorders. It yielded 2 factors: the first factor consisted of all the borderline personality disorder criteria, odd beliefs/magical thinking, and unusual perceptual experiences and could be called the borderline factor; the second factor consisted of the paranoid and the social avoidance criteria and could be called the interpersonal hypersensitivity factor. A confirmatory factor analysis showed that this two-factor model provided a good fit to the data (GFI=0.82, CFI=0,91, RMSR=0.10). The correlation between factors was weak (0.25). These results suggest that odd beliefs/magical thinking and unusual perceptual experiences are a component of borderline symptomatology in adolescents. The high frequency of major depressive disorder and personality disorders in the interviewed sample may be due to the possibility that adolescents with psychological problems have used the interview as a way to obtain attention and support from a psychologist. The interviewed sample, which was characterized by a high intensity of depressive symptomatology and by a high frequency of borderline personality disorder, could thus be seen as intermediate between a clinical and a community sample. Our results may be more generalizable to an outpatients population of adolescents. This study found conflicting results about the construct validity of borderline personality disorder in adolescent. The high internal consistency and the one-factor structure of the borderline personality disorder criteria argue for their validity in adolescents. However, the high rates of comorbidity of borderline personality disorder with depression and other personality disorders, extended to clusters A, B and C and to optional diagnoses, suggest the lack of construct validity of either borderline personality or cluster B disorders in adolescents. Borderline symptomatology in adolescents appears more in adequacy with a dimensional model than with a typological classification. More studies are needed to assess and improve the construct validity of borderline personality disorder in adolescents.

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I have listed some of the ways in which the lowland tropics are not such a warm and wonderful place for the farmer, some of the reasons why it may be unreasonable to expect him to cope with the problems, and some of the ways in which the temperate zones make his task more difficult. The tropics are very close to being a tragedy of the commons on a global scale (69, 103), and it is the temperate zone's shepherds and sheep who are among the greatest offenders (31). Given that the temperate zones have some limited amount of resources with which they are willing to repay the tropics, how can these resources best be spent? The first answer, without doubt, is education, and the incorporation of what is already known about the tropics into that education. Second should be the generation of secure psychological and physical resources for governments that show they are enthusiastic about the development of an SYTA. Third should be support of intensive research needed to generate the set of site-specific rules for specific, clearly identified SYTA's. The subject matter of youths' cultural programming is presumably determined by what they will need during the rest of their lives. A major component of this programming should be the teaching of the socioeconomic rules of a sustained-yield, nonexpanding economy, tuned to the concept of living within the carrying capacity of the country's or region's resources. Incorporating such a process into tropical school systems will cause a major upheaval, if for no other reason than that it will involve an evaluation of the country's resources, what standard of living is to be accepted by those living on them, and who is presently harvesting them. Of even greater impact, it will have to evaluate resources in terms of their ability to raise the standard of living by Y amount for X proportion of the people in the region, rather than in terms of their cash value on the world market. For such a change to be technologically successful, it will require a great deal of pantropical information exchange. This information exchange will cost a great deal of resource, not only in travel funds and support of on-site study, but in insurance policies for the countries that are willing to take the risk of trying to change from an exploitative agroecosystem to an SYTA. For such an experiment to be sociologically successful, it will require a complete change in tropical educational systems, from emphasizing descriptions of events as they now stand, to emphasizing analysis of why things happen the way they do. This will also be very expensive, not only in retreading the technology and mind-sets of current teaching programs, but in gathering the facts on why the tropics have met their current fate. There is a surfeit of biological and agricultural reports dealing with ecological experiments and generalities which suggest that such and such will be the outcome if such and such form of resource harvest is attempted. It is clear that human desiderata regarding a particular site are often radically different from the needs of the "average" wild animals and plants that formed the basis for such experiments and generalities. A finely tuned SYTA will come close to providing a unique solution for each region. The generalities that will rule it are highly stochastic. The more tropical the region, the more evenly weighted the suboutcomes will be, and thus the more likely each region will be to have a unique overall outcome. For example, it is easy to imagine four different parts of the tropics, each with the same kind of soil and the same climate, with four different, successful SYTA's, one based on paddy rice, one on shelterwood forestry, one on tourism, and one on shifting maize culture. A regional experiment station working holistically toward an SYTA is potentially one of the best solutions available. As currently structured, however, almost all tropical experiment stations are inadequate for such a mission. Most commonly they are structured around a single export crop such as coffee, sugar, rubber, cotton, cacao, or tea. A major portion of their budgets comes directly or indirectly from the industry concerned. This industry can hardly be expected to wish to see its production integrated with a sustained-yield system that charges real costs for its materials. When an experiment station is centered around a major food crop, such as rice or maize, the goal becomes one of maximizing production per acre rather than per unit of resource spent; this goal may often be translated into one of generating more people. More general experiment stations tend to be established in the most productive regions of the country and, therefore, receive the most funding. Such regions (islands, intermediate elevations, areas with severe dry seasons) need experiment stations the least because they can often be successfully farmed with only slightly modified temperate zone technologies and philosophies. The administrators of tropical experiment stations often regard their job as a hardship post and tend to orient their research toward the hand that feeds them, which is certainly not the farming communities in which they have been placed. The tropics do not need more hard cash for tractors; they need a program that will show when, where, and how hand care should be replaced with draft animals, and draft animals with tractors. The tropics do not need more randomly gathered, esoteric or applied agricultural research: they need a means to integrate what is already known into the process of developing SYTA's. The tropics do not need more food as much as a means of evaluating the resources they have and generating social systems that will maximize the standard of living possible with those resources, whatever the size. The tropics need a realistic set of expectations.

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In this third and final part, the Spine Study Group (AG WS) of the German Trauma Association (DGU) presents the follow-up (NU) data of its second, prospective, internet-based multicenter study (MCS II) for the treatment of thoracic and lumbar spinal injuries including 865 patients from 8 trauma centers. Part I described in detail the epidemiologic data of the patient collective and the subgroups, whereas part II analyzed the different methods of treatment and radiologic findings. The study period covered the years 2002 to 2006 including a 30-month follow-up period from 01.01.2004 until 31.05.2006. Follow-up data of 638 (74%) patients were collected with a new internet-based database system and analyzed. Results in part III will be presented on the basis of the same characteristic treatment subgroups (OP, KONS, PLASTIE) and surgical treatment subgroups (Dorsal, Ventral, Kombi) in consideration of the level of injury (thoracic spine, thoracolumbar junction, lumbar spine). After the initial treatment and discharge from hospital, the average duration of subsequent inpatient rehabilitation was 4 weeks, which lasted significantly longer in patients with persistent neurologic deficits (mean 10.9 weeks) or polytraumatized patients (mean 8.6 weeks). Following rehabilitation on an inpatient basis, subsequent outpatient rehabilitation lasted on average 4 months. Physical therapy was administered significantly longer to patients with neurologic deficits (mean 8.7 months) or type C injuries (mean 8.6 months). The level of injury had no influence of the duration of the inpatient or outpatient rehabilitation. A total of 382 (72.2%) patients who were either operated from posterior approach only or in a combined postero-anterior approach had an implant removal after an average 12 months. During the follow-up period 56 (8.8%) patients with complications were registered and of these 18 (2.8%) had to have surgical revision. The most common complications reported were infection, loss of correction, or implant-associated complications. Clinical data showed a 2.9 higher relative risk for smokers compared to non-smokers to suffer from wound healing problems. The neurologic status of 81 (60.4%) out of 134 patients with neurologic deficits at the time of injury improved until follow-up. Neurologic deterioration was documented in 8 (1.3%) cases. Complete neurologic deficits after injury to the thoracic spine improved in 9% of the cases, whereas 59% of the cases with complete neurologic deficit improved after injury to the thoracolumbar junction. The surgical approach (posterior or combined postero-anterior) had no significant influence on neurological results at follow-up. Patient age, sex and neurologic deficits showed a statistically significant influence (p&lt;0.05) on the fingertip-floor distance (FBA) at follow-up. Patient back function improved during the follow-up period. More than 2 years after the time of injury 32.2% of the patients had no complaints with respect to back function. The relative frequency of patients with unrestrained back function was greater after posterior surgery (24.2%), than anterior surgery (13.8%), or combined surgery (17.3%) (p=0.005; chi(2)-test). At follow-up there were no statistically significant differences of unrestrained back function between different levels of injury (thoracic spine 17.4%, TL junction 22.5% and lumbar spine 13.6%). The relative frequency of patients with injury to the thoracolumbar junction who reported "no complaints from the anterior approach" at follow-up, was calculated to be 55.6% after open versus 63.8% after endoscopic approaches with no significant differences. Of the patients 56.3% reported no donor site morbidity following iliac crest bone harvesting. The VAS spine score at follow-up was calculated within different treatment subgroups: OP 58.4 points, KONS 59.8 points, and PLASTIE 59.7 points. Statistically significant differences of the VAS spine score between posterior (64.9 points) versus combined surgery (47.8 points) were only verified at the level of injury of the thoracic spine (p=0.004). The relative frequency of patients regaining at least 80% of the initial score level was OP (posterior 60.4%, anterior 61.1%, combined 51.4%), 52.9% KONS and 67.6% PLASTIE. After surgery the mean period of incapacity from work was 4 months. Patients with a sedentary occupation before the time of injury were fully reintegrated into work in 71.1% of the cases. Patients with a physical occupation were fully reintegrated in 38.9% of the cases at follow-up. At follow-up 87 (31.2%) patients after posterior and 50 (20.1%) after combined surgery had no restrictions to their recreational activities (p=0.001). Treatment subgroups PLASTIE and KONS show a similar radiological result at follow-up with a bisegmental kyphotic deformity (GDW) of -9 degrees and -8.5 degrees, respectively. With all operative methods it was possible to correct or partly correct the posttraumatic kyphotic deformity. Until follow-up there was a loss of correction depending on the surgical approach and level of injury. Combined postero-anterior stabilization gave statistically significant better radiological results with less kyphotic deformity (-3.8 degrees) than posterior stabilization alone (-6.1 degrees) (p=0.005; ANOVA). Thus combined surgery was superior in its capability to restore spinal alignment within the observational period. At follow-up the use of titanium vertebral body replacement implants (cages) to reconstruct and support the anterior column showed significantly better radiological results with less kyphotic deformity and loss of correction (GDW 0.3 degrees) than the use of iliac bone strut grafts (-3.7 degrees ) (p&lt;0.001). Neither additional anterior plates nor the combination of anterior plates with a cage or bone graft had a statistically significant influence on the kyphotic deformity measured at follow-up. A matched-pair analysis of anterior surgery alone versus combined surgery for the treatment of compression fractures (type A) at the thoracolumbar junction showed a significantly greater intraoperative blood loss but better radiological results in terms of monosegmental and bisegmental kyphotic deformity after combined surgery (p&lt;0.05). A matched-pair analysis of treatment results between non-operative and operative treatment for burst fractures (type A3.1-2) showed a period of inability to work (6 months) which was twice as long for the non-operative treatment group. At the same time significantly better radiological results at follow-up were achieved after operative treatment of these fractures (p&lt;0.05).

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Hysterosalpingography (HSG) is a method of testing for tubal patency. However, women struggle to tolerate the procedure, as it is associated with some discomfort. Various pharmacological strategies are available that may reduce pain during the procedure, though there is no consensus as to the best method. To compare the effectiveness of different types of pharmacological interventions for pain relief in women undergoing HSG for investigation of subfertility. This review has drawn on the search strategy developed for the Cochrane Menstrual Disorders and Subfertility Group (MDSG). We searched the following databases to 15 April 2015: MDSG Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO. All identified randomised controlled trials investigating pharmacological interventions for pain relief during HSG were investigated for selection. Four review authors independently extracted data. We combined data to calculate mean differences (MDs) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. The search identified 23 trials (1272 women) that were eligible for inclusion into the study. Oral opioid analgesia versus placebo/no treatmentThere was no evidence of effect for oral opioid analgesia in reducing pain during the procedure (MD -0.91, 95% CI -1.88 to 0.06, 1 study, n = 128, low quality evidence) or more than 30 minutes after the procedure (MD -0.99, 95% CI -1.75 to -0.23, 1 study, n = 128, moderate quality evidence)No studies reported on the effect of oral opioid analgesia, when taken prior to the procedure, in reducing pain within 30 minutes after the procedureThere was insufficient evidence to reach conclusions regarding adverse effects. Intravenous opioid analgesia versus placebo/no treatmentThere was evidence that intravenous opioids may improve pain relief during the procedure compared to no treatment (MD -3.53, 95% CI -4.29 to -2.77, 1 study, n = 62, moderate quality evidence)No studies reported on the effect of intravenous opioid analgesia, when taken prior to the procedure, in reducing pain within 30 minutes and more than 30 minutes after the procedureIn terms of adverse effects, one trial reported 1/32 participants had apnoea with intravenous remifentanil. Recovery time was nearly 4 minutes longer in the remifentanil group compared to the control. Oral non-opioid analgesia versus placebo/no treatmentThere was no evidence of effect for oral non-opioid analgesia in reducing pain during the procedure (MD -0.13, 95% CI -0.48 to 0.23, 3 studies, n = 133, I² = 61%, low quality evidence), less than 30 minutes after the procedure (MD -0.30, 95% CI -1.03 to 0.43, 2 studies, n = 45, I² = 97%, very low quality evidence), or more than 30 minutes after the procedure (MD -0.36, 95% CI -1.06 to 0.34, 3 studies, n = 133, I² = 58%, low quality evidence).There was insufficient evidence to reach conclusions regarding adverse effects. Topical anaesthesia versus placebo/no treatmentThere was evidence that topical anaesthetics may reduce pain during the procedure (MD -0.63, 95% CI -1.06 to -0.19, 9 studies, n = 613, I² = 66%, low quality evidence).There was no evidence of effect for topical anaesthesia, when applied prior to the procedure, in reducing pain less than 30 minutes after the procedure (MD 0.42, 95% CI -0.03 to 0.86, 5 studies, n = 373, I² = 59%, very low quality evidence).There was evidence of effect for topical anaesthesia, when applied prior to the procedure, in reducing pain more than 30 minutes after the procedure (MD -1.38, 95% CI -3.44 to -0.68, 2 studies, n = 166, I² = 92%, very low quality evidence).There was insufficient evidence to reach conclusions regarding adverse effects. Locally injected anaesthesia versus placebo/no treatmentThere was evidence of effect that locally injected anaesthetic can reduce pain during the procedure (MD -1.31, 95% CI -1.55 to -1.07, 2 studies, n = 125, I² = 0%, very low quality evidence).There was no evidence of effect for locally injected anaesthesia, when applied prior to the procedure, in reducing pain less than 30 minutes after the procedure (MD -1.31, 95% CI -2.14 to -0.49, 2 studies, n = 125, I² = 46%, low quality evidence).No studies were included into the analysis of the effect of locally injected anaesthesia, when injected prior to the procedure, in reducing pain more than 30 minutes after the procedure.There was insufficient evidence to reach conclusions regarding adverse effects. Any analgesic versus any other analgesicThere was no evidence of a difference between the groups when oral non-opioid analgesia was compared to opioid analgesia for pain relief during the procedure (MD 1.10, 95% CI -0.26 to 2.46, 1 study, n = 91, low quality evidence); less than 30 minutes following the procedure (MD -0.30, 95% CI -1.00 to 0.40, 1 study, n = 91, low quality evidence); and more than 30 minutes following the procedure (MD -0.60, 95% CI -1.56 to 0.36, 1 study, n = 91, low quality evidence). Topical anaesthetics were found to be more effective than paracervical block for pain relief during HSG (MD -2.73, 95% CI -3.86 to -1.60, 1 study, n = 20, moderate quality evidence). This benefit did not extend to within 30 minutes following HSG (MD -1.03, 95% CI -2.52 to 0.46, 1 study, n = 20, low quality evidence); or 30 minutes or more after HSG (MD 0.31, 95% CI -0.87 to 1.49, 1 study, n = 20, low quality evidence).There was insufficient evidence to reach conclusions regarding adverse effects. Topical anaesthetic applied before the procedure may be associated with effective pain relief during HSG, though the quality of this evidence is low. Intravenous opioids may also be effective in pain relief, though this must be weighed against their side effects and their effects on the recovery time. There is insufficient evidence to draw conclusions on the efficacy of other analgesics for HSG, or to reach any other conclusions regarding adverse effects.

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One-third of subfertile couples have no identifiable cause for their inability to conceive. In vitro fertilisation (IVF) is a widely accepted treatment for this condition; however, this treatment is invasive and expensive and is associated with risks. To evaluate the effectiveness and safety of IVF compared with expectant management, unstimulated intrauterine insemination (IUI) or intrauterine insemination along with ovarian stimulation with gonadotropins (IUI + gonadotropins) or clomiphene (IUI + CC) or letrozole (IUI + letrozole) in improving pregnancy outcomes. This review has drawn on the search strategy developed by the Cochrane Menstrual Disorders and Subfertility Group. We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, first quarter), MEDLINE (1946 to May 2015), EMBASE (1985 to May 2015), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (May 2015) and reference lists of articles. We searched the following trial registries: clinicaltrials.gov (http://www.clinicaltrials.gov) and the World Health Organization International Trials Registry Platform search portal (http://www.who.int/trialsearch/Default.aspx). We searched the Web of Science (http://wokinfo.com/) as another source of trials and conference abstracts, OpenGrey (http://www.opengrey.eu/) for unpublished literature from Europe and the Latin American Caribbean Health Sciences Literature (LILACS) database (http://regional.bvsalud.org/php/index.php?lang=en). Moreover, we handsearched relevant conference proceedings and contacted study authors to ask about additional publications.Two review authors independently assessed trial eligibility, extracted data and assessed risk of bias. The primary review outcome was cumulative live birth rate. Multiple pregnancy and other adverse effects were secondary outcomes. We combined data to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity by using the I(2) statistic. We assessed the overall quality of evidence for the main comparisons using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods. We included randomised controlled trials (RCTs) in which the effectiveness of IVF in couples with unexplained subfertility was compared with that of other treatments, including expectant management, unstimulated IUI and stimulated IUI using gonadotropins or clomiphene or letrozole.Live birth rate (LBR) per woman was the primary outcome. Two review authors independently assessed the eligibility and quality of trials and evaluated the quality of the evidence by using GRADE criteria. IVF versus expectant management (two RCTs):Live birth rate per woman was higher with IVF than with expectant management (odds ratio (OR) 22.00, 95% confidence interval (CI) 2.56 to 189.37, one RCT, 51 women, very low quality evidence). Multiple pregnancy rates (MPRs), ovarian hyperstimulation syndrome (OHSS) and miscarriage were not reported. IVF versus unstimulated IUI (two RCTs):Live birth rate was higher with IVF than with unstimulated IUI (OR 2.47, 95% CI 1.19 to 5.12, two RCTs, 156 women, I(2) = 60%, low quality evidence). There was no evidence of a difference between the groups in multiple pregnancy rates (OR 1.03, 95% CI 0.04 to 27.29, one RCT, 43 women, very low quality evidence) IVF versus IUI + ovarian stimulation with gonadotropins (three RCTs) or clomiphene (one RCT) or letrozole (no RCTs):Data from these trials could not be pooled because of high statistical heterogeneity (I(2) = 93.3%). Heterogeneity was eliminated when studies were stratified by pretreatment status.In trials comparing IVF versus IUI + gonadotropins among treatment-naive women, there was no conclusive evidence of a difference between the groups in live birth rates (OR 1.27, 95% CI 0.94 to 1.73, four RCTs, 745 women, I(2) = 8.0%, moderate-quality evidence). In women pretreated with IUI + clomiphene, a higher live birth rate was reported among those who underwent IVF than those given IUI + gonadotropins (OR 3.90, 95% CI 2.32 to 6.57, one RCT, 280 women, moderate-quality evidence).There was no conclusive evidence of a difference in live birth rates between IVF and IUI + CC in treatment-naive women (OR 2.51, 95% CI 0.96 to 6.55, one RCT, 103 women, low quality evidence).In treatment-naive women, there was no evidence of a difference in rates of multiple pregnancy between women who underwent IVF and those who received IUI + gonadotropins (OR 0.79, 95% CI 0.45 to 1.39, four RCTs, 745 women, I(2) = 0%, moderate quality evidence). There was no evidence of a difference in MPRs between women who underwent IVF compared with those given IUI + CC (OR 1.02, 95% CI 0.20 to 5.31, one RCT, 103 women, low-quality evidence).There was no evidence of a difference in ovarian hyperstimulation syndrome rate between treatment-naive women who underwent IVF and those given IUI + gonadotropins (OR 1.23, 95% CI 0.36 to 4.14, two RCTs, 221 women, low quality evidence). There was no evidence of a difference in OHSS rates between groups receiving IVF versus those receiving IUI + CC (OR 1.02, 95% CI 0.20 to 5.31, one RCT, 103 women, low-quality evidence).In treatment naive women, there was no evidence of a difference in miscarriage rates between IVF and IUI + CC (OR 1.16, 95% CI 0.44 to 3.02, one RCT, 103 women, low-quality evidence), nor between women treated with IVF versus those receiving IUI+ gonadotropins (OR 1.16, 95% CI 0.44 to 3.02, one RCT, 103 women).No studies compared IVF with IUI + letrozole.The quality of the evidence ranged from very low to moderate. The main limitation was serious imprecision resulting from small study numbers and low event rates. IVF may be associated with higher live birth rates than expectant management, but there is insufficient evidence to draw firm conclusions. IVF may also be associated with higher live birth rates than unstimulated IUI. In women pretreated with clomiphene + IUI, IVF appears to be associated with higher birth rates than IUI + gonadotropins. However in women who are treatment-naive there is no conclusive evidence of a difference in live birth rates between IVF and IUI + gonadotropins or between IVF and IUI + clomiphene. Adverse events associated with these interventions could not be adequately assessed owing to lack of evidence.

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Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently approved by the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency) for tuberous sclerosis complex-associated renal angiomyolipoma and subependymal giant cell astrocytoma, applications for other manifestations of tuberous sclerosis complex have not yet been established. A systematic review is necessary to establish the clinical value of rapamycin or rapalogs for various manifestations in tuberous sclerosis complex. To determine the effectiveness of rapamycin or rapalogs in people with tuberous sclerosis complex for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects. Relevant studies were identified by authors from the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, and clinicaltrials.gov. Relevant resources were also searched by the authors, such as conference proceedings and abstract books of conferences, from e.g. the Tuberous Sclerosis Complex International Research Conferences, other tuberous sclerosis complex-related conferences and the Human Genome Meeting. We did not restrict the searches by language as long as English translations were available for non-English reports.Date of the last searches: 14 March 2016. Randomized or quasi-randomized studies of rapamycin or rapalogs in people with tuberous sclerosis complex. Data were independently extracted by two authors using standard acquisition forms. The data collection was verified by one author. The risk of bias of each study was independently assessed by two authors and verified by one author. Three placebo-controlled studies with a total of 263 participants (age range 0.8 to 61 years old, 122 males and 141 females, with variable lengths of study duration) were included in the review. We found high-quality evidence except for response to skin lesions which was judged to be low quality due to the risk of attrition bias. Overall, there are 175 participants in the treatment arm (rapamycin or everolimus) and 88 in the placebo arm. Participants all had tuberous sclerosis complex as proven by consensus diagnostic criteria as a minimum. The quality in the description of the study methods was mixed, although we assessed most domains as having a low risk of bias. Blinding of treatment arms was successfully carried out in all of the studies. However, two studies did not report allocation concealment. Two of the included studies were funded by Novartis Pharmaceuticals.Two studies (235 participants) used oral (systemic) administration of everolimus (rapalog). These studies reported response to tumour size in terms of the number of individuals with a reduction in the total volume of tumours to 50% or more relative to baseline. Significantly more participants in the treatment arm (two studies, 162 participants, high quality evidence) achieved a 50% reduction in renal angiomyolipoma size, risk ratio 24.69 (95% confidence interval 3.51 to 173.41) (P = 0.001). For the sub-ependymal giant cell astrocytoma, our analysis of one study (117 participants, high quality evidence) showed significantly more participants in the treatment arm achieved a 50% reduction in tumour size, risk ratio 27.85 (95% confidence interval 1.74 to 444.82) (P = 0.02). The proportion of participants who showed a skin response from the two included studies analysed was significantly increased in the treatment arms, risk ratio 5.78 (95% confidence interval 2.30 to 14.52) (P = 0.0002) (two studies, 224 participants, high quality evidence). In one study (117 participants), the median change of seizure frequency was -2.9 in 24 hours (95% confidence interval -4.0 to -1.0) in the treatment group versus -4.1 in 24 hour (95% confidence interval -10.9 to 5.8) in the placebo group. In one study, one out of 79 participants in the treatment group versus three of 39 in placebo group had increased blood creatinine levels, while the median percentage change of forced expiratory volume at one second in the treatment arm was -1% compared to -4% in the placebo arm. In one study (117 participants, high quality evidence), we found that those participants who received treatment had a similar risk of experiencing adverse events compared to those who did not, risk ratio 1.07 (95% confidence interval 0.96 - 1.20) (P = 0.24). However, as seen from two studies (235 participants, high quality evidence), the treatment itself led to significantly more adverse events resulting in withdrawal, interruption of treatment, or reduction in dose level, risk ratio 3.14 (95% confidence interval 1.82 to 5.42) (P &lt; 0.0001).One study (28 participants) used topical (skin) administration of rapamycin. This study reported response to skin lesions in terms of participants' perception towards their skin appearance following the treatment. There was a tendency of an improvement in the participants' perception of their skin appearance, although not significant, risk ratio 1.81 (95% confidence interval 0.80 to 4.06, low quality evidence) (P = 0.15). This study reported that there were no serious adverse events related to the study product and there was no detectable systemic absorption of the rapamycin during the study period. We found evidence that oral everolimus significantly increased the proportion of people who achieved a 50% reduction in the size of sub-ependymal giant cell astrocytoma and renal angiomyolipoma. Although we were unable to ascertain the relationship between the reported adverse events and the treatment, participants who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. Nevertheless, the treatment itself significantly increased the risk of having dose reduction, interruption or withdrawal. This supports ongoing clinical applications of oral everolimus for renal angiomyolipoma and subependymal giant cell astrocytoma. Although oral everolimus showed beneficial effect on skin lesions, topical rapamycin only showed a non-significant tendency of improvement. Efficacy on skin lesions should be further established in future research. The beneficial effects of rapamycin or rapalogs on tuberous sclerosis complex should be further studied on other manifestations of the condition.

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<bObjective:</b To observe the effects of Huanglian ointment on wound healing of mice with full-thickness skin defect, and to explore the related mechanism. <bMethods:</b Thirty male C57BL/6J mice were divided into Huanglian ointment group and vehicle group according to the random number table after round wounds of full-thickness skin defect with diameter of 7.5 mm were inflicted on the back of each mouse, with 15 mice in each group. Wounds of mice in Huanglian ointment group and vehicle group were treated with Huanglian ointment and vehicle respectively from post injury day (PID) 1 on, 2 times each day. Five mice from each group were selected to observe wound changes on PID 0, 3, 7, 10, and 14, and wound healing rates were calculated. Five mice out of the 10 mice that hadn't been used for general observation in each group were sacrificed on PID 3 and 7 respectively, and 5 mice after being used for general observation in each group were sacrificed on PID 14. Wound and skin tissue within 2 mm from the edge of wound was collected. Histologic scoring was conducted based on the histomorphological observation with HE staining. The expression of double positive cells of alpha smooth muscle actin (α-SMA) and Ki-67 (myofibroblast) in tissue of wounds of mice was observed by immunofluorescence staining. Protein expressions of transforming growth factor beta (TGF-β) and collagen in tissue of wounds of mice were determined by enzyme-linked immunosorbent assay. Data were processed with analysis of variance for repeated measurement, analysis of variance of factorial design, <it</i test of two independent samples, one-way analysis of variance, and Bonferronni test or correction. <bResults:</b (1) Wounds of mice in two groups were red and swollen on PID 0, while they were neither red nor swollen with scabs on PID 3 and 7. On PID 10, woundsof mice in Huanglian ointment group contracted obviously, while the contracted wounds of mice in vehicle group were smaller than those in Huanglian ointment group. On PID 14, wounds of most mice in Huanglian ointment group were healed, while wounds of some mice in vehicle group failed to heal. Wound healing rates of mice in two groups were close on PID 3 and 7 (with <it</i values respectively 0.64 and 1.90, <iP</i values above 0.05). Wound healing rates of mice in Huanglian ointment group on PID 10 and 14 were (76±7)% and (93±5)% respectively, significantly higher than those of vehicle group [(48±9)% and (68±11)%, with <it</i values respectively 7.44 and 3.89, <iP</i values below 0.01]. Wound healing rates of mice in two groups on PID 7, 10, and 14 were significantly higher than those on the previous time points of the same group (with <iP</i values below 0.01). (2) Histologic scores of wounds of mice in two groups were close on PID 3 (<it</i=-0.76, <iP</i&gt;0.05). Histologic scores of wounds of mice in Huanglian ointment group on PID 7 and 14 were (7.0±1.6) and (11.6±2.1) points respectively, significantly higher than those of vehicle group [(4.2±1.3) and (7.2±1.3) points, with <it</i values respectively 1.96 and 2.50, <iP</i&lt;0.05 or <iP</i&lt;0.01]. Histologic scores of wounds of mice in two groups on PID 7 and 14 were significantly higher than those on the previous time points of the same group (with <iP</i values below 0.01). (3) Percentages of double positive cells of α-SMA and Ki-67 in tissue of wounds of mice in Huanglian ointment group on PID 3 and 7 were (35±12)% and (62±10)% respectively, significantly higher than those of vehicle group [(17±12)% and (34±6)%, with <it</i values respectively -2.48 and -5.25, <iP</i&lt;0.05 or <iP</i&lt;0.01]. The percentage of double positive cells of α-SMA and Ki-67 in tissue of wounds of mice in Huanglian ointment group on PID 14 was (25±5)%, significantly lower than that of vehicle group [(44±17)%, <it</i=2.50, <iP</i&lt;0.05]. The percentage of double positive cells of α-SMA and Ki-67 in tissue of wounds of mice on PID 7 was significantly higher than that on PID 3 or 14 in Huanglian ointment group (with <iP</i values below 0.01). Percentages of double positive cells of α-SMA and Ki-67 in tissue of wounds of mice on PID 7 and 14 were significantly higher than those on the previous time points in vehicle group (with <iP</i values below 0.05). (4) Protein expressions of TGF-β in tissue of wounds of mice in Huanglian ointment group on PID 3 and 7 were (396±45) and (722±96) pg/mL respectively, significantly higher than those of vehicle group [(290±42) and (382±62) pg/mL, with <it</i values respectively -8.17 and -6.65, <iP</i values below 0.01]. Protein expressions of TGF-β in tissue of wounds of mice in two groups were close on PID 14 (<it</i=1.60, <iP</i&gt;0.05). The protein expression of TGF-β in tissue of wounds of mice in Huanglian ointment group on PID 7 was significantly higher than that on PID 3 or 14 (with <iP</i values below 0.01). Protein expressions of TGF-β in tissue of wounds of mice in vehicle group on PID 7 and 14 were significantly higher than those on the previous time points (with <iP</i values below 0.05). Protein expressions of collagen in tissue of wounds of mice in two groups were close on PID 3 (<it</i=1.99, <iP</i&gt;0.05). Protein expressions of collagen in tissue of wounds of mice in Huanglian ointment on PID 7 and 14 were (47±10) and (70±14) ng/mL respectively, significantly higher than those of vehicle group [(34±10) and (42±12) ng/mL, with <it</i values respectively 3.15 and 3.52, <iP</i&lt;0.05 or <iP</i&lt;0.01]. Protein expressions of collagen in tissue of wounds of mice in two groups on PID 7 and 14 were significantly higher than those on the previous time points of the same group (<iP</i&lt;0.05 or <iP</i&lt;0.01). <bConclusions:</b Huanglian ointment can promote wound healing of full-thickness skin defect of mice through increasing production of myofibroblasts and protein expressions of TGF-β and collagen.

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This is an updated version of the original Cochrane Review published in the Cochrane Library 2013, Issue 9. Despite good evidence for the health benefits of regular exercise for people living with or beyond cancer, understanding how to promote sustainable exercise behaviour change in sedentary cancer survivors, particularly over the long term, is not as well understood. A large majority of people living with or recovering from cancer do not meet current exercise recommendations. Hence, reviewing the evidence on how to promote and sustain exercise behaviour is important for understanding the most effective strategies to ensure benefit in the patient population and identify research gaps. To assess the effects of interventions designed to promote exercise behaviour in sedentary people living with and beyond cancer and to address the following secondary questions: Which interventions are most effective in improving aerobic fitness and skeletal muscle strength and endurance? Which interventions are most effective in improving exercise behaviour amongst patients with different cancers? Which interventions are most likely to promote long-term (12 months or longer) exercise behaviour? What frequency of contact with exercise professionals and/or healthcare professionals is associated with increased exercise behaviour? What theoretical basis is most often associated with better behavioural outcomes? What behaviour change techniques (BCTs) are most often associated with increased exercise behaviour? What adverse effects are attributed to different exercise interventions? We used standard methodological procedures expected by Cochrane. We updated our 2013 Cochrane systematic review by updating the searches of the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, Embase, AMED, CINAHL, PsycLIT/PsycINFO, SportDiscus and PEDro up to May 2018. We also searched the grey literature, trial registries, wrote to leading experts in the field and searched reference lists of included studies and other related recent systematic reviews. We included only randomised controlled trials (RCTs) that compared an exercise intervention with usual care or 'waiting list' control in sedentary people over the age of 18 with a homogenous primary cancer diagnosis. In the update, review authors independently screened all titles and abstracts to identify studies that might meet the inclusion criteria, or that could not be safely excluded without assessment of the full text (e.g. when no abstract is available). We extracted data from all eligible papers with at least two members of the author team working independently (RT, LS and RG). We coded BCTs according to the CALO-RE taxonomy. Risk of bias was assessed using the Cochrane's tool for assessing risk of bias. When possible, and if appropriate, we performed a fixed-effect meta-analysis of study outcomes. If statistical heterogeneity was noted, a meta-analysis was performed using a random-effects model. For continuous outcomes (e.g. cardiorespiratory fitness), we extracted the final value, the standard deviation (SD) of the outcome of interest and the number of participants assessed at follow-up in each treatment arm, to estimate the standardised mean difference (SMD) between treatment arms. SMD was used, as investigators used heterogeneous methods to assess individual outcomes. If a meta-analysis was not possible or was not appropriate, we narratively synthesised studies. The quality of the evidence was assessed using the GRADE approach with the GRADE profiler. We included 23 studies in this review, involving a total of 1372 participants (an addition of 10 studies, 724 participants from the original review); 227 full texts were screened in the update and 377 full texts were screened in the original review leaving 35 publications from a total of 23 unique studies included in the review. We planned to include all cancers, but only studies involving breast, prostate, colorectal and lung cancer met the inclusion criteria. Thirteen studies incorporated a target level of exercise that could meet current recommendations for moderate-intensity aerobic exercise (i.e.150 minutes per week); or resistance exercise (i.e. strength training exercises at least two days per week).Adherence to exercise interventions, which is crucial for understanding treatment dose, is still reported inconsistently. Eight studies reported intervention adherence of 75% or greater to an exercise prescription that met current guidelines. These studies all included a component of supervision: in our analysis of BCTs we designated these studies as 'Tier 1 trials'. Six studies reported intervention adherence of 75% or greater to an aerobic exercise goal that was less than the current guideline recommendations: in our analysis of BCTs we designated these studies as 'Tier 2 trials.' A hierarchy of BCTs was developed for Tier 1 and Tier 2 trials, with programme goal setting, setting of graded tasks and instruction of how to perform behaviour being amongst the most frequent BCTs. Despite the uncertainty surrounding adherence in some of the included studies, interventions resulted in improvements in aerobic exercise tolerance at eight to 12 weeks (SMD 0.54, 95% CI 0.37 to 0.70; 604 participants, 10 studies; low-quality evidence) versus usual care. At six months, aerobic exercise tolerance was also improved (SMD 0.56, 95% CI 0.39 to 0.72; 591 participants; 7 studies; low-quality evidence). Since the last version of this review, none of the new relevant studies have provided additional information to change the conclusions. We have found some improved understanding of how to encourage previously inactive cancer survivors to achieve international physical activity guidelines. Goal setting, setting of graded tasks and instruction of how to perform behaviour, feature in interventions that meet recommendations targets and report adherence of 75% or more. However, long-term follow-up data are still limited, and the majority of studies are in white women with breast cancer. There are still a considerable number of published studies with numerous and varied issues related to high risk of bias and poor reporting standards. Additionally, the meta-analyses were often graded as consisting of low- to very low-certainty evidence. A very small number of serious adverse effects were reported amongst the studies, providing reassurance exercise is safe for this population.

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Laparoscopy is a common procedure used to diagnose and treat various gynaecological conditions. Shoulder-tip pain (STP) as a result of the laparoscopy occurs in up to 80% of women, with potential for significant morbidity, delayed discharge and readmission. Interventions at the time of gynaecological laparoscopy have been developed in an attempt to reduce the incidence and severity of STP. To determine the effectiveness and safety of methods for reducing the incidence and severity of shoulder-tip pain (STP) following gynaecological laparoscopy. We searched the following databases: Cochrane Gynaecology and Fertility (CGF) Specialised Register, the Cochrane Central Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO and CINAHL from inception to 8 August 2018. We also searched the reference lists of relevant articles and registers of ongoing trials. Randomised controlled trials (RCTs) of interventions used during or immediately after gynaecological laparoscopy to reduce the incidence or severity of STP. We used standard methodological procedures expected by Cochrane. Primary outcomes: incidence or severity of STP and adverse events of the interventions; secondary outcomes: analgesia usage, delay in discharge, readmission rates, quality-of-life scores and healthcare costs. We included 32 studies (3284 women). Laparoscopic procedures in these studies varied from diagnostic procedures to complex operations. The quality of the evidence ranged from very low to moderate. The main limitations were risk of bias, imprecision and inconsistency.Specific technique versus "standard" technique for releasing the pneumoperitoneumUse of a specific technique of releasing the pneumoperitoneum (pulmonary recruitment manoeuvre, extended assisted ventilation or actively aspirating intra-abdominal gas) reduced the severity of STP at 24 hours (standardised mean difference (SMD) -0.66, 95% confidence interval (CI) -0.82 to -0.50; 5 RCTs; 670 participants; I<sup2</sup = 0%, low-quality evidence) and reduced analgesia usage (SMD -0.53, 95% CI -0.70 to -0.35; 4 RCTs; 570 participants; I<sup2</sup = 91%, low-quality evidence). There appeared to be little or no difference in the incidence of STP at 24 hours (odds ratio (OR) 0.87, 95% CI 0.41 to 1.82; 1 RCT; 118 participants; low-quality evidence).No adverse events occurred in the only study assessing this outcome.Fluid instillation versus no fluid instillationFluid instillation is probably associated with a reduction in STP incidence (OR 0.38, 95% CI 0.22 to 0.66; 2 RCTs; 220 participants; I<sup2</sup = 0%, moderate-quality evidence) and severity (mean difference (MD) (0 to 10 visual analogue scale (VAS) scale) -2.27, 95% CI -3.06 to -1.48; 2 RCTs; 220 participants; I<sup2</sup = 29%, moderate-quality evidence) at 24 hours, and may reduce analgesia usage (MD -12.02, 95% CI -23.97 to -0.06; 2 RCTs; 205 participants, low-quality evidence).No study measured adverse events.Intraperitoneal drain versus no intraperitoneal drainUsing an intraperitoneal drain may reduce the incidence of STP at 24 hours (OR 0.30, 95% CI 0.20 to 0.46; 3 RCTs; 417 participants; I<sup2</sup = 90%, low-quality evidence) and may reduce analgesia use within 48 hours post-operatively (SMD -1.84, 95% CI -2.14 to -1.54; 2 RCTs; 253 participants; I<sup2</sup = 90%). We are uncertain whether it reduces the severity of STP at 24 hours, as the evidence was very low quality (MD (0 to 10 VAS scale) -1.85, 95% CI -2.15 to -1.55; 3 RCTs; 320 participants; I<sup2</sup = 70%).No study measured adverse events.Subdiaphragmatic intraperitoneal local anaesthetic versus control (no fluid instillation, normal saline or Ringer's lactate)There is probably little or no difference between the groups in incidence of STP (OR 0.72, 95% CI 0.42 to 1.23; 4 RCTs; 336 participants; I<sup2</sup = 0%; moderate-quality evidence) and there may be no difference in STP severity (MD -1.13, 95% CI -2.52 to 0.26; 1 RCT; 50 participants; low-quality evidence), both measured at 24 hours. However, the intervention may reduce post-operative analgesia use (SMD-0.57, 95% CI -0.94 to -0.21; 2 RCTs; 129 participants; I<sup2</sup = 51%, low-quality evidence).No adverse events occurred in any study.Local anaesthetic into peritoneal cavity (not subdiaphragmatic) versus normal salineLocal anaesthetic into the peritoneal cavity may reduce the incidence of STP at 4 to 8 hours post-operatively (OR 0.23, 95% CI 0.06 to 0.93; 2 RCTs; 157 participants; I<sup2</sup = 56%; low-quality evidence). Our other outcomes of interest were not assessed.Warmed, or warmed and humidified CO<sub2</sub versus unwarmed and unhumidified CO<sub2</subThere may be no difference between these interventions in incidence of STP at 24 to 48 hours (OR 0.81 95% CI 0.45 to 1.49; 2 RCTs; 194 participants; I<sup2</sup = 12%; low-quality evidence) or in analgesia usage within 48 hours (MD -4.97 mg morphine, 95% CI -11.25 to 1.31; 1 RCT; 95 participants; low-quality evidence); there is probably little or no difference in STP severity at 24 hours (MD (0 to 10 VAS scale) 0.11, 95% CI -0.75 to 0.97; 2 RCTs; 157 participants; I<sup2</sup = 50%; moderate-quality evidence).No study measured adverse events.Gasless laparoscopy versus CO<sub2</sub insufflationGasless laparoscopy may be associated with increased severity of STP within 72 hours post-operatively when compared with standard treatment (MD 3.8 (0 to 30 VAS scale), 95% CI 0.76 to 6.84; 1 RCT; 54 participants, low-quality evidence), and there may be no difference in the risk of adverse events (OR 2.56, 95% CI 0.25 to 26.28; 1 RCT; 54 participants; low-quality evidence).No study measured the incidence of STP. There is low to moderate-quality evidence that the following interventions are associated with a reduction in the incidence or severity, or both, of STP, or a reduction in analgesia requirements for women undergoing gynaecological laparoscopy: a specific technique for releasing the pneumoperitoneum; intraperitoneal fluid instillation; an intraperitoneal drain; and local anaesthetic applied to the peritoneal cavity (not subdiaphragmatic).There is low to moderate-quality evidence that subdiaphragmatic intraperitoneal local anaesthetic and warmed and humidified insufflating gas may not make a difference to the incidence or severity of STP.There is low-quality evidence that gasless laparoscopy may increase the severity of STP, compared with standard treatment.Few studies reported data on adverse events. Some potentially useful interventions have not been studied by RCTs of gynaecological laparoscopy.

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Inflammatory bowel disease (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic mucosal inflammation, frequent hospitalizations, adverse health economics, and compromised quality of life. Diet has been hypothesised to influence IBD activity. To evaluate the efficacy and safety of dietary interventions on IBD outcomes. We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, Embase, Web of Science, Clinicaltrials.gov and the WHO ICTRP from inception to 31 January 2019. We also scanned reference lists of included studies, relevant reviews and guidelines. We included randomized controlled trials (RCTs) that compared the effects of dietary manipulations to other diets in participants with IBD. Studies that exclusively focused on enteral nutrition, oral nutrient supplementation, medical foods, probiotics, and parenteral nutrition were excluded. Two review authors independently performed study selection, extracted data and assessed bias using the risk of bias tool. We conducted meta-analyses where possible using a random-effects model and calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes. We assessed the certainty of evidence using GRADE. The review included 18 RCTs with 1878 participants. The studies assessed different dietary interventions for active CD (six studies), inactive CD (seven studies), active UC (one study) and inactive UC (four studies). Dietary interventions involved either the consumption of low amounts or complete exclusion of one or more food groups known to trigger IBD symptoms. There was limited scope for data pooling as the interventions and control diets were diverse. The studies were mostly inadequately powered. Fourteen studies were rated as high risk of bias. The other studies were rated as unclear risk of bias.The effect of high fiber, low refined carbohydrates, low microparticle diet, low calcium diet, symptoms-guided diet and highly restricted organic diet on clinical remission in active CD is uncertain. At 4 weeks, remission was induced in: 100% (4/4) of participants in the low refined carbohydrates diet group compared to 0% (0/3) of participants in the control group (RR 7.20, 95% CI 0.53 to 97.83; 7 participants; 1 study; very low certainty evidence). At 16 weeks, 44% (23/52) of participants in the low microparticle diet achieved clinical remission compared to 25% (13/51) of control-group participants (RR 3.13, 95% CI 0.22 to 43.84; 103 participants; 2 studies; I² = 73%; very low certainty evidence). Fifty per cent (16/32) of participants in the symptoms-guided diet group achieved clinical remission compared to 0% (0/19) of control group participants (RR 20.00, 95% CI 1.27 to 315.40; 51 participants ; 1 study; very low certainty evidence) (follow-up unclear). At 24 weeks, 50% (4/8) of participants in the highly restricted organic diet achieved clinical remission compared to 50% (5/10) of participants in the control group (RR 1.00, 95% CI 0.39 to 2.53; 18 participants; 1 study; very low certainty evidence). At 16 weeks, 37% (16/43) participants following a low calcium diet achieved clinical remission compared to 30% (12/40) in the control group (RR 1.24, 95% CI 0.67 to 2.29; 83 participants; 1 study; very low certainty evidence).The effect of low refined carbohydrate diets, symptoms-guided diets and low red processed meat diets on relapse in inactive CD is uncertain. At 12 to 24 months, 67% (176/264) of participants in low refined carbohydrate diet relapsed compared to 64% (193/303) in the control group (RR 1.04, 95% CI 0.87 to 1.25; 567 participants; 3 studies; I² = 35%; low certainty evidence). At 6 to 24 months, 48% (24/50) of participants in the symptoms-guided diet group relapsed compared to 83% (40/48) participants in the control diet (RR 0.53, 95% CI 0.28 to 1.01; 98 participants ; 2 studies; I² = 54%; low certainty evidence). At 48 weeks, 66% (63/96) of participants in the low red and processed meat diet group relapsed compared to 63% (75/118) of the control group (RR 1.03, 95% CI 0.85 to 1.26; 214 participants; 1 study; low certainty evidence). At 12 months, 0% (0/16) of participants on an exclusion diet comprised of low disaccharides / grains / saturated fats / red and processed meat experienced clinical relapse compared to 26% (10/38) of participants on a control group (RR 0.11, 95% CI 0.01 to 1.76; 54 participants; 1 study; very low certainty evidence).The effect of a symptoms-guided diet on clinical remission in active UC is uncertain. At six weeks, 36% (4/11) of symptoms-guided diet participants achieved remission compared to 0% (0/10) of usual diet participants (RR 8.25, 95% CI 0.50 to 136.33; 21 participants; 1 study; very low certainty evidence).The effect of the Alberta-based anti-inflammatory diet, the Carrageenan-free diet or milk-free diet on relapse rates in inactive UC is uncertain. At 6 months, 36% (5/14) of participants in the Alberta-based anti-inflammatory diet group relapsed compared to 29% (4/14) of participants in the control group (RR 1.25, 95% CI 0.42 to 3.70; 28 participants; 1 study; very low certainty evidence). Thirty per cent (3/10) of participants following the carrageenan-free diet for 12 months relapsed compared to 60% (3/5) of the participants in the control group (RR 0.50, 95% CI 0.15 to 1.64; 15 participants; 1 study; very low certainty evidence). At 12 months, 59% (23/39) of milk free diet participants relapsed compared to 68% (26/38) of control diet participants (RR 0.83, 95% CI 0.60 to 1.15; 77 participants; 2 studies; I² = 0%; low certainty evidence).None of the included studies reported on diet-related adverse events. The effects of dietary interventions on CD and UC are uncertain. Thus no firm conclusions regarding the benefits and harms of dietary interventions in CD and UC can be drawn. There is need for consensus on the composition of dietary interventions in IBD and more RCTs are required to evaluate these interventions. Currently, there are at least five ongoing studies (estimated enrollment of 498 participants). This review will be updated when the results of these studies are available.

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An erratum was issued for: Scalable Fabrication of Stretchable, Dual Channel, Microfluidic Organ Chips.  The Representative Results, Discussion, and References sections have been updated. In the Representative Results section, the legend for Figure 5 has been updated from: Figure 5: Permeability of inert tracer Cascade Blue through the microporous PDMS membrane. Cascade Blue hydrazide dye in medium was loaded into the top channel of the Organ Chip and perfused at 60 µL/h to measure the flux of the dye across the membrane into the bottom channel containing medium. Empty chips were compared to Gut Chips with Caco2-BBe1 cells in the apical channel and human vascular endothelial cells (HUVEC) in the basal channel cultured for 6 days. Error bars indicate standard error of the mean. to: Figure 5: Permeability of inert tracer Cascade Blue through the microporous PDMS membrane. Cascade Blue hydrazide dye in medium was loaded into the top channel of the Organ Chip and perfused at 60 µl/h to measure the flux of the dye across the membrane into the bottom channel containing medium. Empty chips were compared to Gut Chips with Caco2-BBe1 cells in the apical channel and human vascular endothelial cells (HUVEC) in the basal channel cultured for 6 days. The apparent permeability (Papp, cm/s) of the microporous PDMS membrane was determined using the dye concentration in the outlet channels. The gut chip cell layers provide a significantly increased barrier to permeability. Error bars indicate standard error of the mean. In the Discussion section, the fourth paragraph has been updated from: Troubleshooting the resulting Organ Chips takes place at two levels: during the fabrication process and during Organ Chip culture. We have developed a visual method for quality assurance (QA) of through-hole formation in the cast membranes that greatly accelerates the production process while improving the quality and reliability of assembled Organ Chips. This QA method allows for process troubleshooting, and we recommend keeping a record of process conditions to enable tracking fabrication problems that may occur during cell culture. During Organ Chip culture, inert tracer dyes are the simplest method of measuring barrier function to troubleshoot the fabrication process and cell culture steps. Lucifer Yellow has been used historically due to its small molecular mass and innate fluorescence, but Cascade Blue offers similar properties with a narrower emission spectrum that is less likely to interfere with downstream assays. Larger molecules, such as poly-ethyleneglycol (PEG)- or dextran-conjugated fluorophores are larger and consequently result in lower permeability overall and lower sensitivity. The apparent permeability (Papp, cm/s) of tracer dyes can be used to determine barrier function properties of organs or tissues (Figure 4). The following equation can be used to calculate Papp between the dosing channel and receiving channel and is derived from equations used primarily for Transwell studies<sup19</sup <sup,</sup <sup20</sup and corrects for tracer dye loss caused by absorption into PDMS by comparing the two output flows and not relying on mass balance assumptions at the outflow. to: Troubleshooting the resulting Organ Chips takes place at two levels: during the fabrication process and during Organ Chip culture. We have developed a visual method for quality assurance (QA) of through-hole formation in the cast membranes that greatly accelerates the production process while improving the quality and reliability of assembled Organ Chips. This QA method allows for process troubleshooting, and we recommend keeping a record of process conditions to enable tracking fabrication problems that may occur during cell culture. During Organ Chip culture, inert tracer dyes are the simplest method of measuring barrier function to troubleshoot the fabrication process and cell culture steps. Lucifer Yellow has been used historically due to its small molecular mass and innate fluorescence, but Cascade Blue offers similar properties with a narrower emission spectrum that is less likely to interfere with downstream assays. Larger molecules, such as poly-ethyleneglycol (PEG)- or dextran-conjugated fluorophores are larger and consequently result in lower permeability overall and lower sensitivity. The apparent permeability (Papp, cm/s) of tracer dyes can be used to determine barrier function properties of organs or tissues (Figure 5). The following equation derived by Tran, et al.<sup19</sup can be used to calculate Papp between the dosing channel and receiving channel, which partially corrects for tracer dye loss caused by absorption into PDMS by averaging the two output flows and not relying on mass balance assumptions at the outflow. The References section has been updated from: Blaser, D.W. Determination of drug absorption parameters in Caco-2 cell monolayers with a mathematical model encompassing passive diffusion, carrier-mediated efflux, non-specific binding and phase II metabolism. at &lt;http://edoc.unibas.ch/655/1/DissB_7998.pdf&gt; (2007). Hubatsch, I., Ragnarsson, E.G.E., Artursson, P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nature Protocols. 2 (9), 2111-2119 (2007). Henry, O.Y.F. et al. Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (TEER) measurements of human epithelial barrier function. Lab on a Chip. 17 (13), 2264-2271 (2017). Maoz, B.M. et al. Organs-on-Chips with combined multi-electrode array and transepithelial electrical resistance measurement capabilities. Lab on a Chip. 17 (13), 2294-2302 (2017). Benam, K.H. et al. Matched-Comparative Modeling of Normal and Diseased Human Airway Responses Using a Microengineered Breathing Lung Chip. Cell Systems. 3 (5), 456-466.e4 (2016). to: Tran, T.T. et al. Exact kinetic analysis of passive transport across a polarized confluent MDCK cell monolayer modeled as a single barrier. Journal of Pharmaceutical Sciences. 93 (8), 2108-2123 (2004). Henry, O.Y.F. et al. Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (TEER) measurements of human epithelial barrier function. Lab on a Chip. 17 (13), 2264-2271 (2017). Maoz, B.M. et al. Organs-on-Chips with combined multi-electrode array and transepithelial electrical resistance measurement capabilities. Lab on a Chip. 17 (13), 2294-2302 (2017). Benam, K.H. et al. Matched-Comparative Modeling of Normal and Diseased Human Airway Responses Using a Microengineered Breathing Lung Chip. Cell Systems. 3 (5), 456-466.e4 (2016).

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Intra-uterine insemination (IUI) is a widely-used fertility treatment for couples with unexplained subfertility. Although IUI is less invasive and less expensive than in vitro fertilisation (IVF), the safety of IUI in combination with ovarian hyperstimulation (OH) is debated. The main concern about IUI treatment with OH is the increase in multiple pregnancy rates. To determine whether, for couples with unexplained subfertility, the live birth rate is improved following IUI treatment with or without OH compared to timed intercourse (TI) or expectant management with or without OH, or following IUI treatment with OH compared to IUI in a natural cycle. We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 17 October 2019, together with reference checking and contact with study authors for missing or unpublished data. Randomised controlled trials (RCTs) comparing IUI with TI or expectant management, both in stimulated or natural cycles, or IUI in stimulated cycles with IUI in natural cycles in couples with unexplained subfertility. Two review authors independently performed study selection, quality assessment and data extraction. Primary review outcomes were live birth rate and multiple pregnancy rate. We include 15 trials with 2068 women. The evidence was of very low to moderate quality. The main limitation was very serious imprecision. IUI in a natural cycle versus timed intercourse or expectant management in a natural cycle It is uncertain whether treatment with IUI in a natural cycle improves live birth rate compared to treatment with expectant management in a natural cycle (odds ratio (OR) 1.60, 95% confidence interval (CI) 0.92 to 2.78; 1 RCT, 334 women; low-quality evidence). If we assume the chance of a live birth with expectant management in a natural cycle to be 16%, that of IUI in a natural cycle would be between 15% and 34%. It is uncertain whether treatment with IUI in a natural cycle reduces multiple pregnancy rates compared to control (OR 0.50, 95% CI 0.04 to 5.53; 1 RCT, 334 women; low-quality evidence). IUI in a stimulated cycle versus timed intercourse or expectant management in a stimulated cycle It is uncertain whether treatment with IUI in a stimulated cycle improves live birth rates compared to treatment with TI in a stimulated cycle (OR 1.59, 95% CI 0.88 to 2.88; 2 RCTs, 208 women; I<sup2</sup = 72%; low-quality evidence). If we assume the chance of achieving a live birth with TI in a stimulated cycle was 26%, the chance with IUI in a stimulated cycle would be between 23% and 50%. It is uncertain whether treatment with IUI in a stimulated cycle reduces multiple pregnancy rates compared to control (OR 1.46, 95% CI 0.55 to 3.87; 4 RCTs, 316 women; I<sup2</sup = 0%; low-quality evidence). IUI in a stimulated cycle versus timed intercourse or expectant management in a natural cycle In couples with a low prediction score of natural conception, treatment with IUI combined with clomiphene citrate or letrozole probably results in a higher live birth rate compared to treatment with expectant management in a natural cycle (OR 4.48, 95% CI 2.00 to 10.01; 1 RCT; 201 women; moderate-quality evidence). If we assume the chance of a live birth with expectant management in a natural cycle was 9%, the chance of a live birth with IUI in a stimulated cycle would be between 17% and 50%. It is uncertain whether treatment with IUI in a stimulated cycle results in a lower multiple pregnancy rate compared to control (OR 3.01, 95% CI 0.47 to 19.28; 2 RCTs, 454 women; I<sup2</sup = 0%; low-quality evidence). IUI in a natural cycle versus timed intercourse or expectant management in a stimulated cycle Treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with expectant management in a stimulated cycle (OR 1.95, 95% CI 1.10 to 3.44; 1 RCT, 342 women: moderate-quality evidence). If we assume the chance of a live birth with expectant management in a stimulated cycle was 13%, the chance of a live birth with IUI in a natural cycle would be between 14% and 34%. It is uncertain whether treatment with IUI in a natural cycle results in a lower multiple pregnancy rate compared to control (OR 1.05, 95% CI 0.07 to 16.90; 1 RCT, 342 women; low-quality evidence). IUI in a stimulated cycle versus IUI in a natural cycle Treatment with IUI in a stimulated cycle may result in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle (OR 2.07, 95% CI 1.22 to 3.50; 4 RCTs, 396 women; I<sup2</sup = 0%; low-quality evidence). If we assume the chance of a live birth with IUI in a natural cycle was 14%, the chance of a live birth with IUI in a stimulated cycle would be between 17% and 36%. It is uncertain whether treatment with IUI in a stimulated cycle results in a higher multiple pregnancy rate compared to control (OR 3.00, 95% CI 0.11 to 78.27; 2 RCTs, 65 women; low-quality evidence). Due to insufficient data, it is uncertain whether treatment with IUI with or without OH compared to timed intercourse or expectant management with or without OH improves cumulative live birth rates with acceptable multiple pregnancy rates in couples with unexplained subfertility. However, treatment with IUI with OH probably results in a higher cumulative live birth rate compared to expectant management without OH in couples with a low prediction score of natural conception. Similarly, treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with timed intercourse with OH. Treatment with IUI in a stimulated cycle may result in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle.

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Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition which leads to glucocorticoid deficiency and is the most common cause of adrenal insufficiency in children. In over 90% of cases, 21-hydroxylase enzyme deficiency is found which is caused by mutations in the 21-hydroxylase gene. Managing individuals with CAH due to 21-hydroxylase deficiency involves replacing glucocorticoids with oral glucocorticoids (including prednisolone and hydrocortisone), suppressing adrenocorticotrophic hormones and replacing mineralocorticoids to prevent salt wasting. During childhood, the main aims of treatment are to prevent adrenal crises and to achieve normal stature, optimal adult height and to undergo normal puberty. In adults, treatment aims to prevent adrenal crises, ensure normal fertility and to avoid the long-term consequences of glucocorticoid use. Current glucocorticoid treatment regimens can not optimally replicate the normal physiological cortisol level and over-treatment or under-treatment is often reported. To compare and determine the efficacy and safety of different glucocorticoid replacement regimens in the treatment of CAH due to 21-hydroxylase deficiency in children and adults. We searched the Cochrane Inborn Errors of Metabolism Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews, and trial registries (ClinicalTrials.gov and WHO ICTRP). Date of last search of trials register: 24 June 2019. Randomised controlled trials (RCTs) or quasi-RCTs comparing different glucocorticoid replacement regimens for treating CAH due to 21-hydroxylase deficiency in children and adults. The authors independently extracted and analysed the data from different interventions. They undertook the comparisons separately and used GRADE to assess the quality of the evidence. Searches identified 1729 records with 43 records subject to further examination. After screening, we included five RCTs (six references) with a total of 101 participants and identified a further six ongoing RCTs. The number of participants in each trial varied from six to 44, with participants' ages ranging from 3.6 months to 21 years. Four trials were of cross-over design and one was of parallel design. Duration of treatment ranged from two weeks to six months per treatment arm with an overall follow-up between six and 12 months for all trials. Overall, we judged the quality of the trials to be at moderate to high risk of bias; with lack of methodological detail leading to unclear or high risk of bias judgements across many of the domains. All trials employed an oral glucocorticoid replacement therapy, but with different daily schedules and dose levels. Three trials compared different dose schedules of hydrocortisone (HC), one three-arm trial compared HC to prednisolone (PD) and dexamethasone (DXA) and one trial compared HC with fludrocortisone to PD with fludrocortisone. Due to the heterogeneity of the trials and the limited amount of evidence, we were unable to perform any meta-analyses. No trials reported on quality of life, prevention of adrenal crisis, presence of osteopenia, presence of testicular or ovarian adrenal rest tumours, subfertility or final adult height. Five trials (101 participants) reported androgen normalisation but using different measurements (very low-quality evidence for all measurements). Five trials reported 17 hydroxyprogesterone (17 OHP) levels, four trials reported androstenedione, three trials reported testosterone and one trial reported dehydroepiandrosterone sulphate (DHEAS). After four weeks, results from one trial (15 participants) showed a high morning dose of HC or a high evening dose made little or no difference in 17 OHP, testosterone, androstenedione and DHEAS. One trial (27 participants) found that HC and DXA treatment suppressed 17 OHP and androstenedione more than PD treatment after six weeks and a further trial (eight participants) reported no difference in 17 OHP between the five different dosing schedules of HC at between four and six weeks. One trial (44 participants) comparing HC and PD found no differences in the values of 17 OHP, androstenedione and testosterone at one year. One trial (26 participants) of HC versus HC plus fludrocortisone found that at six months 17 OHP and androstenedione levels were more suppressed on HC alone, but there were no differences noted in testosterone levels. While no trials reported on absolute final adult height, we reported some surrogate markers. Three trials reported on growth and bone maturation and two trials reported on height velocity. One trial found height velocity was reduced at six months in 26 participants given once daily HC 25 mg/m²/day compared to once daily HC 15 mg/m²/day (both groups also received fludrocortisone 0.1 mg/day), but as the quality of the evidence was very low we are unsure whether the variation in HC dose caused the difference. There were no differences noted in growth hormone or IGF1 levels. The results from another trial (44 participants) indicate no difference in growth velocity between HC and PD at one year (very low-quality evidence), but this trial did report that once daily PD treatment may lead to better control of bone maturation compared to HC in prepubertal children and that the absolute change in bone age/chronological age ratio was higher in the HC group compared to the PD group. There are currently limited trials comparing the efficacy and safety of different glucocorticoid replacement regimens for treating 21-hydroxylase deficiency CAH in children and adults and we were unable to draw any firm conclusions based on the evidence that was presented in the included trials. No trials included long-term outcomes such as quality of life, prevention of adrenal crisis, presence of osteopenia, presence of testicular or ovarian adrenal rest tumours, subfertility and final adult height. There were no trials examining a modified-release formulation of HC or use of 24-hour circadian continuous subcutaneous infusion of hydrocortisone. As a consequence, uncertainty remains about the most effective form of glucocorticoid replacement therapy in CAH for children and adults. Future trials should include both children and adults with CAH. A longer duration of follow-up is required to monitor biochemical and clinical outcomes.

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Pine bark (Pinus spp.) extract is rich in bioflavonoids, predominantly proanthocyanidins, which are antioxidants. Commercially-available extract supplements are marketed for preventing or treating various chronic conditions associated with oxidative stress. This is an update of a previously published review. To assess the efficacy and safety of pine bark extract supplements for treating chronic disorders. We searched three databases and three trial registries; latest search: 30 September 2019. We contacted the manufacturers of pine bark extracts to identify additional studies and hand-searched bibliographies of included studies. Randomised controlled trials (RCTs) evaluating pine bark extract supplements in adults or children with any chronic disorder. Two authors independently assessed trial eligibility, extracted data and assessed risk of bias. Where possible, we pooled data in meta-analyses. We used GRADE to evaluate the certainty of evidence. Primary outcomes were participant- and investigator-reported clinical outcomes directly related to each disorder and all-cause mortality. We also assessed adverse events and biomarkers of oxidative stress. This review included 27 RCTs (22 parallel and five cross-over designs; 1641 participants) evaluating pine bark extract supplements across 10 chronic disorders: asthma (two studies; 86 participants); attention deficit hyperactivity disorder (ADHD) (one study; 61 participants), cardiovascular disease (CVD) and risk factors (seven studies; 338 participants), chronic venous insufficiency (CVI) (two studies; 60 participants), diabetes mellitus (DM) (six studies; 339 participants), erectile dysfunction (three studies; 277 participants), female sexual dysfunction (one study; 83 participants), osteoarthritis (three studies; 293 participants), osteopenia (one study; 44 participants) and traumatic brain injury (one study; 60 participants). Two studies exclusively recruited children; the remainder recruited adults. Trials lasted between four weeks and six months. Placebo was the control in 24 studies. Overall risk of bias was low for four, high for one and unclear for 22 studies. In adults with asthma, we do not know whether pine bark extract increases change in forced expiratory volume in one second (FEV<sub1</sub) % predicted/forced vital capacity (FVC) (mean difference (MD) 7.70, 95% confidence interval (CI) 3.19 to 12.21; one study; 44 participants; very low-certainty evidence), increases change in FEV<sub1</sub % predicted (MD 7.00, 95% CI 0.10 to 13.90; one study; 44 participants; very low-certainty evidence), improves asthma symptoms (risk ratio (RR) 1.85, 95% CI 1.32 to 2.58; one study; 60 participants; very low-certainty evidence) or increases the number of people able to stop using albuterol inhalers (RR 6.00, 95% CI 1.97 to 18.25; one study; 60 participants; very low-certainty evidence). In children with ADHD, we do not know whether pine bark extract decreases inattention and hyperactivity assessed by parent- and teacher-rating scales (narrative synthesis; one study; 57 participants; very low-certainty evidence) or increases the change in visual-motoric coordination and concentration (MD 3.37, 95% CI 2.41 to 4.33; one study; 57 participants; very low-certainty evidence). In participants with CVD, we do not know whether pine bark extract decreases diastolic blood pressure (MD -3.00 mm Hg, 95% CI -4.51 to -1.49; one study; 61 participants; very low-certainty evidence); increases HDL cholesterol (MD 0.05 mmol/L, 95% CI -0.01 to 0.11; one study; 61 participants; very low-certainty evidence) or decreases LDL cholesterol (MD -0.03 mmol/L, 95% CI -0.05 to 0.00; one study; 61 participants; very low-certainty evidence). In participants with CVI, we do not know whether pine bark extract decreases pain scores (MD -0.59, 95% CI -1.02 to -0.16; one study; 40 participants; very low-certainty evidence), increases the disappearance of pain (RR 25.0, 95% CI 1.58 to 395.48; one study; 40 participants; very low-certainty evidence) or increases physician-judged treatment efficacy (RR 4.75, 95% CI 1.97 to 11.48; 1 study; 40 participants; very low-certainty evidence). In type 2 DM, we do not know whether pine bark extract leads to a greater reduction in fasting blood glucose (MD 1.0 mmol/L, 95% CI 0.91 to 1.09; one study; 48 participants;very low-certainty evidence) or decreases HbA1c (MD -0.90 %, 95% CI -1.78 to -0.02; 1 study; 48 participants; very low-certainty evidence). In a mixed group of participants with type 1 and type 2 DM we do not know whether pine bark extract decreases HbA1c (MD -0.20 %, 95% CI -1.83 to 1.43; one study; 67 participants; very low-certainty evidence). In men with erectile dysfunction, we do not know whether pine bark extract supplements increase International Index of Erectile Function-5 scores (not pooled; two studies; 147 participants; very low-certainty evidence). In women with sexual dysfunction, we do not know whether pine bark extract increases satisfaction as measured by the Female Sexual Function Index (MD 5.10, 95% CI 3.49 to 6.71; one study; 75 participants; very low-certainty evidence) or leads to a greater reduction of pain scores (MD 4.30, 95% CI 2.69 to 5.91; one study; 75 participants; very low-certainty evidence). In adults with osteoarthritis of the knee, we do not know whether pine bark extract decreases composite Western Ontario and McMaster Universities Osteoarthritis Index scores (MD -730.00, 95% CI -1011.95 to -448.05; one study; 37 participants; very low-certainty evidence) or the use of non-steroidal anti-inflammatory medication (MD -18.30, 95% CI -25.14 to -11.46; one study; 35 participants; very low-certainty evidence). We do not know whether pine bark extract increases bone alkaline phosphatase in post-menopausal women with osteopenia (MD 1.16 ug/L, 95% CI -2.37 to 4.69; one study; 40 participants; very low-certainty evidence). In individuals with traumatic brain injury, we do not know whether pine bark extract decreases cognitive failure scores (MD -2.24, 95% CI -11.17 to 6.69; one study; 56 participants; very low-certainty evidence) or post-concussion symptoms (MD -0.76, 95% CI -5.39 to 3.87; one study; 56 participants; very low-certainty evidence). For most comparisons, studies did not report outcomes of hospital admissions or serious adverse events. Small sample sizes, limited numbers of RCTs per condition, variation in outcome measures, and poor reporting of the included RCTs mean no definitive conclusions regarding the efficacy or safety of pine bark extract supplements are possible.

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Virtual reality (VR) computer technology creates a simulated environment, perceived as comparable to the real world, with which users can actively interact. The effectiveness of VR distraction on acute pain intensity in children is uncertain. To assess the effectiveness and adverse effects of virtual reality (VR) distraction interventions for children (0 to 18 years) with acute pain in any healthcare setting. We searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO and four trial registries to October 2019. We also searched reference lists of eligible studies, handsearched relevant journals and contacted study authors. Randomised controlled trials (RCTs), including cross-over and cluster-RCTs, comparing VR distraction to no distraction, non-VR distraction or other VR distraction. We used standard Cochrane methodological processes. Two reviewers assessed risk of bias and extracted data independently. The primary outcome was acute pain intensity (during procedure, and up to one hour post-procedure). Secondary outcomes were adverse effects, child satisfaction with VR, pain-related distress, parent anxiety, rescue analgesia and cost. We used GRADE and created 'Summary of findings' tables. We included 17 RCTs (1008 participants aged four to 18 years) undergoing various procedures in healthcare settings. We did not pool data because the heterogeneity in population (i.e. diverse ages and developmental stages of children and their different perceptions and reactions to pain) and variations in procedural conditions (e.g. phlebotomy, burn wound dressings, physical therapy sessions), and consequent level of pain experienced, made statistical pooling of data impossible. We narratively describe results. We judged most studies to be at unclear risk of selection bias, high risk of performance and detection bias, and high risk of bias for small sample sizes. Across all comparisons and outcomes, we downgraded the certainty of evidence to low or very low due to serious study limitations and serious or very serious indirectness. We also downgraded some of the evidence for very serious imprecision. 1: VR distraction versus no distraction Acute pain intensity: during procedure Self-report: one study (42 participants) found no beneficial effect of non-immersive VR (very low-certainty evidence). Observer-report: no data. Behavioural measurements (observer-report): two studies, 62 participants; low-certainty evidence. One study (n = 42) found no beneficial effect of non-immersive VR. One study (n = 20) found a beneficial effect favouring immersive VR. Acute pain intensity: post-procedure Self-report: 10 studies, 461 participants; very low-certainty evidence. Four studies (n = 95) found no beneficial effect of immersive and semi-immersive or non-immersive VR. Five studies (n = 357) found a beneficial effect favouring immersive VR. Another study (n = 9) reported less pain in the VR group. Observer-report: two studies (216 participants; low-certainty evidence) found a beneficial effect of immersive VR, as reported by primary caregiver/parents or nurses. One study (n = 80) found a beneficial effect of immersive VR, as reported by researchers. Behavioural measurements (observer-report): one study (42 participants) found no beneficial effect of non-immersive VR (very low-certainty evidence). Adverse effects: five studies, 154 participants; very low-certainty evidence. Three studies (n = 53) reported no adverse effects. Two studies (n = 101) reported mild adverse effects (e.g. nausea) in the VR group. 2: VR distraction versus other non-VR distraction Acute pain intensity: during procedure Self-report, observer-report and behavioural measurements (observer-report): two studies, 106 participants: Self-report: one study (n = 65) found a beneficial effect favouring immersive VR and one (n = 41) found no evidence of a difference in mean pain change scores (very low-certainty evidence). Observer-report: one study (n = 65) found a beneficial effect favouring immersive VR and one (n = 41) found no evidence of a difference in mean pain change scores (low-certainty evidence). Behavioural measurements (observer-report): one study (n = 65) found a beneficial effect favouring immersive VR and one (n = 41) reported a difference in mean pain change scores with fewer pain behaviours in VR group (low-certainty evidence). Acute pain intensity: post-procedure Self-report: eight studies, 575 participants; very low-certainty evidence. Two studies (n = 146) found a beneficial effect favouring immersive VR. Two studies (n = 252) reported a between-group difference favouring immersive VR. One study (n = 59) found no beneficial effect of immersive VR versus television and Child Life non-VR distraction. One study (n = 18) found no beneficial effect of semi-immersive VR. Two studies (n = 100) reported no between-group difference. Observer-report: three studies, 187 participants; low-certainty evidence. One study (n = 81) found a beneficial effect favouring immersive VR for parent, nurse and researcher reports. One study (n = 65) found a beneficial effect favouring immersive VR for caregiver reports. Another study (n = 41) reported no evidence of a difference in mean pain change scores. Behavioural measurements (observer-report): two studies, 106 participants; low-certainty evidence. One study (n = 65) found a beneficial effect favouring immersive VR. Another study (n = 41) reported no evidence of a difference in mean pain change scores. Adverse effects: six studies, 429 participants; very low-certainty evidence. Three studies (n = 229) found no evidence of a difference between groups. Two studies (n = 141) reported no adverse effects in VR group. One study (n = 59) reported no beneficial effect in reducing estimated cyber-sickness before and after VR immersion. 3: VR distraction versus other VR distraction We did not identify any studies for this comparison. We found low-certainty and very low-certainty evidence of the effectiveness of VR distraction compared to no distraction or other non-VR distraction in reducing acute pain intensity in children in any healthcare setting. This level of uncertainty makes it difficult to interpret the benefits or lack of benefits of VR distraction for acute pain in children. Most of the review primary outcomes were assessed by only two or three small studies. We found limited data for adverse effects and other secondary outcomes. Future well-designed, large, high-quality trials may have an important impact on our confidence in the results.

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Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Ultra) are World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. This review builds on our recent extensive Cochrane Review of Xpert MTB/RIF accuracy. To compare the diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for the detection of pulmonary tuberculosis and detection of rifampicin resistance in adults with presumptive pulmonary tuberculosis. For pulmonary tuberculosis and rifampicin resistance, we also investigated potential sources of heterogeneity. We also summarized the frequency of Xpert Ultra trace-positive results, and estimated the accuracy of Xpert Ultra after repeat testing in those with trace-positive results. We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, LILACS, Scopus, the WHO ICTRP, the ISRCTN registry, and ProQuest to 28 January 2020 with no language restriction. We included diagnostic accuracy studies using respiratory specimens in adults with presumptive pulmonary tuberculosis that directly compared the index tests. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based drug susceptibility testing and line probe assays. Two review authors independently extracted data using a standardized form, including data by smear and HIV status. We assessed risk of bias using QUADAS-2 and QUADAS-C. We performed meta-analyses comparing pooled sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection, and separately by reference standard. Most analyses used a bivariate random-effects model. For tuberculosis detection, we estimated accuracy in studies in participants who were not selected based on prior microscopy testing or history of tuberculosis. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarized Xpert Ultra trace results. We identified nine studies (3500 participants): seven had unselected participants (2834 participants). All compared Xpert Ultra and Xpert MTB/RIF for pulmonary tuberculosis detection; seven studies used a paired comparative accuracy design, and two studies used a randomized design. Five studies compared Xpert Ultra and Xpert MTB/RIF for rifampicin resistance detection; four studies used a paired design, and one study used a randomized design. Of the nine included studies, seven (78%) were mainly or exclusively in high tuberculosis burden countries. For pulmonary tuberculosis detection, most studies had low risk of bias in all domains. Pulmonary tuberculosis detection Xpert Ultra pooled sensitivity and specificity (95% credible interval) against culture were 90.9% (86.2 to 94.7) and 95.6% (93.0 to 97.4) (7 studies, 2834 participants; high-certainty evidence) versus Xpert MTB/RIF pooled sensitivity and specificity of 84.7% (78.6 to 89.9) and 98.4% (97.0 to 99.3) (7 studies, 2835 participants; high-certainty evidence). The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at 6.3% (0.1 to 12.8) for sensitivity and -2.7% (-5.7 to -0.5) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss 9 cases, and Xpert MTB/RIF will miss 15 cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 40 with Xpert Ultra and 14 with Xpert MTB/RIF. In smear-negative, culture-positive participants, pooled sensitivity was 77.5% (67.6 to 85.6) for Xpert Ultra versus 60.6% (48.4 to 71.7) for Xpert MTB/RIF; pooled specificity was 95.8% (92.9 to 97.7) for Xpert Ultra versus 98.8% (97.7 to 99.5) for Xpert MTB/RIF (6 studies). In people living with HIV, pooled sensitivity was 87.6% (75.4 to 94.1) for Xpert Ultra versus 74.9% (58.7 to 86.2) for Xpert MTB/RIF; pooled specificity was 92.8% (82.3 to 97.0) for Xpert Ultra versus 99.7% (98.6 to 100.0) for Xpert MTB/RIF (3 studies). In participants with a history of tuberculosis, pooled sensitivity was 84.2% (72.5 to 91.7) for Xpert Ultra versus 81.8% (68.7 to 90.0) for Xpert MTB/RIF; pooled specificity was 88.2% (70.5 to 96.6) for Xpert Ultra versus 97.4% (91.7 to 99.5) for Xpert MTB/RIF (4 studies). The proportion of Ultra trace-positive results ranged from 3.0% to 30.4%. Data were insufficient to estimate the accuracy of Xpert Ultra repeat testing in individuals with initial trace-positive results. Rifampicin resistance detection Pooled sensitivity and specificity were 94.9% (88.9 to 97.9) and 99.1% (97.7 to 99.8) (5 studies, 921 participants; high-certainty evidence) for Xpert Ultra versus 95.3% (90.0 to 98.1) and 98.8% (97.2 to 99.6) (5 studies, 930 participants; high-certainty evidence) for Xpert MTB/RIF. The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at -0.3% (-6.9 to 5.7) for sensitivity and 0.3% (-1.2 to 2.0) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss 5 cases, and Xpert MTB/RIF will miss 5 cases. The number of people wrongly diagnosed with rifampicin resistance would be 8 with Xpert Ultra and 11 with Xpert MTB/RIF. We identified a higher number of rifampicin resistance indeterminate results with Xpert Ultra, pooled proportion 7.6% (2.4 to 21.0) compared to Xpert MTB/RIF pooled proportion 0.8% (0.2 to 2.4). The estimated difference in the pooled proportion of indeterminate rifampicin resistance results for Xpert Ultra versus Xpert MTB/RIF was 6.7% (1.4 to 20.1). Xpert Ultra has higher sensitivity and lower specificity than Xpert MTB/RIF for pulmonary tuberculosis, especially in smear-negative participants and people living with HIV. Xpert Ultra specificity was lower than that of Xpert MTB/RIF in participants with a history of tuberculosis. The sensitivity and specificity trade-off would be expected to vary by setting. For detection of rifampicin resistance, Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity. Ultra trace-positive results were common. Xpert Ultra and Xpert MTB/RIF provide accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multidrug-resistant tuberculosis.

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Asthma affects 350 million people worldwide including 45% to 70% with mild disease. Treatment is mainly with inhalers containing beta₂-agonists, typically taken as required to relieve bronchospasm, and inhaled corticosteroids (ICS) as regular preventive therapy. Poor adherence to regular therapy is common and increases the risk of exacerbations, morbidity and mortality. Fixed-dose combination inhalers containing both a steroid and a fast-acting beta₂-agonist (FABA) in the same device simplify inhalers regimens and ensure symptomatic relief is accompanied by preventative therapy. Their use is established in moderate asthma, but they may also have potential utility in mild asthma. To evaluate the efficacy and safety of single combined (fast-onset beta₂-agonist plus an inhaled corticosteroid (ICS)) inhaler only used as needed in people with mild asthma. We searched the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, ClinicalTrials.gov and the World Health Organization (WHO) trials portal. We contacted trial authors for further information and requested details regarding the possibility of unpublished trials. The most recent search was conducted on 19 March 2021. We included randomised controlled trials (RCTs) and cross-over trials with at least one week washout period. We included studies of a single fixed-dose FABA/ICS inhaler used as required compared with no treatment, placebo, short-acting beta agonist (SABA) as required, regular ICS with SABA as required, regular fixed-dose combination ICS/long-acting beta agonist (LABA), or regular fixed-dose combination ICS/FABA with as required ICS/FABA. We planned to include cluster-randomised trials if the data had been or could be adjusted for clustering. We excluded trials shorter than 12 weeks. We included full texts, abstracts and unpublished data. Two review authors independently extracted data. We analysed dichotomous data as odds ratios (OR) or rate ratios (RR) and continuous data as mean difference (MD). We reported 95% confidence intervals (CIs). We used Cochrane's standard methodological procedures of meta-analysis. We applied the GRADE approach to summarise results and to assess the overall certainty of evidence. Primary outcomes were exacerbations requiring systemic steroids, hospital admissions/emergency department or urgent care visits for asthma, and measures of asthma control. We included six studies of which five contributed results to the meta-analyses. All five used budesonide 200 μg and formoterol 6 μg in a dry powder formulation as the combination inhaler. Comparator fast-acting bronchodilators included terbutaline and formoterol. Two studies included children aged 12+ and adults; two studies were open-label. A total of 9657 participants were included, with a mean age of 36 to 43 years. 2.3% to 11% were current smokers. FABA / ICS as required versus FABA as required Compared with as-required FABA alone, as-required FABA/ICS reduced exacerbations requiring systemic steroids (OR 0.45, 95% CI 0.34 to 0.60, 2 RCTs, 2997 participants, high-certainty evidence), equivalent to 109 people out of 1000 in the FABA alone group experiencing an exacerbation requiring systemic steroids, compared to 52 (95% CI 40 to 68) out of 1000 in the FABA/ICS as-required group. FABA/ICS as required may also reduce the odds of an asthma-related hospital admission or emergency department or urgent care visit (OR 0.35, 95% CI 0.20 to 0.60, 2 RCTs, 2997 participants, low-certainty evidence). Compared with as-required FABA alone, any changes in asthma control or spirometry, though favouring as-required FABA/ICS, were small and less than the minimal clinically-important differences. We did not find evidence of differences in asthma-associated quality of life or mortality. For other secondary outcomes FABA/ICS as required was associated with reductions in fractional exhaled nitric oxide, probably reduces the odds of an adverse event (OR 0.82, 95% CI 0.71 to 0.95, 2 RCTs, 3002 participants, moderate-certainty evidence) and may reduce total systemic steroid dose (MD -9.90, 95% CI -19.38 to -0.42, 1 RCT, 443 participants, low-certainty evidence), and with an increase in the daily inhaled steroid dose (MD 77 μg beclomethasone equiv./day, 95% CI 69 to 84, 2 RCTs, 2554 participants, moderate-certainty evidence). FABA/ICS as required versus regular ICS plus FABA as required There may be little or no difference in the number of people with asthma exacerbations requiring systemic steroid with FABA/ICS as required compared with regular ICS (OR 0.79, 95% CI 0.59 to 1.07, 4 RCTs, 8065 participants, low-certainty evidence), equivalent to 81 people out of 1000 in the regular ICS plus FABA group experiencing an exacerbation requiring systemic steroids, compared to 65 (95% CI 49 to 86) out of 1000 FABA/ICS as required group. The odds of an asthma-related hospital admission or emergency department or urgent care visit may be reduced in those taking FABA/ICS as required (OR 0.63, 95% CI 0.44 to 0.91, 4 RCTs, 8065 participants, low-certainty evidence). Compared with regular ICS, any changes in asthma control, spirometry, peak flow rates (PFR), or asthma-associated quality of life, though favouring regular ICS, were small and less than the minimal clinically important differences (MCID). Adverse events, serious adverse events, total systemic corticosteroid dose and mortality were similar between groups, although deaths were rare, so confidence intervals for this analysis were wide. We found moderate-certainty evidence from four trials involving 7180 participants that FABA/ICS as required was likely associated with less average daily exposure to inhaled corticosteroids than those on regular ICS (MD -154.51 μg/day, 95% CI -207.94 to -101.09). We found FABA/ICS as required is clinically effective in adults and adolescents with mild asthma. Their use instead of FABA as required alone reduced exacerbations, hospital admissions or unscheduled healthcare visits and exposure to systemic corticosteroids and probably reduces adverse events. FABA/ICS as required is as effective as regular ICS and reduced asthma-related hospital admissions or unscheduled healthcare visits, and average exposure to ICS, and is unlikely to be associated with an increase in adverse events. Further research is needed to explore use of FABA/ICS as required in children under 12 years of age, use of other FABA/ICS preparations, and long-term outcomes beyond 52 weeks.

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Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. This is an updated version of a Cochrane Review previously published in 2017. To evaluate primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; and also to evaluate any other drug intervention where there is a sound biological rationale for its use. For the latest update we searched the following databases on 3 February 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 31 January 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including the Cochrane Epilepsy Group. We imposed no language restrictions and contacted researchers to identify continuing or unpublished studies. Trials using randomised or quasi-randomised participant allocation that compared the use of antiepileptics, antipyretics or recognised Central Nervous System active agents with each other, placebo, or no treatment. For the original review, two review authors independently applied predefined criteria to select trials for inclusion and extracted the predefined relevant data, recording methods for randomisation, blinding, and exclusions. For the 2016 update, a third review author checked all original inclusions, data analyses, and updated the search. For the 2020 update, one review author updated the search and performed the data analysis following a peer-review process with the original review authors. We assessed seizure recurrence at 6, 12, 18, 24, 36, 48 months, and where data were available at age 5 to 6 years along with recorded adverse effects. We evaluated the presence of publication bias using funnel plots. We included 42 articles describing 32 randomised trials, with 4431 randomised participants used in the analysis of this review. We analysed 15 interventions of continuous or intermittent prophylaxis and their control treatments. Methodological quality was moderate to poor in most studies. We found no significant benefit for intermittent phenobarbital, phenytoin, valproate, pyridoxine, ibuprofen, or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, paracetamol, or placebo; nor for continuous phenobarbital versus diazepam, intermittent rectal diazepam versus intermittent valproate, or oral diazepam versus clobazam. There was a significant reduction of recurrent febrile seizures with intermittent diazepam versus placebo or no treatment at six months (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.48 to 0.85; 6 studies, 1151 participants; moderate-certainty evidence), 12 months (RR 0.69, 95% CI 0.56 to 0.84; 8 studies, 1416 participants; moderate-certainty evidence), 18 months (RR 0.37, 95% CI 0.23 to 0.60; 1 study, 289 participants; low-certainty evidence), 24 months (RR 0.73, 95% CI 0.56 to 0.95; 4 studies, 739 participants; high-certainty evidence), 36 months (RR 0.58, 95% CI 0.40 to 0.85; 1 study, 139 participants; low-certainty evidence), 48 months (RR 0.36, 95% CI 0.15 to 0.89; 1 study, 110 participants; moderate-certainty evidence), with no benefit at 60 to 72 months (RR 0.08, 95% CI 0.00 to 1.31; 1 study, 60 participants; very low-certainty evidence). Phenobarbital versus placebo or no treatment reduced seizures at six months (RR 0.59, 95% CI 0.42 to 0.83; 6 studies, 833 participants; moderate-certainty evidence), 12 months (RR 0.54, 95% CI 0.42 to 0.70; 7 studies, 807 participants; low-certainty evidence), and 24 months (RR 0.69, 95% CI 0.53 to 0.89; 3 studies, 533 participants; moderate-certainty evidence), but not at 18 months (RR 0.77, 95% CI 0.56 to 1.05; 2 studies, 264 participants) or 60 to 72 months follow-up (RR 1.50, 95% CI 0.61 to 3.69; 1 study, 60 participants; very low-certainty evidence). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64; 1 study, 60 participants; low-certainty evidence), an effect found against an extremely high (83.3%) recurrence rate in the controls, a result that needs replication. When compared to intermittent diazepam, intermittent oral melatonin did not significantly reduce seizures at six months (RR 0.45, 95% CI 0.18 to 1.15; 1 study, 60 participants; very-low certainty evidence). When compared to placebo, intermittent oral levetiracetam significantly reduced recurrent seizures at 12 months (RR 0.27, 95% CI 0.15 to 0.52; 1 study, 115 participants; very low-certainty evidence). The recording of adverse effects was variable. Two studies reported lower comprehension scores in phenobarbital-treated children. Adverse effects were recorded in up to 30% of children in the phenobarbital-treated groups and 36% in benzodiazepine-treated groups. We found evidence of publication bias in the meta-analyses of comparisons for phenobarbital versus placebo (seven studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months. There were too few studies to identify publication bias for the other comparisons. The methodological quality of most of the included studies was low or very low. Methods of randomisation and allocation concealment often did not meet current standards, and 'treatment versus no treatment' was more commonly seen than 'treatment versus placebo', leading to obvious risks of bias.  AUTHORS' CONCLUSIONS: We found reduced recurrence rates for intermittent diazepam and continuous phenobarbital, with adverse effects in up to 30% of children. The apparent benefit for clobazam treatment in one trial needs to be replicated. Levetiracetam also shows benefit with a good safety profile; however, further study is required. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management, and, most importantly, the benign nature of the phenomenon.

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Maternal complications, including psychological/mental health problems and neonatal morbidity, have commonly been observed in the postpartum period. Home visits by health professionals or lay supporters in the weeks following birth may prevent health problems from becoming chronic, with long-term effects. This is an update of a review last published in 2017. The primary objective of this review is to assess the effects of different home-visiting schedules on maternal and newborn mortality during the early postpartum period. The review focuses on the frequency of home visits (how many home visits in total), the timing (when visits started, e.g. within 48 hours of the birth), duration (when visits ended), intensity (how many visits per week), and different types of home-visiting interventions. For this update, we searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (19 May 2021), and checked reference lists of retrieved studies. Randomised controlled trials (RCTs) (including cluster-, quasi-RCTs and studies available only as abstracts) comparing different home-visiting interventions that enrolled participants in the early postpartum period (up to 42 days after birth) were eligible for inclusion. We excluded studies in which women were enrolled and received an intervention during the antenatal period (even if the intervention continued into the postnatal period), and studies recruiting only women from specific high-risk groups (e.g. women with alcohol or drug problems). Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We used the GRADE approach to assess the certainty of the evidence. We included 16 randomised trials with data for 12,080 women. The trials were carried out in countries across the world, in both high- and low-resource settings. In low-resource settings, women receiving usual care may have received no additional postnatal care after early hospital discharge. The interventions and controls varied considerably across studies. Trials focused on three broad types of comparisons, as detailed below. In all but four of the included studies, postnatal care at home was delivered by healthcare professionals. The aim of all interventions was broadly to assess the well-being of mothers and babies, and to provide education and support. However, some interventions had more specific aims, such as to encourage breastfeeding, or to provide practical support. For most of our outcomes, only one or two studies provided data, and results were inconsistent overall. All studies had several domains with high or unclear risk of bias. More versus fewer home visits (five studies, 2102 women) The evidence is very uncertain about whether home visits have any effect on maternal and neonatal mortality (very low-certainty evidence). Mean postnatal depression scores as measured with the Edinburgh Postnatal Depression Scale (EPDS) may be slightly higher (worse) with more home visits, though the difference in scores was not clinically meaningful (mean difference (MD) 1.02, 95% confidence interval (CI) 0.25 to 1.79; two studies, 767 women; low-certainty evidence). Two separate analyses indicated conflicting results for maternal satisfaction (both low-certainty evidence); one indicated that there may be benefit with fewer visits, though the 95% CI just crossed the line of no effect (risk ratio (RR) 0.96, 95% CI 0.90 to 1.02; two studies, 862 women). However, in another study, the additional support provided by health visitors was associated with increased mean satisfaction scores (MD 14.70, 95% CI 8.43 to 20.97; one study, 280 women; low-certainty evidence). Infant healthcare utilisation may be decreased with more home visits (RR 0.48, 95% CI 0.36 to 0.64; four studies, 1365 infants) and exclusive breastfeeding at six weeks may be increased (RR 1.17, 95% CI 1.01 to 1.36; three studies, 960 women; low-certainty evidence). Serious neonatal morbidity up to six months was not reported in any trial. Different models of postnatal care (three studies, 4394 women) In a cluster-RCT comparing usual care with individualised care by midwives, extended up to three months after the birth, there may be little or no difference in neonatal mortality (RR 0.97, 95% CI 0.85 to 1.12; one study, 696 infants). The proportion of women with EPDS scores ≥ 13 at four months is probably reduced with individualised care (RR 0.68, 95% CI 0.53 to 0.86; one study, 1295 women). One study suggests there may be little to no difference between home visits and telephone screening in neonatal morbidity up to 28 days (RR 0.97, 95% CI 0.85 to 1.12; one study, 696 women). In a different study, there was no difference between breastfeeding promotion and routine visits in exclusive breastfeeding rates at six months (RR 1.47, 95% CI 0.81 to 2.69; one study, 656 women). Home versus facility-based postnatal care (eight studies, 5179 women) The evidence suggests there may be little to no difference in postnatal depression rates at 42 days postpartum and also as measured on an EPDS scale at 60 days. Maternal satisfaction with postnatal care may be better with home visits (RR 1.36, 95% CI 1.14 to 1.62; three studies, 2368 women). There may be little to no difference in infant emergency health care visits or infant hospital readmissions (RR 1.15, 95% CI 0.95 to 1.38; three studies, 3257 women) or in exclusive breastfeeding at two weeks (RR 1.05, 95% CI 0.93 to 1.18; 1 study, 513 women). The evidence is very uncertain about the effect of home visits on maternal and neonatal mortality. Individualised care as part of a package of home visits probably improves depression scores at four months and increasing the frequency of home visits may improve exclusive breastfeeding rates and infant healthcare utilisation. Maternal satisfaction may also be better with home visits compared to hospital check-ups. Overall, the certainty of evidence was found to be low and findings were not consistent among studies and comparisons. Further well designed RCTs evaluating this complex intervention will be required to formulate the optimal package.

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<bObjective:</b To investigate the effects of exosomes from human adipose-derived mesenchymal stem cells (ADSCs) on pulmonary vascular endothelial cells (PMVECs) injury in septic mice and its mechanism. <bMethods:</b The experimental research method was adopted. The primary ADSCs were isolated and cultured from the discarded fresh adipose tissue of 3 patients (female, 10-25 years old), who were admitted to the First Affiliated Hospital of Air Force Medical University undergoing abdominal surgery, and the cell morphology was observed by inverted phase contrast microscope on the 5<supth</sup day. The expressions of CD29, CD34, CD44, CD45, CD73, and CD90 of ADSCs in the third passage were detected by flow cytometry. The third to the fifth passage of ADSCs were collected, and their exosomes from the cell supernatant were obtained by differential ultracentrifugation, and the shape, particle size, and the protein expressions of CD9, CD63, tumor susceptibility gene 101 (TSG101), and β-actin of exosomes were detected, respectively, by transmission electron microscopy, nano-particle tracking analysis and Western blotting. Twenty-four adult male BALB/c mice were adopted and were divided into normal control group, caecal ligation perforation (CLP) alone group, and CLP+ADSC-exosome group with each group of 8 according to random number table (the same grouping method below) and were treated accordingly. At 24 h after operation, tumor necrosis factor (TNF-α) and interleukin 1β (IL-1β) levels of mice serum were detected by enzyme-linked immunosorbent assay, and lung tissue morphology of mice was detected by hematoxylin-eosin and myeloperoxidase staining, and the expression of 8-hydroxy-deoxyguanosine (8-OHdG) of mouse lung cells was detected by immunofluorescence method. Primary PMVECs were obtained from 1-month-old C57 mice regardless gender by tissue block method. The expression of CD31 of PMVECs was detected by immunofluorescence and flow cytometry. The third passage of PMVECs was co-cultured with ADSCs derived exosomes for 12 h, and the phagocytosis of exosomes by PMVECs was detected by PKH26 kit. The third passage of PMVECs were adopted and were divided into blank control group, macrophage supernatant alone group, and macrophage supernatant+ADSC-exosome group, with 3 wells in each group, which were treated accordingly. After 24 h, the content of reactive oxygen species in cells was detected by flow cytometry, the expression of 8-OHdG in cells was detected by immunofluorescence, and Transwell assay was used to determine the permeability of cell monolayer. The number of samples in above were all 3. Data were statistically analyzed with one-way analysis of variance and least significant difference <it</i test. <bResults:</b The primary ADSCs were isolated and cultured to day 5, growing densely in a spindle shape with a typical swirl-like. The percentages of CD29, CD44, CD73 and CD90 positive cells of ADSCs in the third passage were all &gt;90%, and the percentages of CD34 and CD45 positive cells were &lt;5%. Exosomes derived from ADSCs of the third to fifth passages showed a typical double-cavity disc-like structure with an average particle size of 103 nm, and the protein expressions of CD9, CD63 and TSG101 of exosomes were positive, while the protein expression of β-actin of exosomes was negative. At 24 h after operation, compared with those in normal control group, both the levels of TNF-α and IL-1β of mice serum in CLP alone group were significantly increased (with <it</i values of 28.76 and 29.69, respectively, <iP</i&lt;0.01); compared with those in CLP alone group, both the content of TNF-α and IL-1β of mice serum in CLP+ADSC-exosome group was significantly decreased (with <it</i values of 9.90 and 4.76, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01). At 24 h after surgery, the pulmonary tissue structure of mice in normal control group was clear and complete without inflammatory cell infiltration; compared with those in normal control group, the pulmonary tissue edema and inflammatory cell infiltration of mice in CLP alone group were more obvious; compared with those in CLP alone group, the pulmonary tissue edema and inflammatory cell infiltration of mice in CLP+ADSC-exosome group were significantly reduced. At 24 h after operation, endothelial cells in lung tissues of mice in 3 groups showed positive expression of CD31; compared with that in normal control group, the fluorescence intensity of 8-OHdG positive cells of the lung tissues of mice in CLP alone group was significantly increased, and compared with that in CLP alone group, the fluorescence intensity of 8-OHdG positive cells in the lung tissues of mice in CLP+ADSC-exosome group was significantly decreased. The PMVECs in the 3<suprd</sup passage showed CD31 positive expression by immunofluorescence, and the result of flow cytometry showed that CD31 positive cells accounted for 99.5%. At 12 h after co-culture, ADSC-derived exosomes were successfully phagocytose by PMVECs and entered its cytoplasm. At 12 h after culture of the third passage of PMVECs, compared with that in blank control group, the fluorescence intensity of reactive oxygen species of PMVECs in macrophage supernatant alone group was significantly increased (<it</i=15.73, <iP</i&lt;0.01); compared with that in macrophage supernatant alone group, the fluorescence intensity of reactive oxygen species of PMVECs in macrophage supernatant+ADSC-exosome group was significantly decreased (<it</i=4.72, <iP</i&lt;0.01). At 12 h after culture of the third passage of PMVECs, and the 8-OHdG positive fluorescence intensity of PMVECs in macrophage supernatant alone group was significantly increased; and compared with that in blank control group, the 8-OHdG positive fluorescence intensity of PMVECs in macrophage+ADSC-exosome supernatant group was between blank control group and macrophage supernatant alone group. At 12 h after culture of the third passage PMVECs, compared with that in blank control group, the permeability of PMVECs monolayer in macrophage supernatant alone group was significantly increased (<it</i=6.34, <iP</i&lt;0.01); compared with that in macrophage supernatant alone group, the permeability of PMVECs monolayer cells in macrophage supernatant+ADSC-exosome group was significantly decreased (<it</i=2.93, <iP</i&lt;0.05). <bConclusions:</b Exosomes derived from ADSCs can ameliorate oxidative damage in mouse lung tissue, decrease the level of reactive oxygen species, 8-OHdG expression, and permeability of PMVECs induced by macrophage supernatant.

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To date, very few studies have been conducted on the neurodevelopmental well-being of children conceived through intracytoplasmic sperm injection (ICSI). The limitations of these studies often include a lack of comparison with a demographically matched, naturally conceived (NC) group and the investigation of only very young children, with relatively small samples sizes. One study showed that there were no differences in IQ scores among ICSI-conceived, in vitro fertilization (IVF)-conceived, and NC children at 5 years of age. Unfortunately, psychomotor development was not assessed in that study. Because findings regarding these children's cognitive and motor development are inconclusive, the aim of this study was to shed more light on the cognitive and motor development of 5-year-old ICSI-conceived children. A total of 511 ICSI-conceived children were compared with 424 IVF-conceived children and 488 NC controls. Children were recruited in 5 European countries, ie, Belgium, Denmark, Greece, Sweden, and the United Kingdom. Participation rates ranged from 45% to 96% in the ICSI and IVF groups and from 34% to 78% in the NC group. Cognitive and motor development was assessed with the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) and McCarthy Scales of Children's Abilities (MSCA) Motor Scale, respectively. The WPPSI-R consists of 2 major scales, ie, Verbal and Performance, each including 6 subtests. The 6 Performance Scale subtests are object assembly, geometric design, block design, mazes, picture completion, and animal pegs. The 6 Verbal Scale subtests are information, comprehension, arithmetic, vocabulary, similarities, and sentences. Scores on the Performance and Verbal Scale subtests are summed to yield the performance IQ (PIQ) and verbal IQ (VIQ), respectively. Scores on both the Performance Scale and the Verbal Scale yield the full-scale IQ (FSIQ). IQ scales have a mean score of 100 and a SD of 15. Each subtest has a mean score of 10 and a SD of 3. The MSCA consists of 6 scales, ie, Verbal, Perceptual-Performance, Quantitative, General Cognitive, Memory, and Motor Scale. In this study, only the Motor Scale was administered. This scale assesses the child's coordination during performance of a variety of gross- and fine-motor tasks. Leg coordination, arm coordination, and imitative action tests provide measures of gross-motor ability. Draw-a-design and draw-a-child assess fine-motor coordination, as revealed by the levels of hand coordination and finger dexterity. The mean score for this test is 50, with a SD of . No differences were identified among ICSI, IVF, and NC children with respect to VIQ, PIQ, or FSIQ scores of the WPPSI-R. Furthermore, there were no differences between groups regarding the discrepancy between VIQ and PIQ scores. These results were not influenced by gender, country, or maternal educational level. However, in the subgroup of firstborn children with mothers who gave birth at an older age (33-45 years), NC children obtained significantly better VIQ and FSIQ scores than did children conceived through assisted reproductive technologies. These differences in VIQ and FSIQ scores between ICSI/IVF and NC children were relative, because NC children scored &lt;1 IQ point higher than ICSI/IVF children. Therefore, these scores show no clinical relevance. For Verbal Scale subtests, variables such as age of the mother at the time of the birth, educational level of the mother, and gender and nationality of the child interacted with mode of conception, resulting in clinically irrelevant differences between scores for the ICSI/IVF and NC groups on the arithmetic, vocabulary, and comprehension subtests. For Performance Scale subtests, these same demographic factors interacted with mode of conception for the block design, object assembly, and animal pegs subtests, again resulting in clinically irrelevant differences among groups. In the 3 groups (ICSI, IVF, and NC), we observed equal numbers of children scoring below 1 SD from the mean on the WPPSI-R and the MSCA. This study includes a substantial number of children from several European countries. Apart from a few interaction effects between mode of conception and demographic variables, no differences were found when ICSI, IVF, and NC scores on the WPPSI-R and MSCA Motor Scale were compared. Nevertheless, the aforementioned interaction effects could indicate that demographic variables such as maternal age at the time of the birth and maternal educational level play different roles in the cognitive development of IVF and ICSI children, compared with NC children. Additional research is needed to explore and verify this finding. Previous studies revealed that ICSI children, in comparison with NC children, more frequently obtained scores below 1 SD from the mean on 3 subtests of the Performance Scale (object assembly, block design, and mazes) or showed a trend of 5.2% of ICSI children, compared with 2.5% of IVF children and 0.9% of NC children, obtaining a score below 1 SD from the mean, but those findings were not confirmed in this study. Here no differences were found among the 3 groups in the numbers of children scoring below 1 SD from the mean on the VIQ, PIQ, and FSIQ tests and the Verbal and Performance Scale subtests. Motor development results were somewhat more conclusive. There were no differences between the scores of ICSI, IVF, and NC children on the MCSA Motor Scale. No interaction effects were found between mode of conception and demographic variables, indicating that these results are not influenced by gender, nationality, maternal educational level, or maternal age at the time of the birth. Furthermore, equal proportions of children in all 3 groups scored below 1 SD from the mean. The results of this study are reassuring for parents who conceived through ICSI (or IVF). The findings indicate that the motor and cognitive development of their offspring is very similar to that of NC children. However, demographic factors such as maternal educational level and maternal age at the time of the birth might play different roles in the cognitive development of ICSI and IVF children, compared with NC children.

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This publication presents the 2005 American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) of the pediatric patient and the 2005 American Academy of Pediatrics/AHA guidelines for CPR and ECC of the neonate. The guidelines are based on the evidence evaluation from the 2005 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, hosted by the American Heart Association in Dallas, Texas, January 23-30, 2005. The "2005 AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care" contain recommendations designed to improve survival from sudden cardiac arrest and acute life-threatening cardiopulmonary problems. The evidence evaluation process that was the basis for these guidelines was accomplished in collaboration with the International Liaison Committee on Resuscitation (ILCOR). The ILCOR process is described in more detail in the "International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations." The recommendations in the "2005 AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care" confirm the safety and effectiveness of many approaches, acknowledge that other approaches may not be optimal, and recommend new treatments that have undergone evidence evaluation. These new recommendations do not imply that care involving the use of earlier guidelines is unsafe. In addition, it is important to note that these guidelines will not apply to all rescuers and all victims in all situations. The leader of a resuscitation attempt may need to adapt application of the guidelines to unique circumstances. The following are the major pediatric advanced life support changes in the 2005 guidelines: There is further caution about the use of endotracheal tubes. Laryngeal mask airways are acceptable when used by experienced providers. Cuffed endotracheal tubes may be used in infants (except newborns) and children in in-hospital settings provided that cuff inflation pressure is kept &lt;20 cm H2O. Confirmation of tube placement requires clinical assessment and assessment of exhaled carbon dioxide (CO2); esophageal detector devices may be considered for use in children weighing &gt;20 kg who have a perfusing rhythm. Correct placement must be verified when the tube is inserted, during transport, and whenever the patient is moved. During CPR with an advanced airway in place, rescuers will no longer perform "cycles" of CPR. Instead, the rescuer performing chest compressions will perform them continuously at a rate of 100/minute without pauses for ventilation. The rescuer providing ventilation will deliver 8 to 10 breaths per minute (1 breath approximately every 6-8 seconds). Timing of 1 shock, CPR, and drug administration during pulseless arrest has changed and now is identical to that for advanced cardiac life support. Routine use of high-dose epinephrine is not recommended. Lidocaine is de-emphasized, but it can be used for treatment of ventricular fibrillation/pulseless ventricular tachycardia if amiodarone is not available. Induced hypothermia (32-34 degrees C for 12-24 hours) may be considered if the child remains comatose after resuscitation. Indications for the use of inodilators are mentioned in the postresuscitation section. Termination of resuscitative efforts is discussed. It is noted that intact survival has been reported following prolonged resuscitation and absence of spontaneous circulation despite 2 doses of epinephrine. The following are the major neonatal resuscitation changes in the 2005 guidelines: Supplementary oxygen is recommended whenever positive-pressure ventilation is indicated for resuscitation; free-flow oxygen should be administered to infants who are breathing but have central cyanosis. Although the standard approach to resuscitation is to use 100% oxygen, it is reasonable to begin resuscitation with an oxygen concentration of less than 100% or to start with no supplementary oxygen (ie, start with room air). If the clinician begins resuscitation with room air, it is recommended that supplementary oxygen be available to use if there is no appreciable improvement within 90 seconds after birth. In situations where supplementary oxygen is not readily available, positive-pressure ventilation should be administered with room air. Current recommendations no longer advise routine intrapartum oropharyngeal and nasopharyngeal suctioning for infants born to mothers with meconium staining of amniotic fluid. Endotracheal suctioning for infants who are not vigorous should be performed immediately after birth. A self-inflating bag, a flow-inflating bag, or a T-piece (a valved mechanical device designed to regulate pressure and limit flow) can be used to ventilate a newborn. An increase in heart rate is the primary sign of improved ventilation during resuscitation. Exhaled CO2 detection is the recommended primary technique to confirm correct endotracheal tube placement when a prompt increase in heart rate does not occur after intubation. The recommended intravenous (IV) epinephrine dose is 0.01 to 0.03 mg/kg per dose. Higher IV doses are not recommended, and IV administration is the preferred route. Although access is being obtained, administration of a higher dose (up to 0.1 mg/kg) through the endotracheal tube may be considered. It is possible to identify conditions associated with high mortality and poor outcome in which withholding resuscitative efforts may be considered reasonable, particularly when there has been the opportunity for parental agreement. The following guidelines must be interpreted according to current regional outcomes: When gestation, birth weight, or congenital anomalies are associated with almost certain early death and when unacceptably high morbidity is likely among the rare survivors, resuscitation is not indicated. Examples are provided in the guidelines. In conditions associated with a high rate of survival and acceptable morbidity, resuscitation is nearly always indicated. In conditions associated with uncertain prognosis in which survival is borderline, the morbidity rate is relatively high, and the anticipated burden to the child is high, parental desires concerning initiation of resuscitation should be supported. Infants without signs of life (no heartbeat and no respiratory effort) after 10 minutes of resuscitation show either a high mortality rate or severe neurodevelopmental disability. After 10 minutes of continuous and adequate resuscitative efforts, discontinuation of resuscitation may be justified if there are no signs of life.

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Although the function of rhythmic contractions in the vascular wall - vasomotion - is still under debate, it has been suggested to play a significant role for tissue oxygen homeostasis and under pathological conditions where tissue perfusion is affected. Vasomotion has further been suggested to be important for blood pressure control and has been shown to be reduced in diabetes. Vasomotion is initiated by the coordinated activation of smooth muscle cells (SMCs) in the vascular wall leading to rhythmic contractions. We have suggested the model for generation of this rhythmic activity and have shown that vasomotion initiates via interaction between intracellular calcium released from the sarcoplasmic reticulum and changes in membrane potential. Rhythmic changes in intracellular calcium induce, under certain conditions (in the presence of sufficient concentration of cGMP), changes in membrane potential that lock the electrically-connected SMCs into phase. Synchronized depolarization induces synchronous calcium influx and thus produces rhythmic contraction of blood vessels. I have demonstrated and characterized a new chloride channel in vascular SMCs, which has properties necessary to coordinate SMCs in the vascular wall. Chloride channels have been investigated for many years but remained somewhat in the shadow of cation channels. We know now the molecular structures of some chloride channels, i.e. GABA receptors, "cystic fibrosis transmem-brane conductance regulator" (CFTR) and the ClC chloride channel family. There is one particular group of chloride channels, the calcium activated chloride channels (CaCCs), whose molecular structure is debated still. There are currently no pharmacological tools that activate or inhibit CaCCs with any significant selectivity. The existence of CaCCs in almost all cells in the body has been known for many years based on electrophysiological and other functional studies. CaCCs have been suggested to be important for regulation of membrane potential and cellular volume, as well as for body homeostasis. CaCCs are well characterized in vascular tissues but only at the functional level. The lack of their molecular structure makes it difficult to study the clinical significance of these channels. Based on patch clamp measurements of ion currents, I have previously characterized in SMCs a chloride current with unique properties. This chloride current activated by cGMP, has very high sensitivity to calcium and can be inhibited by low concentrations of zinc ions, while the traditional inhibitors of CaCCs affect this current only at very high concentrations. This cGMP-dependent, calcium-activated chloride current has a linear volt-age-dependence, which differs from previously characterized CaCCs, and it has characteristic anion permeability. This current has been detected in SMCs isolated from a number of different vascular beds but, importantly, it has not been detected in pulmonary arteries. Moreover, this current has been shown in SMCs isolated intestine indicating its broad distribution. Based on unique characteristics I have suggested that the cGMP-dependent calcium-activated chloride current can synchronize SMCs in the vascular wall and that bestrophin protein could be the molecular substrate for this current. Bestrophin has been characterized first as a gene in which mutations cause vitelliform macular dystrophy (VMD) or Best diseases. Based on heterologous expression it has been suggested that bestrophin is a chloride channel. This question is nevertheless controversial since caution should be taken in heterologous expression of calcium-activated chloride channel candidates. The presence of chloride channels in virtually all living cells is an essential problem as well as the dependence of ion channel properties on the complex interaction of many cellular proteins. I was the first who coupled the endogenous chloride current to one of four known bestrophin isoforms. PCR and Western blot studies on different blood vessels demonstrated the presence of bestrophin-3 protein with the exception of pulmonary arteries where the cGMP-dependent current is also absent). There was a strong indication that bestrophin-3 expression could be essential for the cGMP-dependent calcium-activated chloride current. To couple bestrophin-3 expression and this current I have used small interfering RNA (siRNA) technique to downregulate the expression of the candidate (bestrophin-3) and have studied the effect of this specific downregulation on chloride currents. I showed that bestrophin-3 expression is associated with the cGMP-dependent calcium-activated chloride current. This study does not tell us whether bestrophin-3 forms the channel or it is an essential subunit but the previous mutagenic experiments suggested the first possibility. Electrical communication between SMCs is essential for successful synchronization and depends on channels between the cells called gap junctions. The majority of cardiovascular diseases (e.g. hypertension and atherosclerosis) are associated with defects in intercellular communications or in gap junction regulation. The molecular mechanisms responsible for these defects are un-known because of lack of specific experimental tools. Our comprehensive study on the often used gap junction inhibitors heptanol and 18β-glycyrrhetinic acid demonstrated unspecific effects of these drugs at the concentrations where they have no or little gap junctions effects. Other drugs, e.g. 18α-glycyrrhetinic acid and connexin-mimetic peptides are better to inhibit gap junctions but also have demonstrated unspecific effects. Previous studies suggested that channels and transporters in the cell membrane do not function independently but interact as functional units in the spatially restricted areas of the cell. I have demonstrated a close functional interaction between gap junctions and Na+,K+-ATPase, Na+/Ca2+-exchanger and ATP-dependent K+ channels in the spatially restricted manner. I have shown that inhibition of the ouabain-sensitive Na+, K+-ATPase inhibits calcium efflux by the Na+/Ca2+-exchanger and this leads to the local elevation of intracellular calcium and inhibition of intercellular communications. This explains the inhibitory action of ouabain on vasomotion. I have also found that the ATP-dependent K+ channel is an important player in this functional unit and this interaction is reciprocal, since K+ channel supplies Na+, K+-ATPase with K+ ions while the ATP-dependent K+ channel current also regulates the Na+, K+-ATPase. This dissertation is based on nine scientific publications where I have suggested the model for generation of vasomotion and characterized the essential elements of this model.

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Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell transfusions.Repeated transfusions result in an excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. Desferrioxamine mesylate (desferrioxamine) is one of the most widely used iron chelators. Substantial data have shown the beneficial effects of desferrioxamine, although adherence to desferrioxamine therapy is a challenge. Alternative oral iron chelators, deferiprone and deferasirox, are now commonly used. Important questions exist about whether desferrioxamine, as monotherapy or in combination with an oral iron chelator, is the best treatment for iron chelation therapy. To determine the effectiveness (dose and method of administration) of desferrioxamine in people with transfusion-dependent thalassaemia.To summarise data from trials on the clinical efficacy and safety of desferrioxamine for thalassaemia and to compare these with deferiprone and deferasirox. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched MEDLINE, EMBASE, CENTRAL (The Cochrane Library), LILACS and other international medical databases, plus ongoing trials registers and the Transfusion Evidence Library (www.transfusionevidencelibrary.com). All searches were updated to 5 March 2013. Randomised controlled trials comparing desferrioxamine with placebo, with another iron chelator, or comparing two schedules or doses of desferrioxamine, in people with transfusion-dependent thalassaemia. Six authors working independently were involved in trial quality assessment and data extraction. For one trial, investigators supplied additional data upon request. A total of 22 trials involving 2187 participants (range 11 to 586 people) were included. These trials included eight comparisons between desferrioxamine alone and deferiprone alone; five comparisons between desferrioxamine combined with deferiprone and deferiprone alone; eight comparisons between desferrioxamine alone and desferrioxamine combined with deferiprone; two comparisons of desferrioxamine with deferasirox; and two comparisons of different routes of desferrioxamine administration (bolus versus continuous infusion). Overall, few trials measured the same or long-term outcomes. Seven trials reported cardiac function or liver fibrosis as measures of end organ damage; none of these included a comparison with deferasirox.Five trials reported a total of seven deaths; three in patients who received desferrioxamine alone, two in patients who received desferrioxamine and deferiprone. A further death occurred in a patient who received deferiprone in another who received deferasirox alone. One trial reported five further deaths in patients who withdrew from randomised treatment (deferiprone with or without desferrioxamine) and switched to desferrioxamine alone.One trial planned five years of follow up but was stopped early due to the beneficial effects of a reduction in serum ferritin levels in those receiving combined desferrioxamine and deferiprone treatment compared with deferiprone alone. The results of this and three other trials suggest an advantage of combined therapy with desferrioxamine and deferiprone over monotherapy to reduce iron stores as measured by serum ferritin. There is, however, no evidence for the improved efficacy of combined desferrioxamine and deferiprone therapy against monotherapy from direct or indirect measures of liver iron.Earlier trials measuring the cardiac iron load indirectly by measurement of the magnetic resonance imaging T2* signal had suggested deferiprone may reduce cardiac iron more quickly than desferrioxamine. However, meta-analysis of two trials showed a significantly lower left ventricular ejection fraction in patients who received desferrioxamine alone compared with those who received combination therapy using desferrioxamine with deferiprone.Adverse events were recorded by 18 trials. These occurred with all treatments, but were significantly less likely with desferrioxamine than deferiprone in one trial, relative risk 0.45 (95% confidence interval 0.24 to 0.84) and significantly less likely with desferrioxamine alone than desferrioxamine combined with deferiprone in two other trials, relative risk 0.33 (95% confidence interval 0.13 to 0.84). In particular, four studies reported permanent treatment withdrawal due to adverse events from deferiprone; only one of these reported permanent withdrawals associated with desferrioxamine. Adverse events also occurred at a higher frequency in patients who received deferasirox than desferrioxamine in one trial. Eight trials reported local adverse reactions at the site of desferrioxamine infusion including pain and swelling. Adverse events associated with deferiprone included joint pain, gastrointestinal disturbance, increases in liver enzymes and neutropenia; adverse events associated with deferasirox comprised increases in liver enzymes and renal impairment. Regular monitoring of white cell counts has been recommended for deferiprone and monitoring of liver and renal function for deferasirox.In summary, desferrioxamine and the oral iron chelators deferiprone and deferasirox produce significant reductions in iron stores in transfusion-dependent, iron-overloaded people. There is no evidence from randomised clinical trials to suggest that any one of these has a greater reduction of clinically significant end organ damage, although in two trials, combination therapy with desferrioxamine and deferiprone showed a greater improvement in left ventricular ejection fraction than desferrioxamine used alone. Desferrioxamine is the recommended first-line therapy for iron overload in people with thalassaemia major and deferiprone or deferasirox are indicated for treating iron overload when desferrioxamine is contraindicated or inadequate. Oral deferasirox has been licensed for use in children aged over six years who receive frequent blood transfusions and in children aged two to five years who receive infrequent blood transfusions. In the absence of randomised controlled trials with long-term follow up, there is no compelling evidence to change this conclusion.Worsening iron deposition in the myocardium in patients receiving desferrioxamine alone would suggest a change of therapy by intensification of desferrioxamine treatment or the use of desferrioxamine and deferiprone combination therapy.Adverse events are increased in patients treated with deferiprone compared with desferrioxamine and in patients treated with combined deferiprone and desferrioxamine compared with desferrioxamine alone. People treated with all chelators must be kept under close medical supervision and treatment with deferiprone or deferasirox requires regular monitoring of neutrophil counts or renal function respectively. There is an urgent need for adequately-powered, high-quality trials comparing the overall clinical efficacy and long-term outcomes of deferiprone, deferasirox and desferrioxamine.

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Fractures of the femoral shaft in children are relatively uncommon but serious injuries that disrupt the lives of children and their carers and can result in significant long-term disability. Treatment involves either surgical fixation, such as intramedullary nailing or external fixation, or conservative treatment involving prolonged immobilisation, often in hospital. To assess the effects (benefits and harms) of interventions for treating femoral shaft fractures in children and adolescents. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (accessed 16 August 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013 Issue 7), MEDLINE (1946 to August Week 1 2013), EMBASE (1980 to 2012 week 9), CINAHL (16 August 2013), clinical trials registries, conference proceedings and reference lists; and contacted trial authors and experts in the field. Randomised and quasi-randomised controlled trials comparing conservative and surgical interventions for diaphyseal fractures of the femur in children under 18 years of age. Our primary outcomes were functional outcome measures, unacceptable malunion, and serious adverse events. Two authors independently screened and selected trials, assessed risk of bias and extracted data. We assessed the overall quality of the evidence for each outcome for each comparison using the GRADE approach. We pooled data using a fixed-effect model. We included 10 trials (six randomised and four quasi-randomised) involving a total of 527 children (531 fractures). All trials were at some risk of bias, including performance bias as care provider blinding was not practical, but to a differing extent. Just one trial was at low risk of selection bias. Reflecting both the risk of bias and the imprecision of findings, we judged the quality of evidence to be 'low' for most outcomes, meaning that we are unsure about the estimates of effect. Most trials failed to report on self-assessed function or when children resumed their usual activities. The trials evaluated 10 different comparisons, belonging to three main categories. Surgical versus conservative treatment Four trials presenting data for 264 children aged 4 to 12 years made this comparison. Low quality evidence (one trial, 101 children) showed children had very similar function assessed using the RAND health status score at two years after surgery (external fixation) compared with conservative treatment (spica cast): mean 69 versus 68. The other three trials did not report on function. There was moderate quality evidence (four trials, 264 children, aged 4 to 12 years, followed up 3 to 24 months) that surgery reduced the risk of malunion (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.15 to 0.59, 4 trials). Assuming an illustrative baseline risk of 115 malunions per 1000 in children treated conservatively, these data equate to 81 fewer (95% CI 47 to 97 fewer) malunions per 1000 in surgically-treated children. Conversely, low quality evidence indicated that there were more serious adverse events such as infections after surgery (RR 2.39, 95% CI 1.10 to 5.17, 4 trials). Assuming an illustrative baseline risk of 40 serious adverse events per 1000 for conservative treatment, these data equate to 56 more (95% CI 4 to 167 more) serious adverse events per 1000 children treated surgically. There was low quality evidence (one trial, 101 children) of similar satisfaction levels in children and parents with surgery involving external fixation and plaster cast only. However, there was low quality evidence (one trial, 46 children) that more parents were satisfied with intramedullary nailing than with traction followed by a cast, and that surgery reduced the time taken off from school. Comparisons of different methods of conservative treatmentThe three trials in this category made three different comparisons. We are very unsure if unacceptable malunion rates differ between immediate hip spica versus skeletal traction followed by spica in children aged 3 to 10 years followed up for six to eight weeks (RR 4.0, 95% CI 0.5 to 32.9; one trial, 42 children; very low quality evidence). Malunion rates at 5 to 10 years may not differ between traction followed by functional orthosis versus traction followed by spica cast in children aged 5 to 13 years (RR 0.98, 95% CI 0.46 to 2.12; one trial, 43 children; low quality evidence). We are very unsure (very low quality evidence) if either function or serious adverse events (zero events reported) differ between single-leg versus double-leg spica casts (one trial, 52 young children aged two to seven years). Low quality evidence on the same comparison indicates that single-leg casts are less awkward to manage by parents, more comfortable for the child and may require less time off work by the caregiver. Comparisons of different methods of surgical treatmentThe three trials in this category made three different comparisons. Very low quality evidence means that we are very unsure if the rates of malunion, serious adverse events, time to return to school or parental satisfaction actually differ in children whose fractures were fixed using elastic stable intramedullary nailing or external fixation (one trial, 19 children). The same applies to the rates of serious adverse events and time to resume full weight-bearing in children treated with dynamic versus static external fixation (one trial, 52 children). Very low quality evidence (one trial, 47 children) means that we do not know if malunion, serious adverse events and time to resume weight-bearing actually differ between intramedullary nailing versus submuscular plating. However, there could be more difficulties in plate removal subsequently. There is insufficient evidence to determine if long-term function differs between surgical and conservative treatment. Surgery results in lower rates of malunion in children aged 4 to 12 years, but may increase the risk of serious adverse events. Elastic stable intramedullary nailing may reduce recovery time.There is insufficient evidence from comparisons of different methods of conservative treatment or of different methods of surgical treatment to draw conclusions on the relative effects of the treatments compared in the included trials.

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Breast engorgement is a painful condition affecting large numbers of women in the early postpartum period. It may lead to premature weaning, cracked nipples, mastitis and breast abscess. Various forms of treatment for engorgement have been studied but so far little evidence has been found on an effective intervention. This is an update of a systematic review first published by Snowden et al. in 2001 and subsequently published in 2010. The objective of this update is to seek new information on the best forms of treatment for breast engorgement in lactating women. We identified studies for inclusion through the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2015) and searched reference lists of retrieved studies. Randomised and quasi-randomised controlled trials. Two review authors independently assessed trials for eligibility, extracted data and conducted 'Risk of bias' assessments. Where insufficient data were presented in trial reports, we attempted to contact study authors and obtain necessary information. We assessed the quality of the evidence using the GRADE approach. In total, we included 13 studies with 919 women. In 10 studies individual women were the unit of analysis and in three studies, individual breasts were the unit of analysis. Four out of 13 studies were funded by an agency with a commercial interest, two received charitable funding, and two were funded by government agencies.Trials examined interventions including non-medical treatments: cabbage leaves (three studies), acupuncture (two studies), ultrasound (one study), acupressure (one study), scraping therapy (Gua Sha) (one study), cold breast-packs and electromechanical massage (one study), and medical treatments: serrapeptase (one study), protease (one study) and subcutaneous oxytocin (one study). The studies were small and used different comparisons with only single studies contributing data to outcomes of this review. We were unable to pool results in meta-analysis and only seven studies provided outcome data that could be included in data and analysis. Non-medical No differences were observed in the one study comparing acupuncture with usual care (advice and oxytocin spray) (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.13 to 1.92; one study; 140 women) in terms of cessation of breastfeeding. However, women in the acupuncture group were less likely to develop an abscess (RR 0.20, 95% CI 0.04 to 1.01; one study; 210 women), had less severe symptoms on day five (RR 0.84, 95% CI 0.70 to 0.99), and had a lower rate of pyrexia (RR 0.82, 95% CI 0.72 to 0.94) than women in the usual care group.In another study with 39 women comparing cabbage leaf extract with placebo, no differences were observed in breast pain (mean difference (MD) 0.40, 95% CI -0.67 to 1.47; low-quality evidence) or breast engorgement (MD 0.20, 95% CI -0.18 to 0.58; low-quality evidence). There was no difference between ultrasound and sham treatment in analgesic requirement (RR 0.98, 95% CI 0.63 to 1.51; one study; 45 women; low-quality evidence). A study comparing Gua-Sha therapy with hot packs and massage found a marked difference in breast engorgement (MD -2.42, 95% CI -2.98 to -1.86; one study; 54 women), breast pain (MD -2.01, 95% CI -2.60 to -1.42; one study; 54 women) and breast discomfort (MD -2.33, 95% CI -2.81 to -1.85; one study; 54 women) in favour of Gua-Sha therapy five minutes post-intervention, though both interventions significantly decreased breast temperature, engorgement, pain and discomfort at five and 30 minutes post-treatment.Results from individual trials that could not be included in data analysis suggested that there were no differences between room temperature and chilled cabbage leaves and between chilled cabbage leaves and gel packs, with all interventions producing some relief. Intermittent hot/cold packs applied for 20 minutes twice a day were found to be more effective than acupressure (P &lt; 0.001). Acupuncture did not improve maternal satisfaction with breastfeeding. In another study, women who received breast-shaped cold packs were more likely to experience a reduction in pain intensity than women who received usual care; however, the differences between groups at baseline, and the failure to observe randomisation, make this study at high risk of bias. One study found a decrease in breast temperature (P = 0.03) following electromechanical massage and pumping in comparison to manual methods; however, the high level of attrition and alternating method of sequence generation place this study at high risk of bias. MedicalWomen treated with protease complex were less likely to have no improvement in pain (RR 0.17, 95% CI 0.04 to 0.74; one study; 59 women) and swelling (RR 0.34, 95% CI 0.15 to 0.79; one study; 59 women) on the fourth day of treatment and less likely to experience no overall change in their symptoms or worsening of symptoms (RR 0.26, 95% CI 0.12 to 0.56). It should be noted that it is more than 40 years since the study was carried out, and we are not aware that this preparation is used in current practice. Subcutaneous oxytocin provided no relief at all in symptoms at three days (RR 3.13, 95% CI 0.68 to 14.44; one study; 45 women).Serrapeptase was found to produce some relief in breast pain, induration and swelling, when compared to placebo, with a fewer number of women experiencing slight to no improvement in overallbreast engorgement, swelling and breast pain.Overall, the risk of bias of studies in the review is high. The overall quality as assessed using the GRADE approach was found to be low due to limitations in study design and the small number of women in the included studies, with only single studies providing data for analysis. Although some interventions such as hot/cold packs, Gua-Sha (scraping therapy), acupuncture, cabbage leaves and proteolytic enzymes may be promising for the treatment of breast engorgement during lactation, there is insufficient evidence from published trials on any intervention to justify widespread implementation. More robust research is urgently needed on the treatment of breast engorgement.

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This is an update of a Cochrane Review first published in 1999. Corticosteroids are widely used in inflammatory conditions as an immunosuppressive agent. Bone loss is a serious side effect of this therapy. Several studies have examined the use of bisphosphonates in the prevention and treatment of glucocorticosteroid-induced osteoporosis (GIOP) and have reported varying magnitudes of effect. To assess the benefits and harms of bisphosphonates for the prevention and treatment of GIOP in adults. We searched CENTRAL, MEDLINE and Embase up to April 2016 and International Pharmaceutical Abstracts (IPA) via OVID up to January 2012 for relevant articles and conference proceedings with no language restrictions. We searched two clinical trial registries for ongoing and recently completed studies (ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal). We also reviewed reference lists of relevant review articles. We included randomised controlled trials (RCTs) satisfying the following criteria: 1) prevention or treatment of GIOP; 2) adults taking a mean steroid dose of 5.0 mg/day or more; 3) active treatment including bisphosphonates of any type alone or in combination with calcium or vitamin D; 4) comparator treatment including a control of calcium or vitamin D, or both, alone or with placebo; and 4) reporting relevant outcomes. We excluded trials that included people with transplant-associated steroid use. At least two review authors independently selected trials for inclusion, extracted data, performed 'risk of bias' assessment and evaluated the certainty of evidence using the GRADE approach. Major outcomes of interest were the incidence of vertebral and nonvertebral fractures after 12 to 24 months; the change in bone mineral density (BMD) at the lumbar spine and femoral neck after 12 months; serious adverse events; withdrawals due to adverse events; and quality of life. We used standard Cochrane methodological procedures. We included a total of 27 RCTs with 3075 participants in the review. Pooled analysis for incident vertebral fractures included 12 trials (1343 participants) with high-certainty evidence and low risk of bias. In this analysis 46/597 (or 77 per 1000) people experienced new vertebral fractures in the control group compared with 31/746 (or 44 per 1000; range 27 to 70) in the bisphosphonate group; relative improvement of 43% (9% to 65% better) with bisphosphonates; absolute increased benefit of 2% fewer people sustaining fractures with bisphosphonates (5% fewer to 1% more); number needed to treat for an additional beneficial outcome (NNTB) was 31 (20 to 145) meaning that approximately 31 people would need to be treated with bisphosphonates to prevent new vertebral fractures in one person.Pooled analysis for incident nonvertebral fractures included nine trials with 1245 participants with low-certainty evidence (downgraded for imprecision and serious risk of bias as a patient-reported outcome). In this analysis 30/546 (or 55 per 1000) people experienced new nonvertebral fracture in the control group compared with 29/699 (or 42 per 1000; range 25 to 69) in the bisphosphonate group; relative improvement of 21% with bisphosphonates (33% worse to 53% better); absolute increased benefit of 1% fewer people with fractures with bisphosphonates (4% fewer to 1% more).Pooled analysis on BMD change at the lumbar spine after 12 months included 23 trials with 2042 patients. Eighteen trials with 1665 participants were included in the pooled analysis on BMD at the femoral neck after 12 months. Evidence for both outcomes was moderate-certainty (downgraded for indirectness as a surrogate marker for osteoporosis) with low risk of bias. Overall, the bisphosphonate groups reported stabilisation or increase in BMD, while the control groups showed decreased BMD over the study period. At the lumbar spine, there was an absolute increase in BMD of 3.5% with bisphosphonates (2.90% to 4.10% higher) with a relative improvement of 1.10% with bisphosphonates (0.91% to 1.29%); NNTB 3 (2 to 3). At the femoral neck, the absolute difference in BMD was 2.06% higher in the bisphosphonate group compared to the control group (1.45% to 2.68% higher) with a relative improvement of 1.29% (0.91% to 1.69%); NNTB 5 (4 to 7).Pooled analysis on serious adverse events included 15 trials (1703 participants) with low-certainty evidence (downgraded for imprecision and risk of bias). In this analysis 131/811 (or 162 per 1000) people experienced serious adverse events in the control group compared to 136/892 (or 147 per 1000; range 120 to 181) in the bisphosphonate group; absolute increased harm of 0% more serious adverse events (2% fewer to 2% more); a relative per cent change with 9% improvement (12% worse to 26% better).Pooled analysis for withdrawals due to adverse events included 15 trials (1790 patients) with low-certainty evidence (downgraded for imprecision and risk of bias). In this analysis 63/866 (or 73 per 1000) people withdrew in the control group compared to 76/924 (or 77 per 1000; range 56 to 107) in the bisphosphonate group; an absolute increased harm of 1% more withdrawals with bisphosphonates (95% CI 1% fewer to 3% more); a relative per cent change 6% worse (95% CI 47% worse to 23% better).Quality of life was not assessed in any of the trials. There was high-certainty evidence that bisphosphonates are beneficial in reducing the risk of vertebral fractures with data extending to 24 months of use. There was low-certainty evidence that bisphosphonates may make little or no difference in preventing nonvertebral fractures. There was moderate-certainty evidence that bisphosphonates are beneficial in preventing and treating corticosteroid-induced bone loss at both the lumbar spine and femoral neck. Regarding harm, there was low-certainty evidence that bisphosphonates may make little or no difference in the occurrence of serious adverse events or withdrawals due to adverse events. We are cautious in interpreting these data as markers for harm and tolerability due to the potential for bias.Overall, our review supports the use of bisphosphonates to reduce the risk of vertebral fractures and the prevention and treatment of steroid-induced bone loss.

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Opioid use, abuse, and adverse consequences, including death, have escalated at an alarming rate since the 1990s. In an attempt to control opioid abuse, numerous regulations and guidelines for responsible opioid prescribing have been developed by various organizations. However, the US opioid epidemic is continuing and drug dose deaths tripled during 1999 to 2015. Recent data show a continuing increase in deaths due to natural and semisynthetic opioids, a decline in methadone deaths, and an explosive increase in the rates of deaths involving other opioids, specifically heroin and illicit synthetic fentanyl. Contrary to scientific evidence of efficacy and negative recommendations, a significant proportion of physicians and patients (92%) believe that opioids reduce pain and a smaller proportion (57%) report better quality of life. In preparation of the current guidelines, we have focused on the means to reduce the abuse and diversion of opioids without jeopardizing access for those patients suffering from non-cancer pain who have an appropriate medical indication for opioid use. To provide guidance for the prescription of opioids for the management of chronic non-cancer pain, to develop a consistent philosophy among the many diverse groups with an interest in opioid use as to how appropriately prescribe opioids, to improve the treatment of chronic non-cancer pain and to reduce the likelihood of drug abuse and diversion. These guidelines are intended to provide a systematic and standardized approach to this complex and difficult arena of practice, while recognizing that every clinical situation is unique. The methodology utilized included the development of objectives and key questions. The methodology also utilized trustworthy standards, appropriate disclosures of conflicts of interest, as well as a panel of experts from various specialties and groups. The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed, with a best evidence synthesis of the available literature, and utilized grading for recommendation as described by the Agency for Healthcare Research and Quality (AHRQ).Summary of Recommendations:i. Initial Steps of Opioid Therapy 1. Comprehensive assessment and documentation. (Evidence: Level I; Strength of Recommendation: Strong) 2. Screening for opioid abuse to identify opioid abusers. (Evidence: Level II-III; Strength of Recommendation: Moderate) 3. Utilization of prescription drug monitoring programs (PDMPs). (Evidence: Level I-II; Strength of Recommendation: Moderate to strong) 4. Utilization of urine drug testing (UDT). (Evidence: Level II; Strength of Recommendation: Moderate) 5. Establish appropriate physical diagnosis and psychological diagnosis if available. (Evidence: Level I; Strength of Recommendation: Strong) 6. Consider appropriate imaging, physical diagnosis, and psychological status to collaborate with subjective complaints. (Evidence: Level III; Strength of Recommendation: Moderate) 7. Establish medical necessity based on average moderate to severe (≥ 4 on a scale of 0 - 10) pain and/or disability. (Evidence: Level II; Strength of Recommendation: Moderate) 8. Stratify patients based on risk. (Evidence: Level I-II; Strength of Recommendation: Moderate) 9. Establish treatment goals of opioid therapy with regard to pain relief and improvement in function. (Evidence: Level I-II; Strength of Recommendation: Moderate) 10. Obtain a robust opioid agreement, which is followed by all parties. (Evidence: Level III; Strength of Recommendation: Moderate)ii. Assessment of Effectiveness of Long-Term Opioid Therapy 11. Initiate opioid therapy with low dose, short-acting drugs, with appropriate monitoring. (Evidence: Level II; Strength of Recommendation: Moderate) 12. Consider up to 40 morphine milligram equivalent (MME) as low dose, 41 to 90 MME as a moderate dose, and greater than 91 MME as high dose. (Evidence: Level II; Strength of Recommendation: Moderate) 13. Avoid long-acting opioids for the initiation of opioid therapy. (Evidence: Level I; Strength of Recommendation: Strong) 14. Recommend methadone only for use after failure of other opioid therapy and only by clinicians with specific training in its risks and uses, within FDA recommended doses. (Evidence: Level I; Strength of Recommendation: Strong) 15. Understand and educate the patients of the effectiveness and adverse consequences. (Evidence: Level I; Strength of Recommendation: Strong) 16. Similar effectiveness for long-acting and short-acting opioids with increased adverse consequences of long-acting opioids. (Evidence: Level I-II; Strength of recommendation: Moderate to strong) 17. Periodically assess pain relief and/or functional status improvement of ≥ 30% without adverse consequences. (Evidence: Level II; Strength of recommendation: Moderate) 18. Recommend long-acting or high dose opioids only in specific circumstances with severe intractable pain. (Evidence: Level I; Strength of Recommendation: Strong)iii. Monitoring for Adherence and Side Effects 19. Monitor for adherence, abuse, and noncompliance by UDT and PDMPs. (Evidence: Level I-II; Strength of Recommendation: Moderate to strong) 20. Monitor patients on methadone with an electrocardiogram periodically. (Evidence: Level I; Strength of Recommendation: Strong). 21. Monitor for side effects including constipation and manage them appropriately, including discontinuation of opioids when indicated. (Evidence: Level I; Strength of Recommendation: Strong)iv. Final Phase 22. May continue with monitoring with continued medical necessity, with appropriate outcomes. (Evidence: Level I-II; Strength of Recommendation: Moderate) 23. Discontinue opioid therapy for lack of response, adverse consequences, and abuse with rehabilitation. (Evidence: Level III; Strength of Recommendation: Moderate) CONCLUSIONS: These guidelines were developed based on comprehensive review of the literature, consensus among the panelists, in consonance with patient preferences, shared decision-making, and practice patterns with limited evidence, based on randomized controlled trials (RCTs) to improve pain and function in chronic non-cancer pain on a long-term basis. Consequently, chronic opioid therapy should be provided only to patients with proven medical necessity and stability with improvement in pain and function, independently or in conjunction with other modalities of treatments in low doses with appropriate adherence monitoring and understanding of adverse events.Key words: Chronic pain, persistent pain, non-cancer pain, controlled substances, substance abuse, prescription drug abuse, dependency, opioids, prescription monitoring, drug testing, adherence monitoring, diversionDisclaimer: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."

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Pelvic inflammatory disease (PID) is an infection that affects 4% to 12% of young women, and is one of the most common causes of morbidity in this age group. The main intervention for acute PID is the use of broad-spectrum antibiotics which cover Chlamydia trachomatis, Neisseria gonorrhoeae, and anaerobic bacteria, administered intravenously, intramuscularly, or orally. In this review, we assessed the optimal treatment regimen for PID. To assess the effectiveness and safety of antibiotic regimens used to treat pelvic inflammatory disease. We searched the Cochrane Sexually Transmitted Infections Review Group's Specialized Register, which included randomized controlled trials (RCTs) from 1944 to 2016, located through electronic searching and handsearching; the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid platform (1991 to July 2016); MEDLINE (1946 to July 2016); Embase (1947 to July 2016); LILACS, iAHx interface (1982 to July 2016); World Health Organization International Clinical Trials Registry Platform (July 2016); Web of Science (2001 to July 2016); OpenGrey (1990, 1992, 1995, 1996, and 1997); and abstracts in selected publications. We included RCTs comparing the use of antibiotics with placebo or other antibiotics for the treatment of PID in women of reproductive age, either as inpatient or outpatient treatment. We limited our review to comparison of drugs in current use that are recommended for consideration by the 2015 US Centers for Disease Control and Prevention (CDC) guidelines for treatment of PID. At least two review authors independently selected trials for inclusion, extracted data, and assessed risk of bias. We contacted investigators to obtain missing information. We resolved disagreements by consensus or by consulting a fourth review author if necessary. We assessed the quality of the evidence using GRADE criteria, classifying it as high, moderate, low, or very low. We calculated Mantel-Haenszel risk ratios (RR), using either random-effects or fixed-effect models and number needed to treat for an additional beneficial outcome or for an additional harmful outcome, with their 95% confidence interval (CI), to measure the effect of the treatments. We conducted sensitivity analyses limited to studies at low risk of bias, for comparisons where such studies were available. We included 37 RCTs (6348 women). The quality of the evidence ranged from very low to high, the main limitations being serious risk of bias (due to poor reporting of study methods and lack of blinding), serious inconsistency, and serious imprecision. Azithromycin versus doxycyclineThere was no clear evidence of a difference between the two drugs in rates of cure for mild-moderate PID (RR 1.18, 95% CI 0.89 to 1.55, I<sup2</sup = 72%, 2 RCTs, 243 women, very low-quality evidence), severe PID (RR 1.00, 95% CI 0.96 to 1.05, 1 RCT, 309 women, low-quality evidence), or adverse effects leading to discontinuation of treatment (RR 0.71, 95% CI 0.38 to 1.34, 3 RCTs, 552 women, I<sup2</sup = 0%, low-quality evidence). In a sensitivity analysis limited to a single study at low risk of bias, azithromycin was superior to doxycycline in achieving cure in mild-moderate PID (RR 1.35, 95% CI 1.10 to 1.67, 133 women, moderate-quality evidence). Quinolone versus cephalosporinThere was no clear evidence of a difference between the two drugs in rates of cure for mild-moderate PID (RR 1.04, 95% CI 0.98 to 1.10, 3 RCTs, 459 women, I<sup2</sup = 5%, low-quality evidence), severe PID (RR 1.06, 95% CI 0.91 to 1.23, 2 RCTs, 313 women, I<sup2</sup = 7%, low-quality evidence), or adverse effects leading to discontinuation of treatment (RR 2.24, 95% CI 0.52 to 9.72, 5 RCTs, 772 women, I<sup2</sup = 0%, very low-quality evidence). Nitroimidazole versus no use of nitroimidazoleThere was no conclusive evidence of a difference between the nitroimidazoles (metronidazole) group and the group receiving other drugs with activity over anaerobes (e.g. amoxicillin-clavulanate) in rates of cure for mild-moderate PID (RR 1.01, 95% CI 0.93 to 1.10, 5 RCTs, 2427 women, I<sup2</sup = 60%, moderate-quality evidence), severe PID (RR 0.96, 95% CI 0.92 to 1.01, 11 RCTs, 1383 women, I<sup2</sup = 0%, moderate-quality evidence), or adverse effects leading to discontinuation of treatment (RR 1.00, 95% CI 0.63 to 1.59; participants = 3788; studies = 16; I<sup2</sup = 0% , low-quality evidence). In a sensitivity analysis limited to studies at low risk of bias, findings did not differ substantially from the main analysis (RR 1.06, 95% CI 0.98 to 1.15, 2 RCTs, 1201 women, I<sup2</sup = 32%, high-quality evidence). Clindamycin plus aminoglycoside versus quinoloneThere was no evidence of a difference between the two groups in rates of cure for mild-moderate PID (RR 0.88, 95% CI 0.69 to 1.13, 1 RCT, 25 women, very low-quality evidence), severe PID (RR 1.02, 95% CI 0.87 to 1.19, 2 studies, 151 women, I<sup2</sup = 0%, low-quality evidence), or adverse effects leading to discontinuation of treatment (RR 0.21, 95% CI 0.02 to 1.72, 3 RCTs, 163 women, very low-quality evidence). Clindamycin plus aminoglycoside versus cephalosporinThere was no clear evidence of a difference between the two groups in rates of cure for mild-moderate PID (RR 1.02, 95% CI 0.95 to 1.09, 2 RCTs, 150 women, I<sup2</sup = 0%, low-quality evidence), severe PID (RR 1.00, 95% CI 0.95 to 1.06, 10 RCTs, 959 women, I<sup2</sup = 21%, moderate-quality evidence), or adverse effects leading to discontinuation of treatment (RR 0.78, 95% CI 0.18 to 3.42, 10 RCTs, 1172 women, I<sup2</sup = 0%, very low-quality evidence). We found no conclusive evidence that one regimen of antibiotics was safer or more effective than any other for the cure of PID, and there was no clear evidence for the use of nitroimidazoles (metronidazole) compared to use of other drugs with activity over anaerobes. Moderate-quality evidence from a single study at low risk of bias suggested that a macrolide (azithromycin) may be more effective than a tetracycline (doxycycline) for curing mild-moderate PID. Our review considered only the drugs that are currently used and mentioned by the CDC.

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Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. To assess the benefits and harms of DAAs in people with chronic HCV. We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.

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The mean age of women undergoing local treatment for pre-invasive cervical disease (cervical intra-epithelial neoplasia; CIN) or early cervical cancer (stage IA1) is around their 30s and similar to the age of women having their first child. Local cervical treatment has been correlated to adverse reproductive morbidity in a subsequent pregnancy, however, published studies and meta-analyses have reached contradictory conclusions. To assess the effect of local cervical treatment for CIN and early cervical cancer on obstetric outcomes (after 24 weeks of gestation) and to correlate these to the cone depth and comparison group used. We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library, 2017, Issue 5), MEDLINE (up to June week 4, 2017) and Embase (up to week 26, 2017). In an attempt to identify articles missed by the search or unpublished data, we contacted experts in the field and we handsearched the references of the retrieved articles and conference proceedings. We included all studies reporting on obstetric outcomes (more than 24 weeks of gestation) in women with or without a previous local cervical treatment for any grade of CIN or early cervical cancer (stage IA1). Treatment included both excisional and ablative methods. We excluded studies that had no untreated reference population, reported outcomes in women who had undergone treatment during pregnancy or had a high-risk treated or comparison group, or both DATA COLLECTION AND ANALYSIS: We classified studies according to the type of treatment and the obstetric endpoint. Studies were classified according to method and obstetric endpoint. Pooled risk ratios (RR) and 95% confidence intervals (CIs) were calculated using a random-effects model and inverse variance. Inter-study heterogeneity was assessed with I<sup2</sup statistics. We assessed maternal outcomes that included preterm birth (PTB) (spontaneous and threatened), preterm premature rupture of the membranes (pPROM), chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage and cervical stenosis. The neonatal outcomes included low birth weight (LBW), neonatal intensive care unit (NICU) admission, stillbirth, perinatal mortality and Apgar scores. We included 69 studies (6,357,823 pregnancies: 65,098 pregnancies of treated and 6,292,725 pregnancies of untreated women). Many of the studies included only small numbers of women, were of heterogenous design and in their majority retrospective and therefore at high risk of bias. Many outcomes were assessed to be of low or very low quality (GRADE assessment) and therefore results should be interpreted with caution. Women who had treatment were at increased overall risk of preterm birth (PTB) (less than 37 weeks) (10.7% versus 5.4%, RR 1.75, 95% CI 1.57 to 1.96, 59 studies, 5,242,917 participants, very low quality), severe (less than 32 to 34 weeks) (3.5% versus 1.4%, RR 2.25, 95% CI 1.79 to 2.82), 24 studies, 3,793,874 participants, very low quality), and extreme prematurity (less than 28 to 30 weeks) (1.0% versus 0.3%, (RR 2.23, 95% CI 1.55 to 3.22, 8 studies, 3,910,629 participants, very low quality), as compared to women who had no treatment.The risk of overall prematurity was higher for excisional (excision versus no treatment: 11.2% versus 5.5%, RR 1.87, 95% CI 1.64 to 2.12, 53 studies, 4,599,416 participants) than ablative (ablation versus no treatment: 7.7% versus 4.6%, RR 1.35, 95% CI 1.20 to 1.52, 14 studies, 602,370 participants) treatments and the effect was higher for more radical excisional techniques (less than 37 weeks: cold knife conisation (CKC) (RR 2.70, 95% CI 2.14 to 3.40, 12 studies, 39,102 participants), laser conisation (LC) (RR 2.11, 95% CI 1.26 to 3.54, 9 studies, 1509 participants), large loop excision of the transformation zone (LLETZ) (RR 1.58, 95% CI 1.37 to 1.81, 25 studies, 1,445,104 participants). Repeat treatment multiplied the risk of overall prematurity (repeat versus no treatment: 13.2% versus 4.1%, RR 3.78, 95% CI 2.65 to 5.39, 11 studies, 1,317,284 participants, very low quality). The risk of overall prematurity increased with increasing cone depth (less than 10 mm to 12 mm versus no treatment: 7.1% versus 3.4%, RR 1.54, 95% CI 1.09 to 2.18, 8 studies, 550,929 participants, very low quality; more than 10 mm to 12 mm versus no treatment: 9.8% versus 3.4%, RR 1.93, 95% CI 1.62 to 2.31, 8 studies, 552,711 participants, low quality; more than 15 mm to 17 mm versus no treatment: 10.1 versus 3.4%, RR 2.77, 95% CI 1.95 to 3.93, 4 studies, 544,986 participants, very low quality; 20 mm or more versus no treatment: 10.2% versus 3.4%, RR 4.91, 95% CI 2.06 to 11.68, 3 studies, 543,750 participants, very low quality). The comparison group affected the magnitude of effect that was higher for external, followed by internal comparators and ultimately women with disease, but no treatment. Untreated women with disease and the pre-treatment pregnancies of the women who were treated subsequently had higher risk of overall prematurity than the general population (5.9% versus 5.6%, RR 1.24, 95% CI 1.14 to 1.34, 15 studies, 4,357,998 participants, very low quality).pPROM (6.1% versus 3.4%, RR 2.36, 95% CI 1.76 to 3.17, 21 studies, 477,011 participants, very low quality), low birth weight (7.9% versus 3.7%, RR 1.81, 95% CI 1.58 to 2.07, 30 studies, 1,348,206 participants, very low quality), NICU admission rate (12.6% versus 8.9%, RR 1.45, 95% CI 1.16 to 1.81, 8 studies, 2557 participants, low quality) and perinatal mortality (0.9% versus 0.7%, RR 1.51, 95% CI 1.13 to 2.03, 23 studies, 1,659,433 participants, low quality) were also increased after treatment. Women with CIN have a higher baseline risk for prematurity. Excisional and ablative treatment appears to further increases that risk. The frequency and severity of adverse sequelae increases with increasing cone depth and is higher for excision than it is for ablation. However, the results should be interpreted with caution as they were based on low or very low quality (GRADE assessment) observational studies, most of which were retrospective.

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Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008. To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis. We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co-ordinators, directors, clinicians, WHO-EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE. Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound. Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search. We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow-up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow-up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons. There was very low-certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well-designed international studies that evaluate long-term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.

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Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008. To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis. We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co-ordinators, directors, clinicians, WHO-EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE. Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound. Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search. We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow-up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow-up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons. There was very low-certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well-designed international studies that evaluate long-term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.

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Computer users frequently complain about problems with seeing and functioning of the eyes. Asthenopia is a term generally used to describe symptoms related to (prolonged) use of the eyes like ocular fatigue, headache, pain or aching around the eyes, and burning and itchiness of the eyelids. The prevalence of asthenopia during or after work on a computer ranges from 46.3% to 68.5%. Uncorrected or under-corrected refractive error can contribute to the development of asthenopia. A refractive error is an error in the focusing of light by the eye and can lead to reduced visual acuity. There are various possibilities for optical correction of refractive errors including eyeglasses, contact lenses and refractive surgery. To examine the evidence on the effectiveness, safety and applicability of optical correction of refractive error for reducing and preventing eye symptoms in computer users. We searched the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; Embase; Web of Science; and OSH update, all to 20 December 2017. Additionally, we searched trial registries and checked references of included studies. We included randomised controlled trials (RCTs) and quasi-randomised trials of interventions evaluating optical correction for computer workers with refractive error for preventing or treating asthenopia and their effect on health related quality of life. Two authors independently assessed study eligibility and risk of bias, and extracted data. Where appropriate, we combined studies in a meta-analysis. We included eight studies with 381 participants. Three were parallel group RCTs, three were cross-over RCTs and two were quasi-randomised cross-over trials. All studies evaluated eyeglasses, there were no studies that evaluated contact lenses or surgery. Seven studies evaluated computer glasses with at least one focal area for the distance of the computer screen with or without additional focal areas in presbyopic persons. Six studies compared computer glasses to other types of glasses; and one study compared them to an ergonomic workplace assessment. The eighth study compared optimal correction of refractive error with the actual spectacle correction in use. Two studies evaluated computer glasses in persons with asthenopia but for the others the glasses were offered to all workers regardless of symptoms. The risk of bias was unclear in five, high in two and low in one study. Asthenopia was measured as eyestrain or a summary score of symptoms but there were no studies on health-related quality of life. Adverse events were measured as headache, nausea or dizziness. Median asthenopia scores at baseline were about 30% of the maximum possible score.Progressive computer glasses versus monofocal glassesOne study found no considerable difference in asthenopia between various progressive computer glasses and monofocal computer glasses after one-year follow-up (mean difference (MD) change scores 0.23, 95% confidence interval (CI) -5.0 to 5.4 on a 100 mm VAS scale, low quality evidence). For headache the results were in favour of progressive glasses.Progressive computer glasses with an intermediate focus in the upper part of the glasses versus other glassesIn two studies progressive computer glasses with intermediate focus led to a small decrease in asthenopia symptoms (SMD -0.49, 95% CI -0.75 to -0.23, low-quality evidence) but not in headache score in the short-term compared to general purpose progressive glasses. There were similar small decreases in dizziness. At medium term follow-up, in one study the effect size was not statistically significant (SMD -0.64, 95% CI -1.40 to 0.12). The study did not assess adverse events.Another study found no considerable difference in asthenopia between progressive computer glasses and monofocal computer glasses after one-year follow-up (MD change scores 1.44, 95% CI -6.95 to 9.83 on a 100 mm VAS scale, very low quality evidence). For headache the results were inconsistent.Progressive computer glasses with far-distance focus in the upper part of the glasses versus other glassesOne study found no considerable difference in number of persons with asthenopia between progressive computer glasses with far-distance focus and bifocal computer glasses after four weeks' follow-up (OR 1.00, 95% CI 0.40 to 2.50, very low quality evidence). The number of persons with headache, nausea and dizziness was also not different between groups.Another study found no considerable difference in asthenopia between progressive computer glasses with far-distance focus and monofocal computer glasses after one-year follow-up (MD change scores -1.79, 95% CI -11.60 to 8.02 on a 100 mm VAS scale, very low quality evidence). The effects on headaches were inconsistent.One study found no difference between progressive far-distance focus computer glasses and trifocal glasses in effect on eyestrain severity (MD -0.50, 95% CI -1.07 to 0.07, very low quality evidence) or on eyestrain frequency (MD -0.75, 95% CI -1.61 to 0.11, very low quality evidence).Progressive computer glasses versus ergonomic assessment with habitual (computer) glassesOne study found that computer glasses optimised for individual needs reduced asthenopia sum score more than an ergonomic assessment and habitual (computer) glasses (MD -8.9, 95% CI -16.47 to -1.33, scale 0 to 140, very low quality evidence) but there was no effect on the frequency of eyestrain (OR 1.08, 95% CI 0.38 to 3.11, very low quality evidence).We rated the quality of the evidence as low or very low due to risk of bias in the included studies, inconsistency in the results and imprecision. There is low to very low quality evidence that providing computer users with progressive computer glasses does not lead to a considerable decrease in problems with the eyes or headaches compared to other computer glasses. Progressive computer glasses might be slightly better than progressive glasses for daily use in the short term but not in the intermediate term and there is no data on long-term follow-up. The quality of the evidence is low or very low and therefore we are uncertain about this conclusion. Larger studies with several hundreds of participants are needed with proper randomisation, validated outcome measurement methods, and longer follow-up of at least one year to improve the quality of the evidence.

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Critically ill people are at increased risk of malnutrition. Acute and chronic illness, trauma and inflammation induce stress-related catabolism, and drug-induced adverse effects may reduce appetite or increase nausea and vomiting. In addition, patient management in the intensive care unit (ICU) may also interrupt feeding routines. Methods to deliver nutritional requirements include provision of enteral nutrition (EN), or parenteral nutrition (PN), or a combination of both (EN and PN). However, each method is problematic. This review aimed to determine the route of delivery that optimizes uptake of nutrition. To compare the effects of enteral versus parenteral methods of nutrition, and the effects of enteral versus a combination of enteral and parenteral methods of nutrition, among critically ill adults, in terms of mortality, number of ICU-free days up to day 28, and adverse events. We searched CENTRAL, MEDLINE, and Embase on 3 October 2017. We searched clinical trials registries and grey literature, and handsearched reference lists of included studies and related reviews. We included randomized controlled studies (RCTs) and quasi-randomized studies comparing EN given to adults in the ICU versus PN or versus EN and PN. We included participants that were trauma, emergency, and postsurgical patients in the ICU. Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We assessed the certainty of evidence with GRADE. We included 25 studies with 8816 participants; 23 studies were RCTs and two were quasi-randomized studies. All included participants were critically ill in the ICU with a wide range of diagnoses; mechanical ventilation status between study participants varied. We identified 11 studies awaiting classification for which we were unable to assess eligibility, and two ongoing studies.Seventeen studies compared EN versus PN, six compared EN versus EN and PN, two were multi-arm studies comparing EN versus PN versus EN and PN. Most studies reported randomization and allocation concealment inadequately. Most studies reported no methods to blind personnel or outcome assessors to nutrition groups; one study used adequate methods to reduce risk of performance bias.Enteral nutrition versus parenteral nutritionWe found that one feeding route rather than the other (EN or PN) may make little or no difference to mortality in hospital (risk ratio (RR) 1.19, 95% confidence interval (CI) 0.80 to 1.77; 361 participants; 6 studies; low-certainty evidence), or mortality within 30 days (RR 1.02, 95% CI 0.92 to 1.13; 3148 participants; 11 studies; low-certainty evidence). It is uncertain whether one feeding route rather than the other reduces mortality within 90 days because the certainty of the evidence is very low (RR 1.06, 95% CI 0.95 to 1.17; 2461 participants; 3 studies). One study reported mortality at one to four months and we did not combine this in the analysis; we reported this data as mortality within 180 days and it is uncertain whether EN or PN affects the number of deaths within 180 days because the certainty of the evidence is very low (RR 0.33, 95% CI 0.04 to 2.97; 46 participants).No studies reported number of ICU-free days up to day 28, and one study reported number of ventilator-free days up to day 28 and it is uncertain whether one feeding route rather than the other reduces the number of ventilator-free days up to day 28 because the certainty of the evidence is very low (mean difference, inverse variance, 0.00, 95% CI -0.97 to 0.97; 2388 participants).We combined data for adverse events reported by more than one study. It is uncertain whether EN or PN affects aspiration because the certainty of the evidence is very low (RR 1.53, 95% CI 0.46 to 5.03; 2437 participants; 2 studies), and we found that one feeding route rather than the other may make little or no difference to pneumonia (RR 1.10, 95% CI 0.82 to 1.48; 415 participants; 7 studies; low-certainty evidence). We found that EN may reduce sepsis (RR 0.59, 95% CI 0.37 to 0.95; 361 participants; 7 studies; low-certainty evidence), and it is uncertain whether PN reduces vomiting because the certainty of the evidence is very low (RR 3.42, 95% CI 1.15 to 10.16; 2525 participants; 3 studies).Enteral nutrition versus enteral nutrition and parenteral nutritionWe found that one feeding regimen rather than another (EN or combined EN or PN) may make little or no difference to mortality in hospital (RR 0.99, 95% CI 0.84 to 1.16; 5111 participants; 5 studies; low-certainty evidence), and at 90 days (RR 1.00, 95% CI 0.86 to 1.18; 4760 participants; 2 studies; low-certainty evidence). It is uncertain whether combined EN and PN leads to fewer deaths at 30 days because the certainty of the evidence is very low (RR 1.64, 95% CI 1.06 to 2.54; 409 participants; 3 studies). It is uncertain whether one feeding regimen rather than another reduces mortality within 180 days because the certainty of the evidence is very low (RR 1.00, 95% CI 0.65 to 1.55; 120 participants; 1 study).No studies reported number of ICU-free days or ventilator-free days up to day 28. It is uncertain whether either feeding method reduces pneumonia because the certainty of the evidence is very low (RR 1.40, 95% CI 0.91 to 2.15; 205 participants; 2 studies). No studies reported aspiration, sepsis, or vomiting. We found insufficient evidence to determine whether EN is better or worse than PN, or than combined EN and PN for mortality in hospital, at 90 days and at 180 days, and on the number of ventilator-free days and adverse events. We found fewer deaths at 30 days when studies gave combined EN and PN, and reduced sepsis for EN rather than PN. We found no studies that reported number of ICU-free days up to day 28. Certainty of the evidence for all outcomes is either low or very low. The 11 studies awaiting classification may alter the conclusions of the review once assessed.

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The growing prevalence of overweight and obesity has been recognized by WHO as a global obesity pandemic worldwide. The spread of overweight and obesity is also an urgent problem for Russia. <bThe aim</b of this study was to analyze the nutritional status of the Russian adult population and the prevalence of overweight and obesity depending on a number of socio-demographic factors and family income. <bMaterial and methods</b. The assessment of the nutritional status of adults was carried out on the basis of anthropometric parameters obtained by the Federal State Statistics Service in the course of the "Sample observation of the population's diet" in 2018 based on a random sample of 45 thousand households in all constituent entities of the Russian Federation. 76.960 people aged 19 and over were examined, including 41% of men and 59% of women. The nutritional status of adults was assessed based on the calculation of the body mass index (BMI). According to the WHO classification, BMI values in the range of 18.5-24.9 kg/m<sup2</sup were taken as normal, BMI 25.0-29.9 kg/m<sup2</sup was taken as overweight, and BMI≥30.0 kg/m<sup2</sup indicated obesity. The prevalence of obesity was analyzed depending on socio-demographic variables: gender, age, place of residence (city, village, type of settlement in terms of population, federal district), marital status, educational level, and per capita income. <bResults</b. The body weight and height of respondents with a BMI of 18.5-24.9 kg/m<sup2</sup can be considered as the average normal body weight and height of the adult population in Russia, which amounted to 70.6 kg and 175.4 cm for men, and 60.2 kg and 164 cm for women, respectively. The average body weight of all urban men is 1.3 kg more than that of rural men, while the average body weight of urban women is 2.2 kg less than that of rural women. The growth of urban men and women, respectively, is 2.1 cm and 1.1 cm higher than rural ones. The average BMI values of urban and rural men do not differ, while the BMI of rural women is 1.2 kg/m<sup2</sup higher than that of urban ones reflecting higher values of the average body weight. The average BMI values of adult men and women are in the zone of values characteristic of overweight (BMI≥25.0 kg/m<sup2</sup). In general, in 2018, only 34.4% of the adult population (33.2% of men and 35.4% of women) had BMI indices corresponding to normal values. Overweight, including obesity (BMI≥25.0 kg/m<sup2</sup), were detected in 66.1%, men and 63.0% of women, and obesity (BMI≥30.0 kg/m<sup2</sup) in 18.8% of men and 27.4% women. The incidence of obesity among adults of both sexes is significantly higher among rural residents, while the incidence of overweight (BMI 25.0-29.9 kg/m<sup2</sup) does not differ. The prevalence of obesity in urban and rural areas decreases with the increase in their population. The frequency of overweight increases with growth in households' average per capita income with high reliability of differences between the 1st and the 5th quintiles of income (p&lt;0.01). At the same time, the incidence of obesity increases from the 1st to the 3rd quintiles, decreasing in the 4th and the 5th quintiles. For men, the dependence of the average BMI values on household income is almost square with high reliability (p&lt;0.001), while for women, a decrease in BMI was revealed only in the 5th quintile of income. Thus, the incidence of obesity among women in the richest population groups is lower than in the less affluent. The incidence of obesity in men increases linearly with age from 19 to 65, and decreases in the age group over 70 years. In women, the frequency of obesity from 19 to 40 years old increases slowly, then there is a rapid increase up to 65 years, and then, like in men, there is a decrease. In young men, the frequency of overweight, including obesity (BMI≥25.0 kg/m<sup2</sup), is 32.3% at the age of 19-25, and 49.3% at the age of 25-30, which, respectively, by 13.1 and 20.0% higher than among women of the same age. Moreover, the frequency of obesity in these age groups of men and women is the same. The highest incidence of BMI≥25.0 kg/m<sup2</sup in men is observed over 40 (70-76%); in women over 50 (75-83%). The prevalence of obesity (BMI≥30.0 kg/m<sup2</sup) before the age of 50 is approximately the same in men and women, while over the age of 50, the frequency of obesity in women is 12-16% higher than in men. Over the age of 65, there is a decrease of obesity in both sexes, but the incidence remains significantly higher among women than men of a similar age. The prevalence of obesity among urban and rural men in all age groups from 19 to 70 years does not differ significantly. Among rural women the frequency of obesity is significantly higher compared to urban women. Education level affects the prevalence of obesity only in women: the incidence of obesity among women with higher education is considerably lower than among women with less education. <bConclusion</b. Significant differences in the state of nutrition and the prevalence of obesity were revealed depending on the place of residence in urban and rural settlements, the type of settlements in terms of population and the Federal Districts. Noteworthy, there was a significant 10.2% increase in the prevalence of overweight in men in 2018 compared to 2012, while the increase in women was 6.2%. In general, the frequency of overweight increased by 7.8%, amounting to 40.3%. The prevalence of obesity increased in men by 0.9%, while in women decreased by 3.3%. As a result, throughout the adult population, the prevalence of obesity decreased by 1.4%. Based on the available two studies, it is not possible to assert with confidence about the trend of decreasing the prevalence of obesity from 2012 to 2018.

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Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by systemic inflammation, fibrosis, vascular injury, reduced quality of life, and limited treatment options. Autologous hematopoietic stem cell transplantation (HSCT) has emerged as a potential intervention for severe SSc refractory to conventional treatment. To assess the benefits and harms of autologous hematopoietic stem cell transplantation for the treatment of systemic sclerosis (specifically, non-selective myeloablative HSCT versus cyclophosphamide; selective myeloablative HSCT versus cyclophosphamide; non-selective non-myeloablative HSCT versus cyclophosphamide). We searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE, Embase, and trial registries from database insertion to 4 February 2022. We included RCTs that compared HSCT to immunomodulators in the treatment of SSc. Two review authors independently selected studies for inclusion, extracted study data, and performed risk of bias and GRADE assessments to assess the certainty of evidence using standard Cochrane methods. We included three RCTs evaluating: non-myeloablative non-selective HSCT (10 participants), non-myeloablative selective HSCT (79 participants), and myeloablative selective HSCT (36 participants). The comparator in all studies was cyclophosphamide (123 participants). The study examining non-myeloablative non-selective HSCT had a high risk of bias given the differences in baseline characteristics between the two arms. The other studies had a high risk of detection bias for participant-reported outcomes. The studies had follow-up periods of one to 4.5 years. Most participants had severe disease, mean age 40 years, and the duration of disease was less than three years. Efficacy No study demonstrated an overall mortality benefit of HSCT when compared to cyclophosphamide. However, non-myeloablative selective HSCT showed overall survival benefits using Kaplan-Meier curves at 10 years and myeloablative selective HSCT at six years. We graded our certainty of evidence as moderate for non-myeloablative selective HSCT and myeloablative selective HSCT. Certainty of evidence was low for non-myeloablative non-selective HSCT. Event-free survival was improved compared to cyclophosphamide with non-myeloablative selective HSCT at 48 months (hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.16 to 0.74; moderate-certainty evidence). There was no improvement with myeloablative selective HSCT at 54 months (HR 0.54 95% CI 0.23 to 1.27; moderate-certainty evidence). The non-myeloablative non-selective HSCT trial did not report event-free survival. There was improvement in functional ability measured by the Health Assessment Questionnaire Disability Index (HAQ-DI, scale from 0 to 3 with 3 being very severe functional impairment) with non-myeloablative selective HSCT after two years with a mean difference (MD) of -0.39 (95% CI -0.72 to -0.06; absolute treatment benefit (ATB) -13%, 95% CI -24% to -2%; relative percent change (RPC) -27%, 95% CI -50% to -4%; low-certainty evidence). Myeloablative selective HSCT demonstrated a risk ratio (RR) for improvement of 3.4 at 54 months (95% CI 1.5 to 7.6; ATB -37%, 95% CI -18% to -57%; RPC -243%, 95% CI -54% to -662%; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 9; low-certainty evidence). The non-myeloablative non-selective HSCT trial did not report HAQ-DI results. All transplant modalities showed improvement of modified Rodnan skin score (mRSS) (scale from 0 to 51 with the higher number being more severe skin thickness) favoring HSCT over cyclophosphamide. At two years, non-myeloablative selective HSCT showed an MD in mRSS of -11.1 (95% CI -14.9 to -7.3; ATB -22%, 95% CI -29% to -14%; RPC -43%, 95% CI -58% to -28%; moderate-certainty evidence). At 54 months, myeloablative selective HSCT at showed a greater improvement in skin scores than the cyclophosphamide group (RR 1.51, 95% CI 1.06 to 2.13; ATB -27%, 95% CI -6% to -47%; RPC -51%, 95% CI -6% to -113%; moderate-certainty evidence). The NNTB was 4 (95% CI 3 to 18). At one year, for non-myeloablative non-selective HSCT the MD was -16.00 (95% CI -26.5 to -5.5; ATB -31%, 95% CI -52% to -11%; RPC -84%, 95% CI -139% to -29%; low-certainty evidence). No studies reported data on pulmonary arterial hypertension. Adverse events In the non-myeloablative selective HSCT study, there were 51/79 serious adverse events with HSCT and 30/77 with cyclophosphamide (RR 1.7, 95% CI 1.2 to 2.3), with an absolute risk increase of 26% (95% CI 10% to 41%), and a relative percent increase of 66% (95% CI 20% to 129%). The number needed to treat for an additional harmful outcome was 4 (95% CI 3 to 11) (moderate-certainty evidence). In the myeloablative selective HSCT study, there were similar rates of serious adverse events between groups (25/34 with HSCT and 19/37 with cyclophosphamide; RR 1.43, 95% CI 0.99 to 2.08; moderate-certainty evidence). The non-myeloablative non-selective HSCT trial did not clearly report serious adverse events. Non-myeloablative selective and myeloablative selective HSCT had moderate-certainty evidence for improvement in event-free survival, and skin thicknesscompared to cyclophosphamide. There is also low-certainty evidence that these modalities of HSCT improve physical function. However, non-myeloablative selective HSCT and myeloablative selective HSCT resulted in more serious adverse events than cyclophosphamide; highlighting the need for careful risk-benefit considerations for people considering these HSCTs. Evidence for the efficacy and adverse effects of non-myeloablative non-selective HSCT is limited at this time. Due to evidence provided from one study with high risk of bias, we have low-certainty evidence that non-myeloablative non-selective HSCT improves outcomes in skin scores, forced vital capacity, and safety. Two modalities of HSCT appeared to be a promising treatment option for SSc though there is a high risk of early treatment-related mortality and other adverse events. Additional research is needed to determine the effectiveness and adverse effects of non-myeloablative non-selective HSCT in the treatment of SSc. Also, more studies will be needed to determine how HSCT compares to other treatment options such as mycophenolate mofetil, as cyclophosphamide is no longer the first-line treatment for SSc. Finally, there is a need for a greater understanding of the role of HSCT for people with SSc with significant comorbidities or complications from SSc that were excluded from the trial criteria.

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Over the last three decades, the marital family model described by Durkheim at the end of the nineteenth century has undergone numerous changes, e.g. questioning about the principle of authority, women emancipation, occurrence of the "new fathers", the growing influence of the media on the daily life of families, the less frequent and most precious child (due to the reduced number of children per family),... Through clinical, psychoanalytical and developmental models we, here, analyze these changes together with their impact on child. Historical and sociological approaches also allowed us to examine some of the effects induced by consensus and hedonism, the new familial parameters, on the child's life and development. The modern family being classically founded upon duty (central value) and the principle of authority to settle relationships between individuals, its main features are opposed to those of the contemporary family. The latter, which started to emerge over the sixties, is characterized by both the prevalence of parent-child relationships symmetrization and the emergence of the search for immediate pleasure. The change from parental authority to consensus as a principle ruling the relationships within families leads to many consequences later noticed through changes in the construction of the child's psyche along his development and in the relationships dynamics. Authority imposes on child to submit to the parents-mediatized requirements of the society and implies a change in impulses through the setting of Superego agencies and Ego Ideal, which (both ?) represent taboos and social ideals in the psyche. When consensus is at the center of the family, and according to concrete meetings with the other offered by the thousand and one situations met in the daily life, the aims and satisfaction modalities of the child's impulses will evolve into a relation often based on either strength or seduction. As a result, the settlement of classical instances will be affected. It will result in. Considering hedonism as the central value in child education leads one to support the pleasure principle and contributes to making more difficult the switching to the reality principle. The couple " I want, I don't want" is at the origin of most behaviors, and then further leads to the development of the assertive agency, "I do what I want, and thus I am". The libidinal excitation is, therefore, little restricted and reinforced by the media-based environment. The child's Superego is built on the concrete practices of his parents, but not on their Superego, whereas the Ideal of Ego is poorly socialized and driven towards the ideal Ego, early narcissist formation with the signs of child megalomania. Due to these early years of life throughout which the pleasure principle has been favored by their environment, the children are not prepared for life with its restrictions and unavoidable frustrations possibly experienced as persecutions. In the same way, when they have to meet the requirements of life in community, eg the discipline imposed within a college, these rules are more and more often felt by a pupil as unfair, arbitrary persecutions sometimes related to his own personality, "the teacher doesn't like me" of course, it is all the more legitimate to rebel against them as the charter of the pupils' rights, posted up in the school, has been read through very quickly by the teenagers. This mechanism takes one back to the archaically perception of environment by the very young child and to the projection developed by S. Freud in his description of the building "Ego-pure pleasure", (moi-plaisir purifie) (The Ego and the id, 1920). The opposed mechanism is expressed through an experience of shame felt by the subject when he is unable to satisfy, not the requests of his own impulses, but the social group's requirements. From the libidinal point of view, advertisements stimulate one's desires, incite one to consume and are at the origin of consumer needs. As a consequence, there is a resonance between the individual pleasure principle and the promotion of hedonism suggested by the society. The modern children have their mastery of impulse motions hampered by this phenomenon. The temporality of , new children " in new families sounds centered on the present, which is made of moments of eternity, always restarted (cyclic time of the first ages of life) ; it overrides historical time with a start, an end and references to intergeneration difference and filiations. This prevalence of present offers few support to neurotic defenses, with predictable problems in social interactions due to an inability to manage the tensions issued from the time discrepancies between one and his alter ego. Tran cultural studies have shown that to any social and cultural organization corresponds one or several basic personalities; among them, modem society has exuded the standard neurotic personality characterized by an ample mental space, a strict modulation of behaviors governed by the representations play and spreading out in Le théâtre du Je (The I theatre, Mac Dougall, 1982), a conflict between desire and internalized taboo, and the problematic of transgression and guilt. The modern family produces different personality structures. This led us to assume new basic personalities as follows, and to envision some psychopathological consequences: The passive dependent personality with an extreme narcissist fragility and at high risks of depressive disorders; The perverse-anarchistic personality characterized by subjects unable to feel guilty, taking at the best advantage of others to achieve his own ends thanks to his grasping of social situations and to his own seduction, lacking of true empathy; The slightly-psychopathic personality: these subjects can integrate well, but for a short time, in a social structure. They need to frequently find a new job, move in another place or country. Their relationships with others are always disrupted and changing for they can be involved in only short commitments. They are very susceptible to immediate gratifications.

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Immunization is the most common cause of iatrogenic pain in childhood. Despite the availability of various analgesics to manage vaccine injection pain, they have not been incorporated into clinical practice. To date, no systematic review has been published on the effectiveness of pharmacologic and combined interventions for reducing injection pain. The objectives of this article were to assess the effectiveness and tolerability of various pharmacologic and combined interventions for reducing the pain experienced by children during immunization. MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials were searched to identify randomized controlled trials (RCTs) and quasi-RCTs pertaining to pharmacologic and combined interventions to reduce injection pain in children 0 to 18 years of age using validated child self-reported pain or observer-reported assessments of child pain and distress. We included trials that (1) investigated the effects of pharmacologic interventions (ie, topical local anesthetics, sweet-tasting solutions, vapocoolants, and oral analgesics [acetaminophen or ibuprofen]); (2) compared 2 different analgesic interventions; and (3) evaluated combinations of &gt;or= 2 analgesic interventions, including breastfeeding. Meta-analyses were performed using a fixed-effects model. Thirty-two studies, involving 3856 infants and children 2 weeks to 15 years of age, were included in this systematic review; 23 of these trials were included in meta-analyses. Ten trials, including 1156 infants and children, evaluated topical local anesthetics. In a meta-analysis of 2 trials, including 276 children, child self-reported pain ratings were lower in children who received topical local anesthetics than in those who received a placebo. The standardized mean difference (SMD) was -0.25 (95% CI, -0.49 to -0.01; P = 0.04). The use of topical local anesthetics was associated with less pain than was placebo in 4 trials (527 infants) based on the difference between Modified Behavioral Pain Scale scores (range, 0-10) before and after vaccination: the weighted mean difference (WMD) was -0.79 (95% CI, -1.10 to -0.48; P &lt; 0.001) and the SMD was -0.43 (95% CI, -0.60 to -0.26; P = 0.001). Observer-rated pain, using visual analog scale (VAS) scores (range, 0-100 mm), was significantly lower (WMD, -16.56 mm; 95% CI, -22.11 to -11.01; P &lt; 0.001; and SMD, -0.75; 95% CI, -1.00 to -0.49; P &lt; 0.001). The number needed to treat (NNT) to prevent 1 child from having clinically significant pain, measured using the Faces Pain Scale (FPS; score, &gt;-3), was 3.7 (95% CI, 2.5 to 7.7) from 1 study. Eleven trials (1452 infants and children) evaluated sweet-tasting solutions. In a meta-analysis of 6 studies (665 infants), administration of sucrose with or without non-nutritive sucking (NNS; use of a pacifier) was associated with less pain than no intervention or sterile water with or without NNS; the SMD was -0.56 (95% CI, -0.72 to -0.40; P &lt; 0.001). Total cry duration was lower in infants who received sucrose than in those who received sterile water (WMD, -9.41 sec; 95% CI, -13.18 to -5.64; P &lt; 0.001; and SMD, -0.43; 95% CI, -0.61 to -0.25; P &lt; 0.001). The NNT to prevent 1 child from having clinically significant pain, using the Neonatal Infant Pain Scale (score, &gt;3), was 1.4 (95% CI, 1.0 to 2.5). In 3 trials that evaluated sweet-tasting solutions longitudinally, administration of sucrose or glucose (vs sterile water, with or without NNS) was associated with reduced pain based on cry duration or the University of Wisconsin Children's Hospital Pain Scale (all, P &lt; 0.05). Data were pooled for 2 studies conducted in 100 children who received a spray with a vapocoolant or placebo at the injection site before the procedure. Child self-rated pain (4-point scale) was lower in the group treated with the vapo-coolant (SMD, -0.43; 95% CI, -0.83 to -0.02; P = 0.04); significant heterogeneity was reported for this outcome (chi(2) = 5.51; P = 0.02; I(2) = 82%). In 2 studies (117 children), no significant difference was found between vapocoolants and typical care (no treatment) based on child self-reports; significant heterogeneity was reported for this outcome (chi(2) = 9.89; P = 0.02; I(2) = 90%). None of the studies identified in the literature search evaluated oral analgesics (acetaminophen or ibuprofen). Four studies (318 infants and children) compared 2 different analgesic interventions; there was insufficient evidence to suggest superiority of 1 intervention over another. Combinations of &gt;or=2 analgesic interventions were more effective than the individual interventions used alone. Child self-reported pain ratings were combined for 4 studies (350 children); the SMD was -0.52 (95% CI, -0.73 to -0.30; P = 0.001). Data on cry duration were pooled for 3 studies (229 infants and children); the WMD was -18.87 seconds (95% CI, -32.05 to -5.69; P = 0.005). Parent-rated child pain (VAS) scores were combined for 3 studies (365 infants and children); the WMD was -15.66 mm (95% CI, -19.74 to -11.57; P &lt; 0.001). Nurse- or physician-rated child pain (VAS) scores were combined for 3 studies (368 infants and children); the WMD was -17.85 mm (95% CI, -21.43 to -14.28; P &lt; 0.001). In a meta-analysis of 4 studies (474 infants), infants who were breastfed before, during, and after the procedure had less pain than did those who were not breastfed (SMD, -2.03; 95% CI, -2.26 to -1.80; P &lt; 0.001). A meta-analysis of 3 studies (344 infants) found a shorter cry duration for infants who were breastfed than for those who were not breastfed (WMD, -38.00 sec; 95% CI, -42.27 to -33.73; P &lt; 0.001; and SMD, -2.00; 95% CI, -2.27 to -1.73; P &lt; 0.001). The NNT to prevent 1 infant from having clinically significant pain, using the Facial Pain Rating Scale (pain vs no pain), was 7.7 (95% CI, 4.5 to 25.0) from 1 study. Topical local anesthetics, sweet-tasting solutions, and combined analgesic interventions, including breastfeeding, were associated with reduced pain during childhood immunizations and should be recommended for use in clinical practice.

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Patellofemoral pain syndrome (PFPS) is a common knee problem, which particularly affects adolescents and young adults. PFPS, which is characterised by retropatellar (behind the kneecap) or peripatellar (around the kneecap) pain, is often referred to as anterior knee pain. The pain mostly occurs when load is put on the knee extensor mechanism when climbing stairs, squatting, running, cycling or sitting with flexed knees. Exercise therapy is often prescribed for this condition. To assess the effects (benefits and harms) of exercise therapy aimed at reducing knee pain and improving knee function for people with patellofemoral pain syndrome. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (May 2014), the Cochrane Central Register of Controlled Trials (2014, Issue 4), MEDLINE (1946 to May 2014), EMBASE (1980 to 2014 Week 20), PEDro (to June 2014), CINAHL (1982 to May 2014) and AMED (1985 to May 2014), trial registers (to June 2014) and conference abstracts. Randomised and quasi-randomised trials evaluating the effect of exercise therapy on pain, function and recovery in adolescents and adults with patellofemoral pain syndrome. We included comparisons of exercise therapy versus control (e.g. no treatment) or versus another non-surgical therapy; or of different exercises or exercise programmes. Two review authors independently selected trials based on pre-defined inclusion criteria, extracted data and assessed risk of bias. Where appropriate, we pooled data using either fixed-effect or random-effects methods. We selected the following seven outcomes for summarising the available evidence: pain during activity (short-term: ≤ 3 months); usual pain (short-term); pain during activity (long-term: &gt; 3 months); usual pain (long-term); functional ability (short-term); functional ability (long-term); and recovery (long-term). In total, 31 heterogeneous trials including 1690 participants with patellofemoral pain are included in this review. There was considerable between-study variation in patient characteristics (e.g. activity level) and diagnostic criteria for study inclusion (e.g. minimum duration of symptoms) and exercise therapy. Eight trials, six of which were quasi-randomised, were at high risk of selection bias. We assessed most trials as being at high risk of performance bias and detection bias, which resulted from lack of blinding.The included studies, some of which contributed to more than one comparison, provided evidence for the following comparisons: exercise therapy versus control (10 trials); exercise therapy versus other conservative interventions (e.g. taping; eight trials evaluating different interventions); and different exercises or exercise programmes. The latter group comprised: supervised versus home exercises (two trials); closed kinetic chain (KC) versus open KC exercises (four trials); variants of closed KC exercises (two trials making different comparisons); other comparisons of other types of KC or miscellaneous exercises (five trials evaluating different interventions); hip and knee versus knee exercises (seven trials); hip versus knee exercises (two studies); and high- versus low-intensity exercises (one study). There were no trials testing exercise medium (land versus water) or duration of exercises. Where available, the evidence for each of seven main outcomes for all comparisons was of very low quality, generally due to serious flaws in design and small numbers of participants. This means that we are very unsure about the estimates. The evidence for the two largest comparisons is summarised here. Exercise versus control. Pooled data from five studies (375 participants) for pain during activity (short-term) favoured exercise therapy: mean difference (MD) -1.46, 95% confidence interval (CI) -2.39 to -0.54. The CI included the minimal clinically important difference (MCID) of 1.3 (scale 0 to 10), indicating the possibility of a clinically important reduction in pain. The same finding applied for usual pain (short-term; two studies, 41 participants), pain during activity (long-term; two studies, 180 participants) and usual pain (long-term; one study, 94 participants). Pooled data from seven studies (483 participants) for functional ability (short-term) also favoured exercise therapy; standardised mean difference (SMD) 1.10, 95% CI 0.58 to 1.63. Re-expressed in terms of the Anterior Knee Pain Score (AKPS; 0 to 100), this result (estimated MD 12.21 higher, 95% CI 6.44 to 18.09 higher) included the MCID of 10.0, indicating the possibility of a clinically important improvement in function. The same finding applied for functional ability (long-term; three studies, 274 participants). Pooled data (two studies, 166 participants) indicated that, based on the 'recovery' of 250 per 1000 in the control group, 88 more (95% CI 2 fewer to 210 more) participants per 1000 recovered in the long term (12 months) as a result of exercise therapy. Hip plus knee versus knee exercises. Pooled data from three studies (104 participants) for pain during activity (short-term) favoured hip and knee exercise: MD -2.20, 95% CI -3.80 to -0.60; the CI included a clinically important effect. The same applied for usual pain (short-term; two studies, 46 participants). One study (49 participants) found a clinically important reduction in pain during activity (long-term) for hip and knee exercise. Although tending to favour hip and knee exercises, the evidence for functional ability (short-term; four studies, 174 participants; and long-term; two studies, 78 participants) and recovery (one study, 29 participants) did not show that either approach was superior. This review has found very low quality but consistent evidence that exercise therapy for PFPS may result in clinically important reduction in pain and improvement in functional ability, as well as enhancing long-term recovery. However, there is insufficient evidence to determine the best form of exercise therapy and it is unknown whether this result would apply to all people with PFPS. There is some very low quality evidence that hip plus knee exercises may be more effective in reducing pain than knee exercise alone.Further randomised trials are warranted but in order to optimise research effort and engender the large multicentre randomised trials that are required to inform practice, these should be preceded by research that aims to identify priority questions and attain agreement and, where practical, standardisation regarding diagnostic criteria and measurement of outcome.

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Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive.Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms. To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. In February 2015 we searched six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers. We checked for additional trials in the reference lists of relevant reviews and included trials. We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data. We included all randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. At least 75% of participants needed to have an intellectual quotient of at least 70 (i.e. normal intellectual functioning). Outcomes assessed included ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and quality of life. Seventeen review authors participated in data extraction and risk of bias assessment, and two review authors independently performed all tasks. We used standard methodological procedures expected within Cochrane. Data from parallel-group trials and first period data from cross-over trials formed the basis of our primary analyses; separate analyses were undertaken using post-cross-over data from cross-over trials. We used Trial Sequential Analyses to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach for high risk of bias, imprecision, indirectness, heterogeneity and publication bias. The studies.We included 38 parallel-group trials (5111 participants randomised) and 147 cross-over trials (7134 participants randomised). Participants included individuals of both sexes, at a boys-to-girls ratio of 5:1, and participants' ages ranged from 3 to 18 years across most studies (in two studies ages ranged from 3 to 21 years). The average age across all studies was 9.7 years. Most participants were from high-income countries.The duration of methylphenidate treatment ranged from 1 to 425 days, with an average duration of 75 days. Methylphenidate was compared to placebo (175 trials) or no intervention (10 trials). Risk of Bias.All 185 trials were assessed to be at high risk of bias. Primary outcomes. Methylphenidate may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -0.90 to -0.64; 19 trials, 1698 participants; very low-quality evidence). This corresponds to a mean difference (MD) of -9.6 points (95% CI -13.75 to -6.38) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points; DuPaul 1991a). A change of 6.6 points on the ADHD-RS is considered clinically to represent the minimal relevant difference. There was no evidence that methylphenidate was associated with an increase in serious (e.g. life threatening) adverse events (risk ratio (RR) 0.98, 95% CI 0.44 to 2.22; 9 trials, 1532 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 0.91 (CI 0.02 to 33.2). Among those prescribed methylphenidate, 526 per 1000 (range 448 to 615) experienced non-serious adverse events, compared with 408 per 1000 in the control group. This equates to a 29% increase in the overall risk of any non-serious adverse events (RR 1.29, 95% CI 1.10 to 1.51; 21 trials, 3132 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 1.29 (CI 1.06 to 1.56). The most common non-serious adverse events were sleep problems and decreased appetite. Children in the methylphenidate group were at 60% greater risk for trouble sleeping/sleep problems (RR 1.60, 95% CI 1.15 to 2.23; 13 trials, 2416 participants), and 266% greater risk for decreased appetite (RR 3.66, 95% CI 2.56 to 5.23; 16 trials, 2962 participants) than children in the control group.Teacher-rated general behaviour seemed to improve with methylphenidate (SMD -0.87, 95% CI -1.04 to -0.71; 5 trials, 668 participants; very low-quality evidence).A change of seven points on the Child Health Questionnaire (CHQ; range 0 to 100 points; Landgraf 1998) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a MD of 8.0 points (95% CI 5.49 to 10.46) on the CHQ, which suggests that methylphenidate may improve parent-reported quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 3 trials, 514 participants; very low-quality evidence). The results of meta-analyses suggest that methylphenidate may improve teacher-reported ADHD symptoms, teacher-reported general behaviour, and parent-reported quality of life among children and adolescents diagnosed with ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow-up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non-serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases risk of serious adverse events.Better designed trials are needed to assess the benefits of methylphenidate. Given the frequency of non-serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, 'nocebo tablet' controlled trials. These use a placebo-like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. However, for ethical reasons, such trials should first be conducted with adults, who can give their informed consent.Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to age, sex, comorbidity, type of ADHD and dose. Finally, the findings highlight the urgent need for large RCTs of non-pharmacological treatments.

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Both in routine diagnostics and detailed, highly specialized workups, major advances have been observed in many areas of ultrasound due to an increase in expertise and improved technology in recent years. This is particularly true in the case of fetal neurosonography 1 2 3 4. Malformations of the CNS together with fetal heart defects are among the most common congenital anomalies. From the embryonic phase to the late third trimester, the CNS undergoes extensive development and maturation processes. The diagnosis of CNS anomalies is therefore primarily dependent on the time at which the examination is performed and the experience of the examiner. The introduction of transvaginal and 3 D ultrasound for evaluating fetal brain structures has made it possible to diagnose pathological findings of the CNS with increasing accuracy 5. The detection rates for CNS anomalies are up to 90 - 95 % depending on the finding 3 5. Today, detailed fetal neurosonography also includes differential diagnostic evaluation of the posterior cranial fossa, the corpus callosum (CC), and the gyri and therefore exceeds the primarily conspicuous, non-specific diagnosis of "ventricular dilation" often occurring as an accompanying symptom 6 7 The article "Prenatal Diagnosis of Corpus Callosum Anomalies" appearing in this issue shows an increase in the frequency of diagnosis and also shows that it is possible to differentiate between complete and partial corpus callosum agenesis and hypoplasia of the corpus callosum with differentiation between isolated and non-isolated cases is possible on ultrasound. In 4 of 44 cases in which both neurosonography and intrauterine MRI were performed, there was a discrepancy between the ultrasound diagnosis and the intrauterine MRI findings. In a comparison of the sonographic diagnoses and the MRI findings, additional pathologies were seen on MRI but not on ultrasound in only 3 of 44 cases. In a further case of CC hypoplasia, the sonographic diagnosis was superior to the MRI findings.Another study appearing in this issue study of CNS anomalies in fetuses with complex clubfoot also showed additionally diagnosed CNS anomalies in 4 cases on MRI. MRI yielded supplementary findings that were not visible on ultrasound in 6 cases. Although the number of cases is small, it was able to be shown, as in other studies, that a certain percentage of CNS anomalies is able to be evaluated on an additional or supplementary basis on MRI.Since intrauterine MRI has been becoming increasingly important in recent years, it is necessary to determine when MRI is indicated. There is general consensus in the literature that MRI is not a screening method for detecting fetal anomalies but should be viewed as a supplementary method to ultrasound 8 9 10. However, MRI application in pregnancy is increasing. Intrauterine MRI is most commonly used in the case of abnormal ultrasound findings regarding the CNS 11 12 13. This includes morphological evaluation of malformations and recently also of acquired hypoxic-ischemic diseases, bleeding and inflammation such as CMV infections. Thoracic and abdominal malformations are also indications for MRI for the evaluation of the lung volume in diaphragmatic defects and in the case of suspicion of esophageal atresia abnormal placentation. Further possible indications for the use of MRI include monochorial multiple pregnancies with a feto-fetal transfusion syndrome (for the evaluation of neurological development) and select cases with known diseases and syndromes 14. The majority of studies for comparing intrauterine MRI to sonographic diagnosis include a small number of cases with limited or no follow-up. Data regarding sensitivities, specificities, and positive predictive values is limited. Many studies simply calculate the difference in percentages on the basis of a small number of cases. The best available data is in regard to CNS anomalies. In one of the few meta-analyses including 34 studies and documented follow-up in 959 fetuses, intrauterine MRI was correct in 91 % of cases which was an increase of 16 % above that achieved by ultrasound 15. This means a significant diagnostic gain for specific issues. However, it must be taken into consideration that the analysis includes a period of 20 years and fetal neurosonography has made major progress in this time. The diagnostic gain would tend to be smaller today. In many studies the level of experience of the ultrasound examiners often remains unclear A possible bias is also that an examiner with less experience determines an indication for intrauterine MRI faster and more frequently and can thus gain more information compared to highly specialized, experienced ultrasound examiners in prenatal centers. Since advanced training in prenatal diagnosis is becoming increasingly difficult due to the transfer of centers to ambulatory practices, there is a certain risk that crash courses or brief internships in ultrasound will result in intrauterine MRI playing an additional role in fetal differential diagnosis and in the confirmation of findings. Because intrauterine MRI is stressful for pregnant women, indiscriminate indication for MRI cannot be recommended even if no fetal damage is to be expected provided that the appropriate safety measures are observed (examination duration of approx. 30 minutes and implementation of MRI after 18 weeks of gestation). After a properly performed ultrasound examination, little additional morphological information can be gained from MRI 16. However, in the case of an unclear sonographic finding or in the event of therapeutic consequences for the care of the fetus or for the birth, MRI is an excellent supplementary method to ultrasound. Concretely, this means ultrasound first. If the finding is not clear, intrauterine MRI can be used as an adjunct method. In this way the cost-benefit ratio can be optimized. The gains achieved by MRI compared to US depend on the quality of the examination and thus on the expertise of the examiner in both methods. The indications for fetal MRI should also follow defined standards based on a protocol adapted to the particular clinical issue 16.

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