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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 >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 < 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 < 0.001; and SMD, -0.75; 95% CI, -1.00 to -0.49; P < 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, >-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 < 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 < 0.001; and SMD, -0.43; 95% CI, -0.61 to -0.25; P < 0.001). The NNT to prevent 1 child from having clinically significant pain, using the Neonatal Infant Pain Scale (score, >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 < 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 >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 < 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 < 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 < 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 < 0.001; and SMD, -2.00; 95% CI, -2.27 to -1.73; P < 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: > 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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Outpatient care facilities provide a variety of basic healthcare services to individuals who do not require hospitalisation or institutionalisation, and are usually the patient's first contact. The provision of outpatient care contributes to immediate and large gains in health status, and a large portion of total health expenditure goes to outpatient healthcare services. Payment method is one of the most important incentive methods applied by purchasers to guide the performance of outpatient care providers. To assess the impact of different payment methods on the performance of outpatient care facilities and to analyse the differences in impact of payment methods in different settings. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), 2016, Issue 3, part of the Cochrane Library (searched 8 March 2016); MEDLINE, OvidSP (searched 8 March 2016); Embase, OvidSP (searched 24 April 2014); PubMed (NCBI) (searched 8 March 2016); Dissertations and Theses Database, ProQuest (searched 8 March 2016); Conference Proceedings Citation Index (ISI Web of Science) (searched 8 March 2016); IDEAS (searched 8 March 2016); EconLit, ProQuest (searched 8 March 2016); POPLINE, K4Health (searched 8 March 2016); China National Knowledge Infrastructure (searched 8 March 2016); Chinese Medicine Premier (searched 8 March 2016); OpenGrey (searched 8 March 2016); ClinicalTrials.gov, US National Institutes of Health (NIH) (searched 8 March 2016); World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (searched 8 March 2016); and the website of the World Bank (searched 8 March 2016).In addition, we searched the reference lists of included studies and carried out a citation search for the included studies via ISI Web of Science to find other potentially relevant studies. We also contacted authors of the main included studies regarding any further published or unpublished work. Randomised trials, non-randomised trials, controlled before-after studies, interrupted time series, and repeated measures studies that compared different payment methods for outpatient health facilities. We defined outpatient care facilities in this review as facilities that provide health services to individuals who do not require hospitalisation or institutionalisation. We only included methods used to transfer funds from the purchaser of healthcare services to health facilities (including groups of individual professionals). These include global budgets, line-item budgets, capitation, fee-for-service (fixed and unconstrained), pay for performance, and mixed payment. The primary outcomes were service provision outcomes, patient outcomes, healthcare provider outcomes, costs for providers, and any adverse effects. At least two review authors independently extracted data and assessed the risk of bias. We conducted a structured synthesis. We first categorised the comparisons and outcomes and then described the effects of different types of payment methods on different categories of outcomes. We used a fixed-effect model for meta-analysis within a study if a study included more than one indicator in the same category of outcomes. We used a random-effects model for meta-analysis across studies. If the data for meta-analysis were not available in some studies, we calculated the median and interquartile range. We reported the risk ratio (RR) for dichotomous outcomes and the relative change for continuous outcomes. We included 21 studies from Afghanistan, Burundi, China, Democratic Republic of Congo, Rwanda, Tanzania, the United Kingdom, and the United States of health facilities providing primary health care and mental health care. There were three kinds of payment comparisons. 1) Pay for performance (P4P) combined with some existing payment method (capitation or different kinds of input-based payment) compared to the existing payment methodWe included 18 studies in this comparison, however we did not include five studies in the effects analysis due to high risk of bias. From the 13 studies, we found that the extra P4P incentives probably slightly improved the health professionals' use of some tests and treatments (adjusted RR median = 1.095, range 1.01 to 1.17; moderate-certainty evidence), and probably led to little or no difference in adherence to quality assurance criteria (adjusted percentage change median = -1.345%, range -8.49% to 5.8%; moderate-certainty evidence). We also found that P4P incentives may have led to little or no difference in patients' utilisation of health services (adjusted RR median = 1.01, range 0.96 to 1.15; low-certainty evidence) and may have led to little or no difference in the control of blood pressure or cholesterol (adjusted RR = 1.01, range 0.98 to 1.04; low-certainty evidence). 2) Capitation combined with P4P compared to fee-for-service (FFS)One study found that compared with FFS, a capitated budget combined with payment based on providers' performance on antibiotic prescriptions and patient satisfaction probably slightly reduced antibiotic prescriptions in primary health facilities (adjusted RR 0.84, 95% confidence interval 0.74 to 0.96; moderate-certainty evidence). 3) Capitation compared to FFSTwo studies compared capitation to FFS in mental health centres in the United States. Based on these studies, the effects of capitation compared to FFS on the utilisation and costs of services were uncertain (very low-certainty evidence). Our review found that if policymakers intend to apply P4P incentives to pay health facilities providing outpatient services, this intervention will probably lead to a slight improvement in health professionals' use of tests or treatments, particularly for chronic diseases. However, it may lead to little or no improvement in patients' utilisation of health services or health outcomes. When considering using P4P to improve the performance of health facilities, policymakers should carefully consider each component of their P4P design, including the choice of performance measures, the performance target, payment frequency, if there will be additional funding, whether the payment level is sufficient to change the behaviours of health providers, and whether the payment to facilities will be allocated to individual professionals. Unfortunately, the studies included in this review did not help to inform those considerations.Well-designed comparisons of different payment methods for outpatient health facilities in low- and middle-income countries and studies directly comparing different designs (e.g. different payment levels) of the same payment method (e.g. P4P or FFS) are needed.

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Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient. To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD. 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 19 September 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 06 October 2016. Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status. We used standard Cochrane methodological procedures. We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention.Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion.Two trials compared the drug hydroxyurea 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 moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence).No deaths were reported in either trial.Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence).Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial)Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence).We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence).The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial)We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial)We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence).Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence).Neither trial reported on quality of life or cognitive function. We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD.Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises).In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions.Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention.All other evidence in this review is of very low-quality.

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Historically, women have generally been attended and supported by other women during labour. However, in hospitals worldwide, continuous support during labour has often become the exception rather than the routine. The primary objective was to assess the effects, on women and their babies, of continuous, one-to-one intrapartum support compared with usual care, in any setting. Secondary objectives were to determine whether the effects of continuous support are influenced by:1. Routine practices and policies in the birth environment that may affect a woman's autonomy, freedom of movement and ability to cope with labour, including: policies about the presence of support people of the woman's own choosing; epidural analgesia; and continuous electronic fetal monitoring.2. The provider's relationship to the woman and to the facility: staff member of the facility (and thus has additional loyalties or responsibilities); not a staff member and not part of the woman's social network (present solely for the purpose of providing continuous support, e.g. a doula); or a person chosen by the woman from family members and friends;3. Timing of onset (early or later in labour);4. Model of support (support provided only around the time of childbirth or extended to include support during the antenatal and postpartum periods);5. Country income level (high-income compared to low- and middle-income). We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2016), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (1 June 2017) and reference lists of retrieved studies. All published and unpublished randomised controlled trials, cluster-randomised trials comparing continuous support during labour with usual care. Quasi-randomised and cross-over designs were not eligible for inclusion. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We sought additional information from the trial authors. The quality of the evidence was assessed using the GRADE approach. We included a total of 27 trials, and 26 trials involving 15,858 women provided usable outcome data for analysis. These trials were conducted in 17 different countries: 13 trials were conducted in high-income settings; 13 trials in middle-income settings; and no studies in low-income settings. Women allocated to continuous support were more likely to have a spontaneous vaginal birth (average RR 1.08, 95% confidence interval (CI) 1.04 to 1.12; 21 trials, 14,369 women; low-quality evidence) and less likely to report negative ratings of or feelings about their childbirth experience (average RR 0.69, 95% CI 0.59 to 0.79; 11 trials, 11,133 women; low-quality evidence) and to use any intrapartum analgesia (average RR 0.90, 95% CI 0.84 to 0.96; 15 trials, 12,433 women). In addition, their labours were shorter (MD -0.69 hours, 95% CI -1.04 to -0.34; 13 trials, 5429 women; low-quality evidence), they were less likely to have a caesarean birth (average RR 0.75, 95% CI 0.64 to 0.88; 24 trials, 15,347 women; low-quality evidence) or instrumental vaginal birth (RR 0.90, 95% CI 0.85 to 0.96; 19 trials, 14,118 women), regional analgesia (average RR 0.93, 95% CI 0.88 to 0.99; 9 trials, 11,444 women), or a baby with a low five-minute Apgar score (RR 0.62, 95% CI 0.46 to 0.85; 14 trials, 12,615 women). Data from two trials for postpartum depression were not combined due to differences in women, hospitals and care providers included; both trials found fewer women developed depressive symptomatology if they had been supported in birth, although this may have been a chance result in one of the studies (low-quality evidence). There was no apparent impact on other intrapartum interventions, maternal or neonatal complications, such as admission to special care nursery (average RR 0.97, 95% CI 0.76 to 1.25; 7 trials, 8897 women; low-quality evidence), and exclusive or any breastfeeding at any time point (average RR 1.05, 95% CI 0.96 to 1.16; 4 trials, 5584 women; low-quality evidence).Subgroup analyses suggested that continuous support was most effective at reducing caesarean birth, when the provider was present in a doula role, and in settings in which epidural analgesia was not routinely available. Continuous labour support in settings where women were not permitted to have companions of their choosing with them in labour, was associated with greater likelihood of spontaneous vaginal birth and lower likelihood of a caesarean birth. Subgroup analysis of trials conducted in high-income compared with trials in middle-income countries suggests that continuous labour support offers similar benefits to women and babies for most outcomes, with the exception of caesarean birth, where studies from middle-income countries showed a larger reduction in caesarean birth. No conclusions could be drawn about low-income settings, electronic fetal monitoring, the timing of onset of continuous support or model of support.Risk of bias varied in included studies: no study clearly blinded women and personnel; only one study sufficiently blinded outcome assessors. All other domains were of varying degrees of risk of bias. The quality of evidence was downgraded for lack of blinding in studies and other limitations in study designs, inconsistency, or imprecision of effect estimates. Continuous support during labour may improve outcomes for women and infants, including increased spontaneous vaginal birth, shorter duration of labour, and decreased caesarean birth, instrumental vaginal birth, use of any analgesia, use of regional analgesia, low five-minute Apgar score and negative feelings about childbirth experiences. We found no evidence of harms of continuous labour support. Subgroup analyses should be interpreted with caution, and considered as exploratory and hypothesis-generating, but evidence suggests continuous support with certain provider characteristics, in settings where epidural analgesia was not routinely available, in settings where women were not permitted to have companions of their choosing in labour, and in middle-income country settings, may have a favourable impact on outcomes such as caesarean birth. Future research on continuous support during labour could focus on longer-term outcomes (breastfeeding, mother-infant interactions, postpartum depression, self-esteem, difficulty mothering) and include more woman-centred outcomes in low-income settings.

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Occupational exposure to hazardous drugs can decrease fertility and result in miscarriages, stillbirths, and cancers in healthcare staff. Several recommended practices aim to reduce this exposure, including protective clothing, gloves, and biological safety cabinets ('safe handling'). There is significant uncertainty as to whether using closed-system drug-transfer devices (CSTD) in addition to safe handling decreases the contamination and risk of staff exposure to infusional hazardous drugs compared to safe handling alone. To assess the effects of closed-system drug-transfer of infusional hazardous drugs plus safe handling versus safe handling alone for reducing staff exposure to infusional hazardous drugs and risk of staff contamination. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, OSH-UPDATE, CINAHL, Science Citation Index Expanded, economic evaluation databases, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov to October 2017. We included comparative studies of any study design (irrespective of language, blinding, or publication status) that compared CSTD plus safe handling versus safe handling alone for infusional hazardous drugs. Two review authors independently identified trials and extracted data. We calculated the risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CI) using both fixed-effect and random-effects models. We assessed risk of bias according to the risk of bias in non-randomised studies of interventions (ROBINS-I) tool, used an intracluster correlation coefficient of 0.10, and we assessed the quality of the evidence using GRADE. We included 23 observational cluster studies (358 hospitals) in this review. We did not find any randomised controlled trials or formal economic evaluations. In 21 studies, the people who used the intervention (CSTD plus safe handling) and control (safe handling alone) were pharmacists or pharmacy technicians; in the other two studies, the people who used the intervention and control were nurses, pharmacists, or pharmacy technicians. The CSTD used in the studies were PhaSeal (13 studies), Tevadaptor (1 study), SpikeSwan (1 study), PhaSeal and Tevadaptor (1 study), varied (5 studies), and not stated (2 studies). The studies' descriptions of the control groups were varied. Twenty-one studies provide data on one or more outcomes for this systematic review. All the studies are at serious risk of bias. The quality of evidence is very low for all the outcomes.There is no evidence of differences in the proportion of people with positive urine tests for exposure between the CSTD and control groups for cyclophosphamide alone (RR 0.83, 95% CI 0.46 to 1.52; I² = 12%; 2 studies; 2 hospitals; 20 participants; CSTD: 76.1% versus control: 91.7%); cyclophosphamide or ifosfamide (RR 0.09, 95% CI 0.00 to 2.79; 1 study; 1 hospital; 14 participants; CSTD: 6.4% versus control: 71.4%); and cyclophosphamide, ifosfamide, or gemcitabine (RR not estimable; 1 study; 1 hospital; 36 participants; 0% in both groups).There is no evidence of a difference in the proportion of surface samples contaminated in the pharmacy areas or patient-care areas for any of the drugs except 5-fluorouracil, which was lower in the CSTD group than in the control (RR 0.65, 95% CI 0.43 to 0.97; 3 studies, 106 hospitals, 1008 samples; CSTD: 9% versus control: 13.9%).The amount of cyclophosphamide was lower in pharmacy areas in the CSTD group than in the control group (MD -49.34 pg/cm², 95% CI -84.11 to -14.56, I² = 0%, 7 studies; 282 hospitals, 1793 surface samples). Additionally, one interrupted time-series study (3 hospitals; 342 samples) demonstrated a change in the slope between pre-CSTD and CSTD (3.9439 pg/cm², 95% CI 1.2303 to 6.6576; P = 0.010), but not between CSTD and post-CSTD withdrawal (-1.9331 pg/cm², 95% CI -5.1260 to 1.2598; P = 0.20). There is no evidence of difference in the amount of the other drugs between CSTD and control groups in the pharmacy areas or patient-care areas.None of the studies report on atmospheric contamination, blood tests, or other measures of exposure to infusional hazardous drugs such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, or micronuclei induction.None of the studies report short-term health benefits such as reduction in skin rashes, medium-term reproductive health benefits such as fertility and parity, or long-term health benefits related to the development of any type of cancer or adverse events.Five studies (six hospitals) report the potential cost savings through the use of CSTD. The studies used different methods of calculating the costs, and the results were not reported in a format that could be pooled via meta-analysis. There is significant variability between the studies in terms of whether CSTD resulted in cost savings (the point estimates of the average potential cost savings ranged from (2017) USD -642,656 to (2017) USD 221,818). There is currently no evidence to support or refute the routine use of closed-system drug transfer devices in addition to safe handling of infusional hazardous drugs, as there is no evidence of differences in exposure or financial benefits between CSTD plus safe handling versus safe handling alone (very low-quality evidence). None of the studies report health benefits.Well-designed multicentre randomised controlled trials may be feasible depending upon the proportion of people with exposure. The next best study design is interrupted time-series. This design is likely to provide a better estimate than uncontrolled before-after studies or cross-sectional studies. Future studies may involve other alternate ways of reducing exposure in addition to safe handling as one intervention group in a multi-arm parallel design or factorial design trial. Future studies should have designs that decrease the risk of bias and enable measurement of direct health benefits in addition to exposure. Studies using exposure should be tested for a relevant selection of hazardous drugs used in the hospital to provide an estimate of the exposure and health benefits of using CSTD. Steps should be undertaken to ensure that there are no other differences between CSTD and control groups, so that one can obtain a reasonable estimate of the health benefits of using CSTD.

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Water immersion during labour and birth is increasingly popular and is becoming widely accepted across many countries, and particularly in midwifery-led care settings. However, there are concerns around neonatal water inhalation, increased requirement for admission to neonatal intensive care unit (NICU), maternal and/or neonatal infection, and obstetric anal sphincter injuries (OASIS). This is an update of a review last published in 2011. To assess the effects of water immersion during labour and/or birth (first, second and third stage of labour) on women and their infants. We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (18 July 2017), and reference lists of retrieved trials. We included randomised controlled trials (RCTs) comparing water immersion with no immersion, or other non-pharmacological forms of pain management during labour and/or birth in healthy low-risk women at term gestation with a singleton fetus. Quasi-RCTs and cluster-RCTs were eligible for inclusion but none were identified. Cross-over trials were not eligible for inclusion. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two review authors assessed the quality of the evidence using the GRADE approach. This review includes 15 trials conducted between 1990 and 2015 (3663 women): eight involved water immersion during the first stage of labour; two during the second stage only; four during the first and second stages of labour, and one comparing early versus late immersion during the first stage of labour. No trials evaluated different baths/pools, or third-stage labour management. All trials were undertaken in a hospital labour ward setting, with a varying degree of medical intervention considered as routine practice. No study was carried out in a midwifery-led care setting. Most trial authors did not specify the parity of women. Trials were subject to varying degrees of bias: the intervention could not be blinded and there was a lack of information about randomisation, and whether analyses were undertaken by intention-to-treat.Immersion in water versus no immersion (first stage of labour)There is probably little or no difference in spontaneous vaginal birth between immersion and no immersion (82% versus 83%; risk ratio (RR) 1.01, 95% confidence interval (CI) 0.97 to 1.04; 6 trials; 2559 women; moderate-quality evidence); instrumental vaginal birth (14% versus 12%; RR 0.86, 95% CI 0.70 to 1.05; 6 trials; 2559 women; low-quality evidence); and caesarean section (4% versus 5%; RR 1.27, 95% CI 0.91 to 1.79; 7 trials; 2652 women; low-quality evidence). There is insufficient evidence to determine the effect of immersion on estimated blood loss (mean difference (MD) -14.33 mL, 95% CI -63.03 to 34.37; 2 trials; 153 women; very low-quality evidence) and third- or fourth-degree tears (3% versus 3%; RR 1.36, 95% CI 0.85 to 2.18; 4 trials; 2341 women; moderate-quality evidence). There was a small reduction in the risk of using regional analgesia for women allocated to water immersion from 43% to 39% (RR 0.91, 95% CI 0.83 to 0.99; 5 trials; 2439 women; moderate-quality evidence). Perinatal deaths were not reported, and there is insufficient evidence to determine the impact on neonatal intensive care unit (NICU) admissions (6% versus 8%; average RR 1.30, 95% CI 0.42 to 3.97; 2 trials; 1511 infants; I² = 36%; low-quality evidence), or on neonatal infection rates (1% versus 1%; RR 2.00, 95% CI 0.50 to 7.94; 5 trials; 1295 infants; very low-quality evidence).Immersion in water versus no immersion (second stage of labour)There were no clear differences between groups for spontaneous vaginal birth (97% versus 99%; RR 1.02, 95% CI 0.96 to 1.08; 120 women; 1 trial; low-quality evidence); instrumental vaginal birth (2% versus 2%; RR 1.00, 95% CI 0.06 to 15.62; 1 trial; 120 women; very low-quality evidence); caesarean section (2% versus 1%; RR 0.33, 95% CI 0.01 to 8.02; 1 trial; 120 women; very low-quality evidence), and NICU admissions (11% versus 9%; RR 0.78, 95% CI 0.38 to 1.59; 2 trials; 291 women; very low-quality evidence). Use of regional analgesia was not relevant to the second stage of labour. Third- or fourth-degree tears, and estimated blood loss were not reported in either trial. No trial reported neonatal infection but did report neonatal temperature less than 36.2°C at birth (9% versus 9%; RR 0.98, 95% CI 0.30 to 3.20; 1 trial; 109 infants; very low-quality evidence), greater than 37.5°C at birth (6% versus 15%; RR 2.62, 95% CI 0.73 to 9.35; 1 trial; 109 infants; very low-quality evidence), and fever reported in first week (5% versus 2%; RR 0.53, 95% CI 0.10 to 2.82; 1 trial; 171 infants; very low-quality evidence), with no clear effect between groups being observed. One perinatal death occurred in the immersion group in one trial (RR 3.00, 95% CI 0.12 to 72.20; 1 trial; 120 infants; very low-quality evidence). The infant was born to a mother with HIV and the cause of death was deemed to be intrauterine infection.There is no evidence of increased adverse effects to the baby or woman from either the first or second stage of labour.Only one trial (200 women) compared early and late entry into the water and there were insufficient data to show any clear differences. In healthy women at low risk of complications there is moderate to low-quality evidence that water immersion during the first stage of labour probably has little effect on mode of birth or perineal trauma, but may reduce the use of regional analgesia. The evidence for immersion during the second stage of labour is limited and does not show clear differences on maternal or neonatal outcomes intensive care. There is no evidence of increased adverse effects to the fetus/neonate or woman from labouring or giving birth in water. Available evidence is limited by clinical variability and heterogeneity across trials, and no trial has been conducted in a midwifery-led setting.

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Adequate nutrients early in life promote cognitive development and are critical for proper growth and functioning. The effect of individual nutrients consumed through food is often not the same as consuming the same nutrients in supplementary form due to 'food synergy', the biological and chemical interrelations that occur between nutrients. Animal-source foods, such as eggs, meat, fish, and dairy, are energy dense and contain multiple micronutrients and essential fatty acids with high bioavailability. The benefits of animal-source foods may include higher food synergy relative to fortified foods as well as decreasing dependence on external suppliers of fortified foods. To assess the effectiveness of animal-source foods compared to any other feeding interventions or no intervention in improving growth and developmental outcomes in children aged 6 to 59 months. We searched CENTRAL, MEDLINE, Embase, CINAHL, 18 other databases, and three trials registers up to August 2018. We also contacted authors and known experts in the field for assistance in identifying ongoing or unpublished data, and searched the reference lists of included studies and reviews, and websites of relevant organizations, for other studies that may not have been captured by our electronic searches. We included randomized controlled trials and quasi-randomized controlled trials of any duration, where children between 5 months and 59 months (6 years) of age were provided with an animal-source food (e.g. consumption of milk, meat, or eggs), prepared with any cooking method, compared with any intervention or no intervention. Two review authors independently assessed trial eligibility using prespecified criteria, extracted data, assessed risk of bias, and graded the quality of the evidence using the GRADE approach. Study characteristicsWe included 6 studies that analyzed data from 3036 children aged 5 to 50 months. The studies were conducted in China, the Democratic Republic of Congo, Ecuador, Guatemala, Pakistan, the USA, and Zambia, and lasted between 5 and 12 months. Three studies were funded, in part, by government entities; one study was supported by a nonprofit organization. Two studies did not report a funding source.Three studies compared the effects of feeding an animal-source food with a fortified (iron or iron and zinc), or unfortified cereal; two used a control group with no intervention; one compared a meat-based diet to a dairy-based diet. The types of animal-source foods tested included yogurt, eggs, cheese, lyophilized (freeze-dried) beef product, ground and frozen pork, puréed and jarred beef with gravy or pork, and powdered whey protein.We judged four studies to be at unclear risk of bias overall; three studies because they were funded by an industry with a plausible interest in the outcome of the intervention; and one study because there was insufficient information to assess five of the seven bias 'Risk of bias' domains. We judged two of the six studies to be at high risk of bias overall; one study because there was significant baseline imbalance in length-for-age z scores (LAZ) between groups and evidence of selective reporting; the other study because there there was both a significant baseline imbalance in LAZ and weight-for-age z scores (WAZ) between groups, and a large-scale social media campaign that may have influenced care received at home in the control group.Key resultsAnimal-source foods versus cereal-based foods or no interventionFive studies (2972 children) measured change in linear growth with either height-for-age z scores (HAZ) or LAZ. Three studies (592 children) reported a significant increase in HAZ and LAZ in the intervention group compared to the control group. Two studies (2380 children) reported a decline in LAZ in both groups. In one study (1062 children) there was no difference between the groups in the rate of decline; in the other (1318 children) the decrease in LAZ was significantly smaller in the intervention group.Five studies (2972 children) measured weight gain using WAZ. Three studies (592 children) reported a significant increase in WAZ in the intervention group compared to the control group. In two studies (2380 children), WAZ decreased in both groups. In one of these studies (1318 children), the decrease in the intervention group was significantly smaller than in the control group. In the other study (1062 children), there was no difference between the groups.Three studies (1612 children) reported impacts on all-cause morbidity, but metrics were inconsistent between studies. One study with yogurt (402 children) reported a significant reduction in duration and incidence of diarrhea and upper respiratory infections in the intervention group. One study with eggs (148 children) reported a significant increase in the incidence of diarrhea in the intervention group, but this may have been due to cultural associations with eggs and gastrointestional problems. There were no other significant differences in fever, respiratory infections, or skin conditions between groups. The third study (1062 children) found no differences between intervention and control groups across morbidity measures.No studies reported data on anemia.Meat-based diet versus dairy-based dietOne study (64 children) measured change in LAZ and WAZ in infants fed either a meat-based diet or dairy-based diet. There was a significant increase in LAZ among infants consuming the meat-based diet and a significant decrease in LAZ among infants consuming a dairy-based diet. WAZ increased in both groups, with no significant difference between groups.The study did not assess all-cause morbidity or anemia.Quality of the evidenceWe rated the quality of the evidence as very low overall due to baseline imbalances between intervention and control groups, high heterogeneity in meta-analysis, and imprecision due to wide confidence intervals and inconsistent direction of effects. We have little confidence in the results; further research is likely to change the estimate of magnitude and direction of treatment effect. Given the limited quality of the evidence, we are uncertain of the effects of the provision of animal-source food versus cereal products or no intervention on the growth or development of children. More adequately powered trials with deliberately selected animal-source foods are needed.

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In most pregnancies that miscarry, arrest of embryonic or fetal development occurs some time (often weeks) before the miscarriage occurs. Ultrasound examination can reveal abnormal findings during this phase by demonstrating anembryonic pregnancies or embryonic or fetal death. Treatment has traditionally been surgical but medical treatments may be effective, safe, and acceptable, as may be waiting for spontaneous miscarriage. This is an update of a review first published in 2006. To assess, from clinical trials, the effectiveness and safety of different medical treatments for the termination of non-viable pregnancies. For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (24 October 2018) and reference lists of retrieved studies. Randomised trials comparing medical treatment with another treatment (e.g. surgical evacuation), or placebo, or no treatment for early pregnancy failure. Quasi-randomised studies were excluded. Cluster-randomised trials were eligible for inclusion, as were studies reported in abstract form, if sufficient information was available to assess eligibility. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. Forty-three studies (4966 women) were included. The main interventions examined were vaginal, sublingual, oral and buccal misoprostol, mifepristone and vaginal gemeprost. These were compared with surgical management, expectant management, placebo, or different types of medical interventions were compared with each other. The review includes a wide variety of different interventions which have been analysed across 23 different comparisons. Many of the comparisons consist of single studies. We limited the grading of the quality of evidence to two main comparisons: vaginal misoprostol versus placebo and vaginal misoprostol versus surgical evacuation of the uterus. Risk of bias varied widely among the included trials. The quality of the evidence varied between the different comparisons, but was mainly found to be very-low or low quality.Vaginal misoprostol versus placeboVaginal misoprostol may hasten miscarriage when compared with placebo: e.g. complete miscarriage (5 trials, 305 women, risk ratio (RR) 4.23, 95% confidence interval (CI) 3.01 to 5.94; low-quality evidence). No trial reported on pelvic infection rate for this comparison. Vaginal misoprostol made little difference to rates of nausea (2 trials, 88 women, RR 1.38, 95% CI 0.43 to 4.40; low-quality evidence), diarrhoea (2 trials, 88 women, RR 2.21, 95% CI 0.35 to 14.06; low-quality evidence) or to whether women were satisfied with the acceptability of the method (1 trial, 32 women, RR 1.17, 95% CI 0.83 to 1.64; low-quality evidence). It is uncertain whether vaginal misoprostol reduces blood loss (haemoglobin difference > 10 g/L) (1 trial, 50 women, RR 1.25, 95% CI 0.38 to 4.12; very-low quality) or pain (opiate use) (1 trial, 84 women, RR 5.00, 95% CI 0.25 to 101.11; very-low quality), because the quality of the evidence for these outcomes was found to be very low.Vaginal misoprostol versus surgical evacuation Vaginal misoprostol may be less effective in accomplishing a complete miscarriage compared to surgical management (6 trials, 943 women, average RR 0.40, 95% CI 0.32 to 0.50; Heterogeneity: Tau² = 0.03, I² = 46%; low-quality evidence) and may be associated with more nausea (1 trial, 154 women, RR 21.85, 95% CI 1.31 to 364.37; low-quality evidence) and diarrhoea (1 trial, 154 women, RR 40.85, 95% CI 2.52 to 662.57; low-quality evidence). There may be little or no difference between vaginal misoprostol and surgical evacuation for pelvic infection (1 trial, 618 women, RR 0.73, 95% CI 0.39 to 1.37; low-quality evidence), blood loss (post-treatment haematocrit (%) (1 trial, 50 women, mean difference (MD) 1.40%, 95% CI -3.51 to 0.71; low-quality evidence), pain relief (1 trial, 154 women, RR 1.42, 95% CI 0.82 to 2.46; low-quality evidence) or women's satisfaction/acceptability of method (1 trial, 45 women, RR 0.67, 95% CI 0.40 to 1.11; low-quality evidence).Other comparisonsBased on findings from a single trial, vaginal misoprostol was more effective at accomplishing complete miscarriage than expectant management (614 women, RR 1.25, 95% CI 1.09 to 1.45). There was little difference between vaginal misoprostol and sublingual misoprostol (5 trials, 513 women, average RR 0.84, 95% CI 0.61 to 1.16; Heterogeneity: Tau² = 0.10, I² = 871%; or between oral and vaginal misoprostol in terms of complete miscarriage at less than 13 weeks (4 trials, 418 women), average RR 0.68, 95% CI 0.45 to 1.03; Heterogeneity: Tau² = 0.13, I² = 90%). However, there was less abdominal pain with vaginal misoprostol in comparison to sublingual (3 trials, 392 women, RR 0.58, 95% CI 0.46 to 0.74). A single study (46 women) found mifepristone to be more effective than placebo: miscarriage complete by day five after treatment (46 women, RR 9.50, 95% CI 2.49 to 36.19). However the quality of this evidence is very low: there is a very serious risk of bias with signs of incomplete data and no proper intention-to-treat analysis in the included study; and serious imprecision with wide confidence intervals. Mifepristone did not appear to further hasten miscarriage when added to a misoprostol regimen (3 trials, 447 women, RR 1.18, 95% CI 0.95 to 1.47). Available evidence from randomised trials suggests that medical treatment with vaginal misoprostol may be an acceptable alternative to surgical evacuation or expectant management. In general, side effects of medical treatment were minor, consisting mainly of nausea and diarrhoea. There were no major differences in effectiveness between different routes of administration. Treatment satisfaction was addressed in only a few studies, in which the majority of women were satisfied with the received intervention. Since the quality of evidence is low or very low for several comparisons, mainly because they included only one or two (small) trials; further research is necessary to assess the effectiveness, safety and side effects, optimal route of administration and dose of different medical treatments for early fetal death.

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The World Health Organization (WHO) recommends treating all school children at regular intervals with deworming drugs in areas where helminth infection is common. Global advocacy organizations claim routine deworming has substantive health and societal effects beyond the removal of worms. In this update of the 2015 edition we included six new trials, additional data from included trials, and addressed comments and criticisms. To summarize the effects of public health programmes to regularly treat all children with deworming drugs on child growth, haemoglobin, cognition, school attendance, school performance, physical fitness, and mortality. We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; LILACS; the metaRegister of Controlled Trials (mRCT); reference lists; and registers of ongoing and completed trials up to 19 September 2018. We included randomized controlled trials (RCTs) and quasi-RCTs that compared deworming drugs for soil-transmitted helminths (STHs) with placebo or no treatment in children aged 16 years or less, reporting on weight, height, haemoglobin, and formal tests of cognition. We also sought data on other measures of growth, school attendance, school performance, physical fitness, and mortality. At least two review authors independently assessed the trials for inclusion, risk of bias, and extracted data. We analysed continuous data using the mean difference (MD) with 95% confidence intervals (CIs). Where data were missing, we contacted trial authors. We stratified the analysis based on the background burden of STH infection. We used outcomes at time of longest follow-up. We assessed the certainty of the evidence using the GRADE approach. We identified 51 trials, including 10 cluster-RCTs, that met the inclusion criteria. One trial evaluating mortality included over one million children, and the remaining 50 trials included a total of 84,336 participants. Twenty-four trials were in populations categorized as high burden, including nine trials in children selected because they were helminth-stool positive; 18 with intermediate burden; and nine as low burden.First or single dose of deworming drugsFourteen trials reported on weight after a single dose of deworming drugs (4970 participants, 14 RCTs). The effects were variable. There was little or no effect in studies conducted in low and intermediate worm burden groups. In the high-burden group, there was little or no effect in most studies, except for a large effect detected from one study area in Kenya reported in two trials carried out over 30 years ago. These trials result in qualitative heterogeneity and uncertainty in the meta-analysis across all studies (I<sup2</sup statistic = 90%), with GRADE assessment assessed as very low-certainty, which means we do not know if a first dose or single dose of deworming impacts on weight.For height, most studies showed little or no effect after a single dose, with one of the two trials in Kenya from 30 years ago showing a large average difference (2621 participants, 10 trials, low-certainty evidence). Single dose probably had no effect on average haemoglobin (MD 0.10 g/dL, 95% CI 0.03 lower to 0.22 higher; 1252 participants, five trials, moderate-certainty evidence), or on average cognition (1596 participants, five trials, low-certainty evidence). The data are insufficient to know if there is an effect on school attendance and performance (304 participants, one trial, low-certainty evidence), or on physical fitness (280 participants, three trials, very low-certainty evidence). No trials reported on mortality.Multiple doses of deworming drugsThe effect of regularly treating children with deworming drugs given every three to six months on weight was reported in 18 trials, with follow-up times of between six months and three years; there was little or no effect on average weight in all but two trials, irrespective of worm prevalence-intensity. The two trials with large average weight gain included one in the high burden area in Kenya carried out over 30 years ago, and one study from India in a low prevalence area where subsequent studies in the same area did not show an effect. This heterogeneity causes uncertainty in any meta-analysis (I<sup2</sup = 78%). Post-hoc analysis excluding trials published prior to 2000 gave an estimate of average difference in weight gain of 0.02 kg (95%CI from 0.04 kg loss to 0.08 gain, I<sup2</sup = 0%). Thus we conclude that we do not know if repeated doses of deworming drugs impact on average weight, with a fewer older studies showing large gains, and studies since 2000 showing little or no average gain.Regular treatment probably had little or no effect on the following parameters: average height (MD 0.02 cm higher, 95% CI 0.09 lower to 0.13 cm higher; 13,700 participants, 13 trials, moderate-certainty evidence); average haemoglobin (MD 0.01 g/dL lower; 95% CI 0.05 g/dL lower to 0.07 g/dL higher; 5498 participants, nine trials, moderate-certainty evidence); formal tests of cognition (35,394 participants, 8 trials, moderate-certainty evidence); school performance (34,967 participants, four trials, moderate-certainty evidence). The evidence assessing an effect on school attendance is inconsistent, and at risk of bias (mean attendance 2% higher, 95% CI 5% lower to 8% higher; 20,650 participants, three trials, very low-certainty evidence). No trials reported on physical fitness. No effect was shown on mortality (1,005,135 participants, three trials, low-certainty evidence). Public health programmes to regularly treat all children with deworming drugs do not appear to improve height, haemoglobin, cognition, school performance, or mortality. We do not know if there is an effect on school attendance, since the evidence is inconsistent and at risk of bias, and there is insufficient data on physical fitness. Studies conducted in two settings over 20 years ago showed large effects on weight gain, but this is not a finding in more recent, larger studies. We would caution against selecting only the evidence from these older studies as a rationale for contemporary mass treatment programmes as this ignores the recent studies that have not shown benefit.The conclusions of the 2015 edition have not changed in this update.

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Lumbosacral radicular pain (commonly called sciatica) is a syndrome involving patients who report radiating leg pain. Epidural corticosteroid injections deliver a corticosteroid dose into the epidural space, with the aim of reducing the local inflammatory process and, consequently, relieving the symptoms of lumbosacral radicular pain. This Cochrane Review is an update of a review published in Annals of Internal Medicine in 2012. Some placebo-controlled trials have been published recently, which highlights the importance of updating the previous review. To investigate the efficacy and safety of epidural corticosteroid injections compared with placebo injection on pain and disability in patients with lumbosacral radicular pain. We searched the following databases without language limitations up to 25 September 2019: Cochrane Back and Neck group trial register, CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, International Pharmaceutical Abstracts, and two trial registers. We also performed citation tracking of included studies and relevant systematic reviews in the field. We included studies that compared epidural corticosteroid injections of any corticosteroid drug to placebo injections in patients with lumbosacral radicular pain. We accepted all three anatomical approaches (caudal, interlaminar, and transforaminal) to delivering corticosteroids into the epidural space. We considered trials that included a placebo treatment as delivery of an inert substance (i.e. one with no pharmacologic activity), an innocuous substance (e.g. normal saline solution), or a pharmacologically active substance but not one considered to provide sustained benefit (e.g. local anaesthetic), either into the epidural space (i.e. to mimic epidural corticosteroid injection) or adjacent spinal tissue (i.e. subcutaneous, intramuscular, or interspinous tissue). We also included trials in which a local anaesthetic with a short duration of action was used as a placebo and injected together with corticosteroid in the intervention group. Two authors independently performed the screening, data extraction, and 'Risk of bias' assessments. In case of insufficient information, we contacted the authors of the original studies or estimated the data. We grouped the outcome data into four time points of assessment: immediate (≤ 2 weeks), short term (&gt; 2 weeks but ≤ 3 months), intermediate term (&gt; 3 months but &lt; 12 months), and long term (≥ 12 months). We assessed the overall quality of evidence for each outcome and time point using the GRADE approach. We included 25 clinical trials (from 29 publications) investigating the effects of epidural corticosteroid injections compared to placebo in patients with lumbosacral radicular pain. The included studies provided data for a total of 2470 participants with a mean age ranging from 37.3 to 52.8 years. Seventeen studies included participants with lumbosacral radicular pain with a diagnosis based on clinical assessment and 15 studies included participants with mixed duration of symptoms. The included studies were conducted mainly in North America and Europe. Fifteen studies did not report funding sources, five studies reported not receiving funding, and five reported receiving funding from a non-profit or government source. Eight trials reported data on pain intensity, 12 reported data on disability, and eight studies reported data on adverse events. The duration of the follow-up assessments ranged from 12 hours to 1 year. We considered eight trials to be of high quality because we judged them as having low risk of bias in four out of the five bias domains. We identified one ongoing trial in a trial registry. Epidural corticosteroid injections were probably slightly more effective compared to placebo in reducing leg pain at short-term follow-up (mean difference (MD) -4.93, 95% confidence interval (CI) -8.77 to -1.09 on a 0 to 100 scale; 8 trials, n = 949; moderate-quality evidence (downgraded for risk of bias)). For disability, epidural corticosteroid injections were probably slightly more effective compared to placebo in reducing disability at short-term follow-up (MD -4.18, 95% CI -6.04 to -2.17, on a 0 to 100 scale; 12 trials, n = 1367; moderate-quality evidence (downgraded for risk of bias)). The treatment effects are small, however, and may not be considered clinically important by patients and clinicians (i.e. MD lower than 10%). Most trials provided insufficient information on how or when adverse events were assessed (immediate or short-term follow-up) and only reported adverse drug reactions - that is, adverse events that the trialists attributed to the study treatment. We are very uncertain that epidural corticosteroid injections make no difference compared to placebo injection in the frequency of minor adverse events (risk ratio (RR) 1.14, 95% CI 0.91 to 1.42; 8 trials, n = 877; very low quality evidence (downgraded for risk of bias, inconsistency and imprecision)). Minor adverse events included increased pain during or after the injection, non-specific headache, post-dural puncture headache, irregular periods, accidental dural puncture, thoracic pain, non-local rash, sinusitis, vasovagal response, hypotension, nausea, and tinnitus. One study reported a major drug reaction for one patient on anticoagulant therapy who had a retroperitoneal haematoma as a complication of the corticosteroid injection. This study found that epidural corticosteroid injections probably slightly reduced leg pain and disability at short-term follow-up in people with lumbosacral radicular pain. In addition, no minor or major adverse events were reported at short-term follow-up after epidural corticosteroid injections or placebo injection. Although the current review identified additional clinical trials, the available evidence still provides only limited support for the use of epidural corticosteroid injections in people with lumbosacral radicular pain as the treatment effects are small, mainly evident at short-term follow-up and may not be considered clinically important by patients and clinicians (i.e. mean difference lower than 10%). According to GRADE, the quality of the evidence ranged from very low to moderate, suggesting that further studies are likely to play an important role in clarifying the efficacy and tolerability of this treatment. We recommend that further trials should attend to methodological features such as appropriate allocation concealment and blinding of care providers to minimise the potential for biased estimates of treatment and harmful effects.

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Despite the health benefits of breastfeeding, initiation and duration rates continue to fall short of international guidelines. Many factors influence a woman's decision to wean; the main reason cited for weaning is associated with lactation complications, such as mastitis. Mastitis is an inflammation of the breast, with or without infection. It can be viewed as a continuum of disease, from non-infective inflammation of the breast to infection that may lead to abscess formation. To assess the effectiveness of preventive strategies (for example, breastfeeding education, pharmacological treatments and alternative therapies) on the occurrence or recurrence of non-infective or infective mastitis in breastfeeding women post-childbirth. We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (3 October 2019), and reference lists of retrieved studies. We included randomised controlled trials of interventions for preventing mastitis in postpartum breastfeeding women. Quasi-randomised controlled trials and trials reported only in abstract form were eligible. We attempted to contact the authors to obtain any unpublished results, wherever possible.  Interventions for preventing mastitis may include: probiotics, specialist breastfeeding advice and holistic approaches.   DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and assessed the certainty of the evidence using GRADE. We included 10 trials (3034 women). Nine trials (2395 women) contributed data. Generally, the trials were at low risk of bias in most domains but some were high risk for blinding, attrition bias, and selective reporting. Selection bias (allocation concealment) was generally unclear. The certainty of evidence was downgraded due to risk of bias and to imprecision (low numbers of women participating in the trials). Conflicts of interest on the part of trial authors, and the involvement of industry funders may also have had an impact on the certainty of the evidence. Most trials reported our primary outcome of incidence of mastitis but there were almost no data relating to adverse effects, breast pain, duration of breastfeeding, nipple damage, breast abscess or recurrence of mastitis. Probiotics versus placebo Probiotics may reduce the risk of mastitis more than placebo (risk ratio (RR) 0.51, 95% confidence interval (CI) 0.35 to 0.75; 2 trials; 399 women; low-certainty evidence). It is uncertain if probiotics reduce the risk of breast pain or nipple damage because the certainty of evidence is very low. Results for the biggest of these trials (639 women) are currently unavailable due to a contractual agreement between the probiotics supplier and the trialists. Adverse effects were reported in one trial, where no woman in either group experienced any adverse effects. Antibiotics versus placebo or usual care The risk of mastitis may be similar between antibiotics and usual care or placebo (RR 0.37, 95% CI 0.10 to 1.34; 3 trials; 429 women; low-certainty evidence). The risk of mastitis may be similar between antibiotics and fusidic acid ointment (RR 0.22, 95% CI 0.03 to 1.81; 1 trial; 36 women; low-certainty evidence) or mupirocin ointment (RR 0.44, 95% CI 0.05 to 3.89; 1 trial; 44 women; low-certainty evidence) but we are uncertain due to the wide CIs. None of the trials reported adverse effects. Topical treatments versus breastfeeding advice The risk of mastitis may be similar between fusidic acid ointment and breastfeeding advice (RR 0.77, 95% CI 0.27 to 2.22; 1 trial; 40 women; low-certainty evidence) and mupirocin ointment and breastfeeding advice (RR 0.39, 95% CI 0.12 to 1.35; 1 trial; 48 women; low-certainty evidence) but we are uncertain due to the wide CIs. One trial (42 women) compared topical treatments to each other. The risk of mastitis may be similar between fusidic acid and mupirocin (RR 0.51, 95% CI 0.13 to 2.00; low-certainty evidence) but we are uncertain due to the wide CIs. Adverse events were not reported. Specialist breastfeeding education versus usual care The risk of mastitis (RR 0.93, 95% CI 0.17 to 4.95; 1 trial; 203 women; low-certainty evidence) and breast pain (RR 0.93, 95% CI 0.36 to 2.37; 1 trial; 203 women; low-certainty evidence) may be similar but we are uncertain due to the wide CIs. Adverse events were not reported. Anti-secretory factor-inducing cereal versus standard cereal The risk of mastitis (RR 0.24, 95% CI 0.03 to 1.72; 1 trial; 29 women; low-certainty evidence) and recurrence of mastitis (RR 0.39, 95% CI 0.03 to 4.57; 1 trial; 7 women; low-certainty evidence) may be similar but we are uncertain due to the wide CIs. Adverse events were not reported. Acupoint massage versus routine care Acupoint massage probably reduces the risk of mastitis compared to routine care (RR 0.38, 95% CI 0.19 to 0.78;1 trial; 400 women; moderate-certainty evidence) and breast pain (RR 0.13, 95% CI 0.07 to 0.23; 1 trial; 400 women; moderate-certainty evidence). Adverse events were not reported. Breast massage and low frequency pulse treatment versus routine care Breast massage and low frequency pulse treatment may reduce risk of mastitis (RR 0.03, 95% CI 0.00 to 0.21; 1 trial; 300 women; low-certainty evidence). Adverse events were not reported. There is some evidence that acupoint massage is probably better than routine care, probiotics may be better than placebo, and breast massage and low frequency pulse treatment may be better than routine care for preventing mastitis. However, it is important to note that we are aware of at least one large trial investigating probiotics whose results have not been made public, therefore, the evidence presented here is incomplete. The available evidence regarding other interventions, including breastfeeding education, pharmacological treatments and alternative therapies, suggests these may be little better than routine care for preventing mastitis but our conclusions are uncertain due to the low certainty of the evidence. Future trials should recruit sufficiently large numbers of women in order to detect clinically important differences between interventions and results of future trials should be made publicly available.

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The experiments strongly suggested that the reason why Purkinje cells die so easily after global brain ischemia relates to deficiencies in aldolase C and EAAT4 that allow them to survive pathologically intense synaptic input from the inferior olive after the restoration of blood flow. This conclusion is based on: (a) the remarkably tight correspondence between the regional absence of aldolase C and EAAT4 in Purkinje cells and the patterned loss of Purkinje cells after a bout of global brain ischemia; (b) the necessity of the olivocerebellar pathway for the ischemic death of Purkinje cells; and (c) the build-up of pathologically synchronous and high-frequency burst activity within the inferior olive during recovery from ischemia. Indeed, the correspondence between the absence of aldolase C and EAAT4 to sensitivity to ischemia could be demonstrated for zones of Purkinje cells as small as two neurons. A second finding was that Purkinje cells are not uniformly sensitive to transient ischemia, since they die most frequently in zones where aldolase C and EAAT4 are absent. One implication of the experiment is that factors beyond the unique synaptic and membrane properties of Purkinje cells play an important role in determining this neuron's high sensitivity to ischemia. The data strongly imply that two properties of Purkinje cells that make them susceptible to ischemic death are their reduced capability to sequester glutamate and reduced ability to generate energy during anoxia. The patterned death of Purkinje cells is sufficient to induce a form of audiogenic myoclonus, as determined with a neurotoxic dose of ibogaine. Ibogaine-induced myoclonus is recognized behaviorally as a reduced ability to habituate to a startle stimulus and resembles the myoclonic jerk of rats during recovery from a prolonged bout of global brain ischemia. Commonalities of ischemia and ibogaine-induced neurodegeneration are the intricately striped Purkinje cell loss in the posterior lobe and a nearly complete deafferentation of the lateral aspect of the fastigial nucleus from the cerebellar cortex, in particular the dorsolateral protuberance. Thus, the data point strongly to a cerebellar contribution to audiogenic myoclonus. Single-neuron electrophysiology experiments in monkeys have demonstrated that the evoked activity in the deep cerebellar nuclei occurs too late to initiate the startle response (60) and electromyography of the postischemic myoclonus of rats corroborates this view (see Chapter 31) (20). However, the nearly complete loss of GABAergic terminals in the dorsolateral protuberance after Purkinje cell death would be expected to dramatically increase its tonic firing and the background excitation of the brain-stem structures that it innervates. The fastigial nucleus innervates a large number of autonomic and motor structures in the brainstem and diencephalon, including the ventrolateral nucleus of the thalamus and the gigantocellular reticular nucleus in the medulla--structures that have been implicated in human posthypoxic myoclonus (6, 7). We propose that the posthypoxic myoclonic jerk of rats is, at least in part, due to disinhibition of the fastigial nucleus produced by patterned Purkinje cell death in the vermis. The argument is as follows: the loss of GABAergic inhibition in the fastigial nucleus after ischemia leads to diaschisis of the motor thalamus and reticular formation which, in turn, is responsible for enhanced motor excitability and myoclonus. That the audiogenic myoclonus after global brain ischemia in the rat gradually resolves over a period of 2 to 3 weeks is consistent with this view, as restoration of background excitability after CNS damage in rats has been documented to occur within this time-frame (61). Our view brings together the physiologic finding that posthypoxic myoclonus appears to originate in the sensory-motor cortices and/or reticular formation with the consistent anatomical finding of Purkinje cell loss after ischemia, and explains the puzzle of Marsden's unique cases of myoclonus associated with coeliac disease (1). Moreover, our argument is consistent with findings both in rats (62, 63) and humans (64) that damage to the vermis impairs the long-term habituation of the startle reflex. It remains to be determined whether the pathologically enhanced startle responses after vermal damage resemble brain-stem reticular or cortical myoclonus at the electrophysiologic level of analysis. What is the purpose of the regional expression of aldolase C and EAAT4 in Purkinje cells? The close correspondence between the spatial distribution of aldolase C and the parasagittal anatomy of the cerebellum (48) has led to the view that aldolase C may help specify connectivity during development. While the present experiments do not address this issue, they underscore the fact that aldolase plays a fundamental role in metabolism. Because Purkinje cells have a repressed expression of aldolase A (31), whatever role the absence of aldolase C may play during development comes at the price of metabolic frailty later in adulthood. From another point of view, aldolase C and EAAT4 appear to confer upon Purkinje cells the ability to survive their own climbing fiber. Indeed, climbing fibers form a distributed synapse that synchronously releases glutamate (or aspartate) at all levels of the dendritic tree simultaneously (65, 66). Such synchronous activation triggers calcium influx throughout the Purkinje cell dendrites at a magnitude that is unparalleled in the nervous system (12), and, thus, places an extraordinarily high metabolic demand on the Purkinje cell. The apparently reduced level of aldolase in a subpopulation of Purkinje cells provides the condition for energy failure and death during anoxia so long as the climbing fibers are intact or when climbing fiber activation is pharmacologically enhanced under normoxic conditions, such as after ibogaine (53-56). Lastly, the argument that diaschisis produced by patterned cerebellar degeneration leads to thalamo-cortical and reticular hyperexcitability agrees with C. David Marsden and his colleagues' bold demonstration of an inhibitory influence of cerebellar cortex on motor cortex in humans (67). Our anatomic data indicate that the spatially distinct zones of Purkinje cells, which are killed by global brain ischemia, may be the origin of such inhibition.

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To assess the risk of clinical complications associated with thrombophilia in three high-risk patient groups: women using oral oestrogen preparations, women during pregnancy and patients undergoing major orthopaedic surgery. To assess the effectiveness of prophylactic treatments in preventing venous thromboembolism (VTE) and adverse pregnancy outcomes in women with thrombophilia during pregnancy and VTE in patients with thrombophilia, undergoing major orthopaedic surgery. To evaluate the relative cost-effectiveness of universal and selective VTE history-based screening for thrombophilia compared with no screening in the three high-risk patient groups. Electronic databases including MEDLINE, EMBASE, and four other major databases were searched up to June 2003. In order to assess the risk of clinical complications associated with thrombophilia, a systematic review of the literature on VTE and thrombophilia in women using oral oestrogen preparations and patients undergoing major orthopaedic surgery; and studies of VTE and adverse obstetric complications in women with thrombophilia during pregnancy was carried out. Meta-analysis was used to calculate pooled odds ratios (ORs) associated with individual clinical outcomes, stratified by thrombophilia type and were calculated for each patient group. To assess the effectiveness of prophylaxis, a systematic review was carried out on the use of prophylaxis in the prevention of VTE and pregnancy loss in pregnant women with thrombophilic defects and the use of thromboprophylaxis in the prevention of VTE in patients with thrombophilia undergoing major elective orthopaedic surgery. Relevant data were summarised according to the patient groups and stratified according to the types of prophylaxis. A narrative summary was provided; where appropriate, meta-analysis was conducted. An incremental cost-effectiveness analysis was then carried out, from the perspective of the NHS in the UK. A decision analytical model was developed to simulate the clinical consequences of four thrombophilia screening scenarios. Results from the meta-analyses, information from the literature and results of two Delphi studies of clinical management of VTE and adverse pregnancy complications were incorporated into the model. Only direct health service costs were measured and unit costs for all healthcare resources used were obtained from routinely collected data and the literature. Cost-effectiveness was expressed as incremental cost-effectiveness ratios (ICERs); an estimate of the cost per adverse clinical complication prevented, comparing screening with no screening, were calculated for each patient group. In the review of risk of clinical complications, 81 studies were included, nine for oral oestrogen preparations, 72 for pregnancy and eight for orthopaedic surgery. For oral contraceptive use, significant associations of the risk of VTE were found in women with factor V Leiden (FVL); deficiencies of antithrombin, protein C, or protein S, elevated levels of factor VIIIc; and FVL and prothrombin G20210A. For hormone replacement therapy (HRT), a significant association was found in women with FVL. The highest risk in pregnancy was found for FVL and VTE, in particular, homozygous carriers of this mutation are 34 times more likely to develop VTE in pregnancy than non-carriers. Significant risks for individual thrombophilic defects were also established for early, recurrent and late pregnancy loss; preeclampsia; placental abruption; and intrauterine growth restriction. Significant associations were found between FVL and high factor VIIIc and postoperative VTE following elective hip or knee replacement surgery. Prothrombin G20210A was significantly associated with postoperative pulmonary embolism. However, antithrombin deficiency, MTHFR and hyperhomocysteinaemia were not associated with increased risk of postoperative VTE. In the review of the effectiveness of prophylaxis, based on available data from eight studies, low-dose aspirin and heparin was found to be the most effective in preventing pregnancy loss in thrombophilic women during pregnancy, while aspirin alone was the most effective in preventing minor bleeding. All the studies on thrombophilia and major elective orthopaedic surgery included in the review of risk complications were also used in the review of the effectiveness of thromboprophylaxis. However, there were insufficient data to determine the relative effectiveness of different thromboprophylaxis in preventing VTE in this patient group. For the cost-effectiveness analysis, of all the patient groups evaluated, universal screening of women prior to prescribing HRT was the most cost-effective (ICER pound6824). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy (ICER pound202,402). Selective thrombophilia screening based on previous personal and/or family history of VTE was more cost-effective than universal screening in all the patient groups evaluated. Thrombophilia is associated with increased risks of VTE in women taking oral oestrogen preparations and patients undergoing major elective orthopaedic surgery, and of VTE and adverse pregnancy outcomes in women with thrombophilia during pregnancy. There is considerable difference in the magnitude of the risks among different patient groups with different thrombophilic defects. In women who are on combined oral contraceptives, the OR of VTE among those who are carriers of the FVL mutation was 15.62 (95% confidence interval 8.66 to 28.15). However, in view of the prevalence of thrombophilia and the low prevalence of VTE in non-users of combined oral contraceptives, the absolute risk remains low. Significant risks for VTE and adverse pregnancy outcomes have been established with individual thrombophilic defects. Thrombophilic defects including FVL, high plasma factor VIIIc levels and prothrombin G20210A are associated with the occurrence of postoperative VTE in elective hip or knee replacement therapy. These associations are observed in patients who were given preoperative thromboprophylaxis and are, therefore, of clinical significance. Universal thrombophilia screening in women prior to prescribing oral oestrogen preparations, in women during pregnancy and in patients undergoing major orthopaedic surgery is not supported by current evidence. The findings from this study show that selective screening based on prior VTE history is more cost-effective than universal screening. Large prospective studies should be undertaken to refine the risks and establish the associations of thrombophilias with VTE among hormone users and in patients undergoing orthopaedic surgery. The relative value of a thrombophilia screening programme to other healthcare programmes needs to be established.

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A new theory of bio-energy transport along protein molecules in living systems, where the energy is released by hydrolysis of adenosine triphosphate (ATP), is proposed based on some physical and biological reasons. In the new theory, the Davydov's Hamiltonian and wave function of the systems are simultaneously modified and extended. A new interaction has been added into Davydov's Hamiltonian. The wave function of the excitation state of single particles for the excitons in the Davydov model is replaced by a new wave function of two-quanta quasicoherent state. In such a case, the bio-energy is transported by the new soliton, which differs from the Davydov's soliton. The soliton is formed through self- trapping of two excitons interacting amino acid residues. The exciton is generated by vibrations of amide-I (CO stretching) arising from the energy of hydrolysis of ATP. The properties of the new soliton are extensively studied by analytical method and its lifetime is calculated using the nonlinear quantum perturbation theory and a wide ranges of parameter values relevant to protein molecules. The lifetime of the new soliton at the biological temperature 300 K is enough large and belongs to the order of 10⁻¹⁰ s, or τ/τ₀≥700, in which the soliton can transports over several hundreds amino acid residues. These studied results show clearly that the new soliton is thermally stable and has so larger lifetime that it can play an important role in biological processes. Thus the new model is a candidate of the bio-energy transport mechanism in protein molecules. In the meanwhile, the influences of structure nonuniformity in protein molecules and temperature of the systems on the states and properties of the soliton transport of bio-energy are numerically simulated and studied by the fourth-order Runge-Kutta method. The structure nonuniformity arises from the disorder distributions of masses of amino acid residues, side groups and impurities, which results also in the fluctuations of the spring constant of protein molecules, dipole-dipole interaction between the neighboring amides, exciton-phonon (vibration of amino acids)interaction, chain-chain interaction among the three channels and ground state energy of the systems. We investigated the behaviors and states of the new solitons in a single protein molecular chain and α-Helix protein molecules with three channels under influences of the structure nonuniformity. We prove first that the bio-energy is transported by a soliton, which can move without dispersion, retaining its shape, velocity and energy in a uniform and periodic protein molecule. When the structure nonuniformity exists, although the fluctuations of the spring constant, dipole-dipole interaction constant, exciton-phonon coupling constant and ground state energy and the nonuniformity distributions of masses of amino acid residues can change the states and properties of motion of new soliton, they are still quite stable and very robust against these structure nonuniformities, i.e., even there are a larger structure nonuniformity in the protein molecules, the new solitons cannot be still dispersed. If the effects of thermal perturbation of medium on the soliton in nonuniform proteins is considered again, the new soliton can transport also over a larger spacing of 400 amino acids and has a longer time period of 300 ps, it is still thermally stable up to 320 K under the influence of the above structure nonuniformities. However, the new soliton disperses in the case of a higher temperature of 325 K and in more large structure nonuniformity. Thus, we determine that the new soliton's lifetime and critical temperature are 300 ps and 320 K, respectively. These results are also consistent with analytical data obtained via quantum perturbed theory. For α-Helix protein molecules with three channels, the results obtained show that the structure nonuniformity and quantum fluctuation can change the states and features of the new solitons, for example, the amplitudes, energies and velocities of the new soliton are decreased, but the solitons have been not destroyed, they can still transport steadily along the molecular chains retaining energy and momentum. When the quantum fluctuations are larger, such as, structure disorders and quantum fluctuations of 0.67&lt;α(K)&lt;2, ΔW=±8%W¯, ΔJ=±1%J¯, Δ(χ₁+χ₂)=±3%(χ¯₁+χ¯₂) and ΔL=±1%L¯ and Δɛ₀=ɛ|β(n)|, ɛ=0.1 meV, |β(n)|&lt;0.5, the new soliton is still stable. Therefore, the new solitons are quite robust against these nonuniform effects. However, they will be dispersed or disrupted in cases of very large structure nonuniformity. When the influence of temperature on solitons is considered, we find that the new solitons can transport steadily over 333 amino acid residues in the case of a long time period of 120 ps, in which the soliton can retain its shape and energy to travel forward along protein molecules after their mutual collision at the biological temperature of 300 K. However, the soliton disperses in cases of higher temperatures 325 K under action of a larger structure disorder. Thus, its critical temperature is about 320 K. When the effects of structure nonuniformity and temperature are considered simultaneously, then the new soliton has still high thermal stability and can transport also along the protein molecular chains retaining its amplitude, energy and velocity, they will disperses in the larger fluctuations, for example, 0.67 M¯&lt;M(k)&lt;2M¯, ΔW=±6%W¯, ΔJ=±1.3%J¯, Δ(χ₁+χ₂)=±2%(χ¯₁+χ¯₂), ΔL=±1.5%L¯ and Δɛ₀=ɛ|β(n)|, ɛ=0.82 meV, |β(n)|≤0.5 at T=300 K, or at higher temperatures 320 K and the fluctuations of 0.67M¯&lt;M(k)&lt;2M¯, Δ(χ₁+χ₂=±1%(χ¯₁+χ¯₂), ΔJ=±0.7%J¯, ΔW=±7%W¯, ΔL=±0.8%L¯ and Δɛ₀=ɛ|β(n)|, ɛ=0.4 meV, |β(n)|≤0.5. These results mean that the critical temperature of the new soliton is 315K in this condition. Thus, we can conclude from these investigations that the new soliton is quite robust against the structure nonuniformities and thermal perturbation of proteins at 300 K in α-helix protein molecules, then it is a carrier of bio-energy transport and the improved model is a candidate for the mechanism of the bio-energy transport in the protein molecules. Finally we gave some experimental evidences for real existence of the soliton and validity of the theory of bio-energy transport in proteins.

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There is uncertainty as to the optimal approach for screening and diagnosis of gestational diabetes mellitus (GDM). Based on systematic reviews published in 2003 and 2008, the U.S. Preventive Services Task Force concluded that there was insufficient evidence upon which to make a recommendation regarding routine screening of all pregnant women. (1) Identify properties of screening tests for GDM, (2) evaluate benefits and harms of screening for GDM, (3) assess the effects of different screening and diagnostic thresholds on outcomes for mothers and their offspring, and (4) determine the benefits and harms of treatment for a diagnosis of GDM. We searched 15 electronic databases from 1995 to May 2012, including MEDLINE and Cochrane Central Register of Controlled Trials (which contains the Cochrane Pregnancy and Childbirth Group registry); gray literature; Web sites of relevant organizations; trial registries; and reference lists. Two reviewers independently conducted study selection and quality assessment. One reviewer extracted data, and a second reviewer verified the data. We included published randomized and nonrandomized controlled trials and prospective and retrospective cohort studies that compared any screening or diagnostic test with any other screening or diagnostic test; any screening with no screening; women who met various thresholds for GDM with those who did not meet various criteria, where women in both groups did not receive treatment; any treatment for GDM with no treatment. We conducted a descriptive analysis for all studies and meta-analyses when appropriate. Key outcomes included preeclampsia, maternal weight gain, birth injury, shoulder dystocia, neonatal hypoglycemia, macrosomia, and long-term metabolic outcomes for the child and mother. The search identified 14,398 citations and included 97 studies (6 randomized controlled trials, 63 prospective cohort studies, and 28 retrospective cohort studies). Prevalence of GDM varied across studies and diagnostic criteria: American Diabetes Association (75 g) 2 to 19 percent; Carpenter and Coustan 3.6 to 38 percent; National Diabetes Data Group 1.4 to 50 percent; and World Health Organization 2 to 24.5 percent. Lack of a gold standard for the diagnosis of GDM and little evidence about the accuracy of screening strategies for GDM remain problematic. The 50 g oral glucose challenge test with a glucose threshold of 130 mg/dL versus 140 mg/dL improves sensitivity and reduces specificity. Both thresholds have high negative predictive values (NPV) but variable positive predictive values (PPVs) across a range of prevalence. There was limited evidence for the screening of GDM diagnosed less than 24 weeks' gestation (three studies). One study compared the International Association of Diabetes in Pregnancy Study Groups' (IADPSG) diagnostic criteria with a two-step strategy. Sensitivity was 82 percent, specificity was 94 percent. Only two studies examined the effects on health outcomes from screening for GDM. One retrospective cohort study (n=1,000) showed more cesarean deliveries in the screened group. A survey within a prospective cohort study (n=93) found the same incidence of macrosomia (≥4.3 kg) in screened and unscreened groups (7 percent each group). Thirty-eight studies examined health outcomes for women who met different criteria for GDM and did not undergo treatment. Methodologically strong studies showed a continuous positive relationship between increasing glucose levels and the incidence of primary cesarean section and macrosomia. One of these studies also found significantly fewer cases of preeclampsia, cesarean section, shoulder dystocia and/or birth injury, clinical neonatal hypoglycemia, and hyperbilirubinemia for women without GDM compared with those meeting IADPSG criteria. Among the other studies, fewer cases of preeclampsia were observed for women with no GDM and women who were false positive versus those meeting Carpenter and Coustan criteria. For maternal weight gain, few comparisons showed differences. For fetal birth trauma, single studies showed no differences for women with Carpenter and Coustan GDM and World Health Organization impaired glucose tolerance versus women without GDM. Women diagnosed based on National Diabetes Data Group GDM had more fetal birth trauma compared with women without GDM. Fewer cases of macrosomia were seen in the group without GDM compared with Carpenter and Coustan GDM, Carpenter and Coustan 1 abnormal oral glucose tolerance test, National Diabetes Data Group GDM, National Diabetes Data Group false positives, and World Health Organization impaired glucose tolerance. Fewer cases of neonatal hypoglycemia were found among patient groups without GDM compared with those meeting Carpenter and Coustan criteria. There was more childhood obesity for Carpenter and Coustan GDM versus patient groups with no GDM. Eleven studies compared diet modification, glucose monitoring, and insulin as needed with no treatment. Moderate evidence showed fewer cases of preeclampsia in the treated group. The evidence was insufficient for maternal weight gain and birth injury. Moderate evidence found less shoulder dystocia with treatment for GDM. Low evidence showed no difference for neonatal hypoglycemia between treated and untreated GDM. Moderate evidence showed benefits of treatment for reduction of macrosomia (&gt;4,000 g). There was insufficient evidence for long-term metabolic outcomes among offspring. Five studies provided data on harms of treating GDM. No difference was found for cesarean delivery, induction of labor, small for gestational age, or admission to a neonatal intensive care unit. There were significantly more prenatal visits among those treated. While evidence supports a positive association with increasing plasma glucose on a 75 g or 100 g oral glucose tolerance test and macrosomia and primary cesarean section, clear thresholds for increased risk were not found. The 50 g oral glucose challenge test has high NPV but variable PPV. Treatment of GDM results in less preeclampsia and macrosomia. Current evidence does not show that treatment of GDM has an effect on neonatal hypoglycemia or future poor metabolic outcomes. There is little evidence of short-term harm from treating GDM other than an increased demand for services. Research is needed on the long-term metabolic outcome for offspring as a result of GDM and its treatment, and the "real world" effects of GDM treatment on use of care.

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Many systematic reviews exist on interventions to improve safe and effective medicines use by consumers, but research is distributed across diseases, populations and settings. The scope and focus of such reviews also vary widely, creating challenges for decision-makers seeking to inform decisions by using the evidence on consumers' medicines use.This is an update of a 2011 overview of systematic reviews, which synthesises the evidence, irrespective of disease, medicine type, population or setting, on the effectiveness of interventions to improve consumers' medicines use. To assess the effects of interventions which target healthcare consumers to promote safe and effective medicines use, by synthesising review-level evidence. We included systematic reviews published on the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects. We identified relevant reviews by handsearching databases from their start dates to March 2012. We screened and ranked reviews based on relevance to consumers' medicines use, using criteria developed for this overview. We used standardised forms to extract data, and assessed reviews for methodological quality using the AMSTAR tool. We used standardised language to summarise results within and across reviews; and gave bottom-line statements about intervention effectiveness. Two review authors screened and selected reviews, and extracted and analysed data. We used a taxonomy of interventions to categorise reviews and guide syntheses. We included 75 systematic reviews of varied methodological quality. Reviews assessed interventions with diverse aims including support for behaviour change, risk minimisation and skills acquisition. No reviews aimed to promote systems-level consumer participation in medicines-related activities. Medicines adherence was the most frequently-reported outcome, but others such as knowledge, clinical and service-use outcomes were also reported. Adverse events were less commonly identified, while those associated with the interventions themselves, or costs, were rarely reported.Looking across reviews, for most outcomes, medicines self-monitoring and self-management programmes appear generally effective to improve medicines use, adherence, adverse events and clinical outcomes; and to reduce mortality in people self-managing antithrombotic therapy. However, some participants were unable to complete these interventions, suggesting they may not be suitable for everyone.Other promising interventions to improve adherence and other key medicines-use outcomes, which require further investigation to be more certain of their effects, include:· simplified dosing regimens: with positive effects on adherence;· interventions involving pharmacists in medicines management, such as medicines reviews (with positive effects on adherence and use, medicines problems and clinical outcomes) and pharmaceutical care services (consultation between pharmacist and patient to resolve medicines problems, develop a care plan and provide follow-up; with positive effects on adherence and knowledge).Several other strategies showed some positive effects, particularly relating to adherence, and other outcomes, but their effects were less consistent overall and so need further study. These included:· delayed antibiotic prescriptions: effective to decrease antibiotic use but with mixed effects on clinical outcomes, adverse effects and satisfaction;· practical strategies like reminders, cues and/or organisers, reminder packaging and material incentives: with positive, although somewhat mixed effects on adherence;· education delivered with self-management skills training, counselling, support, training or enhanced follow-up; information and counselling delivered together; or education/information as part of pharmacist-delivered packages of care: with positive effects on adherence, medicines use, clinical outcomes and knowledge, but with mixed effects in some studies;· financial incentives: with positive, but mixed, effects on adherence.Several strategies also showed promise in promoting immunisation uptake, but require further study to be more certain of their effects. These included organisational interventions; reminders and recall; financial incentives; home visits; free vaccination; lay health worker interventions; and facilitators working with physicians to promote immunisation uptake. Education and/or information strategies also showed some positive but even less consistent effects on immunisation uptake, and need further assessment of effectiveness and investigation of heterogeneity.There are many different potential pathways through which consumers' use of medicines could be targeted to improve outcomes, and simple interventions may be as effective as complex strategies. However, no single intervention assessed was effective to improve all medicines-use outcomes across all diseases, medicines, populations or settings.Even where interventions showed promise, the assembled evidence often only provided part of the picture: for example, simplified dosing regimens seem effective for improving adherence, but there is not yet sufficient information to identify an optimal regimen.In some instances interventions appear ineffective: for example, the evidence suggests that directly observed therapy may be generally ineffective for improving treatment completion, adherence or clinical outcomes.In other cases, interventions may have variable effects across outcomes. As an example, strategies providing information or education as single interventions appear ineffective to improve medicines adherence or clinical outcomes, but may be effective to improve knowledge; an important outcome for promoting consumers' informed medicines choices.Despite a doubling in the number of reviews included in this updated overview, uncertainty still exists about the effectiveness of many interventions, and the evidence on what works remains sparse for several populations, including children and young people, carers, and people with multimorbidity. This overview presents evidence from 75 reviews that have synthesised trials and other studies evaluating the effects of interventions to improve consumers' medicines use.Systematically assembling the evidence across reviews allows identification of effective or promising interventions to improve consumers' medicines use, as well as those for which the evidence indicates ineffectiveness or uncertainty.Decision makers faced with implementing interventions to improve consumers' medicines use can use this overview to inform decisions about which interventions may be most promising to improve particular outcomes. The intervention taxonomy may also assist people to consider the strategies available in relation to specific purposes, for example, gaining skills or being involved in decision making. Researchers and funders can use this overview to identify where more research is needed and assess its priority. The limitations of the available literature due to the lack of evidence for important outcomes and important populations, such as people with multimorbidity, should also be considered in practice and policy decisions.

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Obtaining high plant yield is not always achievable in agricultural activity as it is determined by various factors, including cultivar quality, nutrient and water supplies, degree of infection by pathogens, natural calamities and soil conditions, which affect plant growth and development. More noticeably, sustainable plant productivity to provide sufficient food for the increasing human population has become a thorny issue to scientists in the era of unpredictable global climatic changes, appearance of more tremendous or multiple stresses, and land restriction for cultivation. Well-established agricultural management by agrotechnological means has shown no longer to be effective enough to confront with this challenge. Instead, in order to maximize the production, it is advisable to implement such practices in combination with biological applications. Nowadays, high technologies are widely adopted into agricultural production, biological diversity conservation and crop improvement. Wang et al. has nicely outlined the utilization of DNA-based technologies in this field. Among these are the applications of (i) DNA markers into cultivar identification, seed purity analysis, germplasm resource evaluation, heterosis prediction, genetic mapping, cloning and breeding; and (ii) gene expression data in supporting the description of crop phenology, the analytic comparison of crop growth under stress versus non-stress conditions, or the study of fertilizer effects. Besides, various purposes of using transgenic technologies in agriculture, such as generating cultivars with better product quality, better tolerance to biotic or abiotic stress, are also discussed in the review. One of the important highlights in this issue is the review of the benefits brought by high-throughput sequencing technology, which is also known as next-generation sequencing (NGS). It is not so difficult to recognize that its application has allowed us to carry out biological studies at much deeper level and larger scale. In their article, Onda and Mochida detailed how to use these technologies in fully characterizing the genetic diversity or multigenecity within a particular plant species. The authors discussed the constant innovation of sequencing platforms which has made sequencing technologies become more superior and more powerful than ever before. Additionally, the efforts result in not only further cut down of the sequencing cost and increase in the sequencing speed, but also improvement in sequencing accuracy and extended sequencing application to studies at both DNA and RNA levels. Such knowledge will help the scientists interpret, at least partially, how plants can adapt to various environmental conditions, or how different cultivars can respond differently to the same stress. Another article by Ong et al. also laid emphasis on the importance of various high-throughput sequencing platforms, thanks to which a large number of genomic databases supplied with detailed annotation and useful bioinformatics tools have been established to assist geneticists. Readers can find in this review the summary of available plant-specific genomic databases up-to-date and popular web-based resources that are relevant for comparative genomics, plant evolution and phylogenomics studies. These, along with other approaches, such as quantitative trait locus and genome-wide association study, will lay foundation for prediction and identification of genes or alleles responsible for valuable agronomic traits, contributing to the enhancement of plant productivity by genetic engineering approach. In this thematic issue, specific examples for crop improvement are also demonstrated. The first showcase is given by Nongpiur et al. who provided evidence that synergistic employment of genomics approaches and high-throughput gene expression methods have aided in dissecting the salinity-responsive signaling pathway, identifying genes involved in the stress response and selecting candidate genes for further characterization aimed at generating new cultivars with better salinity stress tolerance. This paper is also a good reference source for readers who wish to get an overview about the general process from gene prediction to validation by experiments, including the details on techniques and approaches used. Another demonstration is provided by Khan et al. whose interest is enhancement of drought tolerance in crops. The focus of this article is to overview our current understanding of mechanisms regulating plants responses to drought. Evaluation of plant performance to drought and production of new elite varieties with better drought tolerance on the basis of using phenotyping and genomics-assisted breeding are also well discussed. In addition to the topics of environmental stress tolerance in plants, current knowledge on improving biotic stress tolerance is also summarized in our issue. Current picture on crosstalk of signaling mechanisms in rice between its immune system and symbiosis with microorganisms is presented by Akamatsu et al. Rice responses to bacteria and fungi via interactions between the plant pattern recognition receptors and the molecular microbe-associated molecular patterns are described in detail and suggested as targets for manipulation in order to increase disease resistance in crops. On the other hand, Bouain et al. are concerned about nutrient deficiency; specifically, how plant root system develops under growing conditions with inadequate phosphate. The authors overviewed our current understanding of the low phosphate-responsive mechanisms in Arabidopsis model plant, which was gained by using a combination of various advanced methods, including high-througput phenotyping, system biology analysis and "omics" technologies. Stress management in plants is proposed to be also achievable by regulating activities of cyclic nucleotide-gated ion channels. As emphasized in the paper of Jha et al., the application of such channels is important in mediating cellular ion homeostasis and plant tolerance to both biotic and abiotic stresses. In summary, with recent progresses in biological and biotechnological areas, especially rapid development of advanced technologies in biological system modeling, functional genomics, computer-based analyzing tools, genetic engineering and molecular breeding, biological control and biotechnological applications in agriculture have brought about an extraordinary revolution and have been considered the most powerful approaches in maintaining or even increasing crop yield. Therefore, in this issue, we would like to introduce to the audience a collection of various strategies used for enhancing crop productivity, with the focus on advanced biological-biotechnological platforms in the post-genomics era.

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The goal of fetal monitoring in labour is the early detection of a hypoxic baby. There are a variety of tools and methods available for intermittent auscultation (IA) of the fetal heart rate (FHR). Low- and middle-income countries usually have only access to a Pinard/Laënnec or the use of a hand-held Doppler device. Currently, there is no robust evidence to guide clinical practice on the most effective IA tool to use, timing intervals and length of listening to the fetal heart for women during established labour. To evaluate the effectiveness of different tools for IA of the fetal heart rate during labour including frequency and duration of auscultation. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (19 September 2016), contacted experts and searched reference lists of retrieved articles. All published and unpublished randomised controlled trials (RCTs) or cluster-RCTs comparing different tools and methods used for intermittent fetal auscultation during labour for fetal and maternal well-being. Quasi-RCTs, and cross-over designs were not eligible for inclusion. All review authors independently assessed eligibility, extracted data and assessed risk of bias for each trial. Data were checked for accuracy. We included three studies (6241 women and 6241 babies), but only two studies are included in the meta-analyses (3242 women and 3242 babies). Both were judged as high risk for performance bias due to the inability to blind the participants and healthcare providers to the interventions. Evidence was graded as moderate to very low quality; the main reasons for downgrading were study design limitations and imprecision of effect estimates. Intermittent Electronic Fetal Monitoring (EFM) using Cardiotocography (CTG) with routine Pinard (one trial)There was no clear difference between groups in low Apgar scores at five minutes (reported as &lt; six at five minutes after birth) (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.24 to 1.83, 633 babies, very low-quality evidence). There were no clear differences for perinatal mortality (RR 0.88, 95% CI 0.34 to 2.25; 633 infants, very low-quality evidence). Neonatal seizures were reduced in the EFM group (RR 0.05, 95% CI 0.00 to 0.89; 633 infants, very low-quality evidence). Other important infant outcomes were not reported: mortality or serious morbidity (composite outcome), cerebral palsy or neurosensory disability. For maternal outcomes, women allocated to intermittent electronic fetal monitoring (EFM) (CTG) had higher rates of caesarean section for fetal distress (RR 2.92, 95% CI 1.78 to 4.80, 633 women, moderate-quality evidence) compared with women allocated to routine Pinard. There was no clear difference between groups in instrumental vaginal births (RR 1.46, 95% CI 0.86 to 2.49, low-quality evidence). Other outcomes were not reported (maternal mortality, instrumental vaginal birth for fetal distress and or acidosis, analgesia in labour, mobility or restriction during labour, and postnatal depression). Doppler ultrasonography with routine Pinard (two trials)There was no clear difference between groups in Apgar scores &lt; seven at five minutes after birth (reported as &lt; six in one of the trials) (average RR 0.76, 95% CI 0.20 to 2.87; two trials, 2598 babies, I<sup2</sup = 72%, very low-quality evidence); there was high heterogeneity for this outcome. There was no clear difference between groups for perinatal mortality (RR 0.69, 95% CI 0.09 to 5.40; 2597 infants, two studies, very low-quality evidence), or neonatal seizures (RR 0.05, 95% CI 0.00 to 0.91; 627 infants, one study, very low-quality evidence). Other important infant outcomes were not reported (cord blood acidosis, composite of mortality and serious morbidity, cerebral palsy, neurosensory disability). Only one study reported maternal outcomes. Women allocated to Doppler ultrasonography had higher rates of caesarean section for fetal distress compared with those allocated to routine Pinard (RR 2.71, 95% CI 1.64 to 4.48, 627 women, moderate-quality evidence). There was no clear difference in instrumental vaginal births between groups (RR 1.35, 95% CI 0.78 to 2.32, 627 women, low-quality evidence). Other maternal outcomes were not reported. Intensive Pinard versus routine Pinard (one trial)One trial compared intensive Pinard (a research midwife following the protocol in a one-to-one care situation) with routine Pinard (as per protocol but midwife may be caring for more than one woman in labour). There was no clear difference between groups in low Apgar score (reported as &lt; six this trial) (RR 0.90, 95% CI 0.35 to 2.31, 625 babies, very low-quality evidence). There were also no clear differences identified for perinatal mortality (RR 0.56, 95% CI 0.19 to 1.67; 625 infants, very low-quality evidence), or neonatal seizures (RR 0.68, 95% CI 0.24 to 1.88, 625 infants, very low-quality evidence)). Other infant outcomes were not reported. For maternal outcomes, there were no clear differences between groups for caesarean section or instrumental delivery (RR 0.70, 95% CI 0.35 to 1.38, and RR 1.21, 95% CI 0.69 to 2.11, respectively, 625 women, both low-quality evidence)) Other outcomes were not reported. Using a hand-held (battery and wind-up) Doppler and intermittent CTG with an abdominal transducer without paper tracing for IA in labour was associated with an increase in caesarean sections due to fetal distress. There was no clear difference in neonatal outcomes (low Apgar scores at five minutes after birth, neonatal seizures or perinatal mortality). Long-term outcomes for the baby (including neurodevelopmental disability and cerebral palsy) were not reported. The quality of the evidence was assessed as moderate to very low and several important outcomes were not reported which means that uncertainty remains regarding the use of IA of FHR in labour.As intermittent CTG and Doppler were associated with higher rates of caesarean sections compared with routine Pinard monitoring, women, health practitioners and policy makers need to consider these results in the absence of evidence of short- and long-term benefits for the mother or baby.Large high-quality randomised trials, particularly in low-income settings, are needed. Trials should assess both short- and long-term health outcomes, comparing different monitoring tools and timing for IA.

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Platelet transfusions are used to prevent and treat bleeding in people who are thrombocytopenic. Despite improvements in donor screening and laboratory testing, a small risk of viral, bacterial, or protozoal contamination of platelets remains. There is also an ongoing risk from newly emerging blood transfusion-transmitted infections for which laboratory tests may not be available at the time of initial outbreak.One solution to reduce the risk of blood transfusion-transmitted infections from platelet transfusion is photochemical pathogen reduction, in which pathogens are either inactivated or significantly depleted in number, thereby reducing the chance of transmission. This process might offer additional benefits, including platelet shelf-life extension, and negate the requirement for gamma-irradiation of platelets. Although current pathogen-reduction technologies have been proven to reduce pathogen load in platelet concentrates, a number of published clinical studies have raised concerns about the effectiveness of pathogen-reduced platelets for post-transfusion platelet count recovery and the prevention of bleeding when compared with standard platelets.This is an update of a Cochrane review first published in 2013. To assess the effectiveness of pathogen-reduced platelets for the prevention of bleeding in people of any age requiring platelet transfusions. We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 9), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 24 October 2016. We included RCTs comparing the transfusion of pathogen-reduced platelets with standard platelets, or comparing different types of pathogen-reduced platelets. We used the standard methodological procedures expected by Cochrane. We identified five new trials in this update of the review. A total of 15 trials were eligible for inclusion in this review, 12 completed trials (2075 participants) and three ongoing trials. Ten of the 12 completed trials were included in the original review. We did not identify any RCTs comparing the transfusion of one type of pathogen-reduced platelets with another.Nine trials compared Intercept® pathogen-reduced platelets to standard platelets, two trials compared Mirasol® pathogen-reduced platelets to standard platelets; and one trial compared both pathogen-reduced platelets types to standard platelets. Three RCTs were randomised cross-over trials, and nine were parallel-group trials. Of the 2075 participants enrolled in the trials, 1981 participants received at least one platelet transfusion (1662 participants in Intercept® platelet trials and 319 in Mirasol® platelet trials).One trial included children requiring cardiac surgery (16 participants) or adults requiring a liver transplant (28 participants). All of the other participants were thrombocytopenic individuals who had a haematological or oncological diagnosis. Eight trials included only adults.Four of the included studies were at low risk of bias in every domain, while the remaining eight included studies had some threats to validity.Overall, the quality of the evidence was low to high across different outcomes according to GRADE methodology.We are very uncertain as to whether pathogen-reduced platelets increase the risk of any bleeding (World Health Organization (WHO) Grade 1 to 4) (5 trials, 1085 participants; fixed-effect risk ratio (RR) 1.09, 95% confidence interval (CI) 1.02 to 1.15; I<sup2</sup = 59%, random-effect RR 1.14, 95% CI 0.93 to 1.38; I<sup2</sup = 59%; low-quality evidence).There was no evidence of a difference between pathogen-reduced platelets and standard platelets in the incidence of clinically significant bleeding complications (WHO Grade 2 or higher) (5 trials, 1392 participants; RR 1.10, 95% CI 0.97 to 1.25; I<sup2</sup = 0%; moderate-quality evidence), and there is probably no difference in the risk of developing severe bleeding (WHO Grade 3 or higher) (6 trials, 1495 participants; RR 1.24, 95% CI 0.76 to 2.02; I<sup2</sup = 32%; moderate-quality evidence).There is probably no difference between pathogen-reduced platelets and standard platelets in the incidence of all-cause mortality at 4 to 12 weeks (6 trials, 1509 participants; RR 0.81, 95% CI 0.50 to 1.29; I<sup2</sup = 26%; moderate-quality evidence).There is probably no difference between pathogen-reduced platelets and standard platelets in the incidence of serious adverse events (7 trials, 1340 participants; RR 1.09, 95% CI 0.88 to 1.35; I<sup2</sup = 0%; moderate-quality evidence). However, no bacterial transfusion-transmitted infections occurred in the six trials that reported this outcome.Participants who received pathogen-reduced platelet transfusions had an increased risk of developing platelet refractoriness (7 trials, 1525 participants; RR 2.94, 95% CI 2.08 to 4.16; I<sup2</sup = 0%; high-quality evidence), though the definition of platelet refractoriness differed between trials.Participants who received pathogen-reduced platelet transfusions required more platelet transfusions (6 trials, 1509 participants; mean difference (MD) 1.23, 95% CI 0.86 to 1.61; I<sup2</sup = 27%; high-quality evidence), and there was probably a shorter time interval between transfusions (6 trials, 1489 participants; MD -0.42, 95% CI -0.53 to -0.32; I<sup2</sup = 29%; moderate-quality evidence). Participants who received pathogen-reduced platelet transfusions had a lower 24-hour corrected-count increment (7 trials, 1681 participants; MD -3.02, 95% CI -3.57 to -2.48; I<sup2</sup = 15%; high-quality evidence).None of the studies reported quality of life.We did not evaluate any economic outcomes.There was evidence of subgroup differences in multiple transfusion trials between the two pathogen-reduced platelet technologies assessed in this review (Intercept® and Mirasol®) for all-cause mortality and the interval between platelet transfusions (favouring Intercept®). Findings from this review were based on 12 trials, and of the 1981 participants who received a platelet transfusion only 44 did not have a haematological or oncological diagnosis.In people with haematological or oncological disorders who are thrombocytopenic due to their disease or its treatment, we found high-quality evidence that pathogen-reduced platelet transfusions increase the risk of platelet refractoriness and the platelet transfusion requirement. We found moderate-quality evidence that pathogen-reduced platelet transfusions do not affect all-cause mortality, the risk of clinically significant or severe bleeding, or the risk of a serious adverse event. There was insufficient evidence for people with other diagnoses.All three ongoing trials are in adults (planned recruitment 1375 participants) with a haematological or oncological diagnosis.

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This is an updated version of the original Cochrane Review published in the Cochrane Library, Issue 5, 2015.Yoga may induce relaxation and stress reduction, and influence the electroencephalogram and the autonomic nervous system, thereby controlling seizures. Yoga would be an attractive therapeutic option for epilepsy if proved effective. To assess whether people with epilepsy treated with yoga:(a) have a greater probability of becoming seizure free;(b) have a significant reduction in the frequency or duration of seizures, or both; and(c) have a better quality of life. For this update, we searched the Cochrane Epilepsy Group Specialized Register (3 January 2017), the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12) in the Cochrane Library (searched 3 January 2017), MEDLINE (Ovid, 1946 to 3 January 2017), SCOPUS (1823 to 3 January 2017), ClinicalTrials.gov (searched 3 January 2017), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (searched 3 January 2017), and also registries of the Yoga Biomedical Trust and the Research Council for Complementary Medicine. In addition, we searched the references of all the identified studies. No language restrictions were imposed. The following study designs were eligible for inclusion: randomised controlled trials (RCT) of treatment of epilepsy with yoga. The studies could be double-, single- or unblinded. Eligible participants were adults with uncontrolled epilepsy comparing yoga with no treatment or different behavioural treatments. Two review authors independently assessed the trials for inclusion and extracted data. The following outcomes were assessed: (a) percentage of people rendered seizure free; (b) seizure frequency and duration; (c) quality of life. Analyses were on an intention-to-treat basis. Odds ratio (OR) with 95% confidence intervals (95% Cls) were estimated for the outcomes. We did not identify any new studies for this update, therefore the results are unchanged.For the previous version of the review, the authors found two unblinded trials in people with refractory epilepsy. In total these two studies included 50 people (18 treated with yoga and 32 to control interventions). Antiepileptic drugs were continued in all the participants. Baseline phase lasted three months in both studies and treatment phase from five weeks to six months in the two trials. Randomisation was by roll of a die in one study and using a computerised randomisation table in the other one but neither study provided details of concealment of allocation and were rated as unclear risk of bias. Overall, the two studies were rated as low risk of bias (all participants were included in the analysis; all expected and pre-expected outcomes were reported; no other sources of bias).The overall ORs with 95% CI were as follows: (i) seizure free for six months - for yoga versus sham yoga the OR was 14.54 (95% CI 0.67 to 316.69) and for yoga versus 'no treatment' group it was 17.31 (95% CI 0.80 to 373.45); for Acceptance and Commitment Therapy (ACT) versus yoga the OR was 1.00 (95% Cl 0.16 to 6.42); (ii) reduction in seizure frequency - the mean difference between yoga versus sham yoga group was -2.10 (95% CI -3.15 to -1.05) and for yoga versus 'no treatment' group it was -1.10 (95% CI -1.80 to -0.40); (iii) more than 50% reduction in seizure frequency - for yoga versus sham yoga group, OR was 81.00 (95% CI 4.36 to 1504.46) and for the yoga versus 'no treatment' group it was 158.33 (95% CI 5.78 to 4335.63); ACT versus yoga OR was 0.78 (95% Cl 0.04 to 14.75); (iv) more than 50% reduction in seizure duration - for yoga versus sham yoga group OR was 45.00 (95% CI 2.01 to 1006.75) and for yoga versus 'no treatment' group it was 53.57 (95% CI 2.42 to 1187.26); ACT versus yoga OR was 0.67 (95% Cl 0.10 to 4.35).In addition in Panjwani 1996 the authors reported that the one-way analysis of variance revealed no statistically significant differences between the three groups. A P-Lambda test taking into account the P values between the three groups also indicated that the duration of epilepsy in the three groups was not comparable. No data were available regarding quality of life. In Lundgren 2008 the authors reported that there was no significant difference between the yoga and ACT groups in seizure-free rates, 50% or greater reduction in seizure frequency or seizure duration at one-year follow-up. The yoga group showed significant improvement in their quality of life according to the Satisfaction With Life Scale (SWLS) (P &lt; 0.05), while the ACT group had significant improvement in the World Health Organization Quality of Life-BREF (WHOQOL-BREF) scale (P &lt; 0.01).Overall, we assessed the quality of evidence as low; no reliable conclusions can be drawn at present regarding the efficacy of yoga as a treatment for epilepsy. A study of 50 subjects with epilepsy from two trials reveals a possible beneficial effect in control of seizures. Results of the overall efficacy analysis show that yoga treatment was better when compared with no intervention or interventions other than yoga (postural exercises mimicking yoga). There was no difference between yoga and Acceptance and Commitment Therapy. However no reliable conclusions can be drawn regarding the efficacy of yoga as a treatment for uncontrolled epilepsy, in view of methodological deficiencies such as limited number of studies, limited number of participants randomised to yoga, lack of blinding and limited data on quality-of-life outcome. Physician blinding would normally be taken to be the person delivering the intervention, whereas we think the 'physician' would in fact be the outcome assessor (who could be blinded), so that would be a reduction in detection bias rather than performance bias. In addition, evidence to inform outcomes is limited and of low quality. Further high-quality research is needed to fully evaluate the efficacy of yoga for refractory epilepsy.Since we did not find any new studies, our conclusions remain unchanged.

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Intermittent claudication (IC) is the classic symptomatic form of peripheral arterial disease affecting an estimated 4.5% of the general population aged 40 years and older. Patients with IC experience limitations in their ambulatory function resulting in functional disability and impaired quality of life (QoL). Endovascular revascularisation has been proposed as an effective treatment for patients with IC and is increasingly performed. The main objective of this systematic review is to summarise the (added) effects of endovascular revascularisation on functional performance and QoL in the management of IC. For this review the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (February 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1). The CIS also searched trials registries for details of ongoing and unpublished studies. Randomised controlled trials (RCTs) comparing endovascular revascularisation (± conservative therapy consisting of supervised exercise or pharmacotherapy) versus no therapy (except advice to exercise) or versus conservative therapy (i.e. supervised exercise or pharmacotherapy) for IC. Two review authors independently selected studies, extracted data, and assessed the methodological quality of studies. Given large variation in the intensity of treadmill protocols to assess walking distances and use of different instruments to assess QoL, we used standardised mean difference (SMD) as treatment effect for continuous outcome measures to allow standardisation of results and calculated the pooled SMD as treatment effect size in meta-analyses. We interpreted pooled SMDs using rules of thumb (&lt; 0.40 = small, 0.40 to 0.70 = moderate, &gt; 0.70 = large effect) according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated the pooled treatment effect size for dichotomous outcome measures as odds ratio (OR). We identified ten RCTs (1087 participants) assessing the value of endovascular revascularisation in the management of IC. These RCTs compared endovascular revascularisation versus no specific treatment for IC or conservative therapy or a combination therapy of endovascular revascularisation plus conservative therapy versus conservative therapy alone. In the included studies, conservative treatment consisted of supervised exercise or pharmacotherapy with cilostazol 100 mg twice daily. The quality of the evidence ranged from low to high and was downgraded mainly owing to substantial heterogeneity and small sample size.Comparing endovascular revascularisation versus no specific treatment for IC (except advice to exercise) showed a moderate effect on maximum walking distance (MWD) (SMD 0.70, 95% confidence interval (CI) 0.31 to 1.08; 3 studies; 125 participants; moderate-quality evidence) and a large effect on pain-free walking distance (PFWD) (SMD 1.29, 95% CI 0.90 to 1.68; 3 studies; 125 participants; moderate-quality evidence) in favour of endovascular revascularisation. Long-term follow-up in two studies (103 participants) showed no clear differences between groups for MWD (SMD 0.67, 95% CI -0.30 to 1.63; low-quality evidence) and PFWD (SMD 0.69, 95% CI -0.45 to 1.82; low-quality evidence). The number of secondary invasive interventions (OR 0.81, 95% CI 0.12 to 5.28; 2 studies; 118 participants; moderate-quality evidence) was also not different between groups. One study reported no differences in disease-specific QoL after two years.Data from five studies (n = 345) comparing endovascular revascularisation versus supervised exercise showed no clear differences between groups for MWD (SMD -0.42, 95% CI -0.87 to 0.04; moderate-quality evidence) and PFWD (SMD -0.05, 95% CI -0.38 to 0.29; moderate-quality evidence). Similarliy, long-term follow-up in three studies (184 participants) revealed no differences between groups for MWD (SMD -0.02, 95% CI -0.36 to 0.32; moderate-quality evidence) and PFWD (SMD 0.11, 95% CI -0.26 to 0.48; moderate-quality evidence). In addition, high-quality evidence showed no difference between groups in the number of secondary invasive interventions (OR 1.40, 95% CI 0.70 to 2.80; 4 studies; 395 participants) and in disease-specific QoL (SMD 0.18, 95% CI -0.04 to 0.41; 3 studies; 301 participants).Comparing endovascular revascularisation plus supervised exercise versus supervised exercise alone showed no clear differences between groups for MWD (SMD 0.26, 95% CI -0.13 to 0.64; 3 studies; 432 participants; moderate-quality evidence) and PFWD (SMD 0.33, 95% CI -0.26 to 0.93; 2 studies; 305 participants; moderate-quality evidence). Long-term follow-up in one study (106 participants) revealed a large effect on MWD (SMD 1.18, 95% CI 0.65 to 1.70; low-quality evidence) in favour of the combination therapy. Reports indicate that disease-specific QoL was comparable between groups (SMD 0.25, 95% CI -0.05 to 0.56; 2 studies; 330 participants; moderate-quality evidence) and that the number of secondary invasive interventions (OR 0.27, 95% CI 0.13 to 0.55; 3 studies; 457 participants; high-quality evidence) was lower following combination therapy.Two studies comparing endovascular revascularisation plus pharmacotherapy (cilostazol) versus pharmacotherapy alone provided data showing a small effect on MWD (SMD 0.38, 95% CI 0.08 to 0.68; 186 participants; high-quality evidence), a moderate effect on PFWD (SMD 0.63, 95% CI 0.33 to 0.94; 186 participants; high-quality evidence), and a moderate effect on disease-specific QoL (SMD 0.59, 95% CI 0.27 to 0.91; 170 participants; high-quality evidence) in favour of combination therapy. Long-term follow-up in one study (47 participants) revealed a moderate effect on MWD (SMD 0.72, 95% CI 0.09 to 1.36; P = 0.02) in favour of combination therapy and no clear differences in PFWD between groups (SMD 0.54, 95% CI -0.08 to 1.17; P = 0.09). The number of secondary invasive interventions was comparable between groups (OR 1.83, 95% CI 0.49 to 6.83; 199 participants; high-quality evidence). In the management of patients with IC, endovascular revascularisation does not provide significant benefits compared with supervised exercise alone in terms of improvement in functional performance or QoL. Although the number of studies is small and clinical heterogeneity underlines the need for more homogenous and larger studies, evidence suggests that a synergetic effect may occur when endovascular revascularisation is combined with a conservative therapy of supervised exercise or pharmacotherapy with cilostazol: the combination therapy seems to result in greater improvements in functional performance and in QoL scores than are seen with conservative therapy alone.

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Acute otitis media (AOM) is one of the most common childhood illnesses. While many children experience sporadic AOM episodes, an important group suffer from recurrent AOM (rAOM), defined as three or more episodes in six months, or four or more in one year. In this subset of children AOM poses a true burden through frequent episodes of ear pain, general illness, sleepless nights and time lost from nursery or school. Grommets, also called ventilation or tympanostomy tubes, can be offered for rAOM. To assess the benefits and harms of bilateral grommet insertion with or without concurrent adenoidectomy in children with rAOM. The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; CENTRAL; MEDLINE; EMBASE; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 4 December 2017. Randomised controlled trials (RCTs) comparing bilateral grommet insertion with or without concurrent adenoidectomy and no ear surgery in children up to age 16 years with rAOM. We planned to apply two main scenarios: grommets as a single surgical intervention and grommets as concurrent treatment with adenoidectomy (i.e. children in both the intervention and comparator groups underwent adenoidectomy). The comparators included active monitoring, antibiotic prophylaxis and placebo medication. We used the standard methodological procedures expected by Cochrane. Primary outcomes were: proportion of children who have no AOM recurrences at three to six months follow-up (intermediate-term) and persistent tympanic membrane perforation (significant adverse event). Secondary outcomes were: proportion of children who have no AOM recurrences at six to 12 months follow-up (long-term); total number of AOM recurrences, disease-specific and generic health-related quality of life, presence of middle ear effusion and other adverse events at short-term, intermediate-term and long-term follow-up. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. Five RCTs (805 children) with unclear or high risk of bias were included. All studies were conducted prior to the introduction of pneumococcal vaccination in the countries' national immunisation programmes. In none of the trials was adenoidectomy performed concurrently in both groups.Grommets versus active monitoringGrommets were more effective than active monitoring in terms of:- proportion of children who had no AOM recurrence at six months (one study, 95 children, 46% versus 5%; risk ratio (RR) 9.49, 95% confidence interval (CI) 2.38 to 37.80, number needed to treat to benefit (NNTB) 3; low-quality evidence);- proportion of children who had no AOM recurrence at 12 months (one study, 200 children, 48% versus 34%; RR 1.41, 95% CI 1.00 to 1.99, NNTB 8; low-quality evidence);- number of AOM recurrences at six months (one study, 95 children, mean number of AOM recurrences per child: 0.67 versus 2.17, mean difference (MD) -1.50, 95% CI -1.99 to -1.01; low-quality evidence);- number of AOM recurrences at 12 months (one study, 200 children, one-year AOM incidence rate: 1.15 versus 1.70, incidence rate difference -0.55, 95% -0.17 to -0.93; low-quality evidence).Children receiving grommets did not have better disease-specific health-related quality of life (Otitis Media-6 questionnaire) at four (one study, 85 children) or 12 months (one study, 81 children) than those managed by active monitoring (low-quality evidence).One study reported no persistent tympanic membrane perforations among 54 children receiving grommets (low-quality evidence).Grommets versus antibiotic prophylaxisIt is uncertain whether or not grommets are more effective than antibiotic prophylaxis in terms of:- proportion of children who had no AOM recurrence at six months (two studies, 96 children, 60% versus 35%; RR 1.68, 95% CI 1.07 to 2.65, I<sup2</sup = 0%, fixed-effect model, NNTB 5; very low-quality evidence);- number of AOM recurrences at six months (one study, 43 children, mean number of AOM recurrences per child: 0.86 versus 1.38, MD -0.52, 95% CI -1.37 to 0.33; very low-quality evidence).Grommets versus placebo medicationGrommets were more effective than placebo medication in terms of:- proportion of children who had no AOM recurrence at six months (one study, 42 children, 55% versus 15%; RR 3.64, 95% CI 1.20 to 11.04, NNTB 3; very low-quality evidence);- number of AOM recurrences at six months (one study, 42 children, mean number of AOM recurrences per child: 0.86 versus 2.0, MD -1.14, 95% CI -2.06 to -0.22; very low-quality evidence).One study reported persistent tympanic membrane perforations in 3 of 76 children (4%) receiving grommets (low-quality evidence).Subgroup analysisThere were insufficient data to determine whether presence of middle ear effusion at randomisation, type of grommet or age modified the effectiveness of grommets. Current evidence on the effectiveness of grommets in children with rAOM is limited to five RCTs with unclear or high risk of bias, which were conducted prior to the introduction of pneumococcal vaccination. Low to very low-quality evidence suggests that children receiving grommets are less likely to have AOM recurrences compared to those managed by active monitoring and placebo medication, but the magnitude of the effect is modest with around one fewer episode at six months and a less noticeable effect by 12 months. The low to very low quality of the evidence means that these numbers need to be interpreted with caution since the true effects may be substantially different. It is uncertain whether or not grommets are more effective than antibiotic prophylaxis. The risk of persistent tympanic membrane perforation after grommet insertion was low.Widespread use of pneumococcal vaccination has changed the bacteriology and epidemiology of AOM, and how this might impact the results of prior trials is unknown. New and high-quality RCTs of grommet insertion in children with rAOM are therefore needed. These trials should not only focus on the frequency of AOM recurrences, but also collect data on the severity of AOM episodes, antibiotic consumption and adverse effects of both surgery and antibiotics. This is particularly important since grommets may reduce the severity of AOM recurrences and allow for topical rather than oral antibiotic treatment.

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This is an updated version of the original Cochrane Review published in Issue 11, 2006 of the Cochrane Database of Systematic Reviews.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 to go into long-term remission shortly after starting drug therapy with a single antiepileptic drug (AED) in monotherapy.The correct choice of first-line AED for individuals with newly diagnosed seizures is of great importance. It is important that the choice of AEDs for an individual is made using the highest quality evidence regarding the potential benefits and harms of the various treatments.Carbamazepine or lamotrigine are recommended as first-line treatments for new onset focal seizures and as a first- or second-line treatment for generalised tonic-clonic seizures. Performing a synthesis of the evidence from existing trials will increase the precision of the results for outcomes relating to efficacy and tolerability and may assist in informing a choice between the two drugs. To review the time to treatment failure, remission and first seizure with lamotrigine compared to carbamazepine 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). We conducted the first searches for this review in 1997. For the most recent update, we searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE, Clinical Trials.gov and the WHO International Clinical Trials Registry Platform on 26 February 2018, without language restrictions SELECTION CRITERIA: Randomised controlled trials comparing monotherapy with either carbamazepine or lamotrigine in children or adults with focal onset seizures or generalised onset tonic-clonic seizures DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was time to treatment failure and our secondary outcomes were time to first seizure post randomisation, time to six-month, 12-month and 24-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. We included 14 trials in this review. Individual participant data were available for 2572 participants out of 3787 eligible individuals from nine out of 14 trials: 68% of the potential data. For remission outcomes, a HR of less than one indicated an advantage for carbamazepine; and for first seizure and treatment failure outcomes, a HR of less than one indicated an advantage for lamotrigine.The main overall results were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type: 0.71, 95% CI 0.62 to 0.82, moderate-quality evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type: 0.55 (95% CI 0.45 to 0.66, moderate-quality evidence), time to treatment failure due to lack of efficacy (pooled HR for all participants: 1.03 (95% CI 0.75 to 1.41), moderate-quality evidence) showing a significant advantage for lamotrigine compared to carbamazepine in terms of treatment failure for any reason related to treatment and treatment failure due to adverse events, but no different between drugs for treatment failure due to lack of efficacy.Time to first seizure (pooled HR adjusted for seizure type: 1.26, 95% CI 1.12 to 1.41, high-quality evidence) and time to six-month remission (pooled HR adjusted for seizure type: 0.86, 95% CI 0.76 to 0.97, high-quality evidence), showed a significant advantage for carbamazepine compared to lamotrigine for first seizure and six-month remission. We found no difference between the drugs for time to 12-month remission (pooled HR for all participants 0.91, 95% CI 0.77 to 1.07, high-quality evidence) or time to 24-month remission (HR for all participants 1.00, 95% CI 0.80 to 1.25, high-quality evidence), however only two trials followed up participants for more than one year so evidence is limited.The results of this review are applicable mainly to individuals with focal onset seizures; 88% of included individuals experienced seizures of this type at baseline. Up to 50% of the limited number of individuals classified as experiencing generalised onset seizures at baseline may have had their seizure type misclassified, therefore we recommend caution when interpreting the results of this review for individuals with generalised onset seizures.The most commonly reported adverse events for both of the drugs across all of the included trials were dizziness, fatigue, gastrointestinal disturbances, headache and skin problems. The rate of adverse events was similar across the two drugs.The methodological quality of the included trials was generally good, however there is some evidence that the design choice of masked or open-label treatment may have influenced the treatment failure and withdrawal rates of the trials. Hence, we judged the quality of the evidence for the primary outcome of treatment failure to be moderate for individuals with focal onset seizures and low for individuals with generalised onset seizures. For efficacy outcomes (first seizure, remission), we judged the quality of evidence to be high for individuals with focal onset seizures and moderate for individuals with generalised onset seizures. Moderate quality evidence indicates that treatment failure for any reason related to treatment or due to adverse events occurs significantly earlier on carbamazepine than lamotrigine, but the results for time to first seizure suggested that carbamazepine may be superior in terms of seizure control. The choice between these first-line treatments must be made with careful consideration. We recommend that future trials should 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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Iodine deficiency disorders (IDD) affect close to 1.9 billion people worldwide, and are a major public health concern in many countries. Among children, iodine deficiency is the main cause of potentially preventable deficits of central nervous system development and impairment of cognitive function, as well as goitre and hypothyroidism in people of all ages. Salt iodisation is the preferred strategy for IDD prevention and control, however, in some instances where salt is not the major condiment, alternate vehicles for iodine fortification have been considered. To assess the effects of fortifying foods, beverages, condiments, or seasonings other than salt with iodine alone or in conjunction with other micronutrients, on iodine status and health-related outcomes in all populations. Studies were identified through systematic searches of the following databases from their start date to January 2018: Cochrane Public Health Group Specialised Register; CENTRAL; MEDLINE; MEDLINE in Process; Embase; Web of Science; CINAHL; POPLINE; AGRICOLA; BIOSIS; Food Science and Technology Abstracts; OpenGrey; Bibliomap and TRoPHI; AGRIS; IBECS; Scielo; Global Index Medicus-AFRO and EMRO; LILACS; PAHO; WHOLIS; WPRO; IMSEAR; IndMED; and Native Health Research Database. We also searched reference list of relevant articles, conference proceedings, and databases of ongoing trials, and contacted experts and relevant organisations to identify any unpublished work. We applied no language or date restrictions. Studies were eligible if they were randomised or quasi-randomised controlled trials (RCT) with randomisation at either the individual or cluster level (including cross-over trials), non-randomised RCTs, or prospective observational studies with a control group, such as cohort studies, controlled before-and-after studies, and interrupted time series. We included studies that examined the effects of fortification of food, beverage, condiment, or seasoning with iodine alone, or in combination with other micronutrients versus the same unfortified food, or no intervention. We considered the following measures: death (all-cause), goitre, physical development, mental development, cognitive function and motor skill development, cretinism, hypothyroidism, adverse effects (any reported by trialists), urinary iodine concentration, thyroid-stimulating hormone (TSH) concentration, and serum thyroglobulin concentration. We included all populations, including pregnant women, from any country. Two review authors independently assessed study eligibility, extracted data, and assessed risk of bias of included studies.We used random-effects meta-analyses to combine data and generate an overall estimate of treatment effect, when more than one study examined the same outcome measure. The overall effect estimate was calculated as the mean difference (MD) or standardised mean difference (SMD) between the intervention group and the comparison group for continuous outcomes, and as odds ratio (OR) for dichotomous outcomes. We assessed the level of heterogeneity through the I² statistic. We conducted post-hoc subgroup analyses to explore possible sources of heterogeneity, and sensitivity analyses to check the robustness of the findings from the primary analyses. We assessed the quality of the evidence for each outcome using the GRADE framework.Where it was not possible to pool the results in a meta-analysis, we provided a narrative summary of the outcomes. Eleven studies met the criteria, providing 14 comparisons, and capturing data on 4317 participants. Seven studies were RCTs, three were cluster non-RCTs, and one was a randomised cross-over design. Seven studies were carried out among school children (N = 3636), three among women of reproductive age (N = 648), and one among infants (N = 33). The studies used diverse types of food as vehicle for iodine delivery: biscuits, milk, fish sauce, drinking water, yoghourt, fruit beverage, seasoning powder, and infant formula milk. Daily amounts of iodine provided ranged from 35 µg/day to 220 µg/day; trial duration ranged from 11 days to 48 weeks. Five studies examined the effect of iodine fortification alone, two against the same unfortified food, and three against no intervention. Six studies evaluated the effect of cofortification of iodine with other micronutrients versus the same food without iodine but with different levels of other micronutrients. We assessed one study to be at low risk of bias for all bias domains, three at low risk of bias for all domains apart from selective reporting, and seven at an overall rating of high risk of bias.No study assessed the primary outcomes of death, mental development, cognitive function, cretinism, or hypothyroidism, or secondary outcomes of TSH or serum thyroglobulin concentration. Two studies reported the effects on goitre, one on physical development measures, and one on adverse effects. All studies assessed urinary iodine concentration.The effects of iodine fortification compared to control on goitre prevalence (OR 1.60, 95% CI 0.60 to 4.31; 1 non-RCT, 83 participants; very low-quality evidence), and five physical development measures were uncertain (1 non-RCT, 83 participants; very low-quality evidence): weight (MD 0.23 kg, 95% CI -6.30 to 6.77); height (MD -0.66 cm, 95% CI -4.64 to 3.33); weight-for-age (MD 0.05, 95% CI -0.59 to 0.69); height-for-age (MD -0.30, 95% CI -0.75 to 0.15); and weight-for-height (MD -0.21, 95% CI -0.51 to 0.10). One study reported that there were no adverse events observed during the cross-over trial (low-quality evidence).Pooled results from RCTs showed that urinary iodine concentration significantly increased following iodine fortification (SMD 0.59, 95% CI 0.37 to 0.81; 6 RCTs, 2032 participants; moderate-quality evidence). This is equivalent to an increase of 38.32 µg/L (95% CI 24.03 to 52.61 µg/L). This effect was not observed in the meta-analysis of non-RCTs (SMD 0.25, 95% CI -0.16 to 0.66; 3 non-RCTs, 262 participants; very low-quality evidence). Sensitivity analyses did not change the effect observed in the primary analyses. The evidence on the effect of iodine fortification of foods, beverages, condiments, or seasonings other than salt on reducing goitre, improving physical development measures, and any adverse effects is uncertain. However, our findings suggest that the intervention likely increases urinary iodine concentration. Additional, adequately powered, high-quality studies on the effects of iodine fortification of foods on these, and other important outcomes, as well as its efficacy and safety, are required.

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Infantile seborrhoeic dermatitis (ISD) is a chronic, inflammatory, scaling skin condition, which causes redness and a greasy scaling rash in infants and young children. It can last from weeks to months, but rarely years. When it occurs on the scalp, it is referred to as 'cradle cap'. While benign and self-limiting, irrelevant of its location on the body, it can distress parents. The effectiveness of commonly promoted treatments is unclear. To assess the effects of interventions for infantile seborrhoeic dermatitis in children from birth to 24 months of age. We searched the following databases up to 22 May 2018: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We searched trials registers and checked reference lists of included studies for further references to randomised controlled trials (RCTs). We searched for unpublished RCTs and grey literature via web search engines, and wrote to authors and pharmaceutical companies. We included RCTs of interventions for ISD in children from birth up to 24 months who were clinically diagnosed by a healthcare practitioner with ISD or cradle cap. We allowed comparison of any treatment to no treatment or placebo, and the comparison of two or more treatments or a combination of treatments. We used standard methodological procedures expected by Cochrane. The primary outcome measures were 'Change in severity score from baseline to end of study' and 'Percentage of infants treated who develop adverse effects or intolerance to treatment'. The secondary outcome was 'Improvement in quality of life (QoL) as reported by parents'. We included six RCTs (one with a cross-over design) randomising 310 children and reporting outcomes for 297 children. Most participants were aged under seven months with only two participants aged over one year (seven and 12 years old); where specified, 60% were boys. In two studies, condition severity was mild to moderate; one study included two participants with severe ISD; the other studies did not describe baseline severity or described it as body surface area affected.The study setting was not always clear but likely a paediatric outpatient clinic in the following countries: Thailand, Israel, USA, France, and Australia.Two studies compared oral biotin (a B group vitamin) against placebo, two studies compared proprietary products against placebo cream or a control shampoo, and two studies compared topical corticosteroids against other products. The studies were generally short-term, between 10 and 42 days' duration; only one study followed the participants until resolution of the rash or eight months of age.We assessed the risk of bias as unclear for most aspects due to lack of reporting, but two of the studies were at high risk of performance and detection bias due to the appearance of the intervention, the trial design (open-label), or use of overlabelled tubes. Two trials had a high risk of attrition bias.All the results given below were based on very low-quality evidence. Treatment duration ranged from one week to three weeks.For the two trials comparing biotin versus placebo (n = 35), one did not report a measure of change in severity (only change in duration of rash) while the other did not report raw data (only 'no statistically significant difference'), measured at three weeks. Neither trial reported on adverse events.Two trials compared proprietary products against placebo (n = 160). One trial assessed change in severity via percentage success (96% of participants in non-steroidal cream Promiseb versus 92% in placebo), and reported no adverse events (both assessed at day 14). The other trial assessed change in severity via reduction in lesional score (surface area covered), finding better results for lactamide MEA gel (a moisturising agent) plus shampoo (81.4%) compared with shampoo only (70.2%; P = 0.0092). No adverse events were described, but signs of discomfort were similar in both groups (both assessed at day 21).In the comparison of topical steroids versus another product, change in severity was measured through evaluation of cure and body surface (n = 102).In one trial comparing hydrocortisone 1% lotion with licochalcone 0.025% lotion, there was no significant difference in participants cured (95.8% with hydrocortisone compared to 97.1% with licochalcone). One person in the licochalcone group developed more erythema, but there were no other adverse events (both outcomes assessed at day 14). In the trial comparing flumethasone pivalate 0.02% ointment versus eosin 2% aqueous solution, a reduction in body surface area affected was seen in both groups at day 10 (9% with corticosteroid versus 7% with aqueous solution), with all infants showing less than 10% involvement. There were no adverse events (both outcomes assessed at day 10).No studies measured QoL.We found no trials testing commonly used treatments such as mineral oils, salicylic acid, or antifungals. Our review identified only a limited number of studies investigating the effects of interventions for ISD in infants and young children. Unlike the reviews investigating the effects of treatments in adults, our results showed that there is uncertainty regarding the effectiveness and safety of studied treatments due to the very low-certainty evidence for all comparisons and outcomes.We assessed most bias domains as at unclear risk, but there was a high risk of bias for (mainly) performance, attrition, and detection bias. Evidence was limited further by imprecision (small studies, low number of events), indirectness (mainly with the outcomes assessed), and poor trial reporting. In most studies, the prognosis for the condition was favourable regardless of intervention but interpretation is limited by the very low-certainty evidence.Further research is needed with large, well-conducted, and well-reported intervention trials, particularly of interventions commonly recommended or used, such as emollients or shampoos and brushing, antifungals, or steroids. All studies should report standardised and validated relevant outcome measures, including adverse events, severity, and QoL, and they should be conducted in primary care settings where the majority of ISD is managed. Future trials should compare against placebo, no treatment, or standard care.

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This is the first update of a review published in 2015, Issue 1. Chronic pain is common during childhood and adolescence and is associated with negative outcomes, such as increased severity of pain, reduced function, and low mood. Psychological therapies, traditionally delivered face-to-face with a therapist, are efficacious at reducing pain intensity and disability. To address barriers to treatment access, such as distance and cost of treatment, technology is being used to deliver these psychological therapies remotely. Therapies delivered remotely, such as via the Internet, computer-based programmes, and smartphone applications, can be used to deliver treatment to children and adolescents with chronic pain. To determine the efficacy of psychological therapies delivered remotely compared to waiting list, treatment as usual, or active control treatments, for the management of chronic pain in children and adolescents. We searched four databases (CENTRAL, MEDLINE, Embase, and PsycINFO) from inception to May 2018 for randomised controlled trials (RCTs) of remotely-delivered psychological interventions for children and adolescents with chronic pain. We searched for chronic pain conditions including, but not exclusive to, headache, recurrent abdominal pain, musculoskeletal pain, and neuropathic pain. We also searched online trial registries, reference sections, and citations of included studies for potential trials. We included RCTs that investigated the efficacy of a psychological therapy delivered remotely via technology in comparison to an active, treatment as usual, or waiting-list control. We considered blended treatments, which used a combination of technology and up to 30% face-to-face interaction. Interventions had to be delivered primarily via technology to be included, and we excluded interventions delivered via telephone. We included studies that delivered interventions to children and adolescents (up to 18 years of age) with a chronic pain condition or where chronic pain was a primary symptom of their condition (e.g. juvenile arthritis). We included studies that reported 10 or more participants in each comparator arm, at each extraction point. We combined all psychological therapies in the analyses. We split pain conditions into headache and mixed (non-headache) pain and analysed them separately. We extracted pain severity/intensity, disability, depression, anxiety, and adverse events as primary outcomes, and satisfaction with treatment as a secondary outcome. We considered outcomes at two time points: first immediately following the end of treatment (known as 'post-treatment'), and second, any follow-up time point post-treatment between three and 12 months (known as 'follow-up'). We assessed risk of bias and all outcomes for quality using the GRADE assessment. We found 10 studies with 697 participants (an additional 4 studies with 326 participants since the previous review) that delivered treatment remotely; four studies investigated children with headache conditions, one study was with children with juvenile idiopathic arthritis, one included children with sickle cell disease, one included children with irritable bowel syndrome, and three studies included children with different chronic pain conditions (i.e. headache, recurrent abdominal pain, musculoskeletal pain). The average age of children receiving treatment was 13.17 years.We judged selection, detection, and reporting biases to be mostly low risk. However, we judged performance and attrition biases to be mostly unclear. Out of the 16 planned analyses, we were able to conduct 13 meta-analyses. We downgraded outcomes for imprecision, indirectness of evidence, inconsistency of results, or because the analysis only included one study.Headache conditionsFor headache pain conditions, we found headache severity was reduced post-treatment (risk ratio (RR) 2.02, 95% confidence interval (CI) 1.35 to 3.01); P &lt; 0.001, number needed to treat to benefit (NNTB) = 5.36, 7 studies, 379 participants; very low-quality evidence). No effect was found at follow-up (very low-quality evidence). There were no effects of psychological therapies delivered remotely for disability post-treatment (standardised mean difference (SMD) -0.16, 95% CI -0.46 to 0.13; P = 0.28, 5 studies, 440 participants) or follow-up (both very low-quality evidence). Similarly, no effect was found for the outcomes of depression (SMD -0.04, 95% CI -0.15 to 0.23, P = 0.69, 4 studies, 422 participants) or anxiety (SMD -0.08, 95% CI -0.28 to 0.12; P = 0.45, 3 studies, 380 participants) at post-treatment, or follow-up (both very low-quality evidence).Mixed chronic pain conditionsWe did not find any beneficial effects of psychological therapies for reducing pain intensity post-treatment for mixed chronic pain conditions (SMD -0.90, 95% CI -1.95 to 0.16; P = 0.10, 5 studies, 501 participants) or at follow-up. There were no beneficial effects of psychological therapies delivered remotely for disability post-treatment (SMD -0.28, 95% CI -0.74 to 0.18; P = 0.24, 3 studies, 363 participants) and a lack of data at follow-up meant no analysis could be run. We found no beneficial effects for the outcomes of depression (SMD 0.04, 95% CI -0.18 to 0.26; P = 0.73, 2 studies, 317 participants) and anxiety (SMD 0.53, 95% CI -0.63 to 1.68; P = 0.37, 2 studies, 370 participants) post-treatment, however, we are cautious of our findings as we could only include two studies in the analyses. We could not conduct analyses at follow-up. We judged the evidence for all outcomes to be very low quality.All conditionsAcross all chronic pain conditions, six studies reported minor adverse events which were not attributed to the psychological therapies. Satisfaction with treatment is described qualitatively and was overall positive. However, we judged both these outcomes as very low quality. There are currently a small number of trials investigating psychological therapies delivered remotely, primarily via the Internet. We are cautious in our interpretations of analyses. We found one beneficial effect of therapies to reduce headache severity post-treatment. For the remaining outcomes there was either no beneficial effect at post-treatment or follow-up, or lack of evidence to determine an effect. Overall, participant satisfaction with treatment was positive. We judged the quality of the evidence to be very low, meaning we are very uncertain about the estimate. Further studies are needed to increase our confidence in this potentially promising field.

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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 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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Hepatic encephalopathy is a common complication of cirrhosis, with high related morbidity and mortality. Its presence is associated with a wide spectrum of change ranging from clinically obvious neuropsychiatric features, known as 'overt' hepatic encephalopathy, to abnormalities manifest only on psychometric or electrophysiological testing, 'minimal' hepatic encephalopathy. The exact pathogenesis of the syndrome is unknown but ammonia plays a key role. Drugs that specifically target ammonia include sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST-120 (spherical carbon adsorbent), and polyethylene glycol. To evaluate the beneficial and harmful effects of pharmacotherapies that specifically target ammonia versus placebo, no intervention, or other active interventions, for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. We searched the Cochrane Hepato-Biliary Controlled Trials Register, CENTRAL, MEDLINE, Embase, and three other databases to March 2019. We also searched online trials registries such as ClinicalTrials.gov, European Medicines Agency, WHO International Clinical Trial Registry Platform, and the Food and Drug Administration for ongoing or unpublished trials. In addition, we searched conference proceedings, checked bibliographies, and corresponded with investigators. We included randomised clinical trials comparing sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST-120, and polyethylene glycol versus placebo or non-absorbable disaccharides, irrespective of blinding, language, or publication status. We included participants with minimal or overt hepatic encephalopathy or participants who were at risk of developing hepatic encephalopathy. Two review authors independently extracted data from the included reports. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I<sup2</sup statistic values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the certainty of the evidence using GRADE. We identified 11 randomised clinical trials that fulfilled our inclusion criteria. Two trials evaluated the prevention of hepatic encephalopathy while nine evaluated the treatment of hepatic encephalopathy. The trials assessed sodium benzoate (three trials), glycerol phenylbutyrate (one trial), ornithine phenylacetate (two trials), AST-120 (two trials), and polyethylene glycol (three trials). Overall, 499 participants received these pharmacotherapies while 444 participants received a placebo preparation or a non-absorbable disaccharide. We classified eight of the 11 trials as at 'high risk of bias' and downgraded the certainty of the evidence to very low for all outcomes.Eleven trials, involving 943 participants, reported mortality data, although there were no events in five trials. Our analyses found no beneficial or harmful effects of sodium benzoate versus non-absorbable disaccharides (RR 1.26, 95% CI 0.49 to 3.28; 101 participants; 2 trials; I<sup2</sup = 0%), glycerol phenylbutyrate versus placebo (RR 0.65, 95% CI 0.11 to 3.81; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.73, 95% CI 0.35 to 1.51; 269 participants; 2 trials; I<sup2</sup = 0%), AST-120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial), or polyethylene glycol versus lactulose (RR 0.50, 95% CI 0.09 to 2.64; 190 participants; 3 trials; I<sup2</sup = 0%).Seven trials involving 521 participants reported data on hepatic encephalopathy. Our analyses showed a beneficial effect of glycerol phenylbutyrate versus placebo (RR 0.57, 95% CI 0.36 to 0.90; 178 participants; 1 trial; number needed to treat for an additional beneficial outcome (NNTB) 6), and of polyethylene glycol versus lactulose (RR 0.19, 95% CI 0.08 to 0.44; 190 participants; 3 trials; NNTB 4). We did not observe beneficial effects in the remaining three trials with extractable data: sodium benzoate versus non-absorbable disaccharides (RR 1.22, 95% CI 0.51 to 2.93; 74 participants; 1 trial); ornithine phenylacetate versus placebo (RR 2.71, 95% CI 0.12 to 62.70; 38 participants; 1 trial); or AST-120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial).Ten trials, involving 790 participants, reported a total of 130 serious adverse events. Our analyses found no evidence of beneficial or harmful effects of sodium benzoate versus non-absorbable disaccharides (RR 1.08, 95% CI 0.44 to 2.68; 101 participants; 2 trials), glycerol phenylbutyrate versus placebo (RR 1.63, 95% CI 0.85 to 3.13; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.92, 95% CI 0.62 to 1.36; 264 participants; 2 trials; I<sup2</sup = 0%), or polyethylene glycol versus lactulose (RR 0.57, 95% CI 0.18 to 1.82; 190 participants; 3 trials; I<sup2</sup = 0%). Likewise, eight trials, involving 782 participants, reported a total of 374 non-serious adverse events and again our analyses found no beneficial or harmful effects of the pharmacotherapies under review when compared to placebo or to lactulose/lactitol.Nine trials, involving 733 participants, reported data on blood ammonia. We observed significant reductions in blood ammonia in placebo-controlled trials evaluating sodium benzoate (MD -32.00, 95% CI -46.85 to -17.15; 16 participants; 1 trial), glycerol phenylbutyrate (MD -12.00, 95% CI -23.37 to -0.63; 178 participants; 1 trial), ornithine phenylacetate (MD -27.10, 95% CI -48.55 to -5.65; 231 participants; 1 trial), and AST-120 (MD -22.00, 95% CI -26.75 to -17.25; 98 participants; 1 trial). However, there were no significant differences in blood ammonia concentrations in comparison with lactulose/lactitol with sodium benzoate (MD 9.00, 95% CI -1.10 to 19.11; 85 participants; 2 trials; I<sup2</sup = 0%), AST-120 (MD 5.20, 95% CI -2.75 to 13.15; 35 participants; 1 trial), and polyethylene glycol (MD -29.28, 95% CI -95.96 to 37.39; 90 participants; 2 trials; I<sup2</sup = 88%). Five trials received support from pharmaceutical companies while four did not; two did not provide this information. There is insufficient evidence to determine the effects of these pharmacotherapies on the prevention and treatment of hepatic encephalopathy in adults with cirrhosis. They have the potential to reduce blood ammonia concentrations when compared to placebo, but their overall effects on clinical outcomes of interest and the potential harms associated with their use remain uncertain. Further evidence is needed to evaluate the potential beneficial and harmful effects of these pharmacotherapies in this clinical setting.

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Chronic non-cancer pain, a disabling and distressing condition, is common in adults. It is a global public health problem and economic burden on health and social care systems and on people with chronic pain. Psychological treatments aim to reduce pain, disability and distress. This review updates and extends its previous version, published in 2012. To determine the clinical efficacy and safety of psychological interventions for chronic pain in adults (age &gt; 18 years) compared with active controls, or waiting list/treatment as usual (TAU). We identified randomised controlled trials (RCTs) of psychological therapies by searching CENTRAL, MEDLINE, Embase and PsycINFO to 16 April 2020. We also examined reference lists and trial registries, and searched for studies citing retrieved trials. RCTs of psychological treatments compared with active control or TAU of face-to-face therapies for adults with chronic pain. We excluded studies of headache or malignant disease, and those with fewer than 20 participants in any arm at treatment end. Two or more authors rated risk of bias, extracted data, and judged quality of evidence (GRADE). We compared cognitive behavioural therapy (CBT), behavioural therapy (BT), and acceptance and commitment therapy (ACT) with active control or TAU at treatment end, and at six month to 12 month follow-up. We did not analyse the few trials of other psychological treatments. We assessed treatment effectiveness for pain intensity, disability, and distress. We extracted data on adverse events (AEs) associated with treatment. We added 41 studies (6255 participants) to 34 of the previous review's 42 studies, and now have 75 studies in total (9401 participants at treatment end). Most participants had fibromyalgia, chronic low back pain, rheumatoid arthritis, or mixed chronic pain. Most risk of bias domains were at high or unclear risk of bias, with selective reporting and treatment expectations mostly at unclear risk of bias. AEs were inadequately recorded and/or reported across studies. CBT The largest evidence base was for CBT (59 studies). CBT versus active control showed very small benefit at treatment end for pain (standardised mean difference (SMD) -0.09, 95% confidence interval (CI) -0.17 to -0.01; 3235 participants; 23 studies; moderate-quality evidence), disability (SMD -0.12, 95% CI -0.20 to -0.04; 2543 participants; 19 studies; moderate-quality evidence), and distress (SMD -0.09, 95% CI -0.18 to -0.00; 3297 participants; 24 studies; moderate-quality evidence). We found small benefits for CBT over TAU at treatment end for pain (SMD -0.22, 95% CI -0.33 to -0.10; 2572 participants; 29 studies; moderate-quality evidence), disability (SMD -0.32, 95% CI -0.45 to -0.19; 2524 participants; 28 studies; low-quality evidence), and distress (SMD -0.34, 95% CI -0.44 to -0.24; 2559 participants; 27 studies; moderate-quality evidence). Effects were largely maintained at follow-up for CBT versus TAU, but not for CBT versus active control. Evidence quality for CBT outcomes ranged from moderate to low. We rated evidence for AEs as very low quality for both comparisons. BT We analysed eight studies (647 participants). We found no evidence of difference between BT and active control at treatment end (pain SMD -0.67, 95% CI -2.54 to 1.20, very low-quality evidence; disability SMD -0.65, 95% CI -1.85 to 0.54, very low-quality evidence; or distress SMD -0.73, 95% CI -1.47 to 0.01, very low-quality evidence). At follow-up, effects were similar. We found no evidence of difference between BT and TAU (pain SMD -0.08, 95% CI -0.33 to 0.17, low-quality evidence; disability SMD -0.02, 95% CI -0.24 to 0.19, moderate-quality evidence; distress SMD 0.22, 95% CI -0.10 to 0.54, low-quality evidence) at treatment end. At follow-up, we found one to three studies with no evidence of difference between BT and TAU. We rated evidence for all BT versus active control outcomes as very low quality; for BT versus TAU. Evidence quality ranged from moderate to very low. We rated evidence for AEs as very low quality for BT versus active control. No studies of BT versus TAU reported AEs. ACT We analysed five studies (443 participants). There was no evidence of difference between ACT and active control for pain (SMD -0.54, 95% CI -1.20 to 0.11, very low-quality evidence), disability (SMD -1.51, 95% CI -3.05 to 0.03, very low-quality evidence) or distress (SMD -0.61, 95% CI -1.30 to 0.07, very low-quality evidence) at treatment end. At follow-up, there was no evidence of effect for pain or distress (both very low-quality evidence), but two studies showed a large benefit for reducing disability (SMD -2.56, 95% CI -4.22 to -0.89, very low-quality evidence). Two studies compared ACT to TAU at treatment end. Results should be interpreted with caution. We found large benefits of ACT for pain (SMD -0.83, 95% CI -1.57 to -0.09, very low-quality evidence), but none for disability (SMD -1.39, 95% CI -3.20 to 0.41, very low-quality evidence), or distress (SMD -1.16, 95% CI -2.51 to 0.20, very low-quality evidence). Lack of data precluded analysis at follow-up. We rated evidence quality for AEs to be very low. We encourage caution when interpreting very low-quality evidence because the estimates are uncertain and could be easily overturned. We found sufficient evidence across a large evidence base (59 studies, over 5000 participants) that CBT has small or very small beneficial effects for reducing pain, disability, and distress in chronic pain, but we found insufficient evidence to assess AEs. Quality of evidence for CBT was mostly moderate, except for disability, which we rated as low quality. Further trials may provide more precise estimates of treatment effects, but to inform improvements, research should explore sources of variation in treatment effects. Evidence from trials of BT and ACT was of moderate to very low quality, so we are very uncertain about benefits or lack of benefits of these treatments for adults with chronic pain; other treatments were not analysed. These conclusions are similar to our 2012 review, apart from the separate analysis of ACT.

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The present paper describes 16 new species and one new genus from French Guiana and numerous taxonomic changes are proposed prior to the publication of a comprehensive guide to the Phasmatodea of French Guiana. The following 16 new species are described and illustrated: Phanocles procerus n. sp., Phanocloidea lobulatipes n. sp., Cladomorphus guianensis n. sp., Hirtuleius gracilis n. sp., Parastratocles rosanti n. sp., Parastratocles fuscomarginatus n. sp., Paraprisopus apterus n. sp., Paraprisopus multicolorus n. sp., Agrostia longicerca n. sp., Isagoras similis n. sp., Paragrostia brulei n. sp., Prexaspes globosicaput n. sp., Prexaspes guianensis n. sp., Dinelytron cahureli n. sp., Prisopus clarus n. sp. and Prisopus conocephalus n. sp.. The new genus Paragrostia n. gen. is established for the newly described Paragrostia brulei n. sp. and Paragrostia flavimaculata (Heleodoro, Mendes Rafael, 2017) n. comb. the latter of which is here transferred from Agrostia Redtenbacher, 1906.                Fifty-six new combinations are proposed with species transferred to other genera: Bacteria pallidenotata Redtenbacher, 1908, is transferred to Phanocloidea Zompro, 2001 (n. comb.); Bacteria maroniensis Chopard, 1911 is transferred to Phanocles Stål, 1875 (n. comb.); Cladomorphus gibbosus (Chopard, 1911) is transferred to Hirtuleius Stål, 1875 (n. comb.); Stratocles soror Redtenbacher, 1906, Parastratocles lugubris (Redtenbacher, 1906) and Parastratocles cryptochloris (Rehn, 1904) are transferred to Brizoides Redtenbacher, 1906 (n. comb.); Stratocles xanthomela (Olivier, 1792), Stratocles forcipatus Bolívar, 1896 and Stratocles tessulatus (Olivier, 1792) are transferred to Parastratocles (n. comb.); Olcyphides cinereus (Olivier, 1792), Perliodes affinis Redtenbacher, 1906, Perliodes nigrogranulosus Redtenbacher, 1906, Perliodes sexmaculatus Redtenbacher, 1906, Isagoras rugicollis (Gray, 1835), Isagoras sauropterus Rehn, 1947, Brizoides viridipes (Rehn, 1905) and Brizoides graminea Redtenbacher, 1906 are transferred to Agrostia Redtenbacher, 1906 (n. comb.); Agrostia flavimaculata Heleodoro, Mendes Rafael, 2017 is transferred to Paragrostia n. gen. (n. comb.); Isagoras affinis Chopard, 1911, Isagoras chocoensis Hebard, 1921, Isagoras metricus Rehn, 1947 and Isagoras schraderi Rehn, 1947 are transferred to Tenerella Redtenbacher, 1906 (n. comb.); Xerosoma glyptomerion Rehn, 1904 is transferred to Isagoras Stål, 1875 (n. comb.); Isagoras venosus (Burmeister, 1838), Paraphasma paulense Rehn, 1918 and Paraphasma quadratum (Bates, 1865) are transferred to Prexaspes Stål, 1875 (n. comb.); Prexaspes (Prexaspes) cneius (Westwood, 1859) is transferred to Tenerella Redtenbacher, 1906 (n. comb.); Prexaspes lateralis (Fabricius, 1775) is transferred to Paraphasma Redtenbacher, 1906 (n. comb.); Isagoras santara (Westwood, 1859) and Prexaspes olivaceus Chopard, 1911 are transferred to Periphloea Redtenbacher, 1906 (n. comb.); Dinelytron agrion Westwood, 1859 is transferred to Paraprisopus Redtenbacher, 1906 (n. comb.); Anarchodes atrophicus (Pallas, 1772) is transferred to Ignacia Rehn, 1904 (n. comb.); Planudes asperus Bellanger Conle, 2013, Planudes brunni Redtenbacher, 1906, Planudes cortex Hebard, 1919, Planudes crenulipes Rehn, 1904, Planudes funestus Redtenbacher, 1906, Planudes melzeri Piza, 1937, Planudes molorchus (Westwood, 1859), Planudes paxillus (Westwood, 1859), Planudes perillus Stål, 1875, Planudes pygmaeus (Redtenbacher, 1906) and Planudes taeniatus Piza, 1944 are transferred to Isagoras Stål, 1875 (n. comb.); Prisopoides atrobrunneus Heleodoro Rafael, 2020, Prisopoides brunnescens Heleodoro Rafael, 2020, Prisopoides caatingaensis Heleodoro Rafael, 2020 and Prisopoides villosipes (Redtenbacher, 1906) are transferred to Prisopus Peletier de Saint Fargeau Serville, 1828 (n. comb.); Melophasma antillarum (Caudell, 1914), Melophasma brachypterum Conle, Hennemann Gutiérrez, 2011, Melophasma colombianum Conle, Hennemann Gutiérrez, 2011 and Melophasma vermiculare Redtenbacher, 1906 are transferred to Paraprisopus Redtenbacher, 1906 (n. comb.); Prexaspes (Elasia) ambiguus (Stoll, 1813), Prexaspes (Elasia) brevipennis (Burmeister, 1838), Prexaspes (Elasia) pholcus (Westwood, 1859), Prexaspes (Elasia) viridipes Redtenbacher, 1906 and Prexaspes (Elasia) vittata (Piza, 1985) are transferred to Prexaspes Stål, 1875 (n. comb.).                Twenty-six new synonymies are established: Perliodes Redtenbacher, 1906 and Chlorophasma Redtenbacher, 1906 are synonymised with Agrostia Redtenbacher, 1906 (n. syn.); Chlorophasma Redtenbacher, 1906 is synonymised with Agrostia Redtenbacher, 1906 (n. syn.); Elasia Redtenbacher, 1906 is synonymised with Prexaspes Stål, 1875 (n. syn.); Prisopoides Heleodoro Rafael, 2020 is synonymised with Prisopus Peletier de Saint Fargeau Serville, 1828 (n. syn.); Melophasma Redtenbacher, 1906 is synonymised with Paraprisopus Redtenbacher, 1906 (n. syn.); Bacteria crassipes Chopard, 1911 is synonymised with Bacteria pallidenotata Redtenbacher, 1908 (n. syn.); Perliodes grisescens Redtenbacher, 1906 and Metriophasma (Metriophasma) pallidum (Chopard, 1911) are synonymised with Agrostia cinerea (Olivier, 1792) (n. syn.); Perliodes nigrogranulosus Redtenbacher, 1906 and Metriophasma (Metriophasma) ocellatum (Piza, 1937) are synonymised with Isagoras rugicollis (Gray, 1835) (n. syn.); Isagoras chopardi Hebard, 1933 is synonymised with Tenerella cneius (Westwood, 1859) (n. syn.); Isagoras proximus Redtenbacher, 1906 is synonymised with Isagoras glyptomerion (Rehn, 1904) (n. syn.); Chlorophasma hyalina Redtenbacher, 1906 is synonymised with Agrostia graminea (Redtenbacher, 1906) (n. syn.); Isagoras nitidus Redtenbacher, 1906 is synonymised with Anisa flavomaculatus (Gray, 1835) (n. syn.); Prexaspes acuticornis (Gray, 1835) is synonymised with Prexaspes servillei (Gray, 1835) (n. syn.); Prexaspes nigromaculatus Chopard, 1911 is synonymised with Periphloea santara (Westwood, 1859) (n. syn.); Prexaspes (Elasia) janus Kirby, 1904 is synonymised with Paraphasma maculatum (Gray, 1835) (n. syn.); Prexaspes dictys (Westwood, 1859) is synonymised with Prexaspes brevipennis (Burmeister, 1838) (n. syn.); Parastratocles aeruginosus Redtenbacher, 1906: 107 is synonymised with Parastratocles forcipatus Bolívar, 1896 (n. syn.); Parastratocles carbonarius (Redtenbacher, 1906: 106) is synonymised with Parastratocles lugubris (Redtenbacher, 1906) (n. syn.); Prisopus spinicollis Burmeister, 1838, Prisopus spiniceps Burmeister, 1838 and Prisopus cornutus Gray, 1835 are synonymised with Prisopus ohrtmanni (Lichtenstein, 1802) (n. syn.); the genus Planudes Stål, 1875 is synonymised with Isagoras Stål, 1875 (n. syn.); Pseudophasma annulipes (Redtenbacher, 1906) is synonymised with Pseudophasma blanchardi (Westwood, 1859) (n. syn.); Ignacia appendiculatum (Kirby, 1904) is synonymised with Anarchodes atrophicus (Pallas, 1772) (n. syn.).                Isagoras obscurum Guérin-Méneville, 1838 is shown to have been erroneously synonymised with Isagoras rugicollis (Gray, 1835) and is here re-established as a valid species (rev. stat.). Pseudophasma castaneum (Bates, 1865) is re-established as a valid species here (rev. stat.).                Paraprisopus Redtenbacher, 1906 and the entire tribe Paraprisopodini are transferred to Pseudophasmatidae: Pseudophasmatinae (n. comb.).                Lectotypes are designated for Perliodes grisescens Redtenbacher, 1906, Isagoras plagiatus Redtenbacher, 1906.Neotypes are designated for Agrostia cinerea (Olivier, 1792), Prexaspes ambiguus (Stoll, 1813), Prisopus horridus (Gray, 1835) and Prisopus sacratus (Olivier, 1792).

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The GETAFIX trial will test the hypothesis that favipiravir is a more effective treatment for COVID-19 infection in patients who have early stage disease, compared to current standard of care. This study will also provide an important opportunity to investigate the safety and tolerability of favipiravir, the pharmacokinetic and pharmacodynamic profile of this drug and mechanisms of resistance in the context of COVID-19 infection, as well as the effect of favipiravir on hospitalisation duration and the post COVID-19 health and psycho-social wellbeing of patients recruited to the study. GETAFIX is an open label, parallel group, two arm phase II/III randomised trial with 1:1 treatment allocation ratio. Patients will be randomised to one of two arms and the primary endpoint will assess the superiority of favipiravir plus standard treatment compared to standard treatment alone. This trial will recruit adult patients with confirmed positive valid COVID-19 test, who are not pregnant or breastfeeding and have no prior major co-morbidities. This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Patients must meet all of the following criteria: 1. Age 16 or over at time of consent 2. Exhibiting symptoms associated with COVID-19 3. Positive for SARS-CoV-2 on valid COVID-19 test 4. Point 1, 2, 3, or 4 on the WHO COVID-19 ordinal severity scale at time of randomisation. (Asymptomatic with positive valid COVID-19 test, Symptomatic Independent, Symptomatic assistance needed, Hospitalized, with no oxygen therapy) 5. Have &gt;=10% risk of death should they be admitted to hospital as defined by the ISARIC4C risk index: https://isaric4c.net/risk 6. Able to provide written informed consent 7. Negative pregnancy test (women of childbearing potential*) 8. Able to swallow oral medication Patients will be excluded from the trial if they meet any of the following criteria: 1. Renal impairment requiring, or likely to require, dialysis or haemofiltration 2. Pregnant or breastfeeding 3. Of child bearing potential (women), or with female partners of child bearing potential (men) who do not agree to use adequate contraceptive measures for the duration of the study and for 3 months after the completion of study treatment 4. History of hereditary xanthinuria 5. Other patients judged unsuitable by the Principal Investigator or sub-Investigator 6. Known hypersensitivity to favipiravir, its metabolites or any excipients 7. Severe co-morbidities including: patients with severe hepatic impairment, defined as:  • greater than Child-Pugh grade A  • AST or ALT &gt; 5 x ULN  • AST or ALT &gt;3 x ULN and Total Bilirubin &gt; 2xULN 8. More than 96 hours since first positive COVID-19 test sample was taken 9. Unable to discontinue contra-indicated concomitant medications This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Patients randomised to the experimental arm of GETAFIX will receive standard treatment for COVID-19 at the discretion of the treating clinician plus favipiravir. These patients will receive a loading dose of favipiravir on day 1 of 3600mg (1800mg 12 hours apart). On days 2-10, patients in the experimental arm will receive a maintenance dose of favipiravir of 800mg 12 hours apart (total of 18 doses). Patients randomised to the control arm of the GETAFIX trial will receive standard treatment for COVID-19 at the discretion of the treating clinician. The primary outcome being assessed in the GETAFIX trial is the efficacy of favipiravir in addition to standard treatment in patients with COVID-19 in reducing the severity of disease compared to standard treatment alone. Disease severity will be assessed using WHO COVID 10 point ordinal severity scale at day 15 +/- 48 hours. All randomised participants will be followed up until death or 60 days post-randomisation (whichever is sooner). Patients will be randomised 1:1 to the experimental versus control arm using computer generated random sequence allocation. A minimisation algorithm incorporating a random component will be used to allocate patients. The factors used in the minimisation will be: site, age (16-50/51-70/71+), history of hypertension or currently obsess (BMI&gt;30 or obesity clinically evident; yes/no), 7 days duration of symptoms (yes/no/unknown), sex (male/female), WHO COVID-19 ordinal severity score at baseline (1/2or 3/4). No blinding will be used in the GETAFIX trial. Both participants and those assessing outcomes will be aware of treatment allocation. In total, 302 patients will be randomised to the GETAFIX trial: 151 to the control arm and 151 to the experimental arm. There will be an optional consent form for patients who may want to contribute to more frequent PK and PD sampling. The maximum number of patients who will undergo this testing will be sixteen, eight males and eight females. This option will be offered to all patients who are being treated in hospital at the time of taking informed consent, however only patients in the experimental arm of the trial will be able to undergo this testing. The current GETAFIX protocol is version 4.0 12<supth</sup September 2020. GETAFIX opened to recruitment on 26<supth</sup October 2020 and will recruit patients over a period of approximately six months. GETAFIX was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT) Database on 15<supth</sup April 2020; Reference number 2020-001904-41 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001904-41/GB ). GETAFIX was registered on ISRCTN on 7<supth</sup September 2020; Reference number ISRCTN31062548 ( https://www.isrctn.com/ISRCTN31062548 ). The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (see Additional file 2).

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Varicoceles are associated with male subfertility; however, the mechanisms by which varicoceles affect fertility have yet to be satisfactorily explained. Several treatment options exist, including surgical or radiological treatment, however the safest and most efficient treatment remains unclear.  OBJECTIVES: To evaluate the effectiveness and safety of surgical and radiological treatment of varicoceles on live birth rate, adverse events, pregnancy rate, varicocele recurrence, and quality of life amongst couples where the adult male has a varicocele, and the female partner of childbearing age has no fertility problems. We searched the following databases on 4 April 2020: the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. We also searched the trial registries and reference lists of articles. We included randomised controlled trials (RCTs) if they were relevant to the clinical question posed and compared different forms of surgical ligation, different forms of radiological treatments, surgical treatment compared to radiological treatment, or one of these aforementioned treatment forms compared to non-surgical methods, delayed treatment, or no treatment. We extracted data if the studies reported on live birth, adverse events, pregnancy, varicocele recurrence, and quality of life. Screening of abstracts and full-text publications, alongside data extraction and 'Risk of bias' assessment, were done dually using the Covidence software. When we had sufficient data, we calculated random-effects (Mantel-Haenszel) meta-analyses; otherwise, we reported results narratively. We used the I<sup2</sup statistic to analyse statistical heterogeneity. We planned to use funnel plots to assess publication bias in meta-analyses with at least 10 included studies. We dually rated the risk of bias of studies using the Cochrane 'Risk of bias' tool, and the certainty of evidence for each outcome using the GRADE approach. We identified 1897 citations after de-duplicating the search results. We excluded 1773 during title and abstract screening. From the 113 new full texts assessed in addition to the 10 studies (11 references) included in the previous version of this review, we included 38 new studies, resulting in a total of 48 studies (59 references) in the review providing data for 5384 participants. Two studies (three references) are ongoing studies and two studies are awaiting classification. Treatment versus non-surgical, non-radiological, delayed, or no treatment Two studies comparing surgical or radiological treatment versus no treatment reported on live birth with differing directions of effect. As a result, we are uncertain whether surgical or radiological treatment improves live birth rates when compared to no treatment (risk ratio (RR) 2.27, 95% confidence interval (CI) 0.19 to 26.93; 2 RCTs, N = 204; I<sup2</sup = 74%, very low-certainty evidence). Treatment may improve pregnancy rates compared to delayed or no treatment (RR 1.55, 95% CI 1.06 to 2.26; 13 RCTs, N = 1193; I<sup2</sup = 65%, low-certainty evidence). This suggests that couples with no or delayed treatment have a 21% chance of pregnancy, whilst the pregnancy rate after surgical or radiological treatment is between 22% and 48%. We identified no evidence on adverse events, varicocele recurrence, or quality of life for this comparison. Surgical versus radiological treatment We are uncertain about the effect of surgical versus radiological treatment on live birth and on the following adverse events: hydrocele formation, pain, epididymitis, haematoma, and suture granuloma. We are uncertain about the effect of surgical versus radiological treatment on pregnancy rate (RR 1.13, 95% CI 0.75 to 1.70; 5 RCTs, N = 456, low-certainty evidence) and varicocele recurrence (RR 1.31, 95% CI 0.82 to 2.08; 3 RCTs, N = 380, low-certainty evidence). We identified no evidence on quality of life for this comparison. Surgery versus other surgical treatment We identified 19 studies comparing microscopic subinguinal surgical treatment to any other surgical treatment. Microscopic subinguinal surgical treatment probably improves pregnancy rates slightly compared to other surgical treatments (RR 1.18, 95% CI 1.02 to 1.36; 12 RCTs, N = 1473, moderate-certainty evidence). This suggests that couples with microscopic subinguinal surgical treatment have a 10% to 14% chance of pregnancy after treatment, whilst the pregnancy rate in couples after other surgical treatments is 10%. This procedure also probably reduces the risk of varicocele recurrence (RR 0.48, 95% CI 0.29, 0.79; 14 RCTs, N = 1565, moderate-certainty evidence). This suggests that 0.4% to 1.1% of men undergoing microscopic subinguinal surgical treatment experience recurrent varicocele, whilst 1.4% of men undergoing other surgical treatments do. Results for the following adverse events were inconclusive: hydrocele formation, haematoma, abdominal distension, testicular atrophy, wound infection, scrotal pain, and oedema. We identified no evidence on live birth or quality of life for this comparison. Nine studies compared open inguinal surgical treatment to retroperitoneal surgical treatment. Due to small sample sizes and methodological limitations, we identified neither treatment type as superior or inferior to the other regarding adverse events, pregnancy rates, or varicocele recurrence. We identified no evidence on live birth or quality of life for this comparison. Radiological versus other radiological treatment One study compared two types of radiological treatment (sclerotherapy versus embolisation) and reported 13% varicocele recurrence in both groups. Due to the broad confidence interval, no valid conclusion could be drawn (RR 1.00, 95% CI 0.16 to 6.20; 1 RCT, N = 30, very low-certainty evidence). We identified no evidence on live birth, adverse events, pregnancy, or quality of life for this comparison. Based on the limited evidence, it remains uncertain whether any treatment (surgical or radiological) compared to no treatment in subfertile men may be of benefit on live birth rates; however, treatment may improve the chances for pregnancy. The evidence was also insufficient to determine whether surgical treatment was superior to radiological treatment. However, microscopic subinguinal surgical treatment probably improves pregnancy rates and reduces the risk of varicocele recurrence compared to other surgical treatments. High-quality, head-to-head comparative RCTs focusing on live birth rate and also assessing adverse events and quality of life are warranted.

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Chronic non-invasive ventilation (NIV) is increasingly being used to treat people with COPD who have respiratory failure, but the evidence supporting this treatment has been conflicting. To assess the effects of chronic non-invasive ventilation at home via a facial mask in people with COPD, using a pooled analysis of IPD and meta-analysis. We searched the Cochrane Airways Register of Trials, MEDLINE, Embase, PsycINFO, CINAHL, AMED, proceedings of respiratory conferences, clinical trial registries and bibliographies of relevant studies. We conducted the latest search on 21 December 2020. We included randomised controlled trials (RCTs) comparing chronic NIV for at least five hours per night for three consecutive weeks or more (in addition to standard care) versus standard care alone, in people with COPD. Studies investigating people initiated on NIV in a stable phase and studies investigating NIV commenced after a severe COPD exacerbation were eligible, but we reported and analysed them separately. The primary outcomes were arterial blood gases, health-related quality of life (HRQL), exercise capacity (stable COPD) and admission-free survival (post-exacerbation COPD). Secondary outcomes for both populations were: lung function, COPD exacerbations and admissions, and all-cause mortality. For stable COPD, we also reported respiratory muscle strength, dyspnoea and sleep efficiency. We used standard methodological procedures expected by Cochrane. After inclusion of a study, we requested the IPD. We analysed continuous and time-to-event data using linear- and cox-regression mixed-effect models with a random effect on study level. We analysed dichotomous IPD using generalised estimating equations. We adjusted all models for age and sex. We assessed changes in outcomes after three and 12 months.  We also conducted a meta-analysis on aggregated trial data. We included 14 new RCTs in this review update, in addition to the seven previously included. Seventeen studies investigated chronic NIV in stable COPD and four studies investigated chronic NIV commenced after a severe COPD exacerbation. Three studies compared NIV to sham continuous positive airway pressure (2 to 4 cmH<sub2</subO). Seven studies used a nasal mask, one study used an oronasal mask and eight studies used both interfaces. Five studies did not report the interface. The majority of trials (20/21) were at high risk of performance bias due to an unblinded design. We considered 11 studies to have a low risk of selection bias and 13 to have a low risk of attrition bias. We collected and analysed the IPD from 13 stable COPD studies (n = 778, 68% of the participants included) and from three post-exacerbation studies (n = 364, 96% of the participants included). In the stable COPD group, NIV probably results in a minor benefit on the arterial partial pressure of oxygen (PaO<sub2</sub) after three months (adjusted mean difference (AMD) 0.27 kPa, 95% CI 0.04 to 0.49; 9 studies, 271 participants; moderate-certainty evidence), but there was little to no benefit at 12 months (AMD 0.09 kPa, 95% CI -0.23 to 0.42; 3 studies, 171 participants; low-certainty evidence). The arterial partial pressure of carbon dioxide (PaCO<sub2</sub) was reduced in participants allocated to NIV after three months (AMD -0.61 kPa, 95% CI -0.77 to -0.45; 11 studies, 475 participants; high-certainty evidence) and persisted up to 12 months (AMD -0.42 kPa, 95% CI -0.68 to -0.16; 4 studies, 232 participants; high-certainty evidence).  Exercise capacity was measured with the 6-minute walking distance (minimal clinical important difference: 26 m). There was no clinically relevant effect of NIV on exercise capacity (3 months: AMD 15.5 m, 95% CI -0.8 to 31.7; 8 studies, 330 participants; low-certainty evidence; 12 months: AMD 26.4 m, 95% CI -7.6 to 60.5; 3 studies, 134 participants; very low-certainty evidence). HRQL was measured with the Severe Respiratory Insufficiency and the St. Georges's Respiratory Questionnaire and may be improved by NIV, but only after three months (3 months: standardised mean difference (SMD) 0.39, 95% CI 0.15 to 0.62; 5 studies, 259 participants; very low-certainty evidence; 12 months: SMD 0.15, 95% CI -0.13 to 0.43; 4 studies, 200 participants; very low-certainty evidence). Lastly, the risk for all-cause mortality is likely reduced by NIV (adjusted hazard ratio (AHR) 0.75, 95% CI 0.58 to 0.97; 3 studies, 405 participants; moderate-certainty evidence). In the post-exacerbation COPD group, there was little to no benefit on the PaO<sub2</sub after three months, but there may be a slight decrease after 12 months (3 months: AMD -0.10 kPa, 95% CI -0.65 to 0.45; 3 studies, 234 participants; low-certainty evidence; 12 months: -0.27 kPa, 95% CI -0.86 to 0.32, 3 studies; 170 participants; low-certainty evidence). The PaCO<sub2</sub was reduced by NIV at both three months (AMD -0.40 kPa, 95% CI -0.70 to -0.09; 3 studies, 241 participants; moderate-certainty evidence) and 12 months (AMD -0.52 kPa, 95% CI -0.87 to -0.18; 3 studies, 175 participants; high-certainty evidence). NIV may have little to no benefit on HRQL (3 months: SMD 0.25, 95% CI -0.01 to 0.51; 2 studies, 219 participants; very low-certainty evidence; 12 months: SMD 0.25, 95% -0.06 to 0.55; 2 studies, 164 participants; very low-certainty evidence). Admission-free survival seems improved with NIV (AHR 0.71, 95% CI 0.54 to 0.94; 2 studies, 317 participants; low-certainty evidence), but the risk for all-cause mortality does not seem to improve (AHR 0.97, 95% CI 0.74 to 1.28; 2 studies, 317 participants; low-certainty evidence). Regardless of the timing of initiation, chronic NIV improves daytime hypercapnia. In addition, in stable COPD, survival seems to be improved and there might be a short term HRQL benefit. In people with persistent hypercapnia after a COPD exacerbation, chronic NIV might prolong admission-free survival without a beneficial effect on HRQL. In stable COPD, future RCTs comparing NIV to a control group receiving standard care might no longer be warranted, but research should focus on identifying participant characteristics that would define treatment success. Furthermore, the optimal timing for initiation of NIV after a severe COPD exacerbation is still unknown.

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Anxiety disorders are a potentially disabling group of disorders that frequently co-occur with alcohol use disorders. Comorbid anxiety and alcohol use disorders are associated with poorer outcomes, and are difficult to treat with standard psychosocial interventions. In addition, improved understanding of the biological basis of the conditions has contributed to a growing interest in the use of medications for the treatment of people with both diagnoses. To assess the effects of pharmacotherapy for treating anxiety in people with comorbid alcohol use disorders, specifically: to provide an estimate of the overall effects of medication in improving treatment response and reducing symptom severity in the treatment of anxiety disorders in people with comorbid alcohol use disorders; to determine whether specific medications are more effective and tolerable than other medications in the treatment of particular anxiety disorders; and to identify which factors (clinical, methodological) predict response to pharmacotherapy for anxiety disorders. Review authors searched the specialized registers of The Cochrane Collaboration Depression, Anxiety and Neurosis Review Group (CCDANCTR, to January 2014) and the Cochrane Drugs and Alcohol Group (CDAG, to March 2013) for eligible trials. These registers contain reports of relevant randomized controlled trials (RCT) from: the Cochrane Central Register of Controlled Trials (CENTRAL, all years), MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date). Review authors ran complementary searches on EMBASE, PubMed, PsycINFO and the Alcohol and Alcohol Problems Science Database (ETOH) (to August 2013). We located unpublished trials through the National Institutes of Health (NIH) RePORTER service and the World Health Organization (WHO) International Clinical Trials Registry Platform (to August 2013). We screened reference lists of retrieved articles for additional studies. All true RCTs of pharmacotherapy for treating anxiety disorders with comorbid alcohol use disorders. Trials assessing drugs administered for the treatment of drinking behaviour, such as naltrexone, disulfiram and acomprosate were not eligible for inclusion in this systematic review. A systematic review is a standardised evaluation of all research studies that address a particular clinical issue.Two review authors independently assessed RCTs for inclusion in the review, collated trial data and assessed trial quality. We contacted investigators to obtain missing data. We calculated categorical and continuous treatment effect estimates and their 95% confidence intervals (CI) for treatment using a random-effects model with effect-size variability expressed using Chi(2) and I(2) heterogeneity statistics. We included five placebo-controlled pharmacotherapy RCTs (with 290 participants) in the review. Most of the trials provided little information on how randomization was performed or on whether both participants and study personnel were blinded to the intervention. Two of the three trials reporting superiority of medication compared with placebo on anxiety symptom outcomes were industry funded. We regarded one trial as being at high risk of bias due to selective reporting.Study participants had Diagnostic and Statistical Manual (DSM) III- and DSM IV-diagnosed alcohol use disorders and post-traumatic stress disorder (two studies), social anxiety disorder (SAD; two studies) or generalized anxiety disorder (GAD; one study). Four trials assessed the efficacy of the selective serotonin re-uptake inhibitors (SSRIs: sertraline, paroxetine); one RCT investigated the efficacy of buspirone, a 5-hydroxytryptamine (5-HT) partial agonist. Treatment duration lasted between eight and 24 weeks. Overall, 70% of participants included in the review were male.There was very low quality evidence for an effect of paroxetine on global clinical response to treatment, as assessed by the Clinical Global Impressions - Improvement scale (CGI-I). Global clinical response was observed in more than twice as many participants with paroxetine than with placebo (57.7% with paroxetine versus 25.8% with placebo; risk ratio (RR) 2.23, 95% CI 1.13 to 4.41; 2 trials, 57 participants). However, there was substantial uncertainty regarding the size of the effect of paroxetine due to the small number of studies providing data on clinically diverse patient samples. The second primary outcome measure was reduction of anxiety symptom severity. Although study investigators reported that buspirone (one trial) was superior to placebo in reducing the severity of anxiety symptoms over 12 weeks, no evidence of efficacy was observed for paroxetine (mean difference (MD) -14.70, 95% CI -33.00 to 3.60, 2 trials, 44 participants) and sertraline (one trial). Paroxetine appeared to be equally effective in reducing the severity of post-traumatic stress disorder (PTSD) symptoms as the tricyclic antidepressant desipramine in one RCT. The maximal reduction in anxiety disorder symptom severity was achieved after six weeks with paroxetine (two RCTs) and 12 weeks with buspirone (one RCT), with maintenance of medication efficacy extending to 16 with paroxetine and 24 weeks with buspirone. There was no evidence of an effect for any of the medications tested on abstinence from alcohol use or depression symptoms. There was very low quality evidence that paroxetine was well tolerated, based on drop-out due to treatment-emergent adverse effects. Nevertheless, levels of treatment discontinuation were high, with 43.1% of the participants in the studies withdrawing from medication treatment. Certain adverse effects, such as sexual problems, were commonly reported after treatment with paroxetine and sertraline. The evidence-base for the effectiveness of medication in treating anxiety disorders and comorbid alcohol use disorders is currently inconclusive. There was a small amount of evidence for the efficacy of medication, but this was limited and of very low quality. The majority of the data for the efficacy and tolerability of medication were for SSRIs; there were insufficient data to establish differences in treatment efficacy between medication classes or patient subgroups. There was a small amount of very low quality evidence that medication was well tolerated. There was no evidence that alcohol use was responsive to medication.Large, rigorously conducted RCTs would help supplement the small evidence-base for the efficacy and tolerability of pharmacotherapy for anxiety and comorbid alcohol use disorders. Further research on patient subgroups who may benefit from pharmacological treatment, as well as novel pharmacological interventions, is warranted.

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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. Surgical interventions are more common in people with sickle cell disease, and occur at much younger ages than in the general population. Blood transfusions are frequently used prior to surgery and several regimens are used but there is no consensus over the best method or the necessity of transfusion in specific surgical cases. This is an update of a Cochrane review first published in 2001. To determine whether there is evidence that preoperative blood transfusion in people with sickle cell disease undergoing elective or emergency surgery reduces mortality and perioperative or sickle cell-related serious adverse events.To compare the effectiveness of different transfusion regimens (aggressive or conservative) if preoperative transfusions are indicated in people with sickle cell disease. 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 23 March 2016.We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 18 January 2016. All randomised controlled trials and quasi-randomised controlled trials comparing preoperative blood transfusion regimens to different regimens or no transfusion in people with sickle cell disease undergoing elective or emergency surgery. There was no restriction by outcomes examined, language or publication status. Two authors independently assessed trial eligibility and the risk of bias and extracted data. Three trials with 990 participants were eligible for inclusion in the review. There were no ongoing trials identified. These trials were conducted between 1988 and 2011. The majority of people included had haemoglobin (Hb) SS SCD. The majority of surgical procedures were considered low or intermediate risk for developing sickle cell-related complications. Aggressive versus simple red blood cell transfusions One trial (551 participants) compared an aggressive transfusion regimen (decreasing sickle haemoglobin to less than 30%) to a simple transfusion regimen (increasing haemoglobin to 100 g/l). This trial re-randomised participants and therefore quantitative analysis was only possible on two subsets of data: participants undergoing cholecystectomy (230 participants); and participants undergoing tonsillectomy or adenoidectomy surgeries (107 participants). Data were not combined as we do not know if any participant received both surgeries. Overall, the quality of the evidence was very low across different outcomes according to GRADE methodology. This was due to the trial being at high risk of bias primarily due to lack of blinding, indirectness and the outcome estimates being imprecise. Cholecystectomy subgroup results are reported in the abstract. Results for both subgroups were similar.There was no difference in all-cause mortality between people receiving aggressive transfusions and those receiving conservative transfusions. No deaths occurred in either subgroup.There were no differences between the aggressive transfusion group and conservative transfusion group in the number of people developing:• an acute chest syndrome, risk ratio 0.84 (95% confidence interval 0.38 to 1.84) (one trial, 230 participants, very low quality evidence);• vaso-occlusive crisis, risk ratio 0.30 (95% confidence interval 0.09 to 1.04) (one trial, 230 participants, very low quality evidence);• serious infection, risk ratio 1.75 (95% confidence interval 0.59 to 5.18) (one trial, 230 participants, very low quality evidence);• any perioperative complications, risk ratio 0.75 (95% confidence interval 0.36 to 1.55) (one trial, 230 participants, very low quality evidence);• a transfusion-related complication, risk ratio 1.85 (95% confidence interval 0.89 to 3.88) (one trial, 230 participants, very low quality evidence). Preoperative transfusion versus no preoperative transfusion Two trials (434 participants) compared a preoperative transfusion plus standard care to a group receiving standard care. Overall, the quality of the evidence was low to very low across different outcomes according to GRADE methodology. This was due to the trials being at high risk of bias due to lack of blinding, and outcome estimates being imprecise. One trial was stopped early because more people in the no transfusion arm developed an acute chest syndrome.There was no difference in all-cause mortality between people receiving preoperative transfusions and those receiving no preoperative transfusions (two trials, 434 participants, no deaths occurred).There was significant heterogeneity between the two trials in the number of people developing an acute chest syndrome, a meta-analysis was therefore not performed. One trial showed a reduced number of people developing acute chest syndrome between people receiving preoperative transfusions and those receiving no preoperative transfusions, risk ratio 0.11 (95% confidence interval 0.01 to 0.80) (65 participants), whereas the other trial did not, risk ratio 4.81 (95% confidence interval 0.23 to 99.61) (369 participants).There were no differences between the preoperative transfusion groups and the groups without preoperative transfusion in the number of people developing:• a vaso-occlusive crisis, Peto odds ratio 1.91 (95% confidence interval 0.61 to 6.04) (two trials, 434 participants, very low quality evidence).• a serious infection, Peto odds ratio 1.29 (95% confidence interval 0.29 to 5.71) (two trials, 434 participants, very low quality evidence);• any perioperative complications, risk ratio 0.24 (95% confidence interval 0.03 to 2.05) (one trial, 65 participants, low quality evidence).There was an increase in the number of people developing circulatory overload in those receiving preoperative transfusions compared to those not receiving preoperative transfusions in one of the two trials, and no events were seen in the other trial (no meta-analysis performed). There is insufficient evidence from randomised trials to determine whether conservative preoperative blood transfusion is as effective as aggressive preoperative blood transfusion in preventing sickle-related or surgery-related complications in people with HbSS disease. There is very low quality evidence that preoperative blood transfusion may prevent development of acute chest syndrome.Due to lack of evidence this review cannot comment on management for people with HbSC or HbSβ(+) disease or for those with high baseline haemoglobin concentrations.

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This review is one in a series of Cochrane reviews investigating pain management for childbirth. These reviews all contribute to an overview of systematic reviews of pain management for women in labour, and share a generic protocol. This review updates an earlier version of the review of the same title. To examine the effectiveness and safety of hypnosis for pain management during labour and childbirth. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2015) and the reference lists of primary studies and review articles. Randomised controlled trials (RCTs) and quasi-RCTS comparing preparation for labour using hypnosis and/or use of hypnosis during labour, with or without concurrent use of pharmacological or non-pharmacological pain relief methods versus placebo, no treatment or any analgesic drug or technique. Two review authors independently extracted data and assessed trial quality. Where possible we contacted study authors seeking additional information about data and methodology. We included nine trials randomising a total of 2954 women. The risk of bias in trials was variable, there were several well-designed large trials and some trials where little was reported about trial design. Although eight of the nine trials assessed antenatal hypnotherapy, there were considerable differences between these trials in timing and technique. One trial provided hypnotherapy during labour. In this updated review we compared hypnosis interventions with all control groups (main comparison) and also with specific control conditions: standard care (nine RCTs), supportive counselling (two RCTs) and relaxation training (two RCTs).In the main comparison, women in the hypnosis group were less likely to use pharmacological pain relief or analgesia than those in the control groups, (average risk ratio (RR) 0.73, 95% CI 0.57 to 0.94, eight studies, 2916 women; very low-quality evidence; random-effects model). There were no clear differences between women in the hypnosis group and those in the control groups for most of the other primary outcomes. There were no clear differences for sense of coping with labour (MD 0.22, 95% CI -0.14 to 0.58, one study, 420 women; low-quality evidence) or spontaneous vaginal birth (average RR 1.12, 95% CI 0.96 to 1.32, six studies, 2361 women; low-quality evidence; random-effects model). There were no clear differences for satisfaction with pain relief (measured on a seven-point scale two weeks postnatally) for women in the hypnosis group who also received pethidine (MD 0.41, 95% CI -0.45 to 1.27; one study, 72 women), Entonox (MD 0.19, 95% CI -0.19 to 0.57; one study, 357 women), self-hypnosis (MD 0.28, 95% CI -0.32 to 0.88; one study, 160 women), or epidural (MD -0.03, 95% CI -0.40 to 0.34; one study, 127 women), but a slight benefit in favour of hypnosis was seen for women who received water immersion (MD 0.52, 95% CI 0.04 to 1.00; one study, 174 women (all low-quality evidence). There were no clear differences for satisfaction with pain relief when it was measured as the number of women who reported they had adequate pain relief (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.94 to 1.20, one study, 264 women; low-quality evidence). It should be noted that for pharmacological pain relief and spontaneous vaginal birth, there was evidence of considerable statistical heterogeneity, which could not be fully explained by subgroup analysis.For this review's secondary outcomes, no clear differences were found between women in the hypnosis group and women in the control groups for most outcomes where data were available. There was mixed evidence regarding benefits for women in the hypnosis group compared with all control groups for pain intensity, satisfaction with childbirth experience and postnatal depression. For each of these outcomes, data from more than one trial were available for analysis but could not be combined due to differences in measurement methods. There was evidence that fewer women in the hypnosis group stayed in hospital for more than two days after the birth but this finding was based on one small study (RR 0.11, 95% CI 0.02 to 0.83). No clear differences between women in the hypnosis group and the control groups were found for the other secondary outcomes where data were available.In the comparisons of hypnosis with specific types of control conditions: standard care, supportive counselling and relaxation training, there were no clear differences found between women in the hypnosis group and those in the standard care control groups or the relaxation control groups for the primary outcomes. Compared with the women in the supportive counselling control group, women in the hypnosis group were less likely to use pharmacological analgesia (average RR 0.48, 95% CI 0.32 to 0.73, two studies, 562 women). They were also more likely to have a spontaneous vaginal birth (RR 2.42, 95% CI 1.43 to 4.07), although this finding was based on the results of one small study. Overall these new comparisons displayed much less statistical heterogeneity than the comparison including all control groups. There are still only a relatively small number of studies assessing the use of hypnosis for labour and childbirth. Hypnosis may reduce the overall use of analgesia during labour, but not epidural use. No clear differences were found between women in the hypnosis group and those in the control groups for satisfaction with pain relief, sense of coping with labour or spontaneous vaginal birth. Not enough evidence currently exists regarding satisfaction with pain relief or sense of coping with labour and we would encourage any future research to prioritise the measurement of these outcomes. The evidence for the main comparison was assessed using GRADE as being of low quality for all the primary outcomes with downgrading decisions due to concerns regarding inconsistency of the evidence, limitations in design and imprecision. Further research is needed in the form of large, well-designed randomised controlled trials to assess whether hypnosis is of value for pain management during labour and childbirth.

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Management of rotator cuff disease often includes manual therapy and exercise, usually delivered together as components of a physical therapy intervention. This review is one of a series of reviews that form an update of the Cochrane review, 'Physiotherapy interventions for shoulder pain'. To synthesise available evidence regarding the benefits and harms of manual therapy and exercise, alone or in combination, for the treatment of people with rotator cuff disease. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), Ovid MEDLINE (January 1966 to March 2015), Ovid EMBASE (January 1980 to March 2015), CINAHL Plus (EBSCO, January 1937 to March 2015), ClinicalTrials.gov and the WHO ICTRP clinical trials registries up to March 2015, unrestricted by language, and reviewed the reference lists of review articles and retrieved trials, to identify potentially relevant trials. We included randomised and quasi-randomised trials, including adults with rotator cuff disease, and comparing any manual therapy or exercise intervention with placebo, no intervention, a different type of manual therapy or exercise or any other intervention (e.g. glucocorticoid injection). Interventions included mobilisation, manipulation and supervised or home exercises. Trials investigating the primary or add-on effect of manual therapy and exercise were the main comparisons of interest. Main outcomes of interest were overall pain, function, pain on motion, patient-reported global assessment of treatment success, quality of life and the number of participants experiencing adverse events. Two review authors independently selected trials for inclusion, extracted the data, performed a risk of bias assessment and assessed the quality of the body of evidence for the main outcomes using the GRADE approach. We included 60 trials (3620 participants), although only 10 addressed the main comparisons of interest. Overall risk of bias was low in three, unclear in 14 and high in 43 trials. We were unable to perform any meta-analyses because of clinical heterogeneity or incomplete outcome reporting. One trial compared manual therapy and exercise with placebo (inactive ultrasound therapy) in 120 participants with chronic rotator cuff disease (high quality evidence). At 22 weeks, the mean change in overall pain with placebo was 17.3 points on a 100-point scale, and 24.8 points with manual therapy and exercise (adjusted mean difference (MD) 6.8 points, 95% confidence interval (CI) -0.70 to 14.30 points; absolute risk difference 7%, 1% fewer to 14% more). Mean change in function with placebo was 15.6 points on a 100-point scale, and 22.4 points with manual therapy and exercise (adjusted MD 7.1 points, 95% CI 0.30 to 13.90 points; absolute risk difference 7%, 1% to 14% more). Fifty-seven per cent (31/54) of participants reported treatment success with manual therapy and exercise compared with 41% (24/58) of participants receiving placebo (risk ratio (RR) 1.39, 95% CI 0.94 to 2.03; absolute risk difference 16% (2% fewer to 34% more). Thirty-one per cent (17/55) of participants reported adverse events with manual therapy and exercise compared with 8% (5/61) of participants receiving placebo (RR 3.77, 95% CI 1.49 to 9.54; absolute risk difference 23% (9% to 37% more). However adverse events were mild (short-term pain following treatment).Five trials (low quality evidence) found no important differences between manual therapy and exercise compared with glucocorticoid injection with respect to overall pain, function, active shoulder abduction and quality of life from four weeks up to 12 months. However, global treatment success was more common up to 11 weeks in people receiving glucocorticoid injection (low quality evidence). One trial (low quality evidence) showed no important differences between manual therapy and exercise and arthroscopic subacromial decompression with respect to overall pain, function, active range of motion and strength at six and 12 months, or global treatment success at four to eight years. One trial (low quality evidence) found that manual therapy and exercise may not be as effective as acupuncture plus dietary counselling and Phlogenzym supplement with respect to overall pain, function, active shoulder abduction and quality life at 12 weeks. We are uncertain whether manual therapy and exercise improves function more than oral non-steroidal anti-inflammatory drugs (NSAID), or whether combining manual therapy and exercise with glucocorticoid injection provides additional benefit in function over glucocorticoid injection alone, because of the very low quality evidence in these two trials.Fifty-two trials investigated effects of manual therapy alone or exercise alone, and the evidence was mostly very low quality. There was little or no difference in patient-important outcomes between manual therapy alone and placebo, no treatment, therapeutic ultrasound and kinesiotaping, although manual therapy alone was less effective than glucocorticoid injection. Exercise alone led to less improvement in overall pain, but not function, when compared with surgical repair for rotator cuff tear. There was little or no difference in patient-important outcomes between exercise alone and placebo, radial extracorporeal shockwave treatment, glucocorticoid injection, arthroscopic subacromial decompression and functional brace. Further, manual therapy or exercise provided few or no additional benefits when combined with other physical therapy interventions, and one type of manual therapy or exercise was rarely more effective than another. Despite identifying 60 eligible trials, only one trial compared a combination of manual therapy and exercise reflective of common current practice to placebo. We judged it to be of high quality and found no clinically important differences between groups in any outcome. Effects of manual therapy and exercise may be similar to those of glucocorticoid injection and arthroscopic subacromial decompression, but this is based on low quality evidence. Adverse events associated with manual therapy and exercise are relatively more frequent than placebo but mild in nature. Novel combinations of manual therapy and exercise should be compared with a realistic placebo in future trials. Further trials of manual therapy alone or exercise alone for rotator cuff disease should be based upon a strong rationale and consideration of whether or not they would alter the conclusions of this review.

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Chronic obstructive pulmonary disease (COPD) is characterised by airflow obstruction due to an abnormal inflammatory response of the lungs to noxious particles or gases, for example, cigarette smoke. The pattern of care for people with moderate to very severe COPD often involves regular lengthy hospital admissions, which result in high healthcare costs and an undesirable effect on quality of life. Research over the past decade has focused on innovative methods for developing enabling and assistive technologies that facilitate patient self-management. To evaluate the effectiveness of interventions delivered by computer and by mobile technology versus face-to-face or hard copy/digital documentary-delivered interventions, or both, in facilitating, supporting, and sustaining self-management among people with COPD. In November 2016, we searched the Cochrane Airways Group Specialised Register (CAGR), which contains trial reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, and PsycINFO, and we handsearched respiratory journals and meeting abstracts. We included randomised controlled trials that measured effects of remote and Web 2.0-based interventions defined as technologies including personal computers (PCs) and applications (apps) for mobile technology, such as iPad, Android tablets, smart phones, and Skype, on behavioural change towards self-management of COPD. Comparator interventions included face-to-face and/or hard copy/digital documentary educational/self-management support. Two review authors (CMcC and MMcC) independently screened titles, abstracts, and full-text study reports for inclusion. Two review authors (CMcC and AMB) independently assessed study quality and extracted data. We expressed continuous data as mean differences (MDs) and standardised mean differences (SMDs) for studies using different outcome measurement scales. We included in our review three studies (Moy 2015; Tabak 2013; Voncken-Brewster 2015) with a total of 1580 randomised participants. From Voncken-Brewster 2015, we included the subgroup of individuals with a diagnosis of COPD (284 participants) and excluded those at risk of COPD who had not received a diagnosis (1023 participants). As a result, the total population available for analysis included 557 participants; 319 received smart technology to support self-management and 238 received face-to-face verbal/written or digital information and education about self-management. The average age of participants was 64 years. We included more men than women because the sample from one of the studies consisted of war veterans, most of whom were men. These studies measured five of our nine defined outcomes. None of these studies included outcomes such as self-efficacy, cost-effectiveness, functional capacity, lung function, or anxiety and depression.All three studies included our primary outcome - health-related quality of life (HRQoL) as measured by the Clinical COPD Questionnaire (CCQ) or St George's Respiratory Questionnaire (SGRQ). One study reported our other primary outcomes - hospital admissions and acute exacerbations. Two studies included our secondary outcome of physical activity as measured by daily step counts. One study addressed smoking by providing a narrative analysis. Only one study reported adverse events and noted significant differences between groups, with 43 events noted in the intervention group and eight events in the control group (P = 0.001). For studies that measured outcomes at week four, month four, and month six, the effect of smart technology on self-management and subsequent HRQoL in terms of symptoms and health status was significantly better than when participants received face-to-face/digital and/or written support for self-management of COPD (SMD -0.22, 95% confidence interval (CI) -0.40 to -0.03; P = 0.02). The single study that reported HRQoL at 12 months described no significant between-group differences (MD 1.1, 95% CI -2.2 to 4.5; P = 0.50). Also, hospitalisations (logistic regression odds ratio (OR) 1.6, 95% CI 0.8 to 3.2; P = 0.19) and exacerbations (logistic regression OR 1.4, 95% CI 0.7 to 2.8; P = 0.33) did not differ between groups in the single study that reported these outcomes at 12 months. The activity level of people with COPD at week four, month four, and month six was significantly higher when smart technology was used than when face-to-face/digital and/or written support was provided (MD 864.06 daily steps between groups, 95% CI 369.66 to 1358.46; P = 0.0006). The only study that measured activity levels at 12 months reported no significant differences between groups (mean -108, 95% CI -720 to 505; P = 0.73). Participant engagement in this study was not sustained between four and 12 months. The only study that included smoking cessation found no significant treatment effect (OR 1.06, 95%CI 0.43 to 2.66; P = 0.895). Meta-analyses showed no significant heterogeneity between studies (Chi² = 0.39, P = 0.82; I² = 0% and Chi² = 0.01, P = 0.91; I² = 0%, respectively). Although our review suggests that interventions aimed at facilitating, supporting, and sustaining self-managment in people with COPD and delivered via smart technology significantly improved HRQoL and levels of activity up to six months compared with interventions given through face-to-face/digital and/or written support, no firm conclusions can be drawn. This improvement may not be sustained over a long duration. The only included study that measured outcomes up to 12 months highlighted the need to ensure sustained engagement with the technology over time. Limited evidence suggests that using computer and mobile technology for self-management for people with COPD is not harmful and may be more beneficial for some people than for others, for example, those with an interest in using technology may derive greater benefit.The evidence, provided by three studies at high risk of bias, is of poor quality and is insufficient for advising healthcare professionals, service providers, and members of the public with COPD about the health benefits of using smart technology as an effective means of supporting, encouraging, and sustaining self-management. Further research that focuses on outcomes relevant to different stages of COPD is needed. Researchers should provide clear information on how self-management is assessed and should include longitudinal measures that allow comment on behavioural change.

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This is an update of the original Cochrane Review, last published in 2012 (Loy 2012). Children and youths with disruptive behaviour disorders may present to health services, where they may be treated with atypical antipsychotics. There is increasing usage of atypical antipsychotics in the treatment of disruptive behaviour disorders. To evaluate the effect and safety of atypical antipsychotics, compared to placebo, for treating disruptive behaviour disorders in children and youths. The aim was to evaluate each drug separately rather than the class effect, on the grounds that each atypical antipsychotic has different pharmacologic binding profile (Stahl 2013) and that this is clinically more useful. In January 2017, we searched CENTRAL, MEDLINE, Embase, five other databases and two trials registers. Randomised controlled trials of atypical antipsychotics versus placebo in children and youths aged up to and including 18 years, with a diagnosis of disruptive behaviour disorders, including comorbid ADHD. The primary outcomes were aggression, conduct problems and adverse events (i.e. weight gain/changes and metabolic parameters). The secondary outcomes were general functioning, noncompliance, other adverse events, social functioning, family functioning, parent satisfaction and school functioning. We used standard methodological procedures expected by Cochrane. Two review authors (JL and KS) independently collected, evaluated and extracted data. We used the GRADE approach to assess the quality of the evidence. We performed meta-analyses for each of our primary outcomes, except for metabolic parameters, due to inadequate outcome data. We included 10 trials (spanning 2000 to 2014), involving a total of 896 children and youths aged five to 18 years. Bar two trials, all came from an outpatient setting. Eight trials assessed risperidone, one assessed quetiapine and one assessed ziprasidone. Nine trials assessed acute efficacy (over four to 10 weeks); one of which combined treatment with stimulant medication and parent training. One trial was a six-month maintenance trial assessing symptom recurrence.The quality of the evidence ranged from low to moderate. Nine studies had some degree of pharmaceutical support/funding. Primary outcomesUsing the mean difference (MD), we combined data from three studies (238 participants) in a meta-analysis of aggression, as assessed using the Aberrant Behaviour Checklist (ABC) ‒ Irritability subscale. We found that youths treated with risperidone show reduced aggression compared to youths treated with placebo (MD -6.49, 95% confidence interval (CI) -8.79 to -4.19; low-quality evidence). Using the standardised mean difference (SMD), we pooled data from two risperidone trials (190 participants), which used different scales: the Overt Aggression Scale ‒ Modified (OAS-M) Scale and the Antisocial Behaviour Scale (ABS); as the ABS had two subscales that could not be combined (reactive and proactive aggression), we performed two separate analyses. When we combined the ABS Reactive subscale and the OAS-M, the SMD was -1.30 in favour of risperidone (95% CI -2.21 to -0.40, moderate-quality evidence). When we combined the ABS Proactive subscale and OAS-M, the SMD was -1.12 (95% CI -2.30 to 0.06, moderate-quality evidence), suggesting uncertainty about the estimate of effect, as the confidence intervals overlapped the null value. In summary, there was some evidence that aggression could be reduced by risperidone. Data were lacking on other atypical antipsychotics, like quetiapine and ziprasidone, with regard to their effects on aggression.We pooled data from two risperidone trials (225 participants) in a meta-analysis of conduct problems, as assessed using the Nisonger Child Behaviour Rating Form ‒ Conduct Problem subscale (NCBRF-CP). This yielded a final mean score that was 8.61 points lower in the risperidone group compared to the placebo group (95% CI -11.49 to -5.74; moderate-quality evidence).We investigated the effect on weight by performing two meta-analyses. We wanted to distinguish between the effects of antipsychotic medication only and the combined effect with stimulants, since the latter can have a counteracting effect on weight gain due to appetite suppression. Pooling two trials with risperidone only (138 participants), we found that participants on risperidone gained 2.37 kilograms (kg) more (95% CI 0.26 to 4.49; moderate-quality evidence) than those on placebo. When we added a trial where all participants received a combination of risperidone and stimulants, we found that those on the combined treatment gained 2.14 kg more (95% CI 1.04 to 3.23; 3 studies; 305 participants; low-quality evidence) than those on placebo. Secondary outcomesOut of the 10 included trials, three examined general functioning, social functioning and parent satisfaction. No trials examined family or school functioning. Data on non-compliance/attrition rate and other adverse events were available from all 10 trials. There is some evidence that in the short term risperidone may reduce aggression and conduct problems in children and youths with disruptive behaviour disorders There is also evidence that this intervention is associated with significant weight gain.For aggression, the difference in scores of 6.49 points on the ABC ‒ Irritability subscale (range 0 to 45) may be clinically significant. It is challenging to interpret the clinical significance of the differential findings on two different ABS subscales as it may be difficult to distinguish between reactive and proactive aggression in clinical practice. For conduct problems, the difference in scores of 8.61 points on the NCBRF-CP (range 0 to 48) is likely to be clinically significant. Weight gain remains a concern.Caution is required in interpreting the results due to the limitations of current evidence and the small number of high-quality trials. There is a lack of evidence to support the use of quetiapine, ziprasidone or any other atypical antipsychotic for disruptive behaviour disorders in children and youths and no evidence for children under five years of age. It is uncertain to what degree the efficacy found in clinical trials will translate into real-life clinical practice. Given the effectiveness of parent-training interventions in the management of these disorders, and the somewhat equivocal evidence on the efficacy of medication, it is important not to use medication alone. This is consistent with current clinical guidelines.

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Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia (who are transfusion-dependent or non-transfusion-dependent) are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands; which can be prevented and treated with iron chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and well-being, which may affect adherence. To identify and assess the effectiveness of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) to improve adherence to iron chelation therapy in people with SCD or thalassaemia. We searched CENTRAL (the Cochrane Library), MEDLINE, Embase, CINAHL, PsycINFO, Psychology and Behavioral Sciences Collection, Web of Science Science &amp; Social Sciences Conference Proceedings Indexes and ongoing trial databases (01 February 2017). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (12 December 2017). For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion.For studies including psychological and psychosocial interventions, educational Interventions, or multi-component interventions, non-RCTs, controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion. Three authors independently assessed trial eligibility, risk of bias and extracted data. The quality of the evidence was assessed using GRADE. We included 16 RCTs (1525 participants) published between 1997 and 2017. Most participants had β-thalassaemia major; 195 had SCD and 88 had β-thalassaemia intermedia. Mean age ranged from 11 to 41 years. One trial was of medication management and 15 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral-chelating agents, deferiprone and deferasirox.We rated the quality of evidence as low to very low across all outcomes identified in this review.Three trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL.Deferiprone versus deferoxamineWe are uncertain whether deferiprone increases adherence to iron chelation therapy (four trials, very low-quality evidence). Results could not be combined due to considerable heterogeneity (participants' age and different medication regimens). Medication adherence was high (deferiprone (85% to 94.9%); deferoxamine (71.6% to 93%)).We are uncertain whether deferiprone increases the risk of agranulocytosis, risk ratio (RR) 7.88 (99% confidence interval (CI) 0.18 to 352.39); or has any effect on all-cause mortality, RR 0.44 (95% CI 0.12 to 1.63) (one trial; 88 participants; very low-quality evidence).Deferasirox versus deferoxamineWe are uncertain whether deferasirox increases adherence to iron chelation therapy, mean difference (MD) -1.40 (95% CI -3.66 to 0.86) (one trial; 197 participants; very-low quality evidence). Medication adherence was high (deferasirox (99%); deferoxamine (100%)). We are uncertain whether deferasirox decreases the risk of thalassaemia-related serious adverse events (SAEs), RR 0.95 (95% CI 0.41 to 2.17); or all-cause mortality, RR 0.96 (95% CI 0.06 to 15.06) (two trials; 240 participants; very low-quality evidence).We are uncertain whether deferasirox decreases the risk of SCD-related pain crises, RR 1.05 (95% CI 0.68 to 1.62); or other SCD-related SAEs, RR 1.08 (95% CI 0.77 to 1.51) (one trial; 195 participants; very low-quality evidence).Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT)Deferasirox FCT may make little or no difference to adherence, RR 1.10 (95% CI 0.99 to 1.22) (one trial; 173 participants; low-quality evidence). Medication adherence was high (FCT (92.9%); DT (85.3%)).We are uncertain if deferasirox FCT increases the incidence of SAEs, RR 1.22 (95% CI 0.62 to 2.37); or all-cause mortality, RR 2.97 (95% CI 0.12 to 71.81) (one trial; 173 participants; very low-quality evidence).Deferiprone and deferoxamine combined versus deferiprone alone We are uncertain if deferiprone and deferoxamine combined increases adherence to iron chelation therapy (very low-quality evidence). Medication adherence was high (deferiprone 92.7% (range 37% to 100%) to 93.6% (range 56% to 100%); deferoxamine 70.6% (range 25% to 100%).Combination therapy may make little or no difference to the risk of SAEs, RR 0.15 (95% CI 0.01 to 2.81) (one trial; 213 participants; low-quality evidence).We are uncertain if combination therapy decreases all-cause mortality, RR 0.77 (95% CI 0.18 to 3.35) (two trials; 237 participants; very low-quality evidence).Deferiprone and deferoxamine combined versus deferoxamine aloneDeferiprone and deferoxamine combined may have little or no effect on adherence to iron chelation therapy (four trials; 216 participants; low-quality evidence). Medication adherence was high (deferoxamine 91.4% to 96.1%; deferiprone: 82.4%)Deferiprone and deferoxamine combined, may have little or no difference in SAEs or mortality (low-quality evidence). No SAEs occurred in three trials and were not reported in one trial. No deaths occurred in two trials and were not reported in two trials.Deferiprone and deferoxamine combined versus deferiprone and deferasirox combinedDeferiprone and deferasirox combined may improve adherence to iron chelation therapy, RR 0.84 (95% CI 0.72 to 0.99) (one trial; 96 participants; low-quality evidence). Medication adherence was high (deferiprone and deferoxamine: 80%; deferiprone and deferasirox: 95%).We are uncertain if deferiprone and deferasirox decreases the incidence of SAEs, RR 1.00 (95% CI 0.06 to 15.53) (one trial; 96 participants; very low-quality evidence).There were no deaths in the trial (low-quality evidence).Medication management versus standard careWe are uncertain if medication management improves health-related QoL (one trial; 48 participants; very low-quality evidence). Adherence was only measured in one arm of the trial. The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects.Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation.Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy.Due to lack of evidence this review cannot comment on intervention strategies for different age groups.

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Upper gastrointestinal (GI) bleeding due to stress ulcers contributes to increased morbidity and mortality in people admitted to intensive care units (ICUs). Stress ulceration refers to GI mucosal injury related to the stress of being critically ill. ICU patients with major bleeding as a result of stress ulceration might have mortality rates approaching 48.5% to 65%. However, the incidence of stress-induced GI bleeding in ICUs has decreased, and not all critically ill patients need prophylaxis. Stress ulcer prophylaxis can result in adverse events such as ventilator-associated pneumonia; therefore, it is necessary to evaluate strategies that safely decrease the incidence of GI bleeding. To assess the effect and risk-benefit profile of interventions for preventing upper GI bleeding in people admitted to ICUs. We searched the following databases up to 23 August 2017, using relevant search terms: MEDLINE; Embase; the Cochrane Central Register of Controlled Trials; Latin American Caribbean Health Sciences Literature; and the Cochrane Upper Gastrointestinal and Pancreatic Disease Group Specialised Register, as published in the Cochrane Library (2017, Issue 8). We searched the reference lists of all included studies and those from relevant systematic reviews and meta-analyses to identify additional studies. We also searched the World Health Organization International Clinical Trials Registry Platform search portal and contacted individual researchers working in this field, as well as organisations and pharmaceutical companies, to identify unpublished and ongoing studies. We included randomised controlled trials (RCTs) and quasi-RCTs with participants of any age and gender admitted to ICUs for longer than 48 hours. We excluded studies in which participants were admitted to ICUs primarily for the management of GI bleeding and studies that compared different doses, routes, and regimens of one drug in the same class because we were not interested in intraclass effects of drugs. We used standard methodological procedures as recommended by Cochrane. We identified 2292 unique records.We included 129 records reporting on 121 studies, including 12 ongoing studies and two studies awaiting classification.We judged the overall risk of bias of two studies as low. Selection bias was the most relevant risk of bias domain across the included studies, with 78 studies not clearly reporting the method used for random sequence generation. Reporting bias was the domain with least risk of bias, with 12 studies not reporting all outcomes that researchers intended to investigate.Any intervention versus placebo or no prophylaxisIn comparison with placebo, any intervention seems to have a beneficial effect on the occurrence of upper GI bleeding (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.57; moderate certainty of evidence). The use of any intervention reduced the risk of upper GI bleeding by 10% (95% CI -12.0% to -7%). The effect estimate of any intervention versus placebo or no prophylaxis with respect to the occurrence of nosocomial pneumonia, all-cause mortality in the ICU, duration of ICU stay, duration of intubation (all with low certainty of evidence), the number of participants requiring blood transfusions (moderate certainty of evidence), and the units of blood transfused was consistent with benefits and harms. None of the included studies explicitly reported on serious adverse events.Individual interventions versus placebo or no prophylaxisIn comparison with placebo or no prophylaxis, antacids, H2 receptor antagonists, and sucralfate were effective in preventing upper GI bleeding in ICU patients. Researchers found that with H2 receptor antagonists compared with placebo or no prophylaxis, 11% less developed upper GI bleeding (95% CI -0.16 to -0.06; RR 0.50, 95% CI 0.36 to 0.70; 24 studies; 2149 participants; moderate certainty of evidence). Of ICU patients taking antacids versus placebo or no prophylaxis, 9% less developed upper GI bleeding (95% CI -0.17 to -0.00; RR 0.49, 95% CI 0.25 to 0.99; eight studies; 774 participants; low certainty of evidence). Among ICU patients taking sucralfate versus placebo or no prophylaxis, 5% less had upper GI bleeding (95% CI -0.10 to -0.01; RR 0.53, 95% CI 0.32 to 0.88; seven studies; 598 participants; moderate certainty of evidence). The remaining interventions including proton pump inhibitors did not show a significant effect in preventing upper GI bleeding in ICU patients when compared with placebo or no prophylaxis.Regarding the occurrence of nosocomial pneumonia, the effects of H2 receptor antagonists (RR 1.12, 95% CI 0.85 to 1.48; eight studies; 945 participants; low certainty of evidence) and of sucralfate (RR 1.33, 95% CI 0.86 to 2.04; four studies; 450 participants; low certainty of evidence) were consistent with benefits and harms when compared with placebo or no prophylaxis. None of the studies comparing antacids versus placebo or no prophylaxis provided data regarding nosocomial pneumonia.H2 receptor antagonists versus proton pump inhibitorsH2 receptor antagonists and proton pump inhibitors are most commonly used in practice to prevent upper GI bleeding in ICU patients. Proton pump inhibitors significantly more often prevented upper GI bleeding in ICU patients compared with H2 receptor antagonists (RR 2.90, 95% CI 1.83 to 4.58; 18 studies; 1636 participants; low certainty of evidence). When taking H2 receptor antagonists, 4.8% more patients might experience upper GI bleeding (95% CI 2.1% to 9%). Nosocomial pneumonia occurred in similar proportions of participants taking H2 receptor antagonists and participants taking proton pump inhibitors (RR 1.02, 95% CI 0.77 to 1.35; 10 studies; 1256 participants; low certainty of evidence). This review shows that antacids, sucralfate, and H2 receptor antagonists might be more effective in preventing upper GI bleeding in ICU patients compared with placebo or no prophylaxis. The effect estimates of any treatment versus no prophylaxis on nosocomial pneumonia were consistent with benefits and harms. Evidence of low certainty suggests that proton pump inhibitors might be more effective than H2 receptor antagonists. Therefore, patient-relevant benefits and especially harms of H2 receptor antagonists compared with proton pump inhibitors need to be assessed by larger, high-quality RCTs to confirm the results of previously conducted, smaller, and older studies.

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Eczema is a common, chronic, inflammatory skin condition that is frequently associated with atopic conditions, including asthma. Leukotriene receptor antagonists (LTRAs) have a corticosteroid-sparing role in asthma, but their role in eczema remains controversial. Currently available topical therapies for eczema are often poorly tolerated, and use of systemic agents is restricted by their adverse effect profile. A review of alternative treatments was therefore warranted. To assess the possible benefits and harms of leukotriene receptor antagonists for eczema. We searched the following databases to September 2017: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and the GREAT database. We also searched five trial registries, and handsearched the bibliographies of all extracted studies for further relevant trials. Randomised controlled trials of LTRAs alone or in combination with other (topical or systemic) treatments compared with other treatments alone such as topical corticosteroids or placebo for eczema in the acute or chronic (maintenance) phase of eczema in adults and children. We used the standard methodological procedures expected by Cochrane. The primary outcome measures were change in disease severity, long-term symptom control, and adverse effects of treatment. Secondary outcomes were change in corticosteroid requirement, reduction of pruritis, quality of life, and emollient requirement. We used GRADE to assess the quality of the evidence for each outcome. Only five studies (including a total of 202 participants) met the inclusion criteria, all of which assessed oral montelukast; hence, we found no studies assessing other LTRAs. Treatment ranged from four to eight weeks, and outcomes were assessed at the end of treatment; therefore, we could only report short-term measurements (defined as less than three months follow-up from baseline). Montelukast dosing was 10 mg for adults (age 14 years and above) and 5 mg for children (age 6 years to 14 years). One study included children (aged 6 years and above) among their participants, while the remaining studies only included adults (participant age ranged from 16 to 70 years). The participants were diagnosed with moderate-to-severe eczema in four studies and moderate eczema in one study. The study setting was unclear in two studies, multicentre in two studies, and single centre in one study; the studies were conducted in Europe and Bangladesh. Two studies were industry funded. The comparator was placebo in three studies and conventional treatment in two studies. The conventional treatment comparator was a combination of antihistamines and topical corticosteroids (plus oral antibiotics in one study).Four of the studies did not adequately describe their randomisation or allocation concealment method and were considered as at unclear risk of selection bias. Only one study was at low risk of performance and detection bias. However, we judged all studies to be at low risk of attrition and reporting bias.We found no evidence of a difference in disease severity of moderate-to-severe eczema after short-term use of montelukast (10 mg) when compared with placebo. The outcome was assessed using the modified EASI (Eczema Area and Severity Index) score and SASSAD (Six Area, Six Sign Atopic Dermatitis) severity score (standardised mean difference 0.29, with a positive score showing montelukast is favoured, 95% confidence interval (CI) -0.23 to 0.81; 3 studies; n = 131; low-quality evidence).When short-term montelukast (10 mg) treatment was compared with conventional treatment in one study, the mean improvement in severity of moderate-to-severe eczema was greater in the intervention group (measured using SCORAD (SCORing of Atopic Dermatitis) severity index) (mean difference 10.57, 95% CI 4.58 to 16.56; n = 31); however, another study of 32 participants found no significant difference between groups using the same measure (mean improvement was 25.2 points with montelukast versus 23.9 points with conventional treatment; no further numerical data provided). We judged the quality of the evidence as very low for this outcome, meaning the results are uncertain.All studies reported their adverse event rate during treatment. Four studies (136 participants) reported no adverse events. In one study of 58 participants with moderate eczema who received montelukast 10 mg (compared with placebo), there was one case of septicaemia and one case of dizziness reported in the intervention group, both resulting in study withdrawal, although whether these effects were related to the medication is unclear. Mild side effects (e.g. headache and mild gastrointestinal disturbances) were also noted, but these were fairly evenly distributed between the montelukast and placebo groups. The quality of evidence for this outcome was low.No studies specifically evaluated emollient requirement or quality of life. One study that administered treatment for eight weeks specifically evaluated pruritus improvement at the end treatment and topical corticosteroid use during treatment. We found no evidence of a difference between montelukast (10 mg) and placebo for both outcomes (low-quality evidence, n = 58). No other study assessed these outcomes. The findings of this review are limited to montelukast. There was a lack of evidence addressing the review question, and the quality of the available evidence for most of the measured outcomes was low. Some primary and secondary outcomes were not addressed at all, including long-term control.We found no evidence of a difference between montelukast (10 mg) and placebo on disease severity, pruritus improvement, and topical corticosteroid use. Very low-quality evidence means we are uncertain of the effect of montelukast (10 mg) compared with conventional treatment on disease severity. Participants in only one study reported adverse events, which were mainly mild (low-quality evidence).There is no evidence that LTRA is an effective treatment for eczema. Serious limitations were that all studies focused on montelukast and only included people with moderate-to-severe eczema, who were mainly adults; and that each outcome was evaluated with a small sample size, if at all.Further large randomised controlled trials, with a longer treatment duration, of adults and children who have eczema of all severities may help to evaluate the effect of all types of LTRA, especially on eczema maintenance.

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Epidural analgesia in labour prolongs the second stage and increases instrumental delivery. It has been suggested that a more upright maternal position during all or part of the second stage may counteract these adverse effects. This is an update of a Cochrane Review published in 2017. To assess the effects of different birthing positions (upright or recumbent) during the second stage of labour, on maternal and fetal outcomes for women with epidural analgesia. We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (5 June 2018), and the reference lists of retrieved studies. All randomised or quasi-randomised trials including pregnant women (primigravidae or multigravidae) in the second stage of induced or spontaneous labour receiving epidural analgesia of any kind. Cluster-randomised controlled trials would have been eligible for inclusion but we found none. Studies published in abstract form only were also eligible.We assumed the experimental intervention to be maternal use of any upright position during the second stage of labour, compared with the control condition of remaining in any recumbent position. Two review authors independently assessed trials for inclusion, assessed risks of bias, and extracted data. We contacted study authors to obtain missing data. We assessed the quality of the evidence using the GRADE approach.We carried out a planned sensitivity analysis of the three studies with low risks of bias for allocation concealment and incomplete outcome data reporting, and further excluded one study with a co-intervention (this was not prespecified). We include eight randomised controlled trials, involving 4464 women, comparing upright positions versus recumbent positions in this update. Five were conducted in the UK, one in France and two in Spain.The largest UK trial accounted for three-quarters of all review participants, and we judged it to have low risk of bias. We assessed two other trials as being at low risk of selection and attrition bias. We rated four studies at unclear or high risk of bias for both selection and attrition bias and one study as high risk of bias due to a co-intervention. The trials varied in their comparators, with five studies comparing different positions (upright and recumbent), two comparing ambulation with (recumbent) non-ambulation, and one study comparing postural changes guided by a physiotherapist to a recumbent position.Overall, there may be little or no difference between upright and recumbent positions for our combined primary outcome of operative birth (caesarean or instrumental vaginal): average risk ratio (RR) 0.86, 95% confidence interval (CI) 0.70 to 1.07; 8 trials, 4316 women; I<sup2</sup = 78%; low-quality evidence. It is uncertain whether the upright position has any impact on caesarean section (RR 0.94, 95% CI 0.61 to 1.46; 8 trials, 4316 women; I<sup2</sup = 47%; very low-quality evidence), instrumental vaginal birth (RR 0.90, 95% CI 0.72 to 1.12; 8 trials, 4316 women; I<sup2</sup = 69%) and the duration of the second stage of labour (mean difference (MD) 6.00 minutes, 95% CI -37.46 to 49.46; 3 trials, 456 women; I<sup2</sup = 96%), because we rated the quality of the evidence as very low for these outcomes. Maternal position in the second stage of labour probably makes little or no difference to postpartum haemorrhage (PPH), (PPH requiring blood transfusion): RR 1.20, 95% CI 0.83 to 1.72; 1 trial, 3093 women; moderate-quality evidence. Maternal satisfaction with the overall childbirth experience was slightly lower in the upright group: RR 0.95, 95% CI 0.92 to 0.99; 1 trial, 2373 women. Fewer babies were born with low cord pH in the upright group: RR 0.43, 95% CI 0.20 to 0.90; 2 trials, 3159 infants; moderate-quality evidence.The results were less clear for other maternal or fetal outcomes, including trauma to the birth canal requiring suturing (average RR 1.00, 95% CI 0.89 to 1.13; 3 trials, 3266 women; I<sup2</sup = 46%; low-quality evidence), abnormal fetal heart patterns requiring intervention (RR 1.69, 95% CI 0.32 to 8.84; 1 trial, 107 women; very low-quality evidence), or admission to neonatal intensive care unit (RR 0.54, 95% CI 0.02 to 12.73; 1 trial, 66 infants; very low-quality evidence). However, the CIs around some of these estimates were wide, and we cannot rule out clinically important effects.In our sensitivity analysis of studies at low risk of bias, upright positions increase the chance of women having an operative birth: RR 1.11, 95% CI 1.03 to 1.20; 3 trials, 3609 women; high-quality evidence. In absolute terms, this equates to 63 more operative births per 1000 women (from 17 more to 115 more). This increase appears to be due to the increase in caesarean section in the upright group (RR 1.29; 95% CI 1.05 to 1.57; 3 trials, 3609 women; high-quality evidence), which equates to 25 more caesarean sections per 1000 women (from 4 more to 49 more). In the sensitivity analysis there was no clear impact on instrumental vaginal births: RR 1.08, 95% CI 0.91 to 1.30; 3 trials, 3609 women; low-quality evidence. There may be little or no difference in operative birth between women who adopt recumbent or supine positions during the second stage of labour with an epidural analgesia. However, the studies are heterogeneous, probably related to differing study designs and interventions, differing adherence to the allocated intervention and possible selection and attrition bias. Sensitivity analysis of studies at low risk of bias indicated that recumbent positions may reduce the need for operative birth and caesarean section, without increasing instrumental delivery. Mothers may be more satisfied with their experience of childbirth by adopting a recumbent position. The studies in this review looked at left or right lateral and semi-recumbent positions. Recumbent positions such as flat on the back or lithotomy are not generally used due to the possibility of aorto-caval compression, although we acknowledge that these recumbent positions were not the focus of trials included in this review.

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Are there any differences in the molecular characteristics of the luteal granulosa cells (GC) obtained from stimulated versus non-stimulated (natural) IVF cycles that may help explain the defective luteal phase in the former? Luteal GC of stimulated IVF cycles, particularly those of agonist-triggered antagonist cycles, are less viable ex vivo, express LH receptor and anti-apoptotic genes at lower levels, undergo apoptosis earlier and fail to maintain their estradiol (E2) and progesterone (P4) production in comparison to natural cycle GC. Luteal function is defective in stimulated IVF cycles, which necessitates P4 and/or hCG administration (known as luteal phase support) in order to improve clinical pregnancy rates and prevent miscarriage. The luteal phase becomes shorter and menstruation begins earlier than a natural cycle if a pregnancy cannot be achieved, indicative of early demise of corpus luteum (premature luteolysis). Supra-physiological levels of steroids produced by multiple corpora luteae in the stimulated IVF cycles are believed to inhibit LH release directly via negative feedback actions on the hypothalamic-pituitary-ovarian axis resulting in low circulating levels of LH and a defective luteal phase. We hypothesized that some defects in the viability and steroidogenic activity of the luteal GC of the stimulated IVF cycles might contribute to this defective luteal phase in comparison to natural cycle GC. This issue has not been studied in human before. A comparative translational research study of ex vivo and in vitro models of luteal GC recovered from IVF patients undergoing natural versus stimulated IVF cycles was carried out. Luteinized GC were obtained from 154 IVF patients undergoing either natural (n = 22) or stimulated IVF cycles with recombinant FSH and GnRH agonist (long) (n = 44), or antagonist protocol triggered conventionally either with recombinant hCG (n = 46) or with a GnRH agonist (n = 42). GC were maintained in vitro for up to 6 days. Cellular viability (YO-PRO-1 staining), the expression of the steroidogenic enzymes, pro-apoptotic genes [Bcl-2-associated death promoter (BAD), Bcl-2-associated X protein (BAX) and Caspase-3 (CASP3)], anti-apoptotic genes [RAC-alpha serine/threonine-protein kinase (AKT-1) and Bcl-2-like protein 2 (BCL2-L2)], LH receptor, vascular endothelial growth factor (VEGF) (using real-time quantitative PCR at mRNA level and western blot immunoprecipitation assay at protein level) and in vitro E2 and P4 production (electrochemiluminescence immunoassay) were compared in GC among the groups. Natural cycle GC were significantly more viable ex vivo (88%) compared to their counterparts of the stimulated IVF cycles (66, 64 and 37% for agonist and antagonist cycles triggered with hCG and GnRH agonist respectively, P &lt; 0.01). They were also more capable of maintaining their vitality in culture compared to their counterparts from the stimulated IVF cycles: at the end of the 6-day culture period, 74% of the cells were still viable whereas only 48, 43 and 22% of the cells from the agonist and antagonist cycles triggered with hCG and agonist respectively, were viable (P &lt; 0.01). The mRNA expression of anti-apoptotic genes (AKT-1 and BCL2-L2) was significantly lower, while that of pro-apoptotic genes (BAD, BAX and CASP3) was significantly higher in the stimulated cycles, particularly in the agonist-triggered antagonist cycles, compared to natural cycle GC (P &lt; 0.01 for long protocol and antagonist hCG trigger, P &lt; 0.001 for agonist trigger). The expression of steroidogenic enzymes (stAR, SCC, 3β-HSD and aromatase) and VEGF was significantly higher in the agonist and hCG-triggered antagonist cycles compared to natural cycle GC. Therefore, in vitro E2 and P4 production in cells from the stimulated IVF cycles was significantly higher than their counterparts obtained from the natural cycles in the first 2 days of culture. However, after Day 2, their viability and hormone production began to decline very rapidly with the most drastic decrease being observed in the agonist-triggered cycles. By contrast, natural cycle GC maintained their viability and produced E2 and P4 in increasing amounts in culture up to 6 days. In vitro P production and the mRNA and protein expression of LH receptor, VEGF and 3β-HSD were most defective in the agonist-triggered antagonist cycles compared to natural and agonist and hCG-triggered antagonist cycles. In vitro hCG treatment of a subset of the cells from the agonist-triggered cycles improved their viability, increased E2 and P4 production in vitro and up-regulated the mRNA expression of anti-apoptotic gene BCL-L2 together with steroidogenic enzymes stAR, SCC, 3B-HSD, LH receptor and VEGF. Not applicable. The limitations include analysis of luteinized GC only might not reflect the in vivo mechanisms involved in survival and function of the whole corpus luteum; GC recovered during oocyte retrieval belong to a very early stage of the luteal phase and might not be representative; effects of ovulation triggered with hCG may not equate to the endogenous LH trigger; the clinical characteristics of the patients may vary among the different groups and it was not possible to correlate stimulation-related molecular alterations in luteal GC with the clinical outcome, as no oocytes have been utilized yet. Therefore, our findings do not conclusively rule out the possibility that some other mechanisms in vivo may also account for defective luteal function observed in stimulated IVF cycles. Ovarian stimulation is associated with significant alterations in the viability and steroidogenic activity of luteal GC depending on the stimulation protocol and mode of ovulation trigger. Reduced survival and down-regulated expression of 3B-HSD, LH receptor and VEGF leading to compromised steroid production in stimulated cycles, and particularly in the agonist-triggered cycles, may at least in part help explain why the luteal phase is defective and requires exogenous support in these cycles. This study was funded by the School of Medicine, the Graduate School of Health Sciences of Koc University and Koç University Research Center for Translational Medicine (KUTTAM), equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. All authors declare no conflict of interest.

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Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions: To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives: Review authors performed subgroup analyses of low (≤ 500 IU/kg/week) and high (&gt; 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (≤ 5 mg/kg/d), and high (&gt; 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs: To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance: To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives: To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment. Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I<sup2</sup = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low. Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I<sup2</sup = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate. Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I<sup2</sup = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low. Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the ESA group (weighted mean difference (WMD) 8.22, 95% CI 6.52 to 9.92; I<sup2</sup = 97% (high heterogeneity); 3 studies, 981 children). The quality of the evidence was low. The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced. Data show no significant difference in risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI -0.02 to 0.04; I<sup2</sup = 0% (no heterogeneity) for RR; I<sup2</sup = 34% (low heterogeneity) for RD; 8 studies, 1283 infants). Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL). Early administration of ESAs reduces the use of red blood cell (RBC) transfusions, the volume of RBCs transfused, and donor exposure after study entry. Small reductions are likely to be of limited clinical importance. Donor exposure probably is not avoided, given that all but one study included infants who had received RBC transfusions before trial entry. This update found no significant difference in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age, which has been a topic of concern in earlier versions of this review. Early EPO treatment significantly decreased rates of IVH, PVL, and NEC. Neurodevelopmental outcomes at 18 to 22 months and later varied in published studies. Ongoing research should evaluate current clinical practices that will limit donor exposure. Promising but conflicting results related to the neuro protective effect of early EPO require further study. Very different results from the two largest published trials and high heterogeneity in the analyses indicate that we should wait for the results of two ongoing large trials before drawing firm conclusions. Administration of EPO is not currently recommended because limited benefits have been identified to date. Use of darbepoetin requires further study.

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The Skeletal Oncology Research Group (SORG) machine learning algorithm for predicting survival in patients with chondrosarcoma was developed using data from the Surveillance, Epidemiology, and End Results (SEER) registry. This algorithm was externally validated on a dataset of patients from the United States in an earlier study, where it demonstrated generally good performance but overestimated 5-year survival. In addition, this algorithm has not yet been validated in patients outside the United States; doing so would be important because external validation is necessary as algorithm performance may be misleading when applied in different populations. Does the SORG algorithm retain validity in patients who underwent surgery for primary chondrosarcoma outside the United States, specifically in Italy? A total of 737 patients were treated for chondrosarcoma between January 2000 and October 2014 at the Italian tertiary care center which was used for international validation. We excluded patients whose first surgical procedure was performed elsewhere (n = 25), patients who underwent nonsurgical treatment (n = 27), patients with a chondrosarcoma of the soft tissue or skull (n = 60), and patients with peripheral, periosteal, or mesenchymal chondrosarcoma (n = 161). Thus, 464 patients were ultimately included in this external validation study, as the earlier performed SEER study was used as the training set. Therefore, this study-unlike most of this type-does not have a training and validation set. Although the earlier study overestimated 5-year survival, we did not modify the algorithm in this report, as this is the first international validation and the prior performance in the single-institution validation study from the United States may have been driven by a small sample or non-generalizable patterns related to its single-center setting. Variables needed for the SORG algorithm were manually collected from electronic medical records. These included sex, age, histologic subtype, tumor grade, tumor size, tumor extension, and tumor location. By inputting these variables into the algorithm, we calculated the predicted probabilities of survival for each patient. The performance of the SORG algorithm was assessed in this study through discrimination (the ability of a model to distinguish between a binary outcome), calibration (the agreement of observed and predicted outcomes), overall performance (the accuracy of predictions), and decision curve analysis (establishment on the ability of a model to make a decision better than without using the model). For discrimination, the c-statistic (commonly known as the area under the receiver operating characteristic curve for binary classification) was calculated; this ranged from 0.5 (no better than chance) to 1.0 (excellent discrimination). The agreement between predicted and observed outcomes was visualized with a calibration plot, and the calibration slope and intercept were calculated. Perfect calibration results in a slope of 1 and an intercept of 0. For overall performance, the Brier score and the null-model Brier score were calculated. The Brier score ranges from 0 (perfect prediction) to 1 (poorest prediction). Appropriate interpretation of the Brier score requires comparison with the null-model Brier score. The null-model Brier score is the score for an algorithm that predicts a probability equal to the population prevalence of the outcome for every patient. A decision curve analysis was performed to compare the potential net benefit of the algorithm versus other means of decision support, such as treating all or none of the patients. There were several differences between this study and the earlier SEER study, and such differences are important because they help us to determine the performance of the algorithm in a group different from the initial study population. In this study from Italy, 5-year survival was different from the earlier SEER study (71% [319 of 450 patients] versus 76% [1131 of 1487 patients]; p = 0.03). There were more patients with dedifferentiated chondrosarcoma than in the earlier SEER study (25% [118 of 464 patients] versus 8.5% [131 of 1544 patients]; p &lt; 0.001). In addition, in this study patients were older, tumor size was larger, and there were higher proportions of high-grade tumors than the earlier SEER study (age: 56 years [interquartile range {IQR} 42 to 67] versus 52 years [IQR 40 to 64]; p = 0.007; tumor size: 80 mm [IQR 50 to 120] versus 70 mm [IQR 42 to 105]; p &lt; 0.001; tumor grade: 22% [104 of 464 had Grade 1], 42% [196 of 464 had Grade 2], and 35% [164 of 464 had Grade 3] versus 41% [592 of 1456 had Grade 1], 40% [588 of 1456 had Grade 2], and 19% [276 of 1456 had Grade 3]; p ≤ 0.001). Validation of the SORG algorithm in a primarily Italian population achieved a c-statistic of 0.86 (95% confidence interval 0.82 to 0.89), suggesting good-to-excellent discrimination. The calibration plot showed good agreement between the predicted probability and observed survival in the probability thresholds of 0.8 to 1.0. With predicted survival probabilities lower than 0.8, however, the SORG algorithm underestimated the observed proportion of patients with 5-year survival, reflected in the overall calibration intercept of 0.82 (95% CI 0.67 to 0.98) and calibration slope of 0.68 (95% CI 0.42 to 0.95). The Brier score for 5-year survival was 0.15, compared with a null-model Brier of 0.21. The algorithm showed a favorable decision curve analysis in the validation cohort. The SORG algorithm to predict 5-year survival for patients with chondrosarcoma held good discriminative ability and overall performance on international external validation; however, it underestimated 5-year survival for patients with predicted probabilities from 0 to 0.8 because the calibration plot was not perfectly aligned for the observed outcomes, which resulted in a maximum underestimation of 20%. The differences may reflect the baseline differences noted between the two study populations. The overall performance of the algorithm supports the utility of the algorithm and validation presented here. The freely available digital application for the algorithm is available here: https://sorg-apps.shinyapps.io/extremitymetssurvival/. Level III, prognostic study.

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A frozen embryo transfer (FET) cycle is when one or more embryos (frozen during a previous treatment cycle) are thawed and transferred to the uterus. Some women undergo fresh embryo transfer (ET) cycles with embryos derived from donated oocytes. In both situations, the endometrium is primed with oestrogen and progestogen in different doses and routes of administration. To evaluate the most effective endometrial preparation for women undergoing transfer with frozen embryos or embryos from donor oocytes with regard to the subsequent live birth rate (LBR). The Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trials registers and abstracts of reproductive societies' meetings were searched in June 2020 together with reference checking and contact with study authors and experts in the field to identify additional studies. Randomised controlled trials (RCTs) evaluating endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. We used standard methodological procedures recommended by Cochrane. We analysed all available interventions versus placebo, no treatment, or between each other. The primary review outcome was live birth rate. Secondary outcomes were clinical and multiple pregnancy, miscarriage, cycle cancellation, endometrial thickness and adverse effects. Thirty-one RCTs (5426 women) were included. Evidence was moderate to very low-quality: the main limitations were serious risk of bias due to poor reporting of methods, and serious imprecision. Stimulated versus programmed cycle We are uncertain whether a letrozole-stimulated cycle compared to a programmed cycle, for endometrial preparation, improves LBR (odds ratio (OR) 1.26, 95% confidence interval (CI) 0.49 to 3.26; 100 participants; one study; very low-quality evidence). Stimulating with follicle stimulating hormone (FSH), letrozole or clomiphene citrate may improve clinical pregnancy rate (CPR) (OR 1.63, 95% CI 1.12 to 2.38; 656 participants; five studies; I<sup2</sup = 11%; low-quality evidence). We are uncertain if they reduce miscarriage rate (MR) (OR 0.79, 95% CI 0.36 to 1.71; 355 participants; three studies; I<sup2</sup = 0%; very low-quality evidence). Endometrial thickness (ET) may be reduced with clomiphene citrate (mean difference(MD) -1.04, 95% CI -1.59 to -0.49; 92 participants; one study; low-quality evidence). Other outcomes were not reported. Natural versus programmed cycle We are uncertain of the effect from a natural versus programmed cycle for LBR (OR 0.97, 95% CI 0.74 to 1.28; 1285 participants; four studies; I<sup2</sup = 0%; very low-quality evidence) and CPR (OR 0.79, 95% CI 0.62 to 1.01; 1249 participants; five studies; I<sup2</sup = 60%; very low-quality evidence), while a natural cycle probably reduces the cycle cancellation rate (CCR) (OR 0.60, 95% CI 0.44 to 0.82; 734 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and ET. No study reported other outcomes. Transdermal versus oral oestrogens From low-quality evidence we are uncertain of the effect transdermal compared to oral oestrogens has on CPR (OR 0.86, 95% CI 0.59 to 1.25; 504 participants; three studies; I<sup2</sup = 58%) or MR (OR 0.55, 95% CI 0.27 to 1.09; 414 participants; two studies; I<sup2</sup = 0%). Other outcomes were not reported. Day of starting administration of progestogen When doing a fresh ET using donated oocytes in a synchronised cycle starting progestogen on the day of oocyte pick-up (OPU) or the day after OPU, in comparison with recipients that start progestogen the day prior to OPU, probably increases the CPR (OR 1.87, 95% CI 1.13 to 3.08; 282 participants; one study, moderate-quality evidence). We are uncertain of the effect on multiple pregnancy rate (MPR) or MR. It probably reduces the CCR (OR 0.28, 95% CI 0.11 to 0.74; 282 participants; one study; moderate-quality evidence). No study reported other outcomes. Gonadotropin-releasing hormone (GnRH) agonist versus control A cycle with GnRH agonist compared to without may improve LBR (OR 2.62, 95% CI 1.19 to 5.78; 234 participants; one study; low-quality evidence). From low-quality evidence we are uncertain of the effect on CPR (OR 1.08, 95% CI 0.82 to 1.43; 1289 participants; eight studies; I<sup2</sup = 20%), MR (OR 0.85, 95% CI 0.36 to 2.00; 828 participants; four studies; I<sup2</sup = 0%), CCR (OR 0.49, 95% CI 0.21 to 1.17; 530 participants; two studies; I<sup2</sup = 0%) and ET (MD -0.08, 95% CI -0.33 to 0.16; 697 participants; four studies; I<sup2</sup = 4%). No study reported other outcomes. Among different GnRH agonists From very low-quality evidence we are uncertain if cycles among different GnRH agonists improves CPR or MR. No study reported other outcomes. GnRH agonists versus GnRH antagonists GnRH antagonists compared to agonists probably improves CPR (OR 0.62, 95% CI 0.42 to 0.90; 473 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and MPR. No study reported other outcomes. Aspirin versus control From very low-quality evidence we are uncertain whether a cycle with aspirin versus without improves LBR, CPR, or ET. Steroids versus control From very low-quality evidence we are uncertain whether a cycle with steroids compared to without improves LBR, CPR or MR. No study reported other outcomes. There is insufficient evidence on the use of any particular intervention for endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. In frozen embryo transfers, low-quality evidence showed that clinical pregnancy rates may be improved in a stimulated cycle compared to a programmed one, and we are uncertain of the effect when comparing a programmed cycle to a natural cycle. Cycle cancellation rates are probably reduced in a natural cycle. Although administering a GnRH agonist, compared to without, may improve live birth rates, clinical pregnancy rates will probably be improved in a GnRH antagonist cycle over an agonist cycle. In fresh synchronised oocyte donor cycles, the clinical pregnancy rate is probably improved and cycle cancellation rates are probably reduced when starting progestogen the day of or day after donor oocyte retrieval. Adequately powered studies are needed to evaluate each treatment more accurately.

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Arterial vascular access is a frequently performed procedure, with a high possibility for adverse events (e.g. pneumothorax, haemothorax, haematoma, amputation, death), and additional techniques such as ultrasound may be useful for improving outcomes. However, ultrasound guidance for arterial access in adults is still under debate. To assess the effects of ultrasound guidance for arterial (other than femoral) catheterisation in adults. We searched CENTRAL, MEDLINE, Embase, LILACS, and CINAHL on 21 May 2021. We also searched IBECS, WHO ICTRP, and ClinicalTrials.gov on 16 June 2021, and we checked the reference lists of retrieved articles. Randomised controlled trials (RCTs), including cross-over trials and cluster-RCTs, comparing ultrasound guidance, alone or associated with other forms of guidance, versus other interventions or palpation and landmarks for arterial (other than femoral) guidance in adults. Two review authors independently performed study selection, extracted data, assessed risk of bias, and assessed the certainty of evidence using GRADE. We included 48 studies (7997 participants) that tested palpation and landmarks, Doppler auditory ultrasound assistance (DUA), direct ultrasound guidance with B-mode, or any other modified ultrasound technique for arterial (axillary, dorsalis pedis, and radial) catheterisation in adults. Radial artery Real-time B-mode ultrasound versus palpation and landmarks Real-time B-mode ultrasound guidance may improve first attempt success rate (risk ratio (RR) 1.44, 95% confidence interval (CI) 1.29 to 1.61; 4708 participants, 27 studies; low-certainty evidence) and overall success rate (RR 1.11, 95% CI 1.06 to 1.16; 4955 participants, 28 studies; low-certainty evidence), and may decrease time needed for a successful procedure (mean difference (MD) -0.33 minutes, 95% CI -0.54 to -0.13; 4902 participants, 26 studies; low-certainty evidence) up to one hour compared to palpation and landmarks. Real-time B-mode ultrasound guidance probably decreases major haematomas (RR 0.35, 95% CI 0.23 to 0.56; 2504 participants, 16 studies; moderate-certainty evidence). It is uncertain whether real-time B-mode ultrasound guidance has any effect on pseudoaneurysm, pain, and quality of life (QoL) compared to palpation and landmarks (very low-certainty evidence). Real-time B-mode ultrasound versus DUA One study (493 participants) showed that real-time B-mode ultrasound guidance probably improves first attempt success rate (RR 1.35, 95% CI 1.11 to 1.64; moderate-certainty evidence) and time needed for a successful procedure (MD -1.57 minutes, 95% CI -1.78 to -1.36; moderate-certainty evidence) up to 72 hours compared to DUA. Real-time B-mode ultrasound guidance may improve overall success rate (RR 1.13, 95% CI 0.99 to 1.29; low-certainty evidence) up to 72 hours compared to DUA. Pseudoaneurysm, major haematomas, pain, and QoL were not reported. Real-time B-mode ultrasound versus modified real-time B-mode ultrasound Real-time B-mode ultrasound guidance may decrease first attempt success rate (RR 0.68, 95% CI 0.55 to 0.84; 153 participants, 2 studies; low-certainty evidence), may decrease overall success rate (RR 0.93, 95% CI 0.86 to 1.01; 153 participants, 2 studies; low-certainty evidence), and may lead to no difference in time needed for a successful procedure (MD 0.04 minutes, 95% CI -0.01 to 0.09; 153 participants, 2 studies; low-certainty evidence) up to one hour compared to modified real-time B-mode ultrasound guidance. It is uncertain whether real-time B-mode ultrasound guidance has any effect on major haematomas compared to modified real-time B-mode ultrasound (very low-certainty evidence). Pseudoaneurysm, pain, and QoL were not reported. In-plane versus out-of-plane B-mode ultrasound In-plane real-time B-mode ultrasound guidance may lead to no difference in overall success rate (RR 1.00, 95% CI 0.96 to 1.05; 1051 participants, 8 studies; low-certainty evidence) and in time needed for a successful procedure (MD -0.06 minutes, 95% CI -0.16 to 0.05; 1134 participants, 9 studies; low-certainty evidence) compared to out-of-plane B-mode ultrasound up to one hour. It is uncertain whether in-plane real-time B-mode ultrasound guidance has any effect on first attempt success rate or major haematomas compared to out-of-plane B-mode ultrasound (very low-certainty evidence). Pseudoaneurysm, pain, and QoL were not reported. DUA versus palpation and landmarks DUA may lead to no difference in first attempt success rate (RR 1.01, 95% CI 0.90 to 1.14; 666 participants, 2 studies; low-certainty evidence) or overall success rate (RR 0.99, 95% CI 0.92 to 1.07; 666 participants, 2 studies; low-certainty evidence) and probably increases time needed for a successful procedure (MD 0.45 minutes, 95% CI 0.20 to 0.70; 500 participants, 1 study; moderate-certainty evidence) up to 72 hours compared to palpation and landmarks. Pseudoaneurysm, major haematomas, pain, and QoL were not reported. Oblique-axis versus long-axis in-plane B-mode ultrasound Oblique-axis in-plane B-mode ultrasound guidance may increase overall success rate (RR 1.27, 95% CI 1.05 to 1.53; 215 participants, 2 studies; low-certainty evidence) up to 72 hours compared to long-axis in-plane B-mode ultrasound. It is uncertain whether oblique-axis in-plane B-mode ultrasound guidance has any effect on first attempt success rate, time needed for a successful procedure, and major haematomas compared to long-axis in-plane B-mode ultrasound. Pseudoaneurysm, pain, and QoL were not reported. We are uncertain about effects in the following comparisons due to very low-certainty evidence and unreported outcomes: real-time B-mode ultrasound versus palpation and landmarks (axillary and dorsalis pedis arteries), real-time B-mode ultrasound versus near-infrared laser (radial artery), and dynamic versus static out-of-plane B-mode ultrasound (radial artery). Real-time B-mode ultrasound guidance may improve first attempt success rate, overall success rate, and time needed for a successful procedure for radial artery catheterisation compared to palpation, or DUA. In addition, real-time B-mode ultrasound guidance probably decreases major haematomas compared to palpation. However, we are uncertain about the evidence on major haematomas and pain for other comparisons due to very low-certainty evidence and unreported outcomes. We are also uncertain about the effects on pseudoaneurysm and QoL for axillary and dorsalis pedis arteries catheterisation. Given that first attempt success rate and pseudoaneurysm are the most relevant outcomes for people who underwent arterial catheterisation, future studies must measure both. Future trials must be large enough to detect effects, use validated scales, and report longer-term follow-up.

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The optimal haemoglobin threshold for use of red blood cell (RBC) transfusions in anaemic patients remains an active field of research. Blood is a scarce resource, and in some countries, transfusions are less safe than in others because of inadequate testing for viral pathogens. If a liberal transfusion policy does not improve clinical outcomes, or if it is equivalent, then adopting a more restrictive approach could be recognised as the standard of care.  OBJECTIVES: The aim of this review update was to compare 30-day mortality and other clinical outcomes for participants randomised to restrictive versus liberal red blood cell (RBC) transfusion thresholds (triggers) for all clinical conditions. The restrictive transfusion threshold uses a lower haemoglobin concentration as a threshold for transfusion (most commonly, 7.0 g/dL to 8.0 g/dL), and the liberal transfusion threshold uses a higher haemoglobin concentration as a threshold for transfusion (most commonly, 9.0 g/dL to 10.0 g/dL). We identified trials through updated searches: CENTRAL (2020, Issue 11), MEDLINE (1946 to November 2020), Embase (1974 to November 2020), Transfusion Evidence Library (1950 to November 2020), Web of Science Conference Proceedings Citation Index (1990 to November 2020), and trial registries (November 2020). We  checked the reference lists of other published reviews and relevant papers to identify additional trials. We were aware of one trial identified in earlier searching that was in the process of being published (in February 2021), and we were able to include it before this review was finalised. We included randomised trials of surgical or medical participants that recruited adults or children, or both. We excluded studies that focused on neonates. Eligible trials assigned intervention groups on the basis of different transfusion schedules or thresholds or 'triggers'. These thresholds would be defined by a haemoglobin (Hb) or haematocrit (Hct) concentration below which an RBC transfusion would be administered; the haemoglobin concentration remains the most commonly applied marker of the need for RBC transfusion in clinical practice. We included trials in which investigators had allocated participants to higher thresholds or more liberal transfusion strategies compared to more restrictive ones, which might include no transfusion. As in previous versions of this review, we did not exclude unregistered trials published after 2010 (as per the policy of the Cochrane Injuries Group, 2015), however, we did conduct analyses to consider the differential impact of results of trials for which prospective registration could not be confirmed.   DATA COLLECTION AND ANALYSIS: We identified trials for inclusion and extracted data using Cochrane methods. We pooled risk ratios of clinical outcomes across trials using a random-effects model. Two review authors independently extracted data and assessed risk of bias. We conducted predefined analyses by clinical subgroups. We defined participants randomly allocated to the lower transfusion threshold as being in the 'restrictive transfusion' group and those randomly allocated to the higher transfusion threshold as being in the 'liberal transfusion' group. A total of 48 trials, involving data from 21,433 participants (at baseline), across a range of clinical contexts (e.g. orthopaedic, cardiac, or vascular surgery; critical care; acute blood loss (including gastrointestinal bleeding); acute coronary syndrome; cancer; leukaemia; haematological malignancies), met the eligibility criteria. The haemoglobin concentration used to define the restrictive transfusion group in most trials (36) was between 7.0 g/dL and 8.0 g/dL.  Most trials included only adults; three trials focused on children. The included studies were generally at low risk of bias for key domains including allocation concealment and incomplete outcome data. Restrictive transfusion strategies reduced the risk of receiving at least one RBC transfusion by 41% across a broad range of clinical contexts (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.53 to 0.66; 42 studies, 20,057 participants; high-quality evidence), with a large amount of heterogeneity between trials (I² = 96%). Overall, restrictive transfusion strategies did not increase or decrease the risk of 30-day mortality compared with liberal transfusion strategies (RR 0.99, 95% CI 0.86 to 1.15; 31 studies, 16,729 participants; I² = 30%; moderate-quality evidence) or any of the other outcomes assessed (i.e. cardiac events (low-quality evidence), myocardial infarction, stroke, thromboembolism (all high-quality evidence)). High-quality evidence shows that the liberal transfusion threshold did not affect the risk of infection (pneumonia, wound infection, or bacteraemia). Transfusion-specific reactions are uncommon and were inconsistently reported within trials. We noted less certainty in the strength of evidence to support the safety of restrictive transfusion thresholds for the following predefined clinical subgroups: myocardial infarction, vascular surgery, haematological malignancies, and chronic bone-marrow disorders. Transfusion at a restrictive haemoglobin concentration decreased the proportion of people exposed to RBC transfusion by 41% across a broad range of clinical contexts. Across all trials, no evidence suggests that a restrictive transfusion strategy impacted 30-day mortality, mortality at other time points, or morbidity (i.e. cardiac events, myocardial infarction, stroke, pneumonia, thromboembolism, infection) compared with a liberal transfusion strategy. Despite including 17 more randomised trials (and 8846 participants), data remain insufficient to inform the safety of transfusion policies in important and selected clinical contexts, such as myocardial infarction, chronic cardiovascular disease, neurological injury or traumatic brain injury, stroke, thrombocytopenia, and cancer or haematological malignancies, including chronic bone marrow failure.  Further work is needed to improve our understanding of outcomes other than mortality. Most trials compared only two separate thresholds for haemoglobin concentration, which may not identify the actual optimal threshold for transfusion in a particular patient. Haemoglobin concentration may not be the most informative marker of the need for transfusion in individual patients with different degrees of physiological adaptation to anaemia. Notwithstanding these issues, overall findings provide good evidence that transfusions with allogeneic RBCs can be avoided in most patients with haemoglobin thresholds between the range of 7.0 g/dL and 8.0 g/dL. Some patient subgroups might benefit from RBCs to maintain higher haemoglobin concentrations; research efforts should focus on these clinical contexts.

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Central sleep apnoea (CSA) is characterised by abnormal patterns of ventilation during sleep due to a dysfunctional drive to breathe. Consequently, people with CSA may present poor sleep quality, sleep fragmentation, inattention, fatigue, daytime sleepiness, and reduced quality of life. To assess the effectiveness and safety of non-invasive positive pressure ventilation (NIPV) for the treatment of adults with CSA. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Scopus on 6 September 2021. We applied no restrictions on language of publication. We also searched clinical trials registries for ongoing and unpublished studies, and scanned the reference lists of included studies to identify additional studies. We included randomised controlled trials (RCTs) reported in full text, those published as abstract only, and unpublished data. Two review authors independently selected studies for inclusion, extracted data, and assessed risk of bias of the included studies using the Cochrane risk of bias tool version 1.0, and the certainty of the evidence using the GRADE approach. In the case of disagreement, a third review author was consulted. We included 15 RCTs with a total of 1936 participants, ranging from 10 to 1325 participants. All studies had important methodological limitations. We assessed most studies (11 studies) as at high risk of bias for at least one domain, and all studies as at unclear risk of bias for at least two domains. The trials included participants aged &gt; 18 years old, of which 70% to 100% were men, who were followed from one week to 60 months. The included studies assessed the effects of different modes of NIPV and CSA. Most participants had CSA associated with chronic heart failure. Because CSA encompasses a variety of causes and underlying clinical conditions, data were carefully analysed, and different conditions and populations were not pooled. The findings for the primary outcomes for the seven evaluated comparisons are presented below.  Continuous positive airway pressure (CPAP) plus best supportive care versus best supportive care in CSA associated with chronic heart failure In the short term, CPAP plus best supportive care may reduce central apnoea hypopnoea index (AHI) (mean difference (MD) -14.60, 95% confidence interval (CI) -20.11 to -9.09; 1 study; 205 participants). However, CPAP plus best supportive care may result in little to no difference in cardiovascular mortality compared to best supportive care alone. The evidence for the effect of CPAP plus best supportive care on all-cause mortality is very uncertain. No adverse effects were observed with CPAP, and the results for adverse events in the best supportive care group were not reported. Adaptive servo ventilation (ASV) versus CPAP in CSA associated with chronic heart failure The evidence is very uncertain about the effect of ASV versus CPAP on quality of life evaluated in both the short and medium term. Data on adverse events were not reported, and it is not clear whether data were sought but not found. ASV versus bilevel ventilation in CSA associated with chronic heart failure In the short term, ASV may result in little to no difference in central AHI. No adverse events were detected with ASV, and the results for adverse events in the bilevel ventilation group were not reported. ASV plus best supportive care versus best supportive care in CSA associated with chronic heart failure In the medium term, ASV plus best supportive care may reduce AHI compared to best supportive care alone (MD -20.30, 95% CI -28.75 to -11.85; 1 study; 30 participants). In the long term, ASV plus best supportive care likely increases cardiovascular mortality compared to best supportive care (risk ratio (RR) 1.25, 95% CI 1.04, 1.49; 1 study; 1325 participants). The evidence suggests that ASV plus best supportive care may result in little to no difference in quality of life in the short, medium, and long term, and in all-cause mortality in the medium and long term. Data on adverse events were evaluated but not reported. ASV plus best supportive care versus best supportive care in CSA with acute heart failure with preserved ejection fraction Only adverse events were reported for this comparison, and no adverse events were recorded in either group. ASV versus CPAP maintenance in CPAP-induced CSA In the short term, ASV may slightly reduce central AHI (MD -4.10, 95% CI -6.67 to -1.53; 1 study; 60 participants), but may result in little to no difference in quality of life. Data on adverse events were not reported, and it is not clear whether data were sought but not found. ASV versus bilevel ventilation in CPAP-induced CSA In the short term, ASV may slightly reduce central AHI (MD -8.70, 95% CI -11.42 to -5.98; 1 study; 30 participants) compared to bilevel ventilation. Data on adverse events were not reported, and it is not clear whether data were sought but not found. CPAP plus best supportive care may reduce central AHI in people with CSA associated with chronic heart failure compared to best supportive care alone. Although ASV plus best supportive care may reduce AHI in people with CSA associated with chronic heart failure, it likely increases cardiovascular mortality in these individuals. In people with CPAP-induced CSA, ASV may slightly reduce central AHI compared to bilevel ventilation and to CPAP. In the absence of data showing a favourable impact on meaningful patient-centred outcomes and defining clinically important differences in outcomes in CSA patients, these findings need to be interpreted with caution. Considering the level of certainty of the available evidence and the heterogeneity of participants with CSA, we could draw no definitive conclusions, and further high-quality trials focusing on patient-centred outcomes, such as quality of life, quality of sleep, and longer-term survival, are needed to determine whether one mode of NIPV is better than another or than best supportive care for any particular CSA patient group.

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Ability to study and evaluation is only one example of performance among many others but research and publications concerning this issue for more than 50 years, especially in the context of test anxiety and need of achievement, conferred upon it a prototypical dimension. Investigations about motivation also stimulate many scientists and constitute another foundation of this study (13). The level of performance depends on knowledge and motivation (33). Time devoted to study is essential to succeed; so motivation and procrastination are in competition. The importance of reinforcement (extrinsical motivation) and the desire for learning and knowing (intrinsical motivation) are determinant. Other elements must be emphasized: guarantee of obtaining rewards, self efficacy and causal attribution. These considerations point out the multidimensional and interactive aspects of test anxiety (7, 31). The number of components is not described unanimously but experts agree with emotional, cognitive and behavioral dimensions (25). So, anxiety was approached in its motivational properties, and it was the case until the sixties, in terms of drive corresponding to a need like thirst or hunger (18); then it was conceptualized in a dynamic context broader than that of stress and coping (29, 30). Last, it constitutes the object of theories highlighting cognitive interference (9, 23, 26) or defective skills (8, 32). A lot of questionnaires were built without answering the different aspects and for instance without linking the theoretical and therapeutic components concerning this problem. Committed to the traditional fields of research (test anxiety and need of achievement), to Weiner's work about attribution theory (34) and that of Bandura in self efficacy (4, 5), E. Depreeuw (10) was particularly interested in Heckhausen's model (16, 17), trying to associate experimental conceptions with the clinical reality. On this basis, he elaborated the TASTE (10, 12, 20): test for ability to study and evaluation. At first constituted of 121 items, the self-questionnaire, after factorial analysis, was reduced to 78 items assessing 4 factors which represent the 8 components of Heckhausen's model (16). The first factor (30 items) concerns anxiety in its emotional and cognitive characteristics. Interesting data were observed by Depreeuw and confirmed in the Netherlands and in Greece (19), especially the fact that anxiety of girls is higher than that of boys when they are confronted with an exam. The second one (19 items) represents self-confidence: confidence in ability to succeed and on using adequate strategies. The third factor (14 items) squared with value attributed to performance. It especially comments on the intrinsical component of motivation. The fourth factor (15 items) corresponds to procrastination; study is postponed on behalf of activities which actually reduce the achievement process. The self-report questionnaire (where answers run from total disagreement to total agreement whether they correspond to the way of thinking or acting) takes account of the emotional, cognitive and behavioral dimensions of the model. The multidimensional aspect of this questionnaire, but mainly its connections with theory and clinic, are convincing; we adopted it with other tests in research about fear of failure. Validation of the French translation is the subject of this article. In order to realize this operation, we chose the initial version of TASTE (121 items) to assess a Belgian sample of french-speaking students in the first year of University of Liège (n = 617). They are differentiated by gender, faculty (Economy, Medicine, Philosophy, Psychology, Applied Sciences) and experience of failure, i.e. the fact of repeating a school year. Statistics were realized with SPSS and SAS. A comprehension test and a back translation are satisfactory. The stability over time too: the one week test-retest was achieved with a sample of 33 student nurses; comparing the factors two by two, intra-class correlations ranged from 0.5 to 0.95. The component analysis with Varimax rotation does not allow us to find the four factors of construction. We obtain the same disappointing results with the version of 78 items. According to the screentest, we adopted the solution of five factors which confirms the original construction. A fifth particularly strong factor (Cronbach's alpha 0.82) corresponds to devalorisation. The internal reliability is very satisfactory. If we consider the items strong loading (more than 0.30), the French version is constituted of 94 items. If we consider the items which are specifically loading each factor, we can reduce the questionnaire to 50 items. Internal reliability remains the same. Correlations between the data obtained with this brief version are satisfactory; comparing the factors in pairs. Pearson's coefficients range from 0.8 to 0.89. The study of E. Depreeuw was realized ten years ago with a Belgian sample of Flemish-speaking students; is the cultural context or an evolution in test anxiety which explains such a difference in the results? We are now assessing a sample in another country which used the TASTE in 1996 in order to have some information about comparison of samples. In any case, the questionnaire of E. Depreeuw respects the multidimensional aspect of test anxiety. Our choice of 5 factors according to principal components confirms the original structure of the test but also discriminates another factor which could be predictive of psychopathology (panic, depression). This new dimension measures negative perception of ability and achievement especially when compared with other students. One aim of such a study is to discern clusters of students i.e. groups of students with characteristics such as Covington (7), Depreeuw (20) and Zeidner (35) describe them. This description is very important; the French version is only a part of a very broader study including other tests and could differentiate student's profiles. The French version of 5 factors finally gives results in agreement with the original. The items (10 per factor) are selected according to their highest specificity and after elimination of redundancy. Validity remains in the short version, making it more useful in clinical practice.

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1,6-Hexanediamine (HDA) is an aliphatic amine that is produced in large volumes in the United States. HDA is widely used as a corrosion inhibitor in lubricants and as an intermediate in the industrial synthesis of paints, resins, inks, and textiles. Toxicity studies of the dihydrochloride salt of HDA (HDDC) were conducted in male and female Fischer 344/N rats and B6C3F1 mice by the drinking water (2-week studies only) and whole-body inhalation routes (2-week and 13-week studies). Animals were evaluated for histopathology, clinical chemistry, hematology, and reproductive toxicity. In addition, the genetic toxicity of HDA was assessed in Salmonella typhimurium and in Chinese hamster ovary cells in vitro; HDDC was evaluated in the mouse micronucleus assay in vivo. In the 2-week drinking water studies, groups of 5 rats of each sex received HDDC at doses of 0.75 to 6.7 mg/mL, and groups of 5 mice of each sex received doses of 0.2 to 3.0 mg/mL for 14 or 15 days. All animals survived to the end of the studies. No gross or microscopic pathologic changes and no clinical abnormalities related to HDDC consumption were seen in any dose group. The only statistically significant change was a slight decrease in absolute and/or relative liver weights of female rats in the 1.7, 5.0, and 6.7-mg/mL treatment groups, in male rats in the 3.0 mg/mL treatment group, and in female mice in the 0.8 mg/mL treatment group. Because there was no significant toxicity in these studies, 13-week drinking water studies were not conducted. In the 2-week inhalation studies, 5 rats and 5 mice of each sex were exposed to 0, 10, 30, 89, 267, or 800 mg HDDC/m(3) for 6-hours per day for 12 days. In the highest exposure group (800 mg/m(3)), all male and female rats, all female mice, and 2 male mice died before the end of the studies. In the remaining groups, there was a dose-dependent depression in body weight gain in male and female mice, but not in rats. Clinical signs were primarily related to upper respiratory tract irritation and included dyspnea and nasal discharge in rats and mice. Absolute and relative liver weights were reduced in some male mice, but this did not occur in a dose- dependent manner. In rats, histopathologic lesions that were considered related to chemical exposure included inflammation and necrosis of laryngeal epithelium as well as focal inflammation and ulceration of the respiratory and olfactory nasal mucosa. In mice, focal areas of inflammation and necrosis were present in the respiratory mucosa of the larynx and trachea in the 2 highest exposure groups. Nasal lesions, including focal inflammation and ulceration, and degeneration and necrosis of the olfactory and respiratory epithelium were also seen in mice. In addition, mild testicular degeneration was present in 2 mice from the highest exposure group (800 mg/m(3)). In the 13-week inhalation studies, 10 rats and 10 mice of each sex were exposed to 0, 1.6, 5, 16, 50, or 160 mg HDDC/m(3) for 6 hours per day, 5 days per week for 13 weeks. In addition special groups of 20 male and 40 female rats and mice (mating trial animals) at each exposure level were included to assess the effect of HDDC on reproduction. All rats and mice in the base-study groups survived to the end of the studies, and there were no exposure-related changes in body weight. In the mating trials, 3 female mice exposed to 16 mg/m(3) and 1 female and 1 male mouse exposed to 50 mg/m(3) died before scheduled termination. These deaths, however, were not considered to be chemical related. In male mice in the base study, liver weights were increased relative to controls in the 2-highest exposure groups. No exposure-related changes in absolute or relative organ weights and no exposure-related clinical signs or gross lesions were seen in either species. In female rats, a dose-related decrease in white blood cell count was observed. Chemical-related microscopic lesions in male and female rats and mice were limited to the upper respiratory tract (larynx and nasal passages) in the 2 highest exposure groups and were similar in both species. These lesions included minimal to mild focal erosion/ulceration, inflammation, and hyperplasia of the laryngeal epithelium as well as degeneration of the olfactory and respiratory nasal epithelium. HDDC caused no significant changes in sperm morphology or in the length of the estrous cycle of rats or mice. In mating trials, HDDC demonstrated no adverse effects on reproduction of rats. The only statistically significant changes in reproductive parameters of mice were a slight increase in gestation length in the 50 mg/m(3) and 160 mg/m(3) exposure groups and a decrease in mean pup weight on Day 21 in the highest exposure group. These changes were not considered to be biologically significant. 1,6-Hexanediamine was not mutagenic in 4 strains of Salmonella typhimurium, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were conducted with and without exogenous metabolic activation (S9). Negative results were also obtained in an in vivo test that measured the frequency of micronucleated erythrocytes in peripheral blood of male and female mice. In summary, the toxicity of HDDC to rats and mice resulted from irritant properties of the chemical and was consistent with the effects of other irritant chemicals administered by inhalation. This toxicity was limited to the nose and airways. In the 2-week inhalation studies, deaths occurred in both rats and mice at the highest exposure level (800 mg/m(3)). In the 13-week studies, the no-observed-adverse-effect-level (NOAEL) for respiratory damage was 5 mg/m(3) for rats and mice. HDDC had no adverse effect on reproduction of either species and was not genotoxic. Synonyms: Hexamethylenediamine dihydrochloride; 1,6-diaminohexane dihydrochloride; 1,6-hexamethylenediamine dihydrochloride; 1,6- hexylenediamine dihydrochloride; 1,6-diamino-n-hexane dihydrochloride; HMDA; HDA; HDDC.

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Folates are vitamins essential to the development of the central nervous system. Insufficient folate activity at the time of conception and early pregnancy can result in congenital neural tube defects. In adult life folate deficiency has been known for decades to produce a characteristic form of anaemia ("megaloblastic"). More recently degrees of folate inadequacy, not severe enough to produce anaemia, have been found to be associated with high blood levels of the amino acid homocysteine. Such degrees of folate inadequacy can arise because of insufficient folates in the diet or because of inefficient absorption or metabolic utilisation of folates due to genetic variations. Conventional criteria for diagnosing folate deficiency may be inadequate for identifying people capable of benefiting from dietary supplementation. High blood levels of homocysteine have been linked with the risk of arterial disease, dementia and Alzheimer's disease. There is therefore interest in whether dietary supplements of folic acid (an artificial chemical analogue of naturally occurring folates) can improve cognitive function of people at risk of cognitive decline associated with ageing or dementia, whether by affecting homocysteine metabolism or through other mechanisms. There is a risk that if folic acid is given to people who have undiagnosed deficiency of vitamin B12 it may lead to neurological damage. Vitamin B12 deficiency produces both an anaemia identical to that of folate deficiency but also causes irreversible damage to the central and peripheral nervous systems. Folic acid will correct the anaemia of vitamin B12 deficiency and so delay diagnosis but will not prevent progression to neurological damage. For this reason trials of folic acid supplements may involve simultaneous administration of vitamin B12. Apparent benefit from folic acid given in the combination would therefore need to be "corrected" for any effect of vitamin B12 alone. A separate Cochrane review of vitamin B12 and cognitive function is being prepared. To examine the effects of folic acid supplementation, with or without vitamin B12, on elderly healthy and demented people, in preventing cognitive impairment or retarding its progress. Trials were identified from a search of the Cochrane Dementia and Cognitive Improvement Specialized Register Group on 9 April 2003 using the terms: folic acid, folate, vitamin B9, leucovorin, methyltetrahydrofolate, vitamin B12, cobalamin, cyanocobalamin, dementia, cognitive function, cognitive impairment, Alzheimer's disease, vascular dementia, mixed dementia and controlled trials. MEDLINE and EMBASE (both all years) were searched for additional trials on healthy people. All double-blind placebo-controlled randomized trials, in which supplements of folic acid with or without vitamin B12 were compared with placebo for elderly healthy people or people with any type of dementia or cognitive impairment. The reviewers independently applied the selection criteria and assessed study quality. One reviewer extracted and analysed the data. In comparing intervention with placebo, weighted mean differences, and standardized mean difference or odds ratios were estimated. Four randomized controlled trials fulfilled the inclusion criteria for this review. One trial (Bryan 2002) enrolled healthy women, and three (Fioravanti 1997; Sommer 1998; VITAL 2003) recruited people with mild to moderate cognitive impairment or dementia with or without diagnosed folate deficiency. Fioravanti 1997 enrolled people with mild to moderate cognitive impairment or dementia as judged by scores on the Mini-Mental State Examination (MMSE) and Global Deterioration Scale and with serum folate level&lt;3ng/l. One trial (VITAL 2003) studied the effects of a combination of vitamin B12 and folic acid on patients with mild to moderate cognitive impairment due to Alzheimer's disease or mixed dementia. The analysis from the included trials found no benefit from folic acid with or without vitamin B12 in comparison with placebo on any measures of cognition and mood for healthy or cognitively impaired or demented people: Folic acid effect and healthy participants: there was no benefit from of oral 750 mcg folic acid per day for five weeks compared with placebo on measures of cognition and mood of 19 healthy women aged 65 to 92. Folic acid effect and people with mild to moderate cognitive decline or dementia: there were no statistically significant results in favour of folic acid with or without vitamin B12 on any measures of cognitive function. Scores on the Mini-Mental State Examination (MMSE) revealed no statistically significant benefit from 2 mg per day folic acid plus 1mg vitamin B12 for 12 weeks when compared with placebo (WMD 0.39, 95% CI -0.43 to 1.21, P=0.35). Cognitive scores on the Alzheimer's Disease Scale (ADAS-Cog) showed no statistically significant benefit from 2 mg /day folic acid plus 1 mg /day vitamin B12 for 12 weeks compared with placebo (WMD 0.41, 95% -1.25 to 2.07, P=4.63). The Bristol Activities of Daily Living Scale (BADL) revealed no benefit from 2mg per day of folic acid plus 1 mg vitamin B12 for 12 weeks in comparison with placebo (WMD -0.57, 95%CI -1.95 to 0.81, P=0.42). None of the sub tests of the Randt Memory Test (RMT) showed statistically significant benefit from 15 mg of folic acid orally per day for 9 weeks when compared with placebo. One trial (Sommer 1998) reported a significant decline compared with placebo in two cognitive function tasks in demented patients who had received high doses of folic acid (10 mg /day) for unspecified periods. One trial (VITAL 2003) showed that 2 mg folic acid plus 1 mg vitamin B12 daily for 12 weeks significantly lowered serum homocysteine concentrations (P &lt;0.0001). There was no beneficial effect of 750 mcg of folic acid per day on measures of cognition or mood in older healthy women. In patients with mild to moderate cognitive decline and different forms of dementia there was no benefit from folic acid on measures of cognition or mood. Folic acid plus vitamin B12 was effective in reducing the serum homocysteine concentrations. Folic acid was well tolerated and no adverse effects were reported. More studies are needed.

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The above data relating to the reaction between 16 hour cultures of S. aureus and antistaphylococcus bacteriophage in nutrient broth of pH 7.6 at 36 degrees C. and with mechanical shaking to maintain a uniform B suspension, bring out the following points: (a) B growth in P-B mixtures does not differ from growth in controls without P except in the case of a very high initial P/B ratio as noted below. There is no evidence that lytic destruction of B begins shortly after mixing P and B nor that B growth is stimulated by P, for the B growth curves in the presence of ordinary [P]'s and in controls are identical. Only at the sudden onset of the rapid lytic process does the B curve of a P-B mixture deviate from the control curve. (b) B growth is an essential conditioning factor for P formation. (c) Both B growth and P production exhibit short lags. During this time P diffuses into or becomes adsorbed to B so rapidly that by the end of the lag period only 10 to 30 per cent of the total P present is extracellular, the remainder being associated with the B. (d) During the logarithmic B growth phase, P formation is also logarithmic but proceeds at a much faster rate. That is, d P/d t is proportional to a power of d B/d t. Consequently the statement that each time a B divides a certain amount of P is formed is not correct. (e) As B growth enters the phase of positive acceleration equilibrium between the extracellular and intracellular P fractions becomes established and is maintained up to the onset of lysis, extracellular [P] representing a small constant percentage of total [P]. The distribution of P on a constant percentage basis suggests the manner in which a relatively simple chemical compound would be distributed and is not at all typical of the distribution one would expect if P were a complex organized parasite. (f) When the value of log P/B = 2.1 lysis begins. Obviously, this limiting value for any initial [B] is reached sooner the higher the initial [P]. When log P/B at the time of mixing P and B is already 2.1 or greater, there is no growth of B and lysis soon occurs. (g) While there is good evidence that lysis is brought about by the attainment of a particular [P] per B and not by a certain [P] per ml., it is not clear at this time which of the ratios intracellular P/B, extracellular P/B or total P/B is the major conditioning factor for B lysis. (h) Experimentally the maximal [P]'s of lysates made by mixing a constant initial [B] with widely varying Po's fall within a relatively narrow range. This fact is explained by the large value of d log P/d t as compared to d log B/d t. That is, the loci of points at which log P = 2.1 + log B (maxima-lysis begins) on the curves of log P against t originating in various [Po]'s will lie at a nearly constant level above the abscissa. Because of this same relationship the maximal [P]'s of such a series will be in the reverse order of magnitude of the Po's, i.e., the larger the Po the smaller will be the maximal [P] attained during the reaction (cf. Fig, 16). (i) The lytic destruction of B is logarithmic with time, in this respect being similar to most death rate processes. The value -d log B/d t for a particular initial [B] is constant for various initial values of [P]. There is good evidence that cells need not be growing in order to undergo lysis. (j) During B lysis a considerable percentage of the total maximal P formed is destroyed, the chief loss probably occurring in the intracellular fraction. The major portion (70 to 90 per cent) of the final P present after the completion of bacteriophagy is set free during the brief phase of bacterial dissolution. (k) When the entire process of bacteriophagy is completed the lysates are left with certain [P]'s determined by the foregone P-B reaction. The destruction of P during lysis is sufficiently regular to maintain the relationship established at the maximal [P]'s. Therefore the final [P]'s have the same points in common that were noted in "h" as applying to the maximal [P]'s. That is, they all are grouped within a narrow range of [P] values, those having been made with high Po's being of lower titre than those made with low initial [P]'s. (1) There is a significant difference in the temperature coefficients of P and B formation. Further, the temperature coefficients of P and B destruction during lysis differ in almost the same ratio. Consequently, while all experimental evidence postulates B growth as an essential conditioning factor for P formation, the temperature coefficient data suggest that the two processes are basically separate reactions. A similar interpretation holds in the case of B dissolution and P inactivation. (m) The major events in the complete process of "bacteriophagy" are mathematically predictable. The [B] at which lysis occurs under certain standard conditions for given values of Bo and Po may be calculated from the equation: See PDF for Equation Substitution of this value for log B in the equation: See PDF for Equation gives satisfactory agreement with observed values for t((lysis)). (n) The kinetic analysis of the P-B reaction predicts that the values of log Po plotted against t((lysis)) for a constant Bo will give a straight line. This plot is employed in a method for the quantitative estimation of P described in an earlier paper on the basis of experimental observation alone. Its use is made more rational by the facts given above.

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The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people. To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country. The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27+Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010. The total cost of disorders of the brain was estimated at €798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7; anxiety disorders: €74.4; brain tumor: €5.2; child/adolescent disorders: €21.3; dementia: €105.2; eating disorders: €0.8; epilepsy: €13.8; headache: €43.5; mental retardation: €43.3; mood disorders: €113.4; multiple sclerosis: €14.6; neuromuscular disorders: €7.7; Parkinson's disease: €13.9; personality disorders: €27.3; psychotic disorders: €93.9; sleep disorders: €35.4; somatoform disorder: €21.2; stroke: €64.1; traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US. This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges. Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.

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Fatigue and unintentional weight loss are two of the commonest symptoms experienced by people with advanced progressive illness. Appropriate interventions may bring considerable improvements in function and quality of life to seriously ill people and their families, reducing physical, psychological and spiritual distress. To conduct an overview of the evidence available on the efficacy of interventions used in the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness by reviewing the evidence contained within Cochrane reviews. We searched the Cochrane Database of Systematic Reviews (CDSR) for all systematic reviews evaluating any interventions for the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness (The Cochrane Library 2010, Issue 8). We reviewed titles of interest by abstract. Where the relevance of a review remained unclear we reached a consensus regarding the relevance of the participant group and the outcome measures to the overview. Two overview authors extracted the data independently using a data extraction form. We used the measurement tool AMSTAR (Assessment of Multiple SysTemAtic Reviews) to assess the methodological quality of each systematic review. We included 27 systematic reviews (302 studies with 31,833 participants) in the overview. None of the included systematic reviews reported quantitative data on the efficacy of interventions to manage fatigue or weight loss specific to people with advanced progressive illness. All of the included reviews apart from one were deemed of high methodological quality. For the remaining review we were unable to ascertain the methodological quality of the research strategy as it was described. None of the systematic reviews adequately described whether conflict of interests were present within the included studies.Management of fatigue Amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) - we identified one systematic review (two studies and 52 participants); the intervention was exercise.Cancer - we identified five systematic reviews (116 studies with 17,342 participants); the pharmacological interventions were eicosapentaenoic acid (EPA) and any drug therapy for the management of cancer-related fatigue and the non pharmacological interventions were exercise, interventions by breast care nurses and psychosocial interventions.Chronic obstructive pulmonary disease (COPD) - we identified three systematic reviews (59 studies and 4048 participants); the interventions were self management education programmes, nutritional support and pulmonary rehabilitation.Cystic fibrosis - we identified one systematic review (nine studies and 833 participants); the intervention was physical training.Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) - we identified two systematic reviews (21 studies and 748 participants); the interventions were progressive resistive exercise and aerobic exercise.Multiple sclerosis (MS) - we identified five systematic reviews (23 studies and 1502 participants); the pharmacological interventions were amantadine and carnitine. The non pharmacological interventions were diet, exercise and occupational therapy.Mixed conditions in advanced stages of illness - we identified one systematic review (five studies and 453 participants); the intervention was medically assisted hydration.Management of weight loss ALS/MND - we identified one systematic review but no studies met the inclusion criteria for the systematic review; the intervention was enteral tube feeding.Cancer - we identified three systematic reviews with a fourth systematic review also containing extractable data on cancer (66 studies and 5601 participants); the pharmacological interventions were megestrol acetate and eicosapentaenoic acid (EPA) (this systematic review is also included in the cancer fatigue section above). The non pharmacological interventions were enteral tube feeding and non invasive interventions for patients with lung cancer.COPD - we identified one systematic review (59 studies and 4048 participants); the intervention was nutritional support. This systematic review is also included in the COPD fatigue section.Cystic fibrosis - we identified two systematic reviews (three studies and 131 participants); the interventions were enteral tube feeding and oral calorie supplements.HIV/AIDS - we identified four systematic reviews (42 studies and 2071 participants); the pharmacological intervention was anabolic steroids. The non pharmacological interventions were nutritional interventions, progressive resistive exercise and aerobic exercise. Both of the systematic reviews on exercise interventions were also included in the HIV/AIDS fatigue section.MS - we found no systematic reviews which considered interventions to manage unintentional weight loss for people with a clinical diagnosis of multiple sclerosis at any stage of illness.Mixed conditions in advanced stages of illness - we identified two systematic reviews (32 studies and 4826 participants); the interventions were megestrol acetate and medically assisted nutrition. There is a lack of robust evidence for interventions to manage fatigue and/or unintentional weight loss in the advanced stage of progressive illnesses such as advanced cancer, heart failure, lung failure, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia and AIDS. The evidence contained within this overview provides some insight into interventions which may prove of benefit within this population such as exercise, some pharmacological treatments and support for self management.Researchers could improve the methodological quality of future studies by blinding of outcome assessors. Adopting uniform reporting mechanisms for fatigue and weight loss outcome measures would also allow the opportunity for meta-analysis of small studies.Researchers could also improve the applicability of recommendations for interventions to manage fatigue and unintentional weight loss in advanced progressive illness by including subgroup analysis of this population within systematic reviews of applicable interventions.More research is required to ascertain the best interventions to manage fatigue and/or weight loss in advanced illness. There is a need for standardised reporting of these symptoms and agreement amongst researchers of the minimum duration of studies and minimum percentage change in symptom experience that proves the benefits of an intervention. There are, however, challenges in providing meaningful outcome measurements against a background of deteriorating health through disease progression. Interventions to manage these symptoms must also be mindful of the impact on quality of life and should be focused on patient-orientated rather than purely disease-orientated experiences for patients. Systematic reviews and primary intervention studies should include the impact of the interventions on standardised validated quality of life measures.

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Laparoscopic and endoscopic procedures generally are accepted for repair of primary and recurrent hernias that follow conventional (anterior) repair. This report discusses transabdominal preperitoneal (TAPP) for incarcerated hernias, scrotal hernias, and hernias after radical prostatectomy, as well as hernia recurrences after TAPP and totally extraperitoneal (TEP) procedures (complex hernias). Studies with long-term results of hernia recurrences are missing. This study aimed to determine hernia recurrence rates for adults after a modified TAPP procedure. The records of patients who had hernia repair surgery at a general hospital 2, 7, 12, and 17 years earlier were analyzed. Living patients were requested to complete a questionnaire to complement information from their hospital records. A retrospective analysis was undertaken that included 5,764 patients who had undergone hernia repair surgery 2-17 years earlier at a single large center. Between 1993 and 2009, a modified TAPP procedure was performed for 5,764 patients (median age, 59.1 years) to repair 6,776 hernias (93.9% of all hernia repairs), including 6,126 primary hernias (87.4%) and 884 recurrent hernias (12.6%). These included 994 complicated hernias (14.2%) closed by a modified TAPP (89.3% of all femoral hernias, 85.9% of scrotal hernias, 79.1% of incarcerated hernias, and 92.7% of hernias after radical prostatectomy). Limited financial and staff resources did not permit a quantitative follow-up study within a reasonable time of all 5,764 patients who had hernia surgery 2-18 years earlier. To obtain quantitative results of hernia recurrences after a modified TAPP, the patients were divided into four subgroups and requested to complete a questionnaire. These four patient subgroups whose surgeries had been performed 2 years earlier (241 patients with 277 hernias), 7 years earlier (285 patients with 376 hernias), 12 years earlier (401 patients with 544 hernias), and 17 years earlier (181 patients with 222 hernias) represented the complete group of hernia sufferers. Patients with symptoms after hernia surgery (n = 5) were invited for a medical checkup by a specialist in hernia surgery at our outpatient unit. The sex, age, and the number of complex hernias of the patients did not differ significantly among the four patient subgroups or in comparison with the entire group. The patients who had received surgery in 1994, 1999, 2004, and 2009 were quizzed by a questionnaire and represented all patients who had hernia surgery from 1993 to 2009. The follow-up response of the living patients in each of the subgroups ranged from 89.5% of those who had hernia surgery 17 years earlier to 95.9% of those who had surgery 2 years earlier. The primary end point of the study was the hernia recurrence rate after a modified TAPP for primary, recurrent, and complex hernias performed 2, 7, 12, and 17 years earlier. The secondary end points of the study focused on the following questions: Is a modified TAPP practicable with acceptable recurrence rates for complex hernias? Do relapse rates show individual surgeon-dependent differences in relation to the learning curve? How many years of postoperative follow-up evaluation are required to determine quantitative recurrence rates (&gt;90% recurrence)? All inguinal and femoral hernias were repaired with a modified TAPP procedure. Hernia defects larger than 1 × 1 cm were closed with nonabsorbable sutures before the mesh was implanted. Within 17 years after surgery, 4 (4.3%) of the 94 study participants treated with a modified TAPP procedure for primary or recurrent inguinal and femoral hernias experienced recurrent hernias (4 recurrences after 117 hernioplasties, 3.4%). Within 12 years after surgery, 4 (1 %) of 302 patients experienced recurrent hernias (4 recurrences after 398 modified TAPP procedures, 1%). Within 7 years after surgery for inguinal or femoral hernias, 8 (3.2%) of 251 patients had relapsed (8 recurrences after 337 modified TAPP procedures, 2.4%). Within 2 years after a modified TAPP, only 1 of 230 patients (0.4%) experienced a recurrent hernia (1 relapse after 265 hernioplasties, 0.4%). After the modified TAPP procedure, 52.9% (n = 9) of the patients with a recurrent hernia had a second repair at our hospital, and 35.3% (n = 6) had the second repair at other hospitals, whereas 2 patients (11.8 %) renounced a repeat surgical intervention. The recurrence rate after a modified TAPP procedure for all the patients (n = 896) was 1.8%. The study participants with primary hernias (n = 765) had a 1.7% recurrence rate, whereas the rate for recurrent hernias after anterior repair (n = 131) was 2.3 %. Incarcerated hernias (n = 47) and hernias after radical prostatectomy (n = 22) that were closed by the modified TAPP procedure resulted in no hernia recurrences. Only 1 of 47 patients with scrotal hernias had a hernia relapse. Of all the hernia recurrences between 1993 and 2009 (n = 76), 60.5% (n = 46) developed within 2 years after surgery, whereas 15.8% (n = 12) occurred after more than 5 years, and 4% (n = 3) occurred after more than 10 years. The recurrence rates also were higher for surgeons in the early period after completion of their personal learning curves (&lt;50 modified TAPP procedures performed on their own responsibility). In a retrospective long-term study (2-17 years) from a single center with 1,108 patients and 1,123 modified TAPP procedures (93.9% of all hernia repairs), the hernia recurrence rate was 1.7% for adults with primary hernias (n = 765 patients) and 2.3% for adults with recurrent hernias after anterior repair (n = 131 patients). A modified TAPP procedure with suturing of hernia defects larger than 1 × 1 cm can be used as the standard procedure without recurrences for femoral hernias, incarcerated hernias, and hernias after radical prostatectomy, with low recurrence rates for scrotal hernias (2%). To collect quantitative data on hernia recurrence rates, postoperative follow-up studies longer than 10 years are needed (4% of recurrences developed later than 10 years after surgery).

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Inadvertent perioperative hypothermia is a phenomenon that can occur as a result of the suppression of the central mechanisms of temperature regulation due to anaesthesia, and of prolonged exposure of large surfaces of skin to cold temperatures in operating rooms. Inadvertent perioperative hypothermia has been associated with clinical complications such as surgical site infection and wound-healing delay, increased bleeding or cardiovascular events. One of the most frequently used techniques to prevent inadvertent perioperative hypothermia is active body surface warming systems (ABSW), which generate heat mechanically (heating of air, water or gels) that is transferred to the patient via skin contact. To assess the effectiveness of pre- or intraoperative active body surface warming systems (ABSW), or both, to prevent perioperative complications from unintended hypothermia during surgery in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2015); MEDLINE (PubMed) (1964 to October 2015), EMBASE (Ovid) (1980 to October 2015), and CINAHL (Ovid) (1982 to October 2015). We included randomized controlled trials (RCTs) that compared an ABSW system aimed at maintaining normothermia perioperatively against a control or against any other ABSW system. Eligible studies also had to include relevant clinical outcomes other than measuring temperature alone. Several authors, by pairs, screened references and determined eligibility, extracted data, and assessed risks of bias. We resolved disagreements by discussion and consensus, with the collaboration of a third author. We included 67 trials with 5438 participants that comprised 79 comparisons. Forty-five RCTs compared ABSW versus control, whereas 18 compared two different types of ABSW, and 10 compared two different techniques to administer the same type of ABSW. Forced-air warming (FAW) was by far the most studied intervention.Trials varied widely regarding whether the interventions were applied alone or in combination with other active (based on a different mechanism of heat transfer) and/or passive methods of maintaining normothermia. The type of participants and surgical interventions, as well as anaesthesia management, co-interventions and the timing of outcome measurement, also varied widely. The risk of bias of included studies was largely unclear due to limitations in the reports. Most studies were open-label, due to the nature of the intervention and the fact that temperature was usually the principal outcome. Nevertheless, given that outcome measurement could have been conducted in a blinded manner, we rated the risk of detection and performance bias as high.The comparison of ABSW versus control showed a reduction in the rate of surgical site infection (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.20 to 0.66; 3 RCTs, 589 participants, low-quality evidence). Only one study at low risk of bias observed a beneficial effect with forced-air warming on major cardiovascular complications (RR 0.22, 95% CI 0.05 to 1.00; 1 RCT with 12 events, 300 participants, low-quality evidence) in people at high cardiovascular risk. We found no beneficial effect for mortality. ABSW also reduced blood loss during surgery but the magnitude of this effect seems to be irrelevant (MD -46.17 mL, 95% CI -82.74 to -9.59; I² = 78%; 20 studies, 1372 participants). The same conclusion applies to total fluids infused during surgery (MD -144.49 mL, 95% CI -221.57 to -67.40; I² = 73%; 24 studies, 1491 participants). These effects did not translate into a significant reduction in the number of participants being transfused or the average amount of blood transfused. ABSW was associated with a reduction in shivering (RR 0.39, 95% CI 0.28 to 0.54; 29 studies, 1922 participants) and in thermal comfort (standardized mean difference (SMD) 0.76, 95% CI 0.29 to 1.24; I² = 77%, 4 trials, 364 participants).For the comparison between different types of ABSW system or modes of administration of a particular type of ABSW, we found no evidence for the superiority of any system in terms of clinical outcomes, except for extending systemic warming to the preoperative period in participants undergoing major abdominal surgery (one study at low risk of bias).There were limited data on adverse effects (the most relevant being thermal burns). While some trials included a narrative report mentioning that no adverse effects were observed, the majority made no reference to it. Nothing so far suggests that ABSW involves a significant risk to patients. Forced-air warming seems to have a beneficial effect in terms of a lower rate of surgical site infection and complications, at least in those undergoing abdominal surgery, compared to not applying any active warming system. It also has a beneficial effect on major cardiovascular complications in people with substantial cardiovascular disease, although the evidence is limited to one study. It also improves patient's comfort, although we found high heterogeneity among trials. While the effect on blood loss is statistically significant, this difference does not translate to a significant reduction in transfusions. Again, we noted high heterogeneity among trials for this outcome. The clinical relevance of blood loss reduction is therefore questionable. The evidence for other types of ABSW is scant, although there is some evidence of a beneficial effect in the same direction on chills/shivering with electric or resistive-based heating systems. Some evidence suggests that extending systemic warming to the preoperative period could be more beneficial than limiting it only to during surgery. Nothing suggests that ABSW systems pose a significant risk to patients.The difficulty in observing a clinically-relevant beneficial effect with ABSW in outcomes other than temperature may be explained by the fact that many studies applied concomitant procedures that are routinely in place as co-interventions to prevent hypothermia, whether passive or active warming systems based in other physiological mechanisms (e.g. irrigation fluid or gas warming), as well as a stricter control of temperature in the context of the study compared with usual practice. These may have had a beneficial effect on the participants in the control group, leading to an underestimation of the net benefit of ABSW.

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Breast milk is well recognised as the best food source for infants. The impact of antenatal breastfeeding (BF) education on the duration of BF has not been evaluated. To assess the effectiveness of antenatal breastfeeding (BF) education for increasing BF initiation and duration. We searched Cochrane Pregnancy and Childbirth's Trials Register on 1 March 2016, CENTRAL (The Cochrane Library, 2016, Issue 3), MEDLINE (1966 to 1 March 2016) and Scopus (January 1985 to 1 March 2016). We contacted experts and searched reference lists of retrieved articles. All identified published, unpublished and ongoing randomised controlled trials (RCTs) assessing the effect of formal antenatal BF education or comparing two different methods of formal antenatal BF education, on the duration of BF. We included RCTs that only included antenatal interventions and excluded those that combined antenatal and intrapartum or postpartum BF education components. Cluster-randomised trials were included in this review. Quasi-randomised trials were not eligible for inclusion. We assessed all potential studies identified as a result of the search strategy. Two review authors extracted data from each included study using the agreed form and assessed risk of bias. We resolved discrepancies through discussion. We assessed the quality of the evidence using the GRADE approach. This review update includes 24 studies (10,056 women). Twenty studies (9789 women) contribute data to analyses. Most studies took place in high-income countries such as the USA, UK, Canada and Australia. In the first five comparisons, we display the included trials according to type of intervention without pooling data. For the 'Summary of findings' we pooled data for a summary effect.Five included studies were cluster-randomised trials: all of these adjusted data and reported adjustments as odds ratios (OR). We have analysed the data using the generic inverse variance method and presented results as odds ratios, because we were unable to derive a cluster-adjusted risk ratio from the published cluster-trial. We acknowledge that the use of odds ratio prevents the pooling of these cluster trials in our main analyses. One method of BF education with standard (routine) careThere were no group differences for duration of any BF in days or weeks. There was no evidence that interventions improved the proportion of women with any BF or exclusive BF at three or six months. Single trials of different interventions were unable to show that education improved initiation of BF, apart from one small trial at high risk of attrition bias. Many trial results marginally favoured the intervention but had wide confidence intervals crossing the line of no effect. BF complications such as mastitis and other BF problems were similar in treatment arms in single trials reporting these outcomes. Multiple methods of BF education versus standard careFor all trials included in this comparison we have presented the cluster-adjusted odds ratios as reported in trial publications. One three-arm study found the intervention of BF booklet plus video plus Lactation Consultant versus standard care improved the proportion of women exclusively BF at three months (OR 2.60, 95% CI 1.25 to 5.40; women = 159) and marginally at six months (OR 2.40, 95% CI 1.00 to 5.76; women = 175). For the same trial, an intervention arm without a lactation consultant but with the BF booklet and video did not have the same effect on proportion of women exclusively BF at three months (OR 1.80, 95% CI 0.80 to 4.05; women = 159) or six months (OR 0.90, 95% CI 0.30 to 2.70; women = 184). One study compared monthly BF sessions and weekly cell phone message versus standard care and reported improvements in the proportion of women exclusively BF at both three and six months (three months OR 1.80, 95% CI 1.10 to 2.95; women = 390; six months OR 2.40, 95% CI 1.40 to 4.11; women = 390). One study found monthly BF sessions and weekly cell phone messages improved initiation of BF over standard care (OR 2.61, 95% CI 1.61 to 4.24; women = 380). BF education session versus standard care, pooled analyses for 'Summary of findings' (SoF)This comparison does not include cluster-randomised trials reporting adjusted odds ratios. We did not downgrade any evidence for trials' lack of blinding; no trial had adequate blinding of staff and participants. The SoF table presents risk ratios for all outcomes analysed. For proportion of women exclusively BF there is no evidence that antenatal BF education improved BF at three months (RR 1.06, 95% CI 0.90 to 1.25; women = 822; studies = 3; moderate quality evidence) or at six months (RR 1.07, 95% CI 0.87 to 1.30; women = 2161; studies = 4; moderate quality evidence). For proportion of women with any BF there were no group differences in BF at three (average RR 0.98, 95% CI 0.82 to 1.18; women = 654; studies = 2; I² = 60%; low-quality evidence) or six months (average RR 1.05, 95% CI 0.90 to 1.23; women = 1636; studies = 4; I² = 61%; high-quality evidence). There was no evidence that antenatal BF education could improve initiation of BF (average RR 1.01, 95% CI 0.94 to 1.09; women = 3505; studies = 8; I² = 69%; high-quality evidence). Where we downgraded evidence this was due to small sample size or wide confidence intervals crossing the line of no effect, or both.There was insufficient data for subgroup analysis of mother's occupation or education. There was no conclusive evidence supporting any antenatal BF education for improving initiation of BF, proportion of women giving any BF or exclusively BF at three or six months or the duration of BF. There is an urgent need to conduct a high-quality, randomised controlled study to evaluate the effectiveness and adverse effects of antenatal BF education, especially in low- and middle-income countries. Evidence in this review is primarily relevant to high-income settings.

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Fatigue and unintentional weight loss are two of the commonest symptoms experienced by people with advanced progressive illness. Appropriate interventions may bring considerable improvements in function and quality of life to seriously ill people and their families, reducing physical, psychological and spiritual distress. To conduct an overview of the evidence available on the efficacy of interventions used in the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness by reviewing the evidence contained within Cochrane reviews. We searched the Cochrane Database of Systematic Reviews (CDSR) for all systematic reviews evaluating any interventions for the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness (The Cochrane Library 2010, Issue 8). We reviewed titles of interest by abstract. Where the relevance of a review remained unclear we reached a consensus regarding the relevance of the participant group and the outcome measures to the overview. Two overview authors extracted the data independently using a data extraction form. We used the measurement tool AMSTAR (Assessment of Multiple SysTemAtic Reviews) to assess the methodological quality of each systematic review. We included 27 systematic reviews (302 studies with 31,833 participants) in the overview. None of the included systematic reviews reported quantitative data on the efficacy of interventions to manage fatigue or weight loss specific to people with advanced progressive illness. All of the included reviews apart from one were deemed of high methodological quality. For the remaining review we were unable to ascertain the methodological quality of the research strategy as it was described. None of the systematic reviews adequately described whether conflict of interests were present within the included studies. Management of fatigueAmyotrophic lateral sclerosis/motor neuron disease (ALS/MND) - we identified one systematic review (two studies and 52 participants); the intervention was exercise.Cancer - we identified five systematic reviews (116 studies with 17,342 participants); the pharmacological interventions were eicosapentaenoic acid (EPA) and any drug therapy for the management of cancer-related fatigue and the non pharmacological interventions were exercise, interventions by breast care nurses and psychosocial interventions.Chronic obstructive pulmonary disease (COPD) - we identified three systematic reviews (59 studies and 4048 participants); the interventions were self management education programmes, nutritional support and pulmonary rehabilitation.Cystic fibrosis - we identified one systematic review (nine studies and 833 participants); the intervention was physical training.Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) - we identified two systematic reviews (21 studies and 748 participants); the interventions were progressive resistive exercise and aerobic exercise.Multiple sclerosis (MS) - we identified five systematic reviews (23 studies and 1502 participants); the pharmacological interventions were amantadine and carnitine. The non pharmacological interventions were diet, exercise and occupational therapy.Mixed conditions in advanced stages of illness - we identified one systematic review (five studies and 453 participants); the intervention was medically assisted hydration. Management of weight lossALS/MND - we identified one systematic review but no studies met the inclusion criteria for the systematic review; the intervention was enteral tube feeding.Cancer - we identified three systematic reviews with a fourth systematic review also containing extractable data on cancer (66 studies and 5601 participants); the pharmacological interventions were megestrol acetate and eicosapentaenoic acid (EPA) (this systematic review is also included in the cancer fatigue section above). The non pharmacological interventions were enteral tube feeding and non invasive interventions for patients with lung cancer.COPD - we identified one systematic review (59 studies and 4048 participants); the intervention was nutritional support. This systematic review is also included in the COPD fatigue section.Cystic fibrosis - we identified two systematic reviews (three studies and 131 participants); the interventions were enteral tube feeding and oral calorie supplements.HIV/AIDS - we identified four systematic reviews (42 studies and 2071 participants); the pharmacological intervention was anabolic steroids. The non pharmacological interventions were nutritional interventions, progressive resistive exercise and aerobic exercise. Both of the systematic reviews on exercise interventions were also included in the HIV/AIDS fatigue section.MS - we found no systematic reviews which considered interventions to manage unintentional weight loss for people with a clinical diagnosis of multiple sclerosis at any stage of illness.Mixed conditions in advanced stages of illness - we identified two systematic reviews (32 studies and 4826 participants); the interventions were megestrol acetate and medically assisted nutrition. There is a lack of robust evidence for interventions to manage fatigue and/or unintentional weight loss in the advanced stage of progressive illnesses such as advanced cancer, heart failure, lung failure, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia and AIDS. The evidence contained within this overview provides some insight into interventions which may prove of benefit within this population such as exercise, some pharmacological treatments and support for self management.Researchers could improve the methodological quality of future studies by blinding of outcome assessors. Adopting uniform reporting mechanisms for fatigue and weight loss outcome measures would also allow the opportunity for meta-analysis of small studies.Researchers could also improve the applicability of recommendations for interventions to manage fatigue and unintentional weight loss in advanced progressive illness by including subgroup analysis of this population within systematic reviews of applicable interventions.More research is required to ascertain the best interventions to manage fatigue and/or weight loss in advanced illness. There is a need for standardised reporting of these symptoms and agreement amongst researchers of the minimum duration of studies and minimum percentage change in symptom experience that proves the benefits of an intervention. There are, however, challenges in providing meaningful outcome measurements against a background of deteriorating health through disease progression. Interventions to manage these symptoms must also be mindful of the impact on quality of life and should be focused on patient-orientated rather than purely disease-orientated experiences for patients. Systematic reviews and primary intervention studies should include the impact of the interventions on standardised validated quality of life measures.

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Increasing numbers of incidental pancreatic lesions are being detected each year. Accurate characterisation of pancreatic lesions into benign, precancerous, and cancer masses is crucial in deciding whether to use treatment or surveillance. Distinguishing benign lesions from precancerous and cancerous lesions can prevent patients from undergoing unnecessary major surgery. Despite the importance of accurately classifying pancreatic lesions, there is no clear algorithm for management of focal pancreatic lesions. To determine and compare the diagnostic accuracy of various imaging modalities in detecting cancerous and precancerous lesions in people with focal pancreatic lesions. We searched the CENTRAL, MEDLINE, Embase, and Science Citation Index until 19 July 2016. We searched the references of included studies to identify further studies. We did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively. We planned to include studies reporting cross-sectional information on the index test (CT (computed tomography), MRI (magnetic resonance imaging), PET (positron emission tomography), EUS (endoscopic ultrasound), EUS elastography, and EUS-guided biopsy or FNA (fine-needle aspiration)) and reference standard (confirmation of the nature of the lesion was obtained by histopathological examination of the entire lesion by surgical excision, or histopathological examination for confirmation of precancer or cancer by biopsy and clinical follow-up of at least six months in people with negative index tests) in people with pancreatic lesions irrespective of language or publication status or whether the data were collected prospectively or retrospectively. Two review authors independently searched the references to identify relevant studies and extracted the data. We planned to use the bivariate analysis to calculate the summary sensitivity and specificity with their 95% confidence intervals and the hierarchical summary receiver operating characteristic (HSROC) to compare the tests and assess heterogeneity, but used simpler models (such as univariate random-effects model and univariate fixed-effect model) for combining studies when appropriate because of the sparse data. We were unable to compare the diagnostic performance of the tests using formal statistical methods because of sparse data. We included 54 studies involving a total of 3,196 participants evaluating the diagnostic accuracy of various index tests. In these 54 studies, eight different target conditions were identified with different final diagnoses constituting benign, precancerous, and cancerous lesions. None of the studies was of high methodological quality. None of the comparisons in which single studies were included was of sufficiently high methodological quality to warrant highlighting of the results. For differentiation of cancerous lesions from benign or precancerous lesions, we identified only one study per index test. The second analysis, of studies differentiating cancerous versus benign lesions, provided three tests in which meta-analysis could be performed. The sensitivities and specificities for diagnosing cancer were: EUS-FNA: sensitivity 0.79 (95% confidence interval (CI) 0.07 to 1.00), specificity 1.00 (95% CI 0.91 to 1.00); EUS: sensitivity 0.95 (95% CI 0.84 to 0.99), specificity 0.53 (95% CI 0.31 to 0.74); PET: sensitivity 0.92 (95% CI 0.80 to 0.97), specificity 0.65 (95% CI 0.39 to 0.84). The third analysis, of studies differentiating precancerous or cancerous lesions from benign lesions, only provided one test (EUS-FNA) in which meta-analysis was performed. EUS-FNA had moderate sensitivity for diagnosing precancerous or cancerous lesions (sensitivity 0.73 (95% CI 0.01 to 1.00) and high specificity 0.94 (95% CI 0.15 to 1.00), the extremely wide confidence intervals reflecting the heterogeneity between the studies). The fourth analysis, of studies differentiating cancerous (invasive carcinoma) from precancerous (dysplasia) provided three tests in which meta-analysis was performed. The sensitivities and specificities for diagnosing invasive carcinoma were: CT: sensitivity 0.72 (95% CI 0.50 to 0.87), specificity 0.92 (95% CI 0.81 to 0.97); EUS: sensitivity 0.78 (95% CI 0.44 to 0.94), specificity 0.91 (95% CI 0.61 to 0.98); EUS-FNA: sensitivity 0.66 (95% CI 0.03 to 0.99), specificity 0.92 (95% CI 0.73 to 0.98). The fifth analysis, of studies differentiating cancerous (high-grade dysplasia or invasive carcinoma) versus precancerous (low- or intermediate-grade dysplasia) provided six tests in which meta-analysis was performed. The sensitivities and specificities for diagnosing cancer (high-grade dysplasia or invasive carcinoma) were: CT: sensitivity 0.87 (95% CI 0.00 to 1.00), specificity 0.96 (95% CI 0.00 to 1.00); EUS: sensitivity 0.86 (95% CI 0.74 to 0.92), specificity 0.91 (95% CI 0.83 to 0.96); EUS-FNA: sensitivity 0.47 (95% CI 0.24 to 0.70), specificity 0.91 (95% CI 0.32 to 1.00); EUS-FNA carcinoembryonic antigen 200 ng/mL: sensitivity 0.58 (95% CI 0.28 to 0.83), specificity 0.51 (95% CI 0.19 to 0.81); MRI: sensitivity 0.69 (95% CI 0.44 to 0.86), specificity 0.93 (95% CI 0.43 to 1.00); PET: sensitivity 0.90 (95% CI 0.79 to 0.96), specificity 0.94 (95% CI 0.81 to 0.99). The sixth analysis, of studies differentiating cancerous (invasive carcinoma) from precancerous (low-grade dysplasia) provided no tests in which meta-analysis was performed. The seventh analysis, of studies differentiating precancerous or cancerous (intermediate- or high-grade dysplasia or invasive carcinoma) from precancerous (low-grade dysplasia) provided two tests in which meta-analysis was performed. The sensitivity and specificity for diagnosing cancer were: CT: sensitivity 0.83 (95% CI 0.68 to 0.92), specificity 0.83 (95% CI 0.64 to 0.93) and MRI: sensitivity 0.80 (95% CI 0.58 to 0.92), specificity 0.81 (95% CI 0.53 to 0.95), respectively. The eighth analysis, of studies differentiating precancerous or cancerous (intermediate- or high-grade dysplasia or invasive carcinoma) from precancerous (low-grade dysplasia) or benign lesions provided no test in which meta-analysis was performed.There were no major alterations in the subgroup analysis of cystic pancreatic focal lesions (42 studies; 2086 participants). None of the included studies evaluated EUS elastography or sequential testing. We were unable to arrive at any firm conclusions because of the differences in the way that study authors classified focal pancreatic lesions into cancerous, precancerous, and benign lesions; the inclusion of few studies with wide confidence intervals for each comparison; poor methodological quality in the studies; and heterogeneity in the estimates within comparisons.

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Common fetal aneuploidies include Down syndrome (trisomy 21 or T21), Edward syndrome (trisomy 18 or T18), Patau syndrome (trisomy 13 or T13), Turner syndrome (45,X), Klinefelter syndrome (47,XXY), Triple X syndrome (47,XXX) and 47,XYY syndrome (47,XYY). Prenatal screening for fetal aneuploidies is standard care in many countries, but current biochemical and ultrasound tests have high false negative and false positive rates. The discovery of fetal circulating cell-free DNA (ccfDNA) in maternal blood offers the potential for genomics-based non-invasive prenatal testing (gNIPT) as a more accurate screening method. Two approaches used for gNIPT are massively parallel shotgun sequencing (MPSS) and targeted massively parallel sequencing (TMPS). To evaluate and compare the diagnostic accuracy of MPSS and TMPS for gNIPT as a first-tier test in unselected populations of pregnant women undergoing aneuploidy screening or as a second-tier test in pregnant women considered to be high risk after first-tier screening for common fetal aneuploidies. The gNIPT results were confirmed by a reference standard such as fetal karyotype or neonatal clinical examination. We searched 13 databases (including MEDLINE, Embase and Web of Science) from 1 January 2007 to 12 July 2016 without any language, search filter or publication type restrictions. We also screened reference lists of relevant full-text articles, websites of private prenatal diagnosis companies and conference abstracts. Studies could include pregnant women of any age, ethnicity and gestational age with singleton or multifetal pregnancy. The women must have had a screening test for fetal aneuploidy by MPSS or TMPS and a reference standard such as fetal karyotype or medical records from birth. Two review authors independently carried out study selection, data extraction and quality assessment (using the QUADAS-2 tool). Where possible, hierarchical models or simpler alternatives were used for meta-analysis. Sixty-five studies of 86,139 pregnant women (3141 aneuploids and 82,998 euploids) were included. No study was judged to be at low risk of bias across the four domains of the QUADAS-2 tool but applicability concerns were generally low. Of the 65 studies, 42 enrolled pregnant women at high risk, five recruited an unselected population and 18 recruited cohorts with a mix of prior risk of fetal aneuploidy. Among the 65 studies, 44 evaluated MPSS and 21 evaluated TMPS; of these, five studies also compared gNIPT with a traditional screening test (biochemical, ultrasound or both). Forty-six out of 65 studies (71%) reported gNIPT assay failure rate, which ranged between 0% and 25% for MPSS, and between 0.8% and 7.5% for TMPS.In the population of unselected pregnant women, MPSS was evaluated by only one study; the study assessed T21, T18 and T13. TMPS was assessed for T21 in four studies involving unselected cohorts; three of the studies also assessed T18 and 13. In pooled analyses (88 T21 cases, 22 T18 cases, eight T13 cases and 20,649 unaffected pregnancies (non T21, T18 and T13)), the clinical sensitivity (95% confidence interval (CI)) of TMPS was 99.2% (78.2% to 100%), 90.9% (70.0% to 97.7%) and 65.1% (9.16% to 97.2%) for T21, T18 and T13, respectively. The corresponding clinical specificity was above 99.9% for T21, T18 and T13.In high-risk populations, MPSS was assessed for T21, T18, T13 and 45,X in 30, 28, 20 and 12 studies, respectively. In pooled analyses (1048 T21 cases, 332 T18 cases, 128 T13 cases and 15,797 unaffected pregnancies), the clinical sensitivity (95% confidence interval (CI)) of MPSS was 99.7% (98.0% to 100%), 97.8% (92.5% to 99.4%), 95.8% (86.1% to 98.9%) and 91.7% (78.3% to 97.1%) for T21, T18, T13 and 45,X, respectively. The corresponding clinical specificities (95% CI) were 99.9% (99.8% to 100%), 99.9% (99.8% to 100%), 99.8% (99.8% to 99.9%) and 99.6% (98.9% to 99.8%). In this risk group, TMPS was assessed for T21, T18, T13 and 45,X in six, five, two and four studies. In pooled analyses (246 T21 cases, 112 T18 cases, 20 T13 cases and 4282 unaffected pregnancies), the clinical sensitivity (95% CI) of TMPS was 99.2% (96.8% to 99.8%), 98.2% (93.1% to 99.6%), 100% (83.9% to 100%) and 92.4% (84.1% to 96.5%) for T21, T18, T13 and 45,X respectively. The clinical specificities were above 100% for T21, T18 and T13 and 99.8% (98.3% to 100%) for 45,X. Indirect comparisons of MPSS and TMPS for T21, T18 and 45,X showed no statistical difference in clinical sensitivity, clinical specificity or both. Due to limited data, comparative meta-analysis of MPSS and TMPS was not possible for T13.We were unable to perform meta-analyses of gNIPT for 47,XXX, 47,XXY and 47,XYY because there were very few or no studies in one or more risk groups. These results show that MPSS and TMPS perform similarly in terms of clinical sensitivity and specificity for the detection of fetal T31, T18, T13 and sex chromosome aneuploidy (SCA). However, no study compared the two approaches head-to-head in the same cohort of patients. The accuracy of gNIPT as a prenatal screening test has been mainly evaluated as a second-tier screening test to identify pregnancies at very low risk of fetal aneuploidies (T21, T18 and T13), thus avoiding invasive procedures. Genomics-based non-invasive prenatal testing methods appear to be sensitive and highly specific for detection of fetal trisomies 21, 18 and 13 in high-risk populations. There is paucity of data on the accuracy of gNIPT as a first-tier aneuploidy screening test in a population of unselected pregnant women. With respect to the replacement of invasive tests, the performance of gNIPT observed in this review is not sufficient to replace current invasive diagnostic tests.We conclude that given the current data on the performance of gNIPT, invasive fetal karyotyping is still the required diagnostic approach to confirm the presence of a chromosomal abnormality prior to making irreversible decisions relative to the pregnancy outcome. However, most of the gNIPT studies were prone to bias, especially in terms of the selection of participants.

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Survivors of critical illness often experience a multitude of problems that begin in the intensive care unit (ICU) or present and continue after discharge. These can include muscle weakness, cognitive impairments, psychological difficulties, reduced physical function such as in activities of daily living (ADLs), and decreased quality of life. Early interventions such as mobilizations or active exercise, or both, may diminish the impact of the sequelae of critical illness. To assess the effects of early intervention (mobilization or active exercise), commenced in the ICU, provided to critically ill adults either during or after the mechanical ventilation period, compared with delayed exercise or usual care, on improving physical function or performance, muscle strength and health-related quality of life. We searched CENTRAL, MEDLINE, Embase and CINAHL. We searched conference proceedings, reference lists of retrieved articles, databases of trial registries and contacted experts in the field on 31 August 2017. We did not impose restrictions on language or location of publications. We included all randomized controlled trials (RCTs) or quasi-RCTs that compared early intervention (mobilization or active exercise, or both), delivered in the ICU, with delayed exercise or usual care delivered to critically ill adults either during or after the mechanical ventilation period in the ICU. Two researchers independently screened titles and abstracts and assessed full-text articles against the inclusion criteria of this review. We resolved any disagreement through discussion with a third review author as required. We presented data descriptively using mean differences or medians, risk ratios and 95% confidence intervals. A meta-analysis was not possible due to the heterogeneity of the included studies. We assessed the quality of evidence with GRADE. We included four RCTs (a total of 690 participants), in this review. Participants were adults who were mechanically ventilated in a general, medical or surgical ICU, with mean or median age in the studies ranging from 56 to 62 years. Admitting diagnoses in three of the four studies were indicative of critical illness, while participants in the fourth study had undergone cardiac surgery. Three studies included range-of-motion exercises, bed mobility activities, transfers and ambulation. The fourth study involved only upper limb exercises. Included studies were at high risk of performance bias, as they were not blinded to participants and personnel, and two of four did not blind outcome assessors. Three of four studies reported only on those participants who completed the study, with high rates of dropout. The description of intervention type, dose, intensity and frequency in the standard care control group was poor in two of four studies.Three studies (a total of 454 participants) reported at least one measure of physical function. One study (104 participants) reported low-quality evidence of beneficial effects in the intervention group on return to independent functional status at hospital discharge (59% versus 35%, risk ratio (RR) 1.71, 95% confidence interval (CI) 1.11 to 2.64); the absolute effect is that 246 more people (95% CI 38 to 567) per 1000 would attain independent functional status when provided with early mobilization. The effects on physical functioning are uncertain for a range measures: Barthel Index scores (early mobilization: median 75 control: versus 55, low quality evidence), number of ADLs achieved at ICU (median of 3 versus 0, low quality evidence) or at hospital discharge (median of 6 versus 4, low quality evidence). The effects of early mobilization on physical function measured at ICU discharge are uncertain, as measured by the Acute Care Index of Function (ACIF) (early mobilization mean: 61.1 versus control: 55, mean difference (MD) 6.10, 95% CI -11.85 to 24.05, low quality evidence) and the Physical Function ICU Test (PFIT) score (5.6 versus 5.4, MD 0.20, 95% CI -0.98 to 1.38, low quality evidence). There is low quality evidence that early mobilization may have little or no effect on physical function measured by the Short Physical Performance Battery score at ICU discharge from one study of 184 participants (mean 1.6 in the intervention group versus 1.9 in usual care, MD -0.30, 95% CI -1.10 to 0.50), or at hospital discharge (MD 0, 95% CI -1.00 to 0.90). The fourth study, which examined postoperative cardiac surgery patients did not measure physical function as an outcome.Adverse effects were reported across the four studies but we could not combine the data. Our certainty in the risk of adverse events with either mobilization strategy is low due to the low rate of events. One study reported that in the intervention group one out of 49 participants (2%) experienced oxygen desaturation less than 80% and one of 49 (2%) had accidental dislodgement of the radial catheter. This study also found cessation of therapy due to participant instability occurred in 19 of 498 (4%) of the intervention sessions. In another study five of 101 (5%) participants in the intervention group and five of 109 (4.6%) participants in the control group had postoperative pulmonary complications deemed to be unrelated to intervention. A third study found one of 150 participants in the intervention group had an episode of asymptomatic bradycardia, but completed the exercise session. The fourth study reported no adverse events. There is insufficient evidence on the effect of early mobilization of critically ill people in the ICU on physical function or performance, adverse events, muscle strength and health-related quality of life at this time. The four studies awaiting classification, and the three ongoing studies may alter the conclusions of the review once these results are available. We assessed that there is currently low-quality evidence for the effect of early mobilization of critically ill adults in the ICU due to small sample sizes, lack of blinding of participants and personnel, variation in the interventions and outcomes used to measure their effect and inadequate descriptions of the interventions delivered as usual care in the studies included in this Cochrane Review.

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Many women would like to avoid pharmacological or invasive methods of pain management in labour, and this may contribute towards the popularity of complementary methods of pain management. This review examined the evidence currently available on manual methods, including massage and reflexology, for pain management in labour. This review is an update of the review first published in 2012. To assess the effect, safety and acceptability of massage, reflexology and other manual methods to manage pain in labour. For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register (30 June 2017), the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 6), MEDLINE (1966 to 30 June 2017, CINAHL (1980 to 30 June 2017), the Australian New Zealand Clinical Trials Registry (4 August 2017), Chinese Clinical Trial Registry (4 August 2017), ClinicalTrials.gov, (4 August 2017), the National Center for Complementary and Integrative Health (4 August 2017), the WHO International Clinical Trials Registry Platform (ICTRP) (4 August 2017) and reference lists of retrieved trials. We included randomised controlled trials comparing manual methods with standard care, other non-pharmacological forms of pain management in labour, no treatment or placebo. We searched for trials of the following modalities: massage, warm packs, thermal manual methods, reflexology, chiropractic, osteopathy, musculo-skeletal manipulation, deep tissue massage, neuro-muscular therapy, shiatsu, tuina, trigger point therapy, myotherapy and zero balancing. We excluded trials for pain management relating to hypnosis, aromatherapy, acupuncture and acupressure; these are included in other Cochrane reviews. Two review authors independently assessed trial quality, extracted data and checked data for accuracy. We contacted trial authors for additional information. We assessed the quality of the evidence using the GRADE approach. We included a total of 14 trials; 10 of these (1055 women) contributed data to meta-analysis. Four trials, involving 274 women, met our inclusion criteria but did not contribute data to the review. Over half the trials had a low risk of bias for random sequence generation and attrition bias. The majority of trials had a high risk of performance bias and detection bias, and an unclear risk of reporting bias. We found no trials examining the effectiveness of reflexology.MassageWe found low-quality evidence that massage provided a greater reduction in pain intensity (measured using self-reported pain scales) than usual care during the first stage of labour (standardised mean difference (SMD) -0.81, 95% confidence interval (CI) -1.06 to -0.56, six trials, 362 women). Two trials reported on pain intensity during the second and third stages of labour, and there was evidence of a reduction in pain scores in favour of massage (SMD -0.98, 95% CI -2.23 to 0.26, 124 women; and SMD -1.03, 95% CI -2.17 to 0.11, 122 women). There was very low-quality evidence showing no clear benefit of massage over usual care for the length of labour (in minutes) (mean difference (MD) 20.64, 95% CI -58.24 to 99.52, six trials, 514 women), and pharmacological pain relief (average risk ratio (RR) 0.81, 95% CI 0.37 to 1.74, four trials, 105 women). There was very low-quality evidence showing no clear benefit of massage for assisted vaginal birth (average RR 0.71, 95% CI 0.44 to 1.13, four trials, 368 women) and caesarean section (RR 0.75, 95% CI 0.51 to 1.09, six trials, 514 women). One trial reported less anxiety during the first stage of labour for women receiving massage (MD -16.27, 95% CI -27.03 to -5.51, 60 women). One trial found an increased sense of control from massage (MD 14.05, 95% CI 3.77 to 24.33, 124 women, low-quality evidence). Two trials examining satisfaction with the childbirth experience reported data on different scales; both found more satisfaction with massage, although the evidence was low quality in one study and very low in the other.Warm packsWe found very low-quality evidence for reduced pain (Visual Analogue Scale/VAS) in the first stage of labour (SMD -0.59, 95% CI -1.18 to -0.00, three trials, 191 women), and the second stage of labour (SMD -1.49, 95% CI -2.85 to -0.13, two trials, 128 women). Very low-quality evidence showed reduced length of labour (minutes) in the warm-pack group (MD -66.15, 95% CI -91.83 to -40.47; two trials; 128 women).Thermal manual methodsOne trial evaluated thermal manual methods versus usual care and found very low-quality evidence of reduced pain intensity during the first phase of labour for women receiving thermal methods (MD -1.44, 95% CI -2.24 to -0.65, one trial, 96 women). There was a reduction in the length of labour (minutes) (MD -78.24, 95% CI -118.75 to -37.73, one trial, 96 women, very low-quality evidence). There was no clear difference for assisted vaginal birth (very low-quality evidence). Results were similar for cold packs versus usual care, and intermittent hot and cold packs versus usual care, for pain intensity, length of labour and assisted vaginal birth.Music One trial that compared manual methods with music found very low-quality evidence of reduced pain intensity during labour in the massage group (RR 0.40, 95% CI 0.18 to 0.89, 101 women). There was no evidence of benefit for reduced use of pharmacological pain relief (RR 0.41, 95% CI 0.16 to 1.08, very low-quality evidence).Of the seven outcomes we assessed using GRADE, only pain intensity was reported in all comparisons. Satisfaction with the childbirth experience, sense of control, and caesarean section were rarely reported in any of the comparisons. Massage, warm pack and thermal manual methods may have a role in reducing pain, reducing length of labour and improving women's sense of control and emotional experience of labour, although the quality of evidence varies from low to very low and few trials reported on the key GRADE outcomes. Few trials reported on safety as an outcome. There is a need for further research to address these outcomes and to examine the effectiveness and efficacy of these manual methods for pain management.

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Ear wax (cerumen) is a normal bodily secretion that can become a problem when it obstructs the ear canal. Symptoms attributed to wax (such as deafness and pain) are among the commonest reasons for patients to present to primary care with ear trouble.Wax is part of the ear's self-cleaning mechanism and is usually naturally expelled from the ear canal without causing problems. When this mechanism fails, wax is retained in the canal and may become impacted; interventions to encourage its removal may then be needed. Application of ear drops is one of these methods. Liquids used to remove and soften wax are of several kinds: oil-based compounds (e.g. olive or almond oil); water-based compounds (e.g. sodium bicarbonate or water itself); a combination of the above or non-water, non-oil-based solutions, such as carbamide peroxide (a hydrogen peroxide-urea compound) and glycerol. To assess the effects of ear drops (or sprays) to remove or aid the removal of ear wax in adults and children. We searched the Cochrane ENT Trials Register; Cochrane Register of Studies; PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 23 March 2018. Randomised controlled trials (RCTs) in which a 'cerumenolytic' was compared with no treatment, water or saline, an alternative liquid treatment (oil or almond oil) or another 'cerumenolytic' in adults or children with obstructing or impacted ear wax. We used the standard methodological procedures expected by Cochrane. The primary outcomes were 1) the proportion of patients (or ears) with complete clearance of ear wax and 2) adverse effects (discomfort, irritation or pain). Secondary outcomes were: extent of wax clearance; proportion of people (or ears) with relief of symptoms due to wax; proportion of people (or ears) requiring further intervention to remove wax; success of mechanical removal of residual wax following treatment; any other adverse effects recorded and cost. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. We included 10 studies, with 623 participants (900 ears). Interventions included: oil-based treatments (triethanolamine polypeptide, almond oil, benzocaine, chlorobutanol), water-based treatments (docusate sodium, carbamide peroxide, phenazone, choline salicylate, urea peroxide, potassium carbonate), other active comparators (e.g. saline or water alone) and no treatment. Nine of the studies were more than 15 years old.The overall risk of bias across the 10 included studies was low or unclear. proportion of patients (or ears) with complete clearance of ear waxSix studies (360 participants; 491 ears) contributed quantitative data and were included in our meta-analyses.Active treatment versus no treatmentOnly one study addressed this comparison. The proportion of ears with complete clearance of ear wax was higher in the active treatment group (22%) compared with the no treatment group (5%) after five days of treatment (risk ratio (RR) 4.09, 95% confidence interval (CI) 1.00 to 16.80); one study; 117 ears; NNTB = 8) (low-quality evidence).Active treatment versus water or salineWe found no evidence of a difference in the proportion of patients (or ears) with complete clearance of ear wax when the active treatment group was compared to the water or saline group (RR 1.47, 95% CI 0.79 to 2.75; three studies; 213 participants; 257 ears) (low-quality evidence). Two studies applied drops for five days, but one study only applied the drops for 15 minutes. When we excluded this study in a sensitivity analysis it did not change the result.Water or saline versus no treatmentThis comparison was only addressed in the single study cited above (active versus no treatment) and there was no evidence of a difference in the proportion of ears with complete wax clearance when comparing water or saline with no treatment after five days of treatment (RR 4.00, 95% CI 0.91 to 17.62; one study; 76 ears) (low-quality evidence).Active treatment A versus active treatment BSeveral single studies evaluated 'head-to-head' comparisons between two active treatments. We found no evidence to show that one was superior to any other.Subgroup analysis of oil-based active treatments versus non-oil based active treatmentsWe found no evidence of a difference in this outcome when oil-based treatments were compared with non-oil-based active treatments. adverse effects: discomfort, irritation or painOnly seven studies planned to measure and did report this outcome. Only two (141 participants;176 ears) provided useable data. There was no evidence of a significant difference in the number of adverse effects between the types of ear drops in these two studies. We summarised the remaining five studies narratively. All events were mild and reported in fewer than 30 participants across the seven studies (low-quality evidence).Secondary outcomesThree studies reported 'other' adverse effects (how many studies planned to report these is unclear). The available information was limited and included occasional reports of dizziness, unpleasant smell, tinnitus and hearing loss. No significant differences between groups were reported. There were no emergencies or serious adverse effects reported in any of the 10 studies.There was very limited or no information available on our remaining secondary outcomes. Although a number of studies aimed to evaluate whether or not one type of cerumenolytic is more effective than another, there is no high-quality evidence to allow a firm conclusion to be drawn and the answer remains uncertain.A single study suggests that applying ear drops for five days may result in a greater likelihood of complete wax clearance than no treatment at all. However, we cannot conclude whether one type of active treatment is more effective than another and there was no evidence of a difference in efficacy between oil-based and water-based active treatments.There is no evidence to show that using saline or water alone is better or worse than commercially produced cerumenolytics. Equally, there is also no evidence to show that using saline or water alone is better than no treatment.

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Many smokers give up smoking on their own, but materials that provide a structured programme for smokers to follow may increase the number who quit successfully. The aims of this review were to determine the effectiveness of different forms of print-based self-help materials that provide a structured programme for smokers to follow, compared with no treatment and with other minimal contact strategies, and to determine the comparative effectiveness of different components and characteristics of print-based self-help, such as computer-generated feedback, additional materials, tailoring of materials to individuals, and targeting of materials at specific groups. We searched the Cochrane Tobacco Addiction Group Trials Register, ClinicalTrials.gov, and the International Clinical Trials Registry Platform (ICTRP). The date of the most recent search was March 2018. We included randomised trials of smoking cessation with follow-up of at least six months, where at least one arm tested print-based materials providing self-help compared with minimal print-based self-help (such as a short leaflet) or a lower-intensity control. We defined 'self-help' as structured programming for smokers trying to quit without intensive contact with a therapist. We extracted data in accordance with standard methodological procedures set out by Cochrane. The main outcome measure was abstinence from smoking after at least six months' follow-up in people smoking at baseline. We used the most rigorous definition of abstinence in each study and biochemically validated rates when available. Where appropriate, we performed meta-analysis using a random-effects model. We identified 75 studies that met our inclusion criteria. Many study reports did not include sufficient detail to allow judgement of risk of bias for some domains. We judged 30 studies (40%) to be at high risk of bias for one or more domains.Thirty-five studies evaluated the effects of standard, non-tailored self-help materials. Eleven studies compared self-help materials alone with no intervention and found a small effect in favour of the intervention (n = 13,241; risk ratio (RR) 1.19, 95% confidence interval (CI) 1.03 to 1.37; I² = 0%). We judged the evidence to be of moderate certainty in accordance with GRADE, downgraded for indirect relevance to populations in low- and middle-income countries because evidence for this comparison came from studies conducted solely in high-income countries and there is reason to believe the intervention might work differently in low- and middle-income countries. This analysis excluded two studies by the same author team with strongly positive outcomes that were clear outliers and introduced significant heterogeneity. Six further studies of structured self-help compared with brief leaflets did not show evidence of an effect of self-help materials on smoking cessation (n = 7023; RR 0.87, 95% CI 0.71 to 1.07; I² = 21%). We found evidence of benefit from standard self-help materials when there was brief contact that did not include smoking cessation advice (4 studies; n = 2822; RR 1.39, 95% CI 1.03 to 1.88; I² = 0%), but not when self-help was provided as an adjunct to face-to-face smoking cessation advice for all participants (11 studies; n = 5365; RR 0.99, 95% CI 0.76 to 1.28; I² = 32%).Thirty-two studies tested materials tailored for the characteristics of individual smokers, with controls receiving no materials, or stage-matched or non-tailored materials. Most of these studies used more than one mailing. Pooling studies that compared tailored self-help with no self-help, either on its own or compared with advice, or as an adjunct to advice, showed a benefit of providing tailored self-help interventions (12 studies; n = 19,190; RR 1.34, 95% CI 1.20 to 1.49; I² = 0%) with little evidence of difference between subgroups (10 studies compared tailored with no materials, n = 14,359; RR 1.34, 95% CI 1.19 to 1.51; I² = 0%; two studies compared tailored materials with brief advice, n = 2992; RR 1.13, 95% CI 0.86 to 1.49; I² = 0%; and two studies evaluated tailored materials as an adjunct to brief advice, n = 1839; RR 1.72, 95% CI 1.17 to 2.53; I² = 10%). When studies compared tailored self-help with non-tailored self-help, results favoured tailored interventions when the tailored interventions involved more mailings than the non-tailored interventions (9 studies; n = 14,166; RR 1.42, 95% CI 1.20 to 1.68; I² = 0%), but not when the two conditions were contact-matched (10 studies; n = 11,024; RR 1.07, 95% CI 0.89 to 1.30; I² = 50%). We judged the evidence to be of moderate certainty in accordance with GRADE, downgraded for risk of bias.Five studies evaluated self-help materials as an adjunct to nicotine replacement therapy; pooling three of these provided no evidence of additional benefit (n = 1769; RR 1.05, 95% CI 0.86 to 1.30; I² = 0%). Four studies evaluating additional written materials favoured the intervention, but the lower confidence interval crossed the line of no effect (RR 1.20, 95% CI 0.91 to 1.58; I² = 73%). A small number of other studies did not detect benefit from using targeted materials, or find differences between different self-help programmes. Moderate-certainty evidence shows that when no other support is available, written self-help materials help more people to stop smoking than no intervention. When people receive advice from a health professional or are using nicotine replacement therapy, there is no evidence that self-help materials add to their effect. However, small benefits cannot be excluded. Moderate-certainty evidence shows that self-help materials that use data from participants to tailor the nature of the advice or support given are more effective than no intervention. However, when tailored self-help materials, which typically involve repeated assessment and mailing, were compared with untailored materials delivered similarly, there was no evidence of benefit.Available evidence tested self-help interventions in high-income countries, where more intensive support is often available. Further research is needed to investigate effects of these interventions in low- and middle-income countries, where more intensive support may not be available.

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Active management of the third stage of labour involves giving a prophylactic uterotonic, early cord clamping and controlled cord traction to deliver the placenta. With expectant management, signs of placental separation are awaited and the placenta is delivered spontaneously. Active management was introduced to try to reduce haemorrhage, a major contributor to maternal mortality in low-income countries. This is an update of a review last published in 2015. To compare the effects of active versus expectant management of the third stage of labour on severe primary postpartum haemorrhage (PPH) and other maternal and infant outcomes.To compare the effects of variations in the packages of active and expectant management of the third stage of labour on severe primary PPH and other maternal and infant outcomes. For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the World health Organization International Clinical Trials Registry Platform (ICTRP), on 22 January 2018, and reference lists of retrieved studies. Randomised and quasi-randomised controlled trials comparing active versus expectant management of the third stage of labour. Cluster-randomised trials were eligible for inclusion, but none were identified. Two review authors independently assessed the studies for inclusion, assessed risk of bias, carried out data extraction and assessed the quality of the evidence using the GRADE approach. We included eight studies, involving analysis of data from 8892 women. The studies were all undertaken in hospitals, seven in higher-income countries and one in a lower-income country. Four studies compared active versus expectant management, and four compared active versus a mixture of managements. We used a random-effects model in the analyses because of clinical heterogeneity. Of the eight studies included, we considered three studies as having low risk of bias in the main aspects of sequence generation, allocation concealment and completeness of data collection. There was an absence of high-quality evidence according to GRADE assessments for our primary outcomes, which is reflected in the cautious language below.The evidence suggested that, for women at mixed levels of risk of bleeding, it is uncertain whether active management reduces the average risk of maternal severe primary PPH (more than 1000 mL) at time of birth (average risk ratio (RR) 0.34, 95% confidence interval (CI) 0.14 to 0.87, 3 studies, 4636 women, I<sup2</sup = 60%; GRADE: very low quality). For incidence of maternal haemoglobin (Hb) less than 9 g/dL following birth, active management of the third stage may reduce the number of women with anaemia after birth (average RR 0.50, 95% CI 0.30 to 0.83, 2 studies, 1572 women; GRADE: low quality). We also found that active management of the third stage may make little or no difference to the number of babies admitted to neonatal units (average RR 0.81, 95% CI 0.60 to 1.11, 2 studies, 3207 infants; GRADE: low quality). It is uncertain whether active management of the third stage reduces the number of babies with jaundice requiring treatment (RR 0.96, 95% CI 0.55 to 1.68, 2 studies, 3142 infants, I<sup2</sup = 66%; GRADE: very low quality). There were no data on our other primary outcomes of very severe PPH at the time of birth (more than 2500 mL), maternal mortality, or neonatal polycythaemia needing treatment.Active management reduces mean maternal blood loss at birth and probably reduces the rate of primary blood loss greater than 500 mL, and the use of therapeutic uterotonics. Active management also probably reduces the mean birthweight of the baby, reflecting the lower blood volume from interference with placental transfusion. In addition, it may reduce the need for maternal blood transfusion. However, active management may increase maternal diastolic blood pressure, vomiting after birth, afterpains, use of analgesia from birth up to discharge from the labour ward, and more women returning to hospital with bleeding (outcome not pre-specified).In the comparison of women at low risk of excessive bleeding, there were similar findings, except it was uncertain whether there was a difference identified between groups for severe primary PPH (average RR 0.31, 95% CI 0.05 to 2.17; 2 studies, 2941 women, I<sup2</sup = 71%), maternal Hb less than 9 g/dL at 24 to 72 hours (average RR 0.17, 95% CI 0.02 to 1.47; 1 study, 193 women) or the need for neonatal admission (average RR 1.02, 95% CI 0.55 to 1.88; 1 study, 1512 women). In this group, active management may make little difference to the rate of neonatal jaundice requiring phototherapy (average RR 1.31, 95% CI 0.78 to 2.18; 1 study, 1447 women).Hypertension and interference with placental transfusion might be avoided by using modifications to the active management package, for example, omitting ergot and deferring cord clamping, but we have no direct evidence of this here. Although the data appeared to show that active management reduced the risk of severe primary PPH greater than 1000 mL at the time of birth, we are uncertain of this finding because of the very low-quality evidence. Active management may reduce the incidence of maternal anaemia (Hb less than 9 g/dL) following birth, but harms such as postnatal hypertension, pain and return to hospital due to bleeding were identified.In women at low risk of excessive bleeding, it is uncertain whether there was a difference between active and expectant management for severe PPH or maternal Hb less than 9 g/dL (at 24 to 72 hours). Women could be given information on the benefits and harms of both methods to support informed choice. Given the concerns about early cord clamping and the potential adverse effects of some uterotonics, it is critical now to look at the individual components of third-stage management. Data are also required from low-income countries.It must be emphasised that this review includes only a small number of studies with relatively small numbers of participants, and the quality of evidence for primary outcomes is low or very low.

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Neuromuscular diseases (NMDs) are a heterogeneous group of diseases affecting the anterior horn cell of spinal cord, neuromuscular junction, peripheral nerves and muscles. NMDs cause physical disability usually due to progressive loss of strength in limb muscles, and some NMDs also cause respiratory muscle weakness. Respiratory muscle training (RMT) might be expected to improve respiratory muscle weakness; however, the effects of RMT are still uncertain. This systematic review will synthesize the available trial evidence on the effectiveness and safety of RMT in people with NMD, to inform clinical practice. To assess the effects of respiratory muscle training (RMT) for neuromuscular disease (NMD) in adults and children, in comparison to sham training, no training, standard treatment, breathing exercises, or other intensities or types of RMT. On 19 November 2018, we searched the Cochrane Neuromuscular Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. On 23 December 2018, we searched the US National Institutes for Health Clinical Trials Registry (ClinicalTrials.gov), the World Health Organization International Clinical Trials Registry Platform, and reference lists of the included studies. We included randomized controlled trials (RCTs) and quasi-RCTs, including cross-over trials, of RMT in adults and children with a diagnosis of NMD of any degree of severity, who were living in the community, and who did not need mechanical ventilation. We compared trials of RMT (inspiratory muscle training (IMT) or expiratory muscle training (EMT), or both), with sham training, no training, standard treatment, different intensities of RMT, different types of RMT, or breathing exercises. We followed standard Cochrane methodological procedures. We included 11 studies involving 250 randomized participants with NMDs: three trials (N = 88) in people with amyotrophic lateral sclerosis (ALS; motor neuron disease), six trials (N = 112) in Duchenne muscular dystrophy (DMD), one trial (N = 23) in people with Becker muscular dystrophy (BMD) or limb-girdle muscular dystrophy, and one trial (N = 27) in people with myasthenia gravis.Nine of the trials were at high risk of bias in at least one domain and many reported insufficient information for accurate assessment of the risk of bias. Populations, interventions, control interventions, and outcome measures were often different, which largely ruled out meta-analysis. All included studies assessed lung capacity, our primary outcome, but four did not provide data for analysis (1 in people with ALS and three cross-over studies in DMD). None provided long-term data (over a year) and only one trial, in ALS, provided information on adverse events. Unscheduled hospitalisations for chest infection or acute exacerbation of chronic respiratory failure were not reported and physical function and quality of life were reported in one (ALS) trial.Amyotrophic lateral sclerosis (ALS)Three trials compared RMT versus sham training in ALS. Short-term (8 weeks) effects of RMT on lung capacity in ALS showed no clear difference in the change of the per cent predicted forced vital capacity (FVC%) between EMT and sham EMT groups (mean difference (MD) 0.70, 95% confidence interval (CI) -8.48 to 9.88; N = 46; low-certainty evidence). The mean difference (MD) in FVC% after four months' treatment was 10.86% in favour of IMT (95% CI -4.25 to 25.97; 1 trial, N = 24; low-certainty evidence), which is larger than the minimal clinically important difference (MCID, as estimated in people with idiopathic pulmonary fibrosis). There was no clear difference between IMT and sham IMT groups, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALFRS; range of possible scores 0 = best to 40 = worst) (MD 0.85, 95% CI -2.16 to 3.85; 1 trial, N = 24; low-certainty evidence) or quality of life, measured on the EuroQol-5D (0 = worst to 100 = best) (MD 0.77, 95% CI -17.09 to 18.62; 1 trial, N = 24; low-certainty evidence) over the medium term (4 months). One trial report stated that the IMT protocol had no adverse effect (very low-certainty evidence).Duchenne muscular dystrophy (DMD)Two DMD trials compared RMT versus sham training in young males with DMD. In one study, the mean post-intervention (6-week) total lung capacity (TLC) favoured RMT (MD 0.45 L, 95% CI -0.24 to 1.14; 1 trial, N = 16; low-certainty evidence). In the other trial there was no clear difference in post-intervention (18 days) FVC between RMT and sham RMT (MD 0.16 L, 95% CI -0.31 to 0.63; 1 trial, N = 20; low-certainty evidence). One RCT and three cross-over trials compared a form of RMT with no training in males with DMD; the cross-over trials did not provide suitable data. Post-intervention (6-month) values showed no clear difference between the RMT and no training groups in per cent predicted vital capacity (VC%) (MD 3.50, 95% CI -14.35 to 21.35; 1 trial, N = 30; low-certainty evidence).Becker or limb-girdle muscular dystrophyOne RCT (N = 21) compared 12 weeks of IMT with breathing exercises in people with Becker or limb-girdle muscular dystrophy. The evidence was of very low certainty and conclusions could not be drawn.Myasthenia gravisIn myasthenia gravis, there may be no clear difference between RMT and breathing exercises on measures of lung capacity, in the short term (TLC MD -0.20 L, 95% CI -1.07 to 0.67; 1 trial, N = 27; low-certainty evidence). Effects of RMT on quality of life are uncertain (1 trial; N = 27).Some trials reported effects of RMT on inspiratory and/or expiratory muscle strength; this evidence was also of low or very low certainty. RMT may improve lung capacity and respiratory muscle strength in some NMDs. In ALS there may not be any clinically meaningful effect of RMT on physical functioning or quality of life and it is uncertain whether it causes adverse effects. Due to clinical heterogeneity between the trials and the small number of participants included in the analysis, together with the risk of bias, these results must be interpreted very cautiously.

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Even low levels of substance misuse by people with a severe mental illness can have detrimental effects. To assess the effects of psychosocial interventions for reduction in substance use in people with a serious mental illness compared with standard care. The Information Specialist of the Cochrane Schizophrenia Group (CSG) searched the CSG Trials Register (2 May 2018), which is based on regular searches of major medical and scientific databases. We included all randomised controlled trials (RCTs) comparing psychosocial interventions for substance misuse with standard care in people with serious mental illness. Review authors independently selected studies, extracted data and appraised study quality. For binary outcomes, we calculated standard estimates of risk ratio (RR) and their 95% confidence intervals (CIs) on an intention-to-treat basis. For continuous outcomes, we calculated the mean difference (MD) between groups. Where meta-analyses were possible, we pooled data using a random-effects model. Using the GRADE approach, we identified seven patient-centred outcomes and assessed the quality of evidence for these within each comparison. Our review now includes 41 trials with a total of 4024 participants. We have identified nine comparisons within the included trials and present a summary of our main findings for seven of these below. We were unable to summarise many findings due to skewed data or because trials did not measure the outcome of interest. In general, evidence was rated as low- or very-low quality due to high or unclear risks of bias because of poor trial methods, or inadequately reported methods, and imprecision due to small sample sizes, low event rates and wide confidence intervals. 1. Integrated models of care versus standard care (36 months) No clear differences were found between treatment groups for loss to treatment (RR 1.09, 95% CI 0.82 to 1.45; participants = 603; studies = 3; low-quality evidence), death (RR 1.18, 95% CI 0.39 to 3.57; participants = 421; studies = 2; low-quality evidence), alcohol use (RR 1.15, 95% CI 0.84 to 1.56; participants = 143; studies = 1; low-quality evidence), substance use (drug) (RR 0.89, 95% CI 0.63 to 1.25; participants = 85; studies = 1; low-quality evidence), global assessment of functioning (GAF) scores (MD 0.40, 95% CI -2.47 to 3.27; participants = 170; studies = 1; low-quality evidence), or general life satisfaction (QOLI) scores (MD 0.10, 95% CI -0.18 to 0.38; participants = 373; studies = 2; moderate-quality evidence). 2. Non-integrated models of care versus standard care There was no clear difference between treatment groups for numbers lost to treatment at 12 months (RR 1.21, 95% CI 0.73 to 1.99; participants = 134; studies = 3; very low-quality evidence). 3. Cognitive behavioural therapy (CBT) versus standard care There was no clear difference between treatment groups for numbers lost to treatment at three months (RR 1.12, 95% CI 0.44 to 2.86; participants = 152; studies = 2; low-quality evidence), cannabis use at six months (RR 1.30, 95% CI 0.79 to 2.15; participants = 47; studies = 1; very low-quality evidence) or mental state insight (IS) scores by three months (MD 0.52, 95% CI -0.78 to 1.82; participants = 105; studies = 1; low-quality evidence). 4. Contingency management versus standard care We found no clear differences between treatment groups for numbers lost to treatment at three months (RR 1.55, 95% CI 1.13 to 2.11; participants = 255; studies = 2; moderate-quality evidence), number of stimulant positive urine tests at six months (RR 0.83, 95% CI 0.65 to 1.06; participants = 176; studies = 1) or hospitalisations (RR 0.21, 95% CI 0.05 to 0.93; participants = 176; studies = 1); both low-quality evidence. 5. Motivational interviewing (MI) versus standard care We found no clear differences between treatment groups for numbers lost to treatment at six months (RR 1.71, 95% CI 0.63 to 4.64; participants = 62; studies = 1). A clear difference, favouring MI, was observed for abstaining from alcohol (RR 0.36, 95% CI 0.17 to 0.75; participants = 28; studies = 1) but not other substances (MD -0.07, 95% CI -0.56 to 0.42; participants = 89; studies = 1), and no differences were observed in mental state general severity (SCL-90-R) scores (MD -0.19, 95% CI -0.59 to 0.21; participants = 30; studies = 1). All very low-quality evidence. 6. Skills training versus standard care At 12 months, there were no clear differences between treatment groups for numbers lost to treatment (RR 1.42, 95% CI 0.20 to 10.10; participants = 122; studies = 3) or death (RR 0.15, 95% CI 0.02 to 1.42; participants = 121; studies = 1). Very low-quality, and low-quality evidence, respectively. 7. CBT + MI versus standard care At 12 months, there was no clear difference between treatment groups for numbers lost to treatment (RR 0.99, 95% CI 0.62 to 1.59; participants = 327; studies = 1; low-quality evidence), number of deaths (RR 0.60, 95% CI 0.20 to 1.76; participants = 603; studies = 4; low-quality evidence), relapse (RR 0.50, 95% CI 0.24 to 1.04; participants = 36; studies = 1; very low-quality evidence), or GAF scores (MD 1.24, 95% CI -1.86 to 4.34; participants = 445; studies = 4; very low-quality evidence). There was also no clear difference in reduction of drug use by six months (MD 0.19, 95% CI -0.22 to 0.60; participants = 119; studies = 1; low-quality evidence). We included 41 RCTs but were unable to use much data for analyses. There is currently no high-quality evidence to support any one psychosocial treatment over standard care for important outcomes such as remaining in treatment, reduction in substance use or improving mental or global state in people with serious mental illnesses and substance misuse. Furthermore, methodological difficulties exist which hinder pooling and interpreting results. Further high-quality trials are required which address these concerns and improve the evidence in this important area.

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Establishing the subgroup analysis of the fallopian tubes (tubes) is a commonly undertaken diagnostic investigation for women with subfertility. This is usually achieved by flushing contrast medium through the tubes and visualising patency on radiographs, ultrasonography or laparoscopy. Many women were noted to conceive in the first three to six months after tubal flushing, raising the possibility that tubal flushing could also be a treatment for infertility. There has been debate about which contrast medium should be used (water-soluble or oil-soluble media) as this may influence pregnancy rates. An important adverse event during tubal flushing is intravasation (backflow of contrast medium into the blood or lymphatic vessels),which could lead to embolism although it is asymptomatic in most cases. To evaluate the effectiveness and safety of tubal flushing with oil-soluble contrast media (OSCM) and water-soluble contrast media (WSCM) on subsequent fertility outcomes in women with subfertility. We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, MEDLINE, Embase, CENTRAL, PsycINFO, reference lists of identified articles and trial registries. The most recent search was conducted in April 2020. Randomised controlled trials (RCTs) comparing tubal flushing with OSCM, WSCM with each other or with no treatment, in women with subfertility. Two review authors independently selected the trials, assessed risk of bias and extracted data. We contacted study authors for additional information. The overall quality of the evidence was assessed using GRADE methods. Fifteen trials involving 3864 women were included in this systematic review. Overall, the quality of evidence varied from very low to moderate: the main limitations were risk of bias, heterogeneity and imprecision. OSCM versus no treatment Four studies (506 women) were included in this comparison. Tubal flushing with OSCM may increase the odds of live birth (odds ratio (OR) 3.27, 95% confidence interval (CI) 1.57 to 6.85, 3 RCTs, 204 women, I<sup2</sup = 0, low-quality evidence). This suggests that if the chance of live birth following no treatment is assumed to be 11%, the chance following tubal flushing with OSCM would be between 16% and 46%. Tubal flushing with OSCM may increase in the odds of clinical pregnancy (OR 3.54, 95% CI 2.08 to 6.02, 4 RCTs, 506 women, I<sup2</sup = 18%, low-quality evidence). This suggests that if the chance of clinical pregnancy following no treatment is assumed to be 9%, the chance following tubal flushing with OSCM would be between 17% and 37%. No study measured intravasation or other adverse events such as infection, haemorrhage and congenital abnormalities. WSCM versus no treatment Only one study (334 women) was included in this comparison. We are uncertain whether tubal flushing with WSCM increase live birth compared to no treatment (OR 1.13, 95% CI 0.67 to 1.91, 1 RCT, 334 women, low-quality evidence). This suggests that if the chance of live birth following no treatment is assumed to be 21%, the chance following tubal flushing with WSCM would be between 15% and 33%. We are uncertain whether tubal flushing with WSCM increases clinical pregnancy compared to no treatment (OR 1.14, 95% CI 0.71 to 1.84, 1 RCT, 334 women, low-quality evidence). This suggests that if the chance of clinical pregnancy following no treatment is assumed to be 27%, the chance following tubal flushing with WSCM would be between 29% and 40%. One case with pelvic infection was reported in the WSCM group and no case with infection in the no treatment group in a one study (334 women). Meta-analysis was not performed due to the rare events. No study measured intravasation or other adverse events such as infection, haemorrhage and congenital abnormalities. OSCM versus WSCM Six studies (2598 women) were included in this comparison. Three studies reported live birth, including two with higher live birth in the OSCM group (OR 1.64, 95% CI 1.27 to 2.11, 1119 women; OR 3.45, 95% CI 1.97 to 6.03, 398 women); and one with insufficient evidence of a difference between groups (OR 0.92, 95% CI 0.60 to 1.40, 533 women). Given the substantial heterogeneity observed (I<sup2</sup = 86%), meta-analysis was not performed. Tubal flushing with OSCM probably increased in the odds of intravasation (asymptomatic) compared to tubal flushing with WSCM (OR 5.00, 95% CI 2.25 to 11.12, 4 RCTs, 1912 women, I<sup2</sup = 0, moderate-quality evidence). This suggests that if the chance of intravasation following tubal flushing with WSCM is assumed to be 1%, the chance following tubal flushing with OSCM would be between 2% and 9%. Tubal flushing with OSCM may increase the odds of clinical pregnancy (OR 1.42, 95% CI 1.10 to 1.85, 6 RCTs, 2598 women, I<sup2</sup = 41%, low-quality evidence). This suggests that if the chance of clinical pregnancy following tubal flushing with WSCM is assumed to be 26%, the chance following tubal flushing with OSCM would be between 28% and 39%. We are uncertain whether tubal flushing with OSCM decreases the odds of infection (OR 0.22, 95% CI 0.04 to 1.22, 2 RCTs, 662 women, I<sup2</sup = 0, very low-quality evidence) or haemorrhage (OR 0.65, 95% CI 0.40 to 1.06, 2 RCTs, 662 women, I<sup2</sup = 0, very low-quality evidence). Three neonates with congenital abnormalities were reported in the OSCM group while no congenital abnormality was reported in the WSCM group in one study (1119 women). No meta-analysis was performed due to the rare events. The evidence suggests that compared to no treatment, tubal flushing with OSCM may increase the chance of live birth and clinical pregnancy, while it is uncertain whether tubal flushing with WSCM improves those outcomes. Compared to tubal flushing with WSCM, OSCM may improve clinical pregnancy while meta-analysis was impossible for live birth due to heterogeneity. Evidence also suggests that OSCM is associated with an increased risk of asymptomatic intravasation. Overall, adverse events, especially long-term adverse events, are poorly reported across studies.

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Most of the detected increment in dental caries among children above the age of six years and adolescents is confined to occlusal surfaces of posterior permanent molars. Dental sealants and fluoride varnishes are much used to prevent caries. As the effectiveness of both interventions in controlling caries as compared with no intervention has been demonstrated previously, this review aimed to evaluate their relative effectiveness. It updates a review published originally in 2006 and updated in 2010 and in 2016. Our primary objective was to evaluate the relative effectiveness of dental sealants (i.e. fissure sealant) compared with fluoride varnishes, or fissure sealants plus fluoride varnishes compared with fluoride varnishes alone, for preventing dental caries in the occlusal surfaces of permanent teeth of children and adolescents. Our secondary objectives were to evaluate whether effectiveness is influenced by sealant material type and length of follow-up, document and report on data concerning adverse events associated with sealants and fluoride varnishes, and report the cost effectiveness of dental sealants versus fluoride varnish in caries prevention. Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 19 March 2020), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2020, Issue 2), MEDLINE Ovid (1946 to 19 March 2020) and Embase Ovid (1980 to 19 March 2020). We searched the US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. There were no restrictions on the language or date of publication. We included randomised controlled trials with at least 12 months of follow-up comparing fissure sealants, or fissure sealants plus fluoride varnishes, versus fluoride varnishes, for preventing caries in the occlusal surfaces of permanent posterior teeth (i.e. premolar or molar teeth), in participants younger than 20 years of age at the start of the study. At least two review authors independently screened search results, extracted data from included studies and assessed their risk of bias. We attempted to contact study authors to obtain missing or unclear information. We grouped and analysed studies on the basis of sealant material type: resin-based sealant or glass ionomer-based sealant (glass ionomer and resin-modified glass ionomer sealant), and different follow-up periods. We calculated the odds ratio (OR) for risk of caries on occlusal surfaces of permanent molar teeth. For trials with a split-mouth design, we used the Becker-Balagtas OR. One cluster-randomised trial provided precise estimates in terms of risk ratio (RR), which we used. For continuous outcomes and data, we used means and standard deviations to obtain mean differences (MD). For meta-analysis, we used the random-effects model when we combined data from four or more studies. We presented all measures with 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE criteria. We included 11 trials with 3374 participants aged five to 10 years when trials started. Three trials are new since the 2016 update. Two trials did not contribute data to our analysis. Sealant versus fluoride varnish Resin-based fissure sealants versus fluoride varnishes Seven trials evaluated this comparison (five contributing data). We are uncertain if resin-based sealants may be better than fluoride varnish, or vice versa, for preventing caries in first permanent molars at two to three years' follow-up (OR 0.67, 95% CI 0.37 to 1.19; I<sup2</sup = 84%; 4 studies, 1683 children evaluated). One study measuring decayed, missing and filled permanent surfaces (DMFS) and decayed, missing and filled permanent teeth (DMFT) increment at two years suggested a small benefit for fissure sealant (DMFS MD -0.09, 95% CI -0.15 to -0.03; DMFT MD -0.08, 95% CI -0.14 to -0.02; 542 participants), though this may not be clinically significant. One small study, at high risk of bias, reported a benefit for sealant after four years in preventing caries (RR 0.42, 95% CI 0.21 to 0.84; 75 children) and at nine years (RR 0.48, 95% CI 0.29 to 0.79; 75 children). We assessed each of these results as having very low certainty. Glass ionomer-based sealants versus fluoride varnishes Three trials evaluated this comparison: one trial with chemically cured glass ionomer and two with resin-modified glass ionomer. Studies were clinically diverse, so we did not conduct a meta-analysis. In general, the studies found no benefit of one intervention over another at one, two and three years, although one study, which also included oral health education, suggested a benefit from sealants over varnish for children at high risk of caries. We assessed this evidence as very low certainty. Sealant plus fluoride varnish versus fluoride varnish alone One split-mouth trial analysing 92 children at two-year follow-up found in favour of resin-based fissure sealant plus fluoride varnish over fluoride varnish only (OR 0.30, 95% CI 0.17 to 0.55), which represented a clinically meaningful effect of a 77% reduction in caries after two years; however, we assessed this evidence as very low certainty. Adverse events Five trials (1801 participants) (four using resin-based sealant material and one using resin-modified glass ionomer) reported that no adverse events resulted from use of sealants or fluoride varnishes over one to nine years. The other studies did not mention adverse events. Applying fluoride varnish or resin-based fissure sealants to first permanent molars helps prevent occlusal caries, but it has not been possible in this review to reach reliable conclusions about which one is better to apply. The available studies do not suggest either intervention is superior, but we assessed this evidence as having very low certainty. We found very low-certainty evidence that placing resin-based sealant as well as applying fluoride varnish works better than applying fluoride varnish alone. Fourteen studies are currently ongoing and their findings may allow us to draw firmer conclusions about whether sealants and varnish work equally well or whether one is better than the other.

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Stillbirth is generally defined as a death prior to birth at or after 22 weeks' gestation. It remains a major public health concern globally. Antenatal interventions may reduce stillbirths and improve maternal and neonatal outcomes in settings with high rates of stillbirth. There are several key antenatal strategies that aim to prevent stillbirth including nutrition, and prevention and management of infections. To summarise the evidence from Cochrane systematic reviews on the effects of antenatal interventions for preventing stillbirth for low risk or unselected populations of women. We collaborated with Cochrane Pregnancy and Childbirth's Information Specialist to identify all their published reviews that specified or reported stillbirth; and we searched the Cochrane Database of Systematic Reviews (search date: 29 Feburary 2020) to identify reviews published within other Cochrane groups. The primary outcome measure was stillbirth but in the absence of stillbirth data, we used perinatal mortality (both stillbirth and death in the first week of life), fetal loss or fetal death as outcomes. Two review authors independently evaluated reviews for inclusion, extracted data and assessed quality of evidence using AMSTAR (A Measurement Tool to Assess Reviews) and GRADE tools. We assigned interventions to categories with graphic icons to classify the effectiveness of interventions as: clear evidence of benefit or harm; clear evidence of no effect or equivalence; possible benefit or harm; or unknown benefit or harm or no effect or equivalence. We identified 43 Cochrane Reviews that included interventions in pregnant women with the potential for preventing stillbirth; all of the included reviews reported our primary outcome 'stillbirth' or in the absence of stillbirth, 'perinatal death' or 'fetal loss/fetal death'. AMSTAR quality was high in 40 reviews with scores ranging from 8 to 11 and moderate in three reviews with a score of 7. Nutrition interventions Clear evidence of benefit: balanced energy/protein supplementation versus no supplementation suggests a probable reduction in stillbirth (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.39 to 0.94, 5 randomised controlled trials (RCTs), 3408 women; moderate-certainty evidence). Clear evidence of no effect or equivalence for stillbirth or perinatal death: vitamin A alone versus placebo or no treatment; and multiple micronutrients with iron and folic acid versus iron with or without folic acid. Unknown benefit or harm or no effect or equivalence: for all other nutrition interventions examined the effects were uncertain. Prevention and management of infections Possible benefit for fetal loss or death: insecticide-treated anti-malarial nets versus no nets (RR 0.67, 95% CI 0.47 to 0.97, 4 RCTs; low-certainty). Unknown evidence of no effect or equivalence: drugs for preventing malaria (stillbirth RR 1.02, 95% CI 0.76 to 1.36, 5 RCTs, 7130 women, moderate certainty in women of all parity; perinatal death RR 1.24, 95% CI 0.94 to 1.63, 4 RCTs, 5216 women, moderate-certainty in women of all parity). Prevention, detection and management of other morbidities Clear evidence of benefit: the following interventions suggest a reduction: midwife-led models of care in settings where the midwife is the primary healthcare provider particularly for low-risk pregnant women (overall fetal loss/neonatal death reduction RR 0.84, 95% CI 0.71 to 0.99, 13 RCTs, 17,561 women; high-certainty), training versus not training traditional birth attendants in rural populations of low- and middle-income countries (stillbirth reduction odds ratio (OR) 0.69, 95% CI 0.57 to 0.83, 1 RCT, 18,699 women, moderate-certainty; perinatal death reduction OR 0.70, 95% CI 0.59 to 0.83, 1 RCT, 18,699 women, moderate-certainty). Clear evidence of harm: a reduced number of antenatal care visits probably results in an increase in perinatal death (RR 1.14 95% CI 1.00 to 1.31, 5 RCTs, 56,431 women; moderate-certainty evidence). Clear evidence of no effect or equivalence: there was evidence of no effect in the risk of stillbirth/fetal loss or perinatal death for the following interventions and comparisons: psychosocial interventions; and providing case notes to women. Possible benefit: community-based intervention packages (including community support groups/women's groups, community mobilisation and home visitation, or training traditional birth attendants who made home visits) may result in a reduction of stillbirth (RR 0.81, 95% CI 0.73 to 0.91, 15 RCTs, 201,181 women; low-certainty) and perinatal death (RR 0.78, 95% CI 0.70 to 0.86, 17 RCTs, 282,327 women; low-certainty). Unknown benefit or harm or no effect or equivalence: the effects were uncertain for other interventions examined. Screening and management of fetal growth and well-being Clear evidence of benefit: computerised antenatal cardiotocography for assessing infant's well-being in utero compared with traditional antenatal cardiotocography (perinatal mortality reduction RR 0.20, 95% CI 0.04 to 0.88, 2 RCTs, 469 women; moderate-certainty). Unknown benefit or harm or no effect or equivalence: the effects were uncertain for other interventions examined. While most interventions were unable to demonstrate a clear effect in reducing stillbirth or perinatal death, several interventions suggested a clear benefit, such as balanced energy/protein supplements, midwife-led models of care, training versus not training traditional birth attendants, and antenatal cardiotocography. Possible benefits were also observed for insecticide-treated anti-malarial nets and community-based intervention packages, whereas a reduced number of antenatal care visits were shown to be harmful. However, there was variation in the effectiveness of interventions across different settings, indicating the need to carefully understand the context in which these interventions were tested. Further high-quality RCTs are needed to evaluate the effects of antenatal preventive interventions and which approaches are most effective to reduce the risk of stillbirth. Stillbirth (or fetal death), perinatal and neonatal death need to be reported separately in future RCTs of antenatal interventions to allow assessment of different interventions on these rare but important outcomes and they need to clearly define the target populations of women where the intervention is most likely to be of benefit. As the high burden of stillbirths occurs in low- and middle-income countries, further high-quality trials need to be conducted in these settings as a priority.

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<bObjective:</b To explore the heterogeneity and growth factor regulatory network of dermal fibroblasts (dFbs) in mouse full-thickness skin defect wounds based on single-cell RNA sequencing. <bMethods:</b The experimental research methods were adopted. The normal skin tissue from 5 healthy 8-week-old male C57BL/6 mice (the same mouse age, sex, and strain below) was harvested, and the wound tissue of another 5 mice with full-thickness skin defect on the back was harvested on post injury day (PID) 7. The cell suspension was obtained by digesting the tissue with collagenase D and DNase Ⅰ, sequencing library was constructed using 10x Genomics platform, and single-cell RNA sequencing was performed by Illumina Novaseq6000 sequencer. The gene expression matrices of cells in the two kinds of tissue were obtained by analysis of Seurat 3.0 program of software R4.1.1, and two-dimensional tSNE plots classified by cell group, cell source, and gene labeling of major cells in skin were used for visual display. According to the existing literature and the CellMarker database searching, the expression of marker genes in the gene expression matrices of cells in the two kinds of tissue was analyzed, and each cell group was numbered and defined. The gene expression matrices and cell clustering information were introduced into CellChat 1.1.3 program of software R4.1.1 to analyze the intercellular communication in the two kinds of tissue and the intercellular communication involving vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) signal pathways in the wound tissue, the relative contribution of each pair of FGF subtypes and FGF receptor (FGFR) subtypes (hereinafter referred to as FGF ligand receptor pairs) to FGF signal network in the two kinds of tissue, and the intercellular communication in the signal pathway of FGF ligand receptor pairs with the top 2 relative contributions in the two kinds of tissue. The normal skin tissue from one healthy mouse was harvested, and the wound tissue of one mouse with full-thickness skin defect on the back was harvested on PID 7. The multiple immunofluorescence staining was performed to detect the expression and distribution of FGF7 protein and its co-localized expression with dipeptidyl peptidase 4 (DPP4), stem cell antigen 1 (SCA1), smooth muscle actin (SMA), and PDGF receptor α (PDGFRα) protein. <bResults:</b Both the normal skin tissue of healthy mice and the wound tissue of full-thickness skin defected mice on PID 7 contained 25 cell groups, but the numbers of cells in each cell group between the two kinds of tissue were different. Genes <iPDGFRα</i, platelet endothelial cell adhesion molecule 1, lymphatic endothelial hyaluronic acid receptor 1, receptor protein tyrosine phosphatase C, keratin 10, and keratin 79 all had distinct distributions on two-dimensional tSNE plots, indicating specific cell groups respectively. The 25 cell groups were numbered by C0-C24 and divided into 9 dFb subgroups and 16 non-dFb groups. dFb subgroups included C0 as interstitial progenitor cells, C5 as adipose precursor cells, and C13 as contractile muscle cells related fibroblasts, etc. Non-dFb group included C3 as neutrophils, C8 as T cells, and C18 as erythrocytes, etc. Compared with that of the normal skin tissue of healthy mice, the intercellular communication in the wound tissue of full-thickness skin defected mice on PID 7 was more and denser, and the top 3 cell groups in intercellular communication intensity were dFb subgroups C0, C1, and C2, of which all communicated with other cell groups in the wound tissue. In the wound tissue of full-thickness skin defected mice on PID 7, VEGF signals were mainly sent by the dFb subgroup C0 and received by vascular related cell groups C19 and C21, PDGF signals were mainly sent by peripheral cells C14 and received by multiple dFb subgroups, EGF signals were mainly sent by keratinocyte subgroups C9 and C11 and received by the dFb subgroup C0, and the main sender and receiver of FGF signals were the dFb subgroup C6. In the relative contribution rank of FGF ligand receptor pairs to FGF signal network in the normal skin tissue of healthy mice and the wound tissue of full-thickness skin defected mice on PID 7, FGF7-FGFR1 was the top 1, and FGF7-FGFR2 or FGF10-FGFR1 was in the second place, respectively; compared with those in the normal skin tissue, there was more intercellular communication in FGF7-FGFR1 signal pathway, while the intercellular communication in FGF7-FGFR2 and FGF10-FGFR1 signal pathways decreased slightly or did not change significantly in the wound tissue; the intercellular communication in FGF7-FGFR1 signal pathway in the wound tissue was stronger than that in FGF7-FGFR2 or FGF10-FGFR1 signal pathway; in the two kinds of tissue, FGF7 signal was mainly sent by dFb subgroups C0, C1, and C2, and received by dFb subgroups C6 and C7. Compared with that in the normal skin tissue of healthy mouse, the expression of FGF7 protein was higher in the wound tissue of full-thickness skin defected mouse on PID 7; in the normal skin tissue, FGF7 protein was mainly expressed in the skin interstitium and also expressed in the white adipose tissue near the dermis layer; in the two kinds of tissue, FGF7 protein was co-localized with DPP4 and SCA1 proteins and expressed in the skin interstitium, co-localized with PDGFRα protein and expressed in dFbs, but was not co-localized with SMA protein, with more co-localized expression of FGF7 in the wound tissue than that in the normal skin tissue. <bConclusions:</b In the process of wound healing of mouse full-thickness skin defect wound, dFbs are highly heterogeneous, act as potential major secretory or receiving cell populations of a variety of growth factors, and have a close and complex relationship with the growth factor signal pathways. FGF7-FGFR1 signal pathway is the main FGF signal pathway in the process of wound healing, which targets and regulates multiple dFb subgroups.

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<bObjective:</b To compare the effects of three treatment options: emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery, on the pathological characteris- tics of surgically-resected specimens from patients with completely obstructive colorectal cancer. <bMethods:</b This was a retrospective cohort study analyzing clinicopathological data of patients with complete obstructive colorectal cancer who were admitted to the General Surgery Department of Beijing Chaoyang Hospital, Capital Medical University, between May 2012 and August 2020. The inclusion criteria were diagnosed with complete colorectal obstruction, pathologically confirmed as adenocarcinoma, resectable on imaging assessment, and without distant metastasis, combined with the patients' clinical manifestations and imaging examination findings. Patients with multiple colorectal cancers, refusal to undergo surgery, and concurrent peritonitis or intestinal perforation before stenting of the intestinal obstruction were excluded. Eighty-nine patients with completely obstructive colorectal cancer were enrolled in the study and were divided into emergency surgery group (<in</i=30), stent-surgery group (<in</i=34), and stent-neoadjuvant chemotherapy- surgery group (<in</i=25) according to the treatment strategy. Differences in the pathological features (namely perineural infiltration, lymphovascular infiltration, tumor deposits, specimen intravascular necrosis, inflammatory infiltration, abscesses, mucus lake formation, foreign body giant cells, calcification, and tumor cell ratio) and biomolecular markers (namely cluster of differentiation (CD)34, Ki67, Bcl-2, matrix metalloproteinase-9, and hypoxia-inducible factor alpha) were recorded. Pathological evaluation was based on the presence or absence of qualitative evaluation of pathological features, such as peripheral nerve infiltration, vascular infiltration, and cancer nodules within the specimens. The evaluation criteria for the pathological features of the specimens were as follows: Semi-quantitative graded evaluation based on the proportion of tissue necrosis, inflammatory infiltrates, abscesses, mucus lake formation, foreign body giant cells, calcification, and tumor cells in the field of view within the specimen were classified as: grade 0: not seen within the specimen; grade 1: 0-25%; grade 2: 25%-50%; grade 3: 50%-75%; and grade 4: 75%-100%. The intensity of cellular immunity was classified as none (0 points), weak (1 point), moderate (2 points), and strong (3 points). The two evaluation scores were then multiplied to obtain a total score of 0-12. The immunohistochemical results were also evaluated comprehensively, and the results were defined as: negative (grade 0): 0 points; weakly positive (grade 1): 1-3 points; moderately positive (grade 2): 4-6 points; strongly positive (grade 3): 7-9 points; and very strong positive (grade 4): 10-12 points. Normally-distributed values were expressed as mean±standard deviation, and one-way analysis of variance was used to analyze the differences between the groups. Non-normally-distributed values were expressed as median (interquartile range: <iQ</i1, <iQ</i3). A nonparametric test (Kruskal-Wallis H test) was used for comparisons between groups. <bResults:</b The differences were not statistically significant when comparing the baseline data for age, gender, tumor site, American Society of Anesthesiologists score, tumor T-stage, N-stage, and degree of differentiation among the three groups (all <iP</i&gt;0.05). The differences were not statistically significant when comparing the pathological characteristics of the resected tumor specimens, such as foreign body giant cells, inflammatory infiltration, and mucus lake formation among the three groups (all <iP</i&gt;0.05). The rates of vascular infiltration were 56.6% (17/30), 41.2% (15/34), and 20.0% (5/25) in the emergency surgery, stent-surgery, and stent- neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences between the groups (χ<sup2</sup=7.142, <iP</i=0.028). Additionally, the rate of vascular infiltration was significantly lower in the stent-neoadjuvant chemotherapy-surgery group than that in the emergency surgery group (<iP</i=0.038). Peripheral nerve infiltration rates were 55.3% (16/30), 41.2% (14/34), and 16.0% (4/25), in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences (χ<sup2</sup=7.735, <iP</i=0.021). The infiltration peripheral nerve rates in the stent-neoadjuvant chemotherapy-surgery group were significantly lower than those in the emergency surgery group (<iP</i=0.032). The necrosis grade was 2 (1, 2), 2 (1, 3), and 2 (2, 3) in the emergency surgery, stent- surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences (<iH</i=10.090, <iP</i=0.006). <iPost hoc</i comparison revealed that the necrosis grade was higher in the stent-surgery and stent-neoadjuvant chemotherapy-surgery groups compared with the emergency surgery group (both <iP</i&lt;0.05). The abscess grade was 2 (1, 2), 3 (1, 3), and 2 (2, 3) in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences (<iH</i=6.584, <iP</i=0.037). <iPost hoc</i comparison revealed that the abscess grade in the emergency surgery group was significantly lower than that in the stent-surgery group (<iP</i=0.037). The fibrosis grade was 2 (1, 3), 3 (2, 3), and 3 (2, 3), in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences (<iH</i=11.078, <iP</i=0.004). <iPost hoc</i analysis revealed that the fibrosis degree was higher in both the stent-surgery group and the stent- neoadjuvant chemotherapy-surgery group compared with the emergency surgery group (both, <iP</i&lt;0.05). The tumor cell ratio grades were 4 (3, 4), 4 (3, 4), and 3 (2, 4), in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences (<iH</i=8.594, <iP</i=0.014). <iPost hoc</i analysis showed that the tumor cell ratio in the stent-neoadjuvant chemotherapy-surgery group was significantly lower than that in the emergency surgery group (<iP</i=0.012). The CD34 grades were 2 (2, 3), 3 (2, 4), and 3 (2, 3) in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, and the difference was statistically significant (<iH</i=9.786, <iP</i=0.007). <iPost hoc</i analysis showed that the CD34 grades in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups were 2 (2, 3), 3 (2, 4), and 3 (2,3), respectively. <iPost hoc</i analysis revealed that the CD34 concentration was higher in the stent-surgery group than that in the emergency surgery group (<iP</i=0.005). <bConclusion:</b Stenting may increase the risk of distant metastases in obstructive colorectal cancer. The stent-neoadjuvant chemotherapy-surgery treatment model promotes tumor cell necrosis and fibrosis and reduces the proportion of tumor cells, vascular infiltration, and peripheral nerve infiltration, which may help decrease local tumor infiltration and distant metastasis in completely obstructive colorectal cancer after stent placement.

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Antipsychotics are widely used in geriatric psychiatric disorders. A growing number of atypical antipsychotics are available, expanding clinical options but complicating decision-making. Many questions about use of antipsychotics in older patients remain unanswered by available clinical literature. We therefore surveyed expert opinion on antipsychotic use in older patients (65 years of age or older) for recommendations concerning indications for antipsychotics, choice of antipsychotics for different conditions (e.g., delirium, dementia, schizophrenia, delusional disorder, psychotic mood disorders) and for patients with comorbid conditions or history of side effects, dosing strategies, duration of treatment, and medication combinations. Based on a literature review, a 47-question survey with 1,411 options was developed. Approximately three quarters of the options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions. For other options, experts were asked to write in answers. The survey was sent to 52 American experts on treatment of older adults (38 geriatric psychiatrists, 14 geriatric internists/family physicians), 48 (92%) of whom completed it. In analyzing responses to items rated on the 9-point scale, consensus was defined as a nonrandom distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred, second line/alternate, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean. Guidelines indicating preferred treatment strategies were then developed for key clinical situations. The expert panel reached consensus on 78% of options rated on the 9-point scale. The experts did not recommend using antipsychotics in panic disorder, generalized anxiety disorder, nonpsychotic major depression, hypochondriasis, neuropathic pain, severe nausea, motion sickness, or irritability, hostility, and sleep disturbance in the absence of a major psychiatric syndrome. However, antipsychotics were favored in several other disorders. For agitated dementia with delusions, the experts' first-line recommendation is an antipsychotic drug alone; they would also consider adding a mood stabilizer. Risperidone (0.5-2.0 mg/day) was first line followed by quetiapine (50-150 mg/day) and olanzapine (5.0-7.5 mg/day) as high second-line options. There was no first-line recommendation for agitated dementia without delusions; an antipsychotic alone was high second line (rated first line by 60% of the experts). The experts'first-line recommendation for late-life schizophrenia was risperidone (1.25-3.5 mg/day). Quetiapine (100-300 mg/day), olanzapine (7.5-15 mg/day), and aripiprazole (15-30 mg/day) were high second line. For older patients with delusional disorder, an antipsychotic was the only treatment recommended. For agitated nonpsychotic major depression in an older patient, the experts' first-line recommendation was an antidepressant alone (77% first line); second-line options were an antidepressant plus an antipsychotic, electroconvulsive therapy (ECT), an antidepressant plus a benzodiazepine, and an antidepressant plus a mood stabilizer. For nonpsychotic major depression with severe anxiety, the experts recommended an antidepressant alone (79% first line) and would also consider adding a benzodiazepine or mood stabilizer to the antidepressant. If an older patient with adequate dosages for adequate duration, there was limited support for adding an atypical antipsychotic to the antidepressant (36% first line after two failed antidepressant trials). Treatment of choice for geriatric psychotic major depression was an antipsychotic plus an antidepressant (98% first line), with ECT another first-line option (71% first line). For mild geriatric nonpsychotic mania, the first-line recommendation is a mood stabilizer alone; the experts would also consider discontinuing an antidepressant if the patient is receiving one. For severe nonpsychotic mania, the experts recommend a mood stabilizer alone; the experts would also consider discontinuing an antidepressant if the patient is receiving one. For severe nonpsychotic mania, the experts recommend a mood stabilizer plus an antipsychotic (57%; first line) or a mood stabilizer alone (48%; first line) and would discontinue any antidepressant the patient is receiving. For psychotic mania, treatment of choice is a mood stabilizer plus an antipsychotic (98%; first line). Risperidone (1.25-3.0 mg/day) and olanzapine (5-15 mg/day) were first-line options in combination with a mood stabilizer for mania with psychosis, with quetiapine (50-250 mg/day) high second line. If a patient has responded well, the experts recommended the following duration of treatment before attempting to taper and discontinue the antipsychotic: delirium, 1 week; agitated dementia, taper within 3-6 months to determine the lowest effective maintenance dose; schizophrenia, indefinite treatment at the lowest effective dose; delusional disorder, 6 months-indefinitely at the lowest effective dose; psychotic major depression, 6 months; and mania with psychosis, 3 months. For patients with diabetes, dyslipidemia, or obesity, the experts would avoid clozapine, olanzapine, and conventional antipsychotics (especially low- and mid-potency). Quetiapine is first line for a patient with Parkinson's disease. Clozapine, ziprasidone, and conventional antipsychotics (especially low- and mid-potency) should be avoided in patients with QTc prolongation or congestive heart failure. For patients with cognitive impairment, constipation, diabetes, diabetic neuropathy, dyslipidemia, xerophthalmia, and xerostomia, the experts prefer risperidone, with quetiapine high second line. More than a quarter of the experts considered these combinations contraindicated: clozapine + carbamazepine, ziprasidone + tricyclic antidepressant (TCA), and a low-potency conventional antipsychotic + fluoxetine. In combining antidepressants and antipsychotics, the experts would be much more cautious with selective serotonin reuptake inhibitors that are more potent inhibitors of the CYP 450 enzymes (i.e., fluoxetine, fluvoxamine, paroxetine) and with nefazodone, TCAs, and monoamine oxidase inhibitors. The experts recommended extra monitoring when combining any antipsychotic with lithium, carbamazepine, lamotrigine, or valproate (except aripiprazole, risperidone, or a high-potency conventional plus valproate) or with codeine, phenytoin, or tramadol. The experts reached a high level of consensus on many of the key treatment questions. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide direction for common clinical dilemmas in the use of antipsychotics in elderly patients. Clinicians should keep in mind that no guidelines can address the complexities of an individual patient and that sound clinical judgment based on clinical experience should be used in applying these recommendations.

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Wilson's disease is an infrequent, autosomic recessive pathology, resulting from a loss of function of an adenosine triphosphatase (ATP7B or WDNP), secondarily to a change (more than 60 are described currently), insertion or deletion of the ATP7B gene located on the chromosome 13q14.3-q21.1, which involves a reduction or an absence of the transport of copper in the bile and its accumulation in the body, notably the brain. Wilson's disease is transmitted by an autosomic recessive gene located on the long arm of chromosome 13. The prevalence of the heterozygote is evaluated at 1/90 and the homozygote at 1/30,000. Consanguinity, frequent in the socially geographically isolated populations, increases the prevalence of the disease. The toxic quantities of copper, which accumulate in the liver since early childhood and perhaps before, remain concentrated in the body for years. Hence, cytological and histological modifications can be detected in the biopsies, before the appearance of clinical or biological symptoms of hepatic damage. The accumulation of copper in the liver is due to a defect in the biliary excretion of metal and is accompanied invariably by a deficit in ceruloplasmin; protein synthesized from a transferred ATP7B gene, which causes retention of the copper ions in the liver. The detectable cellular anomalies are of two types: hepatic lesions resulting in acute hepatic insufficiency, acute hepatitis and finally advanced cirrhosis and lesions of the central nervous system responsible for the neurological and psychiatric disorders. In approximately 40-50% of the patients, the first manifestation of Wilson's disease affects the central nervous system. Although copper diffuses in the liver towards the blood and then towards other tissues, it has disastrous consequences only in the brain. It can therefore cause either a progressive neurological disease, or psychiatric disorders. Wilson's disease begins in the form of a hepatic, neurological, or psychiatric disease in at least 90% of the patients. In some rare cases, the first manifestations of the disease can be psychiatric which, according to the literature, accounts for only 10% of the cases. The disease can be revealed by isolated behavioral problems, an irrational syndrome, a schizophrenic syndrome, or a manic-depressive syndrome. Damage to the central nervous system can be more severe, thus, several differential diagnoses have been discussed: a psychotic disorder of late appearance; a depressive state; a mental confusion disorder. The clinical syndrome is complex. Indeed, it is the polymorphism, which dominates in the description of the psychiatric demonstrations of the disease. This can lead to prejudicial diagnostic wandering, particularly since heavy sedative treatment may be required to suppress behavioral problems. Clinically, Wilson's disease generally appears between the age of 10 and 20. It rarely remains masked until after the age of 40. The first manifestations are hepatic (40% of the cases), neurological (35%) or psychiatric (10%). The inaugural disorder can finally take on a haematological, renal, or mixed form in approximately 15% of the cases. We have detailed the principal clinical elements. In approximately 40-50% of the patients, the first manifestation of the disease affects the central nervous system, where it can cause either a progressive neurological disease, or psychiatric disorders. The ophthalmologic disorder is dominated by Kayser-Fleischer's ring, representing a green or bronze colored ring on the periphery of the cornea. It occupies the higher pole of the cornea, then the lower pole, and extends to the whole circumference. It is generally only visible under examination with a slit lamp. It disappears on average within 3-5 years following copper chelating therapy. Kayser-Fleischer's ring has been described other than in Wilson's disease, in exceptional cases of prolonged cholestasis. On haematological level, the hyperhaemolysis is due to the toxicity of the ionic copper, released massively in the plasma by hepatocellular necrosis. The other manifestations can be found in the following organs: renal, osteoarticular, cardiac, endocrine, cutaneous, and in the teguments. Until 1952, the diagnosis was evoked only on clinical symptomatology. It can henceforth be marked unambiguous, even in the absence of any symptom, by the description of a ceruloplasmin plasma concentration of less than 200 ml/l, and of a Kayser-Fleischer's ring. Hepatic copper on sample is constantly increased during the disease (from 3 to 25 micromol/g of dry weight). On the other hand, the absence of a reduction in the plasma ceruloplasmin does not make it possible to exclude the diagnosis. Conversely, a reduction in ceruloplasmin can exist other than in Wilson's disease (nephritic syndrome, malabsorption syndrome, or severe hepatic insufficiency). Kayser-Fleischer's ring is quasiconstant among patients with neuropsychiatric demonstrations (thus, its absence represents a very strong argument against the diagnosis). It can on the other hand be lacking during hepatic forms, and in this case, its absence is not an argument against the diagnosis. Magnetic resonance imaging can reveal abnormal signals of the grey cores. A genetic study is conducted by liaison analysis in the event of a family history of the disease. When it is not treated, Wilson's disease induces lesions of the tissues, the outcome of which is always fatal. Treatment relies on the regulation of copper chelation, which improves the prognosis, and zinc, which captures the copper in a nontoxic form. The severe psychiatric disorders observed during Wilson's disease may require tranquilizers, but care should be taken because of potential neurological or hepatic side effects. Lithium seems an interesting treatment and remains theoretically indicated, taking into account the scarcity of the extrapyramidal symptoms and the hepatic dysfunction among patients at the stage of cirrhosis, since it is not metabolized in the liver. Although rare, it is important to approach Wilson's disease in psychiatry because the psychiatric manifestations can precede the somatic disorders and help to pose the diagnosis. We stress the importance of the early diagnosis of the pathology, the outcome of which is fatal in the absence of specific treatment.

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Platelet-rich therapies are being used increasingly in the treatment of musculoskeletal soft tissue injuries such as ligament, muscle and tendon tears and tendinopathies. These therapies can be used as the principal treatment or as an augmentation procedure (application after surgical repair or reconstruction). Platelet-rich therapies are produced by centrifuging a quantity of the patient's own blood and extracting the active, platelet-rich, fraction. The platelet-rich fraction is applied to the injured tissue; for example, by injection. Platelets have the ability to produce several growth factors, so these therapies should enhance tissue healing. There is a need to assess whether this translates into clinical benefit. To assess the effects (benefits and harms) of platelet-rich therapies for treating musculoskeletal soft tissue injuries. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (25 March 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013 Issue 2), MEDLINE (1946 to March 2013), EMBASE (1980 to 2013 Week 12) and LILACS (1982 to March 2012). We also searched trial registers (to Week 2 2013) and conference abstracts (2005 to March 2012). No language or publication restrictions were applied. We included randomised and quasi-randomised controlled trials that compared platelet-rich therapy with either placebo, autologous whole blood, dry needling or no platelet-rich therapy for people with acute or chronic musculoskeletal soft tissue injuries. Primary outcomes were functional status, pain and adverse effects. Two review authors independently extracted data and assessed each study's risk of bias. Disagreement was resolved by discussion or by arbitration by a third author. We contacted trial authors for clarification of methods or missing data. Treatment effects were assessed using risk ratios for dichotomous data and mean differences (MD) or standardised mean differences (SMD) for continuous data, together with 95% confidence intervals. Where appropriate, data were pooled using the fixed-effect model for RR and MD, and the random-effects model for SMD. The quality of the evidence for each outcome was assessed using GRADE criteria. We included data from 19 small single centre trials (17 randomised and two quasi-randomised; 1088 participants) that compared platelet-rich therapy with placebo, autologous whole blood, dry needling or no platelet-rich therapy. These trials covered eight clinical conditions: rotator cuff tears (arthroscopic repair) (six trials); shoulder impingement syndrome surgery (one trial); elbow epicondylitis (three trials); anterior cruciate ligament (ACL) reconstruction (four trials), ACL reconstruction (donor graft site application) (two trials), patellar tendinopathy (one trial), Achilles tendinopathy (one trial) and acute Achilles rupture surgical repair (one trial). We also grouped trials into 'tendinopathies' where platelet-rich therapy (PRT) injections were the main treatment (five trials), and surgical augmentation procedures where PRT was applied during surgery (14 trials). Trial participants were mainly male, except in trials including rotator cuff tears, and elbow and Achilles tendinopathies.Three trials were judged as being at low risk of bias; the other 16 were at high or unclear risk of bias relating to selection, detection, attrition or selective reporting, or combinations of these. The methods of preparing platelet-rich plasma (PRP) varied and lacked standardisation and quantification of the PRP applied to the patient.We were able to pool data for our primary outcomes (function, pain, adverse events) for a maximum of 11 trials and 45% of participants. The evidence for all primary outcomes was judged as being of very low quality.Data assessing function in the short term (up to three months) were pooled from five trials that assessed PRT in three clinical conditions and used four different measures. These showed no significant difference between PRT and control (SMD 0.24; 95% confidence interval (CI) -0.07 to 0.56; P value 0.13; I² = 35%; 273 participants; positive values favour PRT). Medium-term function data (at six months) were pooled from six trials that assessed PRT in five clinical conditions and used six different measures. These also showed no difference between groups (SMD 0.06; 95% CI -0.39 to 0.51; P value 0.79; I² = 64%; 262 participants). Long-term function data (at one year) were pooled from 10 trials that assessed PRT in five clinical conditions and used six different measures. These also showed no difference between groups (SMD 0.25, 95% CI -0.07 to 0.57; P value 0.12; I² = 66%; 484 participants). Although the 95% confidence intervals indicate the possibility of a slightly poorer outcome in the PRT group up to a moderate difference in favour of PRT at short- and long-term follow-up, these do not translate into clinically relevant differences.Data pooled from four trials that assessed PRT in three clinical conditions showed a small reduction in short-term pain in favour of PRT on a 10-point scale (MD -0.95, 95% CI -1.41 to -0.48; I² = 0%; 175 participants). The clinical significance of this result is marginal.Four trials reported adverse events; another seven trials reported an absence of adverse events. There was no difference between treatment groups in the numbers of participants with adverse effects (7/241 versus 5/245; RR 1.31, 95% CI 0.48 to 3.59; I² = 0%; 486 participants).In terms of individual conditions, we pooled heterogeneous data for long-term function from six trials of PRT application during rotator cuff tear surgery. This showed no statistically or clinically significant differences between the two groups (324 participants). Pooled data for short-term function for three elbow epicondylitis trials (179 participants) showed a statistically significant difference in favour of PRT, but the clinical significance of this finding is uncertain.The available evidence is insufficient to indicate whether the effects of PRT will differ importantly in individual clinical conditions. Overall, and for the individual clinical conditions, there is currently insufficient evidence to support the use of PRT for treating musculoskeletal soft tissue injuries. Researchers contemplating RCTs should consider the coverage of currently ongoing trials when assessing the need for future RCTs on specific conditions. There is need for standardisation of PRP preparation methods.

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Available evidence on the effects of vitamin D on mortality has been inconclusive. In a recent systematic review, we found evidence that vitamin D3 may decrease mortality in mostly elderly women. The present systematic review updates and reassesses the benefits and harms of vitamin D supplementation used in primary and secondary prophylaxis of mortality. To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease. We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index-Expanded and Conference Proceedings Citation Index-Science (all up to February 2012). We checked references of included trials and pharmaceutical companies for unidentified relevant trials. Randomised trials that compared any type of vitamin D in any dose with any duration and route of administration versus placebo or no intervention in adult participants. Participants could have been recruited from the general population or from patients diagnosed with a disease in a stable phase. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)). Six review authors extracted data independently. Random-effects and fixed-effect meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RRs). To account for trials with zero events, we performed meta-analyses of dichotomous data using risk differences (RDs) and empirical continuity corrections. We used published data and data obtained by contacting trial authors.To minimise the risk of systematic error, we assessed the risk of bias of the included trials. Trial sequential analyses controlled the risk of random errors possibly caused by cumulative meta-analyses. We identified 159 randomised clinical trials. Ninety-four trials reported no mortality, and nine trials reported mortality but did not report in which intervention group the mortality occurred. Accordingly, 56 randomised trials with 95,286 participants provided usable data on mortality. The age of participants ranged from 18 to 107 years. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. More than half of the trials had a low risk of bias. All trials were conducted in high-income countries. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL).Vitamin D decreased mortality in all 56 trials analysed together (5,920/47,472 (12.5%) vs 6,077/47,814 (12.7%); RR 0.97 (95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I(2) = 0%). More than 8% of participants dropped out. 'Worst-best case' and 'best-worst case' scenario analyses demonstrated that vitamin D could be associated with a dramatic increase or decrease in mortality. When different forms of vitamin D were assessed in separate analyses, only vitamin D3 decreased mortality (4,153/37,817 (11.0%) vs 4,340/38,110 (11.4%); RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I(2) = 0%; 75,927 participants; 38 trials). Vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. A subgroup analysis of trials at high risk of bias suggested that vitamin D2 may even increase mortality, but this finding could be due to random errors. Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. We did not observe any statistically significant differences in the effect of vitamin D on mortality in subgroup analyses of trials at low risk of bias compared with trials at high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 ng/mL at entry compared with trials including participants with vitamin D levels equal to or greater than 20 ng/mL at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of trials using concomitant calcium supplementation compared with trials without calcium; of trials using a dose below 800 IU per day compared with trials using doses above 800 IU per day; and of trials including only women compared with trials including both sexes or only men. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I(2) = 0%; 44,492 participants; 4 trials). Vitamin D3 combined with calcium increased the risk of nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I(2) = 0%; 42,876 participants; 4 trials). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I(2) = 17%; 710 participants; 3 trials). Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium increased nephrolithiasis. Both alfacalcidol and calcitriol increased hypercalcaemia. Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted.

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This is an update of a Cochrane review first published in 2006. Gout is one of the most common rheumatic diseases worldwide. Despite the use of colchicine as one of the first-line therapies for the treatment of acute gout, evidence for its benefits and harms is relatively limited. To evaluate the benefits and harms of colchicine for the treatment of acute gout. We searched the following electronic databases from inception to April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We did not impose any date or language restrictions in the search. We also handsearched conference proceedings of the American College of Rheumatology and the European League against Rheumatism (2010 until 2013) and reference lists of identified studies. We searched the clinical trials register clinicaltrials.gov and the WHO trials register. We considered published randomised controlled trials (RCTs) and controlled clinical trials (CCTs) evaluating colchicine therapy compared with another therapy (active or placebo) in acute gout. The primary benefit outcome of interest was pain, defined as a proportion with 50% or greater decrease in pain, and the primary harm outcome was study participants withdrawal due to adverse events. Two authors independently screened search results for relevant studies, extracted data into a standardised form and assessed the risk of bias of included studies. We pooled data if deemed to be sufficiently clinically homogeneous. We assessed the quality of the body of evidence for each outcome using the GRADE approach. Two RCTs (124 participants) were included in this updated review, including one new RCT. We considered one trial to be at low risk of bias, while we considered the newly included trial to be at unclear risk of bias. Both trials included a placebo and a high-dose colchicine arm, although the colchicine regimens varied. In one trial 0.5 mg colchicine was given every two hours until there was either complete relief of symptoms or toxicity and the total doses were not specified. In the other trial a total of 4.8 mg colchicine was given over six hours. The newly identified trial also included a low-dose colchicine arm (total 1.8 mg over one hour).Based upon pooled data from two trials (124 participants), there is low-quality evidence that a greater proportion of people receiving high-dose colchicine experience a 50% or greater decrease in pain from baseline up to 32 to 36 hours compared with placebo (35/74 in the high-dose colchicine group versus 12/50 in the placebo group (risk ratio (RR) 2.16, 95% confidence interval (CI) 1.28 to 3.65), with a number needed to treat to benefit (NNTB) of 4 (95% CI 3 to 12). However, the total number of adverse events (diarrhoea, vomiting or nausea) is greater in those who receive high-dose colchicine versus placebo (62/74 in the high-dose colchicine group versus 11/50 in the placebo group (RR 3.81, 95% CI 2.28 to 6.38), with a number needed to treat to harm (NNTH) of 2 (95% CI 2 to 5). Only one trial included reduction of inflammation as part of a composite measure comprising pain, tenderness, swelling and erythema, each graded on a four-point scale (none 0 to severe 3) to derive a maximum score for any one joint of 12. They reported the proportion of people who achieved a 50% reduction in this composite score. Based upon one trial (43 participants), there was low-quality evidence that more people in the high-dose colchicine group had a 50% or greater decrease in composite score from baseline up to 32 to 36 hours than people in the placebo group (11/22 in the high-dose colchicine group versus 1/21 in the placebo group (RR 10.50, 95% CI 1.48 to 74.38) and 45% absolute difference).Based upon data from one trial (103 participants), there was low-quality evidence that low-dose colchicine is more efficacious than placebo with respect to the proportion of people who achieve a 50% or greater decrease in pain from baseline to 32 to 36 hours (low-dose colchicine 31/74 versus placebo 5/29 (RR 2.43, 95% CI 1.05 to 5.64)), with a NNTB of 5 (95% CI 2 to 20). There are no additional harms in terms of adverse events (diarrhoea, nausea or vomiting) with low-dose colchicine compared to placebo (19/74 and 6/29 respectively (RR 1.24, 95% CI 0.55 to 2.79)).Based upon data from one trial (126 participants), there is low-quality evidence that there are no additional benefits in terms of the proportion of people achieving 50% or greater decrease in pain from baseline up to 32 to 36 hours with high-dose colchicine compared to low-dose (19/52 and 31/74 respectively (RR 0.87, 95% CI 0.56 to 1.36). However, there were statistically significantly more adverse events in those who received high-dose colchicine (40/52 versus 19/74 in the low-dose group (RR 3.00, 95% CI 1.98 to 4.54)), with a NNTH of 2 (95% CI 2 to 3).No trials reported function of the target joint, patient-reported global assessment of treatment success, health-related quality of life or withdrawals due to adverse events. We identified no studies comparing colchicine to non-steroidal anti-inflammatory drugs (NSAIDs) or other active treatments such as glucocorticoids (by any route). Based upon only two published trials, there is low-quality evidence that low-dose colchicine is likely to be an effective treatment for acute gout. We downgraded the evidence because of a possible risk of selection and reporting biases and imprecision. Both high and low-dose colchicine improve pain when compared to placebo. While there is some uncertainty around the effect estimates, compared with placebo, high-dose but not low-dose colchicine appears to result in a statistically significantly greater number of adverse events. Therefore low-dose colchicine may be the preferred treatment option. There are no trials about the effect of colchicine in populations with comorbidities or in comparison with other commonly used treatments, such as NSAIDs and glucocorticoids.

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No cure for rheumatoid arthritis (RA) is known at present, so treatment often focuses on management of symptoms such as pain, stiffness and mobility. Treatment options include pharmacological interventions, physical therapy treatments and balneotherapy. Balneotherapy is defined as bathing in natural mineral or thermal waters (e.g. mineral baths, sulphur baths, Dead Sea baths), using mudpacks or doing both. Despite its popularity, reported scientific evidence for the effectiveness or efficacy of balneotherapy is sparse. This review, which evaluates the effects of balneotherapy in patients with RA, is an update of a Cochrane review first published in 2003 and updated in 2008. To perform a systematic review on the benefits and harms of balneotherapy in patients with RA in terms of pain, improvement, disability, tender joints, swollen joints and adverse events. We searched the Cochrane 'Rehabilitation and Related Therapies' Field Register (to December 2014), the Cochrane Central Register of Controlled Trials (2014, Issue 1), MEDLIINE (1950 to December 2014), EMBASE (1988 to December 2014), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to December 2014), the Allied and Complementary Medicine Database (AMED) (1985 to December 2014), PsycINFO (1806 to December 2014) and the Physiotherapy Evidence Database (PEDro). We applied no language restrictions; however, studies not reported in English, Dutch, Danish, Swedish, Norwegian, German or French are awaiting assessment. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing and recently completed trials. Studies were eligible if they were randomised controlled trials (RCTs) consisting of participants with definitive or classical RA as defined by the American Rheumatism Association (ARA) criteria of 1958, the ARA/American College of Rheumatology (ACR) criteria of 1988 or the ACR/European League Against Rheumatism (EULAR) criteria of 2010, or by studies using the criteria of Steinbrocker.Balneotherapy had to be the intervention under study, and had to be compared with another intervention or with no intervention.The World Health Organization (WHO) and the International League Against Rheumatism (ILAR) determined in 1992 a core set of eight endpoints in clinical trials concerning patients with RA. We considered pain, improvement, disability, tender joints, swollen joints and adverse events among the main outcome measures. We excluded studies when only laboratory variables were reported as outcome measures. Two review authors independently selected trials, performed data extraction and assessed risk of bias. We resolved disagreements by consensus and, if necessary, by third party adjudication. This review includes two new studies and a total of nine studies involving 579 participants. Unfortunately, most studies showed an unclear risk of bias in most domains. Four out of nine studies did not contribute to the analysis, as they presented no data.One study involving 45 participants with hand RA compared mudpacks versus placebo. We found no statistically significant differences in terms of pain on a 0 to 100-mm visual analogue scale (VAS) (mean difference (MD) 0.50, 95% confidence interval (CI) -0.84 to 1.84), improvement (risk ratio (RR) 0.96, 95% CI 0.54 to 1.70) or number of swollen joints on a scale from 0 to 28 (MD 0.60, 95% CI -0.90 to 2.10) (very low level of evidence). We found a very low level of evidence of reduction in the number of tender joints on a scale from 0 to 28 (MD -4.60, 95% CI -8.72 to -0.48; 16% absolute difference). We reported no physical disability and presented no data on withdrawals due to adverse events or on serious adverse events.Two studies involving 194 participants with RA evaluated the effectiveness of additional radon in carbon dioxide baths. We found no statistically significant differences between groups for all outcomes at three-month follow-up (low to moderate level of evidence). We noted some benefit of additional radon at six months in terms of pain frequency (RR 0.6, 95% CI 0.4 to 0.9; 31% reduction; improvement in one or more points (categories) on a 4-point scale; moderate level of evidence) and 9.6% reduction in pain intensity on a 0 to 100-mm VAS (MD 9.6 mm, 95% CI 1.6 to 17.6; moderate level of evidence). We also observed some benefit in one study including 60 participants in terms of improvement in one or more categories based on a 4-point scale (RR 2.3, 95% CI 1.1 to 4.7; 30% absolute difference; low level of evidence). Study authors did not report physical disability, tender joints, swollen joints, withdrawals due to adverse events or serious adverse events.One study involving 148 participants with RA compared balneotherapy (seated immersion) versus hydrotherapy (exercises in water), land exercises or relaxation therapy. We found no statistically significant differences in pain on the McGill Questionnaire or in physical disability (very low level of evidence) between balneotherapy and the other interventions. No data on improvement, tender joints, swollen joints, withdrawals due to adverse events or serious adverse events were presented.One study involving 57 participants with RA evaluated the effectiveness of mineral baths (balneotherapy) versus Cyclosporin A. We found no statistically significant differences in pain intensity on a 0 to 100-mm VAS (MD 9.64, 95% CI -1.66 to 20.94; low level of evidence) at 8 weeks (absolute difference 10%). We found some benefit of balneotherapy in overall improvement on a 5-point scale at eight weeks of 54% (RR 2.35, 95% CI 1.44 to 3.83). We found no statistically significant differences (low level of evidence) in the number of swollen joints, but some benefit of Cyclosporin A in the number of tender joints (MD 8.9, 95% CI 3.8 to 14; very low level of evidence). Physical disability, withdrawals due to adverse events and serious adverse events were not reported. Overall evidence is insufficient to show that balneotherapy is more effective than no treatment, that one type of bath is more effective than another or that one type of bath is more effective than mudpacks, exercise or relaxation therapy.

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In this paper, we provide background and context regarding the potential for a new data-sharing platform, the Project Data Sphere (PDS) initiative, funded by financial and in-kind contributions from the CEO Roundtable on Cancer, to transform cancer research and improve patient outcomes. Given the relatively modest decline in cancer death rates over the past several years, a new research paradigm is needed to accelerate therapeutic approaches for oncologic diseases. Phase III clinical trials generate large volumes of potentially usable information, often on hundreds of patients, including patients treated with standard of care therapies (i.e., controls). Both nationally and internationally, a variety of stakeholders have pursued data-sharing efforts to make individual patient-level clinical trial data available to the scientific research community. For researchers, shared data have the potential to foster a more collaborative environment, to answer research questions in a shorter time frame than traditional randomized control trials, to reduce duplication of effort, and to improve efficiency. For industry participants, use of trial data to answer additional clinical questions could increase research and development efficiency and guide future projects through validation of surrogate end points, development of prognostic or predictive models, selection of patients for phase II trials, stratification in phase III studies, and identification of patient subgroups for development of novel therapies. Data transparency also helps promote a public image of collaboration and altruism among industry participants. For patient participants, data sharing maximizes their contribution to public health and increases access to information that may be used to develop better treatments. Concerns about data-sharing efforts include protection of patient privacy and confidentiality. To alleviate these concerns, data sets are deidentified to maintain anonymity. To address industry concerns about protection of intellectual property and competitiveness, we illustrate several models for data sharing with varying levels of access to the data and varying relationships between trial sponsors and data access sponsors. PDS is an independent initiative of the CEO Roundtable on Cancer Life Sciences Consortium, built to voluntarily share, integrate, and analyze comparator arms of historical cancer clinical trial data sets to advance future cancer research. The aim is to provide a neutral, broad-access platform for industry and academia to share raw, deidentified data from late-phase oncology clinical trials using comparator-arm data sets. These data are likely to be hypothesis generating or hypothesis confirming but, notably, do not take the place of performing a well-designed trial to address a specific hypothesis. Prospective providers of data to PDS complete and sign a data sharing agreement that includes a description of the data they propose to upload, and then they follow easy instructions on the website for uploading their deidentified data. The SAS Institute has also collaborated with the initiative to provide intrinsic analytic tools accessible within the website itself. As of October 2014, the PDS website has available data from 14 cancer clinical trials covering 9,000 subjects, with hopes to further expand the database to include more than 25,000 subject accruals within the next year. PDS differentiates itself from other data-sharing initiatives by its degree of openness, requiring submission of only a brief application with background information of the individual requesting access and agreement to terms of use. Data from several different sponsors may be pooled to develop a comprehensive cohort for analysis. In order to protect patient privacy, data providers in the U.S. are responsible for deidentifying data according to standards set forth by the Privacy Rule of the U.S. Health Insurance Portability and Accountability Act of 1996. USING DATA SHARING TO IMPROVE OUTCOMES IN CANCER THE "PROSTATE CANCER CHALLENGE": Control-arm data of several studies among patients with metastatic castration-resistant prostate cancer (mCRPC) are currently available through PDS. These data sets have multiple potential uses. The "Prostate Cancer Challenge" will ask the cancer research community to use clinical trial data deposited in the PDS website to address key research questions regarding mCRPC. General themes that could be explored by the cancer community are described in this article: prognostic models evaluating the influence of pretreatment factors on survival and patient-reported outcomes; comparative effectiveness research evaluating the efficacy of standard of care therapies, as illustrated in our companion article comparing mitoxantrone plus prednisone with prednisone alone; effects of practice variation in dose, frequency, and duration of therapy; level of patient adherence to elements of trial protocols to inform the design of future clinical trials; and age of subjects, regional differences in health care, and other confounding factors that might affect outcomes. The number of data sets available and the lack of experimental-arm data limit the potential scope of research using the current PDS. The number of trials is expected to grow exponentially over the next year and may include multiple cancer settings, such as breast, colorectal, lung, hematologic malignancy, and bone marrow transplantation. Other potential limitations include the retrospective nature of the data analyses performed using PDS and its generalizability, given that clinical trials are often conducted among younger, healthier, and less racially diverse patient populations. Methodological challenges exist when combining individual patient data from multiple clinical trials; however, advancements in statistical methods for secondary database analysis offer many tools for reanalyzing data arising from disparate trials, such as propensity score matching. Despite these concerns, few if any comparable data sets include this level of detail across multiple clinical trials and populations. Access to large, late-phase, cancer-trial data sets has the potential to transform cancer research by optimizing research efficiency and accelerating progress toward meaningful improvements in cancer care. This type of platform provides opportunities for unique research projects that can examine relatively neglected areas and that can construct models necessitating large amounts of detailed data. The full potential of PDS will be realized only when multiple tumor types and larger numbers of data sets are available through the website.

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Progesterone prepares the endometrium for pregnancy by stimulating proliferation in response to human chorionic gonadotropin(hCG) produced by the corpus luteum. This occurs in the luteal phase of the menstrual cycle. In assisted reproduction techniques(ART), progesterone and/or hCG levels are low, so the luteal phase is supported with progesterone, hCG or gonadotropin-releasing hormone (GnRH) agonists to improve implantation and pregnancy rates. To determine the relative effectiveness and safety of methods of luteal phase support provided to subfertile women undergoing assisted reproduction. We searched databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and trial registers. We conducted searches in November 2014, and further searches on 4 August 2015. Randomised controlled trials (RCTs) of luteal phase support using progesterone, hCG or GnRH agonist supplementation in ART cycles. Three review authors independently selected trials, extracted data and assessed risk of bias. We calculated odds ratios (ORs) and 95%confidence intervals (CIs) for each comparison and combined data when appropriate using a fixed-effect model. Our primary out come was live birth or ongoing pregnancy. The overall quality of the evidence was assessed using GRADE methods. Ninety-four women RCTs (26,198 women) were included. Most studies had unclear or high risk of bias in most domains. The main limitations in the evidence were poor reporting of study methods and imprecision due to small sample sizes.1. hCG vs placebo/no treatment (five RCTs, 746 women)There was no evidence of differences between groups in live birth or ongoing pregnancy (OR 1.67, 95% CI 0.90 to 3.12, three RCTs,527 women, I2 = 24%, very low-quality evidence, but I2 of 61% was found for the subgroup of ongoing pregnancy) with a random effects model. hCG increased the risk of ovarian hyperstimulation syndrome (OHSS) (1 RCT, OR 4.28, 95% CI 1.91 to 9.6, low quality evidence).2. Progesterone vs placebo/no treatment (eight RCTs, 875 women)Evidence suggests a higher rate of live birth or ongoing pregnancy in the progesterone group (OR 1.77, 95% CI 1.09 to 2.86, five RCTs, 642 women, I2 = 35%, very low-quality evidence). OHSS was not reported.3. Progesterone vs hCG regimens (16 RCTs, 2162 women)hCG regimens included comparisons of progesterone versus hCG and progesterone versus progesterone + hCG. No evidence showed differences between groups in live birth or ongoing pregnancy (OR 0.95, 95% CI 0.65 to 1.38, five RCTs, 833 women, I2 = 0%, low quality evidence) or in the risk of OHSS (four RCTs, 615 women, progesterone vs hCG OR 0.54, 95% CI 0.22 to 1.34; four RCTs,678 women; progesterone vs progesterone plus hCG, OR 0.34, 95% CI 0.09 to 1.26, low-quality evidence).4. Progesterone vs progesterone with oestrogen (16 RCTs, 2577 women)No evidence was found of differences between groups in live birth or ongoing pregnancy (OR 1.12, 95% CI 0.91 to 1.38, nine RCTs,1651 women, I2 = 0%, low-quality evidence) or OHSS (OR 0.56, 95% CI 0.2 to 1.63, two RCTs, 461 women, I2 = 0%, low-quality evidence).5. Progesterone vs progesterone + GnRH agonist (seven RCTs, 1708 women)Live birth or ongoing pregnancy rates were lower in the progesterone-only group and increased in women who received progester one and one or more GnRH agonist doses (OR 0.62, 95% CI 0.48 to 0.81, nine RCTs, 2861 women, I2 = 55%, random effects, low quality evidence). Statistical heterogeneity for this comparison was high because of unexplained variation in the effect size, but the direction of effect was consistent across studies. OHSS was reported in one study only (OR 1.00, 95% CI 0.33 to 3.01, 1 RCT, 300 women, very low quality evidence).6. Progesterone regimens (45 RCTs, 13,814 women)The included studies reported nine different comparisons between progesterone regimens. Findings for live birth or ongoing pregnancy were as follows: intramuscular (IM) versus oral: OR 0.71, 95% CI 0.14 to 3.66 (one RCT, 40 women, very low-quality evidence);IM versus vaginal/rectal: OR 1.24, 95% CI 1.03 to 1.5 (seven RCTs, 2309 women, I2 = 71%, very low-quality evidence); vaginal/rectal versus oral: OR 1.19, 95% CI 0.83 to 1.69 (four RCTs, 857 women, I2 = 32%, low-quality evidence); low-dose versus high-dose vaginal: OR 0.97, 95% CI 0.84 to 1.11 (five RCTs, 3720 women, I2 = 0%, moderate-quality evidence); short versus long protocol:OR 1.04, 95% CI 0.79 to 1.36 (five RCTs, 1205 women, I2 = 0%, low-quality evidence); micronised versus synthetic: OR 0.9, 95%CI 0.53 to 1.55 (two RCTs, 470 women, I2 = 0%, low-quality evidence); vaginal ring versus gel: OR 1.09, 95% CI 0.88 to 1.36 (oneRCT, 1271 women, low-quality evidence); subcutaneous versus vaginal gel: OR 0.92, 95% CI 0.74 to 1.14 (two RCTs, 1465 women,I2 = 0%, low-quality evidence); and vaginal versus rectal: OR 1.28, 95% CI 0.64 to 2.54 (one RCT, 147 women, very low-quality evidence). OHSS rates were reported for only two of these comparisons: IM versus oral, and low versus high-dose vaginal. No evidence showed a difference between groups.7. Progesterone and oestrogen regimens (two RCTs, 1195 women)The included studies compared two different oestrogen protocols. No evidence was found to suggest differences in live birth or ongoing pregnancy rates between a short and a long protocol (OR 1.08, 95% CI 0.81 to 1.43, one RCT, 910 women, low-quality evidence) or between a low dose and a high dose of oestrogen (OR 0.65, 95% CI 0.37 to 1.13, one RCT, 285 women, very low-quality evidence).Neither study reported OHSS. Both progesterone and hCG during the luteal phase are associated with higher rates of live birth or ongoing pregnancy than placebo.The addition of GnRHa to progesterone is associated with an improvement in pregnancy outcomes. OHSS rates are increased with hCG compared to placebo (only study only). The addition of oestrogen does not seem to improve outcomes. The route of progester one administration is not associated with an improvement in outcomes.

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Fracture of the proximal humerus, often termed shoulder fracture, is a common injury in older people. The management of these fractures varies widely. This is an update of a Cochrane Review first published in 2001 and last updated in 2012. To assess the effects (benefits and harms) of treatment and rehabilitation interventions for proximal humeral fractures in adults. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and other databases, conference proceedings and bibliographies of trial reports. The full search ended in November 2014. We considered all randomised controlled trials (RCTs) and quasi-randomised controlled trials pertinent to the management of proximal humeral fractures in adults. Both review authors performed independent study selection, risk of bias assessment and data extraction. Only limited meta-analysis was performed. We included 31 heterogeneous RCTs (1941 participants). Most of the 18 separate treatment comparisons were tested by small single-centre trials. The main exception was the surgical versus non-surgical treatment comparison tested by eight trials. Except for a large multicentre trial, bias in these trials could not be ruled out. The quality of the evidence was either low or very low for all comparisons except the largest comparison.Nine trials evaluated non-surgical treatment in mainly minimally displaced fractures. Four trials compared early (usually one week) versus delayed (three or four weeks) mobilisation after fracture but only limited pooling was possible and most of the data were from one trial (86 participants). This found some evidence that early mobilisation resulted in better recovery and less pain in people with mainly minimally displaced fractures. There was evidence of little difference between the two groups in shoulder complications (2/127 early mobilisation versus 3/132 delayed mobilisation; 4 trials) and fracture displacement and non-union (2/52 versus 1/54; 2 trials).One quasi-randomised trial (28 participants) found the Gilchrist-type sling was generally more comfortable than the Desault-type sling (body bandage). One trial (48 participants) testing pulsed electromagnetic high-frequency energy provided no evidence. Two trials (62 participants) provided evidence indicating little difference in outcome between instruction for home exercises versus supervised physiotherapy. One trial (48 participants) reported, without presentable data, that home exercise alone gave better early and comparable long-term results than supervised exercise in a swimming pool plus home exercise.Eight trials, involving 567 older participants, evaluated surgical intervention for displaced fractures. There was high quality evidence of no clinically important difference in patient-reported shoulder and upper-limb function at one- or two-year follow-up between surgical (primarily locking plate fixation or hemiarthroplasty) and non-surgical treatment (sling immobilisation) for the majority of displaced proximal humeral fractures; and moderate quality evidence of no clinically important difference between the two groups in quality of life at two years (and at interim follow-ups at six and 12 months). There was moderate quality evidence of little difference between groups in mortality in the surgery group (17/248 versus 12/248; risk ratio (RR) 1.40 favouring non-surgical treatment, 95% confidence interval (CI) 0.69 to 2.83; P = 0.35; 6 trials); only one death was explicitly linked with the treatment. There was moderate quality evidence of a higher risk of additional surgery in the surgery group (34/262 versus 16/261; RR 2.06, 95% CI 1.18 to 3.60; P = 0.01; 7 trials). Although there was moderate evidence of a higher risk of adverse events after surgery, the 95% confidence intervals for adverse events also included the potential for a greater risk of adverse events after non-surgical treatment.Different methods of surgical management were tested in 12 trials. One trial (57 participants) comparing two types of locking plate versus a locking nail for treating two-part surgical neck fractures found some evidence of slightly better function after plate fixation but also of a higher rate of surgically-related complications. One trial (61 participants) comparing a locking plate versus minimally invasive fixation with distally inserted intramedullary K-wires found little difference between the two implants at two years. Compared with hemiarthroplasty, one trial (32 participants) found similar results with locking plate fixation in function and re-operation rates, whereas another trial (30 participants) reported all five re-operations occurred in the tension-band fixation group. One trial (62 participants) found better patient-rated (Quick DASH) and composite shoulder function scores at a minimum of two years follow-up and a lower incidence of re-operation and complications after reverse shoulder arthroplasty (RSA) compared with hemiarthroplasty.No important between-group differences were found in one trial (120 participants) comparing the deltoid-split approach versus deltopectoral approach for non-contact bridging plate fixation, and two trials (180 participants) comparing 'polyaxial' and 'monaxial' screws in locking plate fixation. One trial (68 participants) produced some preliminary evidence that tended to support the use of medial support locking screws in locking plate fixation. One trial (54 participants) found fewer adverse events, including re-operations, for the newer of two types of intramedullary nail. One trial (35 participants) found better functional results for one of two types of hemiarthroplasty. One trial (45 participants) found no important effects of tenodesis of the long head of the biceps for people undergoing hemiarthroplasty.Very limited evidence suggested similar outcomes from early versus later mobilisation after either surgical fixation (one trial: 64 participants) or hemiarthroplasty (one trial: 49 participants). There is high or moderate quality evidence that, compared with non-surgical treatment, surgery does not result in a better outcome at one and two years after injury for people with displaced proximal humeral fractures involving the humeral neck and is likely to result in a greater need for subsequent surgery. The evidence does not cover the treatment of two-part tuberosity fractures, fractures in young people, high energy trauma, nor the less common fractures such as fracture dislocations and head splitting fractures.There is insufficient evidence from RCTs to inform the choices between different non-surgical, surgical, or rehabilitation interventions for these fractures.

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Tinea capitis is a common contagious fungal infection of the scalp in children. Systemic therapy is required for treatment and to prevent spread. This is an update of the original Cochrane review. To assess the effects of systemic antifungal drugs for tinea capitis in children. We updated our searches of the following databases to November 2015: the Cochrane Skin Group Specialised Register, CENTRAL (2015, Issue 10), MEDLINE (from 1946), EMBASE (from 1974), LILACS (from 1982), and CINAHL (from 1981). We searched five trial registers and checked the reference lists of studies for references to relevant randomised controlled trials (RCTs). We obtained unpublished, ongoing trials and grey literature via correspondence with experts in the field and from pharmaceutical companies. RCTs of systemic antifungal therapy in children with normal immunity under the age of 18 with tinea capitis confirmed by microscopy, growth of fungi (dermatophytes) in culture or both. We used standard methodological procedures expected by Cochrane. We included 25 studies (N = 4449); 4 studies (N = 2637) were new to this update.Terbinafine for four weeks and griseofulvin for eight weeks showed similar efficacy for the primary outcome of complete (i.e. clinical and mycological) cure in three studies involving 328 participants with Trichophyton species infections (84.2% versus 79.0%; risk ratio (RR) 1.06, 95% confidence interval (CI) 0.98 to 1.15; low quality evidence).Complete cure with itraconazole (two to six weeks) and griseofulvin (six weeks) was similar in two studies (83.6% versus 91.0%; RR 0.92, 95% CI 0.81 to 1.05; N = 134; very low quality evidence). In two studies, there was no difference between itraconazole and terbinafine for two to three weeks treatment (73.8% versus 78.8%; RR 0.93, 95% CI 0.72 to 1.19; N = 160; low quality evidence). In three studies, there was a similar proportion achieving complete cured with two to four weeks of fluconazole or six weeks of griseofulvin (41.4% versus 52.7%; RR 0.92, 95% CI 0.81 to 1.05; N = 615; moderate quality evidence). Current evidence for ketoconazole versus griseofulvin was limited. One study favoured griseofulvin (12 weeks) because ketoconazole (12 weeks) appeared less effective for complete cure (RR 0.76, 95% CI 0.62 to 0.94; low quality evidence). However, their effects appeared to be similar when the treatment lasted 26 weeks (RR 0.95, 95% CI 0.83 to 1.07; low quality evidence). Another study indicated that complete cure was similar for ketoconazole (12 weeks) and griseofulvin (12 weeks) (RR 0.89, 95% CI 0.57 to 1.39; low quality evidence). For one trial, there was no significant difference for complete cure between fluconazole (for two to three weeks) and terbinafine (for two to three weeks) (82.0% versus 94.0%; RR 0.87, 95% CI 0.75 to 1.01; N = 100; low quality evidence). For complete cure, we did not find a significant difference between fluconazole (for two to three weeks) and itraconazole (for two to three weeks) (82.0% versus 82.0%; RR 1.00, 95% CI 0.83 to 1.20; low quality evidence).This update provides new data: in children with Microsporum infections, a meta-analysis of two studies found that the complete cure was lower for terbinafine (6 weeks) than for griseofulvin (6-12 weeks) (34.7% versus 50.9%; RR 0.68, 95% CI 0.53 to 0.86; N = 334; moderate quality evidence). In the original review, there was no significant difference in complete cure between terbinafine (four weeks) and griseofulvin (eight weeks) in children with Microsporum infections in one small study (27.2% versus 60.0%; RR 0.45, 95% CI 0.15 to 1.35; N = 21; low quality evidence).One study provides new evidence that terbinafine and griseofulvin for six weeks show similar efficacy (49.5% versus 37.8%; RR 1.18, 95% CI 0.74 to 1.88; N = 1006; low quality evidence). However, in children infected with T. tonsurans, terbinafine was better than griseofulvin (52.1% versus 35.4%; RR 1.47, 95% CI 1.22 to 1.77; moderate quality evidence). For children infected with T. violaceum, these two regimens have similar effects (41.3% versus 45.1%; RR 0.91, 95% CI 0.68 to 1.24; low quality evidence). Additionally, three weeks of fluconazole was similar to six weeks of fluconazole in one study in 491 participants infected with T. tonsurans and M. canis (30.2% versus 34.1%; RR 0.88, 95% CI 0.68 to 1.14; low quality evidence).The frequency of adverse events attributed to the study drugs was similar for terbinafine and griseofulvin (9.2% versus 8.3%; RR 1.11, 95% CI 0.79 to 1.57; moderate quality evidence), and severe adverse events were rare (0.6% versus 0.6%; RR 0.97, 95% CI 0.24 to 3.88; moderate quality evidence). Adverse events for terbinafine, griseofulvin, itraconazole, ketoconazole, and fluconazole were all mild and reversible.All of the included studies were at either high or unclear risk of bias in at least one domain. Using GRADE to rate the overall quality of the evidence, lower quality evidence resulted in lower confidence in the estimate of effect. Newer treatments including terbinafine, itraconazole and fluconazole are at least similar to griseofulvin in children with tinea capitis caused by Trichophyton species. Limited evidence suggests that terbinafine, itraconazole and fluconazole have similar effects, whereas ketoconazole may be less effective than griseofulvin in children infected with Trichophyton. With some interventions the proportion achieving complete clinical cure was in excess of 90% (e.g. one study of terbinafine or griseofulvin for Trichophyton infections), but in many of the comparisons tested, the proportion cured was much lower.New evidence from this update suggests that terbinafine is more effective than griseofulvin in children with T. tonsurans infection.However, in children with Microsporum infections, new evidence suggests that the effect of griseofulvin is better than terbinafine. We did not find any evidence to support a difference in terms of adherence between four weeks of terbinafine versus eight weeks of griseofulvin. Not all treatments for tinea capitis are available in paediatric formulations but all have reasonable safety profiles.

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The combination of steroid and anti-vascular endothelial growth factor (VEGF) intravitreal therapeutic agents could potentially have synergistic effects for treating diabetic macular oedema (DMO). On the one hand, if combined treatment is more effective than monotherapy, there would be significant implications for improving patient outcomes. Conversely, if there is no added benefit of combination therapy, then people could be potentially exposed to unnecessary local or systemic side effects. To assess the effects of intravitreal agents that block vascular endothelial growth factor activity (anti-VEGF agents) plus intravitreal steroids versus monotherapy with macular laser, intravitreal steroids or intravitreal anti-VEGF agents for managing DMO. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 1); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 21 February 2018. We included randomised controlled trials (RCTs) of intravitreal anti-VEGF combined with intravitreal steroids versus intravitreal anti-VEGF alone, intravitreal steroids alone or macular laser alone for managing DMO. We included people with DMO of all ages and both sexes. We also included trials where both eyes from one participant received different treatments. We used standard methodological procedures recommended by Cochrane.Two authors independently reviewed all the titles and abstracts identified from the electronic and manual searches against the inclusion criteria. Our primary outcome was change in best corrected visual acuity (BCVA) between baseline and one year. Secondary outcomes included change in central macular thickness (CMT), economic data and quality of life. We considered adverse effects including intraocular inflammation, raised intraocular pressure (IOP) and development of cataract. There were eight RCTs (703 participants, 817 eyes) that met our inclusion criteria with only three studies reporting outcomes at one year. The studies took place in Iran (3), USA (2), Brazil (1), Czech Republic (1) and South Korea (1). Seven studies used the unlicensed anti-VEGF agent bevacizumab and one study used licensed ranibizumab. The study that used licensed ranibizumab had a unique design compared with the other studies in that included eyes had persisting DMO after anti-VEGF monotherapy and received three monthly doses of ranibizumab prior to allocation. The anti-VEGF agent was combined with intravitreal triamcinolone in six studies and with an intravitreal dexamethasone implant in two studies. The comparator group was anti-VEGF alone in all studies; two studies had an additional steroid monotherapy arm, another study had an additional macular laser photocoagulation arm. Whilst we judged these studies to be at low risk of bias for most domains, at least one domain was at unclear risk in all studies.When comparing anti-VEGF/steroid with anti-VEGF monotherapy as primary therapy for DMO, we found no meaningful clinical difference in change in BCVA (mean difference (MD) -2.29 visual acuity (VA) letters, 95% confidence interval (CI) -6.03 to 1.45; 3 RCTs; 188 eyes; low-certainty evidence) or change in CMT (MD 0.20 μm, 95% CI -37.14 to 37.53; 3 RCTs; 188 eyes; low-certainty evidence) at one year. There was very low-certainty evidence on intraocular inflammation from 8 studies, with one event in the anti-VEGF/steroid group (313 eyes) and two events in the anti-VEGF group (322 eyes). There was a greater risk of raised IOP (Peto odds ratio (OR) 8.13, 95% CI 4.67 to 14.16; 635 eyes; 8 RCTs; moderate-certainty evidence) and development of cataract (Peto OR 7.49, 95% CI 2.87 to 19.60; 635 eyes; 8 RCTs; moderate-certainty evidence) in eyes receiving anti-VEGF/steroid compared with anti-VEGF monotherapy. There was low-certainty evidence from one study of an increased risk of systemic adverse events in the anti-VEGF/steroid group compared with the anti-VEGF alone group (Peto OR 1.32, 95% CI 0.61 to 2.86; 103 eyes).One study compared anti-VEGF/steroid versus macular laser therapy. At one year investigators did not report a meaningful difference between the groups in change in BCVA (MD 4.00 VA letters 95% CI -2.70 to 10.70; 80 eyes; low-certainty evidence) or change in CMT (MD -16.00 μm, 95% CI -68.93 to 36.93; 80 eyes; low-certainty evidence). There was very low-certainty evidence suggesting an increased risk of cataract in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 4.58, 95% 0.99 to 21.10, 100 eyes) and an increased risk of elevated IOP in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 9.49, 95% CI 2.86 to 31.51; 100 eyes).One study provided very low-certainty evidence comparing anti-VEGF/steroid versus steroid monotherapy at one year. There was no evidence of a meaningful difference in BCVA between treatments at one year (MD 0 VA letters, 95% CI -6.1 to 6.1, low-certainty evidence). Likewise, there was no meaningful difference in the mean CMT at one year (MD - 9 μm, 95% CI -39.87μm to 21.87μm between the anti-VEGF/steroid group and the steroid group. There was very low-certainty evidence on raised IOP at one year comparing the anti-VEGF/steroid versus steroid groups (Peto OR 0.75, 95% CI 0.16 to 3.55).No included study reported impact of treatment on patients' quality of life or economic data. None of the studies reported any cases of endophthalmitis. Combination of intravitreal anti-VEGF plus intravitreal steroids does not appear to offer additional visual benefit compared with monotherapy for DMO; at present the evidence for this is of low-certainty. There was an increased rate of cataract development and raised intraocular pressure in eyes treated with anti-VEGF plus steroid versus anti-VEGF alone. Patients were exposed to potential side effects of both these agents without reported additional benefit. The majority of the evidence comes from studies of bevacizumab and triamcinolone used as primary therapy for DMO. There is limited evidence from studies using licensed intravitreal anti-VEGF agents plus licensed intravitreal steroid implants with at least one year follow-up. It is not known whether treatment response is different in eyes that are phakic and pseudophakic at baseline.

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The use of surgical drains has been considered mandatory after pancreatic surgery. The role of prophylactic abdominal drainage to reduce postoperative complications after pancreatic surgery is controversial. To assess the benefits and harms of routine abdominal drainage after pancreatic surgery, compare the effects of different types of surgical drains, and evaluate the optimal time for drain removal. For the last version of this review, we searched CENTRAL (2016, Issue 8), and MEDLINE, Embase, Science Citation Index Expanded, and Chinese Biomedical Literature Database (CBM) to 28 August 2016). For this updated review, we searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and CBM from 2016 to 15 November 2017. We included all randomized controlled trials that compared abdominal drainage versus no drainage in people undergoing pancreatic surgery. We also included randomized controlled studies that compared different types of drains and different schedules for drain removal in people undergoing pancreatic surgery. We identified six studies (1384 participants). Two review authors independently identified the studies for inclusion, collected the data, and assessed the risk of bias. We performed the meta-analyses using Review Manager 5. We calculated the risk ratio (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). For all analyses, we used the random-effects model. Drain use versus no drain useWe included four studies with 1110 participants, who were randomized to the drainage group (N = 560) and the no drainage group (N = 550) after pancreatic surgery. There was little or no difference in mortality at 30 days between groups (1.5% with drains versus 2.3% with no drains; RR 0.78, 95% CI 0.31 to 1.99; four studies, 1055 participants; moderate-quality evidence). Drain use probably slightly reduced mortality at 90 days (0.8% versus 4.2%; RR 0.23, 95% CI 0.06 to 0.90; two studies, 478 participants; moderate-quality evidence). We were uncertain whether drain use reduced intra-abdominal infection (7.9% versus 8.2%; RR 0.97, 95% CI 0.52 to 1.80; four studies, 1055 participants; very low-quality evidence), or additional radiological interventions for postoperative complications (10.9% versus 12.1%; RR 0.87, 95% CI 0.79 to 2.23; three studies, 660 participants; very low-quality evidence). Drain use may lead to similar amount of wound infection (9.8% versus 9.9%; RR 0.98 , 95% CI 0.68 to 1.41; four studies, 1055 participants; low-quality evidence), and additional open procedures for postoperative complications (9.4% versus 7.1%; RR 1.33, 95% CI 0.79 to 2.23; four studies, 1055 participants; low-quality evidence) when compared with no drain use. There was little or no difference in morbidity (61.7% versus 59.7%; RR 1.03, 95% CI 0.94 to 1.13; four studies, 1055 participants; moderate-quality evidence), or length of hospital stay (MD -0.66 days, 95% CI -1.60 to 0.29; three studies, 711 participants; moderate-quality evidence) between groups. There was one drain-related complication in the drainage group (0.2%). Health-related quality of life was measured with the pancreas-specific quality-of-life questionnaire (FACT-PA; a scale of 0 to 144 with higher values indicating a better quality of life). Drain use may lead to similar quality of life scores, measured at 30 days after pancreatic surgery, when compared with no drain use (105 points versus 104 points; one study, 399 participants; low-quality evidence). Hospital costs and pain were not reported in any of the studies.Type of drainWe included one trial involving 160 participants, who were randomized to the active drain group (N = 82) and the passive drain group (N = 78) after pancreatic surgery. An active drain may lead to similar mortality at 30 days (1.2% with active drain versus 0% with passive drain; low-quality evidence), and morbidity (22.0% versus 32.1%; RR 0.68, 95% CI 0.41 to 1.15; low-quality evidence) when compared with a passive drain. We were uncertain whether an active drain decreased intra-abdominal infection (0% versus 2.6%; very low-quality evidence), wound infection (6.1% versus 9.0%; RR 0.68, 95% CI 0.23 to 2.05; very low-quality evidence), or the number of additional open procedures for postoperative complications (1.2% versus 7.7%; RR 0.16, 95% CI 0.02 to 1.29; very low-quality evidence). Active drain may reduce length of hospital stay slightly (MD -1.90 days, 95% CI -3.67 to -0.13; one study; low-quality evidence; 14.1% decrease of an 'average' length of hospital stay). Additional radiological interventions, pain, and quality of life were not reported in the study.Early versus late drain removalWe included one trial involving 114 participants with a low risk of postoperative pancreatic fistula, who were randomized to the early drain removal group (N = 57) and the late drain removal group (N = 57) after pancreatic surgery. There was no mortality in either group. Early drain removal may slightly reduce morbidity (38.6% with early drain removal versus 61.4% with late drain removal; RR 0.63, 95% CI 0.43 to 0.93; low-quality evidence), length of hospital stay (MD -2.10 days, 95% CI -4.17 to -0.03; low-quality evidence; 21.5% decrease of an 'average' length of hospital stay), and hospital costs (MD -EUR 2069.00, 95% CI -3872.26 to -265.74; low-quality evidence; 17.0% decrease of 'average' hospital costs). We were uncertain whether early drain removal reduced additional open procedures for postoperative complications (0% versus 1.8%; RR 0.33, 95% CI 0.01 to 8.01; one study; very low-quality evidence). Intra-abdominal infection, wound infection, additional radiological interventions, pain, and quality of life were not reported in the study. It was unclear whether routine abdominal drainage had any effect on the reduction of mortality at 30 days, or postoperative complications after pancreatic surgery. Moderate-quality evidence suggested that routine abdominal drainage probably slightly reduced mortality at 90 days. Low-quality evidence suggested that use of an active drain compared to the use of a passive drain may slightly reduce the length of hospital stay after pancreatic surgery, and early removal may be superior to late removal for people with low risk of postoperative pancreatic fistula.

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Studies report that up to 80% of individuals with chronic obstructive pulmonary disease (COPD) may struggle with symptoms of depression. However, this major comorbidity in COPD is rarely managed effectively. A number of recent studies indicate that left untreated, COPD-related depression is associated with worse quality of life, worse compliance with COPD treatment plan, increased exacerbations, hospital admissions, and healthcare costs when compared to individuals with COPD without depression. Regrettably, COPD practice guidelines do not provide conclusive treatment recommendations for the use of antidepressants in patients with COPD, and base their guidelines on findings from trials in the general population. This may be problematic, as there is an elevated risk of respiratory issues associated with antidepressant treatment and COPD. Evaluating effectiveness and safety of pharmacological interventions specifically for patients with COPD and depression was therefore paramount. To assess the effectiveness and safety of pharmacological interventions for the treatment of depression in patients with COPD. The last search was performed on 26 November 2018. We initially searched the following databases via the Specialised Trials Registers of the Cochrane Airways and Common Mental Disorders Groups (to June 2016): MEDLINE, Embase, PsycINFO, CINAHL, AMED, and the Cochrane Library trials register (CENTRAL). Searches from June 2016 to November 2018 were performed directly on Ovid MEDLINE, Embase, PsycINFO and the Cochrane Library (Issue 11, 2018). We searched ClinicalTrials.gov, the ISRCTN registry, and the World Health Organization International Clinical Trials Registry Platform to 26 November 2018. We searched the grey literature databases to identify studies not indexed in major databases and the reference lists of studies initially identified for full-text screening. All published and unpublished randomised controlled trials (RCTs) comparing the efficacy of pharmacological interventions with no intervention, placebo or co-intervention in adults with diagnosed COPD and depression were eligible for inclusion. Two review authors independently assessed articles identified by the search for eligibility. Our primary outcomes were change in depressive symptoms and adverse events. The secondary outcomes were: change in quality of life, change in dyspnoea, change in forced expiratory volume in one second (FEV<sub1</sub), change in exercise tolerance, change in hospital utilisation (length of stay and readmission rates), and cost-effectiveness. For continuous outcomes, we calculated the pooled mean difference (MD) or standardised mean difference (SMD) with 95% confidence interval (CI) as appropriate. For dichotomous outcomes, we calculated the pooled odds ratio (OR) and corresponding 95% CI using a random-effects model. We assessed the quality of evidence using the GRADE framework. Of the 1125 records screened for eligibility, four RCTs (N = 201 participants), and one on-going study, met the inclusion criteria. Two classes of antidepressants were investigated in two separate comparisons with placebo: a tricyclic antidepressant (TCA) and selective serotonin reuptake inhibitors (SSRIs).TCA versus placeboOnly one RCT (N = 30 participants) provided results for this comparison.Primary outcomesThe TCA (nortriptyline) reduced depressive symptoms post-treatment compared to placebo (MD -10.20, 95% CI -16.75 to -3.65; P = 0.007; very low-quality evidence), as measured by the Hamilton Depression Rating Scale (HAM-D). Three participants withdrew from the trial due to adverse events related to the tested antidepressant (dry mouth, sedation, orthostatic hypotension).Secondary outcomesThe overall results post-treatment indicated that nortriptyline was not effective in improving the quality of life of individuals with COPD, as measured by the Sickness Impact Profile (MD -2.80, 95% CI -11.02 to 5.42; P = 0.50; very low-quality evidence).The results for the change in dyspnoea for the domains examined (e.g. dyspnoea scores for 'most day-to-day activities') post-treatment showed no improvement in the intervention group (MD 9.80, 95% CI -6.20 to 25.80; P = 0.23; very low-quality evidence).No data were reported for change in FEV<sub1</sub, change in exercise tolerance, change in hospital utilisation, or cost-effectiveness. The TCA study provided short-term results, with the last follow-up data collection at 12 weeks.The quality of the evidence for all the outcomes evaluated was very low due to a small sample size, imprecision, attrition, and selection and reporting bias.SSRIs versus placeboThree RCTs (N = 171 participants) provided results for this comparison.Primary outcomesThe pooled results for two studies showed no difference for the change in depressive symptoms post-intervention (SMD 0.75, 95% CI -1.14 to 2.64; 148 participants; 2 studies; P = 0.44; very low-quality evidence). High heterogeneity was observed (I² = 95%), limiting the reliability of these findings.While it was not possible to meta-analyse the total adverse events rates across the studies, it was possible to combine the results for two medication-specific adverse effects: nausea and dizziness. There were no significant post-treatment group differences for nausea (OR 2.32, 95% CI 0.66 to 8.12; 171 participants; 3 studies; P = 0.19; very low-quality evidence) or dizziness (OR 0.61, 95% CI 0.09 to 4.06; 143 participants; 2 studies; P = 0.61; very low-quality evidence).Secondary outcomesThe pooled analysis of two trials reporting data for the change in quality of life did not show improvement post-treatment in the intervention group compared to placebo (SMD 1.17, 95% CI -0.80 to 3.15; 148 participants; 2 studies; P = 0.25; very low-quality evidence).There was no difference between groups in change in FEV<sub1</sub post-treatment (MD 0.01, 95% CI -0.03 to 0.05; 148 participants; 2 studies; P = 0.60; low-quality evidence). However, two trials reported improvement in exercise tolerance in the SSRI group versus the placebo group (MD 13.88, 95% CI 11.73 to 16.03; 148 participants; 2 studies; P &lt; 0.001; very low-quality evidence).The trials included in this comparison did not report data related to the change in dyspnoea, hospital utilisation rates, or cost-effectiveness. There is insufficient evidence to make definitive statements about the efficacy or safety of antidepressants for treating COPD-related depression. New RCTs are needed; with better methodological quality and more accurate reporting of the methods used. Moreover, longer-term follow-up data collection is needed, including outcomes such as adverse events, hospital utilisation and cost-effectiveness.

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Active management of the third stage of labour reduces the risk of postpartum blood loss (postpartum haemorrhage (PPH)), and is defined as administration of a prophylactic uterotonic, early umbilical cord clamping and controlled cord traction to facilitate placental delivery. The choice of uterotonic varies across the globe and may have an impact on maternal outcomes. This is an update of a review first published in 2001 and last updated in 2013. To determine the effectiveness of prophylactic oxytocin to prevent PPH and other adverse maternal outcomes in the third stage of labour. For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (6 March 2019) and reference lists of retrieved studies. Randomised, quasi- or cluster-randomised trials including women undergoing vaginal delivery who received prophylactic oxytocin during management of the third stage of labour. Primary outcomes were blood loss 500 mL or more after delivery, need for additional uterotonics, and maternal all-cause mortality. Two review authors independently assessed trials for inclusion, extracted data, and assessed trial quality. Data were checked for accuracy. We assessed the quality of the evidence using the GRADE approach. This review includes 24 trials, with 23 trials involving 10,018 women contributing data. Due to many trials assessed at high risk of bias, evidence grade ranged from very low to moderate quality.Prophylactic oxytocin versus no uterotonics or placebo (nine trials)Prophylactic oxytocin compared with no uterotonics or placebo may reduce the risk of blood loss of 500 mL after delivery (average risk ratio (RR) 0.51, 95% confidence interval (C) 0.37 to 0.72; 4162 women; 6 studies; Tau² = 0.10, I² = 75%; low-quality evidence), and blood loss 1000 mL after delivery (RR 0.59, 95% CI 0.42 to 0.83; 4123 women; 5 studies; low-quality evidence). Prophylactic oxytocin probably reduces the need for additional uterotonics (average RR 0.54, 95% CI 0.36 to 0.80; 3135 women; 4 studies; Tau² = 0.07, I² = 44%; moderate-quality evidence). There may be no difference in the risk of needing a blood transfusion in women receiving oxytocin compared to no uterotonics or placebo (RR 0.88, 95% CI 0.44 to 1.78; 3081 women; 3 studies; low-quality evidence). Oxytocin may be associated with an increased risk of a third stage greater than 30 minutes (RR 2.55, 95% CI 0.88 to 7.44; 1947 women; 1 study; moderate-quality evidence), however the confidence interval is wide and includes 1.0, indicating that there may be little or no difference.Prophylactic oxytocin versus ergot alkaloids (15 trials)It is uncertain whether oxytocin reduces the likelihood of blood loss 500 mL (average RR 0.84, 95% CI 0.56 to 1.25; 3082 women; 10 studies; Tau² = 0.14, I² = 49%; very low-quality evidence) or the need for additional uterotonics compared to ergot alkaloids (average RR 0.89, 95% CI 0.43 to 1.81; 2178 women; 8 studies; Tau² = 0.76, I² = 79%; very low-quality evidence), because the quality of this evidence is very low. The quality of evidence was very low for blood loss of 1000 mL (RR 1.13, 95% CI 0.63 to 2.01; 1577 women; 3 studies; very low-quality evidence), and need for blood transfusion (average RR 1.37, 95% CI 0.34 to 5.51; 1578 women; 7 studies; Tau² = 1.34, I² = 45%; very low-quality evidence), making benefit of oxytocin over ergot alkaloids uncertain. Oxytocin probably increases the risk of a prolonged third stage greater than 30 minutes (RR 4.69, 95% CI 1.63 to 13.45; 450 women; 2 studies; moderate-quality evidence), although it is uncertain if this translates into increased risk of manual placental removal (average RR 1.10, 95% CI 0.39 to 3.10; 3127 women; 8 studies; Tau² = 1.07, I² = 76%; very low-quality evidence). Oxytocin may make little or no difference to risk of diastolic blood pressure &gt; 100 mm Hg (average RR 0.28, 95% CI 0.04 to 2.05; 960 women; 3 studies; Tau² = 1.23, I² = 50%; low-quality evidence), and is probably associated with a lower risk of vomiting (RR 0.09, 95% CI 0.05 to 0.14; 1991 women; 7 studies; moderate-quality evidence), although the impact of oxytocin on headaches is uncertain (average RR 0.19, 95% CI 0.03 to 1.02; 1543 women; 5 studies; Tau² = 2.54, I² = 72%; very low-quality evidence).Prophylactic oxytocin-ergometrine versus ergot alkaloids (four trials)Oxytocin-ergometrine may slightly reduce the risk of blood loss greater than 500 mL after delivery compared to ergot alkaloids (RR 0.44, 95% CI 0.20 to 0.94; 1168 women; 3 studies; low-quality evidence), based on outcomes from quasi-randomised trials with a high risk of bias. There were no maternal deaths reported in either treatment group in the one trial that reported this outcome (RR not estimable; 1 trial, 807 women; moderate-quality evidence). Need for additional uterotonics was not reported.No subgroup differences were observed between active or expectant management, or different routes or doses of oxytocin for any of our comparisons. Prophylactic oxytocin compared with no uterotonics may reduce blood loss and the need for additional uterotonics. The effect of oxytocin compared to ergot alkaloids is uncertain with regards to blood loss, need for additional uterotonics, and blood transfusion. Oxytocin may increase the risk of a prolonged third stage compared to ergot alkaloids, although whether this translates into increased risk of manual placental removal is uncertain. This potential risk must be weighed against the possible increased risk of side effects associated with ergot alkaloids. Oxytocin-ergometrine may reduce blood loss compared to ergot alkaloids, however the certainty of this conclusion is low. More high-quality trials are needed to assess optimal dosing and route of oxytocin administration, with inclusion of important outcomes such as maternal mortality, shock, and transfer to a higher level of care. A network meta-analysis of uterotonics for PPH prevention plans to address issues around optimal dosing and routes of oxytocin and other uterotonics.

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Patient-reported outcome measures such as the Patient-Reported Outcomes Measurement Information System (PROMIS) allow surgeons to evaluate the most important outcomes to patients, including function, pain, and mental well-being. However, PROMIS does not provide surgeons with insight into whether patients are able to successfully cope with their level of physical and/or mental health limitations in day-to-day life; such understanding can be garnered using the Patient-acceptable Symptom State (PASS). It remains unclear whether or not the PASS status for a given patient and his or her health, as evaluated by PROMIS scores, differs based on sociodemographic factors; if it does, that could have important implications regarding interpretation of outcomes and fair delivery of care. In a tertiary-care foot and ankle practice, (1) Is the PASS associated with sociodemographic factors (age, gender, race, ethnicity, and income)? (2) Do PROMIS Physical Function (PF), Pain Interference (PI), and Depression scores differ based on income level? (3) Do PROMIS PF, PI, and Depression thresholds for the PASS differ based on income level? In this retrospective analysis of longitudinally obtained data, all patients with foot and ankle conditions who had new-patient visits (n = 2860) between February 2015 and December 2017 at a single tertiary academic medical center were asked to complete the PROMIS PF, PI, and Depression survey and answer the following single, validated, yes/no PASS question: "Taking into account all the activity you have during your daily life, your level of pain, and also your functional impairment, do you consider that the current state of your foot and ankle is satisfactory?" Of the 2860 new foot and ankle patient visits, 21 patient visits (0.4%) were removed initially because all four outcome measures were not completed. An additional 225 patient visits (8%) were removed because the patient chart did not contain enough information to accurately geocode them; 15 patients visits (0.5%) were removed because the census block group median income data were not available. Lastly, two patient visits (0.1%) were removed because they were duplicates. This left a total of 2597 of 2860 possible patients (91%) in our study sample who had completed all three PROMIS domains and answered the PASS question. Patient sociodemographic factors such as age, gender, race, and ethnicity were recorded. Using census block groups as part of a geocoding method, the income bracket for each patient was recorded. A chi-square analysis was used to determine whether sociodemographic factors were associated with different PASS rates, two-way ANOVA analyses with pairwise comparisons were used to determine if PROMIS scores differed by income bracket, and a receiver operating characteristic (ROC) curve analysis was performed to determine PASS thresholds for the PROMIS score by income bracket. The minimum clinically important difference (MCID) for PROMIS PF in the literature in foot and ankle patients ranges from about 7.9 to 13.2 using anchor-based approaches and 4.5 to 4.7 using the ½ SD, distribution-based method. The MCID for PROMIS PI in the literature in foot and ankle patients ranges from about 5.5 to 12.4 using anchor-based approaches and about 4.1 to 4.3 using the ½ SD, distribution-based method. Both were considered when evaluating our findings. Such MCID cutoffs for PROMIS Depression are not as well established in the foot and ankle literature. Significance was set a priori at p &lt; 0.05. The only sociodemographic factor associated with differences in the proportion of patients achieving PASS was age (15% [312 of 2036] of patients aged 18-64 years versus 11% [60 of 561] of patients aged ≥ 65 years; p = 0.006). PROMIS PF (45 ± 10 for the ≥ USD 100,000 bracket versus 40 ± 10 for the ≤ USD 24,999 bracket, mean difference 5 [95% CI 3 to 7]; p &lt; 0.001), PI (57 ± 8 for ≥ USD 100,000 versus 63 ± 7 for ≤ USD 24,999, mean difference -6 [95% CI -7 to -4]; p &lt; 0.001), and Depression (46 ± 8 for the ≥ USD 100,000 bracket versus 51 ± 11 for ≤ USD 24,999, mean difference -5 [95% CI -7 to -3]; p &lt; 0.001) scores were better for patients in the highest income bracket compared with those in the lowest income bracket. For PROMIS PF, the difference falls within the score change range deemed clinically important when using a ½ SD, distribution-based approach but not when using an anchor-based approach; however, the score difference for PROMIS PI falls within the score change range deemed clinically important for both approaches. The PASS threshold of the PROMIS PF for the highest income bracket was near the mean for the US population (49), while the PASS threshold of the PROMIS PF for the lowest income bracket was more than one SD below the US population mean (39). Similarly, the PASS threshold of the PROMIS PI differed by 6 points when the lowest and highest income brackets were compared. PROMIS Depression was unable to discriminate the PASS. Discussions about functional and pain goals may need to be a greater focus of clinic encounters in the elderly population to ensure that patients understand the risks and benefits of given treatment options at their advanced age. Further, when using PASS in clinical encounters to evaluate patient satisfaction and the ability to cope at different symptom and functionality levels, surgeons should consider income status and its relationship to PASS. This knowledge may help surgeons approach patients with a better idea of patient expectations and which level of symptoms and functionality is satisfactory; this information can assist in ensuring that each patient's health goal is included in shared decision-making discussions. A better understanding of why patients with different income levels are satisfied and able to cope at different symptom and functionality levels is warranted and may best be accomplished using an epidemiologic survey approach. Level III, diagnostic study.

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Routine monitoring of gastric residual in preterm infants on gavage feeds is a common practice that is used to guide initiation and advancement of feeds. Some literature suggests that an increase in/or an altered gastric residual may be predictive of necrotising enterocolitis. Withholding monitoring of gastric residual may take away the early indicator and thus may increase the risk of necrotising enterocolitis. However, routine monitoring of gastric residual as a guide, in the absence of uniform standards, may lead to unnecessary delay in initiation and advancement of feeds and delay in reaching full enteral feeds. This in turn may increase the duration of parenteral nutrition and central venous line usage, increasing their complications. Delay in achieving full enteral feeds increases the risk of extrauterine growth restriction and neurodevelopmental impairment. • To assess the efficacy and safety of routine monitoring of gastric residual versus no monitoring of gastric residual in preterm infants• To assess the efficacy and safety of routine monitoring of gastric residual based on two different criteria for interrupting feeds or decreasing feed volume in preterm infantsWe planned to undertake subgroup analysis based on gestational age (≤ 27 weeks, 28 weeks to 31 weeks, ≥ 32 weeks), birth weight (&lt; 1000 g, 1000 g to 1499 g, ≥ 1500 g), small for gestational age versus appropriate for gestational age infants (classified using birth weight relative to the reference population), type of feed the infant is receiving (human milk or formula milk), and frequency of monitoring of gastric residual (before every feed, before every third feed, etc.) (see "Subgroup analysis and investigation of heterogeneity"). We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 1), MEDLINE via PubMed (1966 to 19 February 2018), Embase (1980 to 19 February 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 19 February 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We selected randomised and quasi-randomised controlled trials that compared routine monitoring of gastric residual versus no monitoring or two different criteria of gastric residual to interrupt feeds in preterm infants. Two review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported the risk ratio and the risk difference for dichotomous data, and the mean difference for continuous data, with respective 95% confidence intervals. We used the GRADE approach to assess the quality of evidence. Two randomised controlled trials with a total of 141 preterm infants met the inclusion criteria for the comparison of routine monitoring versus no monitoring of gastric residual in preterm infants. Both trials were done in infants with birth weight &lt; 1500 g.Routine monitoring of gastric residual may have little or no effect on the incidence of necrotising enterocolitis (risk ratio (RR) 3.07, 95% confidence interval (CI) 0.50 to 18.77; participants = 141; studies = 2; low-quality evidence). Routine monitoring may increase the risk of feed interruption episodes (RR 2.07, 95% CI 1.39 to 3.07; participants = 141; studies = 2; low-quality evidence); the number needed to treat for an additional harmful outcome (NNTH) was 3 (95% CI 2 to 6).Routine monitoring of gastric residual may increase time taken to establish full enteral feeds (mean difference (MD) 3.92, 95% CI 2.06 to 5.77 days; participants = 141; studies = 2; low-quality evidence), time taken to regain birth weight (MD 1.70, 95% CI 0.01 to 3.39 days; participants = 80; studies = 1; low-quality evidence), and number of total parenteral nutrition days (MD 3.29, 95% CI 1.66 to 4.92 days; participants = 141; studies = 2; low-quality evidence).We are uncertain as to the effect of routine monitoring of gastric residual on other outcomes such as incidence of surgical necrotising enterocolitis, extrauterine growth restriction at discharge, parenteral nutrition-associated liver disease, duration of central venous line (CVL) usage, incidence of invasive infection, mortality before discharge, and duration of hospital stay. We found no data for outcomes such as aspiration pneumonia, gastroesophageal reflux, growth measures following discharge, and neurodevelopmental outcome.Only one trial with 87 preterm infants met the inclusion criteria for the comparison of using two different criteria of gastric residual to interrupt feeds while monitoring gastric residual. The trial was done in infants with birth weight of 1500 to 2000 g. We are uncertain as to the effect of using two different criteria of gastric residual on outcomes such as incidence of necrotising enterocolitis or surgical necrotising enterocolitis, time to establish full enteral feeds, time to regain birth weight, number of total parenteral nutrition days, number of infants experiencing feed interruption episodes, extrauterine growth restriction at discharge, parenteral nutrition-associated liver disease, incidence of invasive infection, and mortality before discharge (very low quality evidence). We found no data on duration of CVL usage, aspiration pneumonia, gastroesophageal reflux, duration of hospital stay, growth measures following discharge, and neurodevelopmental outcome. Review authors found insufficient evidence as to whether routine monitoring of gastric residual reduces the incidence of necrotising enterocolitis because trial results are imprecise. Low-quality evidence suggests that routine monitoring of gastric residual increases the risk of feed interruption episodes, increases the time taken to reach full enteral feeds and to regain birth weight, and increases the number of total parenteral nutrition (TPN) days.Available data are insufficient to comment on other major outcomes such as incidence of invasive infection, parenteral nutrition-associated liver disease, mortality before discharge, extrauterine growth restriction at discharge, number of CVL days, and duration of hospital stay. Further randomised controlled trials are warranted to provide more precise estimates of the effects of routine monitoring of gastric residual on important outcomes, especially necrotising enterocolitis, in preterm infants.

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<bObjective:</b To explore the clinical effects of concentrated growth factor (CGF) combined with plasma albumin gel (PAG) in treating facial depressed scar. <bMethods:</b From January 2018 to June 2019, 14 patients in the First Affiliated Hospital of Zhengzhou University and 10 patients in Henan NO.3 Provincial People's Hospital with facial depressed scar who met the inclusion criteria were admitted, and their clinical data were retrospectively analyzed by the method of case-control study. Based on the method of treatment, 8 patients (4 males and 4 females) aged 28.50 (25.50, 31.50) years were enrolled in CGF alone group, 8 patients (3 males and 5 females) aged 32.00 (28.50, 35.00) years were enrolled in PAG alone group, and 8 patients (5 males and 3 females) aged 33.50 (29.00, 35.75) years were enrolled in CGF+ PAG group. Suitable amount of CGF, PAG, and CGF+ PAG (mixed at a ratio of 1.0∶1.0-1.0∶1.5) prepared from autologous blood were injected subcutaneously via a single or multiple entrance (s) into the depressed scar of patients in CGF alone, PAG alone, and CGF+ PAG groups respectively to fill up the concavity, once every 4 weeks for a total of 3 times. Before the first treatment (hereinafter referred to as before treatment) and 3 months after the last treatment (hereinafter referred to as after treatment), the Goodman &amp; Baron Acne Scar Grading System was used for scar grading, and the difference was calculated; the Anxiety Self-Rating Scale was used to score anxiety, and the difference was calculated. The Visual Analogue Score was used to score pain immediately after the first treatment. By one, two, and three months after treatment, the patients' satisfaction to scar treatment was scored, and the Global Aesthetic Improvement Scale was used to score the scar improvement. Adverse reaction of patients after treatment was monitored. Data were statistically analyzed with Fisher's exact probability test, Kruskal-Wallis <iH</i test, Mann-Whitney <iU</i test, Bonferroni correction, and Wilcoxon signed rank sum test. <bResults:</b (1) The scars of patients in the three groups were all graded 4.00 (4.00, 4.00) before treatment (<iχ</i(2)&lt;0.001, <iP</i&gt;0.05). By three months after treatment, compared with 2.00 (1.25, 2.00) of CGF alone group, the scar grades of patients in PAG alone group and CGF+ PAG group (3.00 (2.00, 3.00) and 1.00 (1.00, 1.00), respectively) had no significant change (<iZ</i=2.199, 2.003, <iP</i&gt;0.05). The scar grade of patients in CGF+ PAG group was significantly lower than that in PAG alone group (<iZ</i=3.229, <iP</i&lt;0.01). Compared with those before treatment, the scar grades of patients in CGF alone group, PAG alone group, and CGF+ PAG group were significantly reduced three months after treatment (<iZ</i=2.588, 2.598, 2.640, <iP</i&lt;0.05 or <iP</i&lt;0.01). The difference in scar grade before and after the treatment was significantly higher in CGF+ PAG group than in PAG alone group (<iZ</i=3.229, <iP</i&lt;0.01). (2) The anxiety scores of patients in the three groups were similar before treatment and 3 months after (<iχ</i(2)=2.551, 2.768, <iP</i&gt;0.05). Compared with those before treatment, the anxiety scores of patients in CGF alone group, PAG alone group, and CGF+ PAG group were significantly reduced three months after treatment (<iZ</i=2.395, 2.527, 2.533, <iP</i&lt;0.05). The differences in anxiety score before and after the treatment were similar among the three groups (<iχ</i(2)=1.796, <iP</i&gt;0.05). (3) The pain scores of patients in the three groups were similar immediately after the first treatment (<iχ</i(2)=0.400, <iP</i&gt;0.05). (4) By one and two month (s) after treatment, the patients' satisfaction scores to scar treatment in the three groups were similar (<iχ</i(2)=2.688, 5.989, <iP</i&gt;0.05). By three months after treatment, the patients' satisfaction score to scar treatment in CGF+ PAG group was significantly higher than that in PAG alone group (<iZ</i=2.922, <iP</i&lt;0.01). Compared with those one month after treatment within the same group, the patients' satisfaction scores to scar treatment in CGF alone group, PAG alone group, and CGF+ PAG group were significantly increased two and three months after treatment (<iZ</i=1.121, 2.392, 2.000, 2.828, 2.449, 2.598, <iP</i&lt;0.05 or <iP</i&lt;0.01). Compared with those two months after treatment within the same group, the patients' satisfaction scores to scar treatment in CGF alone group, PAG alone group, and CGF+ PAG group were significantly increased three months after treatment (<iZ</i=2.271, 2.000, 2.646, <iP</i&lt;0.05 or <iP</i&lt;0.01). (5) One month after treatment, the scar improvement scores of patients in the three groups were similar (<iχ</i(2)=4.438, <iP</i&gt;0.05). Two months after treatment, the scar improvement scores of patients in CGF alone group and CGF+ PAG group were 2.00 (2.00, 2.75) and 2.00 (2.00, 2.00) points, respectively, which were significantly higher than 1.00 (1.00, 1.00) point of PAG alone group (<iZ</i=3.303, 3.771, <iP</i&lt;0.01). Three months after treatment, the scar improvement score of patients in CGF+ PAG group was 3.00 (3.00, 3.00) points, which was significantly higher than 2.00 (2.00, 2.75) points of CGF alone group and 1.00 (1.00, 2.00) points of PAG alone group (<iZ</i=2.450, 3.427, <iP</i&lt;0.05 or <iP</i&lt;0.01). Compared with those one month after treatment within the same group, the scar improvement scores of patients were significantly higher in CGF alone group and CGF+ PAG group two and three months after treatment and in PAG alone group three months after treatment (<iZ</i=2.828, 2.828, 2.530, 2.640, 2.121, <iP</i&lt;0.05 or <iP</i&lt;0.01). Compared with that two months after treatment within the same group, the scar improvement score of patients in CGF+ PAG group was significantly higher three months after treatment (<iZ</i=2.449, <iP</i&lt;0.05). (6) After injection, all patients in the three groups had slight redness and swelling at the needle prick point and no other adverse reactions. <bConclusions:</b CGF combined with PAG can reduce the scar grading, anxiety of patients, and enhance patients' satisfaction and scar improvement in the treatment of patients with facial depressed scar. The combined CGF+ PAG injection, without significant adverse reactions, is better than single component injection and is worthy of clinical application.

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Can pronuclear transfer (PNT) or maternal spindle transfer (ST) be applied to overcome poor embryo development associated with advanced maternal age or early embryo arrest in a mouse model? Both PNT and ST may have the potential to restore embryonic developmental potential in a mouse model of reproductive ageing and embryonic developmental arrest. Germline nuclear transfer (NT) techniques, such as PNT and ST, are currently being applied in humans to prevent the transmission of mitochondrial diseases. Yet, there is also growing interest in the translational use of NT for treating infertility and improving IVF outcomes. Nevertheless, direct scientific evidence to support such applications is currently lacking. Moreover, it remains unclear which infertility indications may benefit from these novel assisted reproductive technologies. We applied two mouse models to investigate the potential of germline NT for overcoming infertility. Firstly, we used a model of female reproductive ageing (B6D2F1 mice, n = 155), with ages ranging from 6 to 8 weeks (young), 56 (aged) to 70 weeks (very-aged), corresponding to a maternal age of &lt;30, ∼36 and ∼45 years in humans, respectively. Secondly, we used NZB/OlaHsd female mice (7-14 weeks, n = 107), as a model of early embryo arrest. This mouse strain exhibits a high degree of two-cell block. Metaphase II (MII) oocytes and zygotes were retrieved following superovulation. Ovarian reserve was assessed by histological analysis in the reproductive-aged mice. Mitochondrial membrane potential (△Ψm) was measured by JC-1 staining in MII oocytes, while spindle-chromosomal morphology was examined by confocal microscopy. Reciprocal ST and PNT were performed by transferring the meiotic spindle or pronuclei (PN) from unfertilised or fertilised oocytes (after ICSI) to enucleated oocytes or zygotes between aged or very-aged and young mice. Similarly, NT was also conducted between NZB/OlaHsd (embryo arrest) and B6D2F1 (non-arrest control) mice. Finally, the effect of cytoplasmic transfer (CT) was examined by injecting a small volume (∼5%) of cytoplasm from the oocytes/zygotes of young (B6D2F1) mice to the oocytes/zygotes of aged or very-aged mice or embryo-arrest mice. Overall, embryonic developmental rates of the reconstituted PNT (n = 572), ST (n = 633) and CT (n = 336) embryos were assessed to evaluate the efficiency of these techniques. Finally, chromosomal profiles of individual NT-generated blastocysts were evaluated using next generation sequencing. Compared to young mice, the ovarian reserve in aged and very-aged mice was severely diminished, reflected by a lower number of ovarian follicles and a reduced number of ovulated oocytes (P &lt; 0.001). Furthermore, we reveal that the average △Ψm in both aged and very-aged mouse oocytes was significantly reduced compared to young mouse oocytes (P &lt; 0.001). In contrast, the average △Ψm in ST-reconstructed oocytes (very-aged spindle and young cytoplast) was improved in comparison to very-aged mouse oocytes (P &lt; 0.001). In addition, MII oocytes from aged and very-aged mice exhibited a higher rate of abnormalities in spindle assembly (P &lt; 0.05), and significantly lower fertilisation (60.7% and 45.3%) and blastocyst formation rates (51.4% and 38.5%) following ICSI compared to young mouse oocytes (89.7% and 87.3%) (P &lt; 0.001). Remarkably, PNT from zygotes obtained from aged or very-aged mice to young counterparts significantly improved blastocyst formation rates (74.6% and 69.2%, respectively) (P &lt; 0.05). Similarly, both fertilisation and blastocyst rates were significantly increased after ST between aged and young mice followed by ICSI (P &lt; 0.05). However, we observed no improvement in embryo development rates when performing ST from very-aged to young mouse oocytes following ICSI (P &gt; 0.05). In the second series of experiments, we primarily confirmed that the majority (61.8%) of in vivo zygotes obtained from NZB/OlaHsd mice displayed two-cell block during in vitro culture, coinciding with a significantly reduced blastocyst formation rate compared to the B6D2F1 mice (13.5% vs. 90.7%; P &lt; 0.001). Notably, following the transfer of PN from the embryo-arrest (NZB/OlaHsd) zygotes to enucleated non-arrest (B6D2F1) counterparts, most reconstructed zygotes developed beyond the two-cell stage, leading to a significantly increased blastocyst formation rate (89.7%) (P &lt; 0.001). Similar findings were obtained after implementing ST between NZB/OlaHsd and B6D2F1 mice, followed by ICSI. Conversely, the use of CT did not improve embryo development in reproductive-age mice nor in the embryo-arrest mouse model (P &gt; 0.05). Surprisingly, chromosomal analysis revealed that euploidy rates in PNT and ST blastocysts generated following the transfer of very-aged PN to young cytoplasts and very-aged spindles to young cytoplasts were comparable to ICSI controls (with young mouse oocytes). A high euploidy rate was also observed in the blastocysts obtained from either PNT or ST between young mice. Conversely, the transfer of young PN and young spindles into very-aged cytoplasts led to a higher rate of chromosomal abnormalities in both PNT and ST blastocysts. N/A. The limited number of blastocysts analysed warrants careful interpretation. Furthermore, our observations should be cautiously extrapolated to humans given the inherent differences between mice and women in regards to various biological processes, including centrosome inheritance. The findings suggest that ST or PNT procedures may be able to avoid aneuploidies generated during embryo development, but they are not likely to correct aneuploidies already present in some aged MII oocytes. To our knowledge, this is the first study to evaluate the potential of PNT and ST in the context of advanced maternal age and embryonic developmental arrest in a mouse model. Our data suggest that PNT, and to a lesser extent ST, may represent a novel reproductive strategy to restore embryo development for these indications. M.T. is supported by grants from the China Scholarship Council (CSC) (Grant no. 201506160059) and the Special Research Fund from Ghent University (Bijzonder Onderzoeksfonds, BOF) (Grant no. 01SC2916 and no. 01SC9518). This research is also supported by the FWO-Vlaanderen (Flemish fund for scientific research, Grant no. G051017N, G051516N and G1507816N). The authors declare no competing interests. N/A.

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Although femoral retroversion has been linked to the onset of slipped capital femoral epiphysis (SCFE), and may result from a rotation of the femoral epiphysis around the epiphyseal tubercle leading to femoral retroversion, femoral version has rarely been described in patients with SCFE. Furthermore, the prevalence of actual femoral retroversion and the effect of different measurement methods on femoral version angles has yet to be studied in SCFE. (1) Do femoral version and the prevalence of femoral retroversion differ between hips with SCFE and the asymptomatic contralateral side? (2) How do the mean femoral version angles and the prevalence of femoral retroversion change depending on the measurement method used? (3) What is the interobserver reliability and intraobserver reproducibility of these measurement methods? For this retrospective, controlled, single-center study, we reviewed our institutional database for patients who were treated for unilateral SCFE and who had undergone a pelvic CT scan. During the period in question, the general indication for obtaining a CT scan was to define the surgical strategy based on the assessment of deformity severity in patients with newly diagnosed SCFE or with previous in situ fixation. After applying prespecified inclusion and exclusion criteria, we included 79 patients. The mean age was 15 ± 4 years, 48% (38 of 79) of the patients were male, and 56% (44 of 79) were obese (defined as a BMI &gt; 95th percentile (mean BMI 34 ± 9 kg/m2). One radiology resident (6 years of experience) measured femoral version of the entire study group using five different methods. Femoral neck version was measured as the orientation of the femoral neck. Further measurement methods included the femoral head's center and differed regarding the level of landmarks for the proximal femoral reference axis. From proximal to distal, this included the most-proximal methods (Lee et al. and Reikerås et al.) and most-distal methods (Tomczak et al. and Murphy et al.). Most proximally (Lee et al. method), we used the most cephalic junction of the greater trochanter as the landmark and, most distally, we used the center base of the femoral neck superior to the lesser trochanter (Murphy et al.). The orientation of the distal femoral condyles served as the distal reference axis for all five measurement methods. All five methods were compared side-by-side (involved versus uninvolved hip), and comparisons among all five methods were performed using paired t-tests. The prevalence of femoral retroversion (&lt; 0°) was compared using a chi-square test. A subset of patients was measured twice by the first observer and by a second orthopaedic resident (2 years of experience) to assess intraobserver reproducibility and interobserver reliability; for this assessment, we used intraclass correlation coefficients. The mean femoral neck version was lower in hips with SCFE than in the contralateral side (-2° ± 13° versus 7° ± 11°; p &lt; 0.001). This yielded a mean side-by side difference of -8° ± 11° (95% CI -11° to -6°; p &lt; 0.001) and a higher prevalence of femoral retroversion in hips with SCFE (58% [95% CI 47% to 69%]; p &lt; 0.001) than on the contralateral side (29% [95% CI 19% to 39%]). These differences between hips with SCFE and the contralateral side were higher and ranged from -17° ± 11° (95% CI -20° to -15°; p &lt; 0.001) based on the method of Tomczak et al. to -22° ± 13° (95% CI -25° to -19°; p &lt; 0.001) according to the method of Murphy et al. The mean overall femoral version angles increased for hips with SCFE using more-distal landmarks compared with more-proximal landmarks. The prevalence of femoral retroversion was higher in hips with SCFE for the proximal methods of Lee et al. and Reikerås et al. (91% [95% CI 85% to 97%] and 84% [95% CI 76% to 92%], respectively) than for the distal measurement methods of Tomczak et al. and Murphy et al. (47% [95% CI 36% to 58%] and 60% [95% CI 49% to 71%], respectively [all p &lt; 0.001]). We detected mean differences ranging from -19° to 4° (all p &lt; 0.005) for 8 of 10 pairwise comparisons in hips with SCFE. Among these, the greatest differences were between the most-proximal methods and the more-distal methods, with a mean difference of -19° ± 7° (95% CI -21° to -18°; p &lt; 0.001), comparing the methods of Lee et al. and Tomczak et al. In hips with SCFE, we found excellent agreement (intraclass correlation coefficient [ICC] &gt; 0.80) for intraobserver reproducibility (reader 1, ICC 0.93 to 0.96) and interobserver reliability (ICC 0.95 to 0.98) for all five measurement methods. Analogously, we found excellent agreement (ICC &gt; 0.80) for intraobserver reproducibility (reader 1, range 0.91 to 0.96) and interobserver reliability (range 0.89 to 0.98) for all five measurement methods in healthy contralateral hips. We showed that femoral neck version is asymmetrically decreased in unilateral SCFE, and that differences increase when including the femoral head's center. Thus, to assess the full extent of an SCFE deformity, femoral version measurements should consider the position of the displaced epiphysis. The prevalence of femoral retroversion was high in patients with SCFE and increased when using proximal anatomic landmarks. Since the range of femoral version angles was wide, femoral version cannot be predicted in a given hip and must be assessed individually. Based on these findings, we believe it is worthwhile to add evaluation of femoral version to the diagnostic workup of children with SCFE. Doing so may better inform surgeons as they contemplate when to use isolated offset correction or to perform an additional femoral osteotomy for SCFE correction based on the severity of the slip and the rotational deformity. To facilitate communication among physicians and for the design of future studies, we recommend consistently reporting the applied measurement technique. Level III, prognostic study.

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What is the normal range of cervical mucus patterns and number of days with high or moderate day-specific probability of pregnancy (if intercourse occurs on a specific day) based on cervical mucus secretion, in women without known subfertility, and how are these patterns related to parity and age? The mean days of peak type (estrogenic) mucus per cycle was 6.4, the mean number of potentially fertile days was 12.1; parous versus nulliparous, and younger nulliparous (&lt;30 years) versus older nulliparous women had more days of peak type mucus, and more potentially fertile days in each cycle. The rise in estrogen prior to ovulation supports the secretion of increasing quantity and estrogenic quality of cervical mucus, and the subsequent rise in progesterone after ovulation causes an abrupt decrease in mucus secretion. Cervical mucus secretion on each day correlates highly with the probability of pregnancy if intercourse occurs on that day, and overall cervical mucus quality for the cycle correlates with cycle fecundability. No prior studies have described parity and age jointly in relation to cervical mucus patterns. This study is a secondary data analysis, combining data from three cohorts of women: 'Creighton Model MultiCenter Fecundability Study' (CMFS: retrospective cohort, 1990-1996), 'Time to Pregnancy in Normal Fertility' (TTP: randomized trial, 2003-2006), and 'Creighton Model Effectiveness, Intentions, and Behaviors Assessment' (CEIBA: prospective cohort, 2009-2013). We evaluated cervical mucus patterns and estimated fertile window in 2488 ovulatory cycles of 528 women, followed for up to 1 year. Participants were US or Canadian women age 18-40 years, not pregnant, and without any known subfertility. Women were trained to use a standardized protocol (the Creighton Model) for daily vulvar observation, description, and recording of cervical mucus. The mucus peak day (the last day of estrogenic quality mucus) was used as the estimated day of ovulation. We conducted dichotomous stratified analyses for cervical mucus patterns by age, parity, race, recent oral contraceptive use (within 60 days), partial breast feeding, alcohol, and smoking. Focusing on the clinical characteristics most correlated to cervical mucus patterns, linear mixed models were used to assess continuous cervical mucus parameters and generalized linear models using Poisson regression with robust variance were used to assess dichotomous outcomes, stratifying by women's parity and age, while adjusting for recent oral contraceptive use and breast feeding. The majority of women were &lt;30 years of age (75.4%) (median 27; IQR 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators, and nulliparous (70.8%). The mean (SD) days of estrogenic (peak type) mucus per cycle (a conservative indicator of the fertile window) was 6.4 (4.2) days (median 6; IQR 4-8). The mean (SD) number of any potentially fertile days (a broader clinical indicator of the fertile window) was 12.1 (5.4) days (median 11; IQR 9-14). Taking into account recent oral contraceptive use and breastfeeding, nulliparous women age ≥30 years compared to nulliparous women age &lt;30 years had fewer mean days of peak type mucus per cycle (5.3 versus 6.4 days, P = 0.02), and fewer potentially fertile days (11.8 versus 13.9 days, P &lt; 0.01). Compared to nulliparous women age &lt;30 years, the likelihood of cycles with peak type mucus ≤2 days, potentially fertile days ≤9, and cervical mucus cycle score (for estrogenic quality of mucus) ≤5.0 were significantly higher among nulliparous women age ≥30 years, 1.90 (95% confidence interval (CI) 1.18, 3.06); 1.46 (95% CI 1.12, 1.91); and 1.45 (95% CI 1.03, 2.05), respectively. Between parous women, there was little difference in mucus parameters by age. Thresholds set a priori for within-woman variability of cervical mucus parameters by cycle were examined as follows: most minus fewest days of peak type mucus &gt;3 days (exceeded by 72% of women), most minus fewest days of non-peak type mucus &gt;4 days (exceeded by 54% of women), greatest minus least cervical mucus cycle score &gt;4.0 (exceeded by 73% of women), and most minus fewest potentially fertile days &gt;8 days (found in 50% of women). Race did not have any association with cervical mucus parameters. Recent oral contraceptive use was associated with reduced cervical mucus cycle score and partial breast feeding was associated with a higher number of days of mucus (both peak type and non-peak type), consistent with prior research. Among the women for whom data were available (CEIBA and TTP), alcohol and tobacco use had minimal impact on cervical mucus parameters. We did not have data on some factors that may impact ovulation, hormone levels, and mucus secretion, such as physical activity and body mass index. We cannot exclude the possibility that some women had unknown subfertility or undiagnosed gynecologic disorders. Only 27 women were age 35 or older. Our study participants were geographically dispersed but relatively homogeneous with regard to race, ethnicity, income, and educational level, which may limit the generalizability of the findings. Patterns of cervical mucus secretion observed by women are an indicator of fecundity and the fertile window that are consistent with the known associations of age and parity with fecundity. The number of potentially fertile days (12 days) is likely greater than commonly assumed, while the number of days of highly estrogenic mucus (and higher probability of pregnancy) correlates with prior identifications of the fertile window (6 days). There may be substantial variability in fecundability between cycles for the same woman. Future work can use cervical mucus secretion as an indicator of fecundity and should investigate the distribution of similar cycle parameters in women with various reproductive or gynecologic pathologies. Funding for the three cohorts analyzed was provided by the Robert Wood Johnson Foundation (CMFS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (TTP), and the Office of Family Planning, Office of Population Affairs, Health and Human Services (CEIBA). The authors declare that they have no conflict of interest. N/A.

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Interventions by specialist breast cancer nurses (SBCNs) aim to support women and help them cope with the impact of the disease on their quality of life. To assess the effects of individual interventions carried out by SBCNs on indicators of quality of life, anxiety, depression, and participant satisfaction. In June 2020, we searched MEDLINE, Embase, CENTRAL (Trials only), Cochrane Breast Cancer Group's Specialist Register (CBCG SR), CINAHL, PsycINFO, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and Clinicaltrials.gov. We selected randomised controlled trials (RCTs) of interventions carried out by SBCNs for women with breast cancer, which reported indicators of quality of life, anxiety, depression, and participant satisfaction. The certainty of the evidence was evaluated using the GRADE approach. A narrative description of the results including structured tabulation was carried out. We included 14 RCTs involving 2905 women. With the exception of one study (women with advanced breast cancer), all the women were diagnosed with primary breast cancer. Mean age ranged from 48 to 64 years. Psychosocial nursing interventions compared with standard care for women with primary breast cancer Eight studies (1328 women, low-quality evidence) showed small improvements in general health-related quality of life or no difference in effect between nine weeks and 18 months. Six studies (897 women, low-quality evidence) showed small improvements in cancer-specific quality of life or no difference in effect between nine weeks and 18 months. Six studies (951 women, low-quality evidence) showed small improvements in anxiety and depression between nine weeks and 18 months. Two studies (320 women, low-quality evidence) measured satisfaction during survivorship; one study measured satisfaction only in the intervention group and showed high levels of satisfaction with care; the second study showed equal satisfaction with care in both groups at six months. Psychosocial nursing interventions compared with other supportive care interventions for women with primary breast cancer Two studies (351 women, very-low quality evidence) measured general health-related quality of life. One study reported that psychological morbidity reduced over the 12-month period; scores were consistently lower in women supported by SBCNs alone compared to support from a voluntary organisation. The other study reported that at six months, women receiving psychosocial support by either SBCNs or psychologists clinically improved from "higher levels of distress" to "lower levels of distress". One study (179 women, very-low quality evidence) showed no between-group differences on subscales at all time points up to six months measured using cancer-specific quality of life questionnaires. There were significant group-by-time changes in the global quality of life, nausea and vomiting, and systemic therapy side effects subscales, for women receiving psychosocial support by either SBCNs or psychologists at six months. There were improvements in other subscales over time in both groups. Systemic therapy side effects increased significantly in the psychologist group but not in the SBCN group. Sexual functioning decreased in both groups. Two studies (351 women, very-low quality evidence) measured anxiety and depression. One study reported that anxiety subscale scores and state anxiety scores improved over six months but there was no effect on depression subscale scores in the SBCN group compared to the psychologist group. There was no group-by-time interaction on the anxiety and depression or state anxiety subscales. The other study reported that anxiety and depression scores reduced over the 12-month post-surgery period in the SBCN group; scores were consistently lower in women supported by SBCNs compared to support from a voluntary organisation. SBCN-led telephone interventions delivering follow-up care compared with usual care for women with primary breast cancer Three studies (931 women, moderate-quality evidence) reported general health-related quality of life outcomes. Two studies reported no difference in psychological morbidity scores between SBCN-led follow-up care and standard care at 18 to 24 months. One trial reported no change in feelings of control scores between SBCN-led follow-up care and standard care at 12 months. Two studies (557 women, moderate-quality evidence) reported no between-group difference in cancer-specific quality of life at 18 to 24 months. A SBCN intervention conducted by telephone, as a point-of-need access to specialist care, did not change psychological morbidity compared to routine clinical review at 18 months. Scores for both groups on the breast cancer subscale improved over time, with lower scores at nine and 18 months compared to baseline. The adjusted mean differences between groups at 18 months was 0.7 points in favour of the SBCN intervention (P = 0.058). A second study showed no differences between groups for role and emotional functioning measured using cancer-specific quality of life questionnaires in a SBCN-led telephone intervention compared with standard hospital care, both with and without an educational group programme at 12 months. At 12 months, mean scores were 78.4 (SD = 16.2) and 77.7 (SD = 16.2) respectively for SBCN-led telephone and standard hospital follow-up. The 95% confidence interval difference at 12 months was -1.93 to 4.64. Three studies (1094 women, moderate-quality evidence) reported no between-group difference in anxiety between 12 and 60 months follow-up. One of these studies also measured depression and reported no difference in depression scores between groups at five years (anxiety: RR 1.8; 95% CI 0.6 to 5.1; depression: RR 1.7 95% CI 0.4 to 7.2). Four studies (1331 women, moderate-quality evidence) demonstrated high levels of satisfaction with SBCN-led follow-up care by telephone between 12 and 60 months. Psychosocial nursing interventions compared with usual care for women with advanced breast cancer One study (105 women, low-quality evidence) showed no difference in cancer-specific quality of life outcomes at 3 months. Evidence suggests that psychosocial interventions delivered by SBCNs for women with primary breast cancer may improve or are at least as effective as standard care and other supportive interventions, during diagnosis, treatment and survivorship. SBCN-led telephone follow-up interventions were equally as effective as standard care, for women with primary breast cancer.

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Lower-limb running injuries are common. Running shoes have been proposed as one means of reducing injury risk. However, there is uncertainty as to how effective running shoes are for the prevention of injury. It is also unclear how the effects of different characteristics of running shoes prevent injury. To assess the effects (benefits and harms) of running shoes for preventing lower-limb running injuries in adult runners. We searched the following databases: CENTRAL, MEDLINE, Embase, AMED, CINAHL Plus and SPORTDiscus plus trial registers WHO ICTRP and ClinicalTrials.gov. We also searched additional sources for published and unpublished trials. The date of the search was June 2021. We included randomised controlled trials (RCTs) and quasi-RCTs involving runners or military personnel in basic training that either compared a) a running shoe with a non-running shoe; b) different types of running shoes (minimalist, neutral/cushioned, motion control, stability, soft midsole, hard midsole); or c) footwear recommended and selected on foot posture versus footwear not recommended and not selected on foot posture for preventing lower-limb running injuries. Our primary outcomes were number of people sustaining a lower-limb running injury and number of lower-limb running injuries. Our secondary outcomes were number of runners who failed to return to running or their previous level of running, runner satisfaction with footwear, adverse events other than musculoskeletal injuries, and number of runners requiring hospital admission or surgery, or both, for musculoskeletal injury or adverse event. Two review authors independently assessed study eligibility and performed data extraction and risk of bias assessment. The certainty of the included evidence was assessed using GRADE methodology. We included 12 trials in the analysis which included a total of 11,240 participants, in trials that lasted from 6 to 26 weeks and were carried out in North America, Europe, Australia and South Africa. Most of the evidence was low or very low certainty as it was not possible to blind runners to their allocated running shoe, there was variation in the definition of an injury and characteristics of footwear, and there were too few studies for most comparisons. We did not find any trials that compared running shoes with non-running shoes. Neutral/cushioned versus minimalist (5 studies, 766 participants) Neutral/cushioned shoes may make little or no difference to the number of runners sustaining a lower-limb running injuries when compared with minimalist shoes (low-certainty evidence) (risk ratio (RR) 0.77, 95% confidence interval (CI) 0.59 to 1.01). One trial reported that 67% and 92% of runners were satisfied with their neutral/cushioned or minimalist running shoes, respectively (RR 0.73, 95% CI 0.47 to 1.12). Another trial reported mean satisfaction scores ranged from 4.0 to 4.3 in the neutral/ cushioned group and 3.6 to 3.9 in the minimalist running shoe group out of a total of 5. Hence neutral/cushioned running shoes may make little or no difference to runner satisfaction with footwear (low-certainty evidence). Motion control versus neutral / cushioned (2 studies, 421 participants) It is uncertain whether or not motion control shoes reduce the number of runners sustaining a lower-limb running injuries when compared with neutral / cushioned shoes because the quality of the evidence has been assessed as very low certainty (RR 0.92, 95% CI 0.30 to 2.81). Soft midsole versus hard midsole (2 studies, 1095 participants) Soft midsole shoes may make little or no difference to the number of runners sustaining a lower-limb running injuries when compared with hard midsole shoes (low-certainty of evidence) (RR 0.82, 95% CI 0.61 to 1.10). Stability versus neutral / cushioned (1 study, 57 participants) It is uncertain whether or not stability shoes reduce the number of runners sustaining a lower-limb running injuries when compared with neutral/cushioned shoes because the quality of the evidence has been assessed as very low certainty (RR 0.49, 95% CI 0.18 to 1.31). Motion control versus stability (1 study, 56 participants) It is uncertain whether or not motion control shoes reduce the number of runners sustaining a lower-limb running injuries when compared with stability shoes because the quality of the evidence has been assessed as very low certainty (RR 3.47, 95% CI 1.43 to 8.40). Running shoes prescribed and selected on foot posture (3 studies, 7203 participants) There was no evidence that running shoes prescribed based on static foot posture reduced the number of injuries compared with those who received a shoe not prescribed based on foot posture in military recruits (Rate Ratio 1.03, 95% CI 0.94 to 1.13). Subgroup analysis confirmed these findings were consistent between males and females. Therefore, prescribing running shoes and selecting on foot posture probably makes little or no difference to lower-limb running injuries (moderate-certainty evidence). Data were not available for all other review outcomes. Most evidence demonstrates no reduction in lower-limb running injuries in adults when comparing different types of running shoes. Overall, the certainty of the evidence determining whether different types of running shoes influence running injury rates was very low to low, and as such we are uncertain as to the true effects of different types of running shoes upon injury rates. There is no evidence that prescribing footwear based on foot type reduces running-related lower-limb injures in adults. The evidence for this comparison was rated as moderate and as such we can have more certainty when interpreting these findings. However, all three trials included in this comparison used military populations and as such the findings may differ in recreational runners.  Future researchers should develop a consensus definition of running shoe design to help standardise classification. The definition of a running injury should also be used consistently and confirmed via health practitioners. More researchers should consider a RCT design to increase the evidence in this area. Lastly, future work should look to explore the influence of different types or running shoes upon injury rates in specific subgroups.

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