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Background Studies have pointed to a complicated and mutual relationship between attention deficit hyperactivity disorder (ADHD) and attachment. In an observational follow-up study conducted in 2015 60 children from 7 years to 12 years recently diagnosed with ADHD were included and assessed according to attachment representation showing 85% of the children to be insecurely attached. Aim The aim of this study was to investigate the stability of this remarkably high frequency of insecure attachment in the same cohort of children. Methods Children previously assessed using the child attachment interview (CAI) when diagnosed with ADHD were contacted three years later for a follow-up CAI assessment. Results At follow-up, 31 children participated in the CAI-interviews. Since their diagnosis with ADHD, the children had received treatment as usual. The CAI-interviews showed a continued high rate of insecure attachment with 90% of the children classifying as insecurely attached compared to expected 38% in the normal population. Of these, the majority of children (77%) were classified as dismissing. Conclusion Our findings suggest that targeting ADHD-symptoms with our current treatment strategies does not in itself improve attachment security. Attachment security may in turn be a factor of importance when evaluating general functioning and prognosis.

To summarise latent tuberculosis infection (LTBI) management strategies among household contacts of bacteriologically confirmed pulmonary tuberculosis (TB) patients in high-TB burden countries.PubMed/MEDLINE (NCBI) and Scopus were searched (January 2006 to December 2021) for studies reporting primary data on LTBI management. Study selection, data management and data synthesis were protocol-driven (PROSPERO-CRD42021208715). Primary outcomes were the proportions of LTBI, initiating and completing tuberculosis preventive treatment (TPT). Reported factors influencing the LTBI care cascade were qualitatively synthesised.From 3694 unique records retrieved, 58 studies from 23 countries were included. Most identified contacts were screened (median 99%, interquartile range [IQR] 82%-100%; 46 studies). Random-effects meta-analysis yielded pooled proportions for: LTBI 41% (95% confidence interval [CI] 33%-49%; 21,566 tested contacts); TPT initiation 91% (95% CI 79%-97%; 129,573 eligible contacts, 34 studies); TPT completion 65% (95% CI 54%-74%; 108,679 TPT-initiated contacts, 28 studies). Heterogeneity was significant (IThe proportions of household contacts screened, detected with LTBI and initiated on TPT, though variable was high, but the proportions completing TPT were lower indicating current strategies used for LTBI management in high TB burden countries are not sufficient.

OBJECTIVE To assess the effect of different frequencies of ventilator circuit changes in neonates and children through a systematic review and meta-analysis. INTERVENTIONS (1) "No routine change of ventilator circuit (unless visibly soiled)" versus "routine change at any fixed interval"; (2) routine change of circuit at "less frequent" versus "more frequent" intervals. OUTCOMES Primary outcomes were VAP rate (number of VAP episodes per 1000 ventilator-days) and all-cause mortality before discharge. METHODS MEDLINE, CENTRAL, EMBASE, and CINAHL were systematically searched from inception till November 3, 2020. Two authors assessed trial eligibility and risk of bias, and independently extracted data. Data were synthesized using fixed effects model. GRADE was used to assess certainty of evidence (CoE). RESULTS We identified six studies enrolling 768 participants evaluating circuit changes at two fixed intervals. Meta-analysis of studies on circuit changes "once in less than 7 days" versus "once weekly" showed no difference in VAP rate (risk ratio: 0.83 [0.38-1.81]; one randomized controlled trial (RCT) and 0.94 [0.49-1.81]; two before-after studies) or mortality before discharge (0.67 [0.34-1.3]; one RCT and 1.01 [0.63-1.64]; two before-after studies). CoE was very low. Less frequent circuit changes reduced health-care costs. No study evaluating "circuit changes only when visibly soiled" versus "circuit changes at a fixed interval" was identified. CONCLUSION There is no evidence to suggest that ventilator circuits can be safely left unchanged until visibly soiled in neonates and children. Extending circuit changes interval to "once weekly" may not increase VAP rate (CoE-very low) and reduces healthcare costs.

The literature on the efficacy of erbium lasers for nonsurgical periodontal therapy is inconsistent. The objective of the umbrella review was to collate the information available in the systematic reviews to provide a comprehensive synthesis of clinical and patient reported outcomes following the use of erbium lasers for non-surgical periodontal therapy. An electronic database search was carried out, and systematic reviews/meta-analyses which assessed the efficacy of erbium lasers as monotherapy or as an adjunct to scaling and root planing were included. The methodological quality and reporting quality of the included studies were assessed. 15 Systematic reviews/meta-analyses were obtained after title, abstract, and full text search. The meta-analyses data revealed a clinical attachment level gain, reduction in probing pocket depth at 1 and 3-month follow-up, and no additional benefit at ≥ 6-month follow-up in the erbium laser group. The evidence gap map revealed lack of clinical outcome data at6-month follow-up and dearth in studies assessing patient reported outcome measures and adverse events. Erbium lasers may provide short-term clinical benefits, and further studies with standardized laser parameters evaluating long-term follow-up, patient-reported outcome measures, and adverse events are needed.

Technology-assisted parent-mediated interventions improve accessibility and are acceptable but not proven to be effective. We conducted a systematic search of 6 databases. We included and analysed results from studies on social and communication outcomes. Sixteen Randomised-Controlled-Trials (RCTs) with 748 participants were included. Most studies were rated as of good quality. Meta-analysis suggested that interventions were probably effective in improving emotion recognition. No significant differences were found in social communication, social functioning or language outcomes. At present, isolated tech interventions do not fulfil criteria for promising or established evidence-based interventions for ASD. Future research needs to focus on improving the effectiveness of technology-assisted parent-mediated interventions for ASD. Prospero Registration Number: CRD42020162825.

Background Scrub typhus, a vector-borne zoonotic infection caused by the bacteria Orientia tsutsugamushi, is one of the most common and clinically important rickettsial infections worldwide. An estimated one million cases occur annually with a high case fatality rate. Although scrub typhus is a major public health threat in India, the burden and distribution remains unclear. We aimed to estimate the burden of scrub typhus in India. Methodology We performed a systematic review of published literature on scrub typhus from India to extract information on epidemiology, morbidity, and mortality. Important databases were searched using keywords and appropriate combinations. We identified observational, interventional, and population-based studies and extracted the data to evaluate the number of cases diagnosed using serology or PCR and the number of deaths due to scrub typhus. We conducted a systematic narrative synthesis to summarize included studies. Principal findings In the last decade, there were 18,781 confirmed scrub typhus cases reported in 138 hospital-based studies and two community-based studies. IgM ELISA was used in 122 studies to confirm the cases in majority (89%). The proportion of scrub typhus among acute undifferentiated febrile illness (AUFI) studies was 25.3%, and community seroprevalence was 34.2%. Ninety studies had data published on multiple organ involvement out of which 17.4% of cases had multiple organ dysfunction syndromes, 20.4% patients required ICU admission, and 19.1% needed ventilation. The overall case-fatality rate was 6.3%, and the mortality among those with multi-organ dysfunction syndrome was as high as 38.9%. Conclusion/significance Scrub typhus, a common acute febrile illness in India causing severe morbidity, accounts for a large number of deaths. The burden of the disease has been underappreciated. Early diagnosis and prompt treatment can significantly reduce complications and mortality. Establishing good surveillance and instituting appropriate control measures are urgently needed., Author summary Scrub typhus is an infection that is caused by a rickettsial bacteria called Orientia tsutsugamushi and transmitted to humans through chigger mites. Scrub typhus has re-emerged as one of the most common life-threatening rickettsial infections accounting for a million cases annually. However, it is a largely overlooked public health problem in India. This systematic review aims to integrate data obtained from medical literature over the past 10 years to estimate the burden of scrub typhus in India. It also intends to summarize the diagnostic tests that are most commonly used to confirm scrub typhus cases and to map the distribution of cases across India. The insights provided from this review will further enable policymakers to establish a surveillance system to observe this disease and initiate strategies to effectively control, and prevent the spread of, this neglected disease. In this review, we found that scrub typhus is very common in India and affects multiple organs in the majority of positively tested patients. This increases complications and the risk of death. Improving awareness about this disease, increasing access to testing and initiating appropriate therapy early can help reduce this public health threat in the future.

IntroductionThe heterogeneity in people with borderline personality disorder (BPD) and the range of specialised psychotherapies means that people with certain BPD characteristics might benefit more or less from different types of psychotherapy. Identifying moderating characteristics of individuals is a key to refine and tailor standard treatments so they match the specificities of the individual participant. The objective of this is to improve the quality of care and the individual outcomes. We will do so by performing three systematic reviews with meta-analyses of individual participant data (IPD). The aim of these reviews is to investigate potential predictors and moderating patient characteristics on treatment outcomes for patients with BPD.Methods and analysisWe performed comprehensive searches in 22 databases and trial registries up to October 6th 2020. These will be updated with a top-up search up until June 2021. Our primary meta-analytic method will be the one-stage random-effects approach. To identify predictors, we will use the one-stage model that accounts for interaction between covariates and treatment allocation. Heterogeneity in case-mix will be assessed with a membership model based on a multinomial logistic regression where study membership is the outcome. A random-effects meta-analysis is chosen to account for expected levels of heterogeneity.Ethics and disseminationThe statistical analyses will be conducted on anonymised data that have already been approved by the respective ethical committees that originally assessed the included trials. The three IPD reviews will be published in high-impact factor journals and their results will be presented at international conferences and national seminars.PROSPERO registration numberCRD42021210688.

To estimate the incremental yield of single nucleotide polymorphism (SNP) array over karyotype and to assess the diagnostic accuracy of SNP array as a stand-alone test versus SNP array with karyotype in detecting chromosomal abnormalities for prenatal diagnosis in women with an abnormal fetal ultrasound.Studies in which SNP array and karyotype had been used for diagnosing chromosomal aberrations in fetuses with abnormal ultrasound findings were included. A systematic search of relevant studies published in the English language in EMBASE, PubMed, CENTRAL, CDSR (Cochrane database of systematic reviews), SCOPUS and Web of science between 1996 and May 2020 was performed. Primary outcome was incremental yield of SNP array over karyotype (number of patients with abnormalities detected by SNP array over number of patients with normal karyotype). Other outcomes included diagnostic accuracy of SNP array alone versus SNP array and karyotype for prenatal diagnosis. Pooled sensitivities, specificities, and their 95% confidence intervals (CI) were presented.Seven studies were included. The incremental yield of SNP array over karyotype was 8% (95% Confidence interval, CI 4-12%) while incremental yield of karyotype over SNP array in foetus with abnormal ultrasound was 0% (95% CI 0-1%). The agreement between SNP array and karyotype was 92%. The variant of unknown significance rates ranged between 4 and 8 %. The pooled sensitivity and specificity of SNP array versus SNP array and karyotype was 0.97 (95% CI 0.92-0.99) and 1.00 (95% CI1.00-1.00), respectively.SNP array provides additional information on chromosomal abnormalities over and above conventional karyotype. When used as a stand-alone test, SNP array performs favourably as a diagnostic modality when compared against SNP array and karyotype for prenatal diagnosis with an abnormal fetal ultrasound.

Atomoxetine is prescribed to children with autism spectrum disorder having symptoms of attention deficit hyperactivity disorder. We sought to examine the efficacy and safety of atomoxetine in this population. After screening for inclusion criteria, we identified three randomized placebo controlled trials involving 241 children. We assessed internal validity using standard Cochrane Risk of bias tool for randomized controlled trials (RCTs). We used Revman 5.3 for meta‐analysis and GRADE approach to create summary of findings with grading of the quality of evidence. Atomoxetine had a benefit on improving parent‐rated hyperactivity (standardized mean difference [SMD] = −0.73, 95% Confidence Interval, CI = −1.15 to −0.34) and parent‐rated inattention (SMD = −0.53, 95% CI = −0.93 to −0.12) but the magnitude of effects is uncertain. However, atomoxetine was also associated with increased risk of non‐serious adverse effects like nausea and vomiting, decreased sleep, and decreased appetite. Atomoxetine may be effective in improving hyperactivity and inattention in children with autism spectrum disorder and attention deficit hyperactivity disorder. However, we are uncertain about the true effect of this intervention and need more RCTs trials designed to evaluate this. Autism Research 2019, 12: 542–552. © 2019 International Society for Autism Research, Wiley Periodicals, Inc.\ud \ud \ud \ud Lay Summary\ud \ud Atomoxetine is prescribed for Attention Deficit Hyperactivity Disorder (ADHD). About a third of children and adolescents with autism also suffer from ADHD. We carried out an analysis of data reported from a specific kind of medication trials which had examined the effectiveness and side effects of atomoxetine in this patient population. We could find only three such trials and analyzed the reported data. Our analysis revealed that atomoxetine is effective in improving symptoms of ADHD like hyperactivity and inattention and also causes side effects like nausea, vomiting, decreased sleep, and decreased appetite. However, the existing data are insufficient to provide a conclusive statement with certainty and more trials are needed for this.

Background Health behaviour can change outcomes in both healthy and unhealthy populations and are particularly useful in promoting compliance to treatment and maintaining fidelity to care seeking and follow-up options in chronic diseases. Interventions to change health behaviour based on psychological theory are more often successful than those without any underlying theory. The theory of planned behaviour (TPB) is one such psychological theory which had been found to predict human behaviour with respect to disease prevention and when applied to interventions can change the outcomes of diseases. Most of the research evidence of TPB-based interventions have been from developed world. Evidence is required whether TPB-based interventions can be applied and works in low-resource, low health-literacy settings of low- and middle-income countries (LMICs). Methods The protocol has been developed as per PRISMA-P guidelines and incorporates PICO (population, intervention, comparison, outcomes) framework for describing the methodology. Population above 18 years of age and having any chronic disease (as defined for this systematic review) will be selected, while any health or educational intervention based on constructs of TPB will be included. Comparison will be with non-TPB-based interventions or treatment as usual without any intervention, and the primary outcome will be the behaviour change effected by the TPB-based intervention. Intervention studies will be considered, and relevant databases like MEDLINE, Embase, Cochrane Library and ProQuest will be explored. Data extraction will done in a standardised form, and risk-of-bias assessment will be done using the Cochrane Collaboration’s tools for such assessment. Narrative synthesis of the selected studies will be done to draw the conclusions, and meta-analysis will be done to calculate the effect estimates with I-squared statistics to describe the heterogeneity. Discussion This systematic review will provide new evidence on fidelity and effectiveness of the TPB-based interventions among chronic disease patients from low health literacy, resource-poor background. It will inform of how to plan and use such interventions to change health behaviour in chronic disease patients, particularly in LMIC settings. Systematic review registration PROSPERO CRD42018104890.

Background The World Health Organization has recommended Vitamin A supplementation for children in low- and middle-income countries for many years to reduce child mortality. Nepal still practices routine Vitamin A supplementation. We examined the potential current impact of these programs using national data in Nepal combined with an update of the mortality effect estimate from a meta-analysis of randomized controlled trials. Methods We used the 2017 Cochrane review as a template for an updated meta-analysis. We conducted fresh searches, re-applied the inclusion criteria, re-extracted the data for mortality and constructed a summary of findings table using GRADE. We applied the best estimate of the effect obtained from the trials to the national statistics of the country to estimate the impact of supplementation on under-five mortality in Nepal. Results The effect estimates from well-concealed trials gave a 9% reduction in mortality (Risk Ratio: 0.91, 95% CI 0.85 to 0.97, 6 trials; 1,046,829 participants; low certainty evidence). The funnel plot suggested publication bias, and a meta-analysis of trials published since 2000 gave a smaller effect estimate (Risk Ratio: 0.96, 95% CI 0.89 to 1.03, 2 trials, 1,007,587 participants), with the DEVTA trial contributing 55.1 per cent to this estimate. Applying the estimate from well-concealed trials to Nepal’s under-five mortality rate, there may be a reduction in mortality, and this is small from 28 to 25 per 1000 live births; 3 fewer deaths (95% CI 1 to 4 fewer) for every 1000 children supplemented. Conclusions Vitamin A supplementation may only result in a quantitatively unimportant reduction in child mortality. Stopping blanket supplementation seems reasonable given these data.

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

Background Nutrition is an important aspect of management in severe acute pancreatitis. Enteral nutrition has advantages over parenteral nutrition and is the preferred method of feeding. Enteral feeding via nasojejunal tube is often recommended, but its benefits over nasogastric feeding are unclear. The placement of a nasogastric tube is technically simpler than the placement of a nasojejunal tube. Objectives To compare the mortality, morbidity, and nutritional status outcomes of people with severe acute pancreatitis fed via nasogastric tube versus nasojejunal tube. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS on 17 October 2019 without using any language restrictions. We also searched reference lists and conference proceedings for relevant studies and clinical trial registries for ongoing trials. We contacted authors for additional information. Selection criteria We included randomised controlled trials (RCTs) and quasi-RCTs comparing enteral feeding by nasogastric and nasojejunal tubes in participants with severe acute pancreatitis. Data collection and analysis Two review authors independently screened studies for inclusion, assessed risk of bias of the included studies, and extracted data. This information was independently verified by the other review authors. We used standard methods expected by Cochrane to assess the risk of bias and perform data synthesis. We rated the certainty of evidence according to GRADE. Main results We included five RCTs that randomised a total of 220 adult participants from India, Scotland, and the USA. Two of the trial reports were available only as abstracts. The trials differed in the criteria used to rate the severity of acute pancreatitis, and three trials excluded those who presented in severe shock. The duration of onset of symptoms before presentation in the trials ranged from within one week to four weeks. The trials also differed in the methods used to confirm the placement of the tubes and in what was considered to be nasojejunal placement. We assessed none of the trials as at high risk of bias, though reporting of methods in four trials was insufficient to judge the risk of bias for one or more of the domains assessed. There was no evdence of effect with nasogastric or nasojejunal placement on the primary outcome of mortality (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.36 to 1.17; I2 = 0%; 5 trials, 220 participants; very low-certainty evidence due to indirectness and imprecision). Similarly, there was no evidence of effect on the secondary outcomes for which data were available. These included organ failure (3 trials, 145 participants), rate of infection (2 trials, 108 participants), success rate (3 trials, 159 participants), complications associated with the procedure (2 trials, 80 participants), need for surgical intervention (3 trials, 145 participants), requirement of parenteral nutrition (2 trials, 80 participants), complications associated with feeds (4 trials, 195 participants), and exacerbation of pain (4 trials, 195 participants). However, the certainty of the evidence for these secondary outcomes was also very low due to indirectness and imprecision. Three trials (117 participants) reported on length of hospital stay, but the data were not suitable for meta-analysis. None of the trials reported data suitable for meta-analysis for the other secondary outcomes of this review, which included days taken to achieve full nutrition requirement, duration of tube feeding, and duration of analgesic requirement after feeding tube placement. Authors' conclusions There is insufficient evidence to conclude that there is superiority, inferiority, or equivalence between the nasogastric and nasojejunal mode of enteral tube feeding in people with severe acute pancreatitis.

Early Childhood Caries (ECC) is a serious public health problem in developed as well as developing nations, with high prevalence among children around the world. This systematic review of the national literature was undertaken to document the prevalence of Early Childhood Caries. Studies evaluating the prevalence of Early Childhood Caries (ECC) in the Indian population were investigated. The method under evaluation was the use of a caries experience index to calculate the prevalence of ECC. An extensive literature search was done in the following databases: PubMed, IndMED and Cochrane upto June 2016. A modified version of the Newcastle-Ottawa Scale for cross-sectional studies was used for assessment of the quality of the studies. A systematic literature search yielded 503 publications from the various databases searched. Based on the inclusion and exclusion criteria, the final number of included studies were 54. Among the included studies, 19 studies were carried out in the state of Karnataka. Analysis of all the included studies revealed the overall prevalence of ECC in India to be 49.6%. Andhra Pradesh was found to have the highest prevalence of ECC at 63%, and the lowest prevalence was reported in Sikkim (41.92%). This review has reported a high prevalence of ECC in India. None of the states reported prevalence below 40%. The government should identify ECC as a national priority which requires significant attention.

Background Tuberculosis causes more deaths than any other infectious disease worldwide, with pulmonary tuberculosis being the most common form. Standard first‐line treatment for drug‐sensitive pulmonary tuberculosis for six months comprises isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) for two months, followed by HRE (in areas of high TB drug resistance) or HR, given over a four‐month continuation phase. Many people do not complete this full course. Shortened treatment regimens that are equally effective and safe could improve treatment success. Objectives To evaluate the efficacy and safety of shortened treatment regimens versus the standard six‐month treatment regimen for individuals with drug‐sensitive pulmonary tuberculosis. Search methods We searched the following databases up to 10 July 2019: the Cochrane Infectious Diseases Group Specialized Register; the Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE (PubMed); Embase; the Latin American Caribbean Health Sciences Literature (LILACS); Science Citation Index‐Expanded; Indian Medlars Center; and the South Asian Database of Controlled Clinical Trials. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, the Clinical Trials Unit of the International Union Against Tuberculosis and Lung Disease, the UK Medical Research Council Clinical Trials Unit, and the Clinical Trials Registry India for ongoing trials. We checked the reference lists of identified articles to find additional relevant studies. Selection criteria We searched for randomized controlled trials (RCTs) or quasi‐RCTs that compared shorter‐duration regimens (less than six months) versus the standard six‐month regimen for people of all ages, irrespective of HIV status, who were newly diagnosed with pulmonary tuberculosis by positive sputum culture or GeneXpert, and with presumed or proven drug‐sensitive tuberculosis. The primary outcome of interest was relapse within two years of completion of anti‐tuberculosis treatment (ATT). Data collection and analysis Two review authors independently selected trials, extracted data, and assessed risk of bias for the included trials. For dichotomous outcomes, we used risk ratios (RRs) with 95% confidence intervals (CIs). When appropriate, we pooled data from the included trials in meta‐analyses. We assessed the certainty of evidence using the GRADE approach. Main results We included five randomized trials that compared fluoroquinolone‐containing four‐month ATT regimens versus standard six‐month ATT regimens and recruited 5825 adults with newly diagnosed drug‐sensitive pulmonary tuberculosis from 14 countries with high tuberculosis transmission in Asia, Africa, and Latin Ameria. Three were multi‐country trials that included a total of 572 HIV‐positive people. These trials excluded children, pregnant or lactating women, people with serious comorbid conditions, and those with diabetes mellitus. Four trials had multiple treatment arms. Moxifloxacin replaced ethambutol in standard four‐month, daily or thrice‐weekly ATT regimens in two trials; moxifloxacin replaced isoniazid in four‐month ATT regimens in two trials, was given daily in one trial, and was given with rifapentine instead of rifampicin daily for two months and twice weekly for two months in one trial. Moxifloxacin was added to standard ATT drugs for three to four months in one ongoing trial that reported interim results. Gatifloxacin replaced ethambutol in standard ATT regimens given daily or thrice weekly for four months in two trials. Follow‐up ranged from 12 months to 24 months after treatment completion for the majority of participants. Moxifloxacin‐containing four‐month ATT regimens Moxifloxacin‐containing four‐month ATT regimens that replaced ethambutol or isoniazid probably increased the proportions who experienced relapse after successful treatment compared to standard ATT regimens (RR 3.56, 95% CI 2.37 to 5.37; 2265 participants, 3 trials; moderate‐certainty evidence). For death from any cause, there was probably little or no difference between the two regimens (2760 participants, 3 trials; moderate‐certainty evidence). Treatment failure was rare, and there was probably little or no difference in proportions with treatment failure between ATT regimens (2282 participants, 3 trials; moderate‐certainty evidence). None of the participants given moxifloxacin‐containing regimens developed resistance to rifampicin, and these regimens may not increase the risk of acquired resistance (2282 participants, 3 trials; low‐certainty evidence). Severe adverse events were probably little or no different with moxifloxacin‐containing four‐month regimens that replaced ethambutol or isoniazid, and with three‐ to four‐month regimens that augmented standard ATT with moxifloxacin, when compared to standard six‐month ATT regimens (3548 participants, 4 trials; moderate‐certainty evidence). Gatifloxacin‐containing four‐month ATT regimens Gatifloxacin‐containing four‐month ATT regimens that replaced ethambutol probably increased relapse compared to standard six‐month ATT regimens in adults with drug‐sensitive pulmonary tuberculosis (RR 2.11, 95% CI 1.56 to 2.84; 1633 participants, 2 trials; moderate‐certainty evidence). The four‐month regimen probably made little or no difference in death compared to the six‐month regimen (1886 participants, 2 trials; moderate‐certainty evidence). Treatment failure was uncommon and was probably little or no different between the four‐month and six‐month regimens (1657 participants, 2 trials; moderate‐certainty evidence). Acquired resistance to isoniazid or rifampicin was not detected in those given the gatifloxacin‐containing shortened ATT regimen, but we are uncertain whether acquired drug resistance is any different in the four‐ and six‐month regimens (429 participants, 1 trial; very low‐certainty evidence). Serious adverse events were probably no different with either regimen (1993 participants, 2 trials; moderate‐certainty evidence). Authors' conclusions Evidence to date does not support the use of shortened ATT regimens in adults with newly diagnosed drug‐sensitive pulmonary tuberculosis. Four‐month ATT regimens that replace ethambutol with moxifloxacin or gatifloxacin, or isoniazid with moxifloxacin, increase relapse substantially compared to standard six‐month ATT regimens, although treatment success and serious adverse events are little or no different. The results of six large ongoing trials will help inform decisions on whether shortened ATT regimens can replace standard six‐month ATT regimens. 9 December 2019 Up to date All studies incorporated from most recent search All eligible published studies found in the last search (10 Jul, 2019) were included, Plain language summary Shorter treatment regimens for people with pulmonary tuberculosis What was the aim of this review? The aim of this Cochrane Review was to find out if the duration of anti‐tuberculosis treatment (ATT) for people with newly diagnosed drug‐sensitive pulmonary tuberculosis can be shortened to less than six months. Cochrane Review authors collected and analysed all relevant studies to answer this question and found five relevant studies. Key messages Shortened ATT regimens probably make little or no difference in death, treatment failure, or serious adverse events compared to six‐month ATT regimens, but they probably increase relapse of tuberculosis. Six large ongoing trials are studying this question. What was studied in the review? Tuberculosis is an infectious disease, and tuberculosis affecting the lungs (pulmonary tuberculosis) is the most common presentation of tuberculosis in adults. Tuberculosis is a major public health problem worldwide, and among infectious diseases, it is the leading cause of death. People with pulmonary tuberculosis are currently treated with a six‐month combination of drugs that include isoniazid, rifampicin, ethambutol, and pyrazinamide for two months, followed by isoniazid and rifampicin (with or without ethambutol) for four months. Many people do not finish the treatment or they take the drugs irregularly because of the long treatment duration, or because of drug side effects. Incomplete or irregular treatment can lead to treatment failure and can increase disease relapse. Such treatment can also lead to drug resistance. If newer drug combinations given for less than six months are found to be as effective and safe as the currently recommended six‐month ATT regimens, more people might be adherent and might complete treatment. This could help reduce drug resistance and could help to stop tuberculosis infection worldwide. What are the main results of the review? The five included trials studied 5825 adults with newly diagnosed drug‐sensitive pulmonary tuberculosis from 14 countries with high tuberculosis transmission in Asia, Africa, and Latin Ameria. Three trials included 572 HIV‐positive people, but all excluded people with other serious comorbid conditions and those with diabetes mellitus. This reduced the applicability of study results. All were funded by government or international agencies. Four studies replaced isoniazid or ethambutol with moxifloxacin or gatifloxacin in four‐month ATT regimens. Follow‐up was provided for 12 months to 24 months after treatment completion. In one ongoing study, moxifloxacin was added to four‐month ATT, but study authors provided only interim results. This review shows the following when four‐month ATT regimens are compared to standard six‐month ATT regimens. • Relapse after successful treatment is probably increased (moderate‐certainty evidence). • Death from any cause, treatment failure, and serious adverse events are probably little or no different (moderate‐certainty evidence). • Drug resistance may not be increased with moxifloxacin‐containing four‐month regimens (low‐certainty evidence), but we are uncertain whether this applies to gatifloxacin‐containing regimens (very low‐certainty evidence). How up‐to‐date is this review? The review authors searched for available studies up to 10 July 2019.

Pregnancies resulting from assisted reproductive techniques are at higher risk of adverse perinatal outcomes compared with spontaneous conceptions. Underlying infertility and IVF procedures have been linked to adverse perinatal outcomes. It is important to know if ovarian stimulation influences perinatal outcomes after IVF. A systematic search for relevant studies was conducted up to November 2016 on the following databases: PubMed, EMBASE, DARE and Cochrane Central Register of Controlled Trials. Perinatal outcomes included preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), large for gestational age (LGA) and congenital anomalies. Data from four studies, which included a total of 96,996 and 704 singleton live births after stimulated IVF and natural or modified natural cycle IVF, were included in the meta-analysis. The risk of PTB (RR 1.27, 95% CI 1.03 to 1.58) and LBW (RR 1.95, 95% CI 1.03 to 3.67) were significantly higher after stimulated compared with natural or modified natural cycle IVF. Data from one study were available for SGA, LGA, congenital anomalies and no significant differences were reported between the groups. This study suggests a higher risk of PTB and LBW after stimulated IVF compared with natural or modified natural IVF, although the absolute increase in risk may be low.

We planned a systematic review and meta-analysis of randomized clinical trials (RCTs) to examine the best available evidence regarding the intrauterine instillation of embryo culture supernatant prior to embryo transfer in ART. The outcomes were: (i) live birth; (ii) clinical pregnancy; (iii) multiple pregnancy; and (iv) miscarriage rates. Five RCTs were considered eligible and available for qualitative synthesis. Due to clinical heterogeneity, results from only two trials were combined for the meta-analysis. The live birth rate (risk ratio [RR], 0.47; 95% confidence interval [CI] 0.22–0.98; one study, 60 participants, low-quality evidence) was found to be significantly lower with intrauterine instillation of embryo culture supernatant compared to no intervention. The clinical pregnancy rate was similar between the embryo culture supernatant group and the control group (RR 1.02 RR, 95% CI 0.77–1.36; two trials, 156 participants, I2 = 0%). To conclude, this review did not find any improvement in clinical pregnancy rate with the intrauterine instillation of embryo culture supernatant prior to embryo transfer compared to no intervention in women undergoing ART and we remain uncertain regarding its effect on live birth rate.

In this systematic review, we aimed to assess role of plasma von-Willebrand factor (vWF), an endothelial activation marker, as prognostic marker in patients with chronc liver disease [cirrhosis and acute-on-chronic liver failure (ACLF)]. We searched published databases using predefined keywords to identify all studies up to June 2018, in which plasma vWF (antigen or activity assay) was used as prognostic marker predicting mortality in patients with chronic liver disease. Relevant extracted data from selected studies were narratively summarized. The individual study's area under ROC curve for plasma vWF as a predictor of mortality was pooled and meta-analyzed. Six studies (cirrhosis: 5; ACLF: 1) with an aggregate data of 765 patients (cirrhosis: 715 patients; ACLF: 50 patients) were included. Baseline plasma vWF-antigen was an independent predictor of medium-term mortality in patients with cirrhosis (summary area under the curve: 0.74; 95% confidence interval: 0.70-0.79) with an optimal cutoff of 318% (216-390%; median, range) over a period of 25.6 months (23.6-33 months). Plasma vWF also predicted short-term (over 7 days) mortality in patients with ACLF. Plasma vWF levels correlated with Child's score, model for end-stage liver disease (MELD) score and hepatic venous pressure gradient and performed as well as MELD score in predicting mortality in patients with cirrhosis and ACLF. Baseline plasma vWF level predicts mortality over a medium term (1-3 years) in cirrhosis and over a short term (1 week) in ACLF patients. The marked elevation of baseline plasma vWF levels in ACLF patients was associated with drastic truncation of survival when compared with cirrhosis patients.

Objective.A systematic literature review was performed to document published magnetic resonance imaging (MRI) lesion definitions and scoring systems for enthesitis in spondyloarthritis (SpA).Methods.PubMed, Embase, and Cochrane Library databases were searched for original publications involving adult patients with SpA undergoing MRI of axial/peripheral joints. Selected articles were assessed for quality using a standardized assessment tool and metric indices.Results.Considering the heterogeneous design, quality, and outcome measures of studies, statistical data pooling was considered inappropriate. A qualitative narrative of results was undertaken based on study designs.Conclusion.Lack of a comprehensive, validated score warrants additional research to develop an MRI enthesitis scoring system. PROSPERO registration number: CRD42018090537.

Background Granulocyte-colony stimulating factor (G-CSF) seems to play an important role in the process of embryo implantation and continuation of pregnancy. It has been used during in vitro fertilisation (IVF) treatment for subfertile women with chronically thin endometrium and those with previous multiple IVF failures. It is currently unknown whether G-CSF is effective in improving results following assisted reproductive technology (ART). Objectives To evaluate the effectiveness and safety of G-CSF in women undergoing ART. Search methods We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform in February 2019. We searched reference lists of relevant articles and handsearched relevant conference proceedings. Selection criteria Randomised controlled trials (RCTs) comparing G-CSF administration versus no treatment or placebo in subfertile women undergoing IVF treatment. Data collection and analysis Two review authors independently screened studies, extracted data, and assessed risk of bias. The primary outcomes were live-birth rate and miscarriage rate following G-CSF administration. We have reported ongoing pregnancy rate in cases where studies did not report live birth but reported ongoing pregnancy. Secondary outcomes were clinical pregnancy rate, multiple pregnancy rate, adverse events, ectopic pregnancy rate, small for gestational age at birth, abnormally adherent placenta, and congenital anomaly rate. We analysed data using risk ratio (RR), Peto odds ratio and a fixed-effect model. We assessed the quality of the evidence using the GRADE criteria. Main results We included 15 trials involving 622 women who received G-CSF and 631 women who received placebo or no additional treatment during IVF. The main limitations in the quality of the evidence were inadequate reporting of study methods and high risk of performance bias due to lack of blinding. We assessed only two of the 15 included trials as at a low risk of bias. None of the trials reported the primary effectiveness outcome of live-birth rate. We are uncertain whether G-CSF administration improves ongoing pregnancy rate compared to control in subfertile women undergoing ART (RR 1.42, 95% confidence interval (CI) 0.83 to 2.42; 2 RCTs; participants = 263; I² = 0%; very low-quality evidence). For a typical clinic with 14% ongoing pregnancy rate, G-CSF administration would be expected to result in ongoing pregnancy rates between 12% and 35%. We are uncertain whether G-CSF administration reduces miscarriage rate (Peto odds ratio 0.55, 95% CI 0.17 to 1.83; 3 RCTs; participants = 391; I² = 0%; very low-quality evidence) compared to the control group in subfertile women undergoing ART. We are uncertain whether G-CSF administration improves overall clinical pregnancy rate compared to control in subfertile women undergoing ART (RR 1.63, 95% CI 1.32 to 2.01; 14 RCTs; participants = 1253; I² = 13%; very low-quality evidence). For a typical clinic with 17% clinical pregnancy rate, G-CSF administration would be expected to result in clinical pregnancy rates between 23% and 35%. In the unselected IVF population, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.11, 95% CI 0.77 to 1.60; 3 RCTs; participants = 404; I² = 0%; low-quality evidence). G-CSF administration may improve clinical pregnancy rate in women with two or more previous IVF failures compared to the control group (RR 2.11, 95% CI 1.56 to 2.85; 7 RCTs; participants = 643; I² = 0%; low-quality evidence). In subfertile women with thin endometrium undergoing ART, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.58, 95% CI 0.95 to 2.63; 4 RCTs; participants = 206; I² = 30%; low-quality evidence). No study reported on multiple pregnancy rate. Only four trials reported adverse events as an outcome, and none of them reported any major adverse events following either G-CSF administration or placebo/no treatment. Authors' conclusions In subfertile women undergoing ART, we are uncertain whether the administration of G-CSF improves ongoing pregnancy or overall clinical pregnancy rates or reduces miscarriage rate compared to no treatment or placebo, whether in all women or those with thin endometrium, based on very low-quality evidence. Low-quality evidence suggests that G-CSF administration may improve clinical pregnancy rate in women with two or more IVF failures, but the included studies had unclear allocation concealment or were at high risk of performance bias.

PURPOSE: Although the use of steroids in the management of COVID-19 has been addressed by a few systematic review and meta-analysis, however, they also used data from “SARS-CoV” and “MERS-CoV.” Again, most of these studies addressed only one severity category of patients or addressed only one efficacy endpoint (mortality). In this context, we conducted this meta-analysis to evaluate the efficacy and safety of steroid therapy among all severity categories of patients with COVID-19 (mild to moderate and severe to critical category) in terms of “mortality,” “requirement of mechanical ventilation,” “requirement of ICU” and clinical cure parameters. METHODS: 11 databases were screened. Only randomized controlled trials (RCTs) or high quality (on the basis of risk of bias analysis) comparative-observational studies were included in the analysis. RevMan5.3 was used for the meta-analysis. RESULTS: A total of 15 studies (3 RCT and 12 comparative-observational studies) were included. In the mechanically-ventilated COVID-19 population, treatment with dexamethasone showed significant protection against mortality (single study). Among severe and critically ill combined population, steroid administration was significantly associated with lowered mortality (risk ratio [RR] 0.83 [0.76–0.910]), lowered requirement of mechanical ventilation (RR 0.59 [0.51–0.69]), decreased requirement of intensive care unit (ICU) (RR 0.62 [0.45–0.86]), lowered length of ICU stay (single-study) and decreased duration of mechanical ventilation (two-studies). In mild to moderate population, steroid treatment was associated with a higher “duration of hospital stay,” while no difference was seen in other domains. In patients at risk of progression to “acute respiratory distress syndrome,” steroid administration was associated with “reduced requirement of mechanical ventilation” (single-study). CONCLUSION: This study guides the use of steroid across patients with different severity categories of COVID-19. Among mechanically ventilated patients, steroid therapy may be beneficial in terms of reduced mortality. Among “severe and critical” patients; steroid therapy was associated with lowered mortality, decreased requirement of mechanical ventilation, and ICU. However, no benefit was observed in “mild to moderate” population. To conclude, among properly selected patient populations (based-upon clinical severity and biomarker status), steroid administration may prove beneficial in patients with COVID-19.

BACKGROUND: 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. OBJECTIVES: To assess the effect and risk‐benefit profile of interventions for preventing upper GI bleeding in people admitted to ICUs. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. MAIN RESULTS: 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 prophylaxis In 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 prophylaxis In 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 inhibitors H2 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). AUTHORS' CONCLUSIONS: 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.

Background Edentulism is relatively common and is often treated with the provision of complete or partial removable dentures. Clinicians make final impressions of complete dentures (CD) and removable partial dentures (RPD) using different techniques and materials. Applying the correct impression technique and material, based on an individual's oral condition, improves the quality of the prosthesis, which may improve quality of life. Objectives To assess the effects of different final-impression techniques and materials used to make complete dentures, for retention, stability, comfort, and quality of life in completely edentulous people.To assess the effects of different final-impression techniques and materials used to make removable partial dentures, for stability, comfort, overextension, and quality of life in partially edentulous people. Search methods Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 22 November 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Register of Studies, to 22 November 2017), MEDLINE Ovid (1946 to 22 November 2017), and Embase Ovid (21 December 2015 to 22 November 2017). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on language or publication status when searching the electronic databases, however the search of Embase was restricted by date due to the Cochrane Centralised Search Project to identify all clinical trials and add them to CENTRAL. Selection criteria We included randomised controlled trials (RCTs) comparing different final-impression techniques and materials for treating people with complete dentures (CD) and removable partial dentures (RPD). For CD, we included trials that compared different materials or different techniques or both. In RPD for tooth-supported conditions, we included trials comparing the same material and different techniques, or different materials and the same technique. In tooth- and tissue-supported RPD, we included trials comparing the same material and different dual-impression techniques, and different materials with different dual-impression techniques. Data collection and analysis Two review authors independently, and in duplicate, screened studies for eligibility, extracted data, and assessed the risk of bias for each included trial. We expressed results as risk ratios (RR) for dichotomous outcomes, and as mean differences (MD) or standardised mean differences (SMD) for continuous outcomes, with 95% confidence intervals (CI), using the random-effects model. We constructed 'Summary of findings' tables for the main comparisons and outcomes (participant-reported oral health-related quality of life, quality of the denture, and denture border adjustments). Main results We included nine studies in this review. Eight studies involved 485 participants with CD. We assessed six of the studies to be at high risk of bias, and two to be at low risk of bias. We judged one study on RPD with 72 randomised participants to be at high risk of bias.Overall, the quality of the evidence for each comparison and outcome was either low or very low, therefore, results should be interpreted with caution, as future research is likely to change the findings.Complete denturesTwo studies compared the same material and different techniques (one study contributed data to a secondary outcome only); two studies compared the same technique and different materials; and four studies compared different materials and techniques.One study (10 participants) evaluated two stage-two step, Biofunctional Prosthetic system (BPS) using additional silicone elastomer compared to conventional methods, and found no evidence of a clear difference for oral health-related quality of life, or quality of the dentures (denture satisfaction). The study reported that BPS required fewer adjustments. We assessed the quality of the evidence as very low.One study (27 participants) compared selective pressure final-impression technique using wax versus polysulfide elastomeric (rubber) material. The study did not measure quality of life or dentures, and found no evidence of a clear difference between interventions in the need for adjustments (RR 0.81, 95% CI 0.38 to 1.70). We assessed the quality of the evidence as very low.One study compared two stage-two step final impression with alginate versus silicone elastomer. Oral health-related quality of life measured by the OHIP-EDENT seemed to be better with silicone (MD 7.20, 95% CI 2.71 to 11.69; 144 participants). The study found no clear differences in participant-reported quality of the denture (comfort) after a two-week 'confirmation' period, but reported that silicone was better for stability and chewing efficiency. We assessed the quality of the evidence as low.Three studies compared single-stage impressions with alginate versus two stage-two step with elastomer (silicone, polysulfide, or polyether) impressions. There was no evidence of a clear difference in the OHIP-EDENT at one month (MD 0.05, 95% CI -2.37 to 2.47; two studies, 98 participants). There was no evidence of a clear difference in participant-rated general satisfaction with dentures at six months (MD 0.00, 95% CI -8.23 to 8.23; one study, 105 participants). We assessed the quality of the evidence as very low.One study compared single-stage alginate versus two stage-two step using zinc-oxide eugenol, and found no evidence of a clear difference in OHIP-EDENT (MD 0.50, 95% CI -2.67 to 3.67; 39 participants), or general satisfaction (RR 3.15, 95% CI 0.14 to 72.88; 39 participants) at six months. We assessed the quality of the evidence as very low.Removable partial denturesOne study randomised 72 participants and compared altered-cast technique versus one-piece cast technique. The study did not measure quality of life, but reported that most participants were satisfied with the dentures and there was no evidence of any clear difference between groups for general satisfaction at one-year follow-up (low-quality evidence). There was no evidence of a clear difference in number of intaglio adjustments at one year (RR 1.43, 95% CI 0.61 to 3.34) (very low-quality evidence). Authors' conclusions We conclude that there is no clear evidence that one technique or material has a substantial advantage over another for making complete dentures and removable partial dentures. Available evidence for the relative benefits of different denture fabrication techniques and final-impression materials is limited and is of low or very low quality. More high-quality RCTs are required.

Background: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used medication to treat it. Several studies have investigated the benefits of methylphenidate, showing possible favourable effects on ADHD symptoms, but the true magnitude of the effect is unknown. Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events. Objectives: To assess the adverse events associated with methylphenidate treatment for children and adolescents with ADHD in non-randomised studies. Search methods: In January 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 12 other databases and two trials registers. We also checked reference lists and contacted authors and pharmaceutical companies to identify additional studies. Selection criteria: We included non-randomised study designs. These comprised comparative and non-comparative cohort studies, patient-control studies, patient reports/series and cross-sectional studies of methylphenidate administered at any dosage or formulation. We also included methylphenidate groups from RCTs assessing methylphenidate versus other interventions for ADHD as well as data from follow-up periods in RCTs. Participants had to have an ADHD diagnosis (from the 3rd to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders or the 9th or 10th edition of theInternational Classification of Diseases, with or without comorbid diagnoses. We required that at least 75% of participants had a normal intellectual capacity (intelligence quotient of more than 70 points) and were aged below 20 years. We excluded studies that used another ADHD drug as a co-intervention. Data collection and analysis: Fourteen review authors selected studies independently. Two review authors assessed risk of bias independently using the ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions. All review authors extracted data. We defined serious adverse events according to the International Committee of Harmonization as any lethal, life-threatening or life-changing event. We considered all other adverse events to be non-serious adverse events and conducted meta-analyses of data from comparative studies. We calculated meta-analytic estimates of prevalence from non-comparative cohorts studies and synthesised data from patient reports/series qualitatively. We investigated heterogeneity by conducting subgroup analyses, and we also conducted sensitivity analyses. Main results: We included a total of 260 studies: 7 comparative cohort studies, 6 of which compared 968 patients who were exposed to methylphenidate to 166 controls, and 1 which assessed 1224 patients that were exposed or not exposed to methylphenidate during different time periods; 4 patient-control studies (53,192 exposed to methylphenidate and 19,906 controls); 177 non-comparative cohort studies (2,207,751 participants); 2 cross-sectional studies (96 participants) and 70 patient reports/series (206 participants). Participants' ages ranged from 3 years to 20 years. Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low. Primary outcomes In the comparative studies, methylphenidate increased the risk ratio (RR) of serious adverse events (RR 1.36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention. In the non-comparative cohort studies, the proportion of participants on methylphenidate experiencing any serious adverse event was 1.20% (95% CI 0.70% to 2.00%; 50 studies, 162,422 participants). Withdrawal from methylphenidate due to any serious adverse events occurred in 1.20% (95% CI 0.60% to 2.30%; 7 studies, 1173 participants) and adverse events of unknown severity led to withdrawal in 7.30% of participants (95% CI 5.30% to 10.0%; 22 studies, 3708 participants). Secondary outcomes In the comparative studies, methylphenidate, compared to no intervention, increased the RR of insomnia and sleep problems (RR 2.58, 95% CI 1.24 to 5.34; 3 studies, 425 participants) and decreased appetite (RR 15.06, 95% CI 2.12 to 106.83; 1 study, 335 participants). With non-comparative cohort studies, the proportion of participants on methylphenidate with any non-serious adverse events was 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants). These included difficulty falling asleep, 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants); headache, 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants); abdominal pain, 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants); and decreased appetite, 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants). Withdrawal of methylphenidate due to non-serious adverse events occurred in 6.20% (95% CI 4.80% to 7.90%; 37 studies, 7142 participants), and 16.2% were withdrawn for unknown reasons (95% CI 13.0% to 19.9%; 57 studies, 8340 participants). Authors' conclusions: Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here. Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.

Background Early and accurate diagnosis of tuberculosis is a priority for TB programs globally to initiate treatment early and improve treatment outcomes. Currently, Ziehl–Neelsen (ZN) stain-based microscopy, GeneXpert and Light Emitting Diode-Fluorescence Microscopy (LED-FM) are used for diagnosing pulmonary drug sensitive tuberculosis. Published evidence synthesising the cost-effectiveness of these diagnostic tools is scarce. Methodology PubMed, EMBASE and Cost-effectiveness analysis registry were searched for studies that reported on the cost-effectiveness of GeneXpert and LED-FM, compared to ZN microscopy for diagnosing pulmonary TB. Risk of bias was assessed independently by four authors using the Consensus Health Economic Criteria (CHEC) extended checklist. The data variables included the study settings, population, type of intervention, type of comparator, year of study, duration of study, type of study design, costs for the test and the comparator and effectiveness indicators. Incremental cost-effectiveness ratio (ICER) was used for assessing the relative cost-effectiveness in this review. Results Of the 496 studies identified by the search, thirteen studies were included after removing duplicates and studies that did not fulfil inclusion criteria. Four studies compared LED-FM with ZN and nine studies compared GeneXpert with ZN. Three studies used patient cohorts and eight were modelling studies with hypothetical cohorts used to evaluate cost-effectiveness. All these studies were conducted from a health system perspective, with four studies utilising cost utility analysis. There were considerable variations in costing parameters and effectiveness indicators that precluded meta-analysis. The key findings from the included studies suggest that LED-FM and GeneXpert may be cost effective for pulmonary TB diagnosis from a health system perspective. Conclusion Our review identifies a consistent trend of the cost effectiveness of LED-FM and GeneXpert for pulmonary TB diagnosis in different countries with diverse context of socio-economic condition, HIV burden and geographical distribution. However, all the studies used different parameters to estimate the impact of these tools and this underscores the need for improving the methodological issues related to the conduct and reporting of cost-effectiveness studies.

To summarise the evidence for the efficacy of oral health educational programmes provided to expectant mothers for preventing Early Childhood Caries (ECC) and to determine the most effective intervention programme.The search strategy included clinical trials in the Cochrane Oral Health Group's Trials Register, PubMed, Science Direct, Google Scholar, LILACS and ClinicalKey (up to 26 August 2013) in English. Reference lists of identified randomised controlled trials (RCTs) and review articles were also hand searched. Studies were selected according to predefined inclusion and exclusion criteria.The search identified 392 studies, only four of which were included. Risk ratios (RR) were calculated. The quality of the evidence was assessed by the GRADE approach. Results showed statistically significant decreases in caries incidence (RR = 0.18, 95% CI [from 0.06 to 0.52]) in one study. Meta-analysis could not be performed.Oral health educational programmes for expectant mothers may have a positive impact in preventing ECC, although the evidence is weak.

Background Stringent glycemic control by using insulin as a replacement or in addition to oral hypoglycemic agents (OHAs) has been recommended for people with tuberculosis and diabetes mellitus (TB-DM). This systematic review (PROSPERO 2016:CRD42016039101) analyses whether this improves TB treatment outcomes. Objectives Among people with drug-susceptible TB and DM on anti-TB treatment, to determine the effect of i) glycemic control (stringent or less stringent) compared to poor glycemic control and ii) insulin (only or with OHAs) compared to 'OHAs only' on unsuccessful TB treatment outcome(s). We looked for unfavourable TB treatment outcomes at the end of intensive phase and/or end of TB treatment (minimum six months and maximum 12 months follow up). Secondary outcomes were development of MDR-TB during the course of treatment, recurrence after 6 months and/or after 1 year post successful treatment completion and development of adverse events related to glucose lowering treatment (including hypoglycemic episodes). Methods All interventional studies (with comparison arm) and cohort studies on people with TB-DM on anti-TB treatment reporting glycemic control, DM treatment details and TB treatment outcomes were eligible. We searched electronic databases (EMBASE, PubMed, Google Scholar) and grey literature between 1996 and April 2017. Screening, data extraction and risk of bias assessment were done independently by two investigators and recourse to a third investigator, for resolution of differences. Results After removal of duplicates from 2326 identified articles, 2054 underwent title and abstract screening. Following full text screening of 56 articles, nine cohort studies were included. Considering high methodological and clinical heterogeneity, we decided to report the results qualitatively and not perform a meta-analysis. Eight studies dealt with glycemic control, of which only two were free of the risk of bias (with confounder-adjusted measures of effect). An Indian study reported 30% fewer unsuccessful treatment outcomes (aOR (0.95 CI): 0.72 (0.64-0.81)) and 2.8 times higher odds of 'no recurrence' (aOR (0.95 CI): 2.83 (2.60-2.92)) among patients with optimal glycemic control at baseline. A Peruvian study reported faster culture conversion among those with glycemic control (aHR (0.95 CI): 2.2 (1.1,4)). Two poor quality studies reported the effect of insulin on TB treatment outcomes. Conclusion We identified few studies that were free of the risk of bias. There were limited data and inconsistent findings among available studies. We recommend robustly designed and analyzed studies including randomized controlled trials on the effect of glucose lowering treatment options on TB treatment outcomes.

Granulocyte-colony stimulating factor (G-CSF), a glycoprotein, has been used in women undergoing Assisted Reproductive Technology (ART). We decided to undertake a systematic review to evaluate the effectiveness of G-CSF in women with thin endometrium and recurrent implantation failure (RIF) undergoing ART. The outcomes included an increase in endometrial thickness, live birth, clinical pregnancy rates and adverse effects. We included two trials evaluating women with thin endometrium and another two trials evaluating women with RIF. The pooled data did not reveal statistically significant increase in endometrial thickness following G-CSF in women with thin endometrium (mean difference 0.47, 95% CI -1.36-2.31; I2 82%). However significantly higher clinical pregnancy rate was noted (RR 2.43, 95% CI 1.09-5.40; I2 0%) following G-CSF compared to no intervention and quality of evidence for both these outcomes was very low. In RIF population, the administration of G-CSF was associated with a significantly higher clinical pregnancy rate compared to no intervention with pooled risk ratio of 2.51 (95% CI 1.36-4.63; I2 0%) and quality of evidence being low. Findings of current review suggest a possible benefit of G-CSF in women with thin endometrium undergoing ART and RIF. However these findings need to be further validated in larger trials before G-CSF can be used in routine clinical practice.

Background Gilles de la Tourette syndrome, or Tourette’s syndrome, is defined as the presence of both motor and vocal (phonic) tics for more than 12 months, that manifest before the age of 18 years, in the absence of secondary causes. Treatment of motor and phonic tics is difficult and challenging. Objectives To determine the safety and effectiveness of botulinum toxin in treating motor and phonic tics in people with Tourette's syndrome, and to analyse the effect of botulinum toxin on premonitory urge and sensory tics. Search methods We searched the Cochrane Movement Disorders Group Trials Register, CENTRAL, MEDLINE, and two trials registers to 25 October 2017. We reviewed reference lists of relevant articles for additional trials. Selection criteria We considered all randomised, controlled, double-blind studies comparing botulinum toxin to placebo or other medications for the treatment of motor and phonic tics in Tourette’s syndrome for this review. We sought both parallel group and cross-over studies of children or adults, at any dose, and for any duration. Data collection and analysis We followed standard Cochrane methods to select studies, assess risk of bias, extract and analyse data. All authors independently abstracted data onto standardized forms; disagreements were resolved by mutual discussion. Main results Only one randomised placebo-controlled, double-blind cross-over study met our selection criteria. In this study, 20 participants with motor tics were enrolled over a three-year recruitment period; 18 (14 of whom had a diagnosis of Tourette’s syndrome) completed the study; in total, 21 focal motor tics were treated. Although we considered most bias domains to be at low risk of bias, the study recruited a small number of participants with relatively mild tics and provided limited data for our key outcomes. The effects of botulinum toxin injections on tic frequency, measured by videotape or rated subjectively, and on premonitory urge, are uncertain (very low-quality evidence). The quality of evidence for adverse events following botulinum toxin was very low. Nine people had muscle weakness following the injection, which could have led to unblinding of treatment group assignment. No data were available to evaluate whether botulinum injections led to immunoresistance to botulinum. Authors' conclusions We are uncertain about botulinum toxin effects in the treatment of focal motor and phonic tics in select cases, as we assessed the quality of the evidence as very low. Additional randomised controlled studies are needed to demonstrate the benefits and harms of botulinum toxin therapy for the treatment of motor and phonic tics in patients with Tourette’s syndrome.

BACKGROUND: Cancer sufferers are amongst the most malnourished of all the patient groups. Studies have shown that ghrelin, a gut hormone can be a potential therapeutic agent for cachexia (wasting syndrome) associated with cancer. A variety of mechanisms of action of ghrelin in people with cancer cachexia have been proposed. However, safety and efficacy of ghrelin for cancer‐associated cachexia have not been systematically reviewed. The aim of this review was to assess whether ghrelin is associated with better food intake, body composition and survival than other options for adults with cancer cachexia. OBJECTIVES: To assess the efficacy and safety of ghrelin in improving food intake, body composition and survival in people with cachexia associated with cancer. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase without language restrictions up to July 2017. We also searched for ongoing studies in trials registers, performed handsearching, checked bibliographic references of relevant articles and contacted authors and experts in the field to seek potentially relevant research. We applied no restrictions on language, date, or publication status. SELECTION CRITERIA: We included randomised controlled (parallel‐group or cross‐over) trials comparing ghrelin (any formulation or route of administration) with placebo or an active comparator in adults (aged 18 years and over) who met any of the international criteria for cancer cachexia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. Two review authors then extracted data and assessed the risk of bias for individual studies using standard Cochrane methodology. For dichotomous variables, we planned to calculate risk ratio with 95% confidence intervals (CI) and for continuous data, we planned to calculate mean differences (MD) with 95% CI. We assessed the evidence using GRADE and created 'Summary of findings' tables. MAIN RESULTS: We screened 926 individual references and identified three studies that satisfied the inclusion criteria. Fifty‐nine participants (37 men and 22 women) aged between 54 and 78 years were randomised initially, 47 participants completed the treatment. One study had a parallel design and two had a cross‐over design. The studies included people with a variety of cancers and also differed in the dosage, route of administration, frequency and duration of treatment. One trial, which compared ghrelin with placebo, found that ghrelin improved food intake (very low‐quality evidence) and had no adverse events (very low‐quality evidence). Due to unavailability of data we were unable to report on comparisons for ghrelin versus no treatment or alternative experimental treatment modalities, or ghrelin in combination with other treatments or ghrelin analogues/ghrelin mimetics/ghrelin potentiators. Two studies compared a higher dose of ghrelin with a lower dose of ghrelin, however due to differences in study designs and great diversity in the treatment provided we did not pool the results. In both trials, food intake did not differ between participants on higher‐dose and lower‐dose ghrelin. None of the included studies assessed data on body weight. One study reported higher adverse events with a higher dose as compared to a lower dose of ghrelin. All studies were at high risk of attrition bias and bias for size of the study. Risk of bias in other domains was unclear or low. We rated the overall quality of the evidence for primary outcomes (food intake, body weight, adverse events) as very low. We downgraded the quality of the evidence due to lack of data, high or unclear risk of bias of the studies and small study size. AUTHORS' CONCLUSIONS: There is insufficient evidence to be able to support or refute the use of ghrelin in people with cancer cachexia. Adequately powered randomised controlled trials focusing on evaluation of safety and efficacy of ghrelin in people with cancer cachexia is warranted.

Objective To compare the prevalence of polycystic ovary syndrome (PCOS) phenotypes and obesity among patients detected in referral versus unselected populations. Design Systematic review and meta-analysis. Setting Not applicable. Patient(s) Thirteen thousand seven hundred ninety-six reproductive-age patients with PCOS, as defined by the extended Rotterdam 2003 criteria. Intervention(s) Review of PUBMED, EMBASE, and Cochrane Library, 2003–2016. Only observational studies were included. Data were extracted using a web-based, piloted form and combined for meta-analysis. Main Outcome Measure(s) PCOS phenotypes were classified as follows: phenotype A, clinical and/or biochemical hyperandrogenism (HA) + oligo-/anovulation (OA) + polycystic ovarian morphology (PCOM); phenotype B, HA+OA; phenotype C, HA+PCOM; and phenotype D, OA+PCOM. Result(s) Forty-one eligible studies, reporting on 43 populations, were identified. Pooled estimates of detected PCOS phenotype prevalence were consequently documented in referral versus unselected populations, as [1] phenotype A, 50% (95% confidence interval [CI], 46%–54%) versus 19% (95% CI, 13%–27%); [2] phenotype B, 13% (95% CI, 11%–17%) versus 25% (95% CI, 15%–37%); [3] phenotype C, 14% (95% CI, 12%–16%) versus 34% (95% CI, 25–46%); and [4] phenotype D, 17% (95% CI, 13%–22%) versus 19% (95% CI, 14%–25%). Differences between referral and unselected populations were statistically significant for phenotypes A, B, and C. Referral PCOS subjects had a greater mean body mass index (BMI) than local controls, a difference that was not apparent in unselected PCOS. Conclusion(s) The prevalence of more complete phenotypes in PCOS and mean BMI were higher in subjects identified in referral versus unselected populations, suggesting the presence of significant referral bias.

Background 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. Objectives To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. Search methods 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. Selection criteria 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. Data collection and analysis 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. Main results 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). Secondary outcomes. 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). Authors' conclusions 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.

BACKGROUND: Mammalian bites are a common presentation in emergency and primary healthcare facilities across the world. The World Health Organization recommends postponing the suturing of a bite wound but this has not been evaluated through a systematic review. OBJECTIVES: To assess the effects of primary closure compared with delayed closure or no closure for mammalian bite wounds. SEARCH METHODS: In July 2019 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In‐Process & Other Non‐Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta‐analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We included randomised controlled trials which compared primary closure with delayed or no closure for traumatic wounds due to mammalian bite. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles, abstracts and full‐text publications, applied the inclusion criteria, and extracted data. We pooled data using a random‐effects model, as appropriate. We used the Cochrane 'Risk of bias' tool and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We found three trials (878 participants) that compared primary closure with no closure for dog bites and one trial (120 participants) that compared primary closure with delayed closure. No other mammalian bite studies were identified. The trials were from the UK (one trial), Greece (one trial) and China (two trials). Overall, participants from both sexes and all age groups were represented. We are uncertain whether primary closure improves the proportion of wounds which are infection‐free compared with no closure, as the certainty of evidence for this outcome was judged to be very low (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.97 to 1.05; 2 studies, 782 participants; I(2) = 0%). We downgraded the evidence by one level for high risk of bias and two levels for imprecision. There is no clinically important difference in cosmesis (acceptable physical/cosmetic appearance) of dog bite wounds when primary closure is compared with no closure (mean difference (MD) ‐1.31, 95% CI ‐2.03 to ‐0.59; 1 study, 182 participants). The certainty of evidence for this outcome was judged to be moderate (we downgraded our assessment by one level for imprecision). We are uncertain whether primary closure improves the proportion of dog bite wounds that are infection‐free compared with delayed closure, as the evidence for this outcome was judged to be very low (RR 0.98, 95% CI 0.90 to 1.07; 1 study, 120 participants; I(2) = 0%). We downgraded the evidence by one level for high risk of bias and two levels for imprecision. None of the four trials reported any adverse outcomes such as death or rabies but they were, in any case, unlikely to have been large enough to have satisfactory power to provide precise estimates for these. Important outcomes like time to complete wound healing, proportion of wounds healed, and length of hospital stay were not evaluated. AUTHORS' CONCLUSIONS: All the studies we identified concerned dog bites. There is no high‐certainty evidence to support or refute existing recommendations concerning primary closure for dog bites. The potential benefits and harms of primary closure compared with delayed or no closure for mammalian bites remain uncertain and more robust trials are needed.

Background Oral nifedipine is recommended along with labetalol and hydralazine for treatment of severe hypertension during pregnancy by most authorities. Although nifedipine is cheap and easily administered, the usage pattern among health care providers suggests a strong preference for labetalol despite lack of evidence for the same. Objectives To determine the efficacy and safety of oral nifedipine for treatment of severe hypertension of pregnancy compared with intravenous labetalol. Search strategy We systematically searched for articles comparing oral nifedipine with intravenous labetalol for the treatment of severe hypertension during pregnancy in any language, over Medline, Cochrane Central Register of Clinical Trials and Google Scholar from inception till February 2014. Selection criteria We included all RCTs that compared intravenous labetalol with oral nifedipine for treatment of severe hypertension during pregnancy, addressing relevant efficacy and safety outcomes. Data collection and analysis Eligible studies were reviewed, and data were extracted onto a standard form. We used Cochrane review manager software for quantitative analysis. Data were analysed using a fixed effect model. Main results The pooled analysis of seven trials (four from developing countries) consisting of 363 woman–infant pairs showed that oral nifedipine was associated with less risk of persistent hypertension (RR 0.42, 95% CI 0.18–0.96) and reported maternal side effects (RR 0.57, 95% CI 0.35–0.94). However, on sensitivity analysis the outcome ‘persistent hypertension’ was no longer significant. Other outcomes did not reach statistical significance. Conclusion Oral nifedipine is as efficacious and safe as intravenous labetalol and may have an edge in low resource settings. Tweetable abstract Although studies to date are few in number and small, nifedipine shows promise for severe hypertension in pregnancy.

Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents? Methods Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate with placebo or no intervention in children and adolescents with ADHD. Meta-analyses and trial sequential analyses (TSA) were conducted. Quality was assessed using GRADE. Teachers, parents, and observers rated ADHD symptoms and general behaviour. Study answer and limitations The analyses included 38 parallel group trials (n=5111, median treatment duration 49 days) and 147 crossover trials (n=7134, 14 days). The average age across all studies was 9.7 years. The analysis suggested a beneficial effect of methylphenidate on teacher rated symptoms in 19 parallel group trials (standardised mean difference (SMD) −0.77, n=1698), corresponding to a mean difference of −9.6 points on the ADHD rating scale. There was no evidence that methylphenidate was associated with an increase in serious adverse events (risk ratio 0.98, nine trials, n=1532; TSA adjusted intervention effect RR 0.91). Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD −0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0-100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE. What this study adds The results suggest that among children and adolescents with a diagnosis of ADHD, methylphenidate may improve teacher reported symptoms of ADHD and general behaviour and parent reported quality of life. However, given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain. Methylphenidate is associated with an increased risk of non-serious but not serious adverse events. Funding, competing interests, data sharing Region Zealand Research Foundation and Copenhagen Trial Unit. Competing interests are given in the full paper on bmj.com. Full data are available in the version of this review published in The Cochrane Library., peer-reviewed

Apolipoprotein E (ApoE), a protein primarily involved in lipoprotein metabolism, occurs in three isoforms (E2, E3 and E4). Studies evaluating the association between APOE genotype and incidence of malignancies have given inconclusive results.The objective of the present study was to analyze the association between APOE genotype and incidence of cancer by a meta-analysis.We conducted a literature search in the electronic databases for studies with information on APOE genotype in malignancies. Sixteen studies (14 case-control and 2 cohort; 77,970 controls and 12,010 cases) were included for the present meta-analysis. Pooled odds ratios (OR) with 95 % confidence intervals (CI) were calculated assuming a random-effect model for all the genotypes and alleles. Subgroup analyses based on study design, ethnicity of populations, site of cancer and source of controls were performed as a post hoc measure. Appropriate tests to detect heterogeneity, publication bias and sensitivity were done at all stages. The review protocol is registered with the PROSPERO database vide registration number CRD42013006496.The pooled effect measure for the comparisons did not reveal an association in primary analyses. In the subgroup analyses, we observed a negative association between APOE4+ genotypes and overall risk of cancer in the cohort study subgroup (pooled OR 0.86; 95 % CI 0.82-0.91; p0.00001; I (2) = 0 %). Sensitivity analyses did not alter the overall pooled effect measure, and there were no evidences to suggest a publication bias.Overall, the present meta-analysis did not show any association between APOE alleles and genotypes with incidence of cancer in general.

Objective We sought to evaluate if editorial policies and the reporting quality of randomized controlled trials (RCTs) had improved since our 2004–05 survey of 151 RCTs in 65 Indian journals, and to compare reporting quality of protocols in the Clinical Trials Registry-India (CTRI). Study Design and Setting An observational study of endorsement of Consolidated Standards for the Reporting of Trials (CONSORT) and International Committee of Medical Journal Editors (ICMJE) requirements in the instructions to authors in Indian journals, and compliance with selected requirements in all RCTs published during 2007–08 vs. our previous survey and between all RCT protocols in the CTRI on August 31, 2010 and published RCTs from both surveys. Results Journal policies endorsing the CONSORT statement (22/67, 33%) and ICMJE requirements (35/67, 52%) remained suboptimal, and only 4 of 13 CONSORT items were reported in more than 50% of the 145 RCTs assessed. Reporting of ethical issues had improved significantly, and that of methods addressing internal validity had not improved. Adequate methods were reported significantly more frequently in 768 protocols in the CTRI, than in the 296 published trials. Conclusion The CTRI template facilitates the reporting of valid methods in registered trial protocols. The suboptimal compliance with CONSORT and ICMJE requirements in RCTs published in Indian journals reduces credibility in the reliability of their results.