Lay health workers in primary and community health care for maternal and child health: identification and treatment of wasting in children.

BACKGROUND: Since the early 2010s, there has been a push to enhance the capacity to effectively treat wasting in children through community-based service delivery models and thus reduce morbidity and mortality. OBJECTIVES: To assess the effectiveness of identification and treatment of moderate and severe wasting in children aged five years or under by lay health workers working in the community compared with health providers working in health facilities. SEARCH METHODS: We searched MEDLINE, CENTRAL, two other databases, and two ongoing trials registers to 24 September 2021. We also screened the reference lists of related systematic reviews and all included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies in children aged five years or under with moderate wasting (defined as weight-for-height Z-score (WHZ) below -2 but no lower than ≥ -3, or mid-upper-arm circumference (MUAC) below 125 mm but no lower than 115 mm, and no nutritional oedema) or severe wasting (WHZ below -3 or MUAC below 115 mm or nutritional oedema). Eligible interventions were: • identification by lay health workers (LHWs) of children with wasting (intervention 1); • identification by LHWs of children with wasting and medical complications needing referral (intervention 2); and • identification by LHWs of children with wasting without medical complications needing referral (intervention 3). Eligible comparators were: • identification and treatment of wasting by health professionals such as nurses or doctors (at health facilities); and • identification and treatment of wasting by health facility-based teams, including health professionals and LHWs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened trials, extracted data and assessed risk of bias using the Cochrane risk of bias tool (RoB 2) and Cochrane Effective Practice and Organisation of Care (EPOC) guidelines. We used a random-effects model to meta-analyse data, producing risk ratios (RRs) for dichotomous outcomes in trials with individual allocation, adjusted RRs for dichotomous outcomes in trials with cluster allocation (using the generic inverse variance method in Review Manager 5), and mean differences (MDs) for continuous outcomes. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included two RCTs and five non-RCTs. Six studies were from African countries, and one was from Pakistan. Six studies included children with severe wasting, and one included children with moderate wasting. All studies offered home-based ready-to-use therapeutic food treatment and monitoring. Children received antibiotics in three studies, vitamins or micronutrients in three studies, and deworming treatment in two studies. In three studies, the comparison arm involved LHWs screening children for malnutrition and referring them to health facilities for diagnosis and treatment. All the non-randomised studies had a high overall risk of bias. Interventions 1 and 2 Identification and referral for treatment by LHWs, compared with treatment by health professionals following self-referral, may result in little or no difference in the percentage of children who recover from moderate or severe wasting (MD 1.00%, 95% confidence interval (CI) -2.53 to 4.53; 1 RCT, 29,475 households; low certainty). Intervention 3 Compared with treatment by health professionals following identification by LHWs, identification and treatment of severe wasting in children by LHWs: • may slightly reduce improvement from severe wasting (RR 0.93, 95% CI 0.86 to 0.99; 1 RCT, 789 participants; low certainty); • may slightly increase non-response to treatment (RR 1.44, 95% CI 1.04 to 2.01; 1 RCT, 789 participants; low certainty); • may result in little or no difference in the number of children with WHZ above -2 on discharge (RR 0.94, 95% CI 0.28 to 3.18; 1 RCT, 789 participants; low certainty); • probably results in little or no difference in the number of children with WHZ between -3 and -2 on discharge (RR 1.09, 95% CI 0.87 to 1.36; 1 RCT, 789 participants; moderate certainty); • probably results in little or no difference in the number of children with WHZ below -3 (severe wasting) on discharge (RR 1.23, 95% CI 0.75 to 2.04; 1 RCT, 789 participants; moderate certainty); • probably results in little or no difference in the number of children with MUAC equal to or greater than 115 mm on discharge (RR 0.99, 95% CI 0.93 to 1.06; 1 RCT, 789 participants; moderate certainty); • results in little or no difference in weight gain per day (mean weight gain 0.50 g/kg/day higher, 95% CI 1.74 lower to 2.74 higher; 1 RCT, 571 participants; high certainty); • probably has little or no effect on relapse of severe wasting (RR 1.03, 95% CI 0.69 to 1.54; 1 RCT, 649 participants; moderate certainty); • may have little or no effect on mortality among children with severe wasting (RR 0.46, 95% CI 0.04 to 5.98; 1 RCT, 829 participants; low certainty); • probably has little or no effect on the transfer of children with severe wasting to inpatient care (RR 3.71, 95% CI 0.36 to 38.23; 1 RCT, 829 participants; moderate certainty); and • probably has little or no effect on the default of children with severe wasting (RR 1.48, 95% CI 0.65 to 3.40; 1 RCT, 829 participants; moderate certainty). The evidence was very uncertain for total MUAC gain, MUAC gain per day, total weight gain, treatment coverage, and transfer to another LHW site or health facility. No studies examined sustained recovery, deterioration to severe wasting, appropriate identification of children with wasting or oedema, appropriate referral of children with moderate or severe wasting, adherence, or adverse effects and other harms. AUTHORS' CONCLUSIONS: Identification and treatment of severe wasting in children who do not require inpatient care by LHWs, compared with treatment by health professionals, may lead to similar or slightly poorer outcomes. We found only two RCTs, and the evidence from non-randomised studies was of very low certainty for all outcomes due to serious risks of bias and imprecision. No studies included children aged under 6 months. Future studies must address these methodological issues.

Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis.

BACKGROUND: Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required. OBJECTIVES: To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS. SEARCH METHODS: We searched the following databases from inception to December 2021: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), CINAHL (EBSCO host), LILACS, the Physiotherapy Evidence Database (PEDro), the World Health Organisation International Clinical Trials Registry Platform, the US National Institutes of Health clinical trial register, the European Union Clinical Trials Register, the International Association for Cannabinoid Medicines databank. We hand searched citation lists of included studies and relevant reviews. SELECTION CRITERIA: We included randomised parallel or cross-over trials (RCTs) evaluating any cannabinoid (including herbal Cannabis, Cannabis flowers, plant-based cannabinoids, or synthetic cannabinoids) irrespective of dose, route, frequency, or duration of use for adults with MS. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane Risk of bias 2 tool for parallel RCTs and crossover trials. We rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), withdrawals due to adverse events (AEs) (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders, physical dependence. MAIN RESULTS: We included 25 RCTs with 3763 participants of whom 2290 received cannabinoids. Age ranged from 18 to 60 years, and between 50% and 88% participants across the studies were female.  The included studies were 3 to 48 weeks long and compared nabiximols, an oromucosal spray with a plant derived equal (1:1) combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (13 studies), synthetic cannabinoids mimicking THC (7 studies), an oral THC extract of Cannabis sativa (2 studies), inhaled herbal Cannabis (1 study) against placebo. One study compared dronabinol, THC extract of Cannabis sativa and placebo, one compared inhaled herbal Cannabis, dronabinol and placebo. We identified eight ongoing studies. Critical outcomes • Spasticity: nabiximols probably increases the number of people who report an important reduction of perceived severity of spasticity compared with placebo (odds ratio (OR) 2.51, 95% confidence interval (CI) 1.56 to 4.04; 5 RCTs, 1143 participants; I2 = 67%; moderate-certainty evidence). The absolute effect was 216 more people (95% CI 99 more to 332 more) per 1000 reporting benefit with cannabinoids than with placebo. • Chronic neuropathic pain: we found only one small trial that measured the number of participants reporting substantial pain relief with a synthetic cannabinoid compared with placebo (OR 4.23, 95% CI 1.11 to 16.17; 1 study, 48 participants; very low-certainty evidence). We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity. • Treatment discontinuation due to AEs: cannabinoids may increase slightly the number of participants who discontinue treatment compared with placebo (OR 2.41, 95% CI 1.51 to 3.84; 21 studies, 3110 participants; I² = 17%; low-certainty evidence); the absolute effect is 39 more people (95% CI 15 more to 76 more) per 1000 people. Important outcomes • PGIC: cannabinoids probably increase the number of people who report 'very much' or 'much' improvement in health status compared with placebo (OR 1.80, 95% CI 1.37 to 2.36; 8 studies, 1215 participants; I² = 0%; moderate-certainty evidence). The absolute effect is 113 more people (95% CI 57 more to 175 more) per 1000 people reporting improvement. • HRQoL: cannabinoids may have little to no effect on HRQoL (SMD -0.08, 95% CI -0.17 to 0.02; 8 studies, 1942 participants; I2 = 0%; low-certainty evidence); • SAEs: cannabinoids may result in little to no difference in the number of participants who have SAEs compared with placebo (OR 1.38, 95% CI 0.96 to 1.99; 20 studies, 3124 participants; I² = 0%; low-certainty evidence); • AEs of the nervous system: cannabinoids may increase nervous system disorders compared with placebo (OR 2.61, 95% CI 1.53 to 4.44; 7 studies, 1154 participants; I² = 63%; low-certainty evidence); • Psychiatric disorders: cannabinoids may increase psychiatric disorders compared with placebo (OR 1.94, 95% CI 1.31 to 2.88; 6 studies, 1122 participants; I² = 0%; low-certainty evidence); • Drug tolerance: the evidence is very uncertain about the effect of cannabinoids on drug tolerance (OR 3.07, 95% CI 0.12 to 75.95; 2 studies, 458 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Compared with placebo, nabiximols probably reduces the severity of spasticity in the short-term in people with MS. We are uncertain about the effect on chronic neurological pain and health-related quality of life. Cannabinoids may increase slightly treatment discontinuation due to AEs, nervous system and psychiatric disorders compared with placebo. We are uncertain about the effect on drug tolerance. The overall certainty of evidence is limited by short-term duration of the included studies.

Splinting for the non-operative management of developmental dysplasia of the hip (DDH) in children under six months of age.

BACKGROUND: Developmental dysplasia of the hip (DDH) describes the abnormal development of a hip in childhood, ranging from complete dislocation of the hip joint to subtle immaturity of a hip that is enlocated and stable within the socket. DDH occurs in around 10 per 1000 live births, though only one per 1000 are completely dislocated. There is variation in treatment pathways for DDH, which differs between hospitals and even between clinicians within the same hospital. The variation is related to the severity of dysplasia that is believed to require treatment, and the techniques used to treat dysplasia. OBJECTIVES: To determine the effectiveness of splinting and the optimal treatment strategy for the non-operative management of DDH in babies under six months of age. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, seven other electronic databases, and two trials registers up to November 2021. We also checked reference lists, contacted study authors, and handsearched relevant meetings abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs), including quasi-RCTs, as well as non-RCTs and cohort studies conducted after 1980 were included. Participants were babies with all severities of DDH who were under six months of age. Interventions included dynamic splints, static splints or double nappies (diapers), compared to no splinting or delayed splinting. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data and performed risk of bias and GRADE assessments. The primary outcomes were: measurement of acetabular index at years one, two and five, as determined by radiographs (angle): the need for operative intervention to achieve reduction and to address dysplasia; and complications. We also investigated other outcomes highlighted by parents as important, including the bond between parent and child and the ability of mothers to breastfeed. MAIN RESULTS: We included six RCTs or quasi-RCTs (576 babies). These were supported by 16 non-RCTs (8237 babies). Five studies had non-commercial funding, three studies stated 'no funding' and 14 studies did not state funding source. The RCTs were generally at unclear risk of bias, although we judged three RCTs to be at high risk of bias for incomplete outcome data. The non-RCTs were of moderate and critical risk of bias. We did not undertake meta-analysis due to methodological and clinical differences between studies; instead, we have summarised the results narratively. Dynamic splinting versus delayed or no splinting Four RCTs and nine non-RCTs compared immediate dynamic splinting and delayed dynamic splinting or no splinting. Of the RCTs, two considered stable hips and one considered unstable (dislocatable) hips and one jointly considered unstable and stable hips. No studies considered only dislocated hips. Two RCTs (265 babies, very low-certainty evidence) reported acetabular index at one year amongst stable or dislocatable hips. Both studies found there may be no evidence of a difference in splinting stable hips at first diagnosis compared to a strategy of active surveillance: one reported a mean difference (MD) of 0.10 (95% confidence interval (CI) -0.74 to 0.94), and the other an MD of 0.20 (95% CI -1.65 to 2.05). Two RCTs of stable hips (181 babies, very low-certainty evidence) reported there may be no evidence of a difference between groups for acetabular index at two years: one study reported an MD of -1.90 (95% CI -4.76 to 0.96), and another study reported an MD of -0.10 (95% CI -1.93 to 1.73), but did not take into account hips from the same child. No study reported data at five years. Four RCTs (434 babies, very low-certainty evidence) reported the need for surgical intervention. Three studies reported that no surgical interventions occurred. In the remaining study, two babies in the dynamic splinting group developed instability and were subsequently treated surgically. This study did not explicitly state if this treatment was to achieve concentric reduction or address residual dysplasia. Three RCTs (390 babies, very low-certainty evidence) reported no complications (avascular necrosis and femoral nerve palsy). Dynamic splinting versus static splinting One RCT and five non-RCTs compared dynamic versus static splinting. The RCT (118 hips) reported no occurrences of avascular necrosis (very low-certainty evidence) and did not report radiological outcomes or need for operative intervention. One quasi-RCT compared double nappies versus delayed or no splinting but reported no outcomes of interest. Other comparisons No RCTs compared static splinting versus delayed or no splinting or staged weaning versus immediate removal. AUTHORS' CONCLUSIONS: There is a paucity of RCT evidence for splinting for the non-operative management of DDH: we included only six RCTs with 576 babies. Moreover, there was considerable heterogeneity between the studies, precluding meta-analysis. We judged the RCT evidence for all primary outcomes as being of very low certainty, meaning we are very uncertain about the true effects. Results from individual studies provide limited evidence of intervention effects on different severities of DDH. Amongst stable dysplastic hips, there was no evidence to suggest that treatment at any stage expedited the development of the acetabulum. For dislocatable hips, a delay in treatment onset to six weeks does not appear to result in any evidence of a difference in the development of the acetabulum at one year or increased risk of surgery. However, delayed splinting may reduce the number of babies requiring treatment with a harness. No RCTs compared static splinting with delayed or no splinting, staged weaning versus immediate removal or double nappies versus delayed or no splinting. There were few operative interventions or complications amongst the RCTs and the non-randomised studies. There's no apparent signal to indicate a higher frequency of either outcome in either intervention group. Given the frequency of this disease, and the fact that many countries undertake mandatory DDH screening, there is a clear need to develop an evidence-based pathway for treatment. Particular uncertainties requiring future research are the effectiveness of splinting amongst stable dysplastic hips, the optimal timing for the onset of splinting, the optimal type of splint to use and the need for 'weaning of splints'. Only once a robust pathway for treatment is established, can we properly assess the cost-effectiveness of screening interventions for DDH.

Following the science? Comparison of methodological and reporting quality of covid-19 and other research from the first wave of the pandemic.

BACKGROUND: Following the initial identification of the 2019 coronavirus disease (covid-19), the subsequent months saw substantial increases in published biomedical research. Concerns have been raised in both scientific and lay press around the quality of some of this research. We assessed clinical research from major clinical journals, comparing methodological and reporting quality of covid-19 papers published in the first wave (here defined as December 2019 to May 2020 inclusive) of the viral pandemic with non-covid papers published at the same time. METHODS: We reviewed research publications (print and online) from The BMJ, Journal of the American Medical Association (JAMA), The Lancet, and New England Journal of Medicine, from first publication of a covid-19 research paper (February 2020) to May 2020 inclusive. Paired reviewers were randomly allocated to extract data on methodological quality (risk of bias) and reporting quality (adherence to reporting guidance) from each paper using validated assessment tools. A random 10% of papers were assessed by a third, independent rater. Overall methodological quality for each paper was rated high, low or unclear. Reporting quality was described as percentage of total items reported. RESULTS: From 168 research papers, 165 were eligible, including 54 (33%) papers with a covid-19 focus. For methodological quality, 18 (33%) covid-19 papers and 83 (73%) non-covid papers were rated as low risk of bias, OR 6.32 (95%CI 2.85 to 14.00). The difference in quality was maintained after adjusting for publication date, results, funding, study design, journal and raters (OR 6.09 (95%CI 2.09 to 17.72)). For reporting quality, adherence to reporting guidelines was poorer for covid-19 papers, mean percentage of total items reported 72% (95%CI:66 to 77) for covid-19 papers and 84% (95%CI:81 to 87) for non-covid. CONCLUSIONS: Across various measures, we have demonstrated that covid-19 research from the first wave of the pandemic was potentially of lower quality than contemporaneous non-covid research. While some differences may be an inevitable consequence of conducting research during a viral pandemic, poor reporting should not be accepted.

STrengthening the Reporting Of Pharmacogenetic Studies: Development of the STROPS guideline.

BACKGROUND: Large sample sizes are often required to detect statistically significant associations between pharmacogenetic markers and treatment response. Meta-analysis may be performed to synthesize data from several studies, increasing sample size and, consequently, power to detect significant genetic effects. However, performing robust synthesis of data from pharmacogenetic studies is often challenging because of poor reporting of key data in study reports. There is currently no guideline for the reporting of pharmacogenetic studies that has been developed using a widely accepted robust methodology. The objective of this project was to develop the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline. METHODS AND FINDINGS: We established a preliminary checklist of reporting items to be considered for inclusion in the guideline. We invited representatives of key stakeholder groups to participate in a 2-round Delphi survey. A total of 52 individuals participated in both rounds of the survey, scoring items with regards to their importance for inclusion in the STROPS guideline. We then held a consensus meeting, at which 8 individuals considered the results of the Delphi survey and voted on whether each item ought to be included in the final guideline. The STROPS guideline consists of 54 items and is accompanied by an explanation and elaboration document. The guideline contains items that are particularly important in the field of pharmacogenetics, such as the drug regimen of interest and whether adherence to treatment was accounted for in the conducted analyses. The guideline also requires that outcomes be clearly defined and justified, because in pharmacogenetic studies, there may be a greater number of possible outcomes than in other types of study (for example, disease-gene association studies). A limitation of this project is that our consensus meeting involved a small number of individuals, the majority of whom are based in the United Kingdom. CONCLUSIONS: Our aim is for the STROPS guideline to improve the transparency of reporting of pharmacogenetic studies and also to facilitate the conduct of high-quality systematic reviews and meta-analyses. We encourage authors to adhere to the STROPS guideline when publishing pharmacogenetic studies.

Video calls for reducing social isolation and loneliness in older people: a rapid review.

BACKGROUND: The current COVID-19 pandemic has been identified as a possible trigger for increases in loneliness and social isolation among older people due to the restrictions on movement that many countries have put in place. Loneliness and social isolation are consistently identified as risk factors for poor mental and physical health in older people. Video calls may help older people stay connected during the current crisis by widening the participant's social circle or by increasing the frequency of contact with existing acquaintances. OBJECTIVES: The primary objective of this rapid review is to assess the effectiveness of video calls for reducing social isolation and loneliness in older adults. The review also sought to address the effectiveness of video calls on reducing symptoms of depression and improving quality of life. SEARCH METHODS: We searched CENTRAL, MEDLINE, PsycINFO and CINAHL from 1 January 2004 to 7 April 2020. We also searched the references of relevant systematic reviews. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs (including cluster designs) were eligible for inclusion. We excluded all other study designs. The samples in included studies needed to have a mean age of at least 65 years. We included studies that included participants whether or not they were experiencing symptoms of loneliness or social isolation at baseline. Any intervention in which a core component involved the use of the internet to facilitate video calls or video conferencing through computers, smartphones or tablets with the intention of reducing loneliness or social isolation, or both, in older adults was eligible for inclusion. We included studies in the review if they reported self-report measures of loneliness, social isolation, symptoms of depression or quality of life.  Two review authors screened 25% of abstracts; a third review author resolved conflicts. A single review author screened the remaining abstracts. The second review author screened all excluded abstracts and we resolved conflicts by consensus or by involving a third review author. We followed the same process for full-text articles. DATA COLLECTION AND ANALYSIS: One review author extracted data, which another review author checked. The primary outcomes were loneliness and social isolation and the secondary outcomes were symptoms of depression and quality of life. One review author rated the certainty of evidence for the primary outcomes according to the GRADE approach and another review author checked the ratings. We conducted fixed-effect meta-analyses for the primary outcome, loneliness, and the secondary outcome, symptoms of depression. MAIN RESULTS: We identified three cluster quasi-randomised trials, which together included 201 participants. The included studies compared video call interventions to usual care in nursing homes. None of these studies were conducted during the COVID-19 pandemic.  Each study measured loneliness using the UCLA Loneliness Scale. Total scores range from 20 (least lonely) to 80 (most lonely). The evidence was very uncertain and suggests that video calls may result in little to no difference in scores on the UCLA Loneliness Scale compared to usual care at three months (mean difference (MD) -0.44, 95% confidence interval (CI) -3.28 to 2.41; 3 studies; 201 participants), at six months (MD -0.34, 95% CI -3.41 to 2.72; 2 studies; 152 participants) and at 12 months (MD -2.40, 95% CI -7.20 to 2.40; 1 study; 90 participants). We downgraded the certainty of this evidence by three levels for study limitations, imprecision and indirectness. None of the included studies reported social isolation as an outcome. Each study measured symptoms of depression using the Geriatric Depression Scale. Total scores range from 0 (better) to 30 (worse). The evidence was very uncertain and suggests that video calls may result in little to no difference in scores on the Geriatric Depression Scale compared to usual care at three months' follow-up (MD 0.41, 95% CI -0.90 to 1.72; 3 studies; 201 participants) or six months' follow-up (MD -0.83, 95% CI -2.43 to 0.76; 2 studies, 152 participants). The evidence suggests that video calls may have a small effect on symptoms of depression at one-year follow-up, though this finding is imprecise (MD -2.04, 95% CI -3.98 to -0.10; 1 study; 90 participants). We downgraded the certainty of this evidence by three levels for study limitations, imprecision and indirectness. Only one study, with 62 participants, reported quality of life. The study measured quality of life using a Taiwanese adaptation of the Short-Form 36-question health survey (SF-36), which consists of eight subscales that measure different aspects of quality of life: physical function; physical role; emotional role; social function; pain: vitality; mental health; and physical health. Each subscale is scored from 0 (poor health) to 100 (good health). The evidence is very uncertain and suggests that there may be little to no difference between people allocated to usual care and those allocated to video calls in three-month scores in physical function (MD 2.88, 95% CI -5.01 to 10.77), physical role (MD -7.66, 95% CI -24.08 to 8.76), emotional role (MD -7.18, 95% CI -16.23 to 1.87), social function (MD 2.77, 95% CI -8.87 to 14.41), pain scores (MD -3.25, 95% CI -15.11 to 8.61), vitality scores (MD -3.60, 95% CI -9.01 to 1.81), mental health (MD 9.19, 95% CI 0.36 to 18.02) and physical health (MD 5.16, 95% CI -2.48 to 12.80). We downgraded the certainty of this evidence by three levels for study limitations, imprecision and indirectness. AUTHORS' CONCLUSIONS: Based on this review there is currently very uncertain evidence on the effectiveness of video call interventions to reduce loneliness in older adults. The review did not include any studies that reported evidence of the effectiveness of video call interventions to address social isolation in older adults. The evidence regarding the effectiveness of video calls for outcomes of symptoms of depression was very uncertain. Future research in this area needs to use more rigorous methods and more diverse and representative participants. Specifically, future studies should target older adults, who are demonstrably lonely or socially isolated, or both, across a range of settings to determine whether video call interventions are effective in a population in which these outcomes are in need of improvement.

Impregnated central venous catheters for prevention of bloodstream infection in children (the CATCH trial): a randomised controlled trial.

BACKGROUND: Impregnated central venous catheters are recommended for adults to reduce bloodstream infections but not for children because there is not enough evidence to prove they are effective. We aimed to assess the effectiveness of any type of impregnation (antibiotic or heparin) compared with standard central venous catheters to prevent bloodstream infections in children needing intensive care. METHODS: We did a randomised controlled trial of children admitted to 14 English paediatric intensive care units. Children younger than 16 years were eligible if they were admitted or being prepared for admission to a participating paediatric intensive care unit and were expected to need a central venous catheter for 3 or more days. Children were randomly assigned (1:1:1) to receive a central venous catheter impregnated with antibiotics, a central venous catheter impregnated with heparin, or a standard central venous catheter with computer generated randomisation in blocks of three and six, stratified by method of consent, site, and envelope storage location within the site. The clinician responsible for inserting the central venous catheter was not masked to allocation, but allocation was concealed from patients, their parents, and the paediatric intensive care unit personnel responsible for their care. The primary outcome was time to first bloodstream infection between 48 h after randomisation and 48 h after central venous catheter removal with impregnated (antibiotic or heparin) versus standard central venous catheters, assessed in the intention-to-treat population. Safety analyses compared central venous catheter-related adverse events in the subset of children for whom central venous catheter insertion was attempted (per-protocol population). This trial is registered with ISRCTN number, ISRCTN34884569. FINDINGS: Between Nov 25, 2010, and Nov 30, 2012, 1485 children were recruited to this study. We randomly assigned 502 children to receive standard central venous catheters, 486 to receive antibiotic-impregnated catheters, and 497 to receive heparin-impregnated catheters. Bloodstream infection occurred in 18 (4%) of those in the standard catheters group, 7 (1%) in the antibiotic-impregnated group, and 17 (3%) assigned to heparin-impregnated catheters. Primary analyses showed no effect of impregnated (antibiotic or heparin) catheters compared with standard central venous catheters (hazard ratio [HR] for time to first bloodstream infection 0.71, 95% CI 0.37-1.34). Secondary analyses showed that antibiotic central venous catheters were better than standard central venous catheters (HR 0.43, 0.20-0.96) and heparin central venous catheters (HR 0.42, 0.19-0.93), but heparin did not differ from standard central venous catheters (HR 1.04, 0.53-2.03). Clinically important and statistically significant absolute risk differences were identified only for antibiotic-impregnated catheters versus standard catheters (-2.15%, 95% CI -4.09 to -0.20; number needed to treat [NNT] 47, 95% CI 25-500) and antibiotic-impregnated catheters versus heparin-impregnated catheters (-1.98%, -3.90 to -0.06, NNT 51, 26-1667). Nine children (2%) in the standard central venous catheter group, 14 (3%) in the antibiotic-impregnated group, and 8 (2%) in the heparin-impregnated group had catheter-related adverse events. 45 (8%) in the standard group, 35 (8%) antibiotic-impregnated group, and 29 (6%) in the heparin-impregnated group died during the study. INTERPRETATION: Antibiotic-impregnated central venous catheters significantly reduced the risk of bloodstream infections compared with standard and heparin central venous catheters. Widespread use of antibiotic-impregnated central venous catheters could help prevent bloodstream infections in paediatric intensive care units. FUNDING: National Institute for Health Research, UK.

Transcranial Doppler Screening in a Regional Care Network for Sickle Cell Disease in the United Kingdom.

The risk of stroke in children screened with transcranial Doppler ultrasound in the United Kingdom is not known. We evaluated a clinician-led program using a risk assessment modified from the STOP protocol. High-risk classification included abnormal velocities in the anterior cerebral artery, and single abnormal scan if initial velocity >220 cm/s (high abnormal) or if preceded by at least 2 conditional scans. In total, 1653 scans were performed in 542 children, followed for 2235 patient-years. Fifty-eight (10.7%) high-risk subjects were identified, including 18 (31%) with high abnormal, and 15 (26%) with previous conditional scans. In 2 (3%), abnormal velocity was restricted to the anterior cerebral artery. The estimated proportion of children at high risk, scanned before 6 years of age was >20%. There were 4 cases of acute ischemic stroke (AIS) and 2 of acute hemorrhagic stroke. The incidence of all stroke, AIS, and acute hemorrhagic stroke were 0.27, 0.18, and 0.09 per 100 patient-years, respectively. The proportion of children at high risk is higher than most previous estimates, partly as a result of our modified risk assessment. About 2 children per 1000 screened with transcranial Doppler ultrasound progress to AIS.

Pharmacological treatment of acute agitation associated with psychotic and bipolar disorder: a systematic review and meta-analysis.

OBJECTIVES: We used systematic review methodology to identify and evaluate short-term pharmacological interventions for agitation associated with schizophrenia or bipolar disorder. METHOD: We searched electronic databases for randomised controlled trials involving comparisons between current treatments for agitation, benzodiazepines, antipsychotics and placebo. The patient population was adults with agitation associated with psychotic or bipolar disorder treated in specialist mental health services. The outcome of interest was change in agitation measured by accepted standard scales. Paired meta-analyses and network meta-analyses are presented. RESULTS: Seventeen randomised controlled trials were identified (n = 3841). Treatments included haloperidol, olanzapine, aripiprazole, risperidone and lorazepam. The primary outcome was change in Positive and Negative Syndrome Scale Excited Component scores. Pair-wise comparisons suggest that after 60 min, olanzapine is superior to haloperidol; no other treatment was more effective than any other. At 120 min, loxapine 10 mg is more effective than loxapine 5 mg, and olanzapine is more effective than lorazepam. In the network meta-analyses, no treatment was superior to any other. CONCLUSION: Because of limitations of available research, firm conclusions could not be drawn regarding the efficacy and safety of any identified intervention. Based on our results, there is no evidence that one drug is more effective or preferred over any other and treatment decisions could be made based on individual patient needs or costs. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Bisphosphonate therapy for osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta is caused by a genetic defect resulting in an abnormal type I collagen bone matrix which typically results in multiple fractures with little or no trauma. Bisphosphonates are used in an attempt to increase bone mineral density and reduce these fractures in people with osteogenesis imperfecta. This is an update of a previously published Cochrane Review. OBJECTIVES: To assess the effectiveness and safety of bisphosphonates in increasing bone mineral density, reducing fractures and improving clinical function in people with osteogenesis imperfecta. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of journals and conference proceedings. We additionally searched PubMed and major conference proceedings.Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Register: 28 April 2016. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing bisphosphonates to placebo, no treatment, or comparator interventions in all types of osteogenesis imperfecta. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias of the included trials. MAIN RESULTS: Fourteen trials (819 participants) were included. Overall, the trials were mainly at a low risk of bias, although selective reporting was an issue in several of the trials. Data for oral bisphosphonates versus placebo could not be aggregated; a statistically significant difference favouring oral bisphosphonates in fracture risk reduction and number of fractures was noted in two trials. No differences were reported in the remaining three trials which commented on fracture incidence. Five trials reported data for spine bone mineral density; all found statistically significant increased lumbar spine density z scores for at least one time point studied. For intravenous bisphosphonates versus placebo, aggregated data from two trials showed no statistically significant difference for the number of participants with at least one fracture, risk ratio 0.56 (95% confidence interval 0.30 to 1.06). In the remaining trial no statistically significant difference was noted in fracture incidence. For spine bone mineral density, no statistically significant difference was noted in the aggregated data from two trials, mean difference 9.96 (95% confidence interval -2.51 to 22.43). In the remaining trial a statistically significant difference in mean per cent change in spine bone mineral density z score favoured intravenous bisphosphonates at six and 12 months. Data describing growth, bone pain, and functional outcomes after oral or intravenous bisphosphonate therapy, or both, as compared to placebo were incomplete among all studies, but do not show consistent improvements in these outcomes. Two studies compared different doses of bisphosphonates. No differences were found between doses when bone mineral density, fractures, and height or length z score were assessed. One trial compared oral versus intravenous bisphosphonates and found no differences in primary outcomes. Two studies compared the intravenous bisphosphonates zoledronic acid and pamidronate. There were no significant differences in primary outcome. However, the studies were at odds as to the relative benefit of zoledronic acid over pamidronate for lumbosacral bone mineral density at 12 months. AUTHORS' CONCLUSIONS: Bisphophonates are commonly prescribed to individuals with osteogenesis imperfecta. Current evidence, albeit limited, demonstrates oral or intravenous bisphosphonates increase bone mineral density in children and adults with this condition. These were not shown to be different in their ability to increase bone mineral density. It is unclear whether oral or intravenous bisphosphonate treatment consistently decreases fractures, though multiple studies report this independently and no studies report an increased fracture rate with treatment. The studies included here do not show bisphosphonates conclusively improve clinical status (reduce pain; improve growth and functional mobility) in people with osteogenesis imperfecta. Given their current widespread and expected continued use, the optimal method, duration of therapy and long-term safety of bisphosphonate therapy require further investigation. In addition, attention should be given to long-term fracture reduction and improvement in quality of life indicators.

Vilanterol and fluticasone furoate for asthma.

BACKGROUND: Vilanterol (VI) is a long-acting beta2-agonist (LABA) that binds to the beta2-adrenoceptor on the airway smooth muscle, producing bronchodilation. LABA therapy, which is well established in adults as part of the British Thoracic Society (BTS) Guidelines for the Management of Asthma, leads to improvement in symptoms and lung function and reduction in exacerbations. At present, the commonly used LABAs licensed for use in asthma management (formoterol and salmeterol) require twice-daily administration, whereas VI is a once-daily therapy.Fluticasone furoate (FF) is an inhaled corticosteroid (ICS), and ICS therapy is recommended by the BTS asthma guidelines. ICSs, the mainstay of asthma treatment, lead to a reduction in both airway inflammation and airway hyper-responsiveness. Regular use leads to improvement in symptoms and lung function. ICSs are currently recommended as 'preventer' therapy for patients who use a 'reliever' medication (e.g. short-acting beta2 agonist (SABA), salbutamol) three or more times per week. Most of the commonly used ICS treatments are twice-daily medications, although two once-daily products are currently licensed (ciclesonide and mometasone).At the present time, only one once-daily ICS/LABA combination (FF/VI) is available, and several other combination inhalers are recommended for twice-daily administration. OBJECTIVES: To compare effects of VI and FF in combination versus placebo, or versus other ICSs and/or LABAs, on acute exacerbations and on health-related quality of life (HRQoL) in adults and children with chronic asthma. SEARCH METHODS: We searched the Cochrane Airways Group Register of trials, clinical trial registries, manufacturers' websites and reference lists of included studies up to June 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of adults and children with a diagnosis of asthma. Included studies compared VI and FF combined versus placebo, or versus other ICSs and/or LABAs. Our primary outcomes were health-related quality of life, severe asthma exacerbation, as defined by hospital admissions or treatment with a course of oral corticosteroids, and serious adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and analysed outcomes using a fixed-effect model. We used standard Cochrane methods. MAIN RESULTS: We identified 14 studies that met our inclusion criteria, with a total of 6641 randomised participants, of whom 5638 completed the study. All studies lasted between two and 78 weeks and showed good methodological quality overall.We included 10 comparisons in this review, seven for which the dose of VI and FF was 100/25 mcg (VI/FF 100/25 mcg vs placebo; VI/FF 100/25 mcg vs same dose of FF; VI/FF 100/25 mcg vs same dose of VI; VI/FF 100/25 mcg vs fluticasone propionate (FP) 500 mcg twice-daily; VI/FF 100/25 mcg vs fluticasone propionate/salmeterol (FP/SAL) 250/50 mcg twice-daily; VI/FF 100/25 mcg vs FP/SAL 250/25 mcg twice-daily; FF/VI 100/25 vs FP/SAL500/50) and three for which the dose of VI and FF was 200/25 mcg (VI/FF 200/25 mcg vs placebo; VI/FF 200/25 mcg vs FP 500 mcg; VI/FF 200/25 mcg vs same dose of FF).We found very few opportunities to combine results from the 14 included studies in meta-analyses. We tabulated the data for our pre-specified primary outcomes. In particular, we found insufficient information to assess whether once-daily VI/FF was better or worse than twice-daily FP/SAL in terms of efficacy or safety.Only one of the 14 studies looked at health-related quality of life when comparing VI and FF 100/25 mcg versus placebo and identified a significant advantage of VI/FF 100/25 mcg (mean difference (MD) 0.30, 95% confidence interval (CI) 0.14 to 0.46; 329 participants); we recognised this as moderate-quality evidence. Only two studies compared VI/FF 100/25 mcg versus placebo with respect to exacerbations; both studies reported no exacerbations in either treatment arm. Five studies (VI/FF 100/25 mcg vs placebo) sought information on serious adverse events; all five studies reported no serious adverse events in the VI/FF 100/25 mcg or placebo arms. We found no comparison relevant to our primary outcomes for VI/FF at a higher dose (200/25 mcg) versus placebo.The small number of studies contributing to each comparison precludes the opportunity to draw robust conclusions for clinical practice. These studies were not of sufficient duration to allow conclusions about long-term side effects. AUTHORS' CONCLUSIONS: Some evidence suggests clear advantages for VI/FF, in combination, compared with placebo, particularly for forced expiratory volume in one second (FEV1) and peak expiratory flow; however, the variety of questions addressed in the included studies did not allow review authors to draw firm conclusions. Information was insufficient for assessment of whether once-daily VI/FF was better or worse than twice-daily FP/SAL in terms of efficacy or safety. It is clear that more research is required to reduce the uncertainties that surround interpretation of these studies. It will be necessary for these findings to be replicated in other work before more robust conclusions are revealed. Only five of the 13 included studies provided data on health-related quality of life, and only six recorded asthma exacerbations. Only one study focused on paediatric patients, so no conclusions can be drawn for the paediatric population. More research is needed, particularly in the primary outcome areas selected for this review, so that we can draw firmer conclusions in the next update of this review.

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is emerging as an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men and is less associated with smoking. OBJECTIVES: To assess the clinical effectiveness of single -agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcome was overall survival. Secondary outcomes included progression-free survival, response rate, toxicity, and quality of life. SEARCH METHODS: We conducted electronic searches of the the Cochrane Register of Controlled Trials (CENTRAL) (2015, Issue 6), MEDLINE (1946 to 1 June 2015), EMBASE (1980 to 1 June 2015), and ISI Web of Science (1899 to 1 June 2015). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (1 June 2015); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles. SELECTION CRITERIA: Parallel randomised controlled trials comparing EGFR-targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy-naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent. DATA COLLECTION AND ANALYSIS: Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta-analyses using a fixed-effect model unless there was substantial heterogeneity, in which case we also performed a random-effects analysis as a sensitivity analysis. MAIN RESULTS: Nineteen trials met the inclusion criteria. Seven of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 2317, of whom 1700 were of Asian origin.Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR-targeted treatments against cytotoxic chemotherapy or placebo.Erlotinib was the intervention treatment used in eight trials, gefitinib in seven trials, afatinib in two trials, and cetuximab in two trials. The findings of one trial (FASTACT 2) did report a statistically significant OS gain for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, but this result was based on a small number of participants (n = 97). For progression-free survival (PFS), a pooled analysis of 3 trials (n = 378) demonstrated a statistically significant benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.24 to 0.38).In a pooled analysis with 491 participants administered gefitinib, 2 trials (IPASS and NEJSG) demonstrated a statistically significant PFS benefit of gefitinib compared with cytotoxic chemotherapy (HR 0.39; 95% CI 0.32 to 0.48).Afatinib (n = 709) showed a statistically significant PFS benefit when compared with chemotherapy in a pooled analysis of 2 trials (HR 0.42; 95% CI 0.34 to 0.53).Commonly reported grade 3/4 adverse events for afatinib, erlotinib, and gefitinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms, fatigue and anorexia were also associated with some chemotherapies.No statistically significant PFS or OS benefit for cetuximab plus cytotoxic chemotherapy (n = 81) compared to chemotherapy alone was reported in either of the two trials.Six trials reported on quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, 2 trials showed improvement in one or more indices for the tyrosine-kinase inhibitor (TKI) compared to chemotherapy.The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy. AUTHORS' CONCLUSIONS: Erlotinib, gefitinib, and afatinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged progression-free survival compared to cytotoxic chemotherapy. We also found a beneficial effect of the TKI compared to cytotoxic chemotherapy. However, we found no increase in overall survival for the TKI when compared with standard chemotherapy. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, or afatinib and is associated with greater toxicity. There were no data supporting the use of monoclonal antibody therapy.

A model-based correction for outcome reporting bias in meta-analysis.

It is often suspected (or known) that outcomes published in medical trials are selectively reported. A systematic review for a particular outcome of interest can only include studies where that outcome was reported and so may omit, for example, a study that has considered several outcome measures but only reports those giving significant results. Using the methodology of the Outcome Reporting Bias (ORB) in Trials study of (Kirkham and others, 2010. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. British Medical Journal 340, c365), we suggest a likelihood-based model for estimating the effect of ORB on confidence intervals and p-values in meta-analysis. Correcting for bias has the effect of moving estimated treatment effects toward the null and hence more cautious assessments of significance. The bias can be very substantial, sometimes sufficient to completely overturn previous claims of significance. We re-analyze two contrasting examples, and derive a simple fixed effects approximation that can be used to give an initial estimate of the effect of ORB in practice.

Reporting of adverse events in surgical trials: critical appraisal of current practice.

BACKGROUND: Reporting of surgical outcomes is important for healthcare decision making and includes the reporting of complications. Several classifications have been proposed and validated for postoperative, but not intraoperative, complications. The aim of the present study is to assess the current practice of complication reporting in surgical trials. METHODS: We evaluated the reporting of intra- and postoperative complications in all registered randomized controlled trials that included investigate surgery or invasive interventions in at least one study arm and were published in 2010 in the Annals of Surgery, JAMA Surgery, and the British Journal of Surgery. RESULTS: A total of 46 trials were identified; intra- and postoperative complications were reported separately in 42 % and pooled in 15 %. In 37 % intraoperative, in 2 % postoperative, and in 4 % both intra- and postoperative, complications were not reported at all. Exact definitions were provided in 13 % for intraoperative and in 50 % for postoperative complications. A classification was used in 9 % for intra- and in 54 % for postoperative complications, most frequently according to severity. The type of intervention (surgical vs. other) or whether the primary outcome was the assessment of complications had no significant impact on reporting definitions of adverse events. CONCLUSIONS: Intraoperative complications are frequently pooled with postoperative complications, ill-defined, or not reported at all, hampering informed decision making. As further research, we propose to develop and validate a classification of intraoperative complications. This will facilitate the evaluation of safety and the continuous quality control of surgical interventions with the ultimate goal to contribute to patient safety.

Positive expiratory pressure physiotherapy for airway clearance in people with cystic fibrosis.

BACKGROUND: Chest physiotherapy is widely prescribed to assist the clearance of airway secretions in people with cystic fibrosis. Positive expiratory pressure (PEP) devices provide back pressure to the airways during expiration. This may improve clearance by building up gas behind mucus via collateral ventilation and by temporarily increasing functional residual capacity. Given the widespread use of PEP devices, there is a need to determine the evidence for their effect. This is an update of a previously published review. OBJECTIVES: To determine the effectiveness and acceptability of PEP devices compared to other forms of physiotherapy as a means of improving mucus clearance and other outcomes in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. The electronic database CINAHL was also searched from 1982 to 2013.Most recent search of the Group's Cystic Fibrosis Trial Register: 02 December 2014. SELECTION CRITERIA: Randomised controlled studies in which PEP was compared with any other form of physiotherapy in people with cystic fibrosis. This included, postural drainage and percussion, active cycle of breathing techniques, oscillating PEP devices, thoracic oscillating devices, bilevel positive airway pressure (BiPaP) and exercise. Studies also had to include one or more of the following outcomes: change in forced expiratory volume in one second; number of respiratory exacerbations; a direct measure of mucus clearance; weight of expectorated secretions; other pulmonary function parameters; a measure of exercise tolerance; ventilation scans; cost of intervention; and adherence to treatment. DATA COLLECTION AND ANALYSIS: Three authors independently applied the inclusion and exclusion criteria to publications and assessed the risk of bias of the included studies. MAIN RESULTS: A total of 26 studies (involving 733 participants) were included in the review. Eighteen studies involving 296 participants were cross-over in design. Data were not published in sufficient detail in most of these studies to perform any meta-analysis. These studies compared PEP to active cycle of breathing techniques (ACBT), autogenic drainage (AD), oral oscillating PEP devices, high frequency chest wall oscillation (HFCWO) and Bi level PEP devices (BiPaP) and exercise.Forced expiratory volume in one second was the review's primary outcome and the most frequently reported outcome in the studies. Single interventions or series of treatments that continued for up to three months demonstrated no significant difference in effect between PEP and other methods of airway clearance on this outcome. However, long-term studies had equivocal or conflicting results regarding the effect on this outcome. A second primary outcome was the number of respiratory exacerbations. There was a lower exacerbation rate in participants using PEP compared to other techniques when used with a mask for at least one year. Participant preference was reported in 10 studies; and in all studies with an intervention period of at least one month, this was in favour of PEP. The results for the remaining outcome measures were not examined or reported in sufficient detail to provide any high-level evidence. The only reported adverse event was in a study where infants performing either PEP or postural drainage with percussion experienced some gastro-oesophageal reflux. This was more severe in the postural drainage with percussion group. Many studies had a risk of bias as they did not report how the randomisation sequence was either generated or concealed. Most studies reported the number of dropouts and also reported on all planned outcome measures. AUTHORS' CONCLUSIONS: Following meta-analyses of the effects of PEP versus other airway clearance techniques on lung function and patient preference, this Cochrane review demonstrated that there was a significant reduction in pulmonary exacerbations in people using PEP compared to those using HFCWO in the study where exacerbation rate was a primary outcome measure. It is important to note, however, that there may be individual preferences with respect to airway clearance techniques and that each patient needs to be considered individually for the selection of their optimal treatment regimen in the short and long term, throughout life, as circumstances including developmental stages, pulmonary symptoms and lung function change over time. This also applies as conditions vary between baseline function and pulmonary exacerbations.However, meta-analysis in this Cochrane review has shown a significant reduction in pulmonary exacerbations in people using PEP in the few studies where exacerbation rate was a primary outcome measure.

Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors.

BACKGROUND: In people with haemophilia, therapeutic clotting agents might be recognised as a foreign protein and induce anti-factor VIII antibodies, known as 'inhibitors'. Drugs insensitive to such antibodies, either recombinant or plasma-derived, are called factor VIII 'by-passing' agents and used for treatment of bleeding in people with inhibitors. OBJECTIVES: To determine the clinical effectiveness of recombinant factor VIIa concentrate compared to plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Coagulopathies Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Coagulopathies Trials Register: 23 September 2015. SELECTION CRITERIA: Randomised and quasi-randomised controlled clinical trials comparing recombinant factor VIIa concentrate to human plasma-derived concentrates (high-dose human or recombinant factor VIII or factor IX concentrate; non-activated prothrombin complex concentrates; activated prothrombin complex concentrates) in people with haemophilia. Comparisons with animal-derived products were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the trials (eligibility and risk of bias) and extracted data. No combined meta-analyses were performed due to the unavailability of outcomes and comparisons common to the included trials. MAIN RESULTS: A total of 15 trials were identified, two of which (with data for a total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that recombinant factor VIIa and activated prothrombin complex concentrate appeared to have a similar haemostatic effect in both trials, without increasing thromboembolic risk. AUTHORS' CONCLUSIONS: Based on the separate analysis of the two available randomised trials, recombinant factor VIIa and activated prothrombin complex concentrate were found to be similar in efficacy and safety. However, there is a need for further, well-designed, adequately-powered, randomised controlled trials to assess the relative benefits and risks of using recombinant factor VIIa compared to human plasma-derived concentrates in people with haemophilia with inhibitors. It is advisable that researchers in the field define commonly agreed objective outcome measures in order to enable the pooling of their results, thus increasing the power of comparisons. To date, data could not be combined in a formal meta-analysis. For the same reason reporting concordant and discordant pairs in cross-over trials is recommended.

Mepolizumab versus placebo for asthma.

BACKGROUND: Mepolizumab is a human monoclonal antibody against interleukin-5 (IL-5), the main cytokine involved in the activation of eosinophils, which in turn causes airway inflammation. Recent studies have suggested these agents may have a role in reducing exacerbations and improving health-related quality of life (HRQoL). There are no recommendations for the use of mepolizumab in adults or children in the recent update of the BTS/SIGN guidelines (BTS/SIGN 2014). OBJECTIVES: To compare the effects of mepolizumab with placebo on exacerbations and HRQoL in adults and children with chronic asthma. SEARCH METHODS: We searched the Cochrane Airways Group Register (CAGR) of trials, clinical trial registries, manufacturers' websites and the reference lists of included studies. Searches were conducted in November 2013 and updated in November 2014. SELECTION CRITERIA: We included randomised controlled trials comparing mepolizumab versus placebo in adults and children with asthma. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and analysed outcomes using a random-effects model. We used standard methods expected by The Cochrane Collaboration. MAIN RESULTS: Eight studies on 1707 participants met the inclusion criteria. Only two studies included children (over 12 years of age), but they did not report separate findings for the adolescents. Seven studies involved intravenous mepolizumab alone; one included a subcutaneous arm. There was heterogeneity in the severity and clinical pattern of asthma among the participants in the eight studies, varying from mild to moderate atopic asthma, to persistent asthma and eosinophilic asthma with recurrent exacerbations. Selection bias was a concern in several of the studies included in this review.Four trials compared intravenous mepolizumab to placebo in relation to HRQoL. Two studies measured scores from the Asthma Quality of Life Questionnaire (AQLQ), which showed a non-significant difference between mepolizumab and placebo (mean difference (MD) 0.21, 95% confidence interval (CI) - 0.01 to 0.44; participants = 682), in the direction favouring mepolizumab. The third study used the St. George's Respiratory Questionnaire (SGRQ) and found a significant difference between mepolizumab and placebo (MD 6.40, 95% CI 3.15 to 9.65; participants = 576), which indicated a clinically important benefit favouring mepolizumab. A fourth study noted that there was no significant difference but did not provide any data. The two studies in people with eosinophilic asthma showed a reduction in clinically significant exacerbation rates (Risk Ratio 0.52, 95% CI 0.43 to 0.64; participants = 690). However, an analysis of four studies that were not confined to people with eosinophilic asthma indicated considerable heterogeneity and no significant difference in people with one or more exacerbations between mepolizumab and placebo using a random-effects model (Risk Ratio 0.67, 95% CI 0.34 to 1.31; participants = 468; I(2) = 59%).The analysis of serious adverse events indicated a significant difference favouring mepolizumab (Risk ratio 0.49, 95% CI 0.30 to 0.80; participants = 1441; studies = 5; I(2) = 0%). It was not possible to combine the results for adverse events, and we deemed the quality of this evidence to be low.A single study compared subcutaneous mepolizumab to placebo in 385 adults with severe eosinophilic asthma and found an improvement in HRQoL scores and a reduction in asthma exacerbations, including exacerbations requiring admission to hospital. AUTHORS' CONCLUSIONS: It is not possible to draw firm conclusions from this review with respect to the role of mepolizumab in patients with asthma. Our confidence in the results of this review are limited by the fact that the intravenous route is not currently licensed for mepolizumab, and the evidence for the currently licenced subcutaneous route is limited to a single study in participants with severe eosinophilic asthma.The currently available studies provide evidence that mepolizumab can lead to an improvement in health-related quality of life scores and reduce asthma exacerbations in people with severe eosinophilic asthma.Further research is needed to clarify which subgroups of patients with asthma could potentially benefit from this treatment. Dosage, ideal dosing regimens and duration of treatment need to be clarified, as the studies included in this review differed in their protocols. There are no studies reporting results from children, so we cannot comment on treatment for this age group. At the present time, larger studies using licenced treatment regimens are required to establish the role of mepolizumab in the treatment of severe asthma.

Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis.

BACKGROUND: Cystic fibrosis is the most common inherited life-shortening illness in Caucasians and caused by a mutation in the gene that codes for the cystic fibrosis transmembrane regulator protein (CFTR), which functions as a salt transporter. This mutation most notably affects the airways of people with cystic fibrosis. Excess salt absorption by defective CFTR dehydrates the airway lining and leads to defective mucociliary clearance. Consequent accumulation of thick, sticky mucus makes the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Additionally, abnormalities with CFTR lead to systemic complications like malnutrition, diabetes and subfertility.Since the discovery of the causative gene, our understanding of the structure and function of CFTR and the impact of different mutations has increased and allowed pharmaceutical companies to design new mutation-specific therapies targeting the underlying molecular defect. Therapies targeting mutation classes III and IV (CFTR potentiators) aim to normalise airway surface liquid and help re-establish mucociliary clearance, which then has a beneficial impact on the chronic infection and inflammation that characterizes lung disease in people with cystic fibrosis. These therapies may also affect other mutations. OBJECTIVES: To evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 05 March 2015.We searched the EU Clinical Trials Register, clinicaltrials.gov (US Clinical Trials Register) and the International Clinical Trials Registry Platform (ICTRP). Last search of clinical trial registries: 06 February 2014. SELECTION CRITERIA: Randomised controlled trials of parallel design comparing CFTR potentiators to placebo in people with cystic fibrosis. In a post hoc change we excluded trials combining CFTR potentiators with other mutation-specific therapies. These will be considered in a separate review. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed the risk of bias in included trials; they contacted trial authors for additional data. Meta-analyses were undertaken on outcomes at a number of time points. MAIN RESULTS: We included four randomised controlled trials (n = 378), lasting from 28 days to 48 weeks, comparing the potentiator ivacaftor to placebo. Trials differed in terms of design and participant eligibility criteria, which limited the meta-analyses. The phase 2 trial (n = 19) and two phase 3 trials (adult trial (n = 167), paediatric trial (n = 52)), recruited participants with the G551D mutation (class III). The fourth trial (n = 140) enrolled participants homozygous for the ΔF508 mutation (class II).Risks of bias in the trials were moderate. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented. Participant blinding was less clear throughout all trials; in three trials, some participant data were excluded from the analysis. Selective outcome reporting was apparent in three trials. All trials were sponsored by industry and supported by other non-pharmaceutical funding bodies.No trial reported any deaths. Significantly higher quality of life scores in the respiratory domain were reported by the adult phase 3 G551D trial at 24 weeks, mean difference 8.10 (95% confidence interval (CI) 4.77 to 11.43) and 48 weeks, mean difference 8.60 (95% CI 5.27 to 11.93); but not by the paediatric phase 3 G551D trial. The adult phase 3 G551D trial reported improvements in relative change from baseline in forced expiratory volume at one second at 24 weeks, mean difference 16.90% (95% CI 13.60 to 20.20) and 48 weeks, mean difference 16.80% (95% CI 13.50 to 20.10); as did the paediatric G551D trial at 24 weeks, mean difference 17.4% (P < 0.0001)). No improvements in quality of life or lung function were reported in the ΔF508 participants.Combined data from both phase 3 G551D trials demonstrated increased reporting of cough, odds ratio 0.57 (95% CI 0.33 to 1.00) and increased episodes of decreased pulmonary function, odds ratio 0.29 (95% CI 0.10 to 0.82) in the placebo group. The adult phase 3 G551D trial demonstrated increased reporting of dizziness amongst the ivacaftor group, OR 10.55 (95% CI 1.32 to 84.47). No trial showed a difference between treatment arms in the number of participants interrupting or discontinuing the trial drug.In the phase 3 G551D trials, fewer participants assigned to ivacaftor developed serious pulmonary exacerbations. When considering all data for exacerbations, participants taking ivacaftor in the adult phase 3 G551D study developed fewer exacerbations, odds ratio 0.54 (95% CI 0.29 to 1.01). In the other G551D studies and in the ΔF508 study, there was no difference between groups in the number of participants who developed pulmonary exacerbations.Combined data from both phase 3 G551D trials demonstrated significant improvements in absolute change from baseline in forced expiratory volume at one second (% predicted) at 24 weeks, mean difference 10.80% (95% CI 8.91 to 12.69) and 48 weeks, mean difference 10.44% (95% CI 8.56 to 12.32); also in weight at 24 weeks, mean difference 2.37 kg (95% CI 1.68 to 3.06) and 48 weeks, mean difference 2.75 kg (95% CI 1.74 to 3.75). No improvements in these outcomes were reported in the ΔF508 participants.Significant reductions in sweat chloride concentration were reported in both G551D and ΔF508 participants: in combined data from both phase 3 G551D trials at 24 weeks, mean difference -48.98 mmol/L (95% CI -52.07 to -45.89) and 48 weeks, mean difference -49.03 mmol/L (95% CI -52.11 to -45.94); and from the ΔF508 trial at 16 weeks, mean difference -2.90 mmol/L (95% CI -5.60 to -0.20). AUTHORS' CONCLUSIONS: Both G551D phase 3 trials (n = 219) demonstrated a clinically relevant impact of the potentiator ivacaftor on outcomes at 24 and 48 weeks, providing evidence for the use of this treatment in adults and children (over six years of age) with cystic fibrosis and the G551D mutation (class III). There is no evidence to support the use of ivacaftor in people with the ΔF508 mutation (class II) (n = 140). Trials on ivacaftor in people with different mutations are ongoing.