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Background: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35–3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04–2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86–1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39–0·91; p=0·016). Interpretation: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. Funding: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.

An increasing number of studies has focused on the after-effects of acute aerobic exercise on executive function. To date, empirical evidence lacks consensus regarding whether acute aerobic exercise has beneficial effects on executive function. To identify possible sources of this discrepancy, the present study focused on executive function demands and pre-test cognitive performance, and performed the first meta-analysis of individual participant data (IPD meta-analysis) in this area of research. Results indicated that the beneficial after-effects of acute aerobic exercise on cognitive performance were greater in participants with lower cognitive performance at pre-test. Acute aerobic exercise offered general benefits to cognitive performance irrespective of executive function demands, when pre-test cognitive performance was appropriately controlled. Thus, the present IPD meta-analysis suggests that pre-test cognitive performance is one possible source of the conflicting findings in acute exercise studies. Future research is encouraged to consider pre-test cognitive performance to avoid underestimating the beneficial after-effects of acute exercise.

Individual participant data (IPD) from multiple sources allows external validation of a prognostic model across multiple populations. Often this reveals poor calibration, potentially causing poor predictive performance in some populations. However, rather than discarding the model outright, it may be possible to modify the model to improve performance using recalibration techniques. We use IPD meta-analysis to identify the simplest method to achieve good model performance. We examine four options for recalibrating an existing time-to-event model across multiple populations: (i) shifting the baseline hazard by a constant, (ii) re-estimating the shape of the baseline hazard, (iii) adjusting the prognostic index as a whole, and (iv) adjusting individual predictor effects. For each strategy, IPD meta-analysis examines (heterogeneity in) model performance across populations. Additionally, the probability of achieving good performance in a new population can be calculated allowing ranking of recalibration methods. In an applied example, IPD meta-analysis reveals that the existing model had poor calibration in some populations, and large heterogeneity across populations. However, re-estimation of the intercept substantially improved the expected calibration in new populations, and reduced between-population heterogeneity. Comparing recalibration strategies showed that re-estimating both the magnitude and shape of the baseline hazard gave the highest predicted probability of good performance in a new population. In conclusion, IPD meta-analysis allows a prognostic model to be externally validated in multiple settings, and enables recalibration strategies to be compared and ranked to decide on the least aggressive recalibration strategy to achieve acceptable external model performance without discarding existing model information.

Background Building a dataset of individual participant data (IPD) for meta-analysis represents considerable research investment as well as collaboration across multiple institutions and researchers. Making arrangements to curate and share the dataset beyond the IPD meta-analysis project for which it was established, for reuse in future research projects, would maximise the value of this investment. Methods Our aim was to establish the Cochrane repository for individual patient data from clinical trials in pregnancy and childbirth (CRIB) as an example of how an IPD repository could become part of Cochrane infrastructure. We believed that establishing CRIB under Cochrane auspices would engender trust and encourage trial investigators to share data, and at the same time position Cochrane to take steps towards expanding the number of reviews with IPD synthesis. Results CRIB was designed as a web-based platform to receive, host and facilitate onward sharing of de-identified data. Development was not straightforward and we did not fully achieve our aim as intended. We describe the challenges encountered and suggest ways that future repositories might overcome these. In particular, securing the legal agreements required to facilitate data sharing proved to be the main barrier, being time-consuming and more complex than anticipated. Conclusions We would recommend that researchers conducting IPD meta-analysis should consider discussing the option to transfer the curated IPD datasets to a repository at the end of the initial meta-analysis and this should be recognised within the data sharing agreements made with the original data contributors.

Aims The Carillon Mitral Contour System has been shown to reduce mitral regurgitation and left ventricular volumes in symptomatic heart failure patients with functional mitral regurgitation. We sought to evaluate the effects of the Carillon device on quality of life and functional capacity in these patients. Methods and results An individual participant data meta‐analysis was conducted utilizing data from REDUCE‐FMR, TITAN, and TITAN II studies. The main outcomes assessed were changes from baseline in Kansas City Cardiomyopathy Questionnaire overall summary scores (KCCQ‐OSS), 6 min walk test (6MWT) distance, and New York Heart Association (NYHA) classification at Months 1 and 12 after device implantation. Subgroup analyses were conducted for patients with severe functional mitral regurgitation (Grade 3 or 4). Pooled estimates were calculated using a random‐effects model and are presented as weighted proportions or weighted mean differences along with 95% confidence intervals (CIs). Among 139 patients included in the analysis, Carillon device significantly improved the 6MWT distance (63.0 m; 95% CI 18.8–107.2, P = 0.0056) and KCCQ‐OSS score (15.1; 95% CI 5.6–24.7, P = 0.0022) at 1 month from baseline. These benefits were sustained at 12 months (64.1 m; 95% CI 13.2–115.0, P = 0.0141, for 6MWT distance, and 12.3; 95% CI 4.7–19.8, P = 0.0019, for KCCQ‐OSS score). More than 50% of the patients had improvements in KCCQ‐OSS by ≥5 (60.4%; 95% CI 47.4–72.1) and 10 points (50.5%; 95% CI 34.9–66.0) at 12 months. Almost half of the patients experienced a ≥1 class improvement in NYHA class after implantation of the device at 1 month (67.9%; 95% CI 37.3–88.3) and at 12 months (48.8%; 95% CI 31.8–66.2). Results remained similar for KCCQ‐OSS, 6MWT distance, and NYHA classification when only patients with Grade 3 or 4 mitral regurgitation were analysed. The pooled estimates of 30 day and 1 year all‐cause mortality were 2.2% (95% CI 0.7–6.5) and 17.3% (95% CI 11.8–24.5), respectively. Conclusions The Carillon Mitral Contour System significantly improved patient‐reported quality‐of‐life outcomes in heart failure patients with functional mitral regurgitation.

Purpose Cervical ossification of ligamentum flavum (COLF) is a rare clinical entity which can occasionally contribute to severe myeloradiculopathy. Many orthopedists are unfamiliar with or underestimate this pathology. Therefore, a comprehensive research is obligatory to reappraise the epidemiological, radiological, clinical and histopathological characteristics of COLF-myeloradiculopathy based on synthesis of individual patient data. Methods Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, PubMed, EMBASE, Scopus and Web of Science databases were searched for studies discussing COLF-myeloradiculopathy from the inception to December 2020. Results A total of 94 cases from 54 studies were identified. The annual publications demonstrated a steady increase, and most reports were from Japan and China. The mean age was 58.76±13.39 years and nearly 60% of cases occurred in the 55-64 and 65-74 years age group. The male-female ratio was 1.4:1. Most cases belonged to East Asian population (60.64%). COLF predominately appeared in the lower cervical and cervicothoracic spine (76.60%) and mainly affected C4-5 (23.29%) and C5-6 (21.23%). Single-segment type ossification accounted for 62.76 and 45.45% of ossification lesions distributed bilaterally. The majority of COLF (81.1%) were spontaneous, and motor disturbance (76.4%), spinal ataxia (62.5%) and sensory disturbance (58.9%) were the most common manifestations. Histopathologically, it's a metaplastic process of endochondral ossification with the formation of mature lamellar bone which was distinguished from calcification of ligamentum flavum. About 21.28% of concurrent COLF and COPLL cases were identified as a separated group, with unique characteristics. Conclusion COLF is an underappreciated but potentially growing pathogeny of myeloradiculopathy in aging population, though its distinct epidemiological, radiological, clinical and histopathological features are not fully supported by current evidence. However, our findings will provide several referential data for future researches to shed light on COLF.

Prediction models often yield inaccurate predictions for new individuals. Large data sets from pooled studies or electronic healthcare records may alleviate this with an increased sample size and variability in sample characteristics. However, existing strategies for prediction model development generally do not account for heterogeneity in predictor-outcome associations between different settings and populations. This limits the generalizability of developed models (even from large, combined, clustered data sets) and necessitates local revisions. We aim to develop methodology for producing prediction models that require less tailoring to different settings and populations. We adopt internal-external cross-validation to assess and reduce heterogeneity in models' predictive performance during the development. We propose a predictor selection algorithm that optimizes the (weighted) average performance while minimizing its variability across the hold-out clusters (or studies). Predictors are added iteratively until the estimated generalizability is optimized. We illustrate this by developing a model for predicting the risk of atrial fibrillation and updating an existing one for diagnosing deep vein thrombosis, using individual participant data from 20 cohorts (N = 10 873) and 11 diagnostic studies (N = 10 014), respectively. Meta-analysis of calibration and discrimination performance in each hold-out cluster shows that trade-offs between average and heterogeneity of performance occurred. Our methodology enables the assessment of heterogeneity of prediction model performance during model development in multiple or clustered data sets, thereby informing researchers on predictor selection to improve the generalizability to different settings and populations, and reduce the need for model tailoring. Our methodology has been implemented in the R package metamisc.

Esthesioneuroblastoma (ENB) is an uncommon primary sinonasal tumor which can extend intracranially. Exactly how to classify them pathologically still remains discrepant; the Hyams grading system, for example, has not been universally adopted. This individual patient data (IPD) meta-analysis aimed to investigate the prognostic implication of each Hyams grade on patient outcomes. We accessed two electronic databases including PubMed and Web of Science. Raw patient data from potential articles were extracted. To examine the associations of various clinicopathological factors with the Hyams grades, we utilized Chi-square, t-test, and Mann–Whitney, as appropriate. Log-rank test and Cox regression analysis were used to elucidate the impact of the Hyams grades on recurrence-free survival (RFS), metastasis-free survival (MFS), and overall survival (OS) of ENB patients. We included 33 studies with 492 ENB patients. We found significant associations of Kadish stages, Dulguerov stages, rates of recurrence, metastasis, and patient mortality with Hyams grade. Log-rank tests and Cox regression models demonstrated significant differences in RFS and OS of Hyams grade I – II, grade III, and grade IV patients. There was no statistical difference in RFS and OS of Hyams grade I and II. Radiotherapy was only effective in grade III – IV ENBs and chemotherapy showed no benefits to patients. We verify that the Hyams grading system appears to be a reliable prognostic indicator to assess ENB patient outcomes. Consolidating the Hyams grading system into a three-tier system based on similar clinical outcomes of grades I and II may simplify this classification schema.

Background and Purpose: The factors associated with recovery of language domains after stroke remain uncertain. We described recovery of overall-language-ability, auditory comprehension, naming, and functional-communication across participants’ age, sex, and aphasia chronicity in a large, multilingual, international aphasia dataset. Methods: Individual participant data meta-analysis of systematically sourced aphasia datasets described overall-language ability using the Western Aphasia Battery Aphasia-Quotient; auditory comprehension by Aachen Aphasia Test (AAT) Token Test; naming by Boston Naming Test and functional-communication by AAT Spontaneous-Speech Communication subscale. Multivariable analyses regressed absolute score-changes from baseline across language domains onto covariates identified a priori in randomized controlled trials and all study types. Change-from-baseline scores were presented as estimates of means and 95% CIs. Heterogeneity was described using relative variance. Risk of bias was considered at dataset and meta-analysis level. Results: Assessments at baseline (median=43.6 weeks poststroke; interquartile range [4–165.1]) and first-follow-up (median=10 weeks from baseline; interquartile range [3–26]) were available for n=943 on overall-language ability, n=1056 on auditory comprehension, n=791 on naming and n=974 on functional-communication. Younger age ( Conclusions: Earlier intervention for poststroke aphasia was crucial to maximize language recovery across a range of language domains, although recovery continued to be observed to a lesser extent beyond 6 months poststroke.

© 2020 Elsevier LtdThe patho-etiology of mental disorders with onset in childhood or adolescence remains largely unknown. We conducted an umbrella review of meta-analyses (MAs) on environmental factors associated with mental disorders with onset in childhood/adolescence. We searched Pubmed-MEDLINE/EMBASE/PsycInfo databases, last search April 29th, 2020. Quality of MAs was measured with AMSTAR-2. Out of 6851 initial references, ten articles met inclusion criteria, providing 23 associations between 12 potential environmental factors and nine disorders (cases: 8884; N = 3,660,670). While almost half of the associations were nominally significant, none of them met criteria from either convincing or highly suggestive evidence. A single association was supported by suggestive evidence (maternal exposure to lithium or antipsychotics with neuromotor deficits), but it was affected by confounding by indication. Ten more associations had weak evidence, and 12 associations were not statistically significant. Quality of meta-analyses was rated as high in two, moderate in one, low in four, critically low in two, and not pertinent in one (individual participant data). Methodologically-sound research is needed in this field.

Rory C Monahan,1 Hannelore JL Beaart,1 Rolf Fronczek,2,3 Gisela M Terwindt,2 Liesbeth JJ Beaart-van de Voorde,1 Jeroen de Bresser,4 Margreet Kloppenburg,1,5 Nic JA van der Wee,6 Tom WJ Huizinga,1 Gerda M Steup-Beekman1,7 1Department of Rheumatology, Leiden University Medical Center (LUMC), Leiden, the Netherlands; 2Department of Neurology, LUMC, Leiden, the Netherlands; 3Sleep-Wake Center SEIN, Heemstede, the Netherlands; 4Department of Radiology, LUMC, Leiden, the Netherlands; 5Department of Clinical Epidemiology, LUMC, Leiden, the Netherlands; 6Department of Psychiatry, LUMC, Leiden, the Netherlands; 7Department of Rheumatology, Haaglanden Medical Center, The Hague, the NetherlandsCorrespondence: Rory C MonahanDepartment of Rheumatology, Leiden University Medical Center (LUMC), Leiden 2333 ZA, the NetherlandsTel +3171-5265762Fax +3171-5266752Email r.c.monahan@lumc.nlPurpose: To evaluate the use of immunosuppressive treatment, clinical outcome and diagnostic strategy in patients with systemic lupus erythematosus (SLE) presenting with clinical features of transverse myelitis (TM), but normal MRI of the spinal cord (sMRI) and normal cerebrospinal fluid (CSF) assessment, and to suggest a clinical guideline.Patients and Methods: All patients with SLE and clinical features compatible with (sub)acute TM visiting the NPSLE clinic of the LUMC between 2007 and 2020 were included. Information on baseline characteristics, investigations, treatment and outcomes was collected from electronic medical records. In addition, a systematic review of individual participant data was performed up to April 2020 in PubMed, Embase and Web of Science, identifying all patients with TM, SLE and sMRI assessment. Data regarding sMRI, CSF analysis, treatment and outcome were extracted, and outcome was compared between patients with normal sMRI and CSF (sMRI-/CSF-) and patients with abnormalities.Results: Twelve SLE patients with a clinical diagnosis of TM were identified: four sMRI-/CSF- and one sMRI- with CSF not available. All patients received immunosuppressive treatment, but outcome in sMRI-/CSF- patients was worse: no recovery (n=1) or partial recovery (n=3) compared to partial recovery (n=4) and (nearly) complete recovery (n=3) in MRI+ patients. The systematic literature review yielded 146 articles eligible for inclusion, 90% case reports. A total of 427 SLE patients with TM were identified, of which only four cases were sMRI-/CSF- (1%), showing no improvement (n=1), partial improvement (n=2) and complete recovery (n=1) after immunosuppressive treatment.Conclusion: Outcome in SLE patients presenting with clinically suspected TM with normal sMRI and CSF is less favorable, despite treatment with immunosuppressive therapy. Taking a functional neurological disorder into consideration may be helpful in order to start other therapeutic strategies. We suggest prescribing immunosuppressive treatment for a restricted period of time to evaluate its effect in cases where a functional disorder initially is considered unlikely.Keywords: lupus, neuropsychiatric, transverse myelitis, MRI, CSF

Case mix differences between trials form an important factor that contributes to the statistical heterogeneity observed in a meta-analysis. In this paper, we propose two methods to assess whether important heterogeneity would remain if the different trials in the meta-analysis were conducted in one common population defined by a given case-mix. To achieve this goal, we first standardize results of different trials over the case-mix of a target population. We then quantify the amount of heterogeneity arising from case-mix and beyond case-mix reasons by using corresponding I2 statistics and prediction intervals. These new approaches enable a better understanding of the overall heterogeneity between trial results, and can be used to support standard heterogeneity assessments in individual participant data meta-analysis practice.

Summary Background Exposure to faecal contamination is believed to be associated with child diarrhoea and possibly stunting; however, few studies have explicitly measured the association between faecal contamination and health. We aimed to assess individual participant data (IPD) across multiple trials and observational studies to quantify the relationship for common faecal–oral transmission pathways. Methods We did a systematic review and meta-analysis of IPD from studies identified in an electronic search of PubMed, Web of Science, and Embase on May 21, 2018. The search was done in English, but full texts published in French, Portuguese, and Spanish were also reviewed. Eligible studies quantified (1) household-level faecal indicator bacteria concentrations along common faecal-oral transmission pathways of drinking water, soil, or food, on children's hands or fomites, or fly densities in food preparation areas; and (2) individual-level diarrhoea or linear growth measures for children younger than 5 years in low-income and middle-income countries. For the diarrhoea analysis, all definitions of diarrhoea were eligible but studies were excluded if they used a recall period longer than 7 days. For the linear growth analysis (using height-for-age Z scores [HAZ]), cross-sectional studies were excluded, because of the absence of longitudinal environmental contamination data measured before the growth outcomes. We used multilevel generalised mixed-effects models to estimate the odds ratio (OR) for diarrhoea and the difference in HAZ scores for individual studies associated with a 1-log10 higher measure of faecal contamination. Estimates from each study were combined under a random-effects meta-analysis framework. The study protocol was pre-registered with PROSPERO (CRD42018102114). Findings From 72 eligible studies, we included IPD for 20 studies in the meta-analyses, totalling 54 225 diarrhoea or linear growth observations matched to faecal indicator bacteria concentrations in drinking water, and a further 35 010 observations with faecal contamination data for the other transmission pathways. Child diarrhoea was associated with 1-log10 higher faecal indicator bacteria concentrations in drinking water (OR 1·09, 95% CI 1·04 to 1·13; p=0·0002, I2=34%, 95% CI 0 to 62) and on children's hands (1·11, 1·02 to 1·22; p=0·021, I2=0%, 0 to 71). Lower HAZ scores were associated with 1-log10 higher median faecal indicator bacteria concentrations in drinking water (HAZ −0·04, 95% CI −0·06 to −0·01; p=0·0054; I2=19%, 95% CI 0 to 63) and on fomites (–0·06, −0·12 to 0·00; p=0·044, I2=57%, 0 to 90). Interpretation Although summary measures from individual studies often report little or no effect of measured faecal contamination on child health, this multi-study IPD analysis indicates that household faecal indicator bacteria concentrations are associated with important adverse health outcomes in young children. Improved direct measures of exposure and enteric pathogens could help to better characterise the relationship and inform intervention design in future studies. Funding None.

STUDY QUESTION What is the rate of natural conception leading to ongoing pregnancy or livebirth over 6–12 months for infertile women of age ≥35 years? SUMMARY ANSWER Natural conception rates were still clinically relevant in women aged 35 years and above and were significantly higher in women with unexplained infertility compared to those with other diagnoses. WHAT IS KNOWN ALREADY In recent years, increasing numbers of women have attempted to conceive at a later age, resulting in a commensurate increase in the need for ART. However, there is a lack of data on natural fertility outcomes (i.e. no interventions) in women with increasing age. STUDY DESIGN, SIZE, DURATION A systematic review with individual participant data (IPD) meta-analysis was carried out. PubMed, MEDLINE, EMBASE, the Cochrane Library, clinicaltrials.gov were searched until 1 July 2018 including search terms ‘fertility service’, ‘waiting list’, ‘treatment-independent’ and ‘spontaneous conception’. Language restrictions were not imposed. PARTICIPANTS/MATERIALS, SETTING, METHODS Inclusion criteria were studies (at least partly) reporting on infertile couples with female partner of age ≥35 years who attended fertility services, underwent fertility workup (e.g. history, semen analysis, tubal status and ovulation status) and were exposed to natural conception (e.g. independent of treatment such as IVF, ovulation induction and tubal surgery). Studies that exclusively studied only one infertility diagnosis, without including other women presenting to infertility services for other causes of infertility, were excluded. For studies that met the inclusion criteria, study authors were contacted to provide IPD, after which fertility outcomes for women of age ≥35 years were retrieved. Time to pregnancy or livebirth and the effect of increasing age on fertility outcomes after adjustment for other prognostic factors were analysed. Quality of studies was graded with the Newcastle–Ottawa Scale (non-randomised controlled trials (RCTs)) or the Cochrane Risk of Bias tool (for RCTs). MAIN RESULTS AND THE ROLE OF CHANCE We included nine studies (seven cohort studies and two RCTs) (n = 4379 women of at least age 35 years), with the observed composite primary outcome of ongoing pregnancy or livebirth occurring in 429 women (9.8%) over a median follow-up of 5 months (25th to 75th percentile: 2.5–8.5 months). Studies were of moderate to high quality. The probability of natural conception significantly decreased with any diagnosis of infertility, when compared with unexplained infertility. We found non-linear effects of female age and duration of infertility on ongoing pregnancy and tabulated the predicted probabilities for unexplained infertile women aged 35–42 years with either primary or secondary infertility and with a duration of infertility from 1 to 6 years. For a 35-year-old woman with 2 years of primary unexplained infertility, the predicted probability of natural conception leading to ongoing pregnancy or livebirth was 0.15 (95% CI 0.11–0.19) after 6 months and 0.24 (95% CI 0.17–0.30) after 12 months. For a 42-year-old woman, this decreased to 0.08 (95% CI 0.04–0.11) after 6 months and 0.13 (95% CI 0.07–0.18) after 12 months. LIMITATIONS, REASONS FOR CAUTION In the studies selected, there were different study designs, recruitment strategies in different centres, protocols and countries and different methods of assessment of infertility. Data were limited for women above the age of 40 years. WIDER IMPLICATIONS OF THE FINDINGS Women attending fertility services should be encouraged to pursue natural conception while waiting for treatment to commence and after treatment if it is unsuccessful. Our results may aid in counselling women, and, in particular, for those with unexplained infertility. STUDY FUNDING/COMPETING INTEREST(S) S.J.C. received funding from the University of Adelaide Summer Research Scholarship. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437), B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. B.W.M. reports research support by Merck and Guerbet. PROSPERO REGISTRATION NUMBER CRD42018096552.

Background Network meta-analyses using individual participant data (IPD-NMAs) have been increasingly used to compare the effects of multiple interventions. Although there have been many studies on statistical methods for IPD-NMAs, it is unclear whether there are statistical defects in published IPD-NMAs and whether the reporting of statistical analyses has improved. This study aimed to investigate statistical methods used and assess the reporting and methodological quality of IPD-NMAs. Methods We searched four bibliographic databases to identify published IPD-NMAs. The methodological quality was assessed using AMSTAR-2 and reporting quality assessed based on PRISMA-IPD and PRISMA-NMA. We performed stratified analyses and correlation analyses to explore the factors that might affect quality. Results We identified 21 IPD-NMAs. Only 23.8% of the included IPD-NMAs reported statistical techniques used for missing participant data, 42.9% assessed the consistency, and none assessed the transitivity. None of the included IPD-NMAs reported sources of funding for trials included, only 9.5% stated pre-registration of protocols, and 28.6% assessed the risk of bias in individual studies. For reporting quality, compliance rates were lower than 50.0% for more than half of the items. Less than 15.0% of the IPD-NMAs reported data integrity, presented the network geometry, or clarified risk of bias across studies. IPD-NMAs with statistical or epidemiological authors often better assessed the inconsistency (P = 0.017). IPD-NMAs with a priori protocol were associated with higher reporting quality in terms of search (P = 0.046), data collection process (P = 0.031), and syntheses of results (P = 0.006). Conclusions The reporting of statistical methods and compliance rates of methodological and reporting items of IPD-NMAs were suboptimal. Authors of future IPD-NMAs should address the identified flaws and strictly adhere to methodological and reporting guidelines.

Low-grade canine cutaneous mast cell tumour (cMCT) with metastasis at the time of treatment is uncommonly reported, with few studies focusing on this specific clinical entity. The specific objective of this study was to systematically review the veterinary literature and perform a meta-analysis summarizing the clinical presentation, treatments reported and clinical outcomes from dogs with histologically low-grade cMCT and metastasis present at initial treatment. A total of 980 studies were screened with eight publications providing data on 121 dogs ultimately included. The most common treatments were surgery with adjuvant chemotherapy in 83/121 (69%) dogs; combined surgery, radiation and chemotherapy in 17/121 (14%) dogs; chemotherapy alone in 12/121 (10%) dogs and surgery alone in 7/121 (6%) dogs. Dogs with distant metastasis (n = 22) experienced significantly shorter survival compared with those with regional lymph node (RLN) metastasis (n = 99; median 194 vs 637 days; P < .01). Two variables were significantly associated with increased risk of death: presence of distant (vs RLN) metastasis (hazard ratio = 2.60; P < .01) and not receiving surgery as a component of treatment (hazard ratio = 3.79; P < .01). Risk of bias was judged to be low in terms of selection and performance bias but high in terms of detection and exclusion bias. In conclusion, dogs with cMCT and RLN metastasis can be expected to live significantly longer than those with distant metastasis, and surgery appears to have a role in extending survival of metastatic low-grade cMCT.

Objective Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. Methods MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. Results Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. Conclusions The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. (c) 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Background: Randomized trials have shown that trans-nasal evaporative cooling initiated during CPR (i.e. intra-arrest) effectively lower core body temperature in out-of-hospital cardiac arrest patients. However, these trials may have been underpowered to detect significant differences in neurologic outcome, especially in patients with initial shockable rhythm. Methods: We conducted a post hoc pooled analysis of individual data from two randomized trials including 851 patients who eventually received the allocated intervention and with available outcome (“as-treated” analysis). Primary outcome was survival with favourable neurological outcome at hospital discharge (Cerebral Performance Category [CPC] of 1–2) according to the initial rhythm (shockable vs. non-shockable). Secondary outcomes included complete neurological recovery (CPC 1) at hospital discharge. Results: Among the 325 patients with initial shockable rhythms, favourable neurological outcome was observed in 54/158 (34.2%) patients in the intervention and 40/167 (24.0%) in the control group (RR 1.43 [confidence intervals, CIs 1.01–2.02]). Complete neurological recovery was observed in 40/158 (25.3%) in the intervention and 27/167 (16.2%) in the control group (RR 1.57 [CIs 1.01–2.42]). Among the 526 patients with initial non-shockable rhythms, favourable neurological outcome was in 10/259 (3.8%) in the intervention and 13/267 (4.9%) in the control group (RR 0.88 [CIs 0.52–1.29]; p = 0.67); survival and complete neurological recovery were also similar between groups. No significant benefit was observed for the intervention in the entire population. Conclusions: In this pooled analysis of individual data, intra-arrest cooling was associated with a significant increase in favourable neurological outcome in out-of-hospital cardiac arrest patients with initial shockable rhythms. Future studies are needed to confirm the potential benefits of this intervention in this subgroup of patients., SCOPUS: ar.j, info:eu-repo/semantics/published

Author(s): Dewey, Kathryn G; Wessells, K Ryan; Arnold, Charles D; Prado, Elizabeth L; Abbeddou, Souheila; Adu-Afarwuah, Seth; Ali, Hasmot; Arnold, Benjamin F; Ashorn, Per; Ashorn, Ulla; Ashraf, Sania; Becquey, Elodie; Bendabenda, Jaden; Brown, Kenneth H; Christian, Parul; Colford, John M; Dulience, Sherlie JL; Fernald, Lia CH; Galasso, Emanuela; Hallamaa, Lotta; Hess, Sonja Y; Humphrey, Jean H; Huybregts, Lieven; Iannotti, Lora L; Jannat, Kaniz; Lartey, Anna; Port, Agnes Le; Leroy, Jef L; Luby, Stephen P; Maleta, Kenneth; Matias, Susana L; Mbuya, Mduduzi NN; Mridha, Malay K; Nkhoma, Minyanga; Null, Clair; Paul, Rina R; Okronipa, Harriet; Ouedraogo, Jean-Bosco; Pickering, Amy J; Prendergast, Andrew J; Ruel, Marie; Shaikh, Saijuddin; Weber, Ann M; Wolff, Patricia; Zongrone, Amanda; Stewart, Christine P | Abstract: ABSTRACTBackgroundMeta-analyses have demonstrated that small-quantity lipid-based nutrient supplements (SQ-LNS) reduce stunting and wasting prevalence among infants and young children. Identification of subgroups who benefit most from SQ-LNS may facilitate program design.ObjectiveOur objective was to identify study-level and individual-level modifiers of the effect of SQ-LNS on child growth outcomes.MethodsWe conducted a two-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNS provided to children 6 to 24 months of age in low- and middle-income countries (n=37,066). We generated study-specific and subgroup estimates of SQ-LNS vs. control and pooled the estimates using fixed-effects models, with random-effects models as sensitivity analyses. We used random effects meta-regression to examine study-level effect modifiers. Heterogeneity was assessed using I2 and Tau2 statistics. Sensitivity analyses were conducted to examine whether results differed depending on inclusion criteria for arms within trials and types of comparisons.ResultsSQ-LNS provision decreased stunting (length-for-age z-score l −2) by 12% (relative reduction), wasting (weight-for-length (WLZ) z-score l −2) by 14%, low mid-upper arm circumference (MUAC l 125 mm or MUACZ l −2) by 18%, acute malnutrition (WLZ l −2 or MUAC l 125 mm) by 14%, underweight (weight-for-age z-score l −2) by 13%, and small head size (head-circumference z-score l −2) by 9%. Effects of SQ-LNS on growth outcomes generally did not differ by study-level characteristics including region, stunting burden, malaria prevalence, sanitation, water quality, duration of supplementation, frequency of contact or average reported compliance with SQ-LNS. Effects of SQ-LNS on stunting, wasting, low MUAC and small head size were greater among girls than among boys; effects on stunting, underweight and low MUAC were greater among later-born (vs. first-born) children; and effects on wasting and acute malnutrition were greater among children in households with improved (vs. unimproved) sanitation. Results were similar across sensitivity analyses.ConclusionsThe positive impact of SQ-LNS on growth is apparent across a wide variety of study-level contexts. Policy-makers and program planners should consider including SQ-LNS in the mix of interventions to prevent both stunting and wasting. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592.

Objectives: This study aimed to explore the prespecification and conduct of subgroup analyses in cancer individual participant data meta-analyses (IPDMAs). Study Design and Setting: We searched PubMed, Embase.com, Cochrane Library, and Web of Science to identify IPDMAs of randomized controlled trials evaluating intervention effects for cancer. We evaluated how often cancer IPDMAs prespecify subgroup analyses and statistical approaches for examining treatment-subgroup interactions and handling continuous subgroup variables. Results: We included 89 IPDMAs, of which 41 (46.1%) reported a statistically significant treatment-subgroup interaction (P < 0.05) in at least one subgroup analysis. 47 (52.8%) IPDMAs prespecified methods for conducting subgroup analyses and the remaining 42 (47.2%) did not prespecify subgroup analyses. Of the 47 IPDMAs prespecified subgroup analyses, 19 performed the planned subgroup analyses, 21 added subgroup analyses, 7 reduced subgroup analyses. Eighty IPDMAs examined treatment-subgroup interactions, but 72 IPDMAs did not provide enough information to determine whether an appropriate approach that avoided aggregation bias was used. 85 IPDMAs that used continuous variables in subgroup analyses categorized continuous variables and only 1 IPDMA examined non-linear relationships. Conclusion: Many cancer IPDMAs did not prespecify subgroup analyses, nor did they fully perform planned subgroup analyses. Lack of details for the test of treatment-subgroup interactions and examination of non-linear interactions was suboptimal.

Supplemental Digital Content is available in the text This individual participant data meta-analysis assessed the effect of spinal manipulative therapy for chronic low back pain (LBP). Based on this review, there is no evidence to suggest that specific patients’ characteristics are associated with a clinically better response to spinal manipulative therapy as compared with other recommended treatments for chronic LBP., Study Design. Individual participant data (IPD) meta-analysis. Objective. The aim of this study was to identify which participant characteristics moderate the effect of spinal manipulative therapy (SMT) on pain and functioning in chronic LBP. Summary of Background. The effects of SMT are comparable to other interventions recommended in guidelines for chronic low back pain (LBP); however, it is unclear which patients are more likely to benefit from SMT compared to other therapies. Methods. IPD were requested from randomized controlled trials (RCTs) examining the effect of SMT in adults with chronic LBP for pain and function compared to various other therapies (stratified by comparison). Potential patient moderators (n = 23) were a priori based on their clinical relevance. We investigated each moderator using a one-stage approach with IPD and investigated this interaction with the intervention for each time point (1, 3, 6, and 12 months). Results. We received IPD from 21 of 46 RCTs (n = 4223). The majority (12 RCTs, n = 2249) compared SMT to recommended interventions. The duration of LBP, baseline pain (confirmatory), smoking, and previous exposure to SMT (exploratory) had a small moderating effect across outcomes and follow-up points; these estimates did not represent minimally relevant differences in effects; for example, patients with

Objective : We describe a systematic approach to preparing data in the conduct of Individual Participant Data (IPD) analysis. Study design and setting : A guidance paper proposing methods for preparing individual participant data for meta-analysis from multiple study sources, developed by consultation of relevant guidance and experts in IPD. We present an example of how these steps were applied in checking data for our own IPD meta analysis (IPD-MA). Results : We propose five steps of Processing, Replication, Imputation, Merging, and Evaluation to prepare individual participant data for meta-analysis (PRIME-IPD). Using our own IPD-MA as an exemplar, we found that this approach identified missing variables and potential inconsistencies in the data, facilitated the standardization of indicators across studies, confirmed that the correct data were received from investigators, and resulted in a single, verified dataset for IPD-MA. Conclusion : The PRIME-IPD approach can assist researchers to systematically prepare, manage and conduct important quality checks on IPD from multiple studies for meta-analyses. Further testing of this framework in IPD-MA would be useful to refine these steps.

BackgroundResearch on psychosocial interventions has been focused on the effectiveness of psychosocial interventions on mental health outcomes, without exploring how interventions achieve beneficial effects. Identifying the potential pathways through which interventions work would potentially allow further strengthening of interventions by emphasizing specific components connected with such pathways.MethodsWe conducted a preplanned mediation analysis using individual participant data from a dataset of 11 randomized controlled trials (RCTs) which compared focused psychosocial support interventions versus control conditions for children living in low‐ and middle‐income countries (LMICs) affected by humanitarian crises. Based on an ecological resilience framework, we hypothesized that (a) coping, (b) hope, (c) social support, and (d) functional impairment mediate the relationship between intervention and outcome PTSD symptoms. A systematic search on the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed, PyscARTICLES, Web of Science, and the main local LMICs databases was conducted up to August 2018. The hypotheses were tested by using individual participant data obtained from study authors of all the studies included in the systematic review.ResultsWe included 3,143 children from 11 studies (100% of data from included studies), of which 1,877 from six studies contributed to the mediation analysis. Functional impairment was the strongest mediator for focused psychosocial interventions on PTSD (mediation coefficient −0.087, standard error 0.040). The estimated proportion of effect mediated by functional impairment, and adjusted for confounders, was 31%.ConclusionsFindings did not support the proposed mediation hypotheses for coping, hope, and social support. The mediation through functional impairment may represent unmeasured proxy measures or point to a broader mechanism that impacts self‐efficacy and agency.

BackgroundRisk-stratified approaches to managing cancer therapies and their consequent complications rely on accurate predictions to work effectively. The risk-stratified management of fever with neutropenia is one such very common area of management in paediatric practice. Such rules are frequently produced and promoted without adequate confirmation of their accuracy.MethodsAn individual participant data meta-analytic validation of the ‘Predicting Infectious ComplicatioNs In Children with Cancer’ (PICNICC) prediction model for microbiologically documented infection in paediatric fever with neutropenia was undertaken. Pooled estimates were produced using random-effects meta-analysis of the area under the curve-receiver operating characteristic curve (AUC-ROC), calibration slope and ratios of expected versus observed cases (E/O).ResultsThe PICNICC model was poorly predictive of microbiologically documented infection (MDI) in these validation cohorts. The pooled AUC-ROC was 0.59, 95% CI 0.41 to 0.78, tau2=0, compared with derivation value of 0.72, 95% CI 0.71 to 0.76. There was poor discrimination (pooled slope estimate 0.03, 95% CI −0.19 to 0.26) and calibration in the large (pooled E/O ratio 1.48, 95% CI 0.87 to 2.1). Three different simple recalibration approaches failed to improve performance meaningfully.ConclusionThis meta-analysis shows the PICNICC model should not be used at admission to predict MDI. Further work should focus on validating alternative prediction models. Validation across multiple cohorts from diverse locations is essential before widespread clinical adoption of such rules to avoid overtreating or undertreating children with fever with neutropenia.

One of the biggest challenges for network meta-analysis is inconsistency, which occurs when the direct and indirect evidence conflict. Inconsistency causes problems for the estimation and interpretation of treatment effects and treatment contrasts. Krahn and colleagues proposed the net heat approach as a graphical tool for identifying and locating inconsistency within a network of randomized controlled trials. For networks with a treatment loop, the net heat plot displays statistics calculated by temporarily removing each design one at a time, in turn, and assessing the contribution of each remaining design to the inconsistency. The net heat plot takes the form of a matrix which is displayed graphically with coloring indicating the degree of inconsistency in the network. Applied to a network of individual participant data assessing overall survival in 7531 patients with lung cancer, we were surprised to find no evidence of important inconsistency from the net heat approach; this contradicted other approaches for assessing inconsistency such as the Bucher approach, Cochran's Q statistic, node-splitting, and the inconsistency parameter approach, which all suggested evidence of inconsistency within the network at the 5% level. Further theoretical work shows that the calculations underlying the net heat plot constitute an arbitrary weighting of the direct and indirect evidence which may be misleading. We illustrate this further using a simulation study and a network meta-analysis of 10 treatments for diabetes. We conclude that the net heat plot does not reliably signal inconsistency or identify designs that cause inconsistency.

Smoking has been associated with acquisition and increased persistence of Helicobacter pylori infection, as well as with lower effectiveness of its eradication. A greater prevalence of infection among smokers could contribute to the increased risk for gastric cancer. We aimed to estimate the association between smoking and seropositivity to H. pylori through an individual participant data pooled analysis using controls from 14 case- control studies participating in the Stomach Cancer Pooling Project. Summary odds ratios and prevalence ratios (PRs), adjusted for age, sex and social class, and the corresponding 95% confidence intervals (CIs) were estimated through random-effects meta-analysis. Heterogeneity was quantified using the I 2 statistic and publication bias with Egger’s test. There was no significant association between smoking (ever vs. never) and H. pylori seropositivity (adjusted odds ratio = 1.08; 95% CI: 0.89 – 1.32; adjusted PR = 1.01; 95% CI: 0.98 – 1.05). The strength of the association did not increase with the intensity or duration of smoking; stratified analyses according to sex, age, region or type of sample did not yield a consistent pattern of variation or statistically significant results, except for participants younger than 55 years and who had been smoking for more than 30 years (adjusted PR = 1.08; 95% CI: 1.02 – 1.15). This is the first collaborative analysis providing pooled estimates for the association between smoking and H. pylori seropositivity, based on detailed and uniform information and adjusting for major covariates. The results do not support an association between smoking and H. pylori infection.

Background & aims: Protein-energy malnutrition is a health concern among older adults. Improving nutritional status by increasing energy and protein intake likely benefits health. We therefore aimed to investigate effects of nutritional interventions in older adults (at risk of malnutrition) on change in energy intake and body weight, and explore if the intervention effect was modified by study or participants’ characteristics, analysing pooled individual participant data. Methods: We searched for RCTs investigating the effect of dietary counseling, oral nutritional supplements (ONS) or both on energy intake and weight. Principle investigators of eligible studies provided individual participant data. We investigated the effect of nutritional intervention on meaningful increase in energy intake (>250 kcal/day) and meaningful weight gain (>1.0 kg). Logistic generalized estimating equations were performed and ORs with 95% CIs presented. Results: We included data of nine studies with a total of 990 participants, aged 79.2 ± 8.2 years, 64.5% women and mean baseline BMI 23.9 ± 4.7 kg/m2. An non-significant intervention effect was observed for increase in energy intake (OR:1.59; 95% CI 0.95, 2.66) and a significant intervention effect for weight gain (OR:1.58; 95% CI 1.16, 2.17). Stratifying by type of intervention, an intervention effect on increase in energy intake was only observed for dietary counseling in combination with ONS (OR:2.28; 95% CI 1.90, 2.73). The intervention effect on increase in energy intake was greater for women, older participants, and those with lower BMI. Regarding weight gain, an intervention effect was observed for dietary counseling (OR:1.40; 95% CI 1.14, 1.73) and dietary counseling in combination with ONS (OR:2.48; 95% CI 1.92, 3.31). The intervention effect on weight gain was not influenced by participants’ characteristics. Conclusions: Based on pooled data of older adults (at risk of malnutrition), nutritional interventions have a positive effect on energy intake and body weight. Dietary counseling combined with ONS is the most effective intervention.

Background Helicobacter pylori (H. pylori) infection is more frequent among men, though the magnitude of the association might be inaccurate due to potential misclassification of lifetime infection and publication bias. Moreover, infection is common, and most studies are cross-sectional. Thus, prevalence ratios (PRs) may be easier to interpret than odds ratios (ORs). Aim The aim of this study was to quantify the association between sex and H. pylori infection using controls from 14 studies from the Stomach Cancer Pooling (StoP) Project. Participants and methods H. pylori infection was defined based on IgG serum antibody titers or multiplex serology. Participants were also classified as infected if gastric atrophy was present, based on histological examination or serum pepsinogen (PG) levels (PG I≤70 and PG I/II ratio≤3). Summary ORs and PRs, adjusted for age, social class and smoking, and corresponding 95% confidence intervals (CIs), were estimated through random-effects meta-analysis. Results Men had significantly higher OR (OR: 1.33, 95% CI: 1.04-1.70) and PR (PR: 1.05, 95% CI: 1.00-1.10) of infection, with stronger associations among hospital-based or older controls. Results were similar when considering the presence of gastric atrophy to define infection status, particularly among participants older than 65 years. Conclusion This collaborative pooled-analysis supports an independent effect of sex on the prevalence of H. pylori infection, while minimizing misclassification of lifetime infection status and publication bias.

BACKGROUND: Anterior thoracic spinal cord herniation (ATSCH) is a rare cause of progressive myelopathy. Early surgery is essential, but there is no agreement about the best surgical approach. OBJECTIVE: To identify factors that determine surgical results, and to find evidence for the most favorable technique to correct ATSCH. METHODS: To find relevant literature, computerized databases of PubMed, EMBASE, and ISI Web of Science were searched. The current study comprised case-reports published between 1974 and 2018, and the data-set was completed with 12 cases treated in our own institute. Patient characteristics were analyzed following the principles of an individual participant data (IPD) meta-analysis. RESULTS: Brown-Séquard-like neurological deficit prior to surgery was associated with postoperative motor-function improvement when compared to patients with para-paresis (P=0.04). In the univariate analysis, widening of the dura defect (WDD) was more prevalent among improved patients, whereas anterior dura patch (ADP) and application of Intra Operative Neurophysiological Monitoring (IONM) were not. In the multivariate analysis the favorable association with WDD disappeared, which is explained by the dominant influence of a Brown-Séquard-like deficit on outcome. CONCLUSIONS: In general, postoperative results after surgery for ATSCH are favorable, with a high percentage of patients experiencing postoperative improvement. Postoperative motor function improvement is more likely to occur in patients with a Brown-Séquard-like neurological deficit. The WDD should be favored above the application of a patch as the technique of choice in surgical treatment of ATSCH.

Study Objectives The impact of therapy with continuous positive airway pressure (CPAP) and mandibular advancement device (MAD) has not been directly compared in patients with severe obstructive sleep apnea (OSA). The purpose of this individual participant data meta-analysis was to compare the treatment effects of CPAP and titratable MAD on sleepiness, quality of life, sleep-disordered breathing severity, and sleep structure in patients with severe OSA. Methods Randomized controlled trials (RCTs) that included severe OSA patients were identified in order to compare the impact of the two treatments. Individual data from severe OSA patients were extracted from the databases and pooled for analysis. Results Of the seven studies identified, three crossover RCT and one parallel-group RCT corresponding to 151 patients and 249 observations (125 in the CPAP treatment arm and 124 in the MAD treatment arm) were included in the analysis. Titratable MAD had a similar impact to CPAP on major patient-centered outcomes (sleepiness and quality of life). CPAP was more effective in reducing AHI and ODI. However, the two treatments had a similar impact on sleep structure with an increase of N3 and REM sleep. Finally, treatment adherence and preference were largely in favor of MAD. Conclusion This meta-analysis suggests that MAD represents an effective alternative treatment in severe OSA patients intolerant to CPAP or who prefer alternate therapy.

Shortened versions of self-reported questionnaires may be used to reduce respondent burden. When shortened screening tools are used, it is desirable to maintain equivalent diagnostic accuracy to full-length forms. This manuscript presents a case study that illustrates how external data and individual participant data meta-analysis can be used to assess the equivalence in diagnostic accuracy between a shortened and full-length form. This case study compares the Patient Health Questionnaire-9 (PHQ-9) and a 4-item shortened version (PHQ-Dep-4) that was previously developed using optimal test assembly methods. Using a large database of 75 primary studies (34,698 participants, 3,392 major depression cases), we evaluated whether the PHQ-Dep-4 cutoff of ≥ 4 maintained equivalent diagnostic accuracy to a PHQ-9 cutoff of ≥ 10. Using this external validation dataset, a PHQ-Dep-4 cutoff of ≥ 4 maximized the sum of sensitivity and specificity, with a sensitivity of 0.88 (95% CI 0.81, 0.93), 0.68 (95% CI 0.56, 0.78), and 0.80 (95% CI 0.73, 0.85) for the semi-structured, fully structured, and MINI reference standard categories, respectively, and a specificity of 0.79 (95% CI 0.74, 0.83), 0.85 (95% CI 0.78, 0.90), and 0.83 (95% CI 0.80, 0.86) for the semi-structured, fully structured, and MINI reference standard categories, respectively. While equivalence with a PHQ-9 cutoff of ≥ 10 was not established, we found the sensitivity of the PHQ-Dep-4 to be non-inferior to that of the PHQ-9, and the specificity of the PHQ-Dep-4 to be marginally smaller than the PHQ-9.

Objectives\ud \ud Selectively reported results from only well-performing cutoffs in diagnostic accuracy studies may bias estimates in meta-analyses. We investigated cutoff reporting patterns for the Patient Health Questionnaire-9 (PHQ-9; standard cutoff 10) and Edinburgh Postnatal Depression Scale (EPDS; no standard cutoff, commonly used 10–13) and compared accuracy estimates based on published cutoffs versus all cutoffs.\ud \ud \ud \ud Methods\ud \ud We conducted bivariate random effects meta-analyses using individual participant data to compare accuracy from published versus all cutoffs.\ud \ud \ud \ud Results\ud \ud For the PHQ-9 (30 studies, N = 11,773), published results underestimated sensitivity for cutoffs below 10 (median difference: −0.06) and overestimated for cutoffs above 10 (median difference: 0.07). EPDS (19 studies, N = 3637) sensitivity estimates from published results were similar for cutoffs below 10 (median difference: 0.00) but higher for cutoffs above 13 (median difference: 0.14). Specificity estimates from published and all cutoffs were similar for both tools. The mean cutoff of all reported cutoffs in PHQ-9 studies with optimal cutoff below 10 was 8.8 compared to 11.8 for those with optimal cutoffs above 10. Mean for EPDS studies with optimal cutoffs below 10 was 9.9 compared to 11.8 for those with optimal cutoffs greater than 10.\ud \ud \ud \ud Conclusion\ud \ud Selective cutoff reporting was more pronounced for the PHQ-9 than EPDS.

Clinical question What are the benefits and harms of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists when added to usual care (lifestyle interventions and/or other diabetes drugs) in adults with type 2 diabetes at different risk for cardiovascular and kidney outcomes? Current practice Clinical decisions about treatment of type 2 diabetes have been led by glycaemic control for decades. SGLT-2 inhibitors and GLP-1 receptor agonists are traditionally used in people with elevated glucose level after metformin treatment. This has changed through trials demonstrating atherosclerotic cardiovascular disease (CVD) and chronic kidney disease (CKD) benefits independent of medications’ glucose-lowering potential. Recommendations The guideline panel issued risk-stratified recommendations concerning the use of SGLT-2 inhibitors or GLP-1 receptor agonists in adults with type 2 diabetes • Three or fewer cardiovascular risk factors without established CVD or CKD: Weak recommendation against starting SGLT-2 inhibitors or GLP-1 receptor agonists. • More than three cardiovascular risk factors without established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and weak against starting GLP-1 receptor agonists. • Established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and GLP-1 receptor agonists. • Established CVD and CKD: Strong recommendation for starting SGLT-2 inhibitors and weak recommendation for starting GLP-1 receptor agonists. • For those committed to further reducing their risk for CVD and CKD outcomes: Weak recommendation for starting SGLT-2 inhibitors rather than GLP-1 receptor agonists. How this guideline was created An international panel including patients, clinicians, and methodologists created these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel applied an individual patient perspective. The evidence A linked systematic review and network meta-analysis (764 randomised trials included 421 346 participants) of benefits and harms found that SGLT-2 inhibitors and GLP-1 receptor agonists generally reduce overall death, and incidence of myocardial infarctions, and end-stage kidney disease or kidney failure (moderate to high certainty evidence). These medications exert different effects on stroke, hospitalisations for heart failure, and key adverse events in different subgroups. Absolute effects of benefit varied widely based on patients’ individual risk (for example, from five fewer deaths in the lowest risk to 48 fewer deaths in the highest risk, for 1000 patients treated over five years). A prognosis review identified 14 eligible risk prediction models, one of which (RECODe) informed most baseline risk estimates in evidence summaries to underpin the risk-stratified recommendations. Concerning patients’ values and preferences, the recommendations were supported by evidence from a systematic review of published literature, a patient focus group study, a practical issues summary, and a guideline panel survey. Understanding the recommendation We stratified the recommendations by the levels of risk for CVD and CKD and systematically considered the balance of benefits, harms, other considerations, and practical issues for each risk group. The strong recommendation for SGLT-2 inhibitors in patients with CVD and CKD reflects what the panel considered to be a clear benefit. For all other adults with type 2 diabetes, the weak recommendations reflect what the panel considered to be a finer balance between benefits, harms, and burdens of treatment options. Clinicians using the guideline can identify their patient’s individual risk for cardiovascular and kidney outcomes using credible risk calculators such as RECODe. Interactive evidence summaries and decision aids may support well informed treatment choices, including shared decision making.

This individual participant data meta-analysis is the most intensive possible evaluation of the effectiveness of early intensive applied behaviour analysis–based interventions for pre-school autistic children compared with treatment as usual/eclectic interventions. Data from 491 participants (originally collected in 10 studies) were included. Children receiving early intensive applied behaviour analysis–based interventions improved more on the Vineland adaptive behaviour scale (MD = 7.00; 95% confidence interval = 1.95–12.06) and cognitive ability (intelligence quotient) (MD = 14.13; 95% confidence interval = 9.16–19.10) relative to comparators at 2 years; though effects varied considerably across studies. Evidence for other outcomes was inconclusive due to insufficient evidence and there were few data on longer-term effects. All studies were at risk of bias across several domains, often due to the lack of randomisation or blinding of outcome assessors. Given the emerging evidence of modest, albeit short term, effects of a range of pre-school autism interventions and the limitations of the quality of evaluation studies to date, future research should investigate which supports and interventions are most effective for children and families prioritising outcomes measures that are meaningful for the autism community and longer-term follow-up. Further systematic reviews of the existing evidence are unlikely to add to the findings presented here. Lay abstract Early intensive applied behaviour analysis–based interventions are designed to support young autistic children’s learning and development. Unfortunately, the available evidence about the effectiveness of these interventions remains unclear. Several reviews have focused on the published findings rather than contacting the authors to collect and analyse data about the individual participants in the original studies. Also, most of the studies were carried out by groups involved in delivering the interventions leading to the potential bias in interpreting the results. Our research team (supported by an international advisory group) carried out an independent individual patient data review by collecting the original participant data from the authors of the studies, to examine the effectiveness of these interventions. The results suggested that early intensive applied behaviour analysis–based interventions might lead to some changes in children’s cognitive ability (intelligence quotient) and everyday life skills after 2 years, compared with standard treatments. However, all the studies had problems with the way they were designed. Also, few of the studies looked at outcomes that have been described as most important to autistic people or followed children beyond 2 years. We think that further systematic reviews of the existing evidence are unlikely to add to the findings of our review. Furthermore, we recommend that future research should investigate which types of supports and interventions are most effective for children and families, prioritising outcomes measures that are meaningful for the autism community and include, wherever possible, longer-term follow-up.

We reviewed studies with individual participant data of patients who sustained burn injury and subsequently developed necrotizing skin and soft tissue infections (NSTI). Characteristics and managements were compared between patients who lived and patients who died to determine factors associated with mortality. Six databases (PubMed, EMBASE, Cochrane Library, Web of Science, Scopus, and CINAHL) were searched. PRISMA-IPD guidelines were followed throughout the review. Eligible patients sustained a burn injury, treated in any setting, and diagnosed with a NSTI following burn injury. Comparisons were made between burned patients who lived “non-mortality” and burned patients who died “mortality” following NSTI using non-parametric univariate analyses. Fifty-eight studies with 78 patients were published from 1970 through 2019. Non-mortality resulted in 58 patients and mortality resulted in 20 patients. Patients with mortality had significantly greater median %TBSA burned (45%[IQR:44–64%] vs 35%[IQR:11–59%], P = .033), more intubations (79% vs 43%, P = .013), less debridements (83% vs 98%, P = .039), less skin excisions (83% vs 98%, P = .039), more complications (100% vs 50%, P < .001), management at a burn center (100% vs 71%, P = .008), underwent less flap surgeries (5% vs 35%, P = .014), less graft survival (25% vs 86%, P < .001), and less healed wounds (5% vs 95%, P < .001), compared to patients with non-mortality, respectively. Non-mortality patients had more debridements, skin excised, systemic antimicrobials, skin graft survival, flaps, improvement following surgery, and healed wounds compared to mortality patients. Mortality patients had greater %TBSA burned, intubations, management at a burn center and complications compared to non-mortality patients.

The association between direct-acting antiviral (DAA) therapy and hepatocellular carcinoma (HCC) risk and recurrence was initially introduced by Reig et al .1 In their study, they followed up 58 patients with HCC who had sustained virological response for a median of 5.7 months, 16 had a recurrence of HCC while 42 did not, which raised concerns on the safety of hepatitis C therapy in patients with HCC. Several other studies did not show such association or improved survival.2 3 In 2019, the American Gastroenterological Association provided an expert review4 that stated that “there are no conclusive data that DAA therapy is associated with increased or decreased risk, differential time to recurrence, or aggressiveness of recurrent HCC in patients with complete response to HCC therapy”. The study by Drs Sapena, Enea, Torres, Celsa et al aimed to shed light on this controversy by conducting a massive effort to complete an individual participant data meta-analysis (IPD-MA).5 The authors assessed the recurrence rate of HCC in 977 DAA-treated patients after a complete response from 12 retrospective and 9 prospective studies. The recurrence rate and death risk per 100 person-years (PY) in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2 for statistical heterogeneity=74.6%) and …

Objectives: Estimates of depression prevalence in pregnancy and postpartum are based on the Edinburgh Postnatal Depression Scale (EPDS) more than on any other method. We aimed to determine if any EPDS cutoff can accurately and consistently estimate depression prevalence in individual studies. Methods: We analyzed datasets that compared EPDS scores to Structured Clinical Interview for DSM (SCID) major depression status. Random‐effects meta‐analysis was used to compare prevalence with EPDS cutoffs versus the SCID. Results: Seven thousand three hundred and fifteen participants (1017 SCID major depression) from 29 primary studies were included. For EPDS cutoffs used to estimate prevalence in recent studies (≥9 to ≥14), pooled prevalence estimates ranged from 27.8% (95% CI: 22.0%–34.5%) for EPDS ≥ 9 to 9.0% (95% CI: 6.8%–11.9%) for EPDS ≥ 14; pooled SCID major depression prevalence was 9.0% (95% CI: 6.5%–12.3%). EPDS ≥14 provided pooled prevalence closest to SCID‐based prevalence but differed from SCID prevalence in individual studies by a mean absolute difference of 5.1% (95% prediction interval: 13.7%, 12.3%). Conclusion: EPDS ≥14 approximated SCID‐based prevalence overall, but considerable heterogeneity in individual studies is a barrier to using it for prevalence estimation., This study was funded by the Canadian Institutes of Health Research (CIHR, KRS‐140994). Ms. Lyubenova was supported by the Mitacs Globalink Research Internship Program. Ms. Neupane was supported by G.R. Caverhill Fellowship from the Faculty of Medicine, McGill University. Drs. Levis and Wu were supported by Fonds de recherche du Québec‐Santé (FRQS) Postdoctoral Training Fellowships. Mr. Bhandari was supported by a studentship from the Research Institute of the McGill University Health Centre. Ms. Rice was supported by a Vanier Canada Graduate Scholarship. Ms. Azar was supported by a FRQS Masters Training Award. The primary study by Barnes et al. was supported by a grant from the Health Foundation (1665/608). The primary study by Beck et al. was supported by the Patrick and Catherine Weldon Donaghue Medical Research Foundation and the University of Connecticut Research Foundation. The primary study by Helle et al. was supported by the Werner Otto Foundation, the Kroschke Foundation, and the Feindt Foundation. Prof. Robertas Bunevicius, MD, PhD (1958‐2016) was Principal Investigator of the primary study by Bunevicius et al., but passed away and was unable to participate in this project. The primary study by Chaudron et al. was supported by a grant from the National Institute of Mental Health (grant K23 MH64476). The primary study by Tissot et al. was supported by the Swiss National Science Foundation (grant 32003B 125493). The primary study by Tendais et al. was supported under the project POCI/SAU‐ESP/56397/2004 by the Operational Program Science and Innovation 2010 (POCI 2010) of the Community Support Board III and by the European Community Fund FEDER. The primary study by Garcia‐Esteve et al. was supported by grant 7/98 from the Ministerio de Trabajo y Asuntos Sociales, Women's Institute, Spain. The primary study by Howard et al. was supported by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Numbers RP‐PG‐1210‐12002 and RP‐DG‐1108‐10012) and by the South London Clinical Research Network. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The primary study by Phillips et al. was supported by a scholarship from the National Health and Medical and Research Council (NHMRC). The primary study by Nakić Radoš et al. was supported by the Croatian Ministry of Science, Education, and Sports (134‐0000000‐2421). The primary study by Navarro et al. was supported by grant 13/00 from the Ministry of Work and Social Affairs, Institute of Women, Spain. The primary study by Pawlby et al. was supported by a Medical Research Council UK Project Grant (number G89292999N). The primary study by Quispel et al. was supported by Stichting Achmea Gezondheid (grant number z‐282). Dr. Robertson‐Blackmore was supported by a Young Investigator Award from the Brain and Behavior Research Foundation and NIMH grant K23MH080290. The primary study by Rochat et al. was supported by grants from the University of Oxford (HQ5035), the Tuixen Foundation (9940), the Wellcome Trust (082384/Z/07/Z and 071571), and the American Psychological Association. Dr. Rochat receives salary support from a Wellcome Trust Intermediate Fellowship (211374/Z/18/Z). The primary study by Prenoveau et al. was supported by The Wellcome Trust (grant number 071571). The primary study by Stewart et al. was supported by Professor Francis Creed's Journal of Psychosomatic Research Editorship fund (BA00457) administered through University of Manchester. The primary study by Tandon et al. was funded by the Thomas Wilson Sanitarium. The primary study by Tran et al. was supported by the Myer Foundation who funded the study under its Beyond Australia scheme. Dr. Tran was supported by an early career fellowship from the Australian National Health and Medical Research Council. The primary study by Vega‐Dienstmaier et al. was supported by Tejada Family Foundation, Inc, and Peruvian‐American Endowment, Inc. Drs. Benedetti and Thombs were supported by FRQS researcher salary awards.

© 2021 Elsevier B.V. The prevalence of multimorbidity and polypharmacy increases significantly with age and are associated with negative health consequences. However, most current interventions to optimize medication have failed to show significant effects on patient-relevant outcomes. This may be due to ineffectiveness of interventions themselves but may also reflect other factors: insufficient sample sizes, heterogeneity of population. To address this issue, the international PROPERmed collaboration was set up to obtain/synthesize individual participant data (IPD) from five cluster-randomized trials. The trials took place in Germany and The Netherlands and aimed to optimize medication in older general practice patients with chronic illness. PROPERmed is the first database of IPD to be drawn from multiple trials in this patient population and setting. It offers the opportunity to derive prognostic models with increased statistical power for prediction of patient-relevant outcomes resulting from the interplay of multimorbidity and polypharmacy. This may help patients from this heterogeneous group to be stratified according to risk and enable clinicians to identify patients that are likely to benefit most from resource/time-intensive interventions. The aim of this manuscript is to describe the rationale behind PROPERmed collaboration, characteristics of the included studies/participants, development of the harmonized IPD database and challenges faced during this process.

BackgroundSmall-quantity lipid-based nutrient supplements (SQ-LNS) reduce child stunting and provide many of the fatty acids and micronutrients that are necessary for rapid brain development that occurs during infancy and early childhood. Positive effects of SQ-LNS on developmental outcomes have been found in some trials, but not others.ObjectivesOur objectives were to generate pooled estimates of the effect of SQ-LNS, compared to control groups that received no intervention or an intervention without any nutritional supplement, on developmental outcomes (language, social-emotional, motor, and executive function), and to identify study-level and individual-level modifiers of these effects.MethodsWe conducted a two-stage meta-analysis of individual participant data from 14 intervention versus control group comparisons in 13 randomized trials of SQ-LNS provided to infants and young children age 6 to 24 months in 9 low- or middle-income countries (total n=30,024). We generated study-specific estimates of SQ-LNS vs. control groups (including main effects and subgroup estimates for individual-level effect modifiers) and pooled the estimates using fixed-effects models. We used random effects meta-regression to examine potential study-level effect modifiers.ResultsIn 11-13 intervention versus control group comparisons (n=23,588-24,561), SQ-LNS increased mean language (mean difference: 0.07 standard deviations; 95% CI: 0.04, 0.10), social-emotional (0.08; 0.05, 0.11), and motor scores (0.08; 0.05, 0.11) and reduced the prevalence of children in the lowest decile of these scores by 17% (prevalence ratio: 0.83, 95% CI 0.76, 0.91), 19% (0.81; 0.74, 0.90), and 16% (0.84; 0.77, 0.92), respectively. SQ-LNS also increased the prevalence of children walking without support at 12 months by 9% (1.09; 1.05, 1.14). Effects of SQ-LNS on language, social-emotional, and motor outcomes were larger among study populations with a higher burden (≥ 35%) of child stunting at 18 months (mean difference 0.11-0.13 SD; 8-9 comparisons) than in populations with lower stunting burden (estimates near zero). At the individual level, greater effects of SQ-LNS were found on language among children who were acutely malnourished (mean difference: 0.31) at baseline; on language (0.12), motor (0.11), and executive function (0.06) among children in households with lower socio-economic status; and on motor development among later-born children (0.11), children of older mothers (0.10), and children of mothers with lower education (0.11).ConclusionsSQ-LNS provided daily to children in the range of 6-24 months of age can be expected to result in modest, but potentially important, developmental gains, particularly in populations with high child stunting burden. Certain groups of children who experience higher risk environments, such as those from poor households or with poor baseline nutritional status, have greater potential to benefit from SQ-LNS in developmental outcomes. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42020159971.

Currently, little is known about the extent of interindividual variability in response to beta-alanine (BA) supplementation, nor what proportion of said variability can be attributed to external factors or to the intervention itself (intervention response). To investigate this, individual participant data on the effect of BA supplementation on a high-intensity cycling capacity test (CCT110%) were meta-analyzed. Changes in time to exhaustion (TTE) and muscle carnosine were the primary and secondary outcomes. Multilevel distributional Bayesian models were used to estimate the mean and SD of BA and placebo group change scores. The relative sizes of group SDs were used to infer whether observed variation in change scores were due to intervention or non-intervention-related effects. Six eligible studies were identified, and individual data were obtained from four of these. Analyses showed a group effect of BA supplementation on TTE (7.7, 95% credible interval [CrI] [1.3, 14.3] s) and muscle carnosine (18.1, 95% CrI [14.5, 21.9] mmol/kg DM). A large intervention response variation was identified for muscle carnosine (σIR = 5.8, 95% CrI [4.2, 7.4] mmol/kg DM) while equivalent change score SDs were shown for TTE in both the placebo (16.1, 95% CrI [13.0, 21.3] s) and BA (15.9, 95% CrI [13.0, 20.0] s) conditions, with the probability that SD was greater in placebo being 0.64. In conclusion, the similarity in observed change score SDs between groups for TTE indicates the source of variation is common to both groups, and therefore unrelated to the supplement itself, likely originating instead from external factors such as nutritional intake, sleep patterns, or training status.

Supplemental Digital Content is available in the text., Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02–1.08) and 1.06 (95% CI, 1.02–1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01–1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00–1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01–1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06–1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal. Registration: URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015031227

BackgroundQuality-adjusted life years (QALYs) are widely used to measure the impact of various diseases on both the quality and quantity of life and in their economic valuations. It will be clinically important and informative if we can estimate QALYs based on measurements of depression severity.ObjectiveTo construct a conversion table from the Patient Health Questionnaire-9 (PHQ-9), the most frequently used depression scale in recent years, to the Euro-Qol Five Dimensions Three Levels (EQ-5D-3L), one of the most commonly used instruments to assess QALYs.MethodsWe obtained individual participant data of randomised controlled trials of internet cognitive-behavioural therapy which had administered depression severity scales and the EQ-5D-3L at baseline and at end of treatment. Scores from depression scales were all converted into the PHQ-9 according to the validated algorithms. We used equipercentile linking to establish correspondences between the PHQ-9 and the EQ-5D-3L.FindingsIndividual-level data from five trials (total N=2457) were available. Subthreshold depression (PHQ-9 scores between 5 and 10) corresponded with EQ-5D-3L index values of 0.9–0.8, mild major depression (10–15) with 0.8–0.7, moderate depression (15–20) with 0.7–0.5 and severe depression (20 or higher) with 0.6–0.0. A five-point improvement in PHQ-9 corresponded approximately with an increase in EQ-5D-3L score by 0.03 and a ten-point improvement by approximately 0.25.Conclusions and Clinical ImplicationsThe conversion table between the PHQ-9 and the EQ-5D-3L scores will enable fine-grained assessment of burden of depression at its various levels of severity and of impacts of its various treatments.

BackgroundFor prospective meta-analyses (PMAs), eligible studies are identified, and the PMA hypotheses, selection criteria, and analysis methods are pre-specifiedbeforethe results of any of the studies are known. This reduces publication bias and selective outcome reporting and provides a unique opportunity for outcome standardisation/harmonisation. We conducted a world-first PMA of four trials investigating interventions to prevent early childhood obesity. The aims of this study were to quantitatively analyse the effects of prospective planning on variations across trials, outcome harmonisation, and the power to detect intervention effects, and to derive recommendations for future PMA.MethodsWe examined intervention design, participant characteristics, and outcomes collected across the four trials included in the EPOCH PMA using their registration records, protocol publications, and variable lists. The outcomes that trials planned to collect prior to inclusion in the PMA were compared to the outcomes that trials collected after PMA inclusion. We analysed the proportion of matching outcome definitions across trials, the number of outcomes per trial, and how collaboration increased the statistical power to detect intervention effects.ResultsThe included trials varied in intervention design and participants, this improved external validity and the ability to perform subgroup analyses for the meta-analysis. While individual trials had limited power to detect the main intervention effect (BMIz-score), synthesising data substantially increased statistical power. Prospective planning led to an increase in the number of collected outcome categories (e.g. weight, child’s diet, sleep), and greater outcome harmonisation. Prior to PMA inclusion, only 18% of outcome categories were included in all trials. After PMA inclusion, this increased to 91% of outcome categories. However, while trials mostly collected the same outcome categories after PMA inclusion, some inconsistencies in how the outcomes were measured remained (such as measuring physical activity by hours of outside play versus using an activity monitor).ConclusionProspective planning led to greater outcome harmonisation and greater power to detect intervention effects, while maintaining acceptable variation in trial designs and populations, which improved external validity. Recommendations for future PMA include more detailed harmonisation of outcome measures and careful pre-specification of analyses to avoid research waste by unnecessary over-collection of data.

Background Refugees and asylum seekers face various stressors due to displacement and are especially vulnerable to common mental disorders. To effectively manage psychological distress in this population, innovative interventions are required. The World Health Organization (WHO) Self-Help Plus (SH+) intervention has shown promising outcomes in reducing symptoms of common mental disorders among refugees and asylum seekers. However, individual participant differences in response to SH+ remain largely unknown. The Individual Participant Data (IPD) meta-analysis synthesizes raw datasets of trials to provide cutting-edge evidence of outcomes that cannot be examined by conventional meta-analytic approaches. Objectives This protocol outlines the methods of a series of IPD meta-analyses aimed at examining the effects and potential moderators of SH+ in (a) reducing depressive symptoms at post-intervention and (b) preventing the six-month cumulative incidence of mental disorders in refugees and asylum seekers. Method RCTs on SH+ have been identified through WHO and all authors have agreed to share the datasets of the trials. The primary outcomes of the IPD meta-analyses are (a) reduction in depressive symptoms at post-intervention, and (b) prevention of six-month cumulative incidence of mental disorders. Secondary outcomes include post-traumatic stress disorder symptoms, well-being, functioning, quality of life, and twelve-month cumulative incidence of mental disorders. One-stage IPD meta-analyses will be performed using mixed-effects linear/logistic regression. Missing data will be handled by multiple imputation. Conclusions These results will enrich current knowledge about the response to SH+ and will facilitate its targeted dissemination. The results of these IPD meta-analyses will be published in peer-reviewed journals., HIGHLIGHTS Refugees and asylum seekers face enormous challenges and, thus, are at risk of mental disorders. Low-intensity psychotherapeutic interventions are needed to effectively address symptoms and prevent the full-blown onset of mental disorders in refugees and asylum seekers.

Background and purposeThe Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.Materials and methodsPublished or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT+CT or adding another timing of CT to LRT+CT (main question), or comparing induction CT+radiotherapy to radiotherapy+concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.ResultsFor the main question, 101 trials (18951 patients, median follow-up of 6.5years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p&nbsp

Objective: To investigate if cerebroplacental ratio (CPR) adds to the predictive value of umbilical artery pulsatility index (UA PI) alone–standard of practice–for adverse perinatal outcome in singleton pregnancies. Design and setting: Meta-analysis based on individual participant data (IPD). Population or sample: Ten centres provided 17 data sets for 21661 participants, 18731 of which could be included. Sample sizes per data set ranged from 207 to 9215 individuals. Patient populations varied from uncomplicated to complicated pregnancies. Methods: In a collaborative, pooled analysis, we compared the prognostic value of combining CPR with UA PI, versus UA PI only and CPR only, with a one-stage IPD approach. After multiple imputation of missing values, we used multilevel multivariable logistic regression to develop prediction models. We evaluated the classification performance of all models with receiver operating characteristics analysis. We performed subgroup analyses according to gestational age, birthweight centile and estimated fetal weight centile. Main outcome measures: Composite adverse perinatal outcome, defined as perinatal death, caesarean section for fetal distress or neonatal unit admission. Results: Adverse outcomes occurred in 3423 (18%) participants. The model with UA PI alone resulted in an area under the curve (AUC) of 0.775 (95% CI 0.709–0.828) and with CPR alone in an AUC of 0.778 (95% CI 0.715–0.831). Addition of CPR to the UA PI model resulted in an increase in the AUC of 0.003 points (0.778, 95% CI 0.714–0.831). These results were consistent across all subgroups. Conclusions: Cerebroplacental ratio added no predictive value for adverse perinatal outcome beyond UA PI, when assessing singleton pregnancies, irrespective of gestational age or fetal size. Tweetable abstract: Doppler measurement of cerebroplacental ratio in clinical practice has limited added predictive value to umbilical artery alone.

Chronic kidney disease (CKD) causes substantial global morbidity and increases cardiovascular and all-cause mortality. Unlike other chronic diseases with established strategies for screening, there has been no consensus on whether health systems and governments should prioritize early identification and intervention for CKD. Guidelines on evaluating and managing early CKD are available but have not been universally adopted in the absence of incentives or quality measures for prioritizing CKD care. The burden of CKD falls disproportionately upon persons with lower socioeconomic status, who have a higher prevalence of CKD, limited access to treatment, and poorer outcomes. Therefore, identifying and treating CKD at the earliest stages is an equity imperative. In 2019, Kidney Disease: Improving Global Outcomes (KDIGO) held a controversies conference entitled "Early Identification and Intervention in CKD." Participants identified strategies for screening, risk stratification, and treatment for early CKD and the key health system and economic factors for implementing these processes. A consensus emerged that CKD screening coupled with risk stratification and treatment should be implemented immediately for high-risk persons and that this should ideally occur in primary or community care settings with tailoring to the local context.

Travelling to school by car diminishes opportunities for physical activity and contributes to traffic congestion and associated noise and air pollution. This meta-analysis examined sociodemographic characteristics and built environment associates of travelling to school by car compared to using active transport among New Zealand (NZ) adolescents. Four NZ studies (2163 adolescents) provided data on participants&rsquo, mode of travel to school, individual and school sociodemographic characteristics, distance to school and home-neighbourhood built-environment features. A one-step meta-analysis using individual participant data was performed in SAS. A final multivariable model was developed using stepwise logistic regression. Overall, 60.6% of participants travelled to school by car. When compared with active transport, travelling to school by car was positively associated with distance to school. Participants residing in neighbourhoods with high intersection density and attending medium deprivation schools were less likely to travel to school by car compared with their counterparts. Distance to school, school level deprivation and low home neighbourhood intersection density are associated with higher likelihood of car travel to school compared with active transport among NZ adolescents. Comprehensive interventions focusing on both social and built environment factors are needed to reduce car travel to school.

Background Network meta-analyses using individual participant data (IPD-NMAs) have been increasingly used to compare the effects of multiple interventions. Although there have been many studies on statistical methods for IPD-NMAs, it is unclear whether there are statistical defects in published IPD-NMAs and whether the reporting of statistical analyses has improved. This study aimed to investigate statistical methods used and assess the reporting and methodological quality of IPD-NMAs. Methods We searched four bibliographic databases to identify published IPD-NMAs. The methodological quality was assessed using AMSTAR-2 and reporting quality assessed based on PRISMA-IPD and PRISMA-NMA. We performed stratified analyses and correlation analyses to explore the factors that might affect quality. Results We identified 21 IPD-NMAs. Only 23.8% of the included IPD-NMAs reported statistical techniques used for missing participant data, 42.9% assessed the consistency, and none assessed the transitivity. None of the included IPD-NMAs reported sources of funding for trials included, only 9.5% stated pre-registration of protocols, and 28.6% assessed the risk of bias in individual studies. For reporting quality, compliance rates were lower than 50.0% for more than half of the items. Less than 15.0% of the IPD-NMAs reported data integrity, presented the network geometry, or clarified risk of bias across studies. IPD-NMAs with statistical or epidemiological authors often better assessed the inconsistency (P = 0.017). IPD-NMAs with a priori protocol were associated with higher reporting quality in terms of search (P = 0.046), data collection process (P = 0.031), and syntheses of results (P = 0.006). Conclusions The reporting of statistical methods and compliance rates of methodological and reporting items of IPD-NMAs were suboptimal. Authors of future IPD-NMAs should address the identified flaws and strictly adhere to methodological and reporting guidelines.

Background Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. Objectives To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. Design This was an individual participant data meta-analysis of cohort studies. Setting Source data from secondary and tertiary care. Predictors We identified predictors from systematic reviews, and prioritised for importance in an international survey. Primary outcomes Early-onset (delivery at Analysis We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I 2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. Results The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. Limitations Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. Conclusion For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. Future work Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. Study registration This study is registered as PROSPERO CRD42015029349. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.