Uptake of systematic reviews and meta-analyses based on individual participant data in clinical practice guidelines: descriptive study.

To establish the extent to which systematic reviews and meta-analyses of individual participant data (IPD) are being used to inform the recommendations included in published clinical guidelines

A pipeline to assess disease-associated haplotypes in repeat expansion disorders: The example of MJD/SCA3 locus

At least 40 human diseases are associated with repeat expansions; yet, the mutational origin and instability mechanisms remain unknown for most of them. Previously, genetic epidemiology and predisposing backgrounds for the instability of some expanding loci have been studied in different populations through the analysis of diversity flanking the respective pathogenic repeats. Here, we aimed at developing a pipeline to assess disease-associated haplotypes at oligonucleotide repeat loci, combining analysis of single nucleotide polymorphisms (SNPs) and short tandem repeats (STRs). Machado-Joseph disease (MJD/SCA3), the most frequent dominant ataxia worldwide, was used as an example of a detailed procedure. Thus, to identify genetic backgrounds that segregate with expanded/mutated alleles in MJD, we selected a set of 26 SNPs and 7 STRs flanking the causative CAG repeat. Key criteria and steps for this selection are described, and included (1) haplotype blocks minimizing the occurrence of recombination (for SNPs); and (2) match scores to increase potential for polymorphic information content of repetitive sequences found in Tandem Repeats Finder (for STRs). To directly assess SNP haplotypes in phase with MJD expansions, we optimized a strategy with preferential amplification of normal over expanded alleles, in addition to SNP allele-specific amplifications; this allowed the identification of disease-associated SNP haplotypes, even when only the proband is available in a given family. To infer STR haplotypes, we optimized a multiplex PCR, including 7 STRs plus the MJD_CAG repeat, followed by analysis of segregation or the use of the PHASE software. This protocol is a ready-to-use tool to assess MJD haplotypes in different populations. The pipeline designed can be used to assess disease-associated haplotypes in other repeat-expansion diseases. This should be of great utility to study (1) genetic epidemiology (population-of-origin, age and spreading routes of mutations) and (2) mechanisms responsible for de novo expansions, in these neurological diseases; (3) to detect predisposing haplotypes and (4) phenotype modifiers; (5) to help solving cases of apparent homoallelism (two same-size normal alleles) in diagnosis; and (6) to identify the best targets for the development of allele-specific therapies in ethnically diverse patient populations.This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operacional Program for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). SM is funded by FCT (IF/00930/2013). This article is a result of the project NORTE-01-0145-FEDER-000008, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Sex-specific effects of nutritional supplements in infants born early or small: protocol for an individual participant data meta-analysis (ESSENCE IPD-MA).

INTRODUCTION: Preterm and small for gestational age (SGA) infants are at increased risk of poor growth, disability and delayed development. While growing up they are also at increased risk of obesity, diabetes and later heart disease. The risk of such adverse outcomes may be altered by how preterm and SGA infants are fed after birth. Faltering postnatal growth is common due to failure to achieve recommended high energy and protein intakes, and thus preterm and SGA infants are often provided with supplemental nutrition soon after birth. Enhanced nutrition has been associated with improved early growth and better cognitive development. However, limited evidence suggests that faster growth may increase the risk for later adiposity, metabolic and cardiovascular disease, and that such risks may differ between girls and boys. METHODS AND ANALYSIS: We will search Ovid MEDLINE, Embase, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, controlled-trials.com, ClinicalTrials.gov and anzctr.org.au for randomised trials that studied the effects of macronutrient supplements for preterm and SGA infants on (i) developmental and metabolic and (ii) growth outcomes after hospital discharge. The outcomes will be (i) cognitive impairment and metabolic risk (co-primary) and (ii) body mass index. Individual participant data (IPD) from all available trials will be included using an intention-to-treat approach. A one-stage procedure for IPD meta-analysis (MA) will be used, accounting for clustering of participants within studies. Exploratory subgroup analyses will further investigate sources of heterogeneity, including sex and size of infants, different timing, duration and type of supplements. ETHICS AND DISSEMINATION: This IPD-MA is approved by the University of Auckland Human Participants Ethics Committee (reference number: 019874). Individual studies have approval from relevant local ethics committees. Results will be disseminated in a peer-reviewed journal and presented at international conferences. PROSPERO REGISTRATION NUMBER: CRD42017072683

Individual and Combined Effects of Job Strain Components on Subsequent Morbidity and Mortality

Supplemental Digital Content is available in the text.Non peer reviewe

Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis.

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International lease accounting reform and economic consequences: the views of UK users and preparers

In response to perceived difficulties with extant lease-accounting standards in operation worldwide, the G4+1 issued a discussion paper which proposes that all leases should be recognized on the balance sheet [ASB (1999). Leases: Implementation of a new approach, discussion paper. London: Accounting Standards Board]. Leasing is now on the active agenda of the IASB. A major difficulty faced by standard setters lies in overcoming the preparer/user lobbying imbalance and obtaining ex ante evidence on the likely impact of regulatory reform. This paper contributes to the ongoing international debate by conducting a questionnaire survey of U.K. users and preparers to assess their views on proposals for lease-accounting reform and on the potential economic consequences of their adoption. The results, based on 132 responses, indicate that both groups accept that there are deficiencies in the current rules, but they do not agree on the way forward and believe that the proposals would lead to significant economic consequences for key parties. The impact on respondents' views of familiarity with the proposals, level of lease usage, and company size, is also examined

Cerebroplacental ratio in predicting adverse perinatal outcome : a meta-analysis of individual participant data

Acknowledgement We would like thank Dr F. Figueras, Prof. E. Gratacos, Dr F. Crispi and Dr J. Miranda for sharing data for this project. The CPR IPD Study Group: Asma Khalil (Fetal Medi- cine Unit, St George’s Hospital Medical School and St George’s University of London, London, UK; Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George’s University of London, Lon- don, UK), Basky Thilaganathan (Fetal Medicine Unit, St George’s Hospital Medical School and St George’s Univer- sity of London, London, UK; Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK), Ozhan M Turan (Departments of Obstetrics, Gynecology and Repro- ductive Sciences, University of Maryland School of Medi- cine, Baltimore, MD, USA), Sarah Crimmins (Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA), Chris Harman (Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA), Alis- son M Shannon (Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA), Sailesh Kumar (School of Medicine, The University of Queensland, Brisbane, QLD, Australia; Mater Research Institute – University of Queensland, South Brisbane, QLD, Australia), Patrick Dicker (Department of Epidemiology and Public Health, Royal College of Surgeons in Ireland), Fergal Malone (Departments of Obstetrics and Gynaecology, Royal College of Surgeons in Ireland), Elizabeth C Tully (Departments of Obstetrics and Gynaecology, Royal College of Surgeons in Ireland), Julia Unterscheider (Department of Maternal Fetal Medicine, The Royal Women’s Hospital, Melbourne, VIC, Australia), Isabella Crippa (Department of Obstetrics and Gynaecology, University of Milano-Bicocca, Monza, Italy), Alessandro Ghidini (Department of Obstetrics and Gynae- cology, University of Milano-Bicocca, Monza, Italy), Nadia Roncaglia (Department of Obstetrics and Gynaecology, University of Milano-Bicocca, Monza, Italy), Patrizia Ver- gani (Department of Obstetrics and Gynaecology, Univer- sity of Milano-Bicocca, Monza, Italy), Amarnath Bhide (Fetal Medicine Unit, St George’s Hospital Medical School and St George’s University of London, London, UK), Fran- cesco D’Antonio (Fetal Medicine Unit, St George’s Hospital Medical School and St George’s University of London, London, UK), Gianluigi Pilu (Policlinico S. Orsola-Mal- pighi, University of Bologna, Bologna, Italy), Alberto Galindo (Fetal Medicine Unit-SAMID, Department of Obstetrics and Gynaecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Com- plutense University of Madrid, Madrid, Spain), Ignacio Herraiz (Fetal Medicine Unit-SAMID, Department of Obstetrics and Gynaecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Com- plutense University of Madrid, Madrid, Spain), Alicia Vazquez-Sarandeses(FetalMedicineUnit-SAMID,Depart- ment of Obstetrics and Gynaecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Madrid, Spain), Cath- rine Ebbing (Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway), Synnøve L Johnsen (Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway), Henriette O Karlsen (Research Group for Pregnancy, Fetal Develop- ment and Birth, Department of Clinical Science, University of Bergen, Bergen, Norway).Peer reviewedPublisher PD

Physical inactivity, cardiometabolic disease, and risk of dementia : an individual-participant meta-analysis

OBJECTIVE To examine whether physical inactivity is a risk factor for dementia, with attention to the role of cardiometabolic disease in this association and reverse causation bias that arises from changes in physical activity in the preclinical (prodromal) phase of dementia. DESIGN Meta-analysis of 19 prospective observational cohort studies. DATA SOURCES The Individual-Participant-Data Meta-analysis in Working Populations Consortium, the Inter-University Consortium for Political and Social Research, and the UK Data Service, including a total of 19 of a potential 9741 studies. REVIEW METHOD The search strategy was designed to retrieve individual-participant data from prospective cohort studies. Exposure was physical inactivity; primary outcomes were incident all-cause dementia and Alzheimer's disease; and the secondary outcome was incident cardiometabolic disease (that is, diabetes, coronary heart disease, and stroke). Summary estimates were obtained using random effects meta-analysis. RESULTS Study population included 404 840 people (mean age 45.5 years, 57.7% women) who were initially free of dementia, had a measurement of physical inactivity at study entry, and were linked to electronic health records. In 6.0 million person-years at risk, we recorded 2044 incident cases of all-cause dementia. In studies with data on dementia subtype, the number of incident cases of Alzheimer's disease was 1602 in 5.2 million person-years. When measured = 10 years before dementia onset, no difference in dementia risk between physically active and inactive participants was observed (hazard ratios 1.01 (0.89 to 1.14) and 0.96 (0.85 to 1.08) for the two outcomes). Physical inactivity was consistently associated with increased risk of incident diabetes (hazard ratio 1.42, 1.25 to 1.61), coronary heart disease (1.24, 1.13 to 1.36), and stroke (1.16, 1.05 to 1.27). Among people in whom cardiometabolic disease preceded dementia, physical inactivity was non-significantly associated with dementia (hazard ratio for physical activity assessed > 10 before dementia onset 1.30, 0.79 to 2.14). CONCLUSIONS In analyses that addressed bias due to reverse causation, physical inactivity was not associated with all-cause dementia or Alzheimer's disease, although an indication of excess dementia risk was observed in a subgroup of physically inactive individuals who developed cardiometabolic disease.Peer reviewe

Financial viability appraisals for site-specific planning decisions in England

In England, appraisals of the financial viability of development schemes have become an integral part of planning policy-making, initially in determining the amount of planning obligations that might be obtained via legal agreements (known as Section 106 agreements) and latterly as a basis for establishing charging schedules for the Community Infrastructure Levy (CIL). Local planning authorities set these policies on an area-wide basis but ultimately development proposals require consent on a site-by-site basis. It is at this site-specific level that issues of viability are hotly contested. This paper examines case documents, proofs of evidence and decisions from a sample of planning disputes in order to address major issues within development viability, the application of the models and the distribution of the development gain between the developer, landowner and community. The results have specific application to viability assessment in England and should impact on future policy and practice guidance in this field. They also have relevance to other countries that incorporate assessments of economic viability in their planning systems