Relationship between reproductive success and male plasma vitellogenin concentrations in cunner, Tautogolabrus adspersus

The gene for vitellogenin, an egg yolk protein precursor, is usually silent in male fish but can be induced by estrogen exposure. For this reason, vitellogenin production in male fish has become a widely used indicator of exposure to exogenous estrogens or estrogen mimics in the aquatic environment. The utility of this indicator to predict impacts on fish reproductive success is unclear because information on the relationship between male plasma vitellogenin and reproductive end points in male and female fish is limited. In the research reported in this article, we investigated whether the presence of male plasma vitellogenin is a reliable indicator of decreased reproductive success in mature fish. Adult and sexually mature male and female cunner (Tautogolabrus adspersus) were exposed to 17β-estradiol, ethynylestradiol, or estrone, three steroidal estrogens that elicit the vitellogenic response. Data were gathered and pooled on egg production, egg viability, egg fertility, sperm motility, and male plasma vitellogenin concentrations. All males, including two with plasma vitellogenin levels exceeding 300 mg/mL, produced motile sperm. Neither percent fertile eggs nor percent viable eggs produced by reproductively active fish demonstrated a significant correlation with male plasma vitellogenin concentrations. Male gonadosomatic index and average daily egg production by females showed significant, but weak, negative correlation with male plasma vitellogenin concentrations. Results suggest that male plasma vitellogenin expression is not a reliable indicator of male reproductive dysfunction in adult cunner exposed to estrogens for 2-8 weeks during their reproductive season, at least in relation to capacity to produce motile sperm or fertilize eggs. Male plasma vitellogenin expression may serve as an indicator of reduced female reproductive function caused by estrogen exposure

Characterization of virus-like particles associated with the human faecal and caecal microbiota

This work represents an investigation into the presence, abundance and diversity of virus-like particles (VLPs) associated with human faecal and caecal samples. Various methodologies for the recovery of VLPs from faeces were tested and optimized, including successful down-stream processing of such samples for the purpose of an in-depth electron microscopic analysis, pulsed-field gel electrophoresis and efficient DNA recovery. The applicability of the developed VLP characterization method beyond the use of faecal samples was then verified using samples obtained from human caecal fluid

Statistical analyses and quality of individual participant data network meta-analyses were suboptimal: a cross-sectional study

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

Pulmonary metastasectomy versus continued active monitoring in colorectal cancer (PulMiCC): a multicentre randomised clinical trial

BACKGROUND: Lung metastasectomy in the treatment of advanced colorectal cancer has been widely adopted without good evidence of survival or palliative benefit. We aimed to test its effectiveness in a randomised controlled trial (RCT). METHODS: Multidisciplinary teams in 13 hospitals recruited participants with potentially resectable lung metastases to a multicentre, two-arm RCT comparing active monitoring with or without metastasectomy. Other local or systemic treatments were decided by the local team. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, the number of metastases, and carcinoembryonic antigen level. The central Trial Management Group were blind to patient allocation until completion of the analysis. Analysis was on intention to treat with a margin for non-inferiority of 10%. RESULTS: Between December 2010 and December 2016, 65 participants were randomised. Characteristics were well-matched in the two arms and similar to those in reported studies: age 35 to 86 years (interquartile range (IQR) 60 to 74); primary resection IQR 16 to 35 months previously; stage at resection T1, 2 or 3 in 3, 8 and 46; N1 or N2 in 31 and 26; unknown in 8. Lung metastases 1 to 5 (median 2); 16/65 had previous liver metastases; carcinoembryonic antigen normal in 55/65. There were no other interventions in the first 6 months, no crossovers from control to treatment, and no treatment-related deaths or major adverse events. The Hazard ratio for death within 5 years, comparing metastasectomy with control, was 0.82 (95%CI 0.43, 1.56). CONCLUSIONS: Because of poor and worsening recruitment, the study was stopped. The small number of participants in the trial (N = 65) precludes a conclusive answer to the research question given the large overlap in the confidence intervals in the proportions still alive at all time points. A widely held belief is that the 5-year absolute survival benefit with metastasectomy is about 35%: 40% after metastasectomy compared to < 5% in controls. The estimated survival in this study was 38% (23-62%) for metastasectomy patients and 29% (16-52%) in the well-matched controls. That is the new and important finding of this RCT. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01106261. Registered on 19 April 2010

Cracking the BAFF code.

The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community’s Seventh Framework Programme under grant agreement n8 223175 (HEALTH-F2–2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program and the Ministry of Economic Development, Innovation and Export Trade of Quebec (PSR-SIIRI-701). Additional support for the iCOGS infrastructure was provided by the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The ABCFS and OFBCR work was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products or organizations imply endorsement t by the US Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow and M.C.S. is a NHMRC Senior Research Fellow. The OFBCR work was also supported by the Canadian Institutes of Health Research ‘CIHR Team in Familial Risks of Breast Cancer’ program. The ABCS was funded by the Dutch Cancer Society Grant no. NKI2007-3839 and NKI2009-4363. The ACP study is funded by the Breast Cancer Research Trust, UK. The work of the BBCC was partly funded by ELAN-Programme of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). E.S. is supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, UK. Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). I.T. is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by the Fondation de France, the French National Institute of Cancer (INCa), The National League against Cancer, the National Agency for Environmental l and Occupational Health and Food Safety (ANSES), the National Agency for Research (ANR), and the Association for Research against Cancer (ARC). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital.The CNIO-BCS was supported by the Genome Spain Foundation the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario PI11/00923 and PI081120). The Human Genotyping-CEGEN Unit, CNIO is supported by the Instituto de Salud Carlos III. D.A. was supported by a Fellowship from the Michael Manzella Foundation (MMF) and was a participant in the CNIO Summer Training Program. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence e data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), as well as the Department of Internal Medicine , Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus Bonn, Germany. The HEBCS was supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by a research grant from Takeda Science Foundation , by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan and by National Cancer Center Research and Development Fund. The HMBCS was supported by short-term fellowships from the German Academic Exchange Program (to N.B), and the Friends of Hannover Medical School (to N.B.). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Stockholm Cancer Foundation and the Swedish Cancer Society. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland. kConFab is supported by grants from the National Breast Cancer Foundation , the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC (145684, 288704, 454508). Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), the Cancer Council of Tasmania and Cancer Foundation of Western Australia and the NHMRC (199600). G.C.T. and P.W. are supported by the NHMRC. LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018 and 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute’s Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. LMBC is supported by the ‘Stichting tegen Kanker’ (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I), the Federal Ministry of Education Research (BMBF) Germany (01KH0402), the Hamburg Cancer Society and the German Cancer Research Center (DKFZ). MBCSG is supported by grants from the Italian Association ciation for Cancer Research (AIRC) and by funds from the Italian citizens who allocated a 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 × 1000’). The MCBCS was supported by the NIH grants (CA122340, CA128978) and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The MEC was supported by NIH grants CA63464, CA54281, CA098758 and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research (grant CRN-87521) and the Ministry of Economic Development, Innovation and Export Trade (grant PSR-SIIRI-701). MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19,tel:08/1/35/19./550), Singapore and the National medical Research Council, Singapore (NMRC/CG/SERI/2010). The NBCS was supported by grants from the Norwegian Research council (155218/V40, 175240/S10 to A.L.B.D., FUGE-NFR 181600/ V11 to V.N.K. and a Swizz Bridge Award to A.L.B.D.). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the Academy of Finland, the University of Oulu, and the Oulu University Hospital. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NLCP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. pKARMA is a combination of the KARMA and LIBRO-1 studies. KARMA was supported by Ma¨rit and Hans Rausings Initiative Against Breast Cancer. KARMA and LIBRO-1 were supported the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linnaeus Centre (Contract ID 70867902) financed by the Swedish Research Council. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). SASBAC was supported by funding from the Agency for Science, Technology and Research of Singapore (A∗STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation KC was financed by the Swedish Cancer Society (5128-B07-01PAF). The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The SBCS was supported by Yorkshire Cancer Research S305PA, S299 and S295. Funding for the SCCS was provided by NIH grant R01 CA092447. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the National Medical Research Council Start-up Grant and Centre Grant (NMRC/CG/NCIS /2010). The recruitment of controls by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC) was funded by the Biomedical Research Council (grant number: 05/1/21/19/425). SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. K. J. is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University, supported by the Polish Foundation of Science. The TNBCC was supported by the NIH grant (CA128978), the Breast Cancer Research Foundation , Komen Foundation for the Cure, the Ohio State University Comprehensive Cancer Center, the Stefanie Spielman Fund for Breast Cancer Research and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. Part of the TNBCC (DEMOKRITOS) has been co-financed by the European Union (European Social Fund – ESF) and Greek National Funds through the Operational Program ‘Education and Life-long Learning’ of the National Strategic Reference Framework (NSRF)—Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA. The TWBCS is supported by the Institute of Biomedical Sciences, Academia Sinica and the National Science Council, Taiwan. The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.This is the advanced access published version distributed under a Creative Commons Attribution License 2.0, which can also be viewed on the publisher's webstie at: http://hmg.oxfordjournals.org/content/early/2014/07/04/hmg.ddu311.full.pdf+htm

The influence of dog ownership on objective measures of free-living physical activity and sedentary behaviour in community-dwelling older adults : a longitudinal case-controlled study

Background: There is some evidence to suggest that dog ownership may improve physical activity (PA) among older adults, but to date, studies examining this, have either depended on self-report or incomplete datasets due to the type of activity monitor used to record physical activity. Additionally, the effect of dog ownership on sedentary behaviour (SB) has not been explored. The aim of the current study was to address these issues by using activPAL monitors to evaluate the influence of dog ownership on health enhancing PA and SB in a longitudinal study of independently-mobile, community-dwelling older adults. Methods: Study participants (43 pairs of dog owners and non-dog owners, matched on a range of demographic variables) wore an activPAL monitor continuously for three, one-week data collection periods over the course of a year. Participants also reported information about their own and their dog demographics, caring responsibilities, and completed a diary of wake times. Diary data was used to isolate waking times, and outcome measures of time spent walking, time spent walking at a moderate cadence (>100 steps/min), time spent standing, time spent sitting, number of sitting events (continuous periods of sitting), and the number of and of time spent sitting in prolonged events (>30 min). For each measure, a linear mixed effects model with dog ownership as a fixed effect, and a random effects structure of measurement point nested in participant nested in pair was used to assess the effect of dog ownership. Results: Owning a dog indicated a large, potentially health improving, average effect of 22 min additional time spent walking, 95%CI (12, 34), and 2760 additional steps per day, 95%CI (1667, 3991), with this additional walking undertaken at a moderate intensity cadence. Dog owners had significantly fewer sitting events. However, there were no significant differences between the groups for either the total time spent sitting, or the number or duration of prolonged sedentary events. Conclusions: The scale of the influence of dog ownership on PA found in this study, indicates that future research regarding PA in older adults should assess and report dog ownership and/or dog walking statu

Contacting authors to retrieve individual patient data : study protocol for a randomized controlled trial

BACKGROUND: Individual patient data (IPD) meta-analysis is considered the "gold standard" for exploring the effectiveness of interventions in different subgroups of patients. However, obtaining IPD is time-consuming and contact with the researchers responsible for the original trials is usually required. To date, there are no studies evaluating different strategies to optimize the process for retrieval of IPD from such researchers. Our aim is to examine the impact of providing incentives to the researchers responsible for the trials eligible for a meta-analysis to submit their IPD. METHODS/DESIGN: We updated our previously published systematic reviews for type 1 diabetes mellitus comparing long- and intermediate-acting insulin regimens (from January 2013 to June 2015) and for Alzheimer's dementia comparing cognitive enhancers (from January 2015 to May 2015). Eligible were randomized controlled trials (RCTs) fulfilling the eligibility criteria of the systematic reviews. We will randomly allocate authors of the reports of these RCTs into an intervention or control group. Those allocated to the intervention group will be contacted by email, mail, and phone, and will be asked to provide the IPD from their RCT and will be given a financial incentive. Those allocated to the control group will be contacted by email, mail, and phone, but will not receive a financial incentive. Our primary outcome will be the proportion of authors who provide the IPD. The secondary outcomes will be the time to return the dataset (defined as the period between the information request and the authors' response with the dataset), and completeness of data. We will compare the response rates in the two groups using the odds ratio and the corresponding 95 % confidence interval. We will also use binary logistic regression and cox regression analyses to examine whether different RCT characteristics, such as study size and sponsor information, influence the probability of providing IPD and the time needed to share the data. DISCUSSION: This study will determine whether a financial incentive affects response rates when seeking IPD from the original researchers. We will disseminate our findings in an open access scientific journal and present results at national and international conferences. TRIAL REGISTRATION: This trial is registered in Clinical Trials.gov, ID number NCT02569411 . Date of registration 5 October 2015

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707