Heterogeneity in direct replications in psychology and Its association with effect size

We examined the evidence for heterogeneity (of effect sizes) when only minor changes to sample population and settings were made between studies and explored the association between heterogeneity and average effect size in a sample of 68 meta-analyses from 13 preregistered multilab direct replication projects in social and cognitive psychology. Among the many examined effects, examples include the Stroop effect, the "verbal overshadowing" effect, and various priming effects such as "anchoring" effects. We found limited heterogeneity; 48/68 (71%) meta-analyses had nonsignificant heterogeneity, and most (49/68; 72%) were most likely to have zero to small heterogeneity. Power to detect small heterogeneity (as defined by Higgins, Thompson, Deeks, & Altman, 2003) was low for all projects (mean 43%), but good to excellent for medium and large heterogeneity. Our findings thus show little evidence of widespread heterogeneity in direct replication studies in social and cognitive psychology, suggesting that minor changes in sample population and settings are unlikely to affect research outcomes in these fields of psychology. We also found strong correlations between observed average effect sizes (standardized mean differences and log odds ratios) and heterogeneity in our sample. Our results suggest that heterogeneity and moderation of effects is unlikely for a 0 average true effect size, but increasingly likely for larger average true effect size

Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

HIV Infection and Gut Mucosal Immune Function: Updates on Pathogenesis with Implications for Management and Intervention

HIV is primarily a sexually transmitted infection. However, given that the gastrointestinal tract (GIT) houses most of the body’s lymphocytes, including activated memory CD4+ T cells that are preferential targets for HIV, recent research has focused on the role of the GIT in transmission and pathogenesis. In health, the GIT maintains a balance between immune tolerance and rapid responsiveness. A complex network of innate and adaptive responses maintains this balance, which is severely perturbed in HIV infection. Recent studies have focused on mechanisms of GIT CD4+ T-cell depletion and epithelial disruption in HIV infection, the role of inflammation in accelerating viral dissemination, the kinetics of the adaptive response following transmission, and the extent of T-cell reconstitution following antiretroviral therapy. This review summarizes the results of recent investigations that may have important implications for the development of vaccines, microbicides, and therapeutic interventions for HIV and other mucosal pathogens

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis

Pulmonary Hypertension in Patients With COPD : Results From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)

Funding Information: FUNDING/SUPPORT: This work was supported by the German Center of Lung Research (DZL). COMPERA is funded by unrestricted grants from Acceleron , Actelion Pharmaceuticals , Bayer , OMT , and GSK . Funding Information: Financial/nonfinancial disclosures: The authors have reported to CHEST the following: C. D. V. has received fees for serving as a speaker, consultant, and an advisory board member from the following companies: Acceleron, Actelion, Bayer, Dompè, GSK, Janssen, MSD, Pfizer, and United Therapeutics. M. M. H. has received speaker fees, honoraria, or both for consultations from Acceleron, Actelion, Bayer, Janssen, MSD, and Pfizer. D. H. has received travel compensation from Actelion, Boehringer-Ingelheim, and Shire. D. P. has received fees for consultations from Actelion, Aspen, Biogen, Bayer, Boehringer Ingelheim, Johnson & Johnson, Novartis, Daiichi Sankyo, Sanofi, and Pfizer. N. B. received speaker fees from Bayer/MSD and Actelion/Janssen. K. M. O. has received speaker fees from Actelion, Bayer, and Lilly. H. A. G. has received honorariums for consultations, speaking at conferences, or both from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly, and Novartis. He is member of advisory boards for Bayer HealthCare AG, Pfizer, GSK, Actelion, Lilly, Merck, Encysive, and Ergonex. He also has received governmental grants from the German Research Foundation (DFG), Excellence Cluster Cardiopulmonary Research (ECCPS), State Government of Hessen (LOEWE), and the German Ministry for Education and Research (BMBF). M. Held has received speaker fees and honoraria for consultations from Actelion, Bayer, Boehringer Ingelheim Pharma, Encysive, Glaxo Smith Kline, Lilly, Janssen, Novartis, Pfizer, Nycomed, Roche, and Servier. H. K. has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Lilly, Novartis, Pfizer, and United Therapeutics and research grants from Actelion. T. J. L. has received speaker fees, honoraria for consultations, and research funding from Actelion, Acceleron Pharma, Bayer, GSK, Janssen-Cilag, MSD, and Pfizer. S. R. has received honoraria for lectures, consultancy, or both from Actavis, Actelion, Bayer, GSK, Lilly, Novartis, Pfizer, and United Therapeutics. D. D. declares honoraria for lectures, consultancy, or both from Actelion, Bayer, GSK, Novartis, Pfizer, and Servier; participation in clinical trials for Actelion, Bayer, GSK, and Novartis; and research support to his institution from Actelion. R. B. has received fees from GSK, UT, Dompè, Bayer, Ferrer, MSD, and AOP Orphan Pharmaceuticals. M. C. has received fees for consulting from GSK and speaker fees from Bayer and Pfizer. M. Halank has received speaker fees and/or honoraria for consultations from Acceleron, Actelion, AstraZeneca, Bayer, BayerChemie, GSK, Janssen, MSD and Novartis. A. V.-N. reports receiving lecture fees from Actelion, Bayer, GlaxoSmithKline, Lilly, and Pfizer; serves on the advisory board of Actelion and Bayer; and serves on steering committees for Actelion, Bayer, GlaxoSmithKline, and Pfizer. D. S. received fees for lectures, consulting, research support, or a combination thereof to his institution from Actelion, Bayer, GSK, and Pfizer. R. E. has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Lilly, Novartis, Pfizer, and United Therapeutics. J. S. R. G. has received speaker fees and honoraria for consultations from Acceleron, Actelion, Bayer, Complexa, GSK, MSD, Pfizer, and United Therapeutics. M. D. has received investigator, speaker, consultant, or steering committee member fees from Actelion, Aventis Pharmaceuticals, Bayer, Eli Lilly, Encysive, Gilead (Myogen), GlaxoSmithKline, Nippon Shyniaku, Novartis, Pfizer, Schering, and United Therapeutics; educational grants from Actelion, GlaxoSmithKline, Pfizer, and Therabel; and research grants from Actelion, Pfizer, and GlaxoSmithKline. She is holder of the Actelion Chair for Pulmonary Hypertension and of the GSK chair for research and education in pulmonary vascular pathology at the Catholic University of Leuven. J. C. has received fees for consultancies and lectures from Actelion, Bayer, GSK, United Therapeutics, and Pfizer as well as equipment and educational grants from Actelion. C. O. has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Lilly, Novartis, and Pfizer. H. K. has received honoraria for lectures, consultancy, or both from Actelion-Janssen, Amicus Therapeutics, and Bristol Meyers Squibb. O. D. has or had consultancy relationships, has received research funding (last 3 years), or both from AbbVie, Actelion, Acceleron Pharma, Amgen, AnaMar, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, Catenion, Competitive Corpus, Drug Development International Ltd, CSL Behring, ChemomAb, Ergonex, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, Italfarmaco, iQone, iQvia, Kymera Therapeutics, Lilly, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Target Bio Science, and UCB in the area of potential treatments of scleroderma and its complications including PH. In addition, he has a patent mir-29 for the treatment of systemic sclerosis issued (US8247389, EP2331143). E. G. has received honoraria for consultations, speaking at conferences, or both from Bayer/MSD, Actelion/Janssen, GWT-TUD, and OMT/United Therapeutics. None declared (A. S.). Publisher Copyright: © 2021 The AuthorsBackground: Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. Research Question: Which factors determine the outcome of PH in COPD? Study Design and Methods: We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). Results: The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. Interpretation: Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. Trial Registry: ClinicalTrials.gov; No.: NCT01347216; URL: www.clinicaltrials.govpublishersversionPeer reviewe

miR-155 overexpressing monocytes resemble HLA highISG15 + synovial tissue macrophages from patients with rheumatoid arthritis and induce polyfunctional CD4+ T cell activation

MicroRNAs (miRs) are known to regulate pro-inflammatory effector functions of myeloid cells, and miR dysregulation is implicated in rheumatoid arthritis (RA), a condition characterized by inflammation and destruction of the joints. We showed previously that miR-155 is increased in myeloid cells in RA and induces pro-inflammatory activation of monocytes and macrophages; however, its role at the interface between innate and adaptive immunity was not defined. Here, RNA-sequencing revealed that overexpression of miR-155 in healthy donor monocytes conferred a specific gene profile which bears similarities to that of RA synovial fluid-derived CD14+ cells and HLAhighISG15+ synovial tissue macrophages, both of which are characterized by antigen-presenting pathways. In line with this, monocytes in which miR-155 was overexpressed, displayed increased expression of HLA-DR and both co-stimulatory and co-inhibitory molecules, and induced activation of polyfunctional T cells. Together, these data underpin the notion that miR-155-driven myeloid cell activation in the synovium contributes not only to inflammation but may also influence the adaptive immune response

Muscle strength, gait, and balance in 20 patients with hip osteoarthritis followed for 2 years after THA

Background Patients with hip osteoarthritis (OA) have muscular weakness, impaired balance, and limp. Deficits in the different limb muscles and their recovery courses are largely unknown, however. We hypothesized that there is persisting muscular weakness in lower limb muscles and an impaired balance and gait 2 years after THA

Idiopathic pulmonary arterial hypertension phenotypes determined by cluster analysis from the COMPERA registry

Funding Information: Marius M. Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, MSD, and Pfizer. Nicola Benjamin has received fees for lectures and/or consultations from Actelion. Ekkehard Grünig has received fees for lectures and/or consultations from Actelion, Bayer, GSK, MSD, United Therapeutics, and Pfizer. Karen M. Olsson has received fees for lectures and/or consultations from Actelion, Bayer, United Therapeutics, GSK, and Pfizer. C. Dario Vizza has received fees from Actelion, Bayer, GSK, MSD, Pfizer, and United Therapeutics Europe. Anton Vonk-Noordegraaf has received fees for lectures and/or consultation from Actelion, Bayer, GSK, and MSD. Oliver Distler has/had a consultancy relationship with and/or has received research funding from 4-D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, BMS, ChemoAb, EpiPharm, Ergonex, espeRare foundation, GSK, Genentech/Roche, Inventiva, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Serodapharm, and Sinoxa in the area of potential treatments of scleroderma and its complications including pulmonary arterial hypertension. In addition, Prof Distler has a patent for mir-29 for the treatment of systemic sclerosis licensed. Christian Opitz has received fees from Actelion, Bayer, GSK, Pfizer, and Novartis. J. Simon R. Gibbs has received fees for lectures and/or consultations from Actelion, Bayer, Bellerophon, GSK, MSD, and Pfizer. Marion Delcroix has received fees from Actelion, Bayer, GSK, and MSD. H. Ardeschir Ghofrani has received fees from Actelion, Bayer, Gilead, GSK, MSD, Pfizer, and United Therapeutics. Doerte Huscher has received fees for lectures and consultations from Actelion. David Pittrow has received fees for consultations from Actelion, Biogen, Aspen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi. Stephan Rosenkranz has received fees for lectures and/or consultations from Actelion, Bayer, GSK, Pfizer, Novartis, Gilead, MSD, and United Therapeutics. Martin Claussen reports honoraria for lectures from Boehringer Ingelheim Pharma GmbH and Roche Pharma and for serving on advisory boards from Boehringer Ingelheim, outside the submitted work. Heinrike Wilkens reports personal fees from Boehringer and Roche during the conduct of the study and personal fees from Bayer, Biotest, Actelion, GSK, and Pfizer outside the submitted work. Juergen Behr received grants from Boehringer Ingelheim and personal fees for consultation or lectures from Actelion, Bayer, Boehringer Ingelheim, and Roche. Hubert Wirtz reports personal fees from Boehringer Ingelheim and Roche outside the submitted work. Hening Gall reports personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics outside the submitted work. Elena Pfeuffer-Jovic reports personal fees from Actelion, Boehringer Ingelheim, Novartis, and OMT outside the submitted work. Laura Scelsi reports personal fees from Actelion, Bayer, and MSD outside the submitted work. Siliva Ulrich reports grants from Swiss National Science Foundation, Zurich Lung, Swiss Lung, and Orpha Swiss, and grants and personal fees from Actelion SA/Johnson & Johnson Switzerland and MSD Switzerland outside the submitted work. The remaining authors have no conflicts of interest to disclose. Funding Information: This work was supported by the German Centre of Lung Research (DZL). COMPERA is funded by unrestricted grants from Acceleron , Actelion Pharmaceuticals , Bayer , OMT , and GSK . These companies were not involved in data analysis or the writing of this manuscript. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO; <45% vs ≥45% predicted), smoking status, and presence of comorbidities (obesity, hypertension, coronary heart disease, and diabetes mellitus). A hierarchical agglomerative clustering algorithm was performed using Ward's minimum variance method. The clusters were analyzed in terms of baseline characteristics; survival; and response to pulmonary arterial hypertension (PAH) therapy, expressed as changes from baseline to follow-up in functional class, 6-minute walking distance, cardiac biomarkers, and risk. Three clusters were identified: Cluster 1 (n = 106; 12.6%): median age 45 years, 76% females, no comorbidities, mostly never smokers, DLCO ≥45%; Cluster 2 (n = 301; 35.8%): median age 75 years, 98% females, frequent comorbidities, no smoking history, DLCO mostly ≥45%; and Cluster 3 (n = 434; 51.6%): median age 72 years, 72% males, frequent comorbidities, history of smoking, and low DLCO. Patients in Cluster 1 had a better response to PAH treatment than patients in the 2 other clusters. Survival over 5 years was 84.6% in Cluster 1, 59.2% in Cluster 2, and 42.2% in Cluster 3 (unadjusted p < 0.001 for comparison between all groups). The population of patients diagnosed with IPAH is heterogenous. This cluster analysis identified distinct phenotypes, which differed in clinical presentation, response to therapy, and survival.publishersversionPeer reviewe

First Phase 1 Double-Blind, Placebo-Controlled, Randomized Rectal Microbicide Trial Using UC781 Gel with a Novel Index of Ex Vivo Efficacy

Objectives: Successful control of the HIV/AIDS pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. We report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo. Methods: HIV-1 seronegative, sexually-abstinent men and women (N = 36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1:1:1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint. Results: All 36 subjects enrolled completed the 7-14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1 BaL showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration. Conclusions: Single and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant AEs, high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538). © 2011 Anton et al