Regulation of Lean Mass, Bone Mass, and Exercise Tolerance by the Central Melanocortin System

Signaling via the type 4-melanocortin receptor (MC4R) is an important determinant of body weight in mice and humans, where loss of function mutations lead to significant obesity. Humans with mutations in the MC4R experience an increase in lean mass. However, the simultaneous accrual of fat mass in such individuals may contribute to this effect via mechanical loading. We therefore examined the relationship of fat mass and lean mass in mice lacking the type-4 melanocortin receptor (MC4RKO). We demonstrate that MC4RKO mice display increased lean body mass. Further, this is not dependent on changes in adipose mass, as MC4RKO mice possess more lean body mass than diet-induced obese (DIO) wild type mice with equivalent fat mass. To examine potential sources of the increased lean mass in MC4RKO mice, bone mass and strength were examined in MC4RKO mice. Both parameters increase with age in MC4RKO mice, which likely contributes to increases in lean body mass. We functionally characterized the increased lean mass in MC4RKO mice by examining their capacity for treadmill running. MC4R deficiency results in a decrease in exercise performance. No changes in the ratio of oxidative to glycolytic fibers were seen, however MC4RKO mice demonstrate a significantly reduced heart rate, which may underlie their impaired exercise performance. The reduced exercise capacity we report in the MC4RKO mouse has potential clinical ramifications, as efforts to control body weight in humans with melanocortin deficiency may be ineffective due to poor tolerance for physical activity

Identification of novel loci associated with hip shape:a meta-analysis of genome-wide association studies

This study was funded by Arthritis Research UK project grant 20244, which also provided salary funding for DB and CVG. LP works in the MRC Integrative Epidemiology Unit, a UK MRC‐funded unit (MC_ UU_ 12013/4 & MC_UU_12013/5). ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. ALSPAC data collection was supported by the Wellcome Trust (grants WT092830M; WT088806; WT102215/2/13/2), UK Medical Research Council (G1001357), and University of Bristol. The UK Medical Research Council and the Wellcome Trust (102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Framingham Heart Study: The Framingham Osteoporosis Study is supported by grants from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases and the National Institute on Aging (R01 AR41398, R01 AR 061162, R01 AR050066, and R01 AR061445). The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource project. The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01‐HC‐25195) and its contract with Affymetrix, Inc., for genotyping services (N02‐HL‐6‐4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA‐II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. DK was also supported by Israel Science Foundation grant #1283/14. TDC and DR thank Dr Claire Reardon and the entire Harvard University Bauer Core facility for assistance with ATAC‐seq next generation sequencing. This work was funded in part by the Harvard University Milton Fund, NSF (BCS‐1518596), and NIH NIAMS (1R01AR070139‐01A1) to TDC. MrOS: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study “Replication of candidate gene associations and bone strength phenotype in MrOS” under the grant number R01 AR051124. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2 AR058973. SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. TwinsUK: The study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007‐2013). The study also receives support from the National Institute for Health Research (NIHR)‐funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust in partnership with King's College London. SNP genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. This study was also supported by the Australian National Health and Medical Research Council (project grants 1048216 and 1127156), the Sir Charles Gairdner Hospital RAC (SGW), and the iVEC/Pawsey Supercomputing Centre (project grants Pawsey0162 and Director2025 [SGW]). The salary of BHM was supported by a Raine Medical Research Foundation Priming Grant. The Umeå Fracture and Osteoporosis Study (UFO) is supported by the Swedish Research Council (K20006‐72X‐20155013), the Swedish Sports Research Council (87/06), the Swedish Society of Medicine, the Kempe‐Foundation (JCK‐1021), and by grants from the Medical Faculty of Umeå Unviersity (ALFVLL:968:22‐2005, ALFVL:‐937‐2006, ALFVLL:223:11‐2007, and ALFVLL:78151‐2009) and from the county council of Västerbotten (Spjutspetsanslag VLL:159:33‐2007). This publication is the work of the authors and does not necessarily reflect the views of any funders. None of the funders had any influence on data collection, analysis, interpretation of the results, or writing of the paper. DB will serve as the guarantor of the paper. Authors’ roles: Study conception and design: DAB, JSG, RMA, LP, DK, and JHT. Data collection: DJ, DPK, ESO, SRC, NEL, BHM, FMKW, JBR, SGW, TDC, BGF, DAL, CO, and UP‐L. Data analysis: DAB, DSE, FKK, JSG, FRS, CVG, RJB, RMA, SGW, EG, TDC, DR, and TB. Data interpretation: JSG, RMA, TDC, DR, DME, LP, DK, and JHT. Drafting manuscript: DAB and JHT. Revising manuscript content: JHT. All authors approved the final version of manuscript. DAB takes responsibility for the integrity of the data analysis.Peer reviewedPublisher PD

GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 RIDE2 Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) 050-060-810 Erasmus Medical Center Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission (DG XII) Municipality of Rotterdam National Institutes of Health National Institute on Aging (NIA) R01 AG005407 R01 AR35582 R01 AR35583 R01 AR35584 R01 AG005394 R01 AG027574 R01 AG027576 AG023629 R01AG29451 U01AG009740 RC2 AG036495 RC4 AG039029 P30AG10161 R01AG17917 R01AG15819 R01AG30146 U01-AG023755 U19-AG023122 NHLBI HHSN 268201200036C HHSN268200800007C N01HC55222 N01HC85079 N01HC85080 N01HC85081 N01HC85082 N01HC85083 N01HC 85086 HL080295 HL087652 HL105756 National Institute of Neurological Disorders and Stroke (NINDS) National Center for Advancing Translational Sciences, CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) DK063491 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) National Center for Research Resources (NCRR) NIH Roadmap for Medical Research U01 AR45580 U01 AR45614 U01 AR45632 U01 AR45647 U01 AR45654 U01 AR45583 U01 AG18197 U01-AG027810 UL1 RR024140 NIAMS R01-AR051124 RC2ARO58973 National Heart, Lung and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc N02-HL-6-4278 Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine Boston Medical Center National Institute of Arthritis, Musculoskeletal and Skin Diseases NIA R01 AR/AG 41398 NIH N01-AG-12100 NIA Intramural Research Program Hjartavernd (the Icelandic Heart Association) Althingi (the Icelandic Parliament) Illinois Department of Public Health Translational Genomics Research Institute Italian Ministry of Health ICS110.1/RF97.71 U.S. National Institute on Aging 263 MD 9164 263 MD 821336 Intramural Research Program of the NIH, National Institute on Aging 1R01AG028321 1R01HL09257

A framework for future national pediatric pandemic respiratory disease severity triage: The HHS pediatric COVID-19 data challenge

Abstract Introduction: With persistent incidence, incomplete vaccination rates, confounding respiratory illnesses, and few therapeutic interventions available, COVID-19 continues to be a burden on the pediatric population. During a surge, it is difficult for hospitals to direct limited healthcare resources effectively. While the overwhelming majority of pediatric infections are mild, there have been life-threatening exceptions that illuminated the need to proactively identify pediatric patients at risk of severe COVID-19 and other respiratory infectious diseases. However, a nationwide capability for developing validated computational tools to identify pediatric patients at risk using real-world data does not exist. Methods: HHS ASPR BARDA sought, through the power of competition in a challenge, to create computational models to address two clinically important questions using the National COVID Cohort Collaborative: (1) Of pediatric patients who test positive for COVID-19 in an outpatient setting, who are at risk for hospitalization? (2) Of pediatric patients who test positive for COVID-19 and are hospitalized, who are at risk for needing mechanical ventilation or cardiovascular interventions? Results: This challenge was the first, multi-agency, coordinated computational challenge carried out by the federal government as a response to a public health emergency. Fifty-five computational models were evaluated across both tasks and two winners and three honorable mentions were selected. Conclusion: This challenge serves as a framework for how the government, research communities, and large data repositories can be brought together to source solutions when resources are strapped during a pandemic

Biomarkers in Pediatric ARDS: Future Directions.

Acute respiratory distress syndrome (ARDS) is common among mechanically ventilated children and accompanies up to 30% of all pediatric intensive care unit deaths. Though ARDS diagnosis is based on clinical criteria, biological markers of acute lung damage have been extensively studied in adults and children. Biomarkers of inflammation, alveolar epithelial and capillary endothelial disruption, disordered coagulation, and associated derangements measured in the circulation and other body fluids, such as bronchoalveolar lavage, have improved our understanding of pathobiology of ARDS. The biochemical signature of ARDS has been increasingly well described in adult populations, and this has led to the identification of molecular phenotypes to augment clinical classifications. However, there is a paucity of data from pediatric ARDS (pARDS) patients. Biomarkers and molecular phenotypes have the potential to identify patients at high risk of poor outcomes, and perhaps inform the development of targeted therapies for specific groups of patients. Additionally, because of the lower incidence of and mortality from ARDS in pediatric patients relative to adults and lack of robust clinical predictors of outcome, there is an ongoing interest in biological markers as surrogate outcome measures. The recent definition of pARDS provides additional impetus for the measurement of established and novel biomarkers in future pediatric studies in order to further characterize this disease process. This chapter will review the currently available literature and discuss potential future directions for investigation into biomarkers in ARDS among children

Biomarkers in Pediatric ARDS: Future Directions

Acute respiratory distress syndrome (ARDS) is common among mechanically ventilated children, and accompanies up to 30% of all PICU deaths. Though ARDS diagnosis is based on clinical criteria, biological markers of acute lung damage have been extensively studied in adults and children. Biomarkers of inflammation, alveolar epithelial and capillary endothelial disruption, disordered coagulation, and associated derangements measured in the circulation and other body fluids such as brochoalveolar lavage have improved our understanding of pathobiology of ARDS. The biochemical signature of ARDS has been increasingly well described in adult populations, and this has led to the identification of molecular phenotypes to augment clinical classifications. However, there is a paucity of data from pediatric ARDS patients. Biomarkers and molecular phenotypes have the potential to identify patients at high risk of poor outcomes, and perhaps inform the development of targeted therapies for specific groups of patients. Additionally, because of the lower incidence of and mortality from ARDS in pediatric patients relative to adults and lack of robust clinical predictors of outcome, there is an ongoing interest in biological markers as surrogate outcome measures. The recent definition of pediatric ARDS (pARDS) provides additional impetus for measurement of established and novel biomarkers in future pediatric studies in order to further characterize this disease process. This chapter will review the currently available literature and discuss potential future directions for investigation into biomarkers in ARDS among children

Incorporating Inflammation into Mortality Risk in Pediatric Acute Respiratory Distress Syndrome

ObjectivesIn pediatric acute respiratory distress syndrome, lung injury is mediated by immune activation and severe inflammation. Therefore, we hypothesized that patients with elevated pro- and anti-inflammatory cytokines would have higher mortality rates and that these biomarkers could improve risk stratification of poor outcomes.DesignMulticenter prospective observational study.SettingWe enrolled patients from five academic PICUs between 2008 and 2015.PatientsPatients were 1 month to 18 years old, used noninvasive or invasive ventilation, and met the American European Consensus Conference definition of acute respiratory distress syndrome.InterventionsEight proinflammatory and anti-inflammatory cytokines were measured on acute respiratory distress syndrome day 1 and correlated with mortality, ICU morbidity as measured by survivor Pediatric Logistic Organ Dysfunction score, and biomarkers of endothelial injury, including angiopoietin-2, von Willebrand Factor, and soluble thrombomodulin.Measurements and main resultsWe measured biomarker levels in 194 patients, including 38 acute respiratory distress syndrome nonsurvivors. Interleukin-6, interleukin-8, interleukin-10, interleukin-18, and tumor necrosis factor-R2 were each strongly associated with all-cause mortality, multiple markers of ICU morbidity, and endothelial injury. A multiple logistic regression model incorporating oxygenation index, interleukin-8, and tumor necrosis factor-R2 was superior to a model of oxygenation index alone in predicting the composite outcome of mortality or severe morbidity (area under the receiver operating characteristic, 0.77 [0.70-0.83] vs 0.70 [0.62-0.77]; p = 0.042).ConclusionsIn pediatric acute respiratory distress syndrome, pro- and anti-inflammatory cytokines are strongly associated with mortality, ICU morbidity, and biochemical evidence of endothelial injury. These cytokines significantly improve the ability of the oxygenation index to discriminate risk of mortality or severe morbidity and may allow for identification and enrollment of high-risk subgroups for future studies