Publications by authors named "John Reilly"

520 Publications

CD8 T cells compensate for impaired humoral immunity in COVID-19 patients with hematologic cancer.

Res Sq 2021 Feb 2. Epub 2021 Feb 2.

Cancer patients have increased morbidity and mortality from Coronavirus Disease 2019 (COVID-19), but the underlying immune mechanisms are unknown. In a cohort of 100 cancer patients hospitalized for COVID-19 at the University of Pennsylvania Health System, we found that patients with hematologic cancers had a significantly higher mortality relative to patients with solid cancers after accounting for confounders including ECOG performance status and active cancer status. We performed flow cytometric and serologic analyses of 106 cancer patients and 113 non-cancer controls from two additional cohorts at Penn and Memorial Sloan Kettering Cancer Center. Patients with solid cancers exhibited an immune phenotype similar to non-cancer patients during acute COVID-19 whereas patients with hematologic cancers had significant impairment of B cells and SARS-CoV-2-specific antibody responses. High dimensional analysis of flow cytometric data revealed 5 distinct immune phenotypes. An immune phenotype characterized by CD8 T cell depletion was associated with a high viral load and the highest mortality of 71%, among all cancer patients. In contrast, despite impaired B cell responses, patients with hematologic cancers and preserved CD8 T cells had a lower viral load and mortality. These data highlight the importance of CD8 T cells in acute COVID-19, particularly in the setting of impaired humoral immunity. Further, depletion of B cells with anti-CD20 therapy resulted in almost complete abrogation of SARS-CoV-2-specific IgG and IgM antibodies, but was not associated with increased mortality compared to other hematologic cancers, when adequate CD8 T cells were present. Finally, higher CD8 T cell counts were associated with improved overall survival in patients with hematologic cancers. Thus, CD8 T cells likely compensate for deficient humoral immunity and influence clinical recovery of COVID-19. These observations have important implications for cancer and COVID-19-directed treatments, immunosuppressive therapies, and for understanding the role of B and T cells in acute COVID-19.
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http://dx.doi.org/10.21203/rs.3.rs-162289/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872363PMC
February 2021

Characteristics, Outcomes, and Trends of Patients With COVID-19-Related Critical Illness at a Learning Health System in the United States.

Ann Intern Med 2021 Jan 19. Epub 2021 Jan 19.

University of Pennsylvania Health System, Philadelphia, Pennsylvania (G.L.A., J.J., M.O.H., J.H.A., J.B., C.B., P.J.B., C.L.C., L.M.C., M.F.C., J.M.C., J.D.C., T.C., K.R.C., B.D.F., E.G., J.C.G., S.G., A.H., C.W.H., M.H., P.K., Z.N.K., G.B.K., M.L., N.D.M., M.E.M., D.N., J.L.P., M.B.P., S.C.P., Z.A.Q., J.P.R., J.S., W.D.S., M.J.S., M.G.S., C.P.S., J.K.W., W.W., A.A.W., B.J.A., J.T.G.).

Background: The coronavirus disease 2019 (COVID-19) pandemic continues to surge in the United States and globally.

Objective: To describe the epidemiology of COVID-19-related critical illness, including trends in outcomes and care delivery.

Design: Single-health system, multihospital retrospective cohort study.

Setting: 5 hospitals within the University of Pennsylvania Health System.

Patients: Adults with COVID-19-related critical illness who were admitted to an intensive care unit (ICU) with acute respiratory failure or shock during the initial surge of the pandemic.

Measurements: The primary exposure for outcomes and care delivery trend analyses was longitudinal time during the pandemic. The primary outcome was all-cause 28-day in-hospital mortality. Secondary outcomes were all-cause death at any time, receipt of mechanical ventilation (MV), and readmissions.

Results: Among 468 patients with COVID-19-related critical illness, 319 (68.2%) were treated with MV and 121 (25.9%) with vasopressors. Outcomes were notable for an all-cause 28-day in-hospital mortality rate of 29.9%, a median ICU stay of 8 days (interquartile range [IQR], 3 to 17 days), a median hospital stay of 13 days (IQR, 7 to 25 days), and an all-cause 30-day readmission rate (among nonhospice survivors) of 10.8%. Mortality decreased over time, from 43.5% (95% CI, 31.3% to 53.8%) to 19.2% (CI, 11.6% to 26.7%) between the first and last 15-day periods in the core adjusted model, whereas patient acuity and other factors did not change.

Limitation: Single-health system study; use of, or highly dynamic trends in, other clinical interventions were not evaluated, nor were complications.

Conclusion: Among patients with COVID-19-related critical illness admitted to ICUs of a learning health system in the United States, mortality seemed to decrease over time despite stable patient characteristics. Further studies are necessary to confirm this result and to investigate causal mechanisms.

Primary Funding Source: Agency for Healthcare Research and Quality.
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http://dx.doi.org/10.7326/M20-5327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901669PMC
January 2021

Nature-based early childhood education for child health, wellbeing and development: a mixed-methods systematic review protocol.

Syst Rev 2020 10 2;9(1):226. Epub 2020 Oct 2.

MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, Berkeley Square, 99 Berkeley Street, Glasgow, G3 7HR,, Scotland.

Background: Several systematic reviews have reviewed the evidence relating to nature on aspects of children and adolescent's health and wellbeing; however, none have looked at the associations or effectiveness of attending nature-based early childhood education (ECE). The main objective is to systematically review and synthesise the evidence to determine if nature-based ECE enhances children's health, wellbeing and development.

Methods: We will search the following electronic databases (from inception onwards): MEDLINE, Scopus, PsycINFO, ERIC, SportDiscus, Australian Education Index, British Education Index, Child Development and Adolescent studies, and Applied Social Sciences Index and Abstracts. Grey literature will be identified searching dissertations and reports (e.g. Open Grey, Dissertations Theses Database [ProQuest], and Google Scholar). All types of studies (quantitative and qualitative) conducted in children (aged 2-7 years old) attending ECE who had not started education at primary or elementary school will be included. The exposure of interest will be nature-based ECE settings that integrate nature into their philosophy and/or curriculum and environment. The outcomes of interest will be all aspects of the child's physical, cognitive, social and emotional health wellbeing and development. Two reviewers will independently screen full-text articles. The study methodological quality (or bias) will be appraised using appropriate tools. If feasible, a meta-analysis will be conducted using a random-effect model for studies similar in exposure and outcome. Where studies cannot be included in a meta-analysis, findings will be summarised based on the effect directions and a thematic analysis will be conducted for qualitative studies.

Discussion: This systematic review will capture the state of the current literature on nature-based ECE for child health, wellbeing and development. The results of this study will be of interest to multiple audiences (including researchers and policy makers). Results will be published in a peer-reviewed journal. Gaps for future research will be identified and discussed.

Systematic Review Registration: PROSPERO CRD42019152582.
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http://dx.doi.org/10.1186/s13643-020-01489-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532588PMC
October 2020

The ABO histo-blood group, endothelial activation, and acute respiratory distress syndrome risk in critical illness.

J Clin Invest 2021 Jan;131(1)

Division of Pulmonary, Allergy, and Critical Care.

BACKGROUNDThe ABO histo-blood group is defined by carbohydrate modifications and is associated with risk for multiple diseases, including acute respiratory distress syndrome (ARDS). We hypothesized that genetically determined blood subtype A1 is associated with increased risk of ARDS and markers of microvascular dysfunction and coagulation.METHODSWe conducted analyses in 3 cohorts of critically ill trauma and sepsis patients (n = 3710) genotyped on genome-wide platforms to determine the association of the A1 blood type genotype with ARDS risk. We subsequently determined whether associations were present in FUT2-defined nonsecretors who lack ABO antigens on epithelium, but not endothelium. In a patient subgroup, we determined the associations of blood type with plasma levels of endothelial glycoproteins and disseminated intravascular coagulation (DIC). Lastly, we tested whether blood type A was associated with less donor lung injury recovery during human ex vivo lung perfusion (EVLP).RESULTSThe A1 genotype was associated with a higher risk of moderate to severe ARDS relative to type O in all 3 populations. In sepsis, this relationship was strongest in nonpulmonary infections. The association persisted in nonsecretors, suggesting a vascular mechanism. The A1 genotype was also associated with higher DIC risk as well as concentrations of thrombomodulin and von Willebrand factor, which in turn were associated with ARDS risk. Blood type A was also associated with less lung injury recovery during EVLP.CONCLUSIONWe identified a replicable association between ABO blood type A1 and risk of ARDS among the critically ill, possibly mediated through microvascular dysfunction and coagulation.FUNDINGNIH HL122075, HL125723, HL137006, HL137915, DK097307, HL115354, HL101779, and the University of Pennsylvania McCabe Fund Fellowship Award.
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http://dx.doi.org/10.1172/JCI139700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773362PMC
January 2021

Differences in educational attainment between obese and non-obese Kuwaiti female university students.

J Nutr Sci 2020 24;9:e30. Epub 2020 Jul 24.

School of Psychological Sciences and Health, University of Strathclyde, Glasgow G1 1XQ, UK.

Individuals with obesity tend to perform less well than their non-obese peers in tertiary education, but there is little evidence from non-Western countries and recent studies. The present study aimed to test whether academic attainment differed between female undergraduates with obesity (defined by body mass index (BMI)), and those who were non-obese in Kuwait, a country with very high obesity prevalence. In 400 female Kuwaiti first- and second-year Social Science students (mean age 18⋅0, sd 0⋅6 years), educational attainment was defined as the Grade Point Average (GPA) across all subjects (from 1⋅00 to 4⋅00). The mean GPA (2⋅51, sd 0⋅53) among students defined as obese by the BMI ( 163) was significantly lower than among the students defined as non-obese by the BMI ( 237; 2⋅80, sd 0⋅63; < 0⋅001), and those defined as obese were more likely to be in the lowest quartile for the GPA (OR 3⋅03; 95% CI 1⋅90, 4⋅85), independent of socio-economic status. Similar differences were observed between students defined as having high versus normal body fatness. Female undergraduates in Kuwait with obesity have lower academic attainment than their non-obese peers, and universities should consider measures to mitigate reduced attainment among their female undergraduates.
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http://dx.doi.org/10.1017/jns.2020.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443771PMC
July 2020

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.

J Med Chem 2020 11 24;63(22):13578-13594. Epub 2020 Sep 24.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent antitumor activity. These studies culminated in the discovery of TNO155, (3,4)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01170DOI Listing
November 2020

Hot topics in interventional cardiology: Proceedings from the society for cardiovascular angiography and interventions 2020 think tank.

Catheter Cardiovasc Interv 2020 Nov 25;96(6):1258-1265. Epub 2020 Aug 25.

W. L. Gore & Associates, Flagstaff, Arizona, USA.

The society for cardiovascular angiography and interventions (SCAI) think tank is a collaborative venture that brings together interventional cardiologists, administrative partners, and select members of the cardiovascular industry community for high-level field-wide discussions. The 2020 think tank was organized into four parallel sessions reflective of the field of interventional cardiology: (a) coronary intervention, (b) endovascular medicine, (c) structural heart disease, and (d) congenital heart disease (CHD). Each session was moderated by a senior content expert and co-moderated by a member of SCAI's emerging leader mentorship program. This document presents the proceedings to the wider cardiovascular community in order to enhance participation in this discussion, create additional dialogue from a broader base, and thereby aid SCAI and the industry community in developing specific action items to move these areas forward.
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http://dx.doi.org/10.1002/ccd.29197DOI Listing
November 2020

Obesity in young children and its relationship with diagnosis of asthma, vitamin D deficiency, iron deficiency, specific allergies and flat-footedness: A systematic review and meta-analysis.

Obes Rev 2021 Mar 18;22(3):e13129. Epub 2020 Aug 18.

Physical activity for Health group, School of Psychological Sciences and Health, University of Strathclyde, Glasgow, UK.

There is evidence that a number of medical conditions and co-morbidities are associated with obesity in young children. This review explored whether there is evidence of associations with other conditions or co-morbidities. Observational studies of young children (mean age < 10 years) were identified using electronic searches of five databases (MEDLINE, Embase, CINAHL, AMED and SPORTDiscus). Of 27 028 studies screened, 41 (comprising 44 comparisons) met the inclusion criteria. These studies provided data on five distinct diseases/conditions: asthma (n = 16), vitamin D deficiency (n = 10), iron deficiency (n = 10), allergies (n = 4) and flat-footedness (n = 4). Thirty-two studies were appropriate for meta-analysis using random-effects models, and revealed obesity was significantly associated with having asthma (OR 1.5, 95% CI 1.3-1.7), vitamin D deficiency (OR 1.9, 95% CI 1.4-2.5) and iron deficiency (OR 2.1, 95% CI 1.4-3.2). Heterogeneity (I ) ranged from 57% to 61%. Narrative synthesis was conducted for all studies. There was no evidence of a consistent association between obesity in young children and eczema, dermatitis or rhinitis due to the low number of studies. However, there was an association with flat-footedness. These results have implications for health policy and practice and families. Further research leading to a greater understanding of the associations identified in this review is suggested.
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http://dx.doi.org/10.1111/obr.13129DOI Listing
March 2021

Level of agreement between objectively determined body composition and perceived body image in 6- to 8-year-old South African children: The Body Composition-Isotope Technique study.

PLoS One 2020 10;15(8):e0237399. Epub 2020 Aug 10.

Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa.

To assess the level of agreement between body size self-perception and actual body size determined by body mass index (BMI) z-score and body fatness measured by the deuterium dilution method (DDM) in South African children aged 6-8 years. A cross-sectional sample of 202 children (83 boys and 119 girls) aged 6-8 years from the Body Composition-Isotope Technique study (BC-IT) was taken. Subjective measures of body image (silhouettes) were compared with the objective measures of BMI z-score and body fatness measured by the DDM. The World Health Organization BMI z-scores were used to classify the children as underweight, normal, overweight, or obese. DDM-measured fatness was classified based on the McCarthy centile curves set at 2nd, 85th and 95th in conjunction with fatness cut-off points of 25% in boys and 30% in girls. Data were analyzed using SPSS v26. Of 202 children, 32.2%, 55.1%, 8.8%, and 2.4% perceived their body size as underweight, normal, overweight, and obese, respectively. Based on BMI z-score, 18.8%, 72.8%, 6.9%, and 1.5% were classified as underweight, normal, overweight, and obese, respectively. Body fatness measurement showed that 2.5%, 48.0%, 21.8%, and 29.7% were underweight, normal weight, overweight, and obese, respectively. The application of silhouettes and BMI z-scores resulted in either overestimation or underestimation of own body size. Overall, the levels of agreements (kappa, κ) between body size perception, body fatness, and BMI for age respectively, were small (κ = 0.083, p = 0.053 and κ = 0.154, p<0.001). Level of agreement between body size perception, body fatness, and BMI z-score was poor. The use of silhouettes made children either overestimate their own body size while being underweight or underestimate their own body size while being overweight or obese. Given the potential health implications associated with misclassification of body size during childhood, correct self-assessment of body size is important, and may be key to the adoption of weight control strategies directed at curbing the escalating obesity epidemic in the country. Scalable measures to allow for more accurate self-assessment are urgently needed-one approach is behavior change communication at all levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237399PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417193PMC
October 2020

Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications.

Science 2020 09 15;369(6508). Epub 2020 Jul 15.

Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Coronavirus disease 2019 (COVID-19) is currently a global pandemic, but human immune responses to the virus remain poorly understood. We used high-dimensional cytometry to analyze 125 COVID-19 patients and compare them with recovered and healthy individuals. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable with that in uninfected individuals. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. Our analyses identified three immunotypes associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.
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http://dx.doi.org/10.1126/science.abc8511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402624PMC
September 2020

Women with chronic kidney disease undergoing transcatheter aortic valve replacement: Caveat emptor.

Catheter Cardiovasc Interv 2020 07;96(1):208-209

Division of Cardiovascular Medicine, Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.

Over 60% of women presenting for transcatheter aortic valve replacement (TAVR) have coexisting chronic kidney disease (CKD). In women undergoing TAVR, CKD was associated with significantly higher rates of adverse events, including a twofold higher rate of risk-adjusted mortality at 1 year. This study is an important step forward in our understanding of risk stratification in women with CKD undergoing TAVR and suggests that measures to optimize outcomes warrant further investigation in this high-risk group of patients.
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http://dx.doi.org/10.1002/ccd.29080DOI Listing
July 2020

COVID-19-associated Acute Respiratory Distress Syndrome Clarified: A Vascular Endotype?

Am J Respir Crit Care Med 2020 09;202(5):750-753

University of Pennsylvania School of Veterinary Medicine Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1164/rccm.202006-2598LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462395PMC
September 2020

Public health surveillance of habitual physical activity in adolescents and adults in Namibia: a cross-sectional validation of activity questionnaires against accelerometry.

J Public Health (Oxf) 2020 Jun 16. Epub 2020 Jun 16.

Physical Activity for Health Group, University of Strathclyde, Glasgow G1 1QE, Scotland.

Background: Monitoring population-level physical activity is crucial for examining adherence to global guidelines and addressing obesity. This study validated self-reported moderate-to-vigorous physical activity (MVPA) against an accurate device-based method in Namibia.

Methods: Adolescent girls (n = 52, mean age 16.2 years [SD 1.6]) and adult women (n = 51, mean age 31.3 years [SD 4.7]) completed the PACE+/GPAQ self-report questionnaires and were asked to wear an Actigraph accelerometer for 7 days. Validity of self-reported MVPA was assessed using rank-order correlations between self-report and accelerometry, and classification ability of the questionnaires with Mann-Whitney tests, kappa's, sensitivity and specificity.

Results: In the adolescents, Spearman's rank coefficients between self-reported MVPA (days/week) and accelerometry measured MVPA were positive but not significant (r = 0.240; P = 0.104). In the adults, self-reported MVPA (minutes/day) was moderately and significantly correlated with accelerometer-measured MVPA (r = 0.396; P = 0.008). In both groups, there was fair agreement between accelerometry and questionnaire-defined tertiles of MVPA (adolescents κ = 0.267; P = 0.010; adults κ = 0.284; P = 0.008), and measured MVPA was significantly higher in the individuals self-reporting higher MVPA than those reporting lower MVPA.

Conclusions: The PACE+ and GPAQ questionnaires have a degree of validity in adolescent girls and adult females in Namibia, though more suitable for population than individual level measurement.
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http://dx.doi.org/10.1093/pubmed/fdaa067DOI Listing
June 2020

Erythrocytes Reveal Complement Activation in Patients with COVID-19.

medRxiv 2020 May 22. Epub 2020 May 22.

COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multi-organ failure characterized by respiratory insufficiency, arrhythmias, thromboembolic complications and shock. The mortality of patients hospitalized with COVID-19 is unacceptably high and new strategies are urgently needed to rapidly identify and treat patients at risk for organ failure. Clinical epidemiologic studies demonstrate that vulnerability to organ failure is greatest after viral clearance from the upper airway, which suggests that dysregulation of the host immune response is a critical mediator of clinical deterioration and death. Autopsy and pre-clinical evidence implicate aberrant complement activation in endothelial injury and organ failure. A potential therapeutic strategy warranting investigation is to inhibit complement, with case reports of successful treatment of COVID-19 with inhibitors of complement. However, this approach requires careful balance between the host protective and potential injurious effects of complement activation, and biomarkers to identify the optimal timing and candidates for therapy are lacking. Here we report the presence of complement activation products on circulating erythrocytes from hospitalized COVID-19 patients using flow cytometry. These findings suggest that novel erythrocyte-based diagnostics provide a method to identify patients with dysregulated complement activation.
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http://dx.doi.org/10.1101/2020.05.20.20104398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274235PMC
May 2020

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions.

bioRxiv 2020 May 23. Epub 2020 May 23.

Institute for Immunology, University of Pennsylvania Perelman School of Medicine.

COVID-19 has become a global pandemic. Immune dysregulation has been implicated, but immune responses remain poorly understood. We analyzed 71 COVID-19 patients compared to recovered and healthy subjects using high dimensional cytometry. Integrated analysis of ~200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses could reach >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. These analyses identified three "immunotypes" associated with poor clinical trajectories versus improving health. These immunotypes may have implications for therapeutics and vaccines.
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http://dx.doi.org/10.1101/2020.05.20.106401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263500PMC
May 2020

Paediatric obesity and brain functioning: The role of physical activity-A novel and important expert opinion of the European Childhood Obesity Group.

Pediatr Obes 2020 09 27;15(9):e12649. Epub 2020 May 27.

European Childhood Obesity Group, Brussels, Belgium.

While most of the time unconsidered, child and adolescent obesity has been also associated with impaired brain health and function that can definitely affect their social interaction and integration, and then well-being and mental health. The European Childhood Obesity Group recently gathered experts in the field who discussed the main available and reliable evidence regarding the role of physical activity on brain health and cognitive functioning in children and adolescents with obesity and who propose here their main conclusions and recommendations.
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http://dx.doi.org/10.1111/ijpo.12649DOI Listing
September 2020

Preparedness Tested: Severe Cerebral Malaria Presenting as a High-Risk Person Under Investigation for Ebola Virus Disease at a US Hospital.

Disaster Med Public Health Prep 2020 May 8:1-6. Epub 2020 May 8.

Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

In 2019, a 42-year-old African man who works as an Ebola virus disease (EVD) researcher traveled from the Democratic Republic of Congo (DRC), near an ongoing EVD epidemic, to Philadelphia and presented to the Hospital of the University of Pennsylvania Emergency Department with altered mental status, vomiting, diarrhea, and fever. He was classified as a "wet" person under investigation for EVD, and his arrival activated our hospital emergency management command center and bioresponse teams. He was found to be in septic shock with multisystem organ dysfunction, including circulatory dysfunction, encephalopathy, metabolic lactic acidosis, acute kidney injury, acute liver injury, and diffuse intravascular coagulation. Critical care was delivered within high-risk pathogen isolation in the ED and in our Special Treatment Unit until a diagnosis of severe cerebral malaria was confirmed and EVD was definitively excluded.This report discusses our experience activating a longitudinal preparedness program designed for rare, resource-intensive events at hospitals physically remote from any active epidemic but serving a high-volume international air travel port-of-entry.
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http://dx.doi.org/10.1017/dmp.2020.53DOI Listing
May 2020

Classification Accuracy of Body Mass Index for Excessive Body Fatness in Kuwaiti Adolescent Girls and Young Adult Women.

Diabetes Metab Syndr Obes 2020 5;13:1043-1049. Epub 2020 Apr 5.

University of Strathclyde, Physical Activity for Health Group, Glasgow G1 1XQ, Scotland.

Purpose: Adolescent obesity, as defined by BMI, is amongst the highest in the world in Kuwait. This study aimed to determine the extent to which BMI might be underestimating obesity as defined by excessive fatness in Kuwaiti female adolescents and young adults.

Methods: A total of 400 apparently healthy Kuwaiti female university students (mean age 18.0 years, SD 0.6) were recruited. Excessive fatness was defined as body fat percentage ≥30, measured using the Tanita model TBF-310 Bio-impedance system with the manufacturer's equation. Obesity was defined as recommended by the WHO in adult participants - those aged ≥19.1 years - as BMI≥30 kg/m. In the adolescent participants (age <19.1 years) obesity was defined as recommended by the WHO as a BMI-for-age score of ≥2.00. The accuracy of BMI-defined obesity to identify excessively fat individuals was determined by estimating the prevalence of obesity using high BMI and prevalence of excessive fatness, and by calculating sensitivity and specificity and predictive values.

Results: Median BMI was 27.8 kg/m (range 15.1-51.2) and median body fat percentage was 32.0 (range 5.0-54.0). The prevalence of excessive fatness was 62% (247/400 individuals were excessively fat), while the prevalence of obesity according to BMI was 42% (169/400 individuals were obese according to their BMI). The sensitivity of BMI to identify the excessively fat individuals was moderate (66%) but specificity was high (96%). The positive predictive value of BMI was 96% and the negative predictive value was 64%.

Conclusion: BMI-based measures substantially underestimate the prevalence of excessive fatness in Kuwaiti adolescent females. Obesity is even more prevalent, and requires more urgent attention, than is apparent from BMI-based measures used in most research and national surveys. BMI may also be too crude for use as an exposure or outcome variable in many epidemiological studies of Arab adolescent girls and adult women.
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http://dx.doi.org/10.2147/DMSO.S232545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147618PMC
April 2020

Relationship of body mass index, serum creatine kinase, and acute kidney injury after severe trauma.

J Trauma Acute Care Surg 2020 07;89(1):179-185

From the Department of Surgery (C.R.V., D.N.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Hackensack Meridian School of Medicine at Seton Hall University (T.D.), Nutley, New Jersey; Pulmonary, Allergy, and Critical Care Division (J.P.R., C.M.F., P.N.L., J.D.C., M.G.S.S.), Center for Clinical Epidemiology and Biostatistics (D.N.H., Q.W., J.D.C., M.G.S.S.), Division of Traumatology, Surgical Critical Care, and Emergency Surgery (D.N.H.), and Center for Translational Lung Biology (J.P.R., J.D.C., M.G.S.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Objectives: Body mass index (BMI) is associated with acute kidney injury (AKI) after trauma, but underlying mechanisms are unclear. Body mass index correlates with both excess adiposity and increased muscle mass. Since the latter could predispose to severe rhabdomyolysis after trauma, we hypothesized that the BMI-AKI association may be partially explained by a direct relationship of BMI with serum creatine kinase (CK).

Methods: Prospective cohort study of 463 critically ill patients admitted to a level I trauma center from 2005 to 2015 with Injury Severity Score of >15 and serum CK measured in the first 7 days. We defined AKI by AKI Network creatinine criteria. We used simple linear regression to determine the association of BMI with peak CK and multivariable logistic regression to adjust the BMI-AKI association for peak CK and confounders.

Results: Median age was 43 years, 350 (76%) were male, 366 (79%) had blunt mechanism, and median Injury Severity Score was 24. Body mass index was associated with peak CK (R = 0.05, p < 0.001). Acute kidney injury developed in 148 patients (32%), and median time to peak CK was 29 hours (interquartile range, 15-56 hours) after presentation. Body mass index was significantly associated with AKI in multivariable models adjusted for age, race, sex, diabetes, injury mechanism and severity, and red blood cell transfusions (odds ratio [OR], 1.31 per 5 kg/m; 95% confidence interval [CI], 1.09-1.58; p = 0.004). Adding peak CK to the model partially attenuated the association of BMI with AKI (OR, 1.26 per 5 kg/m; 95% CI, 1.04-1.52; p = 0.018), and peak CK was also associated with AKI (OR, 1.19 per natural log; 95% CI, 1.00-1.41; p = 0.049). Peak CK remained associated with AKI when restricted to patients with values of <5,000 U/L (OR, 1.31 per natural log; 95% CI, 1.01-1.69; p = 0.043).

Conclusion: Serum CK correlated with BMI and partially attenuated the association of BMI with AKI after major trauma, suggesting that excess muscle injury may contribute to the BMI-AKI association.

Level Of Evidence: Epidemiologic study, level III.
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http://dx.doi.org/10.1097/TA.0000000000002714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830741PMC
July 2020

Variations in accelerometry measured physical activity and sedentary time across Europe - harmonized analyses of 47,497 children and adolescents.

Int J Behav Nutr Phys Act 2020 03 18;17(1):38. Epub 2020 Mar 18.

Department of Sports Medicine, Norwegian School of Sport Sciences, PO Box 4014, Ullevål Stadion, 0806, Oslo, Norway.

Background: Levels of physical activity and variation in physical activity and sedentary time by place and person in European children and adolescents are largely unknown. The objective of the study was to assess the variations in objectively measured physical activity and sedentary time in children and adolescents across Europe.

Methods: Six databases were systematically searched to identify pan-European and national data sets on physical activity and sedentary time assessed by the same accelerometer in children (2 to 9.9 years) and adolescents (≥10 to 18 years). We harmonized individual-level data by reprocessing hip-worn raw accelerometer data files from 30 different studies conducted between 1997 and 2014, representing 47,497 individuals (2-18 years) from 18 different European countries.

Results: Overall, a maximum of 29% (95% CI: 25, 33) of children and 29% (95% CI: 25, 32) of adolescents were categorized as sufficiently physically active. We observed substantial country- and region-specific differences in physical activity and sedentary time, with lower physical activity levels and prevalence estimates in Southern European countries. Boys were more active and less sedentary in all age-categories. The onset of age-related lowering or leveling-off of physical activity and increase in sedentary time seems to become apparent at around 6 to 7 years of age.

Conclusions: Two third of European children and adolescents are not sufficiently active. Our findings suggest substantial gender-, country- and region-specific differences in physical activity. These results should encourage policymakers, governments, and local and national stakeholders to take action to facilitate an increase in the physical activity levels of young people across Europe.
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http://dx.doi.org/10.1186/s12966-020-00930-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079516PMC
March 2020

Risk Factors for Short-Term Complication After Open Reduction and Internal Fixation of Ankle Fractures: Analysis of a Large Insurance Claims Database.

J Foot Ankle Surg 2020 Mar - Apr;59(2):239-245

Professor, Texas A&M University, College of Medicine, Temple, TX; Chief, Section of Podiatry, Surgical Services, Central Texas Veterans Affairs Health Care System, Temple, TX; Staff, Department of Surgery, Baylor Scott & White Health, Temple, TX.

Although fractures of the ankle are common injuries treated by surgical podiatrists and orthopaedic surgeons specializing in foot and ankle surgery, postoperative complications can occur, often imposing an economic burden on the patient. As health care in the United States moves toward value-based care, cost reduction has primarily focused on reducing complications and unplanned episodes of care. We used a large modern database of insurance claims to examine patterns of complications after open reduction internal fixation of ankle fractures, identifying diabetes mellitus and history of myocardial infarction as risk factors for postoperative infection within 30 days of surgery. Lateral malleolar repair was less likely to lead to infection, or need for repeated surgery, than was medial malleolar fracture repair. Diabetes mellitus, neuropathy, and chronic obstructive pulmonary disease were associated with development of postoperative cellulitis. Patients with a history of cerebrovascular accident were more likely to return to the emergency department or to have a pulmonary embolism. Male sex, presence of lupus, and increased age were associated with repeat surgery.
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http://dx.doi.org/10.1053/j.jfas.2019.08.003DOI Listing
January 2021

Sustainable ppm level palladium-catalyzed aminations in nanoreactors under mild, aqueous conditions.

Chem Sci 2019 Dec 20;10(45):10556-10561. Epub 2019 Sep 20.

Department of Chemistry and Biochemistry , University of California Santa Barbara , Santa Barbara , CA 93106 , USA . Email:

A 1 : 1 Pd : ligand complex, [-BuXPhos(Pd-π-cinnamyl)]OTf, has been identified as a highly robust pre-catalyst for amination reactions leading to diarylamines, where loadings of metal are typically at 1000 ppm Pd, run in water at temperatures between rt and 45 °C. The protocol is exceptionally simple, is readily scaled, and compares very favorably traditional amination conditions. It has also been shown to successfully lead to key intermediates associated with several physiologically active compounds.
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http://dx.doi.org/10.1039/c9sc03710aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020654PMC
December 2019

Long-term effectiveness of biodegradable patent foramen ovale closure: Are we there yet?

Catheter Cardiovasc Interv 2020 02;95(3):355-356

Division of Cardiovascular Medicine, Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York.

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http://dx.doi.org/10.1002/ccd.28773DOI Listing
February 2020

Sepsis-associated acute respiratory distress syndrome in individuals of European ancestry: a genome-wide association study.

Lancet Respir Med 2020 03 23;8(3):258-266. Epub 2020 Jan 23.

Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain. Electronic address:

Background: Acute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation.

Methods: We did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008-Nov 30, 2017; USA) and the VISEP (April 1, 2003-June 30, 2005) and MAXSEP (Oct 1, 2007-March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants.

Findings: We identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41-0·91, p=5·18 × 10) located within the Fms-related tyrosine kinase 1 (FLT1) gene, which encodes vascular endothelial growth factor receptor 1 (VEGFR-1). The region containing the sentinel variant and its best proxies acted as a silencer for the FLT1 promoter, and alleles with protective effects in ARDS further reduced promoter activity (p=0·0047). A literature mining of all previously described ARDS genes validated the association of vascular endothelial growth factor A (VEGFA; OR 0·55, 95% CI 0·41-0·73; p=4·69 × 10).

Interpretation: A common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target.

Funding: Instituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnológico y de Energías Renovables.
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http://dx.doi.org/10.1016/S2213-2600(19)30368-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772505PMC
March 2020

'Jump start' childcare-based intervention to promote physical activity in pre-schoolers: six-month findings from a cluster randomised trial.

Int J Behav Nutr Phys Act 2020 01 16;17(1). Epub 2020 Jan 16.

Early Start, Faculty of Social Sciences, University of Wollongong, Northfields Ave, Wollongong, New South Wales, 2522, Australia.

Background: Participation in adequate levels of physical activity during the early years is important for health and development. We report the 6-month effects of an 18-month multicomponent intervention on physical activity in early childhood education and care (ECEC) settings in low-income communities.

Methods: A cluster randomised controlled trial was conducted in 43 ECEC settings in disadvantaged areas of New South Wales, Australia. Three-year-old children were recruited and assessed in the first half of 2015 with follow-up 6 months later. The intervention was guided by Social Cognitive Theory and included five components. The primary outcome was minutes per hour in total physical activity during ECEC hours measured using Actigraph accelerometers. Intention-to-treat analysis of the primary outcome was conducted using a generalized linear mixed model.

Results: A total of 658 children were assessed at baseline. Of these, 558 (85%) had valid accelerometer data (mean age 3.38y, 52% boys) and 508 (77%) had valid accelerometry data at 6-month follow-up. Implementation of the intervention components ranged from 38 to 72%. There were no significant intervention effects on mins/hr. spent in physical activity (adjusted difference = - 0.17 mins/hr., 95% CI (- 1.30 to 0.97), p = 0.78). A priori sub-group analyses showed a greater effect among overweight/obese children in the control group compared with the intervention group for mins/hr. of physical activity (2.35mins/hr., [0.28 to 4.43], p = 0.036).

Conclusions: After six-months the Jump Start intervention had no effect on physical activity levels during ECEC. This was largely due to low levels of implementation. Increasing fidelity may result in higher levels of physical activity when outcomes are assessed at 18-months.

Trial Registration: Australian New Zealand Clinical Trials Registry  ACTRN12614000597695.
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http://dx.doi.org/10.1186/s12966-020-0910-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966838PMC
January 2020

The South African 24-Hour Movement Guidelines for Birth to 5 Years: An Integration of Physical Activity, Sitting Behavior, Screen Time, and Sleep.

J Phys Act Health 2020 01;17(1):109-119

Background: In December 2018, the South African 24-hour movement guidelines for birth to 5 years were released. This article describes the process used to develop these guidelines.

Methods: The Grading of Recommendations Assessment, Development, and Evaluation-ADOLOPMENT approach was followed, with some pragmatic adaptions, using the Australian guidelines for the early years as a starting point. A consensus panel, including stakeholders in early childhood development and academics, was formed to assist with the development process.

Results: At a face-to-face meeting of the panel, global and local literatures were considered. Following this meeting, a first draft of the guidelines (including a preamble) was formulated. Further reviews of these drafts by the panel were done via e-mail, and a working draft was sent out for stakeholder consultation. The guidelines and preamble were amended based on stakeholder input, and an infographic was designed. Practical "tips" documents were also developed for caregivers of birth to 5-year-olds and early childhood development practitioners. The guidelines (and accompanying documents) were released at a launch event and disseminated through various media channels.

Conclusions: These are the first movement guidelines for South African and the first such guidelines for this age group from a low- and middle-income country.
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http://dx.doi.org/10.1123/jpah.2019-0187DOI Listing
January 2020

GRADE-ADOLOPMENT Process to Develop 24-Hour Movement Behavior Recommendations and Physical Activity Guidelines for the Under 5s in the United Kingdom, 2019.

J Phys Act Health 2020 01;17(1):101-108

Background: This article summarizes the approach taken to develop UK Chief Medical Officers' physical activity guidelines for the Under 5s, 2019.

Methods: The Grading of Recommendations Assessment, Development and Evaluation (GRADE)-Adaptation, Adoption, De Novo Development (ADOLOPMENT) approach was used, based on the guidelines from Canada and Australia, with evidence updated to February 2018. Recommendations were based on the associations between (1) time spent in sleep, sedentary time, physical activity, and 10 health outcomes and (2) time spent in physical activity and sedentary behavior on sleep outcomes (duration and latency).

Results: For many outcomes, more time spent in physical activity and sleep (up to a point) was beneficial, as was less time spent in sedentary behavior. The authors present, for the first time, evidence in GRADE format on behavior type-outcome associations for infants, toddlers, and preschoolers. Stakeholders supported all recommendations, but recommendations on sleep and screen time were not accepted by the Chief Medical Officers; UK guidelines will refer only to physical activity.

Conclusions: This is the first European use of GRADE-ADOLOPMENT to develop physical activity guidelines. The process is robust, rapid, and inexpensive, but the UK experience illustrates a number of challenges that should help development of physical activity guidelines in future.
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http://dx.doi.org/10.1123/jpah.2019-0139DOI Listing
January 2020

Assessing the acceptability of an adapted preschool obesity prevention programme: ToyBox-Scotland.

Child Care Health Dev 2020 03 15;46(2):213-222. Epub 2020 Jan 15.

Physical Activity for Health Group, School of Psychological Sciences and Health, University of Strathclyde, Glasgow, UK.

Background: Childhood obesity is a global public health issue. Interventions to prevent the onset of obesity in the early years are often implemented in preschool settings. The ToyBox intervention was delivered across Europe and targeted energy balance-related behaviours in preschools and children's homes through teacher-led activities and parental education materials and was adapted for use in Scotland. This study assessed the acceptability of the 18-week adapted intervention to both parents and teachers.

Methods: Mixed methods were employed to collect both qualitative and quantitative data. Preschool staff and children's parents/caregivers completed post-intervention feedback surveys, from which acceptability scores were calculated and presented as proportions. Focus groups were conducted with preschool staff, whereas parents/caregivers participated in semi-structured interviews. A thematic analysis was applied to qualitative data following the development of a coding framework. Quantitative and qualitative data were analysed using SPSS and NVivo 10, respectively.

Results: Preschool staff rated the intervention as highly acceptable based on post-intervention feedback surveys (80%; mean score 8.8/11). Lower acceptability scores were observed for parents/caregivers (49%; 3.9/8). Nine preschool practitioners participated in focus groups (n = 3). User-friendliness of the intervention materials, integration of the intervention with the curriculum, and flexibility of the intervention were identified as facilitators to delivery. Barriers to delivery were time, insufficient space, and conflicting policies within preschools with regard to changing classroom layouts. Parental interviews (n = 4) revealed a lack of time to be a major barrier, which prevented parents from participating in home-based activities. Parents perceived the materials to be simple to understand and visually appealing.

Conclusions: This study identified a number of barriers and facilitators to the delivery and evaluation of the ToyBox Scotland preschool obesity prevention programme, which should be considered before any further scale-up of the intervention.
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http://dx.doi.org/10.1111/cch.12736DOI Listing
March 2020