Changes in Alcohol Consumption and Subsequent Risk of Type 2 Diabetes in Men

OBJECTIVE: The objective of this study was to investigate the association of 4-year changes in alcohol consumption with a subsequent risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: We prospectively examined 38,031 men from the Health Professionals Follow-Up Study who were free of diagnosed diabetes or cancer in 1990. Alcohol consumption was reported on food frequency questionnaires and updated every 4 years. RESULTS: A total of 1,905 cases of type 2 diabetes occurred during 428,497 person-years of follow-up. A 7.5 g/day (approximately half a glass) increase in alcohol consumption over 4 years was associated with lower diabetes risk among initial nondrinkers (multivariable hazard ratio [HR] 0.78; 95% CI: 0.60–1.00) and drinkers initially consuming <15 g/day (HR 0.89; 95% CI: 0.83–0.96), but not among men initially drinking ≥15 g/day (HR 0.99; 95% CI: 0.95–1.02; Pinteraction < 0.01). A similar pattern was observed for levels of total adiponectin and hemoglobin A1c, with a better metabolic profile among abstainers and light drinkers who modestly increased their alcohol intake, compared with men who either drank less or among men who were already moderate drinkers and increased their intake. Likewise, compared with stable light drinkers (0–4.9 g/day), light drinkers who increased their intake to moderate levels (5.0–29.9 g/day) had a significantly lower risk of type 2 diabetes (HR 0.75; 95% CI: 0.62–0.90). CONCLUSIONS: Increases in alcohol consumption over time were associated with lower risk of type 2 diabetes among initially rare and light drinkers. This lower risk was evident within a 4-year period following increased alcohol intake

Changes in Alcohol Consumption and Subsequent Risk of Type 2 Diabetes in Men

Objective -The objective of this study was to investigate the association of four-year changes in alcohol consumption with subsequent risk of type 2 diabetes. Research Design and Methods - We prospectively examined 38,031 men from the Health Professionals Follow-up Study free of diagnosed diabetes or cancer in 1990. Alcohol consumption was reported on food frequency questionnaires and updated every four years. Results - A total of 1905 cases of type 2 diabetes occurred during 428,497 person-years of follow-up. A 7.5 g/day (~half a glass) increase in alcohol consumption over four years was associated with lower diabetes risk among initial nondrinkers (multivariable hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.60-1.00) and drinkers initially consumin

The Role of Dectin-2 for Host Defense Against Disseminated Candidiasis

Acknowledgments This work was supported by European Union ALLFUN (FP7/2007 2013, HEALTH-2010-260338) (Fungi in the setting of inflammation, allergy and autoimmune diseases: Translating basic science into clinical practices ‘‘ALLFUN’’) to D.C.I., F.C., C.F., M.G.N., and N.A.R.G. M.G.N and J.Q. were supported by a Vici grant of The Netherlands Organization of Scientific Research (to M.G.N.). M.G.N. was supported by an ERC Consolidator Grant (nr. 310372). N.A.R.G. was also supported by the Wellcome Trust (086827, 075470, 097377, & 101873).Peer reviewedPublisher PD

Pro-inflammatory Monocyte Phenotype During Acute Progression of Cerebral Small Vessel Disease

Background: The etiology of cerebral small vessel disease (SVD) remains elusive, though evidence is accumulating that inflammation contributes to its pathophysiology. We recently showed retrospectively that pro-inflammatory monocytes are associated with the long-term progression of white matter hyperintensities (WMHs). In this prospective high-frequency imaging study, we hypothesize that the incidence of SVD progression coincides with a pro-inflammatory monocyte phenotype. Methods: Individuals with SVD underwent monthly magnetic resonance imaging (MRI) for 10 consecutive months to detect SVD progression, defined as acute diffusion-weighted imaging-positive (DWI+) lesions, incident microbleeds, incident lacunes, and WMH progression. Circulating inflammatory markers were measured, cytokine production capacity of monocytes was assessed after ex vivo stimulation, and RNA sequencing was performed on isolated monocytes in a subset of participants. Results: 13 out of 35 individuals developed SVD progression (70 ± 6 years, 54% men) based on incident lesions (n = 7) and/or upper quartile WMH progression (n = 9). Circulating E-selectin concentration (p < 0.05) and the cytokine production capacity of interleukin (IL)-1β and IL-6 (p < 0.01) were higher in individuals with SVD progression. Moreover, RNA sequencing revealed a pro-inflammatory monocyte signature including genes involved in myelination, blood–brain barrier, and endothelial–leukocyte interaction. Conclusions: Circulating monocytes of individuals with progressive SVD have an inflammatory phenotype, characterized by an increased cytokine production capacity and a pro-inflammatory transcriptional signature

Exposure to Candida albicans Polarizes a T-Cell Driven Arthritis Model towards Th17 Responses, Resulting in a More Destructive Arthritis

BACKGROUND: Fungal components have been shown very effective in generating Th17 responses. We investigated whether exposure to a minute amount of C. albicans in the arthritic joint altered the local cytokine environment, leading to enhanced Th17 expansion and resulting in a more destructive arthritis. METHODOLOGY: Chronic SCW arthritis was induced by repeated injection with Streptococcus pyogenes (SCW) cell wall fragments into the knee joint of C57Bl/6 mice, alone or in combination with the yeast of C. albicans or Zymosan A. During the chronic phase of the arthritis, the cytokine levels, mRNA expression and histopathological analysis of the joints were performed. To investigate the phenotype of the IL-17 producing T-cells, synovial cells were isolated and analyzed by flowcytometry. PRINCIPAL FINDINGS: Intra-articular injection of either Zymosan A or C. albicans on top of the SCW injection both resulted in enhanced joint swelling and inflammation compared to the normal SCW group. However, only the addition of C. albicans during SCW arthritis resulted in severe chondrocyte death and enhanced destruction of cartilage and bone. Additionally, exposure to C. albicans led to increased IL-17 in the arthritic joint, which was accompanied by an increased synovial mRNA expression of T-bet and RORgammaT. Moreover, the C. albicans-injected mice had significantly more Th17 cells in the synovium, of which a large population also produced IFN-gamma. CONCLUSION: This study clearly shows that minute amounts of fungal components, like C. albicans, are very potent in interfering with the local cytokine environment in an arthritic joint, thereby polarizing arthritis towards a more destructive phenotype

Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis

Copyright © 2021 Gonçalves et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.Activation of immune cells in response to fungal infection involves the reprogramming of their cellular metabolism to support antimicrobial effector functions. Although metabolic pathways such as glycolysis are known to represent critical regulatory nodes in antifungal immunity, it remains undetermined whether these are differentially regulated at the interindividual level. In this study, we identify a key role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the immunometabolic responses to Aspergillus fumigatus. A genetic association study performed in 439 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) and corresponding donors revealed that the donor, but not recipient, rs646564 variant in the PFKFB3 gene increased the risk of invasive pulmonary aspergillosis (IPA) after transplantation. The risk genotype impaired the expression of PFKFB3 by human macrophages in response to fungal infection, which was correlated with a defective activation of glycolysis and the ensuing antifungal effector functions. In patients with IPA, the risk genotype was associated with lower concentrations of cytokines in the bronchoalveolar lavage fluid samples. Collectively, these findings demonstrate the important contribution of genetic variation in PFKFB3 to the risk of IPA in patients undergoing HSCT and support its inclusion in prognostic tools to predict the risk of fungal infection in this clinical setting. IMPORTANCE The fungal pathogen Aspergillus fumigatus can cause severe and life-threatening forms of infection in immunocompromised patients. Activation of glycolysis is essential for innate immune cells to mount effective antifungal responses. In this study, we report the contribution of genetic variation in the key glycolytic activator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) to the risk of invasive pulmonary aspergillosis (IPA) after allogeneic hematopoietic stem cell transplantation. The PFKFB3 genotype associated with increased risk of infection was correlated with an impairment of the antifungal effector functions of macrophages in vitro and in patients with IPA. This work highlights the clinical relevance of genetic variation in PFKFB3 to the risk of IPA and supports its integration in risk stratification and preemptive measures for patients at high risk of IPA.This work was supported by the Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-SER/29635/2017, PTDC/MED-GEN/28778/2017, UIDB/50026/2020, and UIDP/50026/2020), the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000039), the Institut Mérieux (Mérieux Research Grant 2017), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Research Grant 2017), the European Union’s Horizon 2020 research and innovation program under grant agreement no. 847507, and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003. Individual support was provided by FCT (SFRH/BD/136814/2018 to S.M.G., PD/BD/137680/2018 to D.A., CEECIND/04058/2018 to C.C., and CEECIND/03628/2017 to A.C.). M.G.N. was supported by an ERC Advanced Grant and a Spinoza Grant of the Netherlands Organization for Scientific Research.info:eu-repo/semantics/publishedVersio

Research priorities in pediatric parenteral nutrition: a consensus and perspective from ESPGHAN/ESPEN/ESPR/CSPEN

We acknowledge all the authors of the ESPGHAN/ESPR/ESPEN/CSPEN pediatric parenteral nutrition guidelines for their contributions and vote (Christian Braegger, University Children’s Hospital, Zurich, Switzerland; Jiri Bronsky, University Hospital Motol, Prague, Czech Republic; Cristina Campoy, Department of Paediatrics, School of Medicine, University of Granada, Granada, Spain; Magnus Domellof, Department of Clinical Sciences, Pediatrics, Umeå University, Sweden; Nicholas Embleton, Newcastle University, Newcastle upon Tyne, UK; Mary Fewtrell, UCL Great Ormond Street Institute of Child Health, London, UK; Natasa Fidler, University Medical Centre Ljubljana, Ljubljana, Slovenia; Axel Franz, University Children’s Hospital, Tuebingen, Germany; Oliver Goulet, University Sordonne-Paris-Cite; Paris-Descartes Medical School, Paris, France; Corina Hartmann, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel and Carmel Medical Center, Israel; Susan Hill, Great Ormond Street Hospital for Children, NHS Foundation Trust and UCL Institute of Child Health, London, UK; Iva Hojsak, Children’s Hospital Zagreb, University of Zagreb School of Medicine, University of J. J. Strossmayer School of Medicine Osijek, Croatia; Sylvia Iacobelli, CHU La Reunion, Saint Pierre, France; Frank Jochum, Ev. Waldkrankenhaus Spandau, Berlin, Germany; Koen Joosten, Department of Pediatrics and Pediatric Surgery, Intensive Care, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands; Sanja Kolacek, Children’s Hospital, University of Zagreb School of Medicine, Zagreb, Croatia; Alexandre Lapillone, Paris-Descartes University, Paris, France; Szimonetta Lohner, Department of Pediatrics, University of Pecs, Pecs, Hungary; Dieter Mesotten, KU Leuven, Leuven, Belgium; Walter Mihatsch, Ulm University, Ulm, and Helios Hospital, Pforzheim, Germany; Francis Mimouni, Department of Pediatrics, Division of Neonatology, The Wilf Children’s Hospital, the Shaare Zedek Medical Center, Jerusalem, and the Tel Aviv University, Tel Aviv, Israel; Christian Molgaard, Department of Nutrition, Exercise and Sports, University of Copenhagen, and Paediatric Nutrition Unit, Rigshospitalet, Copenhagen, Denmark; Sissel Moltu, Oslo University Hospital, Oslo, Norway; Antonia Nomayo, Ev. Waldkrankenhaus Spandau, Berlin, Germany; John Puntis, The General Infirmary at Leeds, Leeds, UK; Arieh Riskin, Bnai Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel; Miguel Saenz de Pipaon, Department of Neonatology, La Paz University Hospital, Red de Salud Materno Infantil y Desarrollo e SAMID, Universidad Autonoma de Madrid, Madrid, Spain; Raanan Shamir, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel; Tel Aviv University, Tel Aviv, Israel; Peter Szitanyi, General University Hospital, First Faculty of Medicine, Charles University in Prague, Czech Republic; Merit Tabbers, Emma Children’s Hospital, Amsterdam UMC, Amsterdam, The Netherlands; Chris van den Akker, Emma Children’s Hospital, Amsterdam UMC, Amsterdam, The Netherlands; Hans van Goudoever, Emma Children’s Hospital, Amsterdam UMC, Amsterdam, The Netherlands; Sacha Verbruggen, Department of Pediatrics and Pediatric Surgery, Intensive Care, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands; Cai Wei, Shanghai Jiao Tong University, Shanghai, China; Weihui Yan, Department of Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China) and the members of the ESPR Section on Nutrition, Gastroenterology and Metabolism (Fredrik Ahlsson, Uppsala University Children’s Hospital and Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden; Sertac Arslanoglu, Division of Neonatology, Department of Pediatrics, Istanbul Medeniyet University, Istanbul, Turkey; Wolfgang Bernhard, Department of Neonatology, Children’s Hospital, Faculty of Medicine, Eberhard-Karls- University, Tübingen, Germany; Janet Berrington, Newcastle Neonatal Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Signe Bruun, Hans Christian Andersen Hospital for Children and Adolescents, Odense University Hospital, Odense, Denmark; Christoph Fusch, Department of Pediatrics, Paracelsus Medical School, General Hospital of Nuremberg, Nuremberg, Germany; Shalabh Garg, South Tees Hospitals, Middlesborough, UK; Maria Gianni, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Ann Hellstrom, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Claus Klingenberg, Department of Pediatrics and Adolescence Medicine, University Hospital of North Norway, Tromsø, Norway; Helen Mactier, Neonatal Unit, Princess Royal Maternity Hospital, Glasgow, UK; Neena Modi, Section of Neonatal Medicine, Department of Medicine, Chelsea and Westminster Campus, Imperial College London, London, UK; Niels Rochow, Division of Neonatology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; Paola Rogerro, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Umberto Simeoni, Division of Pediatrics, CHUV & University of Lausanne, Lausanne, Switzerland; Atul Singhal, Paediatric Nutrition, UCL Great Ormond Street Institute of Child Health, London, UK.; Ulrich Thome, Department of Neonatology, Universitatsklinikum Leipzig, Leipzig, Germany; Anne Twomey, Department of Neonatology, The National Maternity Hospital, Dublin, Ireland; Mireille Vanpee, Karolinska University Hospital, Stockholm, Sweden; Gitte Zachariassen, Hans Christian Andersen Hospital for Children and Adolescents, Odense University Hospital, Odense, Denmark) for their vote.Parenteral nutrition is used to treat children that cannot be fully fed by the enteral route. While the revised ESPGHAN/ ESPEN/ESPR/CSPEN pediatric parenteral nutrition guidelines provide clear guidance on the use of parenteral nutrition in neonates, infants, and children based on current available evidence, they have helped to crystallize areas where research is lacking or more studies are needed in order to refine recommendations. This paper collates and discusses the research gaps identified by the authors of each section of the guidelines and considers each nutrient or group of nutrients in turn, together with aspects around delivery and organization. The 99 research priorities identified were then ranked in order of importance by clinicians and researchers working in the field using a survey methodology. The highest ranked priority was the need to understand the relationship between total energy intake, rapid catch-up growth, later metabolic function, and neurocognitive outcomes. Research into the optimal intakes of macronutrients needed in order to achieve optimal outcomes also featured prominently. Identifying research priorities in PN should enable research to be focussed on addressing key issues. Multicentre trials, better definition of exposure and outcome variables, and long-term metabolic and developmental follow-up will be key to achieving this

The Genetic Risk for COVID-19 Severity Is Associated With Defective Immune Responses

Recent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity. Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Project (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with ii. increased susceptibility for severe disease in individuals with defective cytokine production; iii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy

Inter- and Intra-Observer Variability and the Effect of Experience in Cine-MRI for Adhesion Detection

Cine-MRI for adhesion detection is a promising novel modality that can help the large group of patients developing pain after abdominal surgery. Few studies into its diagnostic accuracy are available, and none address observer variability. This retrospective study explores the inter- and intra-observer variability, diagnostic accuracy, and the effect of experience. A total of 15 observers with a variety of experience reviewed 61 sagittal cine-MRI slices, placing box annotations with a confidence score at locations suspect for adhesions. Five observers reviewed the slices again one year later. Inter- and intra-observer variability are quantified using Fleiss’ (inter) and Cohen’s (intra) κ and percentage agreement. Diagnostic accuracy is quantified with receiver operating characteristic (ROC) analysis based on a consensus standard. Inter-observer Fleiss’ κ values range from 0.04 to 0.34, showing poor to fair agreement. High general and cine-MRI experience led to significantly (p < 0.001) better agreement among observers. The intra-observer results show Cohen’s κ values between 0.37 and 0.53 for all observers, except one with a low κ of −0.11. Group AUC scores lie between 0.66 and 0.72, with individual observers reaching 0.78. This study confirms that cine-MRI can diagnose adhesions, with respect to a radiologist consensus panel and shows that experience improves reading cine-MRI. Observers without specific experience adapt to this modality quickly after a short online tutorial. Observer agreement is fair at best and area under the receiver operating characteristic curve (AUC) scores leave room for improvement. Consistently interpreting this novel modality needs further research, for instance, by developing reporting guidelines or artificial intelligence-based methods

Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis

Objective: Corticosteroids are used in sepsis treatment to benefit outcome. However, discussion remains on which patients will benefit from treatment. Inter-individual variations in cortisol sensitivity, mediated through the glucocorticoid receptor, might play a role in the observed differences. Our aim was to study changes in mRNA levels of three glucocorticoid receptor splice variants in neutrophils of children with sepsis. Patients and design: Twenty-three children admitted to the pediatric intensive care unit with sepsis or septic shock were included. Neutrophils were isolated at days 0, 3 and 7, and after recovery (>3 months). mRNA levels of the glucocorticoid receptor splice variants GR-α (determining most of the cortisol effect), GR-P (increasing GR-α effect) and GR-β (inhibitor of GR-α) were measured quantitatively. Main results: Neutrophils from sepsis patients showed decreased levels of glucocorticoid receptor mRNA of the GR-α and GR-P splice variants on day 0 compared to after recovery. GR-α and GR-P mRNA levels showed a gradual recovery on days 3 and 7 and normalized after recovery. GR-β mRNA levels did not change significantly during sepsis. GR expression was negatively correlated to interleukin-6 (a measure of disease severity, r = -0.60, P = 0.009). Conclusions: Children with sepsis or septic shock showed a transient depression of glucocorticoid receptor mRNA in their neutrophils. This feature may represent a tissue-specific adaptation during sepsis leading to increased cortisol resistance of neutrophils. Our study adds to understanding the mechanism of cortisol sensitivity in immune cells. Future treatment strategies, aiming at timing and tissue specific regulation of glucocorticoids, might benefit patients with sepsis or septic shock