Ethnicity-specific BMI cutoffs for obesity based on type 2 diabetes risk in England: a population-based cohort study.

BACKGROUND: National and global recommendations for BMI cutoffs to trigger action to prevent obesity-related complications like type 2 diabetes among non-White populations are questionable. We aimed to prospectively identify ethnicity-specific BMI cutoffs for obesity based on the risk of type 2 diabetes that are risk-equivalent to the BMI cutoff for obesity among White populations (≥30 kg/m2). METHODS: In this population-based cohort study, we used electronic health records across primary care (Clinical Practice Research Datalink) linked to secondary care records (Hospital Episodes Statistics) from a network of general practitioner practices in England. Eligible participants were aged 18 years or older, without any past or current diagnosis of type 2 diabetes, had a BMI of 15·0-50·0 kg/m2 and complete ethnicity data, were registered with a general practitioner practice in England at any point between Sept 1, 1990, and Dec 1, 2018, and had at least 1 year of follow-up data. Patients with type 2 diabetes were identified by use of a CALIBER phenotyping algorithm. Self-reported ethnicity was collapsed into five main categories. Age-adjusted and sex-adjusted negative binomial regression models, with fractional polynomials for BMI, were fitted with incident type 2 diabetes and ethnicity data. FINDINGS: 1 472 819 people were included in our study, of whom 1 333 816 (90·6%) were White, 75 956 (5·2%) were south Asian, 49 349 (3·4%) were Black, 10 934 (0·7%) were Chinese, and 2764 (0·2%) were Arab. After a median follow-up of 6·5 years (IQR 3·2-11·2), 97 823 (6·6%) of 1 472 819 individuals were diagnosed with type 2 diabetes. For the equivalent age-adjusted and sex-adjusted incidence of type 2 diabetes at a BMI of 30·0 kg/m2 in White populations, the BMI cutoffs were 23·9 kg/m2 (95% CI 23·6-24·0) in south Asian populations, 28·1 kg/m2 (28·0-28·4) in Black populations, 26·9 kg/m2 (26·7-27·2) in Chinese populations, and 26·6 kg/m2 (26·5-27·0) in Arab populations. INTERPRETATION: Revisions of ethnicity-specific BMI cutoffs are needed to ensure that minority ethnic populations are provided with appropriate clinical surveillance to optimise the prevention, early diagnosis, and timely management of type 2 diabetes. FUNDING: National Institute for Health Research

CARD9⁺ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment

This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, National Institutes of Health, as well as NIH grants awarded to TMH (R01 093808), SGF (R01AI124566) and SRL (R01CA161373). Additional funding was provided by the Burroughs Wellcome Fund (awarded to TMH), the Wellcome Trust (102705, 097377; awarded to GDB), the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1; awarded to GDB). The authors additionally thank Celeste Huaman for care and screening of the Malt1 793 -/- mice.Peer reviewedPostprin

miR-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis.

Neutrophil extracellular traps (NETs) induce a procoagulant response linking inflammation and thrombosis. Low levels of miR-146a, a brake of inflammatory response, are involved in higher risk for cardiovascular events, but the mechanisms explaining how miR-146a exerts its function remain largely undefined. The aim of this study was to explore the impact of miR-146a deficiency in NETosis both, in sterile and non-sterile models in vivo, and to inquire into the underlying mechanism. Two models of inflammation were performed: 1) Ldlr-/- mice transplanted with bone marrow from miR-146a-/- or wild type (WT) were fed high-fat diet, generating an atherosclerosis model; and 2) an acute inflammation model was generated by injecting lipopolysaccharide (LPS) (1 mg/Kg) into miR-146a-/- and WT mice. miR-146a deficiency increased NETosis in both models. Accordingly, miR-146a-/- mice showed significant reduced carotid occlusion time and elevated levels of NETs in thrombi following FeCl3-induced thrombosis. Infusion of DNAse I abolished arterial thrombosis in WT and miR-146a-/- mice. Interestingly, miR-146a deficient mice have aged, hyperreactive and pro-inflammatory neutrophils in circulation that are more prone to form NETs independently of the stimulus. Furthermore, we demonstrated that community acquired pneumonia (CAP) patients with reduced miR-146a levels associated with the T variant of the functional rs2431697, presented an increased risk for cardiovascular events due in part to an increased generation of NETs.This work was supported by research grants from Instituto de Salud Carlos III (ISCIII), Fondo Europeo de Desarrollo Regional “Investing in your future” (PI17/00051 y PI17/01421) (PFIS18/0045: A.M. de los Reyes-García) (CD18/00044: S. Águila), and Fundación Séneca (19873/GERM/15). The CNIC is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades (MCIU), and the Fundación Pro CNIC, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). A.B. Arroyo has a research fellowship from Sociedad Española de Trombosis y Hemostasia (SETH). The MCIU supported A.dM. (predoctoral contract BES-2014-067791).S

Adult videogame consumption as individualised, episodic progress

Drawing from phenomenological interviews with 24 adult videogamers, we explore videogame consumption as a source of individualised, episodic progress. We first consider the relationship between play, progress, technology and the market. We then document adults' accounts of progress through the acquisition of new consoles and software, in the accumulation of in-game resources, and in creative achievements within videogames. Alongside an understanding of technological improvements as representing both technological and personal progress, we see how individuals may also turn to videogames in search of quick and easy episodes of achievement; here, progress is not some grand plan, but a series of small events helpfully structured by the latest game releases. Thus, in a society which aspires to a life where things ‘get better’ and time is usefully spent, adults who fail to actualise progress elsewhere may use videogames and related hardware to perform the idea of achievement as individualised episodes of play. In integrating the accepted cultural idea of progress, perceptions of adult play as ‘frivolous’ can be overcome and such practices may be normalised as a legitimate adult activity. However, play emerges from its frivolousness as legitimate only in compensating for working practices that remain alienated through technology-driven productivity, and through the latest technological commodities. The enjoyable nature of games as a leisure pursuit can become overshadowed by an obligation to achieve at the same time as distancing players from areas of their lives where progress is not experienced

Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as asthma endotypes. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies

Endovascular Thrombectomy for Ischemic Stroke Increases Disability-Free Survival, Quality of Life, and Life Expectancy and Reduces Cost

Background: Endovascular thrombectomy improves functional outcome in large vessel occlusion ischemic stroke. We examined disability, quality of life, survival and acute care costs in the EXTEND-IA trial, which used CT-perfusion imaging selection. Methods: Large vessel ischemic stroke patients with favorable CT-perfusion were randomized to endovascular thrombectomy after alteplase versus alteplase-only. Clinical outcome was prospectively measured using 90-day modified Rankin scale (mRS). Individual patient expected survival and net difference in Disability/Quality-adjusted life years (DALY/QALY) up to 15 years from stroke were modeled using age, sex, 90-day mRS, and utility scores. Level of care within the first 90 days was prospectively measured and used to estimate procedure and inpatient care costs (US$reference year 2014). Results: There were 70 patients, 35 in each arm, mean age 69, median NIHSS 15 (IQR 12-19). The median (IQR) disability-weighted utility score at 90 days was 0.65 (0.00-0.91) in the alteplase-only versus 0.91 (0.65-1.00) in the endovascular group (p = 0.005). Modeled life expectancy was greater in the endovascular versus alteplaseonly group (median 15.6 versus 11.2 years, p = 0.02). The endovascular thrombectomy group had fewer simulated DALYs lost over 15 years [median (IQR) 5.5 (3.2-8.7) versus 8.9 (4.7-13.8), p = 0.02] and more QALY gained [median (IQR) 9.3 (4.2-13.1) versus 4.9 (0.3-8.5), p = 0.03]. Endovascular patients spent less time in hospital [median (IQR) 5 (3-11) days versus 8 (5-14) days, p = 0.04] and rehabilitation [median (IQR) 0 (0-28) versus 27 (0-65) days, p = 0.03]. The estimated inpatient costs in the first 90 days were less in the thrombectomy group (average US$15,689 versus US$30,569, p = 0.008) offsetting the costs of interhospital transport and the thrombectomy procedure (average US$10,515). The average saving per patient treated with thrombectomy was US$4,365. c Conclusion: Thrombectomy patients with large vessel occlusion and salvageable tissue on CT-perfusion had reduced length of stay and overall costs to 90 days. There was evidence of clinically relevant improvement in long-term survival and quality of life.Peer reviewe

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO