Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Clinical standards for drug-susceptible TB in children and adolescents.

BACKGROUND: These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.METHODS: Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.RESULTS: Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.CONCLUSION: These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB

Clinical standards for drug-susceptible TB in children and adolescents

BACKGROUND: These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents. METHODS: Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document. RESULTS: Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent. CONCLUSION: These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.National Institutes of HealthRevisión por pare

Crustal recycling by subduction erosion in the central Mexican Volcanic Belt

Recycling of upper plate crust in subduction zones, or ‘subduction erosion’, is a major mechanism of crustal destruction at convergent margins. However, assessing the impact of eroded crust on arc magmas is difficult owing to the compositional similarity between the eroded crust, trench sediment and arc crustal basement that may all contribute to arc magma formation. Here we compare Sr–Nd–Pb–Hf and trace element data of crustal input material to Sr–Nd–Pb–Hf–He–O isotope chemistry of a well-characterized series of olivine-phyric, high-Mg# basalts to dacites in the central Mexican Volcanic Belt (MVB). Basaltic to andesitic magmas crystallize high-Ni olivines that have high mantle-like 3He/4He = 7–8 Ra and high crustal δ18Omelt = +6.3–8.5‰ implying their host magmas to be near-primary melts from a mantle infiltrated by slab-derived crustal components. Remarkably, their Hf–Nd isotope and Nd/Hf trace element systematics rule out the trench sediment as the recycled crust end member, and imply that the coastal and offshore granodiorites are the dominant recycled crust component. Sr–Nd–Pb–Hf isotope modeling shows that the granodiorites control the highly to moderately incompatible elements in the calc-alkaline arc magmas, together with lesser additions of Pb- and Sr-rich fluids from subducted mid-oceanic ridge basalt (MORB)-type altered oceanic crust (AOC). Nd–Hf mass balance suggests that the granodiorite exceeds the flux of the trench sediment by at least 9–10 times, corresponding to a flux of ⩾79–88 km3/km/Myr into the subduction zone. At an estimated thickness of 1500–1700 m, the granodiorite may buoyantly rise as bulk ‘slab diapirs’ into the mantle melt region and impose its trace element signature (e.g., Th/La, Nb/Ta) on the prevalent calc-alkaline arc magmas. Deep slab melting and local recycling of other slab components such as oceanic seamounts further diversify the MVB magmas by producing rare, strongly fractionated high-La magmas and a minor population of high-Nb magmas, respectively. Overall, the central MVB magmas inherit their striking geochemical diversity principally from the slab, thus emphasizing the importance of continental crust recycling in modern solid Earth relative to its new formation in modern subduction zones

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Management of patients with multidrug-resistant tuberculosis

Funding Information: JH and CL are supported by the German Center for Infection Research (DZIF). TS is supported by The Swedish Heart and Lung Foundation and the Swedish Research Council. KD is supported by the South African Medical Research Council and the European Union (EDCTP) Publisher Copyright: © 2019 The Union.The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDRTB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDRTB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDRTB patients achieving a relapse-free cure.publishersversionPeer reviewe

Clinical standards for the diagnosis, treatment and prevention of TB infection

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT. M E T H O D S: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement. R E S U LT S: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care. C O N C L U S I O N: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI