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Abstract Background Skeletal muscle is a highly plastic tissue crucial for many functions associated with whole‐body health across the life course. Magnetic resonance imaging (MRI) is the current gold standard for measuring skeletal muscle size. However, MRI is expensive, and access to facilities is often limited. B‐mode ultrasonography (U/S) has been proposed as a potential alternative to MRI for the assessment of muscle size. However, to date, no work has explored the utility of U/S to assess disuse muscle atrophy (DMA) across muscles with different atrophy susceptibility profiles, an omission which may limit the clinical application of previous work. Methods To address this significant knowledge gap, 10 young men (22 ± years, 24.1 ± 2.3 kg/m2) underwent 15‐day unilateral leg immobilization using a knee‐brace and air boot. Cross‐sectional area (CSA) and muscle thickness (MT) of the tibialis anterior (TA) and medial gastrocnemius (MG) were assessed via U/S before and after immobilization, with CSA and muscle volume assessed via MRI. Results With both muscles combined, there were good correlations between each U/S and MRI measure, both before (e.g., CSAMRI vs. MTU/S and CSAU/S: r = 0.88 and 0.94, respectively, both P

Abstract In patients with relapsed DLBCL in complete remission (CR), autologous hematopoietic cell transplantation (auto-HCT) and CAR-T therapy are both effective, but it is unknown which modality provides superior outcomes. We compared the efficacy of auto-HCT vs. CAR-T in patients with DLBCL in a CR. A retrospective observational study comparing auto-HCT (2015–2021) vs. CAR-T (2018–2021) using the Center for International Blood & Marrow Transplant Research registry. Median follow-up was 49.7 months for the auto-HCT and 24.7 months for the CAR-T cohort. Patients ages 18 and 75 with a diagnosis of DLBCL were included if they received auto-HCT (n = 281) or commercial CAR-T (n = 79) while in a CR. Patients undergoing auto-HCT with only one prior therapy line and CAR-T patients with a previous history of auto-HCT treatment were excluded. Endpoints included Progression-free survival (PFS), relapse rate, non-relapse mortality (NRM) and overall survival (OS). In univariate analysis, treatment with auto-HCT was associated with a higher rate of 2-year PFS (66.2% vs. 47.8%; p

Resumo Fundamento: As ferramentas de telecardiologia são estratégias valiosas para melhorar a estratificação de risco. Objetivo: Objetivamos avaliar a acurácia da tele-eletrocardiografia (ECG) para predizer anormalidades no ecocardiograma de rastreamento na atenção primária. Métodos: Em 17 meses, 6 profissionais de saúde em 16 unidades de atenção primária foram treinados em protocolos simplificados de ecocardiografia portátil. Tele-ECGs foram registrados para diagnóstico final por um cardiologista. Pacientes consentidos com anormalidades maiores no ECG pelo código de Minnesota e uma amostra 1:5 de indivíduos normais foram submetidos a um questionário clínico e ecocardiograma de rastreamento interpretado remotamente. A doença cardíaca grave foi definida como doença valvular moderada/grave, disfunção/hipertrofia ventricular, derrame pericárdico ou anormalidade da motilidade. A associação entre alterações maiores do ECG e anormalidades ecocardiográficas foi avaliada por regressão logística da seguinte forma: 1) modelo não ajustado; 2) modelo 1 ajustado por idade/sexo; 3) modelo 2 mais fatores de risco (hipertensão/diabetes); 4) modelo 3 mais história de doença cardiovascular (Chagas/cardiopatia reumática/cardiopatia isquêmica/AVC/insuficiência cardíaca). Foram considerados significativos valores de p < 0,05. Resultados: No total, 1.411 pacientes realizaram ecocardiograma, sendo 1.149 (81%) com anormalidades maiores no ECG. A idade mediana foi de 67 anos (intervalo interquartil de 60 a 74) e 51,4% eram do sexo masculino. As anormalidades maiores no ECG se associaram a uma chance 2,4 vezes maior de doença cardíaca grave no ecocardiograma de rastreamento na análise bivariada (OR = 2,42 [IC 95% 1,76 a 3,39]) e permaneceram significativas (p < 0,001) após ajustes no modelo 2 (OR = 2,57 [IC 95% 1,84 a 3,65]), modelo 3 (OR = 2,52 [IC 95% 1,80 a 3,58]) e modelo 4 (OR = 2,23 [IC 95% 1,59 a 3,19]). Idade, sexo masculino, insuficiência cardíaca e doença cardíaca isquêmica também foram preditores independentes de doença cardíaca grave no ecocardiograma. Conclusões: As anormalidades do tele-ECG aumentaram a probabilidade de doença cardíaca grave no ecocardiograma de rastreamento, mesmo após ajustes para variáveis demográficas e clínicas.

Abstract Background Circulating biomarkers of bone formation and resorption are widely used in exercise metabolism research, but their responses to exercise are not clear. This study aimed to quantify group responses and inter-individual variability of P1NP and β-CTX-1 after prolonged, continuous running (60–120 min at 65–75% V̇O2max) in young healthy adult males using individual participant data (IPD) meta-analysis. Methods The protocol was designed following PRISMA-IPD guidelines and was pre-registered on the Open Science Framework prior to implementation ( https://osf.io/y69nd ). Changes in P1NP and β-CTX-1 relative to baseline were measured during, immediately after, and in the hours and days following exercise. Typical hourly and daily variations were estimated from P1NP and β-CTX-1 changes relative to baseline in non-exercise (control) conditions. Group responses and inter-individual variability were quantified with estimates of the mean and standard deviation of the difference, and the proportion of participants exhibiting an increased response. Models were conducted within a Bayesian framework with random intercepts to account for systematic variation across studies. Results P1NP levels increased during and immediately after running, when the proportion of response was close to 100% (75% CrI: 99 to 100%). P1NP levels returned to baseline levels within 1 h and over the next 4 days, showing comparable mean and standard deviation of the difference with typical hourly (0.1 ± 7.6 ng·mL−1) and daily (− 0.4 ± 5.7 ng·mL−1) variation values. β-CTX-1 levels decreased during and up to 4 h after running with distributions comparable to typical hourly variation (− 0.13 ± 0.11 ng·mL−1). There was no evidence of changes in β-CTX-1 levels during the 4 days after the running bout, when distributions were also similar between the running data and typical daily variation (− 0.03 ± 0.10 ng·mL−1). Conclusion Transient increases in P1NP were likely biological artefacts (e.g., connective tissue leakage) and not reflective of bone formation. Comparable small decreases in β-CTX-1 identified in both control and running data, suggested that these changes were due to the markers’ circadian rhythm and not the running intervention. Hence, prolonged continuous treadmill running did not elicit bone responses, as determined by P1NP and β-CTX-1, in this population.

Human health risk assessment is historically built upon animal testing, often following Organisation for Economic Co-operation and Development (OECD) test guidelines and exposure assessments. Using combinations of human relevant in vitro models, chemical analysis and computational (in silico) approaches bring advantages compared to animal studies. These include a greater focus on the human species and on molecular mechanisms and kinetics, identification of Adverse Outcome Pathways and downstream Key Events as well as the possibility of addressing susceptible populations and additional endpoints. Much of the advancement and progress made in the Next Generation Risk Assessment (NGRA) have been primarily focused on new approach methodologies (NAMs) and physiologically based kinetic (PBK) modelling without incorporating human biomonitoring (HBM). The integration of toxicokinetics (TK) and PBK modelling is an essential component of NGRA. PBK models are essential for describing in quantitative terms the TK processes with a focus on the effective dose at the expected target site. Furthermore, the need for PBK models is amplified by the increasing scientific and regulatory interest in aggregate and cumulative exposure as well as interactions of chemicals in mixtures. Since incorporating HBM data strengthens approaches and reduces uncertainties in risk assessment, here we elaborate on the integrated use of TK, PBK modelling and HBM in chemical risk assessment highlighting opportunities as well as challenges and limitations. Examples are provided where HBM and TK/PBK modelling can be used in both exposure assessment and hazard characterization shifting from external exposure and animal dose/response assays to animal-free, internal exposure-based NGRA.

Background American Indians face significant barriers to diagnosis and management of cardiovascular disease. We sought to develop a real‐world implementation model for improving access to echocardiography within the Indian Health Service, the American Indian Structural Heart Disease Partnership. Methods and Results The American Indian Structural Heart Disease Partnership was implemented and evaluated via a 4‐step process of characterizing the system where it would be instituted, building point‐of‐care echocardiography capacity, deploying active case finding for structural heart disease, and evaluating the approach from the perspective of the clinician and patient. Data were collected and analyzed using a parallel convergent mixed methods approach. Twelve health care providers successfully completed training in point‐of‐care echocardiography. While there was perceived usefulness of echocardiography, providers found it difficult to integrate screening point‐of‐care echocardiography into their workday given competing demands. By the end of 12 months, 6 providers continued to actively utilize point‐of‐care echocardiography. Patients who participated in the study felt it was an acceptable and effective approach. They also identified access to transportation as a notable challenge to accessing echocardiograms. Over the 12‐month period, a total of 639 patients were screened, of which 36 (5.6%) had a new clinically significant abnormal finding. Conclusions The American Indian Structural Heart Disease Partnership model exhibited several promising strategies to improve access to screening echocardiography for American Indian populations. However, competing priorities for Indian Health Service providers' time limited the amount of integration of screening echocardiography into outpatient practice. Future endeavors should explore community‐based solutions to develop a more sustainable model with greater impact on case detection, disease management, and improved outcomes.

Abstract The ADP-ribosyltransferase, PARP1 enzymatically generates and applies the post-translational modification, ADP-Ribose (ADPR). PARP1 roles in genome maintenance are well described, but recent work highlights roles in many fundamental processes including cellular identity and energy homeostasis. Herein, we show in both mouse and human skeletal muscle cells that PARP1-mediated PARylation is a regulator of the myogenic program and the muscle transcriptional response to steroid hormones. Chemical PARP1 modulation impacts the expression of major myocellular proteins, including troponins, key in dictating muscle contractile force. Whilst PARP1 in absence of DNA damage is often assumed to be basally inactive, we show PARylation to be acutely sensitive to extracellular glucose concentrations and the steroid hormone class, glucocorticoids which exert considerable authority over muscle tissue mass. Specifically, we find during myogenesis, a transient and significant rise in PAR. This early-stage differentiation event, if blocked with PARP1 inhibition, reduced the abundance of important muscle proteins in the fully differentiated myotubes. This suggests that PAR targets during early-stage differentiation are central to the proper development of the muscle contractile unit. We also show that reduced PARP1 in myoblasts impacts a variety of metabolic pathways in line with the recorded actions of glucocorticoids. Currently, as both regulators of myogenesis and muscle mass loss, glucocorticoids represent a clinical conundrum. Our work goes on to identify that PARP1 influences transcriptional activation by glucocorticoids of a subset of genes critical to human skeletal muscle pathology. These genes may therefore signify a regulatory battery of targets through which selective glucocorticoid modulation could be achieved. Collectively, our data provide clear links between PARP1-mediated PARylation and skeletal muscle homeostatic mechanisms crucial to tissue mass maintenance and endocrine response.

Background: The World Heart Federation (WHF) published the first evidence-based guidelines on the echocardiographic diagnosis of rheumatic heart disease (RHD) in 2012. These guidelines have since been applied internationally in research and clinical practice. Substantial research has assessed the utility of the 2012 WHF criteria, including its applicability in low-resource settings. This article summarises the evidence regarding the performance of the guidelines. Methods: A scoping review assessing the performance of the guidelines was performed. Cochrane, Embase, Medline, PubMed Lilacs, Sielo, and Portal BVS databases were searched for studies on the performance of the guidelines between January 2012–March 2023, and 4047 manuscripts met the search criteria, of which 34 were included. This included papers assessing the specificity, inter-rater reliability, application using hand-carried ultrasound, and modification of the criteria for simplicity. The review followed the PRISMA Extension for Scoping Reviews guideline. Results: The WHF 2012 criteria were 100% specific for definite RHD when applied in low-prevalence populations. The criteria demonstrated substantial and moderate inter-rater reliability for detecting definite and borderline RHD, respectively. The inter-rater reliability for morphological features was lower than for valvular regurgitation. When applied to hand-carried ultrasound performed by an expert, modified versions of the criteria demonstrated a sensitivity and specificity range of 79–90% and 87–93% respectively for detecting any RHD, performing best for definite RHD. The sensitivity and the specificity were reduced when performed in task-sharing but remains moderately accurate. Conclusion: The WHF 2012 criteria provide clear guidance for the echocardiographic diagnosis of RHD that is reproducible and applicable to a range of echocardiographic technology. Furthermore, the criteria are highly specific and particularly accurate for detecting definite RHD. There are limitations in applying all aspects of the criteria in specific settings, including task-sharing. This summary of evidence can inform the updated version of the WHF guidelines to ensure improved applicability in all RHD endemic regions.

Falls and osteoporotic fractures are a major public health problem, particularly among older adults. A third of individuals aged 65 years and over fall at least once each year, with up to 20 % of these resulting in serious injury, including fracture. In conjunction with regular exercise, the importance of diet for musculoskeletal health has largely focused upon calcium, vitamin D, and protein, particularly in the context of preventing falls and fractures. Whilst there is evidence for the benefits of these nutrients for musculoskeletal health, other aspects of the diet remain largely underexplored. For example, vegetables are rich sources of macro- and micronutrients that are essential for muscle function and bone health, which are key factors in the prevention of falls and fractures. Recent work has highlighted the importance of nutrients such as vegetable-derived nitrate and vitamin K1 in optimising muscle strength, physical function, and bone quality. In the context of dietary patterns, vegan/plant-based diets have recently gained popularity due to perceived health benefits, animal welfare, or to tackle climate change. The elimination and/or substitution of animal-based products for plant foods (without careful planning and/or expert dietary guidance) could, however, have long-term negative musculoskeletal consequences; a trend uncovered by recent evidence. Within the overarching theme of nutrition for fall and fracture prevention in older populations, the aim of this review is to (i) summarise the current evidence for calcium, vitamin D and protein; (ii) describe the importance of vegetables and selected nutrients, such as nitrate and vitamin K1, for muscle function and bone structural integrity; and (iii) highlight current evidence around different dietary patterns (e.g., plant-based, diet quality, data driven approaches) and their impact on musculoskeletal health.

Objective: We aim to showcase the impact of applying eight different self-reported and urinary biomarker-based exposure measures for glyphosate and mancozeb on the association with sleep problems in a study among 253 smallholder farmers in Uganda. Methods: The questionnaire-based exposure measures included: (1) the number of application days of any pesticide in the last 7 days (never, 1–2; >2 days) and six glyphosate and mancozeb-specific measures: (2) application status over the last 12 months (yes/no), (3) recent application status (never, last 7 days and last 12 months), (4) the number of application days last 12 months, (5) average exposure-intensity scores (EIS) and (6) EIS-weighted number of application days in last 12 months. Based on 384 repeated urinary biomarker concentrations of ethylene thiourea (ETU) and glyphosate from 84 farmers, we also estimated (7) average biomarker concentrations for all 253 farmers. Also in the 84 farmers the measured pre-work and post-work biomarker concentrations were used (8). Multivariable logistic regression models were used to assess the association between the exposure measures and selected Medical Outcomes Study Sleep Scale (MOS-SS) indices (6-item, sleep inadequacy and snoring). Results: We observed positive associations between (1) any pesticide application in the last 7 days with all three MOS-SS indices. Glyphosate application in the last 7 days (3) and mancozeb application in the last 12 months (3) were associated with the 6-item sleep problem index. The estimated average urinary glyphosate concentrations showed an exposure–response association with the 6-item sleep problem index and sleep inadequacy in the same direction as based on self-reported glyphosate application in the last 7 days. In the analysis with the subset of 84 farmers, both measured and modelled post-work urinary glyphosate concentration showed an association with snoring. Conclusions: Self-reported, estimated average biomarker concentrations and measured urinary biomarker exposure measures of glyphosate and mancozeb showed similar exposure–response associations with sleep outcomes.

The idiom ‘more high-quality research is needed’ has become the slogan for sport and exercise physiology-based research in female athletes. However, in most instances, it is challenging to address this gap of high-quality research in elite female athletes at a single study site due to challenges in recruiting enough participants with numerous menstrual cycle and contraceptive pill permutations. Accordingly, we have assembled an international multisite team to undertake an innovative project for female athletes, which investigates the effects of changes in endogenous and exogenous oestrogen and progesterone/progestins across the menstrual cycle and in response to second-generation combined monophasic contraceptive pill use, on aspects of exercise physiology and athletic performance. This project will employ the current gold-standard methodologies in this area, resulting in an adequately powered dataset. This protocol paper describes the consortium-based approach we will undertake during this study.

Introduction Rheumatic heart disease (RHD) affects over 39 million people worldwide, the majority in low-income and middle-income countries. Secondary antibiotic prophylaxis (SAP), given every 3–4 weeks can improve outcomes, provided more than 80% of doses are received. Poor adherence is strongly correlated with the distance travelled to receive prophylaxis. Decentralising RHD care has the potential to bridge these gaps and at least maintain or potentially increase RHD prophylaxis uptake. A package of implementation strategies was developed with the aim of reducing barriers to optimum SAP uptake.Methods and analysis A hybrid implementation-effectiveness study type III was designed to evaluate the effectiveness of a package of implementation strategies including a digital, cloud-based application to support decentralised RHD care, integrated into the public healthcare system in Uganda. Our overarching hypothesis is that secondary prophylaxis adherence can be maintained or improved via a decentralisation strategy, compared with the centralised delivery strategy, by increasing retention in care. To evaluate this, eligible patients with RHD irrespective of their age enrolled at Lira and Gulu hospital registry sites will be consented for decentralised care at their nearest participating health centre. We estimated a sample size of 150–200 registrants. The primary outcome will be adherence to secondary prophylaxis while detailed implementation measures will be collected to understand barriers and facilitators to decentralisation, digital application tool adoption and ultimately its use and scale-up in the public healthcare system.Ethics and dissemination This study was approved by the Institutional Review Board (IRB) at Cincinnati Children’s Hospital Medical Center (IRB 2021-0160) and Makerere University School of Medicine Research Ethics Committee (Mak-SOMREC-2021-61). Participation will be voluntary and informed consent or assent (>8 but

Abstract Background Given the increased occurrence of pre‐gravid obesity in recent years, and the implications of maternal obesity for maternal and offspring health, it is evident that there is a continued need to investigate antenatal and postnatal weight management strategies and to provide evidence‐based advice for exercise‐based interventions. Given the small number of studies (n = 5) included in an original systematic review by our group in 2015, it was important to add to the dataset by assessing data published since 2015, in order to provide a more in‐depth view of current knowledge. Objective To provide an updated systematic review on studies employing exercise interventions for weight management in pregnant and postpartum women. Methods A systematic review of randomised controlled trials evaluating the effects of an exercise intervention on gestational weight gain and postpartum weight management in normal weight women, and women with overweight and obesity was conducted. PubMed, Scopus, Central Register of Controlled Trials and Web of Science were searched for studies published between September 2013 and June 2021. No restrictions were set on type, intensity, duration, or frequency of exercise intervention. Only studies that targeted body weight or mass as a primary outcome were included. Results Thirteen studies were included in this review: 11 during and two following pregnancy. Exercise significantly reduced gestational weight gain in five of the pregnancy studies and induced significant weight loss in one of the postpartum studies. Across studies, there were large disparities in exercise modality, frequency, and duration, although moderate intensity exercise was consistently employed. Conclusions Some studies showed positive effects of exercise on weight management during and following pregnancy. While there is still no consensus on effective exercise intervention approaches, it is crucial that physical activity, of any safe form, is recommended to encourage healthy weight management during this time.

Introduction: Handheld echocardiography (echo) is the tool of choice for rheumatic heart disease (RHD) screening. We aimed to assess the agreement between screening and standard echo for latent RHD diagnosis in schoolchildren from an endemic setting. Methods: Over 14 months, 3 nonphysicians used handheld machines and the 2012 WHF Criteria to determine RHD prevalence in consented schoolchildren from Brazilian low-income public schools. Studies were interpreted by telemedicine by 3 experts (Brazil, US). RHD-positive children (borderline/definite) and those with congenital heart disease (CHD) were referred for standard echo, acquired and interpreted by a cardiologist. Agreement between screening and standard echo, by WHF subgroups, was assessed. Results: 1390 students were screened in 6 schools, with 110 (7.9%, 95% CI 6.5–9.5) being screen positive (14 ± 2 years, 72% women). Among 16 cases initially diagnosed as definite RHD, 11 (69%) were confirmed, 4 (25%) reclassified to borderline, and 1 to normal. Among 79 cases flagged as borderline RHD, 19 (24%) were confirmed, 50 (63%) reclassified to normal, 8 (10%) reclassified as definite RHD, and 2 had mild CHD. Considering the 4 diagnostic categories, kappa was 0.18. In patients with borderline RHD reclassified to non-RHD, the most frequent WHF criterion was B (isolated mitral regurgitation, 64%), followed by A (2 mitral valve morphological features, 31%). In 1 patient with definite RHD reclassified to normal, the WHF criterion was D (borderline RHD in aortic and mitral valves). After standard echo, RHD prevalence was 3.2% (95% CI 2.3–4.2). Conclusions: Although practical, RHD screening with handheld devices tends to overestimate prevalence.

We report Atacama Large Millimeter/submillimeter Array and Atacama Compact Array observations of atomic carbon ([C i ](1–0)) and dust continuum in 10 enormous Ly α nebulae hosting ultraluminous Type-I QSOs at z = 2.2–2.5, as part of the Survey of Protocluster ELANe Revealing CO/C i in the Ly α Detected CGM. We detect [C i ](1–0) and dust in all 10 QSOs and five companion galaxies. We find that the QSOs and companions have higher gas densities and more intense radiation fields than Luminous Infrared galaxies and high- z main sequence galaxies, with the highest values found in the QSOs. By comparing molecular gas masses derived from [C i ](1–0), CO(4−3), and dust continuum, we find that the QSOs and companions display a similar low CO conversion factor of α _CO ∼ 0.8 M _☉ ${[{\rm{K}}\,\mathrm{km}\,{{\rm{s}}}^{-1}\,{\mathrm{pc}}^{2}]}^{-1}$ . After tapering our data to low resolution, the [C i ](1–0) flux increases for nine QSOs, hinting at the possibility of [C i ](1–0) in the circumgalactic medium (CGM) on a scale of 16−40 kpc. However, the [C i ](1–0) sensitivity is too low to confirm this for individual targets, except for a tentative (2.7 σ ) CGM detection in Q0050+0051 with ${{M}}_{{{\rm{H}}}_{2}}$ = (1.0–2.8) × 10 ^10 M _☉ . The 3 σ mass limits of molecular CGM for the remaining QSO fields are (0.2–1.4) × 10 ^10 M _☉ . This translates into a baryon fraction of

We present continuum observations from the Atacama Large Millimeter/submillimeter Array of 10 high-redshift (2.2 ≤ z ≤ 2.7) ultraluminous quasars (QSOs) and constrain the presence of hot, ionized, circumgalactic gas in a stacking analysis. We measure a Compton- y parameter profile with a peak value of (1.7 ± 1.1) × 10 ^−6 at a radius of ∼50 kpc. We compare our stacked observations to active galactic nucleus feedback wind models and generalized Navarro–Frenk–White pressure profile models to constrain the wind luminosity and halo mass of the stacked QSOs. Our observations constrain the observed average halo mass to M _500 < 1 × 10 ^13 M _⊙ and the average feedback wind power

Venous thromboembolism (VTE) is a serious complication commonly experienced in cancer patients. Incidence of VTE typically brings poor prognosis as it represents the second most common cause of mortality in cancer patients just after the malignancy itself. Studies suggest that multiple myeloma (MM) is among the malignancies with further enhanced risk of VTE, especially in patients undergoing autologous hematopoietic cell transplantation (AHCT). However, risk factors and preventative approaches remain poorly explored. Here, we explore the incidence of VTE in MM patients undergoing AHCT, while also highlighting risk factors and preventions that may aid in preventing VTE in patients who are at higher risk.

The environmental impact on health is an inevitable by-product of human activity. Environmental health sciences is a multidisciplinary field addressing complex issues on how people are exposed to hazardous chemicals that can potentially affect adversely the health of present and future generations. Exposure sciences and environmental epidemiology are becoming increasingly data-driven and their efficiency and effectiveness can significantly improve by implementing the FAIR (findable, accessible, interoperable, reusable) principles for scientific data management and stewardship. This will enable data integration, interoperability and (re)use while also facilitating the use of new and powerful analytical tools such as artificial intelligence and machine learning in the benefit of public health policy, and research, development and innovation (RDI). Early research planning is critical to ensuring data is FAIR at the outset. This entails a well-informed and planned strategy concerning the identification of appropriate data and metadata to be gathered, along with established procedures for their collection, documentation, and management. Furthermore, suitable approaches must be implemented to evaluate and ensure the quality of the data. Therefore, the ‘Europe Regional Chapter of the International Society of Exposure Science’ (ISES Europe) human biomonitoring working group (ISES Europe HBM WG) proposes the development of a FAIR Environment and health registry (FAIREHR) (hereafter FAIREHR). FAIR Environment and health registry offers preregistration of studies on exposure sciences and environmental epidemiology using HBM (as a starting point) across all areas of environmental and occupational health globally. The registry is proposed to receive a dedicated web-based interface, to be electronically searchable and to be available to all relevant data providers, users and stakeholders. Planned Human biomonitoring studies would ideally be registered before formal recruitment of study participants. The resulting FAIREHR would contain public records of metadata such as study design, data management, an audit trail of major changes to planned methods, details of when the study will be completed, and links to resulting publications and data repositories when provided by the authors. The FAIREHR would function as an integrated platform designed to cater to the needs of scientists, companies, publishers, and policymakers by providing user-friendly features. The implementation of FAIREHR is expected to yield significant benefits in terms of enabling more effective utilization of human biomonitoring (HBM) data.

This study examined the relationship between training load and changes in body composition and bone characteristics across a competitive season. Twenty senior male professional football players participated in this prospective longitudinal study. Participants underwent dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) scans on four occasions across the study period, resulting in three phases of the season. Phase 1 (Scan 1-Scan 2: 6-weeks: pre-season), Phase 2 (Scan 2-Scan 3: 24-weeks: first part of the season), and Phase 3 (Scan 3-Scan 4: 13-weeks: second part of the season). External training load was quantified using GPS devices. In Phase 1 there was a significant increase (mean ± SE) in lean mass (from 66.0 ± 1.4 to 67.8 ± 1.4 kg) and a significant decrease in fat mass (from 11.5 ± 0.6 to 10.4 ± 0.6 kg). In Phase 2 there were significant increases in whole-body BMD (from 1.41 ± 0.02 to 1.43 ± 0.02 g/cm2), leg (from 1563 ± 43 to 1572 ± 43 g) and whole-body BMC (from 3807 ± 100 to 3860 ± 100 g), tibial mass (14 % site) (from 3.72 ± 0.08 to 3.74 ± 0.08 g), tibial strength (SSI(POL)14 % site) (from 2331 ± 78 to 2378 ± 78 mm3), and tibial density (4 % site) (from 382 ± 8 to 388 ± 8 mm3). In Phase 3, there was a significant decrease in tibial mass (14 % site) (from 3.74 ± 0.08 to 3.72 ± 0.08 g). Bootstrapped (BCa 95 % CI) Pearson correlations showed that in Phase 2 there were significant positive relationships between the increases in leg BMC and total distance (r = 0.44, 0.01–0.80), accelerations (r = 0.45, 0.08–0.75), and decelerations (r = 0.49, 0.07–0.83), and between the increase in tibial strength (SSI(POL)14 % site) and accelerations (r = 0.53, 0.19–0.80). High magnitude dynamic actions, such as accelerations and decelerations were positively correlated with changes in bone characteristics during a professional football season and should be considered by practitioners when prescribing exercise to induce bone adaptation.

IntroductionThere is limited information regarding the association between external load and estimated bone load in sport, which may be important due to the influence exercise can have on bone accrual and injury risk. The aim of this study was to identify external load measuring tools used by support staff to estimate bone load and assess if these methodologies were supported in research.MethodsA survey was comprised of 19 multiple choice questions and the option to elaborate on if/how they monitor external load and if/how they used them to estimate bone load. A narrative review was performed to assess how external load is associated to bone in research.ResultsParticipants were required to be working as support staff in applied sport. Support staff (n = 71) were recruited worldwide with the majority (85%) working with professional elite athletes. 92% of support staff monitored external load in their organisation, but only 28% used it to estimate bone load.DiscussionGPS is the most commonly used method to estimate bone load, but there is a lack of research assessing GPS metrics with bone load. Accelerometry and force plates were among the most prevalent methods used to assess external load, but a lack of bone specific measurements were reported by support staff. Further research exploring how external load relates to bone is needed as there is no consensus on which method of external load is best to estimate bone load in an applied setting.

The American Heart Association's Strategically Focused Children's Research Network started in July 2017 with 4 unique programs at Children's National Hospital in Washington, DC; Duke University in Durham, North Carolina; University of Utah in Salt Lake City, Utah; and Lurie Children's Hospital/Northwestern University in Chicago, Illinois. The overarching goal of the Children's National center was to develop evidence‐based strategies to strengthen the health system response to rheumatic heart disease through synergistic basic, clinical, and population science research. The overall goals of the Duke center were to determine risk factors for obesity and response to treatment including those that might work on a larger scale in communities across the country. The integrating theme of the Utah center focused on leveraging big data‐science approaches to improve the quality of care and outcomes for children with congenital heart defects, within the context of the patient and their family. The overarching hypothesis of the Northwestern center is that the early course of change in cardiovascular health, from birth onward, reflects factors that result in either subsequent development of cardiovascular risk or preservation of lifetime favorable cardiovascular health. All 4 centers exceeded the original goals of research productivity, fellow training, and collaboration. This article describes details of these accomplishments and highlights challenges, especially around the COVID‐19 pandemic.

Background: Chronic valvular heart disease is a well-known, long-term complication of acute rheumatic fever (ARF), which remains a major public health problem in low- and middle-income countries. Access to surgical management remains limited. Outcomes of the minority proportion of patients that access surgery have not been described in Uganda. Objectives: To describe the volume and type of rheumatic heart disease (RHD) valvular interventions and the outcomes of operated patients in the Uganda RHD registry. Methods: We performed a retrospective cohort study of all valve surgery procedures identified in the Uganda RHD registry through December 2021. Results: Three hundred and sixty-seven surgical procedures were performed among 359 patients. More than half were among young (55.9% were ≤20 years of age), female (59.9%) patients. All patients were censored at 15 years. The median (IQR) follow up period was 43 (22,79) months. Nearly half of surgeries (46.9%) included interventions on multiple valves, and most valvular operations were replacements with mechanical prostheses (96.6%). Over 70% of the procedures were sponsored by charity organizations. The overall mortality of patients who underwent surgery was 13% (47/359), with over half of the mortalities occurring within the first year following surgery (27/47; 57.4%). Fifteen-year survival or freedom from re-operation was not significantly different between those receiving valve replacements and those receiving valve repair (log-rank p = 0.76). Conclusions: There has been increasing access to valve surgery among Ugandan patients with RHD. Post-operative survival is similar to regionally reported rates. The growing cohort of patients living with prosthetic valves necessitates national expansion and decentralization of post-operative care services. Major reliance on charity funding of surgery is unsustainable, thus calling for locally generated and controlled support mechanisms such as a national health insurance scheme. The central illustration (Figure 1) provides a summary of our findings and recommendations.

Introduction: A physiologically based biokinetic model for di (2-ethylhexyl) adipate (DEHA) based on a refined model for di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the metabolism and biokinetics of DEHA following a single oral dosage of 50 mg to two male and two female volunteers.Methods: The model was parameterized using in vitro and in silico methods such as, measured intrinsic hepatic clearance scaled from in vitro to in vivo and algorithmically predicted parameters such as plasma unbound fraction and tissue:blood partition coefficients (PCs). Calibration of the DEHA model was achieved using concentrations of specific downstream metabolites of DEHA excreted in urine. The total fractions of ingested DEHA eliminated as specific metabolites were estimated and were sufficient for interpreting the human biomonitoring data.Results: The specific metabolites of DEHA, mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA) only accounted for ∼0.45% of the ingested DEHA. Importantly, the measurements of adipic acid, a non-specific metabolite of DEHA, proved to be important in model calibration.Discussion: The very prominent trends in the urinary excretion of the metabolites, 5cx-MEPA and 5OH-MEHA allowed the important absorption mechanisms of DEHA to be modelled. The model should be useful for the study of exposure to DEHA of the general human population.

A physiologically based pharmacokinetic model for di-(2-ethylhexyl) terephthalate (DEHTP) based on a refined model for di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the metabolism and biokinetics of DEHTP following a single oral dose of 50 mg to three male volunteers. In vitro and in silico methods were used to generate parameters for the model. For example, measured intrinsic hepatic clearance scaled from in vitro to in vivo and plasma unbound fraction and tissue:blood partition coefficients (PCs) were predicted algorithmically. Whereas the development and calibration of the DPHP model was based upon two data streams, blood concentrations of parent chemical and first metabolite and the urinary excretion of metabolites, the model for DEHTP was calibrated against a single data stream, the urinary excretion of metabolites. Despite the model form and structure being identical significant quantitative differences in lymphatic uptake between the models were observed. In contrast to DPHP the fraction of ingested DEHTP entering lymphatic circulation was much greater and of a similar magnitude to that entering the liver with evidence for the dual uptake mechanisms discernible in the urinary excretion data. Further, the absolute amounts absorbed by the study participants, were much higher for DEHTP relative to DPHP. The in silico algorithm for predicting protein binding performed poorly with an error of more than two orders of magnitude. The extent of plasma protein binding has important implications for the persistence of parent chemical in venous blood—inferences on the behaviour of this class of highly lipophilic chemicals, based on calculations of chemical properties, should be made with extreme caution. Attempting read across for this class of highly lipophilic chemicals should be undertaken with caution since basic adjustments to PCs and metabolism parameters would be insufficient, even when the structure of the model itself is appropriate. Therefore, validation of a model parameterized entirely with in vitro and in silico derived parameters would need to be calibrated against several human biomonitoring data streams to constitute a data rich source chemical to afford confidence for future evaluations of other similar chemicals using the read-across approach.

Type 2 diabetes is a disease characterized by dysregulation of glucose homeostasis, with numerous diabetic complications attributable to the resulting chronic exposure of cells and tissues to elevated concentrations of glucose and fatty acids. This in part results from formation of advanced glycation end-products and advanced lipidation end-products that can form adducts with proteins, lipids, or DNA and disrupt their normal cellular function. There is, however, growing evidence that supplementation with the endogenous histidine-containing dipeptide, carnosine, or its rate-limiting precursor, β-alanine, can ameliorate aspects of metabolic dysregulation that occur in diabetes and related conditions. Here we investigated the scavenging potential of β-alanine in INS-1 pancreatic β-cells and C2C12 skeletal muscle myotubes, and show a significant reduction of >60% in reactive species that were generated by glucolipotoxic metabolic stress in both cell types following incubation with β-alanine for 5 days. Furthermore, β-alanine supplementation resulted in a protective action that helped prevent the damaging action of metabolic stress that otherwise leads to inhibition of mitochondrial function in both cell types. This in turn resulted in >60% preservation of insulin secretion and glucose uptake, in INS-1 cells and C2C12 cells respectively, which would otherwise be inhibited by metabolic stress. This suggests potential therapeutic benefit to taking β-alanine supplements as an alternative to carnosine.

With the US Food and Drug Administration (FDA) approval of four CD19- and one BCMA-targeted chimeric antigen receptor (CAR) therapy for B cell malignancies, CAR T cell therapy has finally reached the status of a medicinal product. The successful manufacturing of autologous CAR T cell products is a key requirement for this promising treatment modality. By analyzing the composition of 214 apheresis products from 210 subjects across eight disease indications, we found that high CD14+ cell content poses a challenge for manufacturing CAR T cells, especially in patients with non-Hodgkin’s lymphoma and multiple myeloma caused by the non-specific phagocytosis of the magnetic beads used to activate CD3+ T cells. We demonstrated that monocyte depletion via rapid plastic surface adhesion significantly reduces the CD14+ monocyte content in the apheresis products and simultaneously boosts the CD3+ content. We established a 40% CD14+ threshold for the stratification of apheresis products across nine clinical trials and demonstrated the effectiveness of this procedure by comparing manufacturing runs in two phase 1 clinical trials. Our study suggests that CD14+ content should be monitored in apheresis products, and that the manufacturing of CAR T cells should incorporate a step that lessens the CD14+ cell content in apheresis products containing more than 40% to maximize the production success.

Background Screening programmes using echocardiography offer opportunity for intervention through identification and treatment of early (latent) rheumatic heart disease (RHD). We aimed to compare two methods for classifying progression or regression of latent RHD: serial review method and blinded, side-by-side review.Methods A four-member expert panel reviewed 799 enrolment (in 2018) and completion (in 2020) echocardiograms from the GOAL Trial of latent RHD in Uganda to make consensus determination of normal, borderline RHD or definite RHD. Serial interpretations (enrolment and completion echocardiograms read at two different time points, 2 years apart, not beside one another) were compared with blinded side-by-side comparisons (enrolment and completion echocardiograms displayed beside one another in random order on same screen) to determine outcomes according to prespecified definitions of disease progression (worsening), regression (improving) or no change. We calculated inter-rater agreement using Cohen’s kappa.Results There were 799 pairs of echocardiogram assessments included. A higher number, 54 vs 38 (6.8% vs 4.5%), were deemed as progression by serial interpretation compared with side-by-side comparison. There was good inter-rater agreement between the serial interpretation and side-by-side comparison methods (kappa 0.89). Disagreement was most often a result of the difference in classification between borderline RHD and mild definite RHD. Most discrepancies between interpretation methods (46 of 47, 98%) resulted from differences in valvular morphological evaluation, with valves judged to be morphologically similar between enrolment and final echocardiograms when compared side by side but classified differently on serial interpretation.Conclusions There was good agreement between the methods of serial and side-by-side interpretation of echocardiograms for change over time, using the World Heart Federation criteria. Side-by-side interpretation has higher specificity for change, with fewer differences in the interpretation of valvular morphology, as compared with serial interpretation.

This paper aims to clarify a point of persistent confusion in the literature: namely, the status of residual verb second. We approach this from both a terminological and typological perspective. Terminologically, traditional usage of residual V2 in the literature has conflated two different senses (one formal, and one historical); we argue that it is essential to keep these two senses separate. We propose a distinction between partial V2 and residual V2 within the general typology of verb second. Following a formal definition of V2 from the recent literature, we define partial-V2 systems as involving genuine instances of V2 that are limited to nondeclarative environments in a given language (e.g. English). By contrast, we (re)define residual V2 as describing purely vestigial structures that do not qualify as formally V2 in the synchronic grammar of a given language, despite their historical origins in an earlier stage in which the language had true V2. In this respect, almost all modern Romance languages provide clear examples of residual V2: the syntax of these languages is only historically related to V2, with all formal traces of V2 having been long lost, even in nondeclaratives. With these clarifications in place, we propose an updated typology of V2 systems, conceiving of it as a spectrum of degrees from partial V2 through strict V2 (as measured by the set of formally-V2 environments that a given language allows).

Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR T failure. The median number of lines of therapy between CAR T infusion and alloHCT was one (range, 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range, 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis,

We examined the relationship between football-specific training and changes in bone structural properties across a 12-week period in 15 male football players aged 16 years (Mean ± 1 SD = 16.6 ± 0.3 years) that belonged to a professional football academy. Tibial scans were performed at 4%, 14% and 38% sites using peripheral quantitative computed tomography immediately before and 12 weeks after increased football-specific training. Training was analysed using GPS to quantify peak speed, average speed, total distance and high-speed distance. Analyses were conducted with bias-corrected and accelerated bootstrapped 95% confidence intervals (BCa 95% CI). There were increases in bone mass at the 4% (mean ∆ = 0.15 g, BCa 95% CI = 0.07, 0.26 g, g = 0.72), 14% (mean ∆ = 0.04 g, BCa 95% CI = 0.02, 0.06 g, g = 1.20), and 38% sites (mean ∆ = 0.03 g, BCa 95% CI = 0.01, 0.05 g, g = 0.61). There were increases in trabecular density (4%), (mean ∆ = 3.57 mg·cm−3, BCa 95% CI = 0.38, 7.05 mg·cm−3, g = 0.53), cortical dentsity (14%) (mean ∆ = 5.08 mg·cm−3, BCa 95% CI = 0.19, 9.92 mg·cm−3, g = 0.49), and cortical density (38%) (mean ∆ = 6.32 mg·cm−3, BCa 95% CI = 4.31, 8.90 mg·cm−3, g = 1.22). Polar stress strain index (mean ∆ = 50.56 mm3, BCa 95% CI = 10.52, 109.95 mm3, g = 0.41), cortical area (mean ∆ = 2.12 mm2, BCa 95% CI = 0.09, 4.37 mm2, g = 0.48) and thickness (mean ∆ = 0.06 mm, BCa 95% CI = 0.01, 0.13 mm, g = 0.45) increased at the 38% site. Correlations revealed positive relationships between total distance and increased cortical density (38%) (r = 0.39, BCa 95% CI = 0.02, 0.66), and between peak speed and increased trabecular density (4%) (r = 0.43, BCa 95% CI = 0.03, 0.73). There were negative correlations between total (r = −0.21, BCa 95% CI = −0.65, −0.12) and high-speed distance (r = −0.29, BCa 95% CI = −0.57, −0.24) with increased polar stress strain index (38%). Results suggest that despite football training relating to increases in bone characteristics in male academy footballers, the specific training variables promoting adaptation over a 12-week period may vary. Further studies conducted over a longer period are required to fully elucidate the time-course of how certain football-specific training characteristics influence bone structural properties.

BackgroundPostpartum women are at an increased risk of pelvic floor dysfunction, musculoskeletal injury, and poor psychological health and have reduced physical fitness compared to before pregnancy. There is no formal, evidence-based rehabilitation and physical development program for returning UK servicewomen to work following childbirth. ObjectiveThis study aims to examine the efficacy of a rehabilitation and physical development intervention for returning postpartum UK servicewomen to occupational fitness. MethodsEligible servicewomen will be assigned to a training or control group in a nonrandomized controlled trial 6 weeks after childbirth. Group allocation will be based on the location of standard pregnancy and postpartum care. The control group will receive standard care, with no prescribed intervention. The training group will start an 18-week core and pelvic health rehabilitation program 6 weeks post partum and a 12-week resistance and high-intensity interval training program 12 weeks post partum. All participants will attend 4 testing sessions at 6, 12, 18, and 24 weeks post partum for the assessment of occupational physical performance, pelvic health, psychological well-being, quality of life, and musculoskeletal health outcomes. Occupational physical performance tests will include vertical jump, mid-thigh pull, seated medicine ball throw, and a timed 2-km run. Pelvic health tests will include the Pelvic Organ Prolapse Quantification system, the PERFECT (power, endurance, repetitions, fast, every contraction timed) scheme for pelvic floor strength, musculoskeletal physiotherapy assessment, the Pelvic Floor Distress Inventory–20 questionnaire, and the International Consultation on Incontinence Questionnaire–Vaginal Symptoms. Psychological well-being and quality of life tests will include the World Health Organization Quality of Life questionnaire and the Edinburgh Postnatal Depression Scale. Musculoskeletal health outcomes will include body composition; whole-body areal bone mineral density; tibial volumetric bone mineral density, geometry, and microarchitecture; patella tendon properties; muscle architecture; muscle protein and collagen turnover; and muscle mass and muscle breakdown. Data will be analyzed using linear mixed-effects models, with participants included as random effects, and group and time as fixed effects to assess within- and between-group differences over time. ResultsThis study received ethical approval in April 2019 and recruitment started in July 2019. The study was paused in March 2020 owing to the COVID-19 pandemic. Recruitment restarted in May 2021. The results are expected in September 2022. ConclusionsThis study will inform the best practice for the safe and optimal return of postpartum servicewomen to physically and mentally demanding jobs. Trial RegistrationClinicalTrials.gov NCT04332757; https://clinicaltrials.gov/ct2/show/NCT04332757 International Registered Report Identifier (IRRID)DERR1-10.2196/32315

Abstract Background Diabetes is a major public health issue and there is a need to develop low-cost, novel interventions to prevent or reduce disease progression. Growing evidence shows that supplementation with carnosine, or its rate-limiting precursor β-alanine, can ameliorate aspects of the metabolic dysregulation that occurs in diabetes. There is, however, a need to develop a better understanding of the magnitude of effect and the factors associated with positive outcomes. The purpose of this systematic review and meta-analysis is to evaluate the effect of carnosine or β-alanine supplementation on markers of glycaemic control and insulin resistance in humans and animals. Methods We will perform a systematic search for randomised and non-randomised controlled trials. Studies will be retrieved by searching electronic databases, clinical trial registers, author review, and cross-referencing. Primary outcomes include changes in (i) fasting glucose, (ii) glycated haemoglobin, and (iii) 2-h glucose following a glucose tolerance test. A set of additional outcomes includes other markers of glycaemic control and insulin resistance. Risk of bias (RoB) will be assessed using the Cochrane RoB 2.0 tool (human studies) and the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) RoB tool (animal studies). Confidence in the cumulative evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. All meta-analyses will be conducted within a Bayesian framework, providing a flexible modelling approach to account for uncertainty in model parameters and underlying structures within the data. Discussion By including all available human and animal data, we will provide the most comprehensive overview on the topic to date. The results will have implications for those working in prediabetes, diabetes, and metabolic health in general and may lead to the development of new treatment approaches. Dissemination Study results will be presented at a professional conference and published in a peer-reviewed journal. Systematic review registration CRD42020191588

Abstract Background Pre-existing maternal cardiac disease is a significant contributor to adverse maternal, fetal, and neonatal outcomes. In 2015–2017, our team conducted the first community-based study of maternal rheumatic heart disease (RHD) in sub-Saharan Africa and identified RHD in 88% of those with pre-existing heart disease. Here we conducted a follow up investigation of women previously identified with RHD, describing clinical and echocardiographic outcomes, identifying barriers to medical adherence and evaluating the personal impact of RHD. Methods A 2 week prospective follow up was completed at sites in Central and Eastern Uganda. Participants underwent a three-step mixed methods study comprising of 1) direct structured interview targeting clinical history and medication adherence, 2) echocardiogram to evaluate left-sided heart valves, and 3) semi-structured guideline interview to elicit personal impacts of RHD. Results The team evaluated 40 (80%) of the original 51 mothers with RHD at a median post-partum time of 2.5 years after delivery (IQR 0.5). Echocardiographic data showed improvement in nine women with the remaining 31 women showing stable echocardiographic findings. Adherence to Benzathine penicillin G (BPG) prophylaxis was poor, with 70% of patients either poorly adherent or non-adherent. Three major themes emerged from interviews: 1) social determinants of health (World Health Organization, Social determinants of health, 2019) negatively affecting healthcare, 2) RHD diagnosis negatively affecting female societal wellbeing, 3) central role of spouse in medical decision making. Conclusions Screening echocardiography can identify women with pre-existing rheumatic heart disease during pregnancy, but long-term follow-up in Uganda reveals adherence to medical care following diagnosis, including BPG, is poor. Additionally, mothers diagnosed with RHD may experience unintended consequences such as social stigmatization. As identification of occult RHD is critical to prevent adverse pregnancy outcomes, further research is needed to determine how to best support women who face a new diagnosis of RHD, and to determine the role of screening echocardiography in high-risk settings.

This collection of eight orginal poems of the Pacific Islands focus on the theme "Environmental artistic practices and indigeneity: In(ter)ventions, recycling, sovereignty". The first group of three poems, "Age of Plastic," "Rings of Fire," and "Halloween in the Anthropocene" address issues of climate change, waste, and capitalist exploitation. The second group of three poems, "Chanting the Waters," "One Fish, Two Fish," and "Praise Song for Oceania" address issues of water and the ocean from an indigenous Pacific perspective. The final group of two poems, "Family Trees," and "Tronkon Niyok (Coconut Tree)" address issues of militarization and its impact on Guam's trees.

Objectives: Group A β-hemolytic Streptococcus (GAS), also known as Streptococcus pyogenes, is responsible for an annual 600 million cases of acute pharyngitis globally, with 92% of those infections occurring in low-resource settings. Further knowledge of the acute streptococcal pharyngitis burden in low-resource settings is essential if serious post-streptococcal complications – rheumatic fever (RF) and its long-term sequel rheumatic heart disease (RHD) – are to be prevented. Methods: Two studies were conducted in school-aged children (5–16 years): a cross-sectional study of streptococcal pharyngeal carriage followed by a prospective cohort study of streptococcal sore throat over 4 weeks from March to April 2017. Results: The cross-sectional study revealed an overall prevalence of GAS carriage of 15.9% (79/496, 95% confidence interval 12.8–19.5%). Among 532 children enrolled in the prospective cohort study, 358 (67%) reported 528 sore throats, with 221 (41.1%) experiencing at least one GAS-positive sore throat. The overall GAS-positive rate for sore throat was 41.8% (221/528). Conclusions: The GAS pharyngeal carriage rates seen in Uganda (15.9%, 95% confidence interval 12.8–19.5%) are higher than the most recent pooled results globally, at 12% (range 6–28%). Additionally, pilot data suggest a substantially higher percentage of sore throat that was GAS-positive (41.8%) compared to pooled global rates when active recruitment is employed. Keywords: Group A β-hemolytic Streptococcus, Uganda, Rheumatic fever, Rheumatic heart disease

Aims: The aim of this publication is to explore occupational exposure trends from biological monitoring data collected over a period of more than 20 years. The data is stored within the HSE database, which holds more than 950,000 results from 120,000 workers in 8,000 companies. The data were collated for all biological monitoring results for lead, mercury, benzene, and hexamethylene diisocyanate exposures where there have been some regulatory drivers within the reported time period of the data searched.Methods: Relevant results from sample analysed were extracted from the database and categorised by year from 1996 to the end of 2019 for individual blood lead results and individual urine results for mercury, benzene, and hexamethylene diisocyanate. Results were classed by broad occupational sector where possible. Data were reported graphically by analytical biomarker result (as 90th percentile (P90)) and number of samples per year as well as with overall summary statistics. To look at longer-term trends, results were also evaluated as P90 over 6-year periods.Results: In the period 1996–2019, 37,474 blood lead, 11,723 urinary mercury, 9,188 urinary S-phenylmercapturic acid (SPMA, benzene metabolite) and 21,955 urinary hexamethylene diamine (HDA, metabolite of hexamethylene diisocyanate, HDI) samples were analysed and reported. Over the time period the blood lead concentrations saw the P90 reduce from 53 μg/dl 1996) to 24 μg/dl in 2019; the P90 urinary mercury levels reduced from 13.7 μmol/mol creatinine to 2.1 μmol/mol creatinine and the P90 urinary SPMA levels reduced from 133.7 μmol/mol creatinine to 1.7 μmol/mol creatinine. For HDI the P90 results reduced from 2 µmol HDA/mol creatinine in 1996–2000 to 0.7 in 2005–2010 but levels have since increased to 1.0 µmol HDA/mol creatinine (2016–2019).Conclusion: There is strong evidence of reductions in exposure of GB workers to lead, benzene and mercury from the data presented here. These reductions may reflect the impact of national, regional and global regulatory action to reduce exposures however, the loss of high exposure industries (from either GB as a whole or just this dataset i.e., samples are being sent elsewhere) and the increase in automation or substitution also need to be considered as potential factors. The results for HDI show that whilst interventions can reduce exposures significantly, such initiatives may need to be refreshed at intervals to maintain the reductions in exposure. We have observed that exposures move between sectors over time. Waste and recycling (lead, mercury) and tunnelling through contaminated land (benzene) were sectors or tasks associated with significant exposures and may be increasingly areas of concern.

Objective To determine the ability to accurately diagnose acute rheumatic fever (ARF) given the resources available at three levels of the Ugandan healthcare system.Methods Using data obtained from a large epidemiological database on ARF conducted in three districts of Uganda, we selected variables that might positively or negatively predict rheumatic fever based on diagnostic capacity at three levels/tiers of the Ugandan healthcare system. Variables were put into three statistical models that were built sequentially. Multiple logistic regression was used to estimate ORs and 95% CI of predictors of ARF. Performance of the models was determined using Akaike information criterion, adjusted R2, concordance C statistic, Brier score and adequacy index.Results A model with clinical predictor variables available at a lower-level health centre (tier 1) predicted ARF with an optimism corrected area under the curve (AUC) (c-statistic) of 0.69. Adding tests available at the district level (tier 2, ECG, complete blood count and malaria testing) increased the AUC to 0.76. A model that additionally included diagnostic tests available at the national referral hospital (tier 3, echocardiography, anti-streptolysin O titres, erythrocyte sedimentation rate/C-reactive protein) had the best performance with an AUC of 0.91.Conclusions Reducing the burden of rheumatic heart disease in low and middle-income countries requires overcoming challenges of ARF diagnosis. Ensuring that possible cases can be evaluated using electrocardiography and relatively simple blood tests will improve diagnostic accuracy somewhat, but access to echocardiography and tests to confirm recent streptococcal infection will have the greatest impact.

To understand how massive galaxies at high z coevolve with enormous reservoirs of halo gas, it is essential to study the coldest phase of the circumgalactic medium (CGM), which directly relates to stellar growth. The SUPERCOLD-CGM survey is the first statistical survey of cold molecular gas on CGM scales. We present Atacama Large Millimeter Array and Atacama Compact Array observations of CO(4–3) and continuum emission from 10 enormous Ly α nebulae (ELANe) around ultraluminous type I quasi-stellar objects (QSOs) at z ∼ 2. We detect CO(4–3) in 100% of our targets, with 60% showing extended CO on scales of 15–100 kpc. Q1228+3128 reveals the most extended CO(4–3) reservoir of ∼100 kpc and is the only radio-loud target in our sample. The CO reservoir is located along the radio axis, which could indicate a link between the inner radio jet and cold halo gas. For the other five radio-quiet ELANe, four of them show extended CO(4–3) predominantly in the direction of their companions. These extended CO(4–3) reservoirs identify enrichment of the CGM and may potentially contribute to widespread star formation. However, there is no evidence from CO(4–3) for diffuse molecular gas spread across the full extent of the Ly α nebulae. One target in our sample (Q0107) shows significant evidence for a massive CO disk associated with the QSO. Moreover, 70% of our QSO fields contain at least one CO companion, two of which reveal extended CO emission outside the ELANe. Our results provide insight into roles of both the cold CGM and companions in driving the early evolution of massive galaxies.

The galaxy cluster Zwicky 3146 is a sloshing cool-core cluster at z = 0.291 that in Sunyaev–Zel’dovich (SZ) imaging does not appear to exhibit significant pressure substructure in the intracluster medium. We perform a surface brightness fluctuation analysis via Fourier amplitude spectra on SZ (MUSTANG-2) and X-ray (XMM-Newton) images of this cluster. These surface brightness fluctuations can be deprojected to infer pressure and density fluctuations from the SZ and X-ray data, respectively. In the central region (Ring 1, r < 100″ = 440 kpc, in our analysis), we find fluctuation spectra that suggest injection scales around 200 kpc (∼140 kpc from pressure fluctuations and ∼250 kpc from density fluctuations). When comparing the pressure and density fluctuations in the central region, we observe a change in the effective thermodynamic state from large to small scales, from isobaric (likely due to the slow sloshing) to adiabatic (due to more vigorous motions). By leveraging scalings from hydrodynamical simulations, we find an average 3D Mach number ≈0.5. We further compare our results to other studies of Zwicky 3146 and, more broadly, to other studies of fluctuations in other clusters.

Exercising women report three to six times more ACL tears than men, which happen, in the majority of cases, with a non-contact mechanism. This sex disparity has, in part, been attributed to the differences in reproductive hormone profiles between men and women. Many studies have shown that anterior knee (AK) laxity and the rate of non-contact ACL injuries vary across the menstrual cycle, but these data are inconsistent. Similarly, several studies have investigated the potential protective effect of hormonal contraceptives on non-contact ACL injuries, but their conclusions are also variable. The purpose of this systematic review and meta-analysis is to, identify, evaluate and summarise the effects of endogenous and exogenous ovarian hormones on AK laxity (primary outcome) and the occurrence of non-contact ACL injuries (secondary outcome) in women. We will perform a systematic search for all observational studies conducted on this topic. Studies will be retrieved by searching electronic databases, clinical trial registers, author’s personal files and cross-referencing selected studies. Risk of bias will be assessed using the Newcastle Ottawa Quality Assessment Scale for Cohort and Case–Control Studies. Certainty in the cumulative evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. The meta-analyses will use a Bayesian approach to address specific research questions in a more intuitive and probabilistic manner. This review is registered on the international database of prospectively registered systematic reviews (PROSPERO; CRD42021252365).

A physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the biokinetics in humans after single oral doses. The model was parameterized with in vitro and in silico derived parameters and uncertainty and sensitivity analysis was used during the model development process to assess structure, biological plausibility and behaviour prior to simulation and analysis of human biological monitoring data. To provide possible explanations for some of the counter-intuitive behaviour of the biological monitoring data the model included a simple lymphatic uptake process for DPHP and enterohepatic recirculation (EHR) for DPHP and the mono ester metabolite mono-(2-propylheptyl) phthalate (MPHP). The model was used to simultaneously simulate the concentration-time profiles of blood DPHP, MPHP and the urinary excretion of two metabolites, mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP) and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). The availability of blood and urine measurements permitted a more robust qualitative and quantitative investigation of the importance of EHR and lymphatic uptake. Satisfactory prediction of blood DPHP and urinary metabolites was obtained whereas blood MPHP was less satisfactory. However, the delayed peak of DPHP concentration relative to MPHP in blood and second order metabolites in urine could be explained as a result of three processes: 1) DPHP entering the systemic circulation from the lymph, 2) rapid and very high protein binding and 3) the efficiency of the liver in removing DPHP absorbed via the hepatic route. The use of sensitivity analysis is considered important in the evaluation of uncertainty around in vitro and in silico derived parameters. By quantifying their impact on model output sufficient confidence in the use of a model should be afforded. This approach could expand the use of PBPK models since parameterization with in silico techniques allows for rapid model development. This in turn could assist in reducing the use of animals in toxicological evaluations by enhancing the utility of “read across” techniques.

Background The natural history of latent rheumatic heart disease (RHD) detected by echocardiography remains unclear. We aimed to assess the accuracy of a simplified score based on the 2012 World Heart Federation criteria in predicting mid‐term RHD echocardiography outcomes in children from 4 different countries. Methods and Results Patient‐level baseline and follow‐up data of children with latent RHD from 4 countries (Australia, n=62; Brazil, n=197; Malawi, n=40; New Zealand, n=94) were combined. A simplified echocardiographic scoring system previously developed from Brazilian and Ugandan cohorts, consisting of 5 point‐based variables with respective weights, was applied: mitral valveanterior leaflet thickening (weight=3), excessive leaflet tip motion (3), regurgitation jet length ≥2 cm (6), aortic valve focal thickening (4), and any regurgitation (5). Unfavorable outcome was defined as worsening diagnostic category, persistent definite RHD or development/worsening of valve regurgitation/stenosis. The score model was updated using methods for recalibration. 393 patients (314 borderline, 79 definite RHD) with median follow‐up of 36 (interquartile range, 25–48) months were included. Median age was 14 (interquartile range, 11–16) years and secondary prophylaxis was prescribed to 16%. The echocardiographic score model applied to this external population showed significant association with unfavorable outcome (hazard ratio, 1.10; 95% CI, 1.04–1.16; P=0.001). Unfavorable outcome rates in low (≤5 points), intermediate (6–9), and high‐risk (≥10) children at 3‐year follow‐up were 14.3%, 20.8%, and 38.5% respectively (P

Abstract INTRODUCTION: Cardiac involvement seems to impact prognosis of COVID-19, being more frequent in critically ill patients. We aimed to assess the prognostic value of right ventricular (RV) and left ventricular (LV) dysfunction, evaluated by bedside echocardiography (echo), in patients hospitalized with COVID-19. METHODS: Patients admitted in 2 reference hospitals in Brazil from Jul to Sept/2020 with confirmed COVID-19 and moderate/severe presentations underwent clinical and laboratory evaluation, and focused bedside echo (GE Vivid-IQ), at the earliest convenience, with remote interpretation. The association between demographics, clinical comorbidities and echo variables with all-cause hospital mortality was assessed, and factors significant at p

Background Recent evaluation of rheumatic heart disease (RHD) mortality demonstrates disproportionate disease burden within the United States. However, there are few contemporary data on US children living with acute rheumatic fever (ARF) and RHD. Methods and Results Twenty‐two US pediatric institutions participated in a 10‐year review (2008–2018) of electronic medical records and echocardiographic databases of children 4 to 17 years diagnosed with ARF/RHD to determine demographics, diagnosis, and management. Geocoding was used to determine a census tract‐based socioeconomic deprivation index. Descriptive statistics of patient characteristics and regression analysis of RHD classification, disease severity, and initial antibiotic prescription according to community deprivation were obtained. Data for 947 cases showed median age at diagnosis of 9 years; 51% and 56% identified as male and non‐White, respectively. Most (89%) had health insurance and were first diagnosed in the United States (82%). Only 13% reported travel to an endemic region before diagnosis. Although 96% of patients were prescribed secondary prophylaxis, only 58% were prescribed intramuscular benzathine penicillin G. Higher deprivation was associated with increasing disease severity (odds ratio, 1.25; 95% CI, 1.08–1.46). Conclusions The majority of recent US cases of ARF and RHD are endemic rather than the result of foreign exposure. Children who live in more deprived communities are at risk for more severe disease. This study demonstrates a need to improve guideline‐based treatment for ARF/RHD with respect to secondary prophylaxis and to increase research efforts to better understand ARF and RHD in the United States.

Histidine-containing dipeptides (HCDs) are abundantly expressed in striated muscles. Although important properties have been ascribed to HCDs, including H+ buffering, regulation of Ca2+ transients and protection against oxidative stress, it remains unknown whether they play relevant functions in vivo. To investigate the in vivo roles of HCDs, we developed the first carnosine synthase knockout (CARNS1−/−) rat strain to investigate the impact of an absence of HCDs on skeletal and cardiac muscle function. Male wild-type (WT) and knockout rats (4 months-old) were used. Skeletal muscle function was assessed by an exercise tolerance test, contractile function in situ and muscle buffering capacity in vitro. Cardiac function was assessed in vivo by echocardiography and cardiac electrical activity by electrocardiography. Cardiomyocyte contractile function was assessed in isolated cardiomyocytes by measuring sarcomere contractility, along with the determination of Ca2+ transient. Markers of oxidative stress, mitochondrial function and expression of proteins were also evaluated in cardiac muscle. Animals were supplemented with carnosine (1.8% in drinking water for 12 weeks) in an attempt to rescue tissue HCDs levels and function. CARNS1−/− resulted in the complete absence of carnosine and anserine, but it did not affect exercise capacity, skeletal muscle force production, fatigability or buffering capacity in vitro, indicating that these are not essential for pH regulation and function in skeletal muscle. In cardiac muscle, however, CARNS1−/− resulted in a significant impairment of contractile function, which was confirmed both in vivo and ex vivo in isolated sarcomeres. Impaired systolic and diastolic dysfunction were accompanied by reduced intracellular Ca2+ peaks and slowed Ca2+ removal, but not by increased markers of oxidative stress or impaired mitochondrial respiration. No relevant increases in muscle carnosine content were observed after carnosine supplementation. Results show that a primary function of HCDs in cardiac muscle is the regulation of Ca2+ handling and excitation-contraction coupling.

ObjectiveDisuse atrophy (DA) describes inactivity-induced skeletal muscle loss, through incompletely defined mechanisms. An intriguing observation is that individual muscles exhibit differing degrees of atrophy, despite exhibiting similar anatomical function/locations. We aimed to develop an innovative experimental paradigm to investigate Atrophy Resistant tibialis anterior (TA) and Atrophy Susceptible medial gastrocnemius (MG) muscles (aRaS) with a future view of uncovering central mechanisms.MethodSeven healthy young men (22 ± 1 year) underwent 15 days unilateral leg immobilisation (ULI). Participants had a single leg immobilised using a knee brace and air-boot to fix the leg (75° knee flexion) and ankle in place. Dual-energy X-ray absorptiometry (DXA), MRI and ultrasound scans of the lower leg were taken before and after the immobilisation period to determine changes in muscle mass. Techniques were developed for conchotome and microneedle TA/MG muscle biopsies following immobilisation (both limbs), and preliminary fibre typing analyses was conducted.ResultsTA/MG muscles displayed comparable fibre type distribution of predominantly type I fibres (TA 67 ± 7%, MG 63 ± 5%). Following 15 days immobilisation, MG muscle volume (–2.8 ± 1.4%, p < 0.05) and muscle thickness decreased (−12.9 ± 1.6%, p < 0.01), with a positive correlation between changes in muscle volume and thickness (R2 = 0.31, p = 0.038). Importantly, both TA muscle volume and thickness remained unchanged.ConclusionThe use of this unique “aRaS” paradigm provides an effective and convenient means by which to study the mechanistic basis of divergent DA susceptibility in humans, which may facilitate new mechanistic insights, and by extension, mitigation of skeletal muscle atrophy during human DA.

Abstract The development of safe and practical strategies to prevent weakening of bone tissue is vital, yet attempts to achieve this have been hindered by a lack of understanding of the short‐term (days‐weeks) physiology of bone collagen turnover. To address this, we have developed a method to quantify bone collagen synthesis in vivo, using deuterium oxide (D2O) tracer incorporation techniques combined with gas chromatography pyrolysis isotope‐ratio mass spectrometry (GC‐pyrolysis‐IRMS). Forty‐six male and female rats from a selectively bred model ingested D2O for 3 weeks. Femur diaphyses (FEM), tibia proximal (T‐PRO), and distal (T‐DIS) epiphyses‐metaphyses and tibia mid‐shaft diaphyses (T‐MID) were obtained from all rats after necropsy. After demineralisation, collagen proteins were isolated and hydrolysed and collagen fractional synthetic rates (FSRs) determined by incorporation of deuterium into protein‐bound alanine via GC‐pyrolysis‐IRMS. The collagen FSR for the FEM (0.131 ± 0.078%/day; 95% CI [0.106–0.156]) was greater than the FSR at T‐MID (0.055 ± 0.049%/day; 95% CI [0.040–0.070]; p