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There is considerably greater variation in metabolic rates between men than between women, in terms of basal, activity and total (daily) energy expenditure (EE). One possible explanation is that EE is associated with male sexual characteristics (which are known to vary more than other traits) such as musculature and athletic capacity. Such traits might be predicted to be most prominent during periods of adolescence and young adulthood, when sexual behaviour develops and peaks. We tested this hypothesis on a large dataset by comparing the amount of male variation and female variation in total EE, activity EE and basal EE, at different life stages, along with several morphological traits: height, fat free mass and fat mass. Total EE, and to some degree also activity EE, exhibit considerable greater male variation (GMV) in young adults, and then a decreasing GMV in progressively older individuals. Arguably, basal EE, and also morphometrics, do not exhibit this pattern. These findings suggest that single male sexual characteristics may not exhibit peak GMV in young adulthood, however total and perhaps also activity EE, associated with many morphological and physiological traits combined, do exhibit GMV most prominently during the reproductive life stages.

Abstract Background Motor alterations and lowered physical activity are common in affective disorders. Previous research has indicated a link between depressive symptoms and declining muscle strength primarily focusing on the elderly but not younger individuals. Thus, we aimed to evaluate the relationship between mood and muscle strength in a sample of N = 73 young to middle-aged hospitalized patients (18–49 years, mean age 30.7 years) diagnosed with major depressive, bipolar and schizoaffective disorder, with a focus on moderating effects of psychopharmacotherapy. The study was carried out as a prospective observational study at a German psychiatric university hospital between September 2021 and March 2022. Methods Employing a standardized strength circuit consisting of computerized strength training devices, we measured the maximal muscle strength (Fmax) using three repetitions maximum across four muscle regions (abdomen, arm, back, leg) at three time points (t1-t3) over four weeks accompanied by psychometric testing (MADRS, BPRS, YRMS) and blood lipid profiling in a clinical setting. For analysis of psychopharmacotherapy, medication was split into activating (AM) and inhibiting (IM) medication and dosages were normalized by the respective WHO defined daily dose. Results While we observed a significant decrease of the MADRS score and increase of the relative total Fmax (rTFmax) in the first two weeks (t1-t2) but not later (both p

Background OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.Methods Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed.Results Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion.Conclusions These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.

Promoting the use of inclusive instruction based on the tenets of Universal Design has occurred in the United States over the past three decades. In this study, a validated measure of university faculty attitudes toward inclusive instruction was translated from English to German and administered to a sample of faculty at a German institution. Responses (n=589) were subjected to an exploratory and confirmatory factor analysis in order to validate the translated items. The exploratory factor analysis yielded seven factors, which were very similar to the English version of the measure. The confirmatory factor analysis indicated the seven-factor solution showed acceptable model fit. Implications are discussed for universities both in the United States and abroad.

Water is essential for survival, but one in three individuals worldwide (2.2 billion people) lacks access to safe drinking water. Water intake requirements largely reflect water turnover (WT), the water used by the body each day. We investigated the determinants of human WT in 5604 people from the ages of 8 days to 96 years from 23 countries using isotope-tracking (2H) methods. Age, body size, and composition were significantly associated with WT, as were physical activity, athletic status, pregnancy, socioeconomic status, and environmental characteristics (latitude, altitude, air temperature, and humidity). People who lived in countries with a low human development index (HDI) had higher WT than people in high-HDI countries. On the basis of this extensive dataset, we provide equations to predict human WT in relation to anthropometric, economic, and environmental factors.

In mammals, trait variation is often reported to be greater among males than females. However, to date, mainly only morphological traits have been studied. Energy expenditure represents the metabolic costs of multiple physical, physiological, and behavioral traits. Energy expenditure could exhibit particularly high greater male variation through a cumulative effect if those traits mostly exhibit greater male variation, or a lack of greater male variation if many of them do not. Sex differences in energy expenditure variation have been little explored. We analyzed a large database on energy expenditure in adult humans (1494 males and 3108 females) to investigate whether humans have evolved sex differences in the degree of interindividual variation in energy expenditure. We found that, even when statistically comparing males and females of the same age, height, and body composition, there is much more variation in total, activity, and basal energy expenditure among males. However, with aging, variation in total energy expenditure decreases, and because this happens more rapidly in males, the magnitude of greater male variation, though still large, is attenuated in older age groups. Considerably greater male variation in both total and activity energy expenditure could be explained by greater male variation in levels of daily activity. The considerably greater male variation in basal energy expenditure is remarkable and may be explained, at least in part, by greater male variation in the size of energy-demanding organs. If energy expenditure is a trait that is of indirect interest to females when choosing a sexual partner, this would suggest that energy expenditure is under sexual selection. However, we present a novel energetics model demonstrating that it is also possible that females have been under stabilizing selection pressure for an intermediate basal energy expenditure to maximize energy available for reproduction.

Outside cities and towns served by conventional sewerage, many residents in the rural Black Belt region of Alabama, USA, have failing or inadequate sanitation infrastructure (1,2). This region was named [...]

Abstract The promises of vaccines based on virus-like particles stimulate demand for universal non-infectious virus-like platforms that can be efficiently grafted with large antigens. Here, we harnessed the modularity and extreme affinity of the decoration protein pb10 for the capsid of bacteriophage T5. SPR experiments demonstrated that pb10 fused to mCherry or to the model antigen ovalbumin (Ova) retained picomolar affinity for DNA-free T5 capsid-like particles (T5-CLPs), while cryo-EM studies attested to the full occupancy of the 120 capsid binding sites. Mice immunization with CLP-bound pb10-Ova chimeras elicited strong long-lasting anti-Ova humoral responses involving a large panel of isotypes, as well as CD8+ T cell responses, without any extrinsic adjuvant. Therefore, T5-CLP constitutes a unique DNA-free bacteriophage capsid able to display a regular array of large antigens through highly efficient chemical-free anchoring. Its ability to elicit robust immune responses paves the way for further development of this novel vaccination platform.

Lower ambient temperature (Ta) requires greater energy expenditure to sustain body temperature. However, effects of Ta on human energetics may be buffered by environmental modification and behavioral compensation. We used the IAEA DLW database for adults in the USA (n = 3213) to determine the effect of Ta (-10 to +30°C) on TEE, basal (BEE) and activity energy expenditure (AEE) and physical activity level (PAL). There were no significant relationships (p > 0.05) between maximum, minimum and average Ta and TEE, BEE, AEE and PAL. After adjustment for fat-free mass, fat mass and age, statistically significant (p

We collected stool from school-age children from 352 households living in the Black Belt region of Alabama, USA, where sanitation infrastructure is lacking. We used quantitative reverse transcription PCR to measure key pathogens in stool that may be associated with water and sanitation, as an indicator of exposure. We detected genes associated with >1 targets in 26% of specimens, most frequently Clostridioides difficile (6.6%), atypical enteropathogenic Escherichia coli (6.1%), and enteroaggregative E. coli (3.9%). We used generalized estimating equations to assess reported risk factors for detecting >1 pathogen in stool. We found no association between lack of sanitation and pathogen detection (adjusted risk ratio 0.95 [95% CI 0.55–1.7]) compared with specimens from children served by sewerage. However, we did observe an increased risk for pathogen detection among children living in homes with well water (adjusted risk ratio 1.7 [95% CI 1.1–2.5]) over those reporting water utility service.

Abstract In this big data era, multitudes of data are generated and collected which contain the potential to gain new insights, e.g., for enhancing business models. To leverage this potential through, e.g., data science and analytics projects, the data must be made available. In this context, data marketplaces are used as platforms to facilitate the exchange and thus, the provisioning of data and data-related services. Data marketplaces are mainly studied for the exchange of data between organizations, i.e., as external data marketplaces. Yet, the data collected within a company also has the potential to provide valuable insights for this same company, for instance to optimize business processes. Studies indicate, however, that a significant amount of data within companies remains unused. In this sense, it is proposed to employ an Enterprise Data Marketplace, a platform to democratize data within a company among its employees. Specifics of the Enterprise Data Marketplace, how it can be implemented or how it makes data available throughout a variety of systems like data lakes has not been investigated in literature so far. Therefore, we present the characteristics and requirements of this kind of marketplace. We also distinguish it from other tools like data catalogs, provide a platform architecture and highlight how it integrates with the company’s system landscape. The presented concepts are demonstrated through an Enterprise Data Marketplace prototype and an experiment reveals that this marketplace significantly improves the data consumer workflows in terms of efficiency and complexity. This paper is based on several interdisciplinary works combining comprehensive research with practical experience from an industrial perspective. We therefore present the Enterprise Data Marketplace as a distinct marketplace type and provide the basis for establishing it within a company.

Low total energy expenditure (TEE, MJ/d) has been a hypothesized risk factor for weight gain, but repeatability of TEE, a critical variable in longitudinal studies of energy balance, is understudied. We examine repeated doubly labeled water (DLW) measurements of TEE in 348 adults and 47 children from the IAEA DLW Database (mean ± SD time interval: 1.9 ± 2.9 y) to assess repeatability of TEE, and to examine if TEE adjusted for age, sex, fat-free mass, and fat mass is associated with changes in weight or body composition. Here, we report that repeatability of TEE is high for adults, but not children. Bivariate Bayesian mixed models show no among or within-individual correlation between body composition (fat mass or percentage) and unadjusted TEE in adults. For adults aged 20-60 y (N = 267; time interval: 7.4 ± 12.2 weeks), increases in adjusted TEE are associated with weight gain but not with changes in body composition; results are similar for subjects with intervals >4 weeks (N = 53; 29.1 ± 12.8 weeks). This suggests low TEE is not a risk factor for, and high TEE is not protective against, weight or body fat gain over the time intervals tested.

BackgroundPhysical activity may be a way to increase and maintain fat-free mass (FFM) in later life, similar to the prevention of fractures by increasing peak bone mass.ObjectivesA study is presented of the association between FFM and physical activity in relation to age.MethodsIn a cross-sectional study, FFM was analyzed in relation to physical activity in a large participant group as compiled in the International Atomic Energy Agency Doubly Labeled Water database. The database included 2000 participants, age 3-96 y, with measurements of total energy expenditure (TEE) and resting energy expenditure (REE) to allow calculation of physical activity level (PAL = TEE/REE), and calculation of FFM from isotope dilution.ResultsPAL was a main determinant of body composition at all ages. Models with age, fat mass (FM), and PAL explained 76% and 85% of the variation in FFM in females and males

Understanding the impacts of activity on energy balance is crucial. Increasing levels of activity may bring diminishing returns in energy expenditure because of compensatory responses in non-activity energy expenditures.1-3 This suggestion has profound implications for both the evolution of metabolism and human health. It implies that a long-term increase in activity does not directly translate into an increase in total energy expenditure (TEE) because other components of TEE may decrease in response-energy compensation. We used the largest dataset compiled on adult TEE and basal energy expenditure (BEE) (n = 1,754) of people living normal lives to find that energy compensation by a typical human averages 28% due to reduced BEE; this suggests that only 72% of the extra calories we burn from additional activity translates into extra calories burned that day. Moreover, the degree of energy compensation varied considerably between people of different body compositions. This association between compensation and adiposity could be due to among-individual differences in compensation: people who compensate more may be more likely to accumulate body fat. Alternatively, the process might occur within individuals: as we get fatter, our body might compensate more strongly for the calories burned during activity, making losing fat progressively more difficult. Determining the causality of the relationship between energy compensation and adiposity will be key to improving public health strategies regarding obesity.

Abstract Background Exercise intensities are prescribed using specific intensity zones (moderate, heavy, and severe) determined by a ‘lower’ and a ‘higher’ threshold. Typically, ventilatory (VT) or blood lactate thresholds (LT), and critical power/speed concepts (CP/CS) are used. Various heart rate variability-derived thresholds (HRVTs) using different HRV indices may constitute applicable alternatives, but a systematic review of the proximity of HRVTs to established threshold concepts is lacking. Objective This systematic review aims to provide an overview of studies that determined HRVTs during endurance exercise in healthy adults in comparison with a reference VT and/or LT concept. Methods A systematic literature search for studies determining HRVTs in healthy individuals during endurance exercise and comparing them with VTs or LTs was conducted in Scopus, PubMed and Web of Science (until January 2022). Studies claiming to describe similar physiological boundaries to delineate moderate from heavy (HRVTlow vs. VTlow and/or LTlow), and heavy from severe intensity zone (HRVThigh vs. VThigh and/or LThigh) were grouped and their results synthesized. Results Twenty-seven included studies (461 participants) showed a mean difference in relative HR between HRVTlow and VTlow of − 0.6%bpm in weighted means and 0.02%bpm between HRVTlow and LTlow. Bias between HR at HRVTlow and VTlow was 1 bpm (limits of agreement (LoA): − 10.9 to 12.8 bpm) and 2.7 bpm (LoA: − 20.4 to 25.8 bpm) between HRVTlow and LTlow. Mean difference in HR between HRVThigh and VThigh was 0.3%bpm in weighted means and 2.9%bpm between HRVThigh and LThigh while bias between HR at HRVThigh and VThigh was − 4 bpm (LoA: − 17.9 to 9.9 bpm) and 2.5 bpm (LoA: − 12.1 to 17.1 bpm) between HRVThigh and LThigh. Conclusion HRVTlow seems to be a promising approach for the determination of a ‘lower’ threshold comparable to VTlow and potentially for HRVThigh compared to VThigh, although the latter needs further empirical evaluation. LoA for both intensity zone boundaries indicates bias of HRVTs on an individual level. Taken together, HRVTs can be a promising alternative for prescribing exercise intensity in healthy, male athletes undertaking endurance activities but due to the heterogeneity of study design, threshold concepts, standardization, and lack of female participants, further research is necessary to draw more robust and nuanced conclusions.

Total daily energy expenditure ("total expenditure") reflects daily energy needs and is a critical variable in human health and physiology, but its trajectory over the life course is poorly studied. We analyzed a large, diverse database of total expenditure measured by the doubly labeled water method for males and females aged 8 days to 95 years. Total expenditure increased with fat-free mass in a power-law manner, with four distinct life stages. Fat-free mass-adjusted expenditure accelerates rapidly in neonates to ~50% above adult values at ~1 year; declines slowly to adult levels by ~20 years; remains stable in adulthood (20 to 60 years), even during pregnancy; then declines in older adults. These changes shed light on human development and aging and should help shape nutrition and health strategies across the life span.

AbstractDespite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. In response to the maturity of AI, Kenner Family Research Fund conducted the 2020 AI and Early Detection of Pancreatic Cancer Virtual Summit (www.pdac-virtualsummit.org) in conjunction with the American Pancreatic Association, with a focus on the potential of AI to advance early detection efforts in this disease. This comprehensive presummit article was prepared based on information provided by each of the interdisciplinary participants on one of the 5 following topics: Progress, Problems, and Prospects for Early Detection; AI and Machine Learning; AI and Pancreatic Cancer-Current Efforts; Collaborative Opportunities; and Moving Forward-Reflections from Government, Industry, and Advocacy. The outcome from the robust Summit conversations, to be presented in a future white paper, indicate that significant progress must be the result of strategic collaboration among investigators and institutions from multidisciplinary backgrounds, supported by committed funders.

The doubly labeled water (DLW) method measures total energy expenditure (TEE) in free-living subjects. Several equations are used to convert isotopic data into TEE. Using the International Atomic Energy Agency (IAEA) DLW database (5,756 measurements of adults and children), we show considerable variability is introduced by different equations. The estimated rCO2 is sensitive to the dilution space ratio (DSR) of the two isotopes. Based on performance in validation studies, we propose a new equation based on a new estimate of the mean DSR. The DSR is lower at low body masses (

Objectives To evaluate the relationship among dysnatraemia at hospital presentation and duration of admission, risk of intensive care unit (ICU) admission and all-cause mortality and to assess the underlying pathophysiological mechanism of hyponatraemia in patients with COVID-19. Our hypothesis is that both hyponatraemia and hypernatraemia at presentation are associated with adverse outcomes.Design Observational study.Setting Secondary care; 11 Dutch hospitals (2 university and 9 general hospitals).Participants An analysis was performed within the retrospective multicentre cohort study COVIDPredict. 7811 patients were included (60% men, 40% women) between 24 February 2020 and 9 August 2022. Patients who were ≥18 years with PCR-confirmed COVID-19 or CT with COVID-19 reporting and data system score≥4 and alternative diagnosis were included. Patients were excluded when serum sodium levels at presentation were not registered in the database or when they had been transferred from another participating hospital.Outcome measures We studied demographics, medical history, symptoms and outcomes. Patients were stratified according to serum sodium concentration and urinary sodium excretion.Results Hyponatraemia was present in 2677 (34.2%) patients and hypernatraemia in 126 (1.6%) patients. Patients with hyponatraemia presented more frequently with diarrhoea, lower blood pressure and tachycardia. Hyponatraemia was, despite a higher risk for ICU admission (OR 1.27 (1.11–1.46; p

Abstract Background Iatrogenic Cushing’s syndrome induced by oral and parenteral glucocorticoid administration is a well-known complication. Immediate withdrawal from exogenous steroids can lead to life-threatening adrenal insufficiency. However, Cushing’s syndrome caused by topical treatment with glucocorticoids, such as dexamethasone eye drops or dermal application, is rarely recognized. Young infants in particular are at high risk of suffering from iatrogenic Cushing’s syndrome when treated with highly potent topical glucocorticoids. Case presentation We present a 6-month-old Syrian boy with cushingoid face after dermal clobetasol cream treatment and a 2-year-old Iranian girl with severe growth retardation after application of dexamethasone eye drops. Both families have a migration background and language barriers. In both cases no endogenous cortisol secretion was initially detected in serum and in 24-hour collected urine. After dose reduction of glucocorticoids, severity of symptoms was reversible and serum cortisol was detectable. Discussion and conclusion Young infants are at high risk of developing Cushing’s syndrome from topically applied highly potent glucocorticoids. Precise recommendations of treatment dosage, duration, and frequency must be given to the parents, and if necessary, with the help of an interpreter. Monitoring of height and weight as well as regular pediatric follow-ups should be scheduled. Physicians should be aware of potential adrenal insufficiency following withdrawal from long-term topical glucocorticoid treatment, and hydrocortisone treatment should be considered.

Super-resolution (SR), a technique to increase the resolution of images, is a pre-processing step in the pipelines of applications of Earth observation (EO) data. The manual design and optimisation of SR models that are specific to every possible EO use case is a laborious process that creates a bottleneck for EO analysis. In this work, we develop an automated machine learning (AutoML) method to automate the creation of dataset-specific SR models. AutoML is the study of the automatic design of high-performance machine learning models. We present the following contributions. (i) We propose AutoSR4EO, an AutoML method for automatically constructing neural networks for SR. We design a search space based on state-of-the-art residual neural networks for SR and incorporate transfer learning. Our search space is extendable, making it possible to adapt AutoSR4EO to future developments in the field. (ii) We introduce a new real-world single-image SR (SISR) dataset, called SENT-NICFI. (iii) We evaluate the performance of AutoSR4EO on four different datasets against the performance of four state-of-the-art baselines and a vanilla AutoML SR method, with AutoSR4EO achieving the highest average ranking. Our results show that AutoSR4EO performs consistently well over all datasets, demonstrating that AutoML is a promising method for improving SR techniques for EO images.

Abstract Background Calmodulin (CaM) is an evolutionarily conserved eukaryotic multifunctional protein that functions as the major sensor of intracellular calcium signaling. Its calcium-modulated function regulates the activity of numerous effector proteins involved in a variety of physiological processes in diverse organs, from proliferation and apoptosis, to memory and immune responses. Due to the pleiotropic roles of CaM in normal and pathological cell functions, CaM antagonists are needed for fundamental studies as well as for potential therapeutic applications. Calmidazolium (CDZ) is a potent small molecule antagonist of CaM and one the most widely used inhibitors of CaM in cell biology. Yet, CDZ, as all other CaM antagonists described thus far, also affects additional cellular targets and its lack of selectivity hinders its application for dissecting calcium/CaM signaling. A better understanding of CaM:CDZ interaction is key to design analogs with improved selectivity. Here, we report a molecular characterization of CaM:CDZ complexes using an integrative structural biology approach combining SEC-SAXS, X-ray crystallography, HDX-MS, and NMR. Results We provide evidence that binding of a single molecule of CDZ induces an open-to-closed conformational reorientation of the two domains of CaM and results in a strong stabilization of its structural elements associated with a reduction of protein dynamics over a large time range. These CDZ-triggered CaM changes mimic those induced by CaM-binding peptides derived from physiological protein targets, despite their distinct chemical natures. CaM residues in close contact with CDZ and involved in the stabilization of the CaM:CDZ complex have been identified. Conclusion Our results provide molecular insights into CDZ-induced dynamics and structural changes of CaM leading to its inhibition and open the way to the rational design of more selective CaM antagonists. Graphical abstract Calmidazolium is a potent and widely used inhibitor of calmodulin, a major mediator of calcium-signaling in eukaryotic cells. Structural characterization of calmidazolium-binding to calmodulin reveals that it triggers open-to-closed conformational changes similar to those induced by calmodulin-binding peptides derived from enzyme targets. These results provide molecular insights into CDZ-induced dynamics and structural changes of CaM leading to its inhibition and open the way to the rational design of more selective CaM antagonists.