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M35 is a young open cluster and home to an extensive binary population. Using Gaia Data Release 3, Pan-STARRS, and Two Micron All Sky Survey photometry with the Bayesian statistical software, BASE-9, we derive precise cluster parameters, identify single and binary cluster members, and extract their masses. We identify 571 binaries down to Gaia G = 20.3 and a lower limit on the binary frequency of f _b = 0.41 ± 0.02. We extend the binary demographics by many magnitudes faint-ward of previous (radial-velocity) studies of this cluster and further away from the cluster center (1.°78, roughly 10 core radii). We find the binary stars to be more centrally concentrated than the single stars in the cluster. Furthermore, we find strong evidence for mass segregation within the binary population itself, with progressively more-massive binary samples becoming more and more centrally concentrated. For the single stars, we find weaker evidence for mass segregation; only the most massive single stars (>2.5 M _⊙ ) appear more centrally concentrated. Given the cluster age of ∼200 Myr, and our derived half-mass relaxation time for the cluster of 230 ± 84 Myr, we estimate ∼47% of the binary stars and ∼12% of single stars in the cluster have had time to become dynamically mass segregated. Importantly, when we investigate only stars with mass segregation timescales greater than the cluster age, we still find the binaries to be more centrally concentrated than the singles, suggesting the binaries may have formed with a primordially different spatial distribution from that of the single stars.

BackgroundColon microbiome composition contributes to the pathogenesis of colorectal cancer (CRC) and prognosis. We analyzed 16S rRNA sequencing data from tumor samples of patients with metastatic CRC and determined the clinical implications.Materials and methodsWe enrolled 133 patients with metastatic CRC at St. Vincent Hospital in Korea. The V3-V4 regions of the 16S rRNA gene from the tumor DNA were amplified, sequenced on an Illumina MiSeq, and analyzed using the DADA2 package.ResultsAfter excluding samples that retained

Environmental rhythms such as the daily light-dark cycle selected for endogenous clocks. These clocks predict regular environmental changes and provide the basis for well-timed adaptive homeostasis in physiology and behavior of organisms. Endogenous clocks are oscillators that are based on positive feedforward and negative feedback loops. They generate stable rhythms even under constant conditions. Since even weak interactions between oscillators allow for autonomous synchronization, coupling/synchronization of oscillators provides the basis of self-organized physiological timing. Amongst the most thoroughly researched clocks are the endogenous circadian clock neurons in mammals and insects. They comprise nuclear clockworks of transcriptional/translational feedback loops (TTFL) that generate ∼24 h rhythms in clock gene expression entrained to the environmental day-night cycle. It is generally assumed that this TTFL clockwork drives all circadian oscillations within and between clock cells, being the basis of any circadian rhythm in physiology and behavior of organisms. Instead of the current gene-based hierarchical clock model we provide here a systems view of timing. We suggest that a coupled system of autonomous TTFL and posttranslational feedback loop (PTFL) oscillators/clocks that run at multiple timescales governs adaptive, dynamic homeostasis of physiology and behavior. We focus on mammalian and insect neurons as endogenous oscillators at multiple timescales. We suggest that neuronal plasma membrane-associated signalosomes constitute specific autonomous PTFL clocks that generate localized but interlinked oscillations of membrane potential and intracellular messengers with specific endogenous frequencies. In each clock neuron multiscale interactions of TTFL and PTFL oscillators/clocks form a temporally structured oscillatory network with a common complex frequency-band comprising superimposed multiscale oscillations. Coupling between oscillator/clock neurons provides the next level of complexity of an oscillatory network. This systemic dynamic network of molecular and cellular oscillators/clocks is suggested to form the basis of any physiological homeostasis that cycles through dynamic homeostatic setpoints with a characteristic frequency-band as hallmark. We propose that mechanisms of homeostatic plasticity maintain the stability of these dynamic setpoints, whereas Hebbian plasticity enables switching between setpoints via coupling factors, like biogenic amines and/or neuropeptides. They reprogram the network to a new common frequency, a new dynamic setpoint. Our novel hypothesis is up for experimental challenge.

IntroductionPatients with chronic vestibular hypofunction typically suffer from dizziness, imbalance and oscillopsia (blurred vision); symptoms that pose challenges to everyday life. Currently, advice on how to deal with such challenges is mainly provided by health care professionals (i.e., ENT-surgeons, neurologists, physiotherapists and psychologists). However, fellow patients with a similar condition and a true appreciation of the lived experiences, are likely to provide valuable support and advice as well. The purpose of this study, therefore, was to collect tips and advice from patients with chronic vestibular hypofunction.MethodsAn exploratory survey was designed to collect tips from fellow chronic vestibular hypofunction patients on how to cope with disease-related challenges in everyday life. The survey was distributed both online and in person. The list of tips was coded and analyzed thematically and deductively, by using the international classification of functioning, disability, and health (ICF) model.ResultsIn total, 425 tips were obtained from the 179 participants. Most tips were coded under “environmental factors” (46%) and “activities and participation” (39%). The remaining tips were categorized as “body functions” (15%). No tips were about “body structures.” The participants coped with their daily struggles by investing in assistive products and technology, like adapted bikes, special footwear, walking frames. They described the importance of ensuring minimal light intensity for visibility (i.e., installing light sources in dark places). During activities, participants gave the advice to avoid bumpy roads and obstacles, and highlighted the necessity of adequate visual fixation to maintain balance. To ensure optimal activity, participants emphasized the importance of managing energy and taking sufficient rest.DiscussionThis study gives insight into how patients with chronic vestibular hypofunction cope with everyday struggles due to their symptoms. These tips can expand advice given by healthcare professionals. Knowing that fellow patients experience similar struggles and learned to deal with their struggles in adequate ways, might offer support and help patients focus on possibilities rather than on disabilities. Further research should investigate the effect of sharing tips to see whether improvement in (mental) health can be achieved in patients with chronic vestibular hypofunction.

This study investigated the multidimensional effects of extensive listening (EL) on learners’ actual language gains, selection of study materials, and practice styles. Language gains were measured through a pre- and a post-test on students’ aural vocabulary test (Listening Vocabulary Levels Test, LVLT) and general listening comprehension (TOEIC), administered before and after the intervention. Fifty-five university student participants took part in the four-month experiment; they were entirely free to select their favorite study materials online or off-line. The results showed that each student spent an average of 1,387 minutes (approximately 87 minutes per week) doing EL practice. The three most popular study materials were the following: Songs (63.64%), movies (49.09%), and talks (43.46%); materials were mainly from YouTube (74.55%), Netflix (49.09%), and other miscellaneous sources (43.63%). Their practice style was unanimously a combination of viewing and listening. From the pre-tests to the post-tests, students made significant gains in both LVLT and TOEIC, but the effect sizes were small. Some suggestions are made for implementing EL.

Objective Mesothelioma varies in clinical phenotype and survival. Clinical trials are unavoidably affected by selection bias, reducing generalisability. ASSESS-meso is a UK, multicentre, prospective, mesothelioma cohort study (ISRCTN61861764). This pre-specified interim analysis, conducted when recruitment reached 25% of target, summarised participant characteristics and evaluated external validity through comparison with real-world and clinical trial cohorts. Methods The study took place at 14 hospitals across the UK. People diagnosed with mesothelioma, at any anatomical site, were eligible. Clinical, radiological and biochemical data were collected at enrolment. In this interim report, the external validity of the cohort was investigated through comparison of baseline demographic data with populations included in the 2020 UK National Mesothelioma Audit (real-world cohort), and CHECKMATE-743 and MAPS trials (clinical trial cohorts). Results 244 patients were enrolled between 7 April 2017 and 1 March 2022. The cohort was predominantly male (195 out of 244; 80%) with a median age of 74 years. Pleural disease and epithelioid subtypes were most prevalent. ASSESS-meso participants were more similar to the real-world population with regard to age, performance status, disease site and stage than the clinical trial population. ASSESS-meso participants were more likely to be formally staged and less likely to have undifferentiated histology compared with the real-world cohort, possibly reflecting high rates of discussion of ASSESS-meso participants at regional mesothelioma multidisciplinary team meetings. As expected, poorer performance status, non-epithelioid histology and neutrophil–lymphocyte ratio were associated with shorter survival in the adjusted analysis. Conclusion ASSESS-meso is representative of the UK mesothelioma population. Future outputs from the cohort will help characterise different mesothelioma phenotypes with high external validity.

Abstract Understanding where, when, and why agroecosystems are changing requires quality information about ecosystems that span land tenure, ecological processes, and spatial scales. Over the past two decades, land management agencies and research groups have adopted a suite of standardized methods for monitoring rangelands, which have been implemented at over 85,000 monitoring locations globally. However, the ability to use these data to understand agroecosystem dynamics and change across scales and across land ownership has been limited because, until now, these data have not been available in a harmonized, accessible format for analyses, modeling, and decision‐support tools. We present the Landscape Data Commons, a cyberinfrastructure platform that harmonizes and aggregates standardized agroecosystem data, enables linkages to models, and facilitates analysis and interpretation of data within decision‐support tools. The Landscape Data Commons provides a community platform for users to contribute data and develop next‐generation tools to support agroecosystem management through the 21st century.

Abstract Long ncRNAs (lncRNAs) have been shown to play a biological and physiological role in various tissues including the heart. We and others have previously established that the lncRNA Oip5os1 (1700020I14Rik, OIP5‐AS1, Cyrano) is enriched in striated muscles, and its deletion in mice leads to defects in both skeletal and cardiac muscle function. In the present study, we investigated the impact of global Oip5os1 deletion on cardiac function in the setting of streptozotocin (STZ)‐induced diabetes. Specifically, we studied male WT and KO mice with or without diabetes for 24 weeks, and phenotyped animals for metabolic and cardiac endpoints. Independent of genotype, diabetes was associated with left ventricular diastolic dysfunction based on a fall in E'/A' ratio. Deletion of Oip5os1 in a setting of diabetes had no significant impact on ventricular function or ventricular weight, but was associated with left atrial dysfunction (reduced fractional shortening) and myopathy which was associated with anesthesia intolerance and premature death in the majority of KO mice tested during cardiac functional assessment. This atrial phenotype was not observed in WT diabetic mice. The most striking molecular difference was a reduction in the metabolic regulator ERRalpha in the atria of KO mice compared with WT mice. There was also a trend for a reduction in Serca2a. These findings highlight Oip5os1 as a gene of interest in aspects of atrial function in the setting of diabetes, highlighting an additional functional role for this lncRNA in cardiac pathological settings.

BackgroundScreening for germline pathogenic BRCA1 or BRCA2 variants (gBRCA) in high-risk breast cancer patients is known to be cost-effective in high-income countries. Nationwide adoption of genetics testing in high-risk breast cancer population remains poor. Our study aimed to assess gBRCA health economics data in the middle-income country setting of Thailand.MethodsDecision tree and Markov model were utilized to assess cost-utility between the testing vs. no-testing groups from a societal and lifetime perspective and lifetime. We interviewed 264 patients with breast/ovarian cancer and their family members to assess relevant costs and quality of life using EQ-5D-5L. One-way sensitivity, probabilistic sensitivity (Monte Carlo simulation), and budget impact analyses were done to estimate the outcome under Thailand's Universal Health Coverage scheme.ResultsThe predicted lifetime cost and Quality-adjusted Life Years (QALY) for those with breast cancer were $13,788 and 10.22 in the testing group and $13,702 and 10.07 in the no-testing group. The incremental cost-effectiveness ratio for gBRCA testing in high-risk breast cancer patients was $573/QALY. The lifetime cost for the family members of those with gBRCA was $14,035 (QALY 9.99), while the no-testing family members group was $14,077 (QALY 9.98). Performing gBRCA testing in family members was cost-saving.ConclusionCost-utility analysis demonstrated a cost-effective result of gBRCA testing in high-risk breast cancer patients and cost-saving in familial cascade testing. The result was endorsed in the national health benefits package in 2022. Other middle-income countries may observe the cost-effective/cost-saving aspects in common genetic diseases under their national health schemes.

In addition to its critical role in encoding individual episodes, the hippocampus is capable of extracting regularities across experiences. This ability is central to category learning, and a growing literature indicates that the hippocampus indeed makes important contributions to this form of learning. Using a neural network model that mirrors the anatomy of the hippocampus, we investigated the mechanisms by which the hippocampus may support novel category learning. We simulated three category learning paradigms and evaluated the network’s ability to categorize and recognize specific exemplars in each. We found that the trisynaptic pathway within the hippocampus—connecting entorhinal cortex to dentate gyrus, CA3, and CA1—was critical for remembering exemplar-specific information, reflecting the rapid binding and pattern separation capabilities of this circuit. The monosynaptic pathway from entorhinal cortex to CA1, in contrast, specialized in detecting the regularities that define category structure across exemplars, supported by the use of distributed representations and a relatively slower learning rate. Together, the simulations provide an account of how the hippocampus and its constituent pathways support novel category learning.

ABSTRACTPediatric patients with high-risk neuroblastoma often relapse with chemotherapy-resistant, incurable disease. Relapsed neuroblastomas harbor chemo-resistant mesenchymal tumor cells and increased expression/activity of the transcriptional co-regulator, the Yes-Associated Protein (YAP). Patients with relapsed neuroblastoma are often treated with immunotherapy such as the anti-GD2 antibody, dinutuximab, in combination with chemotherapy. We have previously shown that YAP mediates both chemotherapy and MEK inhibitor resistance in relapsed RAS mutated neuroblastoma and so posited that YAP might also be involved in anti-GD2 antibody resistance. We now show that YAP genetic inhibition significantly enhances sensitivity of mesenchymal neuroblastomas to dinutuximab and gamma delta (γδ) T cells both in vitro and in vivo. Mechanistically, YAP inhibition induces increased GD2 cell surface expression through upregulation of ST8SIA1, the gene encoding GD3 synthase and the rate-limiting enzyme in GD2 biosynthesis. The mechanism of ST8SIA1 suppression by YAP is independent of PRRX1 expression, a mesenchymal master transcription factor, suggesting YAP may be the downstream effector of mesenchymal GD2 resistance. These results therefore identify YAP as a therapeutic target to augment GD2 immunotherapy responses in patients with neuroblastoma.

Abstract Background Response rates of immune checkpoint inhibitor (ICI) therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are low. Patients and Methods This retrospective multicentre cohort study evaluates the predictive and prognostic value of weight loss and changes in body composition prior and during therapy. Patient, tumor, and treatment characteristics of 98 patients were retrieved, including neutrophil and platelet‐lymphocyte‐ratio (NLR and PLR). Programmed death‐ligand 1 (PD‐L1) expression was determined on residual material. Cachexia was defined according to Fearon et al. (2011). Skeletal muscle (SM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were evaluated on computed tomography scans at the third lumbar vertebrae level. Univariable and multivariable regression analyses were performed for 6 months progression free survival (PFS6m) and overall survival (OS). Results Significant early weight loss (>2%) during the first 6 weeks of therapy was shown in 34 patients (35%). This patient subgroup had a significantly higher NLR and PLR at baseline. NLR and PLR were inversely correlated with SM and VAT index. Independent predictors of PFS6m were lower World Health Organization performance status (HR 0.16 [0.04–0.54] p = 0.003), higher baseline SAT index (HR 1.045 [1.02–1.08] p = 0.003), and weight loss 2% early weight loss remained a predictor of OS, independent of PD‐L1 expression (HR 2.09 [1.11–3.92] p = 0.02, HR 2.18 [1.13–4.21] p = 0.02). Conclusion We conclude that the combination of cachexia at baseline and weight loss during ICI therapy is associated with worse OS in R/M HNSCC patients, independent of PD‐L1 expression.

Abstract Billions of animals migrate to track seasonal pulses in resources. Optimally timing migration is a key strategy, yet the ability of animals to compensate for phenological mismatches en route is largely unknown. Using GPS movement data collected from 72 adult female deer over a 10-year duration, we study a population of mule deer (Odocoileus hemionus) in Wyoming that lack reliable cues on their desert winter range, causing them to start migration 70 days ahead to 52 days behind the wave of spring green-up. We show that individual deer arrive at their summer range within an average 6-day window by adjusting movement speed and stopover use. Late migrants move 2.5 times faster and spend 72% less time on stopovers than early migrants, which allows them to catch the green wave. Our findings suggest that ungulates, and potentially other migratory species, possess cognitive abilities to recognize where they are in space and time relative to key resources. Such behavioral capacity may allow migratory taxa to maintain foraging benefits amid rapidly changing phenology.

Abstract Background Screening for colorectal cancer (CRC) is widely recommended but underused, even though CRC is the third most diagnosed cancer and the second leading cause of cancer death in the USA. The mPATH™ program is an iPad-based application designed to identify patients due for CRC screening, educate them on the commonly used screening tests, and help them select their best option, with the goal of increasing CRC screening rates. Methods The mPATH™ program consists of questions asked of all adult patients at check-in (mPATH™-CheckIn), as well as a module specific for patients due for CRC screening (mPATH™-CRC). In this study, the mPATH™ program is evaluated through a Type III hybrid implementation-effectiveness design. Specifically, the study consists of three parts: (1) a cluster-randomized controlled trial of primary care clinics comparing a “high touch” evidence-based implementation strategy with a “low touch” implementation strategy; (2) a nested pragmatic study evaluating the effectiveness of mPATH-CRC™ on completion of CRC screening; and (3) a mixed-methods study evaluating factors that facilitate or impede the maintenance of interventions like mPATH-CRC™. The primary objective is to compare the proportion of patients aged 50–74 who are eligible for CRC screening who complete mPATH™-CRC in the 6th month following implementation between the “high touch” and “low touch” implementation strategies. Effectiveness of mPATH™-CRC is evaluated by comparing the proportion who complete CRC screening within 16 weeks of their visit to the clinic between a pre-implementation cohort (8 months before implementation) and a post-implementation cohort (8 months after implementation). Discussion This study will provide data on both the implementation of the mPATH™ program and its effectiveness in improving screening rates for CRC. In addition, this work has the potential to have an even broader impact by identifying strategies to support the sustained use of other similar technology-based primary care interventions. Trial registration ClinicalTrials.gov NCT03843957. Registered on 18 February 2019.

Food intake is determined by learned appetitive responses and physiological “appetition” signals after eating begins. Here, authors show melanin-concentrating hormone (MCH)-producing neurons integrate these processes to promote caloric intake.

Abstract Hypoxia develops during the growth of solid tumors and influences tumoral activity in multiple ways. Low oxygen tension is also present in the bone microenvironment where Ewing sarcoma (EwS) – a highly aggressive pediatric cancer – mainly arises. Hypoxia inducible factor 1 subunit alpha (HIF-1-a) is the principal molecular mediator of the hypoxic response in cancer whereas EWSR1::FLI1 constitutes the oncogenic driver of EwS. Interaction of the two proteins has been shown in EwS. Although a growing body of studies investigated hypoxia and HIFs in EwS, their precise role for EwS pathophysiology is not clarified to date. This review summarizes and structures recent findings demonstrating that hypoxia and HIFs play a role in EwS at multiple levels. We propose to view hypoxia and HIFs as independent protagonists in the story of EwS and give a perspective on their potential clinical relevance as prognostic markers and therapeutic targets in EwS treatment.

Abstract Anthropogenic impacts on carnivores can be complex, posing numerous threats to many species, yet also benefits to those able to exploit certain resources. This balancing act is particularly precarious for those adapters that exploit dietary resources provided by humans, but still require other resources only available in native habitat. Here we measure the dietary niche of one such species, the Tasmanian devil (Sarcophilus harrisii), a specialised mammalian scavenger, across an anthropogenic habitat gradient stretching from cleared pasture to undisturbed rainforest. Populations inhabiting areas of greater disturbance showed restricted dietary niches, suggesting that all individuals fed on similar food items, even within regenerated native forest. Populations in undisturbed rainforest habitats had comparatively broad diets and showed evidence of niche partitioning by body size, which may reduce intraspecific competition. Despite the potential benefits of reliable access to high-quality food items in anthropogenically-modified habitats, the constrained niches we observed may be harmful, indicating altered behaviours and potentially increasing the rate of fights between individuals over food. This is of particular concern for a species at risk of extinction due to a deadly cancer primarily transmitted through aggressive interactions. The lack of diversity in devil diets within regenerated native forest compared to those in old-growth rainforest also indicates the conservation value of the latter for both the devil and the species which they consume.

Dreaming, a widely researched aspect of sleep, often mirrors waking-life experiences. Despite the prevalence of sensory perception during wakefulness, sensory experiences in dreams remain relatively unexplored. Free recall dream reports, where individuals describe their dreams freely, may not fully capture sensory dream experiences. In this study, we developed a dream diary with direct questions about sensory dream experiences. Participants reported sensory experiences in their dreams upon awakening, over multiple days, in a home-based setting (n = 3476 diaries). Our findings show that vision was the most common sensory dream experience, followed by audition and touch. Olfaction and gustation were reported at equally low rates. Multisensory dreams were far more prevalent than unisensory dreams. Additionally, the prevalence of sensory dream experiences varied across emotionally positive and negative dreams. A positive relationship was found between on the one hand sensory richness and, on the other emotional intensity of dreams and clarity of dream recall, for both positive and negative dreams. These results underscore the variety of dream experiences and suggest a link between sensory richness, emotional content and dream recall clarity. Systematic registration of sensory dream experiences offers valuable insights into dream manifestation, aiding the understanding of sleep-related memory consolidation and other aspects of sleep-related information processing.

Anorexia nervosa (AN) is a severe eating disorder that predominantly affects females and typically manifests during adolescence. There is increasing evidence that serum cytokine levels are altered in individuals with AN. Previous research has largely focused on adult patients, assuming a low-grade pro-inflammatory state. The serum levels of the cytokine tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and IL-15, which are pro-inflammatory, were examined in 63 female adolescents with AN and 41 age-matched healthy controls (HC). We included three time points (admission, discharge, and 1-year follow-up) and investigated the clinical data to assess whether the gut microbiota was associated with cytokine alterations. Relative to the HC group, serum levels of IL-1β and IL-6 were significantly lower during the acute phase (admission) of AN. IL-1β expression was normalised to control levels after weight recovery. TNF-α levels were not significantly different between the AN and HC groups. IL-15 levels were significantly elevated in patients with AN at all time points. We found associations between cytokines and bodyweight, illness duration, depressive symptoms, and the microbiome. In contrast to most findings for adults, we observed lower levels of the pro-inflammatory cytokines IL-1β and IL-6 in adolescent patients, whereas the level of IL-15 was consistently increased. Thus, the presence of inflammatory dysregulation suggests a varied rather than uniform pro-inflammatory state.

Cyclospora cayetanensis is a foodborne parasite that causes cyclosporiasis, an enteric illness in humans. Genotyping methods are used to genetically discriminate between specimens from cyclosporiasis cases and can complement source attribution investigations if the method is sufficiently sensitive for application to food items. A very sensitive targeted amplicon sequencing (TAS) assay for genotyping C. cayetanensis encompassing 52 loci was recently designed. In this study, we analyzed 66 genetically diverse clinical specimens to assess the change in phylogenetic resolution between the TAS assay and a currently employed eight-marker scheme. Of the 52 markers, ≥50 were successfully haplotyped for all specimens, and these results were used to generate a hierarchical cluster dendrogram. Using a previously described statistical approach to dissect hierarchical trees, the 66 specimens resolved into 24 and 27 distinct genetic clusters for the TAS and an 8-loci scheme, respectively. Although the specimen composition of 15 clusters was identical, there were substantial differences between the two dendrograms, highlighting the importance of both inclusion of additional genome coverage and choice of loci to target for genotyping. To evaluate the ability to genetically link contaminated food samples with clinical specimens, C. cayetanensis was genotyped from DNA extracted from raspberries inoculated with fecal specimens. The contaminated raspberry samples were assigned to clusters with the corresponding clinical specimen, demonstrating the utility of the TAS assay for traceback efforts.

Adverse experiences (e.g., acute stress) and alcohol misuse can both impair skeletal muscle homeostasis, resulting in reduced protein synthesis and greater protein breakdown. Exposure to acute stress is a significant risk factor for engaging in alcohol misuse. However, little is known about how these factors together might further affect skeletal muscle health. To that end, this study investigated the effects of acute stress exposure followed by a period of binge-patterned alcohol drinking on signaling factors along mouse skeletal muscle protein synthesis (MPS) and degradation (MPD) pathways. Young adult male C57BL/6J mice participated in the Drinking in the Dark paradigm, where they received 2–4 h of access to 20% ethanol (alcohol group) or water (control group) for four days to establish baseline drinking levels. Three days later, half of the mice in each group were either exposed to a single episode of uncontrollable tail shocks (acute stress) or remained undisturbed in their home cages (no stress). Three days after stress exposure, mice received 4 h of access to 20% ethanol (alcohol) to model binge-patterned alcohol drinking or water for ten consecutive days. Immediately following the final episode of alcohol access, mouse gastrocnemius muscle was extracted to measure changes in relative protein levels along the Akt-mTOR MPS, as well as the ubiquitin-proteasome pathway (UPP) and autophagy MPD pathways via Western blotting. A single exposure to acute stress impaired Akt singling and reduced rates of MPS, independent of alcohol access. This observation was concurrent with a potent increase in heat shock protein seventy expression in the muscle of stressed mice. Alcohol drinking did not exacerbate stress-induced alterations in the MPS and MPD signaling pathways. Instead, changes in the MPS and MPD signaling factors due to alcohol access were primarily observed in non-stressed mice. Taken together, these data suggest that exposure to a stressor of sufficient intensity may cause prolonged disruptions to signaling factors that impact skeletal muscle health and function beyond what could be further induced by periods of alcohol misuse.

The temporal regularities in our environments support the proactive dynamic anticipation of relevant events. In visual attention, one important outstanding question is whether temporal predictions must be linked to predictions about spatial locations or motor plans to facilitate behaviour. To test this, we developed a task for manipulating temporal expectations and task relevance of visual stimuli appearing within rapidly presented streams, while stimulus location and responding hand remained uncertain. Differently coloured stimuli appeared in one of two concurrent (left and right) streams with distinct temporal probability structures. Targets were defined by colour on a trial-by-trial basis and appeared equiprobably in either stream, requiring a localisation response. Across two experiments, participants were faster and more accurate at detecting temporally predictable targets compared to temporally unpredictable targets. We conclude that temporal expectations learned incidentally from temporal regularities can be called upon flexibly in a goal-driven manner to guide behaviour. Moreover, we show that visual temporal attention can facilitate performance in the absence of concomitant spatial or motor expectations in dynamically unfolding contexts.

Utah Lake is unusual due to its large surface area, shallow depth, phosphorus-rich sediments, and well-mixed, unstratified waters. This creates conditions where water column phosphorous concentrations tend toward equilibrium, with lake sediments containing high concentrations of geologic phosphorus. To help understand the potential impact of phosphorous load reductions, we computed a time history of phosphorus mass in the lake using state and federal records of lake volume, dissolved phosphorus concentrations, and outflow. We show that historically, Utah Lake phosphorus concentrations have remained stable over time, in the range of 0.02 to 0.04 mg/L, despite large changes in lake volume and internal phosphorus mass. We performed sorption calculations using data from the literature, demonstrating that it would take unrealistically large load changes to alter water column phosphorus concentrations under sorption processes. The sorption model produces results consistent with historical data that show relatively constant phosphorous concentrations despite large lake volume changes. We show, through several lines of evidence, that water column phosphorus concentrations are insensitive to external loads. Phosphorous load reduction is unlikely to have a significant effect on phosphorus concentrations in Utah Lake and, by extension, in other sorption-dominated shallow lakes with phosphorus-rich sediment.

Uninfected alligators (Alligator mississippiensis) exhibited high constitutive levels of hepatic gene expression related to immune function, whereas the highest-expressed hepatic genes of uninfected mice were related to metabolism. Intraperitoneal challenge of mice with bacterial lipopolysaccharide results in dramatic inflammatory effects including peritoneal ascites, febrile response, dramatic alterations in electrophoretic serum profile, and mortality. In contrast, coelomic injection of alligators with 200× the murine LD50 of intraperitoneal bacterial lipopolysaccharide resulted in no changes in serum protein profiles, behavioral effects, mortality, and no coelomic ascites. However, injection of juvenile alligators with live bacteria resulted in a titer-dependent decrease in metabolic rate, as measured by oxygen consumption. These results are the opposite of those observed for mammalian and avian species. The decreased oxygen consumption was not accompanied by changes in heart or respiration rate, indicating that this phenomenon was not due to bradycardia or bradypnea. Interestingly, challenge of alligators with bacteria resulted in the complete expulsion of digestive tract contents within four hours. We interpret these activities as temporary minimization of other biological systemic activities to redirect and devote energy to immune function. The reallocation of resources within an organism to fight infection without increases in metabolic rate has not been described in other animals.

Objective This paper aims to report our experience of developing, implementing, and evaluating myHealthE (MHE), a digital innovation for Child and Adolescents Mental Health Services (CAMHS), which automates the remote collection and reporting of Patient-Reported Outcome Measures (PROMs) into National Health Services (NHS) electronic healthcare records. Methods We describe the logistical and governance issues encountered in developing the MHE interface with patient-identifiable information, and the steps taken to overcome these development barriers. We describe the application's architecture and hosting environment to enable its operability within the NHS, as well as the capabilities needed within the technical team to bridge the gap between academic development and NHS operational teams. Results We present evidence on the feasibility and acceptability of this system within clinical services and the process of iterative development, highlighting additional functions that were incorporated to increase system utility. Conclusion This article provides a framework with which to plan, develop, and implement automated PROM collection from remote devices back to NHS infrastructure. The challenges and solutions described in this paper will be pertinent to other digital health innovation researchers aspiring to deploy interoperable systems within NHS clinical systems.

Objectives Health and care resources are under increasing pressure, partly due to the ageing population. Physical activity supports healthy ageing, but motivating exercise is challenging. We aimed to explore staff perceptions towards a virtual reality (VR) omnidirectional treadmill (MOTUS), aimed at increasing physical activity for older adult care home residents.Design Interactive workshops and qualitative evaluation.Settings Eight interactive workshops were held at six care homes and two university sites across Cornwall, England, from September to November 2021.Participants Forty-four staff participated, including care home, supported living, clinical care and compliance managers, carers, activity coordinators, occupational therapists and physiotherapists.Interventions Participants tried the VR treadmill system, followed by focus groups exploring device design, potential usefulness or barriers for care home residents. Focus groups were audio-recorded, transcribed verbatim and thematically analysed. We subsequently conducted a follow-up interview with the technology developer (September 2022) to explore the feedback impact.Results The analysis produced seven key themes: anticipated benefits, acceptability, concerns of use, concerns of negative effects, suitability/unsuitability, improvements and current design. Participants were generally positive towards VR to motivate care home residents’ physical activity and noted several potential benefits (increased exercise, stimulation, social interaction and rehabilitation). Despite the reported potential, staff had safety concerns for frail older residents due to their standing position. Participants suggested design improvements to enhance safety, usability and accessibility. Feedback to the designers resulted in the development of a new seated VR treadmill to address concerns about falls while maintaining motivation to exercise. The follow-up developer interview identified significant value in academia–industry collaboration.Conclusion The use of VR-motivated exercise holds the potential to increase exercise, encourage reminiscence and promote meaningful activity for care home residents. Staff concerns resulted in a redesigned seated treadmill for those too frail to use the standing version. This novel study demonstrates the importance of stakeholder feedback in product design.

IntroductionPeople living with HIV (PLHIV) are characterized by functional reprogramming of innate immune cells even after long-term antiretroviral therapy (ART). In order to assess technical feasibility of omics technologies for application to larger cohorts, we compared multiple omics data layers.MethodsBulk and single-cell transcriptomics, flow cytometry, proteomics, chromatin landscape analysis by ATAC-seq as well as ex vivo drug stimulation were performed in a small number of blood samples derived from PLHIV and healthy controls from the 200-HIV cohort study.ResultsSingle-cell RNA-seq analysis revealed that most immune cells in peripheral blood of PLHIV are altered in their transcriptomes and that a specific functional monocyte state previously described in acute HIV infection is still existing in PLHIV while other monocyte cell states are only occurring acute infection. Further, a reverse transcriptome approach on a rather small number of PLHIV was sufficient to identify drug candidates for reversing the transcriptional phenotype of monocytes in PLHIV.DiscussionThese scientific findings and technological advancements for clinical application of single-cell transcriptomics form the basis for the larger 2000-HIV multicenter cohort study on PLHIV, for which a combination of bulk and single-cell transcriptomics will be included as the leading technology to determine disease endotypes in PLHIV and to predict disease trajectories and outcomes.

Weight recurrence after one-anastomosis gastric bypass (OAGB), the third most common metabolic and bariatric surgery performed worldwide, is observed in a subset of patients due to the chronic, progressive nature of obesity. Endoscopic revision of the OAGB (ER-OAGB) through full-thickness suturing to reduce the gastrojejunal anastomosis and gastric pouch is a potential alternative to surgical revision. Here, we present a case series of ER-OAGB and long-term nutritional support at two international centers with expertise in bariatric endoscopy. Data were retrospectively evaluated from a prospectively maintained database. The primary outcome was total body weight loss (TBWL) at 12 months. Secondary outcomes included TBWL at 3, 6, and 15 months; excess weight loss (EWL) at 3, 6, 12, and 15 months; frequency of new/worsening symptoms of gastroesophageal reflux disease (GERD); and the frequency of serious adverse events. In this series, 17 adults (70.6% female, mean age 46.8 years, mean BMI 39.1 kg/m 2 ) successfully underwent ER-OAGB an average of 8 years (range 2–21 years) after OAGB for a mean weight recurrence of 43.2% (range 10.9–86.9%). TBWL from ER-OAGB was 9.7 ± 1.8% at 3 months, 13.4 ± 3.5% at 6 months, 18.5 ± 2.1% at 12 months, and 18.1 ± 2.2% at 15 months. EWL from ER-OAGB was 30.5 ± 14.7% at 3 months, 42.6 ± 16.2% at 6 months, 54.2 ± 11.3% at 12 months, and 54.2 ± 11.7% at 15 months. There were no instances of new/worsening GERD symptoms or serious adverse events. In this small series of adults who experienced weight recurrence after OAGB, ER-OAGB facilitated safe and clinically meaningful weight loss, without new or worsening GERD symptoms, when performed by experienced bariatric endoscopists in concert with longitudinal nutritional support.

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAFV600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others.

Wavelength conversion via four-wave mixing holds great promise for the construction of broadband and tunable light sources at wavelengths beyond 2 μm. In this work, we design and fabricate a tapered silicon core optical fiber with a dispersion profile that supports efficient conversion spanning the telecom band up to the edge of the mid-infrared spectral region over an extended propagation length. By pumping with a fiber laser centered around 1.99 μm, a tuning range of 690 nm has been measured, although simulations predict that a bandwidth of up to 1255 nm could be observed if a suitable seed source was available. Conversion efficiencies of ∼−30 dB have been obtained over a bandwidth of 380 nm when using an input pump power of only 6 dBm, with a maximum efficiency of −18 dB achieved when the conversion overlaps the strong Raman gain of the silicon core.

Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.

Summary: Spatially resolved omics technologies reveal context-dependent cellular regulatory networks in tissues of interest. Beyond transcriptome analysis, information on epigenetic traits and chromatin accessibility can provide further insights on gene regulation in health and disease. Nevertheless, compared to the enormous advancements in spatial transcriptomics technologies, the field of spatial epigenomics is much younger and still underexplored. In this study, we report laser capture microdissection coupled to ATAC-seq (LCM-ATAC-seq) applied to fresh frozen samples for the spatial characterization of chromatin accessibility. We first demonstrate the efficient use of LCM coupled to in situ tagmentation and evaluate its performance as a function of cell number, microdissected areas, and tissue type. Further, we demonstrate its use for the targeted chromatin accessibility analysis of discrete contiguous or scattered cell populations in tissues via single-nuclei capture based on immunostaining for specific cellular markers. Motivation: Spatial epigenomics is still underexplored compared to the advanced evolution of spatial transcriptomics technologies. Different methods have been proposed recently, with distinct advantages and drawbacks concerning the achievable resolution, the possibility to overlay a morphological staining, and the overall applicability. In this study, we report the targeted use of LCM for the investigation of chromatin accessibility. This spatial methodology enables the analysis of scattered tissue cell populations at a mini-bulk resolution, with the possibility to integrate cellular or morphological stainings on the same processed section.

The structure of pollination networks is critical to ecosystem stability and functioning. We investigated pollinator-plant interactions to understand the foraging preference and develop pollination networks in a semi-arid rangeland of different grazing management categories in Tanzania. Along three line transects, each measuring 100 m, in each of the four grazing management categories (private and communal enclosures, wet and dry season grazing areas), we laid out three quadrats measuring 5 m x 5 m (25 m2,) located 30 m apart. We recorded insects visiting flowering plants for two consecutive days in each quadrat every week at each site from April to May, in 2019 and 2020. Aspilia mossambicensis received the most significant proportion of insect visitors (28%), followed by Justicia debile (21%). The mean protein concentration in sampled pollen varied significantly between plant species (χ² = 25.9, P = 0.001), with Solanum incanum containing the highest concentration (299.3 ± 0.68) g/100 g. We did not notice any correlation between honey bee visitation and protein concentration in pollen (r = −0.471, P = 0.239) nor with fatty acids concentration (r = 0.253, P = 0.546). When comparing pollinator-plant network properties including connectance, nestedness, robustness, number of links, modularity, network diversity and linkage density across rangeland management, we found that the private enclosure contained significantly larger networks than the communal enclosure, the dry and the wet season grazing sites. We conclude that particularly private enclosures are vital to promote pollination networks in our studied rangeland system as they include important pollinator forage plants.

Health behaviours such as being physically active and having good quality sleep have been associated with decreased susceptibility to infection and stronger antibody responses to vaccination. Less is known about how such factors might influence the maintenance of immunity following naturalistic infection and/or prior vaccination, particularly among older adults who may have formed initial antibodies some time ago. This analysis explored antibody levels against a range of common infectious diseases in 104 older adults (60 women) aged 65+ years, and whether these relate to self-reported physical activity (PA) and sleep. PA and sleep were measured subjectively through standardized questions. Antibody levels to a range of common pathogens, including pneumococcal (Pn) and meningococcal (Men) serotypes, Haemophilus influenza type b, diphtheria, and tetanus were assayed using Multiplex technology. Higher PA at baseline related to higher antibody levels against three Pn serotypes and MenY, and higher PA at one month with higher levels against six Pn serotypes. Longer time in bed related to higher antibody levels against Pn4, and longer sleep related to higher levels against Pn19f. More difficulty staying awake in the day related to lower antibodies against Pn19a, Pn19f, MenA and MenY, and more frequent daytime napping related to lower levels against three Pn serotypes and MenY. Using clinically protective antibody thresholds as an outcome showed similar results for PA, but effects for sleep became non-significant, with the exception of time in bed. This extends beyond existing literature demonstrating associations between PA and sleep and peak antibody response to vaccination to antibody maintenance. Longitudinal research with objective measures of health behaviours is warranted.

Migration patterns are fundamentally linked to the spatio-temporal distributions of prey. How migrating animals can respond to changes in their prey's distribution and abundance remains largely unclear. During the last decade, humpback whales (Megaptera novaeangliae) used specific winter foraging sites in fjords of northern Norway, outside of their main summer foraging season, to feed on herring that started overwintering in the area. We used photographic matching to show that whales sighted during summer in the Barents Sea foraged in northern Norway from late October to February, staying up to three months and showing high inter-annual return rates (up to 82%). The number of identified whales in northern Norway totalled 866 individuals by 2019. Genetic sexing and hormone profiling in both areas demonstrate a female bias in northern Norway and suggest higher proportions of pregnancy in northern Norway. This may indicate that the fjord-based winter feeding is important for pregnant females before migration. Our results suggest that humpback whales can respond to foraging opportunities along their migration pathways, in some cases by continuing their feeding season well into winter. This provides an important reminder to implement dynamic ecosystem management that can account for changes in the spatio-temporal distribution of migrating marine mammals.

Summary: Background: Despite significant progress in the areas of prevention, diagnosis, and treatment, HIV continues to result in a substantial number of fatalities on a global scale each year. Gaining insights from epidemiological data can prove instrumental in the development of health promotion strategies, particularly within vulnerable populations, such as indigenous groups. Consequently, our study aimed to investigate the prevalence of HIV infection within the indigenous population residing in the second-largest region of Brazil. Additionally, we sought to explore the subtypes of HIV-1 and detect any drug-resistance mutations present within this population. Methods: In this cross-sectional study, we aimed to evaluate the prevalence of HIV-1 infection and explore its associated characteristics within the indigenous population residing in the villages of Jaguapiru and Bororó, located in the Dourados area of Mato Grosso do Sul (MS), Brazil. Blood samples were collected for rapid HIV screening, serological tests, nucleic acid amplification, and HIV subtyping. Additionally, the HIV-1 viral load and CD4+ T lymphocyte count of the people living with HIV (PLHIV) were assessed at the time of recruitment and 24 weeks later. Findings: Out of the 2190 invited individuals, 1927 (88%) were included in this study. The average age of the participants was 34.2 (±13.8) years, with a majority of 74% being female. Moreover, 68.44% of the participants identified themselves as belonging to the Guarani-Kaiowa ethnic group. HIV seroprevalence was 0.93% (18/1927), and 73.22% (1411/1927) were unaware of their serological status. The prevalence of HIV-1 was higher in single indigenous people [10/617 (1.62%)], who received government benefits [14/1021 (1.37%)], had less than five years of formal education [11/685 (1.61%)], had sexual intercourse with users of injectable drugs [2/21 (9.52%)], with history of sexually transmitted infections (STIs) [10/62 (16.2%)] and incarceration [3/62 (4.84%)]. Of 18 positive samples, 44.4% (8/18) were successfully amplified, and HIV-1 subtype C was prevalent. Furthermore, we identified HIV-1 drug resistance mutations in four patients, specifically from the classes of Protease Inhibitor, Nucleoside Reverse Transcriptase Inhibitor, and Non-Nucleoside Reverse Transcriptase Inhibitor. Notably, three of these patients exhibited a high viral load even after 24 weeks of undergoing antiretroviral therapy. Out of the 18 PLHIV, 66.66% (12/18) had a viral load below 1000 copies/mL, while 50% (9/18) had a CD4+ T lymphocytes count greater than 350 cells/mL after 24 weeks of treatment. Interpretation: Despite the concerted efforts to control HIV infection, the prevalence observed in the indigenous population under study surpassed that reported in other Brazilian indigenous groups. This disparity highlights the disproportionate impact of the disease on this particular group. The detection of drug-resistance mutations further emphasizes the critical need to expand diagnostic coverage, closely monitor treatment strategies, and maintain ongoing molecular surveillance. These measures are imperative for enhancing HIV management within this vulnerable population. Funding: This study was partially funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Estado de Mato Grosso do Sul (FUNDECT), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Secretaria do Estado de Saúde (SES) of Governo do Estado de Mato Grosso do Sul, and Universidade Federal da Grande Dourados (UFGD).

We present here the first climatology of extreme sub-daily rainfall for a large part of western Europe, developed using a newly developed set of sub-daily rainfall indices, derived from a recently created global sub-daily rainfall (GSDR) dataset. The indices describe sub-daily (3-hourly) rainfall extremes in terms of their intensity, frequency and timing. Analysis of the frequency index (number of 3hr periods with >20 mm rain (R3hr20mm)) and a suite of intensity indices including the annual maxima (Rx3hr) and values of the 99.9th percentile at each gauge (R99.9p3hr) indicate a peak in the frequency and intensity of short-duration rainfall extremes in summer across most of western Europe, while areas around the north-west Mediterranean experience the highest intensities and frequencies of 3-hr rainfall in autumn. The index of contribution from 3-h annual maxima to the daily total (Rx3hrP) indicates that these events are often produced by very short-duration or very peaked storms, with a tendency towards a late afternoon or evening peak in the time of occurrence. There are also clear differences in the spatiotemporal occurrence of the sub-daily extremes when compared to extreme daily rainfall indices, which could have repercussions for flood management. Additional analysis of the sub-daily rainfall indices within the context of Köppen-Geiger climate zones indicates Mediterranean-type climate zones experience more intense and more frequent sub-daily extremes, while the intensity of rainfall within cooler climate zones is lower and the most intense events are restricted to summer. The climate zones are found to be a relatively good indicator of the extreme rainfall characteristics that can be expected in a region. Being able to compare sub-daily rainfall characteristics across a wide region in this manner greatly enhances our ability to investigate future variability and change in sub-daily extremes and will aid in high-resolution climate model validation.

Official reports and academic studies call for profound and immediate transformations in how businesses relate to biodiversity. The urgency is such that the first draft of the Post-2020 Global Biodiversity Framework (GBF) of the Convention of Biological Diversity has a specific target aimed at full sustainability in biodiversity practices in businesses by 2030. Brazil—a country with the greatest reservoir of biodiversity and the 12th largest economy on the planet —should be fertile ground for new developments and innovations on this front. However, the shortage of academic engagement with businesses in the country may impede this path. We propose six biodiversity-related innovation fronts and opportunities for engagement between high education institutions and companies in Brazil. We reviewed the literature regarding two sets of practices: pressing issues (including environmental licensing, biodiversity offsets, and conservation in private reserves), and new business opportunities (sustainable bioeconomy, access and benefit sharing – ABS, and environmental and social governance – ESG). Such themes have direct relevance to the Post-2020 GBF business sustainability target and potential national impact. There is plenty of room for academic engagement with businesses in all cases. Examples include supporting definition of metrics and standards, providing information systems to increase transparency, among others. In conclusion, we argue that an innovative mindset from corporations and academics will be necessary before Brazilian businesses can move on to develop innovative and sustainable processes and products related to biodiversity.

Abstract Color vision deficiency impairs one’s ability to perceive and discriminate colors. Color-deficient individuals may face discrimination in various occupations, particularly in medical school admissions. This discussion seeks to compare the existing color vision requirements for entry to medical school in Southeast Asian countries as compared to countries across the world. Following this, we explore the published evidence in this field, to provide recommendations for future guidelines that will maximize the occupational opportunities for color-deficient individuals.

Abstract Background Chronic obstructive pulmonary disease (COPD) is characterized by irreversible lung tissue damage. Novel regenerative strategies are urgently awaited. Cultured mesenchymal stem/stromal cells (MSCs) have shown promising results in experimental models of COPD, but differences between sources may impact on their potential use in therapeutic strategies in patients. Aim To assess the transcriptome of lung-derived MSCs (LMSCs), bone marrow-derived MSCs (BM-MSC) and adipose-derived MSCs (AD-MSCs) from COPD patients and non-COPD controls. Methods We studied differences in gene expression profiles between the MSC-subtypes, as well as between COPD and control using RNA sequencing (RNA-seq). Results We show that besides heterogeneity between donors, MSCs from different sources have strongly divergent gene signatures. The growth factors FGF10 and HGF were predominantly expressed in LMSCs. MSCs from all sources displayed altered expression profiles in COPD, with most pronounced significantly up- and downregulated genes in MSCs from adipose tissue. Pathway analysis revealed that the most differentially expressed genes in COPD-derived AD-MSCs are involved in extracellular matrix (ECM) binding and expression. In LMSCs, the gene that differed most strongly between COPD and control was CSGALNACT1, an ECM modulating gene. Conclusion Autologous MSCs from COPD patients display abnormalities with respect to their transcriptome, which were surprisingly most profound in MSCs from extrapulmonary sources. LMSCs may be optimally equipped for lung tissue repair because of the expression of specific growth factor genes.

Meningiomas are the most frequent central nervous system tumors in adults. The majority of these tumors are benign. Nevertheless, the intraoperative identification of meningioma grade is important for modifying surgical strategy in order to reduce postoperative complications. Here, we set out to investigate the role of intraoperative flow cytometry for the differentiation of low-grade (grade 1) from high-grade (grade 2–3) meningiomas. The study included 59 patients. Intraoperative flow cytometry analysis was performed using the ‘Ioannina Protocol’ which evaluates the G0/G1 phase, S-phase, mitosis and tumor index (S + mitosis phase fraction) of a tumor sample. The results are available within 5 min of sample receipt. There were 41 grade 1, 15 grade 2 and 3 grade 3 meningiomas. High-grade meningiomas had significantly higher S-phase fraction, mitosis fraction and tumor index compared to low-grade meningiomas. High-grade meningiomas had significantly lower G0/G1 phase fraction compared to low-grade meningiomas. Thirty-eight tumors were diploids and twenty-one were aneuploids. No significant difference was found between ploidy status and meningioma grade. ROC analysis indicated 11.4% of tumor index as the optimal cutoff value thresholding the discrimination between low- and high-grade meningiomas with 90.2% sensitivity and 72.2% specificity. In conclusion, intraoperative flow cytometry permits the detection of high-grade meningiomas within 5 min. Thus, surgeons may modify tumor removal strategy.

Two causes of intellectual disability are 15q13.3 deletion syndrome and BRWD3 X-linked intellectual disability. 15q13.3 deletion syndrome causes a heterogenous phenotype including intellectual disability (ID), developmental delay (DD), autism spectrum disorder, epilepsy/seizures, schizophrenia, attention deficit hyperactivity disorder, visual defects, hypotonia, and short stature. BRWD3 variants are rare, and the clinical presentation is largely unknown. Presented here is a 34-month-old male with developmental regression, global DD, hypotonia, and short stature. In this study, the patient and his mother underwent a whole-genome array screening. Sorting intolerant from tolerant (SIFT) and polymorphism phenotyping v2 (PolyPhen-2) analyses were performed to determine the pathogenicity of the BRWD3 mutation. Array comparative genomic hybridization showed a heterozygous, pathogenic deletion of at least 1.6 Mb from the cytogenetic band 15q13.2q13.3 and a BRWD3 variant of unknown clinical significance. This combination of genetic mutations has never been reported together and neither disorder is known to cause developmental regression. The mechanism of developmental regression is undefined but is of great importance due to the opportunity to develop therapies for these patients.

The authors show that the Martian crust, ~4300 km from the InSight landing site, has a subsurface interface similar to that beneath the lander, suggesting it is a regional or global feature that may be related to the closure of pore spaces at depth.

Abstract Background Monitoring the adaptation of microorganisms to the extreme environment of the International Space Station (ISS) is crucial to understanding microbial evolution and infection prevention. Acinetobacter pittii is an opportunistic nosocomial pathogen, primarily impacting immunocompromised patients, that was recently isolated from two missions aboard the ISS. Results Here, we report how ISS-associated A. pittii (n = 20 genomes) has formed its own genetically and functionally discrete clade distinct from most Earth-bound isolates (n = 291 genomes). The antimicrobial susceptibility testing of ISS strains and two related clinical isolates demonstrated that ISS strains acquired more resistance, specifically with regard to expanded-spectrum cephalosporins, despite no prediction of increased resistance based on genomic analysis of resistance genes. By investigating 402 longitudinal environmental and host-associated ISS metagenomes, we observed that viable A. pittii is increasing in relative abundance and therefore potentially exhibiting succession, being identified in >2X more metagenomic samples in back-to-back missions. ISS strains additionally contain functions that enable them to survive in harsh environments, including the transcriptional regulator LexA. Via a genome-wide association study, we identified a high level of mutational burden in methionine sulfoxide reductase genes relative to the most closely related Earth strains. Conclusions Overall, these results indicated a step forward in understanding how microorganisms might evolve and alter their antibiotic resistance phenotype in extreme, resource-limited, human-built environments. Video Abstract

Abstract Background Malaria remains a major cause of morbidity and mortality in sub-Saharan Africa. Using insecticide-treated nets (ITNs) every night, year-round is critical to maximize protection against malaria. This study describes sociodemographic, psychosocial, and household factors associated with consistent ITN use in Cameroon, Côte d’Ivoire and Sierra Leone. Methods Cross-sectional household surveys employed similar sampling procedures, data collection tools, and methods in three countries. The survey sample was nationally representative in Côte d’Ivoire, representative of the North and Far North regions in Cameroon, and representative of Bo and Port Loko districts in Sierra Leone. Analysis used multilevel logistic regression and sociodemographic, ideational, and household independent variables among households with at least one ITN to identify correlates of consistent ITN use, defined as sleeping under an ITN every night the preceding week. Findings Consistent ITN use in Côte d’Ivoire was 65.4%, 72.6% in Cameroon, and 77.1% in Sierra Leone. While several sociodemographic and ideational variables were correlated with consistent ITN use, these varied across countries. Multilevel logistic regression results showed perceived self-efficacy to use ITNs and positive attitudes towards ITN use were variables associated with consistent use in all three countries. The perception of ITN use as a community norm was positively linked with consistent use in Cameroon and Côte d’Ivoire but was not significant in Sierra Leone. Perceived vulnerability to malaria was positively linked with consistent use in Cameroon and Sierra Leone but negatively correlated with the outcome in Côte d’Ivoire. Household net sufficiency was strongly and positively associated with consistent use in all three countries. Finally, the findings revealed strong clustering at the household and enumeration area (EA) levels, suggesting similarities in net use among respondents of the same EA and in the same household. Conclusions There are similarities and differences in the variables associated with consistent ITN use across the three countries and several ideational variables are significant. The findings suggest that a social and behaviour change strategy based on the ideation model is relevant for increasing consistent ITN use and can inform specific strategies for each context. Finally, ensuring household net sufficiency is essential.

Nucleosome profiling from cell-free DNA (cfDNA) represents a potential approach for cancer detection and classification. Here, the authors develop Griffin, a computational framework for tumour subtype classification based on cfDNA nucleosome profiling that can work with ultra-low pass sequencing data.

We describe fatal phaeohyphomycosis due to Veronaea botryosa in captive White’s tree frogs (Litoria caerulea), the first confirmed report in amphibians in North America. Over 15 months, six frogs developed ulcerative dermatitis on distal extremities/ventrum, which in one animal progressed to vasculitis and necrotizing osteomyelitis. All six frogs died. Clinicopathologic findings, diagnostic challenges, and control are discussed. Emerging fungi such as V. botryosa pose serious concerns for zoonosis and potential spread through the pet trade.

Objectives: Venetoclax combinations are a new standard for patients with acute myeloid leukemia (AML). We aimed to evaluate the safety and efficacy of these combinations in a period of accelerated approval in Latin-America. Methods: This observational study evaluated adults with acute myeloid leukemia who received venetoclax-based therapy in 11 public or private centers in Mexico and Peru for both newly diagnosed or relapsed and refractory AML. Results: Fifty patients were included; 28 with newly diagnosed (ND) AML and 22 with relapsed/refractory (RR) disease. ND patients were older (64 vs. 40 years; p < 0.001) with a lower functional capacity (ECOG ≥2 64.3% vs 9%; p < 0.001). Venetoclax was frequently combined with azacytidine (60%) and prophylactic azoles (82%) with a median maximum dose of 200 mg (range, 100–600 mg). Hematologic toxicities were common. Complete response rates including patients with incomplete hematopoietic recovery were 78.6% in ND and 45.5% in RR patients, with a median overall survival of 9.6 (95% CI 3.7–15.5) and 8 months (95% CI 4.8–11.2). Discussion: Our study showed a preferred use of venetoclax plus azacytidine over cyatrabine. Patients in the first-line setting were similar to those in the landmark studies, while most patients with relapsed disease had received prior intensive therapies. Responses were favorable, with a median survival in agreement to other reports, albeit shorter than that observed in the randomized phase-3 trials. Conclusion: Venetoclax-based therapy in AML was effective despite dose reductions and prophylactic antifungals in two middle-income countries outside of a clinical trial setting.