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Testing of ducks in Tennessee, United States, before introduction of highly pathogenic influenza A(H5N1) virus demonstrated a high prevalence of antibodies to influenza A virus but very low prevalence of antibodies to H5 (25%) or H5 and N1 (13%) subtypes. Antibody prevalence increased after H5N1 introduction.

Abstract The Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines, along with the updated ARRIVE 2.0, provide a crucial framework for transparent reporting in animal research. These guidelines enhance the quality and reproducibility of studies while supporting animal welfare. However, concerns persist regarding the reporting practices of biomedical researchers in scientific articles related to anesthesia and analgesia despite the endorsement of ARRIVE guidelines, as has been demonstrated in previous descriptive analyses. The current study systematically reviews articles published from 2016 to 2023 that involve rodent orthopedic surgeries. These procedures were selected as our focus given that anesthetics and analgesics are essential for such high impact procedures. We highlight significant reporting gaps, noting that anesthetic and analgesic details were missing in 29.4% and 74.8% of the articles, respectively. Our findings reveal no correlation between reporting completeness and journal impact factors, indicating that this issue generalized across journals. Furthermore, among articles that did report analgesia use, we observed a low prevalence of multimodal analgesia. Overall, this study underscores the urgent need to develop effective strategies to improve reporting of anesthesia and analgesia in animal studies to enhance ethical standards, animal welfare, and the robustness and reproducibility of research.

Abstract Our group has developed an extra-uterine environment for newborn development (EXTEND) using an ovine model, that aims to mimic the womb to improve short and long-term health outcomes associated with prematurity. This study’s objective was to determine the histologic and transcriptomic consequences of EXTEND on the brain. Histology and RNA-sequencing was conducted on brain tissue from three cohorts of lambs: control pre-term (106–107 days), control late pre-term (127 days), and EXTEND lambs who were born pre-term and supported on EXTEND until late pre-term age (125–128 days). Bioinformatic analysis determined differential gene expression among the three cohorts and across four different brain tissue sections: basal ganglia, cerebellum, hippocampus, and motor cortex. There were no clinically relevant histological differences between the control late pre-term and EXTEND ovine brain tissues. RNA-sequencing demonstrated that there was greater differential gene expression between the control pre-term lambs and EXTEND lambs than between the control late pre-term lambs and EXTEND lambs (Supplemental Figs. 1 and 2). Our study demonstrates that the use of EXTEND to support pre-term lambs until they reach late pre-term gestational age results in brain tissue gene expression that more closely resembles that of the lambs who reached late pre-term gestation within their maternal sheep’s womb than that of the lambs who were born prematurely.

Abstract Background As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant benefit of elamipretide treatment in a genotypically diverse population of adults with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide experienced an improvement in the six-minute walk test (6MWT), while the cohort of subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus placebo. These published findings prompted additional genotype-specific post hoc analyses of the MMPOWER-3 trial. Here, we present these analyses to further investigate the findings and to seek trends and commonalities among those subjects who responded to treatment, to build a more precise Phase 3 trial design for further investigation in likely responders. Results Subjects with mtDNA pathogenic variants or single large-scale mtDNA deletions represented 74% of the MMPOWER-3 population, with 70% in the mtDNA cohort having either single large-scale mtDNA deletions or MT-TL1 pathogenic variants. Most subjects in the nDNA cohort had pathogenic variants in genes required for mtDNA maintenance (mtDNA replisome), the majority of which were in POLG and TWNK. The mtDNA replisome post-hoc cohort displayed an improvement on the 6MWT, trending towards significant, in the elamipretide group when compared with placebo (25.2 ± 8.7 m versus 2.0 ± 8.6 m for placebo group; p = 0.06). The 6MWT results at week 24 in subjects with replisome variants showed a significant change in the elamipretide group subjects who had chronic progressive external ophthalmoplegia (CPEO) (37.3 ± 9.5 m versus − 8.0 ± 10.7 m for the placebo group; p = 0.0024). Pharmacokinetic (exposure–response) analyses in the nDNA cohort showed a weak positive correlation between plasma elamipretide concentration and 6MWT improvement. Conclusions Post hoc analyses indicated that elamipretide had a beneficial effect in PMM patients with mtDNA replisome disorders, underscoring the importance of considering specific genetic subtypes in PMM clinical trials. These data serve as the foundation for a follow-up Phase 3 clinical trial (NuPOWER) which has been designed as described in this paper to determine the efficacy of elamipretide in patients with mtDNA maintenance-related disorders. Classification of evidence Class I ClinicalTrials.gov identifier NCT03323749

Abstract Variably Protease Sensitive Prionopathy (VPSPr) is a rare human prion disease that, like Creutzfeldt-Jakob disease (CJD), results in the deposition of abnormally folded prion protein aggregates in the brain and is ultimately fatal. Neuropathology and clinical features of VPSPr are heterogeneous. However, the key discriminating feature is the relative sensitivity of the pathological prion protein to proteinase digestion compared to that typically seen in other human prion cases. Three major fragments of 23, 17 and 7 kDa are characteristic of the disease following digestion with proteinase K. We recently reported the utility of the highly adaptive and reproducible ProteinSimple™ capillary electrophoresis (CE) system to perform protein separation of PK digested prion protein in CJD. Consequently, we explored capillary-based electrophoresis (CE) technology as a sensitive method to detect and characterize VPSPr in a cohort of 29 cases. The unique 7 kDa fragment has high intensity, particularly in cases with the codon 129 VV genotype, but can be missed by regular Western blotting due to the small size. However, this fragment is readily detected by CE in all cases. In addition, the flexibility of CE produced highly reproducible, semi-quantitative data for determining relative proteinase K sensitivity and epitope mapping of representative cases from each codon 129 genotype (VV, MV and MM).

Abstract Background Dietary intake plays a pivotal role in the prevalence and management of obesity. While women and men exhibit differences in dietary habits and food-related behaviors, sex-based weight loss recommendations are lacking. This study aims to examine the impact of specific foods and food categories on weight reduction in men and women over a two-year period. Methods A total of 8,548 participants from the 10K cohort, from 2019 to 2023, were included in the analysis (53.1% women, mean age 51.7 years). Anthropometric measurements and laboratory results were collected at baseline and at the two-year follow-up visit. Dietary assessment was based on daily food intake digitally logged through an application for at least 3 consecutive days at both timepoints. We compared intake of macronutrients, micronutrients, food groups and daily energy consumption between sex and body mass index (BMI) categories at baseline and weight change categories at follow-up. Using linear regression, we assessed the associations between food categories or specific foods and BMI at baseline as well as weight change percentage at follow-up. Results Dietary habits varied by BMI and sex. Women and men living with obesity (BMI > 30 kg/m2) reported a greater intake of animal-based protein and lower intake of plant-based proteins and fats at baseline, as compared to participants with normal weight. In linear regression models predicting two-year weight change, including age, income, and baseline weight, the explained variance was 5.6% for men and 5.8% for women. Adding food categories and specific foods increased the explained variance to 20.6% for men and 17.5% for women. Weight reduction in men was linked to daily consumption of an egg (1.2% decrease) and beef (1.5% decrease), while in women, the most pronounced reductions were associated with an apple (1.2% decrease) and cashew nuts (3.4% decrease). Notably, total energy intake changes significantly impacted weight outcomes only in women. Conclusions Sex-specific dietary habits significantly influence weight change over time. In men, weight loss was primarily associated with the addition of animal-based protein, while in women, it was linked to caloric deficit and plant-based fat, suggesting that sex-based nutritional interventions may demonstrate greater efficacy. Trial registration NCT05817734 (retrospectively registered January 31, 2023).

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface malignancies. However, surgical morbidity is high, and prediction of severe postoperative complications (SPC) is limited. We hypothesized that the changes in thromboelastogram (TEG) values following CRS could be associated with SPC.

Abstract The gold standard to estimate muscle mass and quality is computed tomography (CT) scan. Lower mass and density (intramuscular fat infiltration) of skeletal muscles are markers of sarcopenia, associated with increased mortality risk, impaired physical function, and poorer prognosis across various populations and medical conditions. We aimed to describe standard reference values in healthy population, prospective kidney donors, and correlate clinical parameters to muscle mass and density. Included in the cohort 384 consecutive kidney donors. Mean age was 44.6 ± 11.5 (range 18.4–74.2), 46% were female and mean BMI was 25.6 ± 3.8 kg/m2. Our quantified reference values for psoas cross -sectional area (CSA) index at L3 level (males/females respectively) were 6.3 ± 1.8 and 4.8 ± 1.9 cm2 /m2, and density was 46.1 ± 5 and 41 ± 5 HU at that level. Older age (standardized beta coefficient − 0.12, p = 0.04), sex (− 0.32, p

Abstract In track cycling, performance in the team pursuit depends on the mechanical and physiological abilities of each member of the team, but also on the choice of racing strategy. Athletes must cover the 4000 m of the race, sharing the effort between them in successive relays. This raises the question of the optimum strategy. We propose a method for resolving this question by coupling a mechanical model of the race to physiological models (digital twins) of the athletes. The mechanical model enables one to predict a theoretical finishing time for a given strategy, while the physiological model enables one to determine whether or not a given strategy is feasible. By coupling the two models and using numerical optimization, an optimal strategy for a given team can then be predicted. Simplified team composition case studies are explored. For each case studied, an optimal strategy to maximize performance is obtained and composed of a set of three variables: relay lengths, power values for each relay, and the starting order of cyclists. The proposed method can be used for real athletes and extended to other disciplines.

Abstract Background Brain metastasis (BM) is a rare but severe complication of head and neck squamous cell carcinoma (HNSCC), with limited knowledge of molecular characteristics and immunogenicity. Methods We analyzed 61 cases of HNSCC-BM from three academic institutions (n = 24) and Foundation Medicine Inc (FMI, n = 37). A subset of cases underwent next-generation sequencing, multiple immunofluorescence, and proximity ligation sequencing. Gene enrichment analysis compared alterations in FMI BM samples (n = 37) with local samples (n = 4082). Results Demographics included: median age of 59 years, 75% male, 55% current/former smokers, 75% oropharyngeal primary, and 67% human papillomavirus (HPV) +. ATM (54%), KMT2A (54%), PTEN (46%), RB1 (46%), and TP53 (46%) were frequently altered in BM samples from academic centers (62% HPV/p16+). Structural rearrangements ranged from 9 to 90 variants by proximity ligation sequencing. BMs had low densities of CD8+, PD-1+, PD-L1+, and FOXP3 + cells, and 92% had PD-L1 combined positive scores

Abstract Background Sex differences in human brain anatomy have been well-documented, though remain significantly underexplored during early development. The neonatal period is a critical stage for brain development and can provide key insights into the role that prenatal and early postnatal factors play in shaping sex differences in the brain. Methods Here, we assessed on-average sex differences in global and regional brain volumes in 514 newborns aged 0–28 days (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. We also assessed sex-by-age interactions to investigate sex differences in early postnatal brain development. Results On average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed significantly greater total cortical gray matter volumes, whilst males showed greater total white matter volumes. After controlling for total brain volume in regional comparisons, females had significantly increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and left caudate nucleus. Males had significantly increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. Significant sex-by-age interactions were noted in the left anterior cingulate gyrus and left superior temporal gyrus (posterior parts). Conclusions Our findings demonstrate that sex differences in brain structure are already present at birth and remain comparatively stable during early postnatal development, highlighting an important role of prenatal factors in shaping sex differences in the brain.

Abstract Although Jewish people in the US are often racialized (i.e., perceived by others) as White, Jewish Americans vary in the extent to which they consider themselves White, and in how strongly they identify with being Jewish. Based on prior findings that identifying with a White ethnic subgroup (e.g., Irish, Italian) can reduce prejudice toward racial and ethnic minorities, we predicted that strongly identified Jewish Americans would exhibit less intergroup bias than weakly identified Jewish Americans. For the present research, we recruited participants whose religious affiliation was Jewish but who self-identified as racially White. In a preregistered correlational study, Jewish identification was associated with lower bias, whereas White identification was associated with greater bias, toward Whites relative to racial/ethnic minorities. The relationship between Jewish identification and intergroup bias was accounted for by high Jewish identifiers’ perceptions that they could personally contribute to diversity in groups and organizations. Across three meta-analyzed experiments, participants whose religious minority (Jewish) identity was made salient exhibited less intergroup bias than did control participants, and in one preregistered experiment, perceived personal contributions to diversity mediated the effect of condition on intergroup bias. Implications for the forms of ethnic identity that predict more versus less intergroup bias in an increasingly multicultural society are discussed.

Abstract A social individual needs to effectively manage the amount of complex information in his or her environment relative to his or her own purpose to obtain relevant information. This paper presents a neural architecture aiming to reproduce attention mechanisms (alerting/orienting/selecting) that are efficient in humans during audiovisual tasks in robots. We evaluated the system based on its ability to identify relevant sources of information on faces of subjects emitting vowels. We propose a developmental model of audio-visual attention (MAVA) combining Hebbian learning and a competition between saliency maps based on visual movement and audio energy. MAVA effectively combines bottom-up and top-down information to orient the system toward pertinent areas. The system has several advantages, including online and autonomous learning abilities, low computation time and robustness to environmental noise. MAVA outperforms other artificial models for detecting speech sources under various noise conditions.

Abstract Background Youth engagement refers to the collaboration between researchers and youth to produce research. Youth engagement in health research has been shown to inform effective interventions aimed at improving health outcomes. However, limited evidence has identified promising practices to meaningfully engage youth. This synthesis aims to describe youth engagement approaches, frameworks, and barriers, as well as provide both evidence-based and youth-generated recommendations for meaningful engagement. Main body This review occurred in two stages: 1) a narrative review of existing literature on youth engagement and 2) a Youth Advisory Council (YAC) to review and supplement findings with their perspectives, experiences, and recommendations. The terms ‘youth engagement’ and ‘health research’ were searched in Google Scholar, PubMed, Web of Science, Scopus, and PsycINFO. Articles and non-peer reviewed research works related to youth engagement in health research were included, reviewed, and summarized. The YAC met with research team members and in separate youth-only forums to complement the narrative review with their perspectives. Types of youth engagement include participation as research participants, advisors, partners, and co-investigators. Barriers to youth engagement were organized into youth- (e.g., time commitments), researcher- (e.g., attitudes towards youth engagement), organizational- (e.g., inadequate infrastructure to support youth engagement), and system-level (e.g., systemic discrimination and exclusion from research). To enhance youth engagement, recommendations focus on preparing and supporting youth by offering flexible communication approaches, mentorship opportunities, diverse and inclusive recruitment, and ensuring youth understand the commitment and benefits involved. Conclusions To harness the potential of youth engagement, researchers need to establish an inclusive and enabling environment that fosters collaboration, trust, and valuable contributions from youth. Future research endeavors should prioritize investigating the dynamics of power-sharing between researchers and youth, assessing the impact of youth engagement on young participants, and youth-specific evaluation frameworks.

Abstract Obesity poses a public health threat, reaching epidemic proportions. Our hypothesis suggests that some of this epidemic stems from its transmission across generations via paternal epigenetic mechanisms. To investigate this possibility, we focused on examining the paternal transmission of CpG methylation. First-generation male Wistar rats were fed either a high-fat diet (HF) or chow and were mated with females fed chow. We collected sperm from these males. The resulting offspring were raised on a chow diet until day 35, after which they underwent a dietary challenge. Diet-induced obese (DIO) male rats passed on the obesogenic trait to both male and female offspring. We observed significant hypermethylation of the Pomc promoter in the sperm of HF-treated males and in the hypothalamic arcuate nucleus (Arc) of their offspring at weaning. However, these differences in Arc methylation decreased later in life. This hypermethylation is correlated with increased expression of DNMT3B. Further investigating genes in the Arc that might be involved in obesogenic transgenerational transmission, using reduced representation bisulfite sequencing (RRBS) we identified 77 differentially methylated regions (DMRs), highlighting pathways associated with neuronal development. These findings support paternal CpG methylation as a mechanism for transmitting obesogenic traits across generations.

Abstract Patients with high-grade glioma (HGG) have an extremely poor prognosis compounded by a lack of advancement in clinical care over the past few decades. Regardless of classification, most newly diagnosed patients receive the same treatment, radiation and temozolomide (RT/TMZ). We developed a functional precision oncology test that prospectively identifies individual patient’s response to this treatment regimen. Tumor tissues isolated from patients with newly diagnosed HGG enrolled in 3D PREDICT REGISTRY were evaluated for response to chemotherapeutic agents using the 3D Predict™ Glioma test. Patients receiving RT/TMZ were followed for 2 years. Clinical outcomes including imaging, assessments, and biomarker measurements were compared to patient matched test-predicted therapy response. Median survival between test-predicted temozolomide responders and test-predicted temozolomide non-responders revealed a statistically significant increase in progression-free survival when using the test to predict response across multiple subgroups including HGG (5.8 months), glioblastoma (4.7 months), and MGMT unmethylated glioblastoma (4.7 months). Overall survival was also positively separated across the subgroups at 7.6, 5.1, and 6.3 months respectively. The strong correlation of 3D Predict Glioma test results with clinical outcomes demonstrates that this functional test is prognostic in patients treated with RT/TMZ and supports aligning clinical treatment to test-predicted response across varying HGG subgroups.

Abstract The COVID-19 pandemic brought forth an urgent need for widespread genomic surveillance for rapid detection and monitoring of emerging SARS-CoV-2 variants. It necessitated design, development, and deployment of a nationwide infrastructure designed for sequestration, consolidation, and characterization of patient samples that disseminates de-identified information to public authorities in tight turnaround times. Here, we describe our development of such an infrastructure, which sequenced 594,832 high coverage SARS-CoV-2 genomes from isolates we collected in the United States (U.S.) from March 13th 2020 to July 3rd 2023. Our sequencing protocol (‘Virseq’) utilizes wet and dry lab procedures to generate mutation-resistant sequencing of the entire SARS-CoV-2 genome, capturing all major lineages. We also characterize 379 clinically relevant SARS-CoV-2 multi-strain co-infections and ensure robust detection of emerging lineages via simulation. The modular infrastructure, sequencing, and analysis capabilities we describe support the U.S. Centers for Disease Control and Prevention national surveillance program and serve as a model for rapid response to emerging pandemics at a national scale.

Abstract Background Medical Foundation Year (FY) doctors demonstrate greater psychological distress compared with the general population and other student groups. This feasibility study investigated FY doctors’ perceptions of mindfulness and the impact of a mindful resilience and effectiveness training (MRET) programme on stress, wellbeing, and performance. Methods Mixed-methods study utilising a questionnaire (study 1, N = 144) and a pre-post analysis design of MRET programme (study 2, N = 13), along with focus groups (N = 7). Results In study 1 28.5% of FY’s reported using mindfulness. All five mindfulness facets were significantly, and positively, associated with mental wellbeing (p

Little is known about environmental transmission of Mycobacterium kansasii. We retrospectively investigated potential environmental acquisition, primarily water sources, of M. kansasii among 216 patients with pulmonary disease from an industrial city in Taiwan during 2015–2017. We analyzed sputum mycobacterial cultures using whole-genome sequencing and used hierarchical Bayesian spatial network methods to evaluate risk factors for genetic relatedness of M. kansasii strains. The mean age of participants was 67 years; 24.1% had previously had tuberculosis. We found that persons from districts served by 2 water purification plants were at higher risk of being infected with genetically related M. kansasii isolates. The adjusted odds ratios were 1.81 (1.25–2.60) for the Weng Park plant and 1.39 (1.12–1.71) for the Fongshan plant. Those findings unveiled the association between water purification plants and M. kansasii pulmonary disease, highlighting the need for further environmental investigations to evaluate the risk for M. kansasii transmission.

New tuberculosis (TB) drugs with little existing antimicrobial resistance enable a pan-TB treatment regimen, intended for universal use without prior drug-susceptibility testing. However, widespread use of such a regimen could contribute to an increasing prevalence of antimicrobial resistance, potentially rendering the pan-TB regimen ineffective or driving clinically problematic patterns of resistance. We developed a model of multiple sequential TB patient cohorts to compare treatment outcomes between continued use of current standards of care (guided by rifampin-susceptibility testing) and a hypothetical pan-TB approach. A pan-TB regimen that met current target profiles was likely to initially outperform the standard of care; however, a rising prevalence of transmitted resistance to component drugs could make underperformance likely among subsequent cohorts. Although the pan-TB approach led to an increased prevalence of resistance to novel drugs, it was unlikely to cause accumulation of concurrent resistance to novel drugs and current first-line drugs.

In Israel, prevalence of sequence type 913, staphylococcal cassette chromosome mecIVa, spa type t991 methicillin-resistant Staphylococcus aureus lineage has surged among pediatric populations, predominantly in Arab and Orthodox Jewish communities. Antimicrobial resistance patterns vary by demographics. This lineage's spread and microevolution in the Middle East underscore the need for ongoing surveillance.

Abstract Avoidance is an essential behaviour for ensuring safety in uncertain and dangerous environments. One way to learn what is dangerous and must be avoided is through observational threat learning. This online study explored the behavioural implications of observed threat learning, examining how participants avoided or approached a learned threat and how this affected their movement patterns. Participants (n = 89) completed an observational threat learning task, rating their fear, discomfort, and physical arousal in response to conditioned stimuli. The retrieval of learned threat was reassessed 24 h later, followed by a reminder of the observed threat associations. Participants subsequently completed a computerised avoidance task, in which they navigated from a starting point to an endpoint by selecting one of two doors, each associated with either safety or danger, relying on observed information. Opting for the safe door entailed increased effort to attain the goal. Results demonstrated that observational threat learning influenced avoidance behaviour and decision-making dependent on baseline effort level. Participants tended to exhibit thigmotaxis, staying close to walls and taking extra steps to reach their goal. This behaviour indirectly mediated the number of steps taken. This study provides valuable insights into avoidance behaviour following observational threat learning in healthy humans.

Abstract The equilibrium theorem provided a fundamental framework for understanding species’ distributions and movement in fragmented ecosystems. Wetland-dependent avian species are model organisms to test insular predictions within protected area networks because their mobility allows surveillance of isolated patches without landscape barriers. We hypothesized size and isolation would influence functional connectivity of sanctuaries by GPS-marked wintering mallards (Anas platyrhynchos) within a mesocosm protected sanctuary area network. We evaluated functional connectivity and sanctuary use, measured by movements between sanctuaries, using a multistate modeling framework. Proximity drove connectivity, underscoring that patch isolation—not size—influenced connectivity, even for an avian species with no ascertainable landscape resistance or barriers. We also found that sanctuary use increased overwintering survival by reducing harvest mortality. Our test of equilibrium theory predictions demonstrated that isolation of protected sanctuary areas supersedes their size in determining functional connectivity for mallards and access to these areas may have direct fitness consequences. Our findings could refine land acquisition, restoration, and management practices with equal or greater emphasis on adjacency in protected area network design, especially for wetland-dependent migratory gamebirds.

Abstract Sjögren syndrome (SS) is an autoimmune disease characterized by chronic inflammatory infiltrates in the salivary and lacrimal glands. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T-cells, predominantly found in mucosal tissues with crucial role in epithelial homeostasis. Thus, MAIT cells may be implicated in mucosal alterations of SS patients. Activation markers, inflammatory and cytotoxic cytokines were examined in 23 SS patients and compared to 23 healthy controls (HC). Tissular MAIT cells in salivary gland (SG) biopsies were also analyzed. Circulating MAIT cells were decreased in SS patients with a higher expression of CD69 and a higher CD4/CD8 ratio of MAIT cells. MAIT cells showed a higher production of IFNγ, TNFα and GzB in SS compare to HC. Tissular MAIT cells were present within inflamed SG of SS patients, while they were absent in SG of HC. Overall, circulating MAIT cells are decreased in the peripheral blood of SS albeit producing higher amounts of IFNγ, TNFα, and GzB. Tissular MAIT cells are detected in salivary glands from SS with a proinflammatory tissular cytokine environment. MAIT cells with abnormal phenotype, functions and tissular homeostasis may contribute to epithelial damage in SS.

Abstract Background Depression, anxiety, and insomnia are prevalent in older people and are associated with increased risk of mortality, dependency, falls and reduced quality of life. Prior to or whilst seeking treatment, older people often manage these symptoms or conditions using products purchased over the counter (OTC), such as medication or herbal products. This review aims to map the evidence available for OTC medications, herbal medicines and dietary supplements for depression, anxiety and insomnia in older adults. Methodology We carried out a scoping review, including searches of five databases to identify relevant randomised controlled trials (inception-Dec 2022). We took an inclusive approach to products to represent the wide range that may be available online. Trials were summarised according to condition and product. Results We included 47 trials and 10 ongoing trial protocols. Most targeted insomnia (n = 25), followed by depression (n = 20), and mixed conditions (n = 2). None evaluated products targeted at anxiety alone. Where reported, most products appeared to be safe for use, but studies rarely included people with multiple comorbidities or taking concomitant medication. Some types of melatonin for insomnia (n = 19) and omega-3 fatty acids for depression (n = 7) had more substantive evidence compared to the other products. Conclusion There is a substantial gap in evidence for OTC products for anxiety in older people. This should be addressed in future trials. Research should also focus on products that are widely used, and these need to be tested in older populations that are similar to those who would use them in practice.

Abstract Background The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. Methods We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features. Results We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p

Abstract Human papillomavirus (HPV) is the cause of almost all cases of cervical cancer, a disease that kills some 340,000 women per year. The timeline from initial infection with HPV to the onset of invasive cervical cancer spans decades, and observational studies of this process are limited to settings in which treatment of precancerous lesions was withheld or inadequate. Such studies have been critical for understanding the natural history of HPV. Modeling can shed additional insight on the natural history of HPV, especially across geographical settings with varying prevalence of factors known to affect the host-side immune response to HPV, such as HIV and tobacco use. In this study, we create models for the 30 most populous countries in Sub-Saharan Africa, each with country-specific demographic, and behavioral inputs. We found that it was not possible to fit the data if we assumed that the natural history parameters were exactly identical for all countries, even after accounting for demographic and behavioral differences, but that we could achieve a good fit with the addition of a single immunocompetence parameter for each country. Our results indicate that variation in host immune responses may play a role in explaining the differences in the burden of cervical cancer between countries, which in turn implies a greater need for more geographically diverse data collection to understand the natural history of HPV.

Abstract SNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.

Summary: Background: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21. Methods: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium–Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. Findings: For both cohorts, the prevalence of mosaicism was

Introduction Real-world data on tofacitinib’s effectiveness is limited and mainly retrospective or registry-based. We elected to conduct a pragmatic prospective study to assess the efficacy of tofacitinib for moderate to severe ulcerative colitis (UC), aiming to evaluate the ability of intestinal ultrasound (IUS) to discriminate responders vs. non-responders in real-time.Methods This pragmatic prospective clinical study included consecutive adult patients starting tofacitinib treatment for active moderate to severe UC. Patients were evaluated at baseline and after 8 weeks of tofacitinib (clinical, biomarker, endoscopy, and IUS). The primary outcome was clinical response defined by a decrease in the full Mayo score (fMS) of ≥3 at week 8. Next, we explored ultrasonographic parameters in the sigmoid colon as potential real-time classifiers to differentiate between responders and non-responders at week 8.Results Overall, 30 adult patients started tofacitinib; the median age was 26.3 years (IQR 22.5–39.8), and 50% were female. Most patients (86.6%) had left-sided or extensive colitis, 96.7% had previously failed biologic therapy, and 60% (18/30) were on oral corticosteroids at the start of tofacitinib. At week 8, clinical response (a decrease in the fMS ≥ 3) and remission (fMS ≤ 2) rates were 40% (12/30) and 20% (6/30), respectively. Biomarker response (FC < 250µg/g) and biomarker normalization (FC ≤ 100µg/g) were achieved in 47.6% (10/21) and 38.1% (8/21) of patients, respectively. Endoscopic healing (endoscopic Mayo sub-score [EMS] ≤ 1) was achieved in 33.3% (10/30) of patients. Sigmoid bowel wall normalization as assessed by IUS (sBWT ≤ 3) was achieved in 18.2% (4/22). The best sBWT cut-off at week 8 to accurately classify endoscopic healing vs. no healing was a sBWT of 3.6 mm (AUC of 0.952 [95% CI: 0.868–1.036], p

Objectives This study aims to evaluate and compare health outcomes and costs between home hospitalisation and traditional hospitalisation for three common diagnoses—cellulitis, urinary tract infection (UTI) and pneumonia.Design A retrospective cohort study.Setting Primary care, nationwide.Participants 1311 patients in home hospitalisation and 992 in traditional hospitalisation.Interventions The primary intervention is home hospitalisation, compared with traditional hospitalisation. The intervention was performed according to medical considerations by a specialised team, and this study was done retrospectively to evaluate it.Primary and secondary outcome measures Primary measures included healthcare costs, length of hospitalisation, referrals for further medical services and mortality.Results Costs of home hospitalisation were lower compared with traditional hospitalisation (6056 vs 9619 NIS for pneumonia, 6011 vs 9767 NIS for cellulitis, 6466 vs 8552 NIS for UTI and p value

Objectives We conducted an implementation science mental health treatment study in western Kenya, testing strategies for scale up of evidence-based mental health services for common adult disorders using a non-specialist workforce, integrated with existing primary care (Sequential Multiple, Assignment Randomized Trial of non-specialist-delivered psychotherapy (Interpersonal Psychotherapy) and/or medication (fluoxetine) for major depression and post-traumatic stress disorder (PTSD) (SMART DAPPER)). Because study launch coincided with the COVID-19 pandemic, participants were allowed to attend treatment visits via mHealth (audio-only mobile phone) or in-person. We conducted a secondary data analysis of the parent study to evaluate preference for mHealth or in-person treatment among our study participants, including rationale for choosing in-person or mHealth treatment modality, and comparison of baseline demographic and clinical characteristics.Design, setting, participants and interventions Participants were public sector primary care patients at Kisumu County Hospital in western Kenya with major depression and/or PTSD and were individually randomised to non-specialist delivery of evidence-based psychotherapy or medication (n=2162).Outcomes Treatment modality preference and rationale were ascertained before randomised assignment to treatment arm (psychotherapy or medication). The parent SMART DAPPER study baseline assessment included core demographic (age, gender, relationship status, income, clinic transport time and cost) and clinical data (eg, depression and PTSD symptoms, trauma exposures, medical comorbidities and history of mental healthcare). Given that this evaluation of mHealth treatment preference sought to identify the demographic and clinical characteristics of participants who chose in-person or mHealth treatment modality, we included most SMART DAPPER core measurement domains (not all subcategories).Results 649 (30.3%) SMART DAPPER participants preferred treatment via mHealth, rather than in person. The most cited rationales for choosing mHealth were affordability (18.5%) (eg, no transportation cost) and convenience (12.9%). On multivariate analysis, compared with those who preferred in-person treatment, participants who chose mHealth were younger and had higher constraints on receiving in-person treatment, including transport time 1.004 (1.00, 1.007) and finances 0.757 (0.612, 0.936). Higher PTSD symptoms 0.527 (0.395, 0.702) and higher disability 0.741 (0.559, 0.982) were associated with preference for in-person treatment.Conclusions To our knowledge, this is the first study of public sector mental healthcare delivered by non-specialists via mHealth for major depression and/or PTSD in Sub-Saharan Africa. Our finding that mHealth treatment is preferred by approximately one-third of participants, particularly younger individuals with barriers to in-person care, may inform future mHealth research to (1) address knowledge gaps in mental health service implementation and (2) improve mental healthcare access to evidence-based treatment.Trial registration number NCT03466346.

BackgroundLifestyle behavior change and mindfulness have direct and synergistic effects on cognitive functioning and may prevent Alzheimer disease and Alzheimer disease–related dementias (AD/ADRD). We are iteratively developing and testing My Healthy Brain (MHB), the first mindfulness-based lifestyle group program targeting AD/ADRD risk factors in older adults with subjective cognitive decline. Our pilot studies (National Institutes of Health [NIH] stage 1A) have shown that MHB is feasible, acceptable, and associated with improvement in lifestyle behavior and cognitive outcomes. ObjectiveWe will compare the feasibility of MHB versus an education control (health enhancement program [HEP]) in 50 older adults (aged ≥60 y) with subjective cognitive decline and AD/ADRD risk factors. In an NIH stage 1B randomized controlled trial (RCT), we will evaluate feasibility benchmarks, improvements in cognitive and lifestyle outcomes, and engagement of hypothesized mechanisms. MethodsWe are recruiting through clinics, flyers, web-based research platforms, and community partnerships. Participants are randomized to MHB or the HEP, both delivered in telehealth groups over 8 weeks. MHB participants learn behavior modification and mindfulness skills to achieve individualized lifestyle goals. HEP participants receive lifestyle education and group support. Assessments are repeated after the intervention and at a 6-month follow-up. Our primary outcomes are feasibility, acceptability, appropriateness, credibility, satisfaction, and fidelity benchmarks. The secondary outcomes are cognitive function and lifestyle (physical activity, sleep, nutrition, alcohol and tobacco use, and mental and social activity) behaviors. Data analyses will include the proportion of MHB and HEP participants who meet each benchmark (primary outcome) and paired samples 2-tailed t tests, Cohen d effect sizes, and the minimal clinically important difference for each measure (secondary outcomes). ResultsRecruitment began in January 2024. We received 225 inquiries. Of these 225 individuals, 40 (17.8%) were eligible. Of the 40 eligible participants, 21 (52.5%) were enrolled in 2 group cohorts, 17 (42.5%) were on hold for future group cohorts, and 2 (5%) withdrew before enrollment. All participants have completed before the intervention assessments. All cohort 1 participants (9/21, 43%) have completed either MHB or the HEP (≥6 of 8 sessions) and after the intervention assessments. The intervention for cohort 2 (12/21, 57%) is ongoing. Adherence rates for the Garmin Vivosmart 5 (128/147, 87.1% weeks) and daily surveys (105/122, 86.1% weeks) are high. No enrolled participants have dropped out. Enrollment is projected to be completed by December 2024. ConclusionsThe RCT will inform the development of a larger efficacy RCT (NIH stage 2) of MHB versus the HEP in a more diverse sample of older adults, testing mechanisms of improvements through theoretically driven mediators and moderators. The integration of mindfulness with lifestyle behavior change in MHB has the potential to be an effective and sustainable approach for increasing the uptake of AD/ADRD risk reduction strategies among older adults. Trial RegistrationClinicalTrials.gov NCT05934136; https://www.clinicaltrials.gov/study/NCT05934136 International Registered Report Identifier (IRRID)DERR1-10.2196/64149

Objective To identify primary care structures and processes that have the highest and lowest impact on chronic disease management and screening and prevention outcomes as well as to assess the feasibility of implementing these structures and processes into practice.Design A two-round Delphi study was conducted to establish consensus on the impact and feasibility of 258 primary care structures and processes.Participants 29 primary care providers, health system leaders and health services researchers in the USA.Outcomes Primary outcomes were (1) consensus on the impact of each structure and process on chronic disease management and screening and prevention outcomes, separately and (2) consensus on feasibility of implementation by primary care practices.Results Consensus on high impact and feasibility of implementation was reached on four items for chronic disease management: ‘Providers use motivational interviewing to help patients set goals’, ‘Practice has designated staff to manage patient panel’, ‘Practice has onsite providers or staff that speak the most dominant, non-English language spoken by patients’ and ‘Practice includes mental health providers and/or behavioural health specialists in care team’ and seven items for screening and prevention: ‘Practice utilizes standing protocols and orders’, ‘Practice generates reports to alert clinicians to missed targets and to identify gaps in care, such as overdue visits, needed vaccinations, screenings or other preventive services’, ‘Practice has designated staff to manage patient panel’, ‘Practice sets performance goals and uses benchmarking to track quality of care’, ‘Practice uses performance feedback to identify practice-specific areas of improvement’, ‘Practice builds quality improvement activities into practice operations’ and ‘Pre-visit planning data are reviewed during daily huddles’. Only ‘Practice has designated staff to manage patient panel’ appeared on both lists.Conclusion Findings suggest that practices need to focus on implementing mostly distinct, rather than common, structures and processes to optimise chronic disease and preventive care.

BackgroundFamily dynamics play an important role in determining the glycemic outcomes of type 1 diabetes (T1D) in children. The time interval immediately following T1D diagnosis is particularly stressful for families, and interventions to support families in adjusting their family practices to support adjustment to and management of T1D in the months following diagnosis may improve glycemic outcomes. Self-guided digital interventions offer a sustainable model for interventions to support caregivers in learning evidence-based family management skills for adjustment to and management of T1D. ObjectiveWe hypothesized that a self-guided, web-based, family skills management program (addressing caregiver social support as well as family problem-solving, communication, and supportive behavior change strategies) initiated at the time of T1D diagnosis would improve glycemic outcomes in children with T1D. In this study, we report on the feasibility and acceptability of this program. MethodsWe prospectively evaluated a sample of 37 children newly diagnosed with T1D recruited from a pediatric endocrinology clinic. Parent participants were asked to complete web-based modules addressing social support, family problem-solving, communication, and supportive behavior change strategies. Module completion was analyzed for percentage completion, patterns of completion, and differences in completion rates by coparenting status. Qualitative open-ended feedback was collected at the completion of each module. ResultsA total of 31 (84%) of the 37 participants initiated the web-based program. Of those 31 participants, 25 (81%) completed some content and 15 (48%) completed all 5 modules. Completion rates were higher when coparenting partners engaged in the intervention together (P=.04). Of the 18 participants given a choice about the spacing of content delivery, 15 (83%) chose to have all sessions delivered at once and 3 (17%) chose to space sessions out at 2-week intervals. Qualitative feedback supported the acceptability of the program for delivery soon after T1D diagnosis. Families reported on positive benefits, including requesting future access to the program and describing helpful changes in personal or family processes for managing T1D. ConclusionsIn this study, we found that a self-guided digital family support intervention initiated at the time of a child’s T1D diagnosis was largely feasible and acceptable. Overall, rates of participation and module completion were similar to or higher than other self-guided digital prevention interventions for mental and physical health outcomes. Self-guided digital programs addressing family management skills may help prevent challenges common with T1D management and can decrease cost, increase access, and add flexibility compared to traditional interventions. Trial RegistrationClinicalTrials.gov NCT03720912; https://clinicaltrials.gov/study/NCT03720912

Summary: Background: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used. Methods: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as “trial-like” based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75ECD, plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated. Findings: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL 100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75ECD, and plasma miR-181ab is more limited. Interpretation: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency. Funding: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).

Objectives Due to substantial regional variability in available caregiving services and supports, culture and health status among informal caregivers in the USA, the study objective was to explore how rural-urban differences in aspects of caregiving—caregiving intensity, distance to care recipient, caregiver burden, caregiver health and caregiving support—vary by US Census region (Northeast, South, Midwest and West) after accounting for other social determinants of health.Design This study was a secondary analysis of multiwave, cross-sectional study data.Setting The data were collected on a representative sample of informal, unpaid caregivers to older adults.Participants A sample of n=3551 informal caregivers from the National Study of Caregiving identified by older adult care recipients from waves 1 (2011) and 5 (2015) of the National Health and Aging Trends Study.Primary and secondary outcome measures Primary outcome measures were caregiving intensity (provided support for/with the number of activities of daily living (ADLs) and instrumental ADL (IADLs)) caregiver assisted with, hours of caregiving per month), caregiver burden (physical, emotional and financial), support services sought (types and total number), caregivers’ self-reported health and health status (individual comorbidities and a total number of comorbidities). Analyses were stratified by US Census region and rural-urban status, as defined by the US Census Bureau, of census tract of caregiver residence.Results Urban caregivers provided higher levels of ADL support in the Northeast (beta=0.19, 95% CI 0.03, 0.35) and West (beta=0.15, 95% CI 0.05,0.26) regions. Urban caregivers provided significantly higher levels of ADL support (p=0.020), IADL support (p=0.033) and total ADLs plus IADLs (p=0.013) than rural caregivers. Caregivers living in the South had higher amounts of monthly hours spent caregiving, ADL support, IADL support and combined ADLs plus IADLs and were more likely to have obesity, report poor or fair health, have heart conditions and experience emotional difficulty from caregiving (all p

Summary: Background: While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID. Methods: A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.). Findings: Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events. Interpretation: As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions. Funding: Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438.

Wellness has recently emerged as an industry sector and a multidimensional academic discipline that includes psychological, physiological, social, demographic and ecological dimensions. Wellness enhances resilience and is therefore a survival imperative that is fundamental to life, yet current Western definitions of wellness do not refer to fundamental a priori principles. Eastern medicine on the other hand does refer to universal principles and suggests that bliss is a natural homeostatic set-point and that wellness can be achieved by living according to the Tao. Congruence between Eastern concepts and thermodynamics further suggests that Qi is related to information and flow, and that wellness arises from maximal flow and minimum entropy production. These principles, which can be represented by an Illness-Wellness Vortex, suggest that the healthiest lifestyle provides maximal enjoyment with minimal waste. Thus, conscious consumption and cultivation of psychological flow can provide the means for achieving wellness through aligning internal and external states. (Contains 3 figures.)

Objective: Because medical residency is a stressful time for training physicians, placing residents at increased risk for psychological distress, the authors studied the prevalence of burnout, perceived stress, and depression in cardiology residents in Argentina and examined the association between sociodemographic characteristics and these syndromes. Methods: The authors conducted a cross-sectional observational study of 106 cardiology residents in Argentina and a comparison group of 104 age- and gender-matched nonmedical professionals. The main outcome measures included the prevalence of burnout with the Maslach Burnout Inventory, distress with the Perceived Stress Scale, and depression with the Beck Depression Inventory. Results: One hundred six residents completed the survey. Of these, 31.3% were women, the mean age was 29.1 years old, and half were married. Respondents worked an average of 64 hours per week, and 60% of the residents needed a second job. High emotional exhaustion and depersonalization was found in the majority of respondents. Significant depressive symptoms were found in less than half of residents, and stress was on average 21.7 points on the Perceived Stress Scale. Residents who had a second job showed high levels of depersonalization. No other association was found with sociodemographic characteristics. There were no differences in sociodemographic characteristics of residents compared with nonmedical professionals, but nonmedical professionals worked less hours per week, had a lower percentage of second jobs, and higher salary. Burnout, depressive symptoms, and perceived stress were significantly lower in the reference group. Conclusion: Cardiology residents in Argentina exhibit high levels of burnout, perceived stress, and depressive symptoms, which warrants greater attention to the psychological needs of residents.

Introduction: Emergency medicine (EM) was recognized as a specialty in Israel in 1999. Fifty-nine of the 234 (25%) attending physicians working in emergency departments (ED) nationwide in 2002 were board-certified emergency physicians (EP). A 2012 study revealed that 123/270 (45%) of ED attendings were EPs, and that there were 71 EM residents. The EPs primarily worked midweek morning shifts, leaving the EDs mostly staffed by other specialties. Our objective in this study was to re-evaluate the EP workforce in Israeli EDs and their employment status and satisfaction 10 years after the last study, which was conducted in 2012. Methods: We performed a three-part, prospective cross-sectional study: 1) a survey, sent to all EDs in Israel, to assess the numbers, level of training, and specialties of physicians working in EDs; 2) an anonymous questionnaire, sent to EPs in Israel, to assess their demographics, training, employment, and work satisfaction; and 3) interviews of a convenience sample of EPs analyzed by a thematic approach. Results: There were 266 board-certified EPs, 141 (53%) of whom were employed in EDs full-time or part-time. Sixty-two non-EPs also worked in EDs. The EPs were present in the EDs primarily during weekday morning shifts. There were 273 EM residents nationwide. A total of 101 questionnaires were completed and revealed that EPs working part-time in the ED worked fewer hours, received higher salaries, and had more years of experience compared to EPs working full time or not working in the ED. Satisfaction correlated only with working part time. Meaningful work, diversity, and rewarding relationships with patients and colleagues were major positive reasons for working in the ED. Feeling undervalued, carrying a heavy caseload, and having complicated relationships with other hospital departments were reasons against working in the ED. Conclusion: Our study findings showed an increase in the number of trained and in-training EPs, and a decrease in the percentage of board-certified EPs who persevere in the EDs. Emergency medicine in Israel is at a crossroads: more physicians are choosing EM than a decade ago, but retention of board-certified EPs is a major concern, as it is worldwide. We recommend taking measures to maintain trained and experienced EPs working in the ED by allowing part-time ED positions, introducing dedicated academic time, and diversifying EP roles, functioning, and work routine.

Abstract To acquire the ability to fertilize the egg, mammalian spermatozoa must undergo a series of changes occurring within the highly synchronized and specialized environment of the female reproductive tract, collectively known as capacitation. In an attempt to replicate this process in vitro, various culture media for mouse sperm were formulated over the past decades, sharing a similar overall composition but differing mainly in ion concentrations and metabolic substrates. The widespread use of the different media to study the mechanisms of capacitation might hinder a comprehensive understanding of this process, as the medium could become a confounding variable in the analysis. In this context, the present side-by-side study compares the influence of four commonly used culture media (FD, HTF and two TYH versions) on mouse sperm capacitation. We evaluated the induction of protein kinase A phosphorylation pathway, motility, hyperactivation and acrosome reaction. Additionally, in vitro fertilization and embryo development were also assessed. By analyzing these outcomes in two mouse colonies with different reproductive performance, our study provides critical insights to improve the global understanding of sperm function. The results obtained highlight the importance of considering variations in medium composition, and their potential implications for the future interpretation of results.

Abstract This study aims to correlate adaptive optics-transscleral flood illumination (AO-TFI) images of the retinal pigment epithelium (RPE) in central serous chorioretinopathy (CSCR) with standard clinical images and compare cell morphological features with those of healthy eyes. After stitching 125 AO-TFI images acquired in CSCR eyes (including 6 active CSCR, 15 resolved CSCR, and 3 from healthy contralateral), 24 montages were correlated with blue-autofluorescence, infrared and optical coherence tomography images. All 68 AO-TFI images acquired in pathological areas exhibited significant RPE contrast changes. Among the 52 healthy areas in clinical images, AO-TFI revealed a normal RPE mosaic in 62% of the images and an altered RPE pattern in 38% of the images. Morphological features of the RPE cells were quantified in 54 AO-TFI images depicting clinically normal areas (from 12 CSCR eyes). Comparison with data from 149 AO-TFI images acquired in 33 healthy eyes revealed significantly increased morphological heterogeneity. In CSCR, AO-TFI not only enabled high-resolution imaging of outer retinal alterations, but also revealed RPE abnormalities undetectable by all other imaging modalities. Further studies are required to estimate the prognosis value of these abnormalities. Imaging of the RPE using AO-TFI holds great promise for improving our understanding of the CSCR pathogenesis.

Abstract The Islamist group ISIS has been particularly successful at recruiting Westerners as terrorists. A hypothesized explanation is their simultaneous use of two types of propaganda: Heroic narratives, emphasizing individual glory, alongside Social narratives, which emphasize oppression against Islamic communities. In the current study, functional MRI was used to measure brain responses to short ISIS propaganda videos distributed online. Participants were shown 4 Heroic and 4 Social videos categorized as such by another independent group of subjects. Persuasiveness was measured using post-scan predictions of recruitment effectiveness. Inter-subject correlation (ISC) was used to measure commonality of brain activity time courses across individuals. ISCs in ventral striatum predicted rated persuasiveness for Heroic videos, while ISCs in mentalizing and default networks, especially in dmPFC, predicted rated persuasiveness for Social videos. This work builds on past findings that engagement of the reward circuit and of mentalizing brain regions predicts preferences and persuasion. The observed dissociation as a function of stimulus type is novel, as is the finding that intersubject synchrony in ventral striatum predicts rated persuasiveness. These exploratory results identify possible neural mechanisms by which political extremists successfully recruit prospective members and specifically support the hypothesized distinction between Heroic and Social narratives for ISIS propaganda.

Abstract Background Sepsis is a life-threatening condition which may arise from infection in any organ system and requires early recognition and management. Healthcare professionals working in any specialty may need to manage patients with sepsis. Educating medical students about this condition may be an effective way to ensure all future doctors have sufficient ability to diagnose and treat septic patients. However, there is currently no consensus on what competencies medical students should achieve regarding sepsis recognition and treatment. This study aims to outline what sepsis-related competencies medical students should achieve by the end of their medical student training in both high or upper-middle incomes countries/regions and in low or lower-middle income countries/regions. Methods Two separate panels from high or upper-middle income and low or lower-middle income countries/regions participated in a Delphi method to suggest and rank sepsis competencies for medical students. Each panel consisted of 13–18 key stakeholders of medical education and doctors in specialties where sepsis is a common problem (both specialists and trainees). Panelists came from all continents, except Antarctica. Results The panels reached consensus on 38 essential sepsis competencies in low or lower-middle income countries/regions and 33 in high or upper-middle incomes countries/regions. These include competencies such as definition of sepsis and septic shock and urgency of antibiotic treatment. In the low or lower-middle income countries/regions group, consensus was also achieved for competencies ranked as very important, and was achieved in 4/5 competencies rated as moderately important. In the high or upper-middle incomes countries/regions group, consensus was achieved in 41/57 competencies rated as very important but only 6/11 competencies rated as moderately important. Conclusion Medical schools should consider developing curricula to address essential competencies, as a minimum, but also consider addressing competencies rated as very or moderately important.

Abstract Vestibular schwannomas (VS) are the most common tumor of the skull base with available treatment options that carry a risk of iatrogenic injury to the facial nerve, which can significantly impact patients’ quality of life. As facial nerve outcomes remain challenging to prognosticate, we endeavored to utilize machine learning to decipher predictive factors relevant to facial nerve outcomes following microsurgical resection of VS. A database of patient-, tumor- and surgery-specific features was constructed via retrospective chart review of 242 consecutive patients who underwent microsurgical resection of VS over a 7-year study period. This database was then used to train non-linear supervised machine learning classifiers to predict facial nerve preservation, defined as House-Brackmann (HB) I vs. facial nerve injury, defined as HB II–VI, as determined at 6-month outpatient follow-up. A random forest algorithm demonstrated 90.5% accuracy, 90% sensitivity and 90% specificity in facial nerve injury prognostication. A random variable (rv) was generated by randomly sampling a Gaussian distribution and used as a benchmark to compare the predictiveness of other features. This analysis revealed age, body mass index (BMI), case length and the tumor dimension representing tumor growth towards the brainstem as prognosticators of facial nerve injury. When validated via prospective assessment of facial nerve injury risk, this model demonstrated 84% accuracy. Here, we describe the development of a machine learning algorithm to predict the likelihood of facial nerve injury following microsurgical resection of VS. In addition to serving as a clinically applicable tool, this highlights the potential of machine learning to reveal non-linear relationships between variables which may have clinical value in prognostication of outcomes for high-risk surgical procedures.