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Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Modern poriferans are classified into four classes—Calcarea, Demospongiae, Hexactinellida and Homoscleromorpha—the recognition of which in fossil specimens almost exclusively relies on spicule morphology and arrangement. Early fossil representatives of the phylum Porifera are morphologically diverse, and many of them problematically display characteristics that are incompatible with the classification scheme developed for modern taxa. Critically, hexactine spicules—a diagnostic feature of hexactinellids among modern taxa—are found in various Cambrian and Ordovician taxa that cannot be accommodated within the hexactinellid body plan. Here we describe a new poriferan from the Drumian Marjum Formation of Utah, Polygoniella turrelli gen. et sp. nov., which exhibits a unique combination of complex anatomical features for a Cambrian form, including a syconoid-like organization, a thick body wall, and a multi-layered hexactin-based skeleton. The hexactinellid-like body wall architecture of this new species supports a Cambrian origin of the hexactinellid body plan and provides valuable insights into character evolution in early glass sponges.

Summary: Tumor acidosis is one of the hallmarks indicating the initiation and progression of various cancers. Here, we present a protocol for preparing a hyperpolarized (HP) 13C-bicarbonate tissue pH MRI imaging contrast agent to detect aggressive tumors. We describe the steps for the formulation and polarization of a precursor molecule 13C-glycerol carbonate (13C-GLC), the post-dissolution reaction, and converting HP 13C-GLC to an injectable HP 13C-bicarbonate solution. We then detail procedures for MRI data acquisition to generate tumor pH maps for assessing tumor aggressiveness.For complete details on the use and execution of this protocol, please refer to Mu et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

In this work, solid-state fermentation (SSF) was applied to babassu mesocarp (BM) for the low-cost bioproduction of natural aroma compounds having Trichoderma harzianum (IOC 4042) and Geotrichum candidum (CCT 1205) as microbial agents. Fermentation was carried out using in natura babassu mesocarp (IN-BM) and defatted babassu mesocarp through soxhlet extraction (DEF-BM) as support, impregnated with hydration solutions of three and seven salts. The compounds produced were analyzed using solid phase microextraction (SPME) and gas chromatography coupled with a mass spectrometer (GC-MS). Among several aroma compounds detected, 6-pentyl-α-pyrone (6-PP)—GRAS 3696, coconut aroma; 2-phenylethanol (2-PE)—GRAS 2858, rose and honey aroma; and hexanal—GRAS 2557, green apple aroma, were the compounds that that were detected with the greatest intensity. The highest concentrations (ppm (w/w)) of 6-PP and 2-PE were obtained in DEF-BM using NS7SG (308.17 ± 3.18 and 414.53 ± 1.96), respectively, while for hexanal, the highest concentration (ppm (w/w)) was obtained in IN-BM using NS7SG (210.83 ± 2.14). The results indicate that producing aroma compounds by G. candidum and T. harzianum through BM SSF is viable, generating value-added compounds.

(1) Background: The aim of this review was to identify and summarize adverse cardiovascular health events associated with the simultaneous consumption of energy drinks (ED) and alcohol. Potential prevention strategies and the implementation of research toward the underlying mechanisms for these pathologies were highlighted to emphasize the need for further investigation and to encourage more attention to this field. (2) Methods: The PubMed database was searched for case reports linked with adverse cardiovascular events after simultaneous ED and alcohol consumption. Inclusion criteria were: the reported age of the patient is between 16 and 35 years and confirmed co-consumption of EDs and alcohol. All relevant articles that met the inclusion criteria were fully read and all relevant data was extracted. The extracted data was summarized and presented in this review of cases. (3) Results: In total, 10 cases were identified. The analysis showed that mainly young adults (median age = 24.5 years), in particular men (80%) were affected. The three parts of the cardiovascular system affected were heart rhythm (42%), myocardial function (33%), and coronary arteries (25%). In 3 cases the outcome was fatal. Moreover, preexisting health conditions and/or potential trigger factors were present in 60% of selected cases. (4) Conclusions: This review of case reports suggests that the simultaneous consumption of EDs and alcohol can lead to adverse cardiovascular health events and even incidents with fatal outcomes were reported. Potential trigger factors and preexisting health conditions seem to increase the probability of adverse cardiovascular health events. Consumers should be informed about the potential risks and follow responsible consumption behavior to prevent future health events. More systematic studies are needed to determine the acute effects on the cardiovascular system in young adults.

A child’s autism diagnosis is life-changing for their parents, due to the complex and long-term nature of the condition. Furthermore, research about the increased prevalence of autism suggests that more parents are being affected globally. However, limited studies have investigated parents’ lived experience of their child being diagnosed with autism. This study aimed to explore the first-hand experience and concerns of parents when their child has been diagnosed with autism. The study employed a qualitative, exploratory design. Parents of a child who had received an autism diagnosis at least 12 months prior were invited to a video interview. Eleven parents participated in an hour-long interview. The interviews were transcribed, and an inductive reflexive thematic analysis was performed. The analysis resulted in four main themes: “Shock and control”, “A thousand little conversations”, “Put your own oxygen mask on first”, and “Reforged identities”, orientating around the period surrounding diagnosis, ongoing communication requirements, the need for self-care and reorientation of identity. These findings identify areas of heightened concern for parents and provide professionals with practical insight when evaluating their engagement approaches with these groups of parents. Findings can help psychologists, therapists, educators and parents themselves to identify strategies to support the well-being of parents who have an autistic child.

Background: Biomedical data are usually collections of longitudinal data assessed at certain points in time. Clinical observations assess the presences and severity of symptoms, which are the basis for the description and modeling of disease progression. Deciphering potential underlying unknowns from the distinct observation would substantially improve the understanding of pathological cascades. Hidden Markov Models (HMMs) have been successfully applied to the processing of possibly noisy continuous signals. We apply ensembles of HMMs to categorically distributed multivariate time series data, leaving space for expert domain knowledge in the prediction process. Methods: We use an ensemble of HMMs to predict the loss of free walking ability as one major clinical deterioration in the most common autosomal dominantly inherited ataxia disorder worldwide. Results: We present a prediction pipeline that processes data paired with a configuration file, enabling us to train, validate and query an ensemble of HMMs. In particular, we provide a theoretical and practical framework for multivariate time-series inference based on HMMs that includes constructing multiple HMMs, each to predict a particular observable variable. Our analysis is conducted on pseudo-data, but also on biomedical data based on Spinocerebellar ataxia type 3 disease. Conclusions: We find that the model shows promising results for the data we tested. The strength of this approach is that HMMs are well understood, probabilistic and interpretable models, setting it apart from most Deep Learning approaches. We publish all code and evaluation pseudo-data in an open-source repository.

Abstract Introduction Cardiovascular (CV) risk factors can limit treatment options for migraine. Rimegepant is an orally administered small-molecule calcitonin gene-related peptide receptor antagonist that does not induce vasoconstriction. The aim of these post hoc subgroup analyses was to assess the safety of rimegepant according to CV risk. Methods In a multicenter, long-term, open-label, phase II/III safety study, participants with a history of 2–14 migraine attacks per month of moderate or severe pain intensity self-administered rimegepant 75 mg, orally, to treat migraine up to once daily for up to 52 weeks. Uncontrolled, unstable, or recently diagnosed CV disease was part of the exclusion criteria. Safety was assessed across subgroups according to number of CV risk factors (0, 1, or ≥ 2) and Framingham Risk Score (

Water distribution networks (WDNs) are critical infrastructures prone to vulnerabilities which lead to failures. Identifying vulnerable components, especially multiple pipe failure combinations, is crucial for effective management and ensuring high reliability. Hydraulic simulations are commonly used for analysing the criticality of WDN, but are time-consuming and highly data-reliant, limiting the number of testable combinations. To address these limitations and constraints, a graph-based method is proposed to quantify the impact magnitude of multiple pipe failure scenarios on performance, enabling the identification of critical combinations. The proposed graph-based approach utilizes structural and topological characteristics of WDNs as well as spatial demand distribution to replicate hydraulic behaviour. The accuracy of the approach is assessed by testing it on three case studies with various pipe failure combinations, and the results are compared with hydraulic analyses. The results demonstrate a strong correlation (Spearman coefficient > 0.75) between graph-based ranking and state-of-the-art hydraulic-based ranking. Additionally, the method exhibits a significant computational gain factor of greater than 30 compared with the hydraulic-based method, rendering it valuable for actively exploring a wide range of critical pipe failure combinations and devising countermeasures. Furthermore, a hybrid-based method that integrates both the graph and hydraulic-based methods is proposed for enhanced accuracy and robust assessments. HIGHLIGHTS An innovative graph-based ranking method for fast and accurate pipe criticality analysis is developed.; The results show a high correlation with the hydraulic-based ranking method with a computational gain factor of more than 30.; A hybrid-based ranking method is presented, combining the advantages of two approaches to address the limitations of the graph-based ranking method and robust assessment of the impact.;

Introduction: Medical cannabis (MC) is available upon certification for one of several qualifying conditions in Florida, USA. Previous studies suggested that some people seek cannabis for medical conditions/symptoms beyond those legally permitted. However, data remain limited on patient motives for seeking MC and their experiences around its impact on their health. We aimed to compare reported qualifying conditions for MC certification with the most frequently self-reported reasons for using MC while assessing the alignment between the two and understanding the perceived impacts of MC on self-reported conditions and symptoms. Methods: We conducted a cross-sectional study using survey data from the Medical Marijuana and Me (M3) Data Bank of individuals receiving MC in Florida, USA, in 2022. Participants were recruited via convenience sampling from nine MC clinics/clinic networks across Florida and were asked to fill out an online survey. The study measures included sociodemographic variables, self-reported health conditions, self-reported main reasons for using MC, self-reported qualifying conditions for MC certification, and self-reported perceived impact of MC on health conditions. We cross-tabulated reported qualifying conditions and reasons for MC use and reported the perceived impact per condition. Results: A total of 632 participants completed the survey, of whom 396 (62.66%) were female and 471 (74.53%) were non-Hispanic white. The median (IQR) age was 45 (35, 58). The most frequently reported qualifying conditions were post-traumatic stress disorder (PTSD) (n = 187, 29.59%), a condition not on the qualifying conditions list (n = 175, 27.69%), medical conditions of the same kind/comparable to those listed (n = 140, 22.15%), and chronic nonmalignant pain (n = 62, 25.63%). The top ten most frequently reported reasons for using MC were anxiety (n = 383, 60.60%), chronic pain (n = 278, 43.99%), depression (n = 252, 39.87%), PTSD (n = 220, 34.81%), headaches/migraine (n = 134, 21.20%), fibromyalgia (n = 67, 10.60%), attention-deficit hyperactivity disorder (ADHD) (n = 59, 9.34%), bipolar disorder (n = 53, 8.39%), high blood pressure (n = 41, 6.49%), and cancer (n = 18,2.85%). Of respondents, 70–90% with each qualifying condition reported it as one of the main reasons for using MC. Most respondents reported improvement of anxiety (n = 430/451, 95.34%), depression (n = 381/392, 97.20%), chronic pain (n = 305/310, 98.39%), insomnia/sleeping problems (n = 225/295, 86.44%), PTSD (n = 247/270, 91.48%), headaches/migraine (n = 172/218, 78.90%), ADHD (n = 82/123, 66.67%), bipolar disorder (n = 79/89, 88.76%), and fibromyalgia (n = 77/82, 93.90%). Most respondents were unsure/reported no change in blood pressure (n = 93/162, 57.41%). A small percentage reported perceived worsening impacts on their conditions. Conclusion: Qualifying conditions and self-reported reasons for using MC aligned for most respondents. Yet, a notable proportion of respondents sought MC for broader treatment effects beyond those delineated by the officially recognized qualifying conditions in Florida, USA. Most patients perceived positive effects, including those with limited available evidence on efficacy.

Abstract Background Telemedicine has expanded rapidly in recent years, and many encounters that were conducted in person now take place remotely. This study aimed to assess primary care physicians’ (PCPs) attitudes towards the different modalities of patient care. Methods This is a cross-sectional nationwide descriptive study conducted in Israel. We asked PCPs to document an entire workday and answer a short questionnaire after each visit. The questions addressed the type of visit (face-to-face, remote synchronous [telephone/video], or remote asynchronous [online requests]), the perceived quality of the visit, and the physicians’ feelings at the end of each visit. Before documenting their working day, we asked the participants to answer a questionnaire about their general attitudes toward different modalities of medical visits and how they affect their well-being and burnout. Results Sixty physicians documented 2,025 visits, of which 39% took place in person, 36% stemmed from online patient requests, 18% were telephone meetings, < 1% were video meetings, and 6% consisted of other types of contact. Mixed effects logistic regressions were used to model the visits’ evaluation. The odds ratios (ORs) for perceived medical quality of visits focused on medical tasks were lower for non-face-to-face visits: OR = 0.39, 95% CI 0.25–0.59 for remote synchronous, and OR = 0.14, 95% CI 0.09–0.23 for remote asynchronous. The perceived medical quality of visits focused on administrative tasks was lower for remote asynchronous than for face-to-face visits (OR = 0.31, 95% CI 0.14–0.65). We found no association between medical quality and patients, physicians, or clinic characteristics. The inappropriateness of the visit modality was also associated with lower medical quality (OR = 0.13, 95% CI 0.09–0.18). We found a correlation between perception of medical quality and physicians’ feelings at the end of the visits, Spearman’s r = 0.82 (p

Abstract Background Despite the global progress in bringing health services closer to the population, mothers and their newborns still receive substandard care leading to morbidity and mortality. Health facilities’ capacity to deliver the service is a prerequisite for quality health care. This study aimed to assess health facilities’ readiness to provide comprehensive emergency obstetric and newborn care (CEmONC), comprising of blood transfusion, caesarean section and basic services, and hence to inform improvement in the quality of care interventions in Tanzania. Methods A cross-sectional assessment of 30 CEmONC health facilities implementing the Safer Births Bundle of Care package in five regions of Tanzania was carried out between December 2020 and January 2021. We adapted the World Health Organization’s Service Availability and Readiness Assessment tool to assess amenities, equipment, trained staff, guidelines, medicines, and diagnostic facilities. Composite readiness scores were calculated for each category and results were compared at the health facility level. For categorical variables, we tested for differences by Fisher’s exact test; for readiness scores, differences were tested by a linear mixed model analysis, taking into account dependencies within the regions. We used p

Abstract Background Adverse childhood experiences (ACEs) are important factors for population mental and physical health. While considerable public health literature demonstrates the global relevance of ACEs, more recent research shows that benevolent childhood experiences (BCEs) might be important to consider in their direct and mitigating roles for psychological distress and other mental health outcomes. There is little evidence of latent class examinations involving both ACEs and BCEs among adults in western nations. The present study sought to replicate and extend prior literature by: (1) assessing the extent to which past latent class groupings reproduce in present samples, and (2) analyzing the association of latent classes of childhood experiences with psychological distress and suicidal thoughts and behaviours (STBs). We examined psychological distress (i.e., depression, anxiety, post-traumatic stress, general wellbeing) and STBs (i.e., suicidal ideation, self-harm ideation and behaviour, entrapment, and defeat). Method Data were drawn from two nationwide cross-sectional online survey studies in the United Kingdom. The first sample (N = 488) was drawn from a study on suicidal behaviour, and the second sample (N = 447) was from a study concerning risk for interpersonal violence. Results Results largely replicated an existing four class solution of childhood experiences: Class 1 (Moderate ACEs/High BCEs; 17.6%), Class 2 (High ACEs/Moderate BCEs; 15.3%), Class 3 (Low ACEs/High BCEs; 48.3%), and Class 4 (Low ACEs/Moderate BCEs; 18.8%). Class 2 (High ACEs/Moderate BCEs) was associated with consistently worse psychological distress and STBs. Classes containing high BCEs (1 and 3) were characterized by generally lower levels of psychological distress and STBs. Conclusions Results affirm the potential value for jointly considering ACEs and BCEs to understand psychological distress and STBs. ACEs and BCEs may serve foundational roles in theories of suicide. The protective role of BCEs hypothesized in resiliency theory may be supported. Prevention practice and research implications are discussed.

Abstract Vitamin K antagonists (VKA) remain the only option of anticoagulation for people with mechanical valve replacement and due to their wider availability and lower acquisition costs, VKA’s remain widely used in low- and middle-income countries. It has been suggested that prolonged use of VKAs can increase the development of vascular and valvular calcification, though this effect has not been examined in larger randomized prospective trials. This investigator-initiated multicenter, prospective, randomized, open-label interventional trial randomized patients with baseline coronary or valvular calcification and an indication for prolonged oral anticoagulation therapy to Marcumar or Rivaroxaban. Patients were followed-up through repeat coronary computed tomographies to measure the progression of coronary and valvular calcification for up to 24 months. 192 patients were randomized between 2013 and 2018 to receive either Rivaroxaban or Marcumar and followed for up to 24 months. Coronary calcification significantly increased over time although there was no significant difference in progression between the groups after 12 and 24 months as measured by the Agatston score [360.7 (90.2; 1075.3) vs 380.4 (136.4; 1546.9) p = 0.69], the volume score [295.8 (93.0; 995.3) vs 335.5 (128.7; 1316.9) p = 0.95] and the mass score [58.5 (15.9; 172.0) vs 71.1 (24.8; 257.3) p = 0.5]. Dephosphorylated, uncarboxylated matrix Gla Protein (Dp-ucMGP) significantly decreased in the VKA group [Δ dp-uc MGP – 95.2 (− 554.1; 156.0) vs 231.3 (− 59.7; 388.1) p

Abstract While the surface-bulk correspondence has been ubiquitously shown in topological phases, the relationship between surface and bulk in Landau-like phases is much less explored. Theoretical investigations since 1970s for semi-infinite systems have predicted the possibility of the surface order emerging at a higher temperature than the bulk, clearly illustrating a counterintuitive situation and greatly enriching phase transitions. But experimental realizations of this prediction remain missing. Here, we demonstrate the higher-temperature surface and lower-temperature bulk phase transitions in CrSBr, a van der Waals (vdW) layered antiferromagnet. We leverage the surface sensitivity of electric dipole second harmonic generation (SHG) to resolve surface magnetism, the bulk nature of electric quadrupole SHG to probe bulk spin correlations, and their interference to capture the two magnetic domain states. Our density functional theory calculations show the suppression of ferromagnetic-antiferromagnetic competition at the surface is responsible for this enhanced surface magnetism. Our results not only show counterintuitive, richer phase transitions in vdW magnets, but also provide viable ways to enhance magnetism in their 2D form.

Abstract In 2022, two new classifications of myeloid neoplasms and acute leukemias were published: the 5th edition WHO Classification (WHO-HAEM5) and the International Consensus Classification (ICC). As with prior classifications, the WHO-HAEM5 and ICC made updates to the prior classification (revised 4th edition WHO Classification, WHO-HAEM4R) based on a consensus of groups of experts, who examined new evidence. Both WHO-HAEM5 and ICC introduced several new disease entities that are based predominantly on genetic features, superseding prior morphologic definitions. While it is encouraging that two groups independently came to similar conclusions in updating the classification of myeloid neoplasms and acute leukemias, there are several divergences in how WHO-HAEM5 and ICC define specific entities as well as differences in nomenclature of certain diseases. In this review, we highlight the similarities and differences between the WHO-HAEM5 and ICC handling of myeloid neoplasms and acute leukemias and present a practical approach to diagnosing and classifying these diseases in this current era of two divergent classification guidelines.

Abstract Introduction Prostate Specific Membrane Antigen (PSMA) imaging with Positron Emission Tomography (PET) plays a crucial role in prostate cancer management. However, there is a lack of comprehensive data on how PSMA PET/CT (Computed Tomography) influences radiotherapeutic decisions, particularly in node-positive prostate cancer cases. This study aims to address this gap by evaluating two primary objectives: (1) Mapping the regional and non-regional lymph nodes (LNs) up to the aortic bifurcation and their distribution using conventional methods with CT compared to PSMA PET/CT, and (2) assessing the impact of PSMA PET/CT findings on radiotherapeutic decisions. Methods A retrospective analysis of 95 node-positive prostate cancer patients who underwent both CT and PSMA PET/CT imaging prior to primary radiotherapy and androgen deprivation therapy (ADT) was conducted. The analysis focused on identifying LNs in various regions including the common iliac, external iliac, internal iliac, obturator, presacral, mesorectal, inguinal, and other stations. Treatment plans were reviewed for modifications based on PSMA PET/CT findings, and statistical analysis was performed to identify predictors for exclusive nodal positivity on PSMA PET/CT scans. Results PSMA PET/CT identified additional positive nodes in 48% of cases, resulting in a staging shift from N0 to N1 in 29% of patients. The most frequent metastatic LNs were located in the external iliac (76 LNs; 34%), internal iliac (43 LNs; 19%), and common iliac (35 LNs; 15%) stations. In patients with nodes only detected on PSMA PET the most common nodes were in the external iliac (27, 40%), internal iliac (13, 19%), obturator (11, 15%) stations. Within the subgroup of 28 patients exclusively demonstrating PSMA PET-detected nodes, changes in radiotherapy treatment fields were implemented in 5 cases (18%), and a dose boost was applied for 23 patients (83%). However, no discernible predictors for exclusive nodal positivity on PSMA PET/CT scans emerged from the analysis. Discussion The study underscores the pivotal role of PSMA PET/CT compared to CT alone in accurately staging node-positive prostate cancer and guiding personalized radiotherapy strategies. The routine integration of PSMA PET/CT into diagnostic protocols is advocated to optimize treatment precision and improve patient outcomes.

Abstract Background The identification of novel toxins from overlooked and taxonomically exceptional species bears potential for various pharmacological applications. The remipede Xibalbanus tulumensis, an underwater cave-dwelling crustacean, is the only crustacean for which a venom system has been described. Its venom contains several xibalbin peptides that have an inhibitor cysteine knot (ICK) scaffold. Results Our screenings revealed that all tested xibalbin variants particularly inhibit potassium channels. Xib1 and xib13 with their eight-cysteine domain similar to spider knottins also inhibit voltage-gated sodium channels. No activity was noted on calcium channels. Expanding the functional testing, we demonstrate that xib1 and xib13 increase PKA-II and Erk1/2 sensitization signaling in nociceptive neurons, which may initiate pain sensitization. Our phylogenetic analysis suggests that xib13 either originates from the common ancestor of pancrustaceans or earlier while xib1 is more restricted to remipedes. The ten-cysteine scaffolded xib2 emerged from xib1, a result that is supported by our phylogenetic and machine learning-based analyses. Conclusions Our functional characterization of synthesized variants of xib1, xib2, and xib13 elucidates their potential as inhibitors of potassium channels in mammalian systems. The specific interaction of xib2 with Kv1.6 channels, which are relevant to treating variants of epilepsy, shows potential for further studies. At higher concentrations, xib1 and xib13 activate the kinases PKA-II and ERK1/2 in mammalian sensory neurons, suggesting pain sensitization and potential applications related to pain research and therapy. While tested insect channels suggest that all probably act as neurotoxins, the biological function of xib1, xib2, and xib13 requires further elucidation. A novel finding on their evolutionary origin is the apparent emergence of X. tulumensis-specific xib2 from xib1. Our study is an important cornerstone for future studies to untangle the origin and function of these enigmatic proteins as important components of remipede but also other pancrustacean and arthropod venoms.

Background: This study assessed the effect of HIV-integrated care delivered within routine primary health care (PHC) in Kano, Nigeria, on the uptake of maternal health and routine childhood immunization services. Methods: A retrospective cohort design was used to review and collect anonymized data from medical records of women and children who accessed health care from the PHC facility between January 2009 and December 2016. Data were analyzed using SPSS version 22. Interrupted time series analysis (ITS) was performed to estimate changes in maternal and childhood immunization service usage over time following the delivery of the integrated care. Results: Uptake of maternal health services increased over time: antenatal care attendance (effect/month [95% confidence interval (CI)]: 6.6 [44.55–8.65], P = 0.0001), family planning (effect/month [95% CI]: 1.3 [0.26–2.26], P = 0.014), and delivery (effect/month [95% CI]: 0.9 [0.39–1.45], P = 0.0009). Uptake of routine immunization also increased over time with the integrated care: Bacille Calmette Guerin (BCG) (Effect/month [95% CI]: 1.8 [0.64–2.88], P = 0.002), and diphtheria, tetanus, and pertussis 1 (DPT1)/Penta 1 vaccinations (Effect/month [95% CI]: 1.0 [0.20–1.73], P = 0.013) also showed a moderate increase over time, but DPT3/Penta 3 vaccination dropped gradually over time (Effect/month [95% CI]: −0.1 [−0.74–0.46], P = 0.649). Conclusion: The integrated care resulted in increased uptake of both maternal health and childhood routine immunization services. This suggests that the reorganization and restructuring of the HIV-integrated care in the Kumbotso Comprehensive Health Centre has had a positive impact on non-HIV services provided at the center. There are still opportunities for further research to refine and elaborate on the novel findings of this study.

Abstract Background The Uganda ministry of Health recommends frequent blood glucose monitoring for the first six months on dolutegravir, in people with HIV (PWH) having pre-diabetes mellitus (pre-DM). We sought to determine if indeed PWH with pre-diabetes started on dolutegravir had worse blood glucose outcomes at 48 weeks compared to those with normal blood glucose. Methods In this matched cohort study, we compared 44 PWH with pre-DM and 88 PWH with normal blood glucose at baseline. The primary outcome was change in mean fasting blood glucose (FBG) from baseline to week 48 and 2-hour blood glucose (2hBG) from baseline to week 36 compared between the two groups. Results There was significant increase in FBG in PWH with normal blood glucose (mean change in FBG(FBG): 3.9 mg/dl, 95% confidence interval (95% CI): (2.2, 5.7), p value (p) =

Abstract Background Early detection of outbreaks requires robust surveillance and reporting at both community and health facility levels. Uganda implements Integrated Disease Surveillance and Response (IDSR) for priority diseases and uses the national District Health Information System (DHIS2) for reporting. However, investigations after the first case in the 2022 Uganda Sudan virus outbreak was confirmed on September 20, 2022 revealed many community deaths among persons with Ebola-like symptoms as far back as August. Most had sought care at private facilities. We explored possible gaps in surveillance that may have resulted in late detection of the Sudan virus disease (SVD) outbreak in Uganda. Methods Using a standardized tool, we evaluated core surveillance capacities at public and private health facilities at the hospital level and below in three sub-counties reporting the earliest SVD cases in the outbreak. Key informant interviews (KIIs) were conducted with 12 purposively-selected participants from the district local government. Focus group discussions (FGDs) were conducted with community members from six villages where early probable SVD cases were identified. KIIs and FGDs focused on experiences with SVD and Viral Hemorrhagic Fever (VHF) surveillance in the district. Thematic data analysis was used for qualitative data. Results Forty-six (85%) of 54 health facilities surveyed were privately-owned, among which 42 (91%) did not report to DHIS2 and 39 (85%) had no health worker trained on IDSR; both metrics were 100% in the eight public facilities. Weak community-based surveillance, poor private facility engagement, low suspicion index for VHF among health workers, inability of facilities to analyze and utilize surveillance data, lack of knowledge about to whom to report, funding constraints for surveillance activities, lack of IDSR training, and lack of all-cause mortality surveillance were identified as gaps potentially contributing to delayed outbreak detection. Conclusion Both systemic and knowledge-related gaps in IDSR surveillance in SVD-affected districts contributed to the delayed detection of the 2022 Uganda SVD outbreak. Targeted interventions to address these gaps in both public and private facilities across Uganda could help avert similar situations in the future.

Abstract Background Dengue fever remains a significant public health challenge in tropical and subtropical regions, with its transmission dynamics being influenced by both environmental factors and human mobility. The Dominican Republic, a biodiversity hotspot in the Caribbean, has experienced recurrent dengue outbreaks, yet detailed understanding of the virus's transmission pathways and the impact of climatic factors remains limited. This study aims to elucidate the recent transmission dynamics of the dengue virus (DENV) in the Dominican Republic, utilizing a combination of genomic sequencing and epidemiological data analysis, alongside an examination of historical climate patterns. Methods We conducted a comprehensive study involving the genomic sequencing of DENV samples collected from patients across different regions of the Dominican Republic over a two-year period. Phylogenetic analyses were performed to identify the circulation of DENV lineages and to trace transmission pathways. Epidemiological data were integrated to analyze trends in dengue incidence and distribution. Additionally, we integrated historical climate data spanning several decades to assess trends in temperature and their potential impact on DENV transmission potential. Results Our results highlight a previously unknown north–south transmission pathway within the country, with the co-circulation of multiple virus lineages. Additionally, we examine the historical climate data, revealing long-term trends towards higher theoretical potential for dengue transmission due to rising temperatures. Conclusion This multidisciplinary study reveals intricate patterns of dengue virus transmission in the Dominican Republic, characterized by the co-circulation of multiple DENV lineages and a novel transmission pathway. The observed correlation between rising temperatures and increased dengue transmission potential emphasizes the need for integrated climate-informed strategies in dengue control efforts. Our findings offer critical insights for public health authorities in the Dominican Republic and similar settings, guiding resource allocation and the development of preparedness strategies to mitigate the impacts of climate change on dengue transmission.

Abstract Objective The COVID-19 pandemic has had significant health and socioeconomic impacts worldwide. Extensive measures, including contact restrictions, were implemented to control the spread of the virus. This study aims to examine the factors that influenced private and professional contact behaviour during the COVID-19 pandemic. Results We used baseline data (January–April 2021) from the SeMaCo study (Serologische Untersuchungen bei Blutspendern des Großraums Magdeburg auf Antikörper gegen SARS-CoV-2), a longitudinal, regional cohort study assessing COVID-19 seroprevalence in blood donors from Magdeburg and surrounding areas in Germany. In the blood donor cohort (n = 2,195), there was a general reduction in private contacts (by 78.9%) and professional contacts (by 54.4%) after March 18, 2020. Individuals with higher education reduced both private (by 84.1%) and professional (by 70.1%) contacts more than those with lower education levels (private contacts 59.5%; professional contacts 37%). Younger age groups (18–30 years) reduced private contacts more frequently (by 85.4%) than older individuals (61–83 years, by 68.6%) and demonstrated a higher likelihood of private contact reduction compared to older age groups (51–60 years: odds ratio (OR) 0.45 [95% [CI] 0.32–0.65]; 61–83 years: OR 0.33 [95% [CI] 0.22–0.48]).

Abstract This study was designed to assess how different prompt engineering techniques, specifically direct prompts, Chain of Thought (CoT), and a modified CoT approach, influence the ability of GPT-3.5 to answer clinical and calculation-based medical questions, particularly those styled like the USMLE Step 1 exams. To achieve this, we analyzed the responses of GPT-3.5 to two distinct sets of questions: a batch of 1000 questions generated by GPT-4, and another set comprising 95 real USMLE Step 1 questions. These questions spanned a range of medical calculations and clinical scenarios across various fields and difficulty levels. Our analysis revealed that there were no significant differences in the accuracy of GPT-3.5's responses when using direct prompts, CoT, or modified CoT methods. For instance, in the USMLE sample, the success rates were 61.7% for direct prompts, 62.8% for CoT, and 57.4% for modified CoT, with a p-value of 0.734. Similar trends were observed in the responses to GPT-4 generated questions, both clinical and calculation-based, with p-values above 0.05 indicating no significant difference between the prompt types. The conclusion drawn from this study is that the use of CoT prompt engineering does not significantly alter GPT-3.5's effectiveness in handling medical calculations or clinical scenario questions styled like those in USMLE exams. This finding is crucial as it suggests that performance of ChatGPT remains consistent regardless of whether a CoT technique is used instead of direct prompts. This consistency could be instrumental in simplifying the integration of AI tools like ChatGPT into medical education, enabling healthcare professionals to utilize these tools with ease, without the necessity for complex prompt engineering.

Abstract Retrospective cohort studies in Cameroon found an association between Onchocerca volvulus microfilarial load in childhood (measured in 1991–1993) and risk of developing epilepsy later in life (measured in 2017). We parameterised and integrated this relationship (across children aged 3–15 years) into the previously published, stochastic transmission model, EPIONCHO-IBM, for Simulium damnosum sensu lato-transmitted onchocerciasis. We simulated 19 years (1998–2017) of annual ivermectin mass drug administration (MDA) reflecting coverage in the study area, and modelled epilepsy prevalence and incidence. Scenario-based simulations of 25 years of (annual and biannual) MDA in hyper- and holoendemic settings, with 65% and 80% therapeutic coverage, were also conducted. EPIONCHO-IBM predicted 7.6% epilepsy prevalence (compared to 8.2% in the Cameroon study) and incidence of 317 cases/100,000 person-years (compared to 350). In hyperendemic areas, 25 years of biannual MDA (80% coverage) eliminated onchocerciasis-associated epilepsy (OAE) and protected untreated under-fives from its development. Strengthening onchocerciasis programmes, implementing alternative strategies, and evaluating treatment for under-fives and school-age children are crucial to prevent OAE in highly-endemic settings.

Abstract Elevated blood pressure (BP) is major risk factor for cardiovascular diseases (CVD). Genome-wide association studies (GWAS) conducted predominantly in populations of European ancestry have identified >2,000 BP-associated loci, but other ancestries have been less well-studied. We conducted GWAS of systolic, diastolic, pulse, and mean arterial BP in 100,453 Chinese adults. We identified 128 non-overlapping loci associated with one or more BP traits, including 74 newly-reported associations. Despite strong genetic correlations between populations, we identified appreciably higher heritability and larger variant effect sizes in Chinese compared with European or Japanese ancestry populations. Using instruments derived from these GWAS, multivariable Mendelian randomisation demonstrated that BP traits contribute differently to the causal associations of BP with CVD. In particular, only pulse pressure was independently causally associated with carotid plaque. These findings reinforce the need for studies in diverse populations to understand the genetic determinants of BP traits and their roles in disease risk.

Abstract Photoionization can initiate structural reorganization of molecular matter and drive formation of new chemical bonds. Here, we used time-resolved extreme ultraviolet (EUV) pump – EUV probe Coulomb explosion imaging of carbon dioxide dimer ion $${\left({{{\rm{C}}}}{{{{\rm{O}}}}}_{2}\right)}_{2}^{+}$$ C O 2 2 + dynamics, that combined with ab initio molecular dynamics simulations, revealed unexpected asymmetric structural rearrangement. We show that ionization by the pump pulse induces rearrangement from the slipped-parallel (C2h) geometry of the neutral $${{{\rm{C}}}}{{{{\rm{O}}}}}_{2}$$ C O 2 dimer towards a T-shaped (C2v) structure on the ~100 fs timescale, although the most stable slipped-parallel (C2h) structure of the ionic dimer. Moreover, we find that excited states of the ionized $${{{\rm{C}}}}{{{{\rm{O}}}}}_{2}$$ C O 2 dimer can exhibit formation of a $${{{{\rm{CO}}}}}_{3}$$ CO 3 moiety in the $${{{{\rm{C}}}}}_{2}{{{{\rm{O}}}}}_{4}^{+}\,$$ C 2 O 4 + complex that can persist even after a suitably time-delayed second photoionization in a metastable $${{{{\rm{C}}}}}_{2}{{{{\rm{O}}}}}_{4}^{2+}$$ C 2 O 4 2 + dication. Our results suggest that charge asymmetry plays an important role in the ionization-induced dynamics in such dimers that are present in $${{{\rm{C}}}}{{{{\rm{O}}}}}_{2}$$ C O 2 rich environments.

Abstract Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG • CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of these have been found in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3, ranging from 118 to 694 repeats, in 35 affected individuals across eight unrelated OPDM families of European ancestry. ABCD3 transcript appears upregulated in fibroblasts and skeletal muscle from OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the CGG • CCG repeat motif and a specific pattern of muscle weakness.

Abstract Salmonella Typhi is a human-restricted pathogen that is transmitted by the faecal–oral route and causative organism of typhoid fever. Using health facility data from 2016 to 2020, this study focuses on modelling the spatial variation in typhoid risk in Ndirande township in Blantyre. To pursue this objective, we developed a marked inhomogeneous Poisson process model that allows us to incorporate both individual-level and environmental risk factors. The results from our analysis indicate that typhoid cases are spatially clustered, with the incidence decreasing by 54% for a unit increase in the water, sanitation, and hygiene (WASH) score. Typhoid intensity was also higher in children aged below 18 years than in adults. However, our results did not show evidence of a strong temporal variation in typhoid incidence. We also discuss the inferential benefits of using point pattern models to characterise the spatial variation in typhoid risk and outline possible extensions of the proposed modelling framework.

Abstract Background Mucopolysaccharidosis (MPS) type IVA is a rare lysosomal storage disorder caused by aberrations of the N-acetyl-galactosamine-6-sulfatase (GALNS) enzyme. MPS IVA is associated with a wide gamut of respiratory and airway disorders that manifest in a continuum of severity. In individuals exhibiting severe phenotypic expression, terminal stages of the disease frequently culminate in life-threatening, critical airway obstruction. These manifestations of end-stage disease are engendered by an insidious progression of multi-level airway pathologies, comprising of tracheomalacia, stenosis, tortuosity and 'buckling'. Historically, the management of end-stage airway disease has predominantly leaned towards palliative modalities. However, contemporary literature has posited that the potential benefits of tracheal resection with aortopexy, performed under cardiopulmonary bypass (CPB), may offer a promising therapeutic option. In this context, we report on outcomes from patients undergoing a novel approach to tracheal resection that is combined with manubrial resection, leading to improved airway calibre, obviating the requisition for CPB. Results In this study, seven patients with severe MPS IVA exhibited clinical symptoms and radiological evidence indicative of advanced airway obstruction. All patients had a tracheal resection with a partial upper manubriectomy via transcervical approach, which did not require CPB. The surgical cohort consisted of 5 females and 2 males, the median age was 16 years (range 11-19) and the median height was 105.6cm (range 96.4-113.4). Postoperatively, significant improvements were seen in forced expiratory volume in 1 second (FEV1), with a mean increase of 0.68 litres (95% CI: 0.45-0.91; SD: 0.20). Notably, other spirometry variables also showed meaningful improvements, providing evidence of positive treatment effects. Furthermore, there were no major long-term complications, and the procedure resulted in a significant enhancement in patient-reported domains using PedsQL (version 4.0). Conclusions This study represents the largest case series to date, on tracheal resection in patients with severe MPS IVA. Our findings demonstrate the effectiveness of the transcervical approach with partial manubriectomy for improving respiratory function and quality of life for individuals with advanced airway obstruction. Tracheal resection presents a promising treatment modality for severe cases of MPS IVA. Successful outcomes rely on meticulous multidisciplinary assessment, judicious decision-making, and appropriate timing of tracheal surgery. Further research and long-term follow-up studies are warranted to validate the long-term efficacy and safety of this approach.

Abstract There is growing evidence suggesting that immunological mechanisms play a significant role in the development of psychiatric symptoms in certain patient subgroups. However, the relationship between clinical red flags for suspected autoimmune psychiatric disease and signs of central nervous system (CNS) pathology (e.g., routine cerebrospinal fluid (CSF) alterations, CNS damage markers, neurophysiological or neuroimaging findings) has received limited attention. Here, we aimed to describe the prevalence and distribution of potential CNS pathologies in psychiatric patients in relation to clinical red flags for autoimmune psychiatric disease and psychiatric symptoms. CSF routine findings and CNS damage markers; neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP) and total Tau (t-Tau), in CSF from 127 patients with psychiatric disease preselected for suspected immunological involvement were related to recently proposed clinical red flags, psychiatric features, and MRI and EEG findings. Twenty-one percent had abnormal routine CSF findings and 27% had elevated levels of CNS damage markers. Six percent had anti-neuronal antibodies in serum and 2% had these antibodies in the CSF. Sixty-six percent of patients examined with MRI (n = 88) had alterations, mostly atrophy or nonspecific white matter lesions. Twenty-seven percent of patients with EEG recordings (n = 70) had abnormal findings. Elevated NfL levels were associated with comorbid autoimmunity and affective dysregulation symptoms. Elevated t-Tau was associated with catatonia and higher ratings of agitation/hyperactivity. Elevated GFAP was associated with acute onset, atypical presentation, infectious prodrome, tics, depressive/anxiety symptom ratings and overall greater psychiatric symptom burden. In conclusion, preselection based on suspected autoimmune psychiatric disease identifies a population with a high prevalence of CSF alterations suggesting CNS pathology. Future studies should examine the value of these markers in predicting treatment responses.

Abstract Recent studies indicate that Generative Pre-trained Transformer 4 with Vision (GPT-4V) outperforms human physicians in medical challenge tasks. However, these evaluations primarily focused on the accuracy of multi-choice questions alone. Our study extends the current scope by conducting a comprehensive analysis of GPT-4V’s rationales of image comprehension, recall of medical knowledge, and step-by-step multimodal reasoning when solving New England Journal of Medicine (NEJM) Image Challenges—an imaging quiz designed to test the knowledge and diagnostic capabilities of medical professionals. Evaluation results confirmed that GPT-4V performs comparatively to human physicians regarding multi-choice accuracy (81.6% vs. 77.8%). GPT-4V also performs well in cases where physicians incorrectly answer, with over 78% accuracy. However, we discovered that GPT-4V frequently presents flawed rationales in cases where it makes the correct final choices (35.5%), most prominent in image comprehension (27.2%). Regardless of GPT-4V’s high accuracy in multi-choice questions, our findings emphasize the necessity for further in-depth evaluations of its rationales before integrating such multimodal AI models into clinical workflows.

Abstract Purpose To evaluate outcomes and complications of prophylactic internal iliac balloon occlusion (PIIBO) in the management of patients with placenta accreta spectrum (PAS) at a large regional referral centre. Materials and methods A retrospective review of all PIIBO for PAS performed over a 12-year period (2010–2022). Information for analysis was gathered from the local RIS/PACS and clinical documentation. Collected data included patient demographics, indication for procedure, sheath insertion and removal time, total duration of balloon inflation and complications that occurred. Results 106 patients underwent temporary internal iliac artery balloon occlusion within the 12-year period. All procedures utilised bilateral common femoral artery punctures, 6Fr sheath and 5Fr Le Maitre occlusion balloons. Catheters were successfully positioned and balloons inflated in obstetric theatre following caesarean delivery in 100% of the cases. The uterus was conserved in every case. There was no maternal mortality or foetal morbidity. Twenty patients (18.9%) had some form of complication that required further intervention. Of these, 7(6.6%) had post-operative PPH, which was treated with uterine artery embolisation; and 13 (12.3%) had arterial thrombus which required aspiration thrombectomy. All procedures were technically successful with no long-term sequelae. Conclusion PIIBO plays an important part in reducing morbidity and mortality in patients with PAS. Clear pathways and multidisciplinary team working is critical in the management of these patients to ensure that any complications are dealt with promptly to avoid long-term sequelae.

Abstract Occurrence of resistance to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) approved in ovarian carcinoma, has already been shown in clinical settings. Identifying combination treatments to sensitize tumor cells and/or overcome resistance to olaparib is critical. Polo-like kinase 1 (PLK1), a master regulator of mitosis, is also involved in the DNA damage response promoting homologous recombination (HR)-mediated DNA repair and in the recovery from the G2/M checkpoint. We hypothesized that PLK1 inhibition could sensitize tumor cells to PARP inhibition. Onvansertib, a highly selective PLK1 inhibitor, and olaparib were tested in vitro and in vivo in BRCA1 mutated and wild-type (wt) ovarian cancer models, including patient-derived xenografts (PDXs) resistant to olaparib. The combination of onvansertib and olaparib was additive or synergic in different ovarian cancer cell lines, causing a G2/M block of the cell cycle, DNA damage, and apoptosis, much more pronounced in cells treated with the two drugs as compared to controls and single agents treated cells. The combined treatment was well tolerated in vivo and resulted in tumor growth inhibition and a statistically increased survival in olaparib-resistant-BRCA1 mutated models. The combination was also active, although to a lesser extent, in BRCA1 wt PDXs. Pharmacodynamic analyses showed an increase in mitotic, apoptotic, and DNA damage markers in tumor samples derived from mice treated with the combination versus vehicle. We could demonstrate that in vitro onvansertib inhibited both HR and non-homologous end-joining repair pathways and in vivo induced a decrease in the number of RAD51 foci-positive tumor cells, supporting its ability to induce HR deficiency and favoring the activity of olaparib. Considering that the combination was well tolerated, these data support and foster the clinical evaluation of onvansertib with PARPis in ovarian cancer, particularly in the PARPis-resistant setting.

Abstract Background Communities affected by Ebola disease (EBOD) may face resulting increases in mental health disorders. We evaluated the prevalence of and factors associated with mental health disorders among persons affected by the 2022 Sudan virus disease (SVD) outbreak in Uganda. Methods We conducted a cross-sectional study among SVD survivors and family members of survivors and fatal cases from 15–31 January 2023. We included only laboratory-confirmed SVD survivors and family members who lived with or cared for confirmed SVD patients during their illness. The Hospital Anxiety and Depression Scale was used to evaluate anxiety and depression. The post-traumatic stress disorder (PTSD) checklist for the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition was used to evaluate PTSD. Modified Poisson regression was used to determine factors associated with each mental health disorder. Results We enrolled 54 survivors and 82 family members; median age was 30 years (range, 15–73) and 54% were female. The prevalence of anxiety (55%) and depression (50%) was higher than PTSD (17%). The prevalence of all mental health disorders was similar between survivors and family members. Household size was associated with both anxiety and PTSD. Number of SVD deaths in the household was associated with depression. Conclusion Approximately two-thirds of SVD survivors and family members of patients in the 2022 outbreak in Uganda had ≥ 1 mental health disorders shortly after the outbreak ended. Strengthening mental health services during and after Ebola virus outbreaks for survivors and family members of patients may enhance the quality of outbreak response.

The Palaearctic species of Aphodius Hellwig, 1798, subgenus Liothorax Motschulsky, 1860 are revised using a combination of chromosome analysis, molecular phylogenetics and morphological statistical analysis. Sixteen species are recognised, one of which is shown to comprise two subspecies. Based mainly on the morphology of the aedeagal endophallus and the phylogenetic analysis, they are placed in two groups: the. niger group, apparently monophyletic, comprising Aphodius (Liothorax) niger Illiger, 1798, A. (L.) muscorum (Ádám, 1994), stat. rest., A. (L.) felix sp. nov., A. (L.) bellumgerens sp. nov., A. (L.) bameuli sp. nov., A. (L.) krelli sp. nov., A. (L.) isikdagensis (Balthasar, 1953), A. (L.) alberti sp. nov. and A. (L.) wilsonae Maté et Angus, 2005, stat. rest.; and the plagiatus group, almost certainly paraphyletic, comprising A. (L.) plagiatus (Linnaeus, 1767), including A. (L.) p. plagiatus and A. (L.) p. sinoplagiatus subsp. nov., A. (L.) rodrigoi sp. nov., A. (L.) discoides A. Schmidt, 1916, stat. rest., A. (L.) rutilipennis (Baudi di Selve, 1870), stat. rest., A. (L.) chellala sp. nov., A. (L.) kraatzi Harold, 1868, and A. (L.) rusakovi Gusakov, 2004. A key to the species is given as well as details of their morphology, distributions, and habitats.

Abstract Background Scientific evidence highlights the influence of biological sex on the relationship between stress and metabolic dysfunctions. However, there is limited understanding of how diet and stress concurrently contribute to metabolic dysregulation in both males and females. Our study aimed to investigate the combined effects of high-fat diet (HFD) induced obesity and repeated stress on fear-related behaviors, metabolic, immune, and hypothalamic outcomes in male and female mice. Methods To investigate this, we used a highly reliable rodent behavioral model that faithfully recapitulates key aspects of post-traumatic stress disorder (PTSD)-like fear. We subjected mice to footshock stressor followed by a weekly singular footshock stressor or no stressor for 14 weeks while on either an HFD or chow diet. At weeks 10 and 14 we conducted glucose tolerance and insulin sensitivity measurements. Additionally, we placed the mice in metabolic chambers to perform indirect calorimetric measurements. Finally, we collected brain and peripheral tissues for cellular analysis. Results We observed that HFD-induced obesity disrupted fear memory extinction, increased glucose intolerance, and affected energy expenditure specifically in male mice. Conversely, female mice on HFD exhibited reduced respiratory exchange ratio (RER), and a significant defect in glucose tolerance only when subjected to repeated stress. Furthermore, the combination of repeated stress and HFD led to sex-specific alterations in proinflammatory markers and hematopoietic stem cells across various peripheral metabolic tissues. Single-nuclei RNA sequencing (snRNAseq) analysis of the ventromedial hypothalamus (VMH) revealed microglial activation in female mice on HFD, while male mice on HFD exhibited astrocytic activation under repeated stress. Conclusions Overall, our findings provide insights into complex interplay between repeated stress, high-fat diet regimen, and their cumulative effects on health, including their potential contribution to the development of PTSD-like stress and metabolic dysfunctions, emphasizing the need for further research to fully understand these interconnected pathways and their implications for health.

Abstract Background Commonly used media for the differentiation of human pluripotent stem cells into cardiomyocytes (hPSC-CMs) contain high concentrations of proteins, in particular albumin, which is prone to quality variations and presents a substantial cost factor, hampering the clinical translation of in vitro-generated cardiomyocytes for heart repair. To overcome these limitations, we have developed chemically defined, entirely protein-free media based on RPMI, supplemented with L-ascorbic acid 2-phosphate (AA-2P) and either the non-ionic surfactant Pluronic F-68 or a specific polyvinyl alcohol (PVA). Methods and Results Both media compositions enable the efficient, directed differentiation of embryonic and induced hPSCs, matching the cell yields and cardiomyocyte purity ranging from 85 to 99% achieved with the widely used protein-based CDM3 medium. The protein-free differentiation approach was readily up-scaled to a 2000 mL process scale in a fully controlled stirred tank bioreactor in suspension culture, producing > 1.3 × 109 cardiomyocytes in a single process run. Transcriptome analysis, flow cytometry, electrophysiology, and contractile force measurements revealed that the mass-produced cardiomyocytes differentiated in protein-free medium exhibit the expected ventricular-like properties equivalent to the well-established characteristics of CDM3-control cells. Conclusions This study promotes the robustness and upscaling of the cardiomyogenic differentiation process, substantially reduces media costs, and provides an important step toward the clinical translation of hPSC-CMs for heart regeneration.

Abstract Through Tanzania’s National Sanitation Campaign, we study the effectiveness of two common elements of behavior change campaigns: endorsements from celebrities and testimonials. Using four experiments in Tanzania in early 2021 as part of the national campaign, we find that including endorsements and testimonials in text messages sent to individuals significantly increases self-reported hygiene behavior. These results mask important heterogeneity based on the source of endorsement or framing of the testimonial and provide insights into cost-effective approaches for changing behavior at scale.

Abstract Banana (Musa spp.) is the most widely consumed fruit globally. Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense (Foc), is a highly threatening disease to banana production. Resistance genes to Foc exist in wild Musa genotypes such as Musa acuminata subsp. burmannicoides var. Calcutta 4. Whilst real-time PCR (RT-qPCR) is appropriate for accurate analysis of gene expression in pathways involved in host defence responses, reference genes with stable expression under specific biotic stress conditions and host tissue types are necessary for normalization of sample variation. In this context, the stability in potential host reference genes ACT1, APT, EF1α, GAPDH, αTUB, RAN, UBIQ1, UBIQ2, βTUB1, βTUB3, L2 and ACTA1 was evaluated in total RNA samples from root tissues in Calcutta 4 (resistant) and Musa sp. cultivar Prata-anã (susceptible) extracted during interaction with Foc subtropical race 4 (STR4). Expression stability was calculated using the algorithms geNorm, NormFinder and BestKeeper. βTUB3 and L2 were identified as the most stable in Calcutta 4, with ACTA1 and GAPDH the most stable in Prata-anã. These reference genes for analysis of gene expression modulation in the Musa-Foc STR4 pathosystem are fundamental for advancing understanding of host defence responses to this important pathogen.

Abstract Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the ACC exhibited diverse levels of species richness. We identified two main microbial subtypes within the ACC: oral-like and gut-like. Oral-like microbiomes, characterized by increased diversity and abundance of Neisseria, Leptotrichia, Actinomyces, Streptococcus, Rothia, and Veillonella (commonly found in healthy oral cavities), were associated with a less aggressive ACC-II molecular subtype and improved patient outcomes. Notably, we identified the same oral genera in oral cancer and head and neck squamous cell carcinomas. In both cancers, they were part of shared oral communities associated with a more diverse microbiome, less aggressive tumor phenotype, and better survival that reveal the genera as potential pancancer biomarkers for favorable microbiomes in ACC and other head and neck cancers. Conversely, gut-like intratumoral microbiomes, which feature low diversity and colonization by gut mucus layer-degrading species, such as Bacteroides, Akkermansia, Blautia, Bifidobacterium, and Enterococcus, were associated with poorer outcomes. Elevated levels of Bacteroides thetaiotaomicron were independently associated with significantly worse survival and positively correlated with tumor cell biosynthesis of glycan-based cell membrane components.

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.

Abstract Adolescents exhibit remarkable heterogeneity in the structural architecture of brain development. However, due to limited large-scale longitudinal neuroimaging studies, existing research has largely focused on population averages, and the neurobiological basis underlying individual heterogeneity remains poorly understood. Here we identify, using the IMAGEN adolescent cohort followed up over 9 years (14–23 y), three groups of adolescents characterized by distinct developmental patterns of whole-brain gray matter volume (GMV). Group 1 show continuously decreasing GMV associated with higher neurocognitive performances than the other two groups during adolescence. Group 2 exhibit a slower rate of GMV decrease and lower neurocognitive performances compared with Group 1, which was associated with epigenetic differences and greater environmental burden. Group 3 show increasing GMV and lower baseline neurocognitive performances due to a genetic variation. Using the UK Biobank, we show these differences may be attenuated in mid-to-late adulthood. Our study reveals clusters of adolescent neurodevelopment based on GMV and the potential long-term impact.

Abstract During each cell cycle, the process of DNA replication timing is tightly regulated to ensure the accurate duplication of the genome. The extent and significance of alterations in this process during malignant transformation have not been extensively explored. Here, we assess the impact of altered replication timing (ART) on cancer evolution by analysing replication-timing sequencing of cancer and normal cell lines and 952 whole-genome sequenced lung and breast tumours. We find that 6%–18% of the cancer genome exhibits ART, with regions with a change from early to late replication displaying an increased mutation rate and distinct mutational signatures. Whereas regions changing from late to early replication contain genes with increased expression and present a preponderance of APOBEC3-mediated mutation clusters and associated driver mutations. We demonstrate that ART occurs relatively early during cancer evolution and that ART may have a stronger correlation with mutation acquisition than alterations in chromatin structure.

Abstract Electrostatic capacitors play a crucial role as energy storage devices in modern electrical systems. Energy density, the figure of merit for electrostatic capacitors, is primarily determined by the choice of dielectric material. Most industry-grade polymer dielectrics are flexible polyolefins or rigid aromatics, possessing high energy density or high thermal stability, but not both. Here, we employ artificial intelligence (AI), established polymer chemistry, and molecular engineering to discover a suite of dielectrics in the polynorbornene and polyimide families. Many of the discovered dielectrics exhibit high thermal stability and high energy density over a broad temperature range. One such dielectric displays an energy density of 8.3 J cc−1 at 200 °C, a value 11 × that of any commercially available polymer dielectric at this temperature. We also evaluate pathways to further enhance the polynorbornene and polyimide families, enabling these capacitors to perform well in demanding applications (e.g., aerospace) while being environmentally sustainable. These findings expand the potential applications of electrostatic capacitors within the 85–200 °C temperature range, at which there is presently no good commercial solution. More broadly, this research demonstrates the impact of AI on chemical structure generation and property prediction, highlighting the potential for materials design advancement beyond electrostatic capacitors.

Abstract DNA N6-adenine methylation (6mA) has recently gained importance as an epigenetic modification in eukaryotes. Its function in lineages with high levels, such as early-diverging fungi (EDF), is of particular interest. Here, we investigated the biological significance and evolutionary implications of 6mA in EDF, which exhibit divergent evolutionary patterns in 6mA usage. The analysis of two Mucorales species displaying extreme 6mA usage reveals that species with high 6mA levels show symmetric methylation enriched in highly expressed genes. In contrast, species with low 6mA levels show mostly asymmetric 6mA. Interestingly, transcriptomic regulation throughout development and in response to environmental cues is associated with changes in the 6mA landscape. Furthermore, we identify an EDF-specific methyltransferase, likely originated from endosymbiotic bacteria, as responsible for asymmetric methylation, while an MTA-70 methylation complex performs symmetric methylation. The distinct phenotypes observed in the corresponding mutants reinforced the critical role of both types of 6mA in EDF.

Abstract Neuronal responses during behavior are diverse, ranging from highly reliable ‘classical’ responses to irregular ‘non-classically responsive’ firing. While a continuum of response properties is observed across neural systems, little is known about the synaptic origins and contributions of diverse responses to network function, perception, and behavior. To capture the heterogeneous responses measured from auditory cortex of rodents performing a frequency recognition task, we use a novel task-performing spiking recurrent neural network incorporating spike-timing-dependent plasticity. Reliable and irregular units contribute differentially to task performance via output and recurrent connections, respectively. Excitatory plasticity shifts the response distribution while inhibition constrains its diversity. Together both improve task performance with full network engagement. The same local patterns of synaptic inputs predict spiking response properties of network units and auditory cortical neurons from in vivo whole-cell recordings during behavior. Thus, diverse neural responses contribute to network function and emerge from synaptic plasticity rules.

Abstract Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we establish independent approaches to achieve the functional correction of trimer assembly defects. Focusing on the prototypical R274Q mutation, we identify an HTRA1 variant that promotes trimer formation thus restoring enzymatic activity in vitro. Genetic experiments in Htra1 R274Q mice further demonstrate that expression of this protein-based corrector in trans is sufficient to stabilize HtrA1-R274Q and restore the proteomic signature of the brain vasculature. An alternative approach employs supramolecular chemical ligands that shift the monomer-trimer equilibrium towards proteolytically active trimers. Moreover, we identify a peptidic ligand that activates HTRA1 monomers. Our findings open perspectives for tailored protein repair strategies.

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as nonalcoholic fatty liver disease, impacts 30% of the global population. This educational pilot focused on the role primary care providers may play in the delivery of guidelines-based metabolic dysfunction-associated steatohepatitis (MASH) care. Objective Accelerate the application of guidelines-based MASH care pathways to clinical workflows. Methods A panel of six hepatologists was convened in 2021 to develop the care pathway and the subsequent pilot occurred between 2022 – 2023. The pilot was conducted across three U.S. health systems: Boston Medical Center (Boston), Methodist Health System (Dallas), and Weill Cornell Medicine (New York). Clinicians were educated on the care pathway and completed baseline/follow-up assessments. 19 primary care clinicians participated in the educational pilot baseline assessment, nine primary care clinicians completed the two-month assessment, and 15 primary care clinicians completed the four-month assessment. The primary endpoint was to assess clinician-reported adherence to and satisfaction with the care pathway. The pilot was deemed exempt by the Western Consensus Group Institutional Review Board. Results At baseline, 38.10% (n = 8) of respondents felt they had received sufficient training on when to refer a patient suspected of metabolic dysfunction-associated liver disease to hepatology, and 42.86% (n = 9) had not referred any patients suspected of metabolic dysfunction-associated liver disease to hepatology within a month. At four months post-intervention, 79% (n = 15) of respondents agreed or strongly agreed they received sufficient training on when to refer a patient suspected of metabolic dysfunction-associated liver disease to hepatology, and there was a 25.7% increase in self-reported adherence to the institution’s referral guidelines. Barriers to care pathway adherence included burden of manually calculating fibrosis-4 scores and difficulty ordering non-invasive diagnostics. Conclusions With therapeutics anticipated to enter the market this year, health systems leadership must consider opportunities to streamline the identification, referral, and management of patients with metabolic dysfunction-associated steatohepatitis. Electronic integration of metabolic dysfunction-associated steatohepatitis care pathways may address implementation challenges.