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Abstract Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The ‘Thr’ PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, ‘Thr’ PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

Abstract To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centers (GCs). Among these, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by utilizing energy provided by oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)−155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Mechanistically, miR-155 regulates H3K36me2 levels in hypoxic conditions by directly repressing the histone lysine demethylase, Kdm2a, whose expression increases in response to hypoxia. The miR-155-Kdm2a interaction is crucial for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia, thereby preventing excessive production of reactive oxygen species and subsequent apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity GC-B cells, ensuring their expansion and consequently affinity maturation.

RESUMO O estudo teve como objetivo adaptar a Optimal Functioning in Society Scale (OFISS) à língua portuguesa brasileira e estimar as primeiras evidências de validade, baseadas na estrutura interna e relação com outras variáveis e precisão. A amostra foi composta por 228 participantes, com idades entre 18 e 72 anos (M=32,3, DP=12,4), sendo 71,5% do sexo feminino. A análise dos juízes, por meio do coeficiente de validade de conteúdo, indicou a adequação dos itens em relação a clareza de linguagem, pertinência prática e relevância teórica. A análise fatorial exploratória demonstrou a adequação da estrutura oblíqua de seis fatores, todos com bons indicadores de precisão, semelhante a proposta original. Por fim, os fatores da OFISS relacionaram-se positivamente com satisfação com a vida e afetos positivos, e negativamente com os afetos negativos. Os resultados sugerem que a OFISS é uma medida adequada do funcionamento ótimo na população brasileira.

There has been considerable discussion for more than 50 years of how scientists and practitioners in elite level sport can work collaboratively to ensure that evidence-based practice augments the sport performance and human development of elite amateur and professional athletes. The bridging of these two, often disparate competencies, science and practice, though considered at the conceptual level, continues to be scarcely evidenced within the international sport science community. Much of the research that frames the experiences of elite athletes and their consequent needs, is heavily influenced by scientists, often without direct reciprocity to bridge science, theory, and applied context. The knowledge influencing these interventions has derived from qualitative methods, such as semi-structured interviews, surveys, and focus groups, as well as a breadth of psychometric assessments. Though these approaches to gathering robust data are a necessary part of inquiry, they often produce decontextualized data collection strategies and results, which can lead to generalized, ineffective practices in sport performance environments. Within this submission, the first author cooperated with an international team of scientist-practitioners who are well versed in elite sport to delineate ecologically sound science-practice reciprocity. The authors consider the strengths and weaknesses of conventional qualitative research strategies in terms of their utility and the parlance of evidence into intervention and world-class performance. Two emerging, context driven approaches to inquiry are proposed; arts-based methods and an idiosyncratic approach to ethnography to encourage the reader toward an expanded selection of inquiry approaches from which better understanding and intervention can be generated. This contribution conclude with summary points to open further possibilities for innovative science to practice approaches.

Extracellular vesicles and nanoparticles (EVPs) are now recognized as a novel form of cell–cell communication. All cells release a wide array of heterogeneous EVPs with distinct protein, lipid, and RNA content, dependent on the pathophysiological state of the donor cell. The overall cargo content in EVPs is not equivalent to cellular levels, implying a regulated pathway for selection and export. In cancer, release and uptake of EVPs within the tumour microenvironment can influence growth, proliferation, invasiveness, and immune evasion. Secreted EVPs can also have distant, systemic effects that can promote metastasis. Here, we review current knowledge of EVP biogenesis and cargo selection with a focus on the role that extracellular RNA plays in oncogenesis and metastasis. Almost all subtypes of RNA have been identified in EVPs, with miRNAs being the best characterized. We review the roles of specific miRNAs that have been detected in EVPs and that play a role in oncogenesis and metastasis.

ABSTRACTAlthough circular RNAs (circRNAs) play important roles in regulating gene expression, the understanding of circRNAs in livestock animals is scarce due to the significant challenge to characterize them from a biological sample. In this study, we assessed the outcomes of bovine circRNA identification using six enrichment approaches with the combination of ribosomal RNAs removal (Ribo); linear RNAs degradation (R); linear RNAs and RNAs with structured 3′ ends degradation (RTP); ribosomal RNAs coupled with linear RNAs elimination (Ribo-R); ribosomal RNA, linear RNAs and RNAs with poly (A) tailing elimination (Ribo-RP); and ribosomal RNA, linear RNAs and RNAs with structured 3′ ends elimination (Ribo-RTP), respectively. RNA-sequencing analysis revealed that different approaches led to varied ratio of uniquely mapped reads, false-positive rate of identifying circRNAs, and the number of circRNAs per million clean reads (Padj

Abstract Prolonged exposure of mammalian cells to hypotonic environments stimulates the development of sometimes large and numerous vacuoles of unknown origin. Here, we investigate the nature and formation of these vacuoles, which we term LateVacs. Vacuolation starts after osmotic cell swelling has subsided and continues for many hours thereafter. Most of the vacuoles are positive for the lysosomal marker LAMP-1 but not for the autophagosomal marker LC3. Vacuoles do not appear to have acidic pH, as they exclude LysoTracker and acridine orange; inhibiting the V-ATPase with bafilomycin A1 has no effect on their formation. No LateVacs were formed in cells with a knockout of the essential LRRC8A subunit of the volume-regulated anion channel (VRAC). Since the main feature of cells recovered from hypotonic swelling should be reduced chloride concentration, we tested if chloride depletion can act as a signal for vacuolation. Indeed, four different low-chloride buffers resulted in the development of similar vacuoles. Moreover, vacuolation was suppressed in WNK1/WNK3 double knockouts or by the inhibition of WNK kinase, which is activated by low chloride; in hypotonic media, the WNK inhibitor had a similar effect. However, exposing cells to a low-sodium, high-potassium medium also resulted in vacuoles, which were insensitive to WNK. We conclude that vacuole development can be triggered either by the loss of chloride or by the loss of sodium.

Abstract In the Kitaev honeycomb model, spins coupled by strongly-frustrated anisotropic interactions do not order at low temperature but instead form a quantum spin liquid with spin fractionalisation into Majorana fermions and static fluxes. The realization of such a model in crystalline materials could lead to major breakthroughs in understanding entangled quantum states, however achieving this in practice is a very challenging task. The recently synthesized honeycomb material RuI3 shows no long-range magnetic order down to the lowest probed temperatures and has been theoretically proposed as a quantum spin liquid candidate material on the verge of an insulator to metal transition. Here we report a comprehensive study of the magnetic anisotropy in un-twinned single crystals via torque magnetometry and detect clear signatures of strongly anisotropic and frustrated magnetic interactions. We attribute the development of sawtooth and six-fold torque signal to strongly anisotropic, bond-dependent magnetic interactions by comparing to theoretical calculations. As a function of magnetic field strength at low temperatures, torque shows an unusual non-parabolic dependence suggestive of a proximity to a field-induced transition. Thus, RuI3, without signatures of long-range magnetic order, displays key hallmarks of an exciting candidate for extended Kitaev magnetism with enhanced quantum fluctuations.

Abstract The details of the pediatric immune system that supports induction of antibodies capable of neutralizing geographically-diverse or heterologous HIV-1 is currently unclear. Here we explore the pediatric immune environment in neonatal macaque undergoing Simian-HIV infection. Simian-HIV infection of 11 pairs of therapy-naive dams and infant rhesus macaques for 24 months results in heterologous HIV-1 neutralizing antibodies in 64% of young macaques compared to 18% of adult macaques. Heterologous HIV-1 neutralizing antibodies emerge by 12 months post-infection in young macaques, in association with lower expression of immunosuppressive genes, fewer germinal center CD4 + T regulatory cells, and a lower ratio of CD4 + T follicular regulatory to helper cells. Antibodies from peripheral blood B cells in two young macaques following SHIV infection neutralize 13% of 119 heterologous HIV-1 strains and map to regions of canonical broadly neutralizing antibody epitopes on the envelope surface protein. Here we show that pediatric immunity to SHIV infection in a macaque model may inform vaccine strategies to induce effective HIV-1 neutralizing antibodies in infants and children prior to viral exposure.

Abstract The cryo-electron microscopy (cryoEM) method has enabled high-resolution structure determination of numerous biomolecules and complexes. Nevertheless, cryoEM sample preparation of challenging proteins and complexes, especially those with low abundance or with preferential orientation, remains a major hurdle. We developed an affinity-grid method employing monodispersed single particle streptavidin on a lipid monolayer to enhance particle absorption on the grid surface and alleviate sample exposure to the air-water interface. Using this approach, we successfully enriched the Thermococcus kodakarensis mini-chromosome maintenance complex 3 (MCM3) on cryoEM grids through biotinylation and resolved its structure. We further utilized this affinity method to tether the biotin-tagged dsDNA to selectively enrich a stable MCM3-ATP-dsDNA complex for cryoEM structure determination. Intriguingly, both MCM3 apo and dsDNA bound structures exhibit left-handed open spiral conformations, distinct from other reported MCM structures. The large open gate is sufficient to accommodate a dsDNA which could potentially be melted. The value of mspSA affinity method was further demonstrated by mitigating the issue of preferential angular distribution of HIV-1 capsid protein hexamer and RNA polymerase II elongation complex from Saccharomyces cerevisiae.

Abstract Delta-like Ligand 3 (DLL3) targeting therapies are promising in small cell lung cancer (SCLC) treatment. However, DLL3 expression in SCLC and other neuroendocrine neoplasms (NEN) is heterogeneous and not well characterized. We describe the landscape of DLL3 at the mRNA and protein levels across SCLC, large cell neuroendocrine carcinoma (LCNEC), and non-small cell lung cancer. Additionally, we explore its expression in extra-pulmonary NEN (EP-NEN) using a standardized DLL3 IHC assay. DLL3 expression is enriched in SCLC, LCNEC along with combined histology lung cancers. Moreover, we find a wide range of DLL3 expression in high-grade EP-NEN. We describe heterogenous DLL3 expression not only in SCLC but also in different NEN types. This comprehensive characterization of DLL3 can help guide future clinical trial design targeting DLL3 in NEN including LCNEC and EP-NEN that are lacking standard of care treatment options.

Abstract P/Q-type (Cav2.1) calcium channels mediate Ca2+ influx essential for neuronal excitability and synaptic transmission. The CACNA1A gene, encoding the Cav2.1 pore forming subunit, is highly expressed throughout the mammalian central nervous system. Alternative splicing of Cav2.1 pre-mRNA generates diverse channel isoforms with distinct biophysical properties and drug affinities, which are differentially expressed in nerve tissues. Splicing variants can also affect channel function under pathological conditions although their phenotypic implication concerning inherited neurological disorders linked to CACNA1A mutations remains unknown. Here, we quantified the expression of Cav2.1 exon 24 (e24) spliced transcripts in human nervous system samples, finding different levels of expression within discrete regions. The corresponding Cav2.1 variants, differing by the presence (+) or absence (Δ) of Ser-Ser-Thr-Arg residues (SSTR) in the domain III S3-S4 linker, were functionally characterized using patch clamp recordings. Further, the + /ΔSSTR isoforms were used to demonstrate the differential impact of the Familial Hemiplegic Migraine Type 1 (FHM-1) S218L mutation, located in the domain I S4-S5 linker, on the molecular structure and electrophysiological properties of Cav2.1 isoforms. S218L has a prominent effect on the voltage-dependence of activation of +SSTR channels when compared to ΔSSTR, indicating a differential effect of the mutation depending on splice-variant context. Structural modeling based upon Cav2.1 cryo-EM data provided further insight reflecting independent contributions of amino acids in distant regions of the channel on gating properties. Our modelling indicates that by increasing hydrophobicity the Leu218 mutation contributes to stabilizing a structural conformation in which the domain I S4-S5 linker is oriented alongside the inner plasma membrane, similar to that occurring when S4 is translocated upon activation.The SSTR insertion appears to exert an influence in the local electric field of domain III due to an change in the distribution of positively charged regions surrounding the voltage sensing domain, which we hypothesize impacts its movement during the transition to the open state. In summary, we reveal molecular changes correlated with distinct functional effects provoked by S218L FHM-1 mutation in hCav2.1 splice isoforms whose differential expression could impact the manifestation of the neurological disorder.

Background: Cardiac magnetic resonance (CMR)-guided catheter ablation of the cavotricuspid isthmus (CTI) has been proven feasible, but determinants of local electrogram (EGM) voltage drops during radiofrequency (RF) applications are unknown. Objective: The purpose of this study was to investigate local atrial bipolar EGM voltage drops and the association with delivered RF energy and anatomical information derived from peri-procedural CMR imaging. Methods: In consecutive patients undergoing CMR-guided CTI ablation procedures, relative EGM voltage drops for RF applications ≥20 seconds were calculated. Pre- and post-ablation CMR imaging was performed. Associations of relative EGM voltage drops with patient characteristics, delivered RF energy, and CTI anatomy were analyzed. Results: In total, 216 RF applications were evaluated from 12 patients (18 ± 5 applications/patient). EGM voltage amplitude at baseline was significantly higher in the group with the strongest relative EGM voltage drop (P < .05), whereas RF ablation settings (duration, power, temperature) and lesion characteristics (impedance drop, slope of impedance drop) did not differ. The EGM voltage amplitude at baseline (P < .001), left ventricular ejection fraction (LVEF) (P = .020), right atrium volume index (RAVI) (P = .027), and CTI line length (P = .026) showed the strongest association with relative EGM voltage drop. Four of 12 patients (33%) underwent a re-do procedure, 2 patients showed a regional late reconnection, which could be visually identified in the T2-weighted images (T2WI) of the index procedure. Conclusion: Local EGM voltage amplitude, LVEF, RAVI, and CTI length are associated with relative EGM voltage drop during CMR-guided CTI ablation. Post-ablation CMR imaging during the index procedure may help to identify areas of late reconnection.

Abstract Ecological character displacement, whereby shifts in resource use in the presence of competing species leads to adaptive evolutionary divergence, is widely considered an important process in community assembly and adaptive radiation. However, most evidence for character displacement has been inferred from macro-scale geographic or phylogenetic patterns; direct tests of the underlying hypothesis of divergent natural selection driving character displacement in the wild are rare. Here, we document character displacement between two ecologically similar lizards (Anolis sagrei and A. cristatellus) experiencing novel contact. We identify directional selection during the incipient stages of sympatry in a new community that corresponds to repeated trait divergence across multiple established sympatric communities. By identifying the role of natural selection as character displacement unfolds, we connect how natural selection operating at short timescales may drive broader patterns of trait distributions at larger spatial and temporal scales.

Abstract Background Light is a key environmental regulator of physiology and behaviour. Mistimed or insufficient light disrupts circadian rhythms and is associated with impaired health and well-being across mammals. Appropriate lighting is therefore crucial for indoor housed mammals. Light is commonly measured in lux. However, this employs a spectral weighting function for human luminance and is not suitable for ‘non-visual’ effects of light or use across species. In humans, a photoreceptor-specific (α-opic) metrology system has been proposed as a more appropriate way of measuring light. Results Here we establish technology to allow this α-opic measurement approach to be readily extended across mammalian species, accounting for differences in photoreceptor types, photopigment spectral sensitivities, and eye anatomy. We develop a high-throughput method to derive spectral sensitivities for recombinantly expressed mammalian opsins and use it to establish the spectral sensitivity of melanopsin from 13 non-human mammals. We further address the need for simple measurement strategies for species-specific α-opic measures by developing an accessible online toolbox for calculating these units and validating an open hardware multichannel light sensor for ‘point and click’ measurement. We finally demonstrate that species-specific α-opic measurements are superior to photopic lux as predictors of physiological responses to light in mice and allow ecologically relevant comparisons of photosensitivity between species. Conclusions Our study presents methods for measuring light in species-specific α-opic units that are superior to the existing unit of photopic lux and holds the promise of improvements to the health and welfare of animals, scientific research reproducibility, agricultural productivity, and energy usage.

Abstract Background Limited information is available about functioning and related impairments of children and adolescents with Cerebral Palsy (CP) in low- and middle-income countries (LMIC) like Brazil. The aim of this study is to describe the characteristics, functioning, and impairments of Brazilian children and adolescents with CP. Methods Cross-sectional preliminary study as part of the PartiCipa Brazil multicentered cohort study. Families of children and adolescents with CP from Brazil, 4 months to 15 years, were enrolled. They responded to an online survey with questions about their child’s health condition, impairments, contextual factors, and functioning according to the Gross Motor Function Classification System (GMFCS) and the Manual Ability Classification System (MACS). Data were described as frequencies, percentages, means, and standard deviations, according to age bands. Results Of the 404 participants (6.5±3.6 years) enrolled in this preliminary analysis, 54.7% are male, 90.4% under 12 years of age, 77.7% have bilateral CP, 49% in GMFCS levels IV and V, and 50.7% in MACS levels II and V. Most participants are from Southeast (63.4%) and Centre-west (19.5%) of Brazil. Regarding the impairments and functioning limitations: 1 in 2 did not talk; 1 in 2 has epilepsy; 2 of 5 reports pain, 1 of 4 has visual impairments, 3 out of 5 did not feed themselves, 1 out of 20 has a hearing impairment and 1 of 4 did not go to school. Conclusion This first preliminar Brazilian study shows a high prevalence of children at MACS levels II and V and GMFCS levels IV and V, representing almost half of the group, indicating more impairments and limitations than children/adolescents from high-income countries. This study provides a preliminary deeper understanding of the key impairments and limitations in activities among children and adolescents with CP from various Brazilian regions.

In the recent years, there has been a burgeoning interest in Takotsubo syndrome (TTS), which is renowned as a specific form of reversible myocardial dysfunction. Despite the extensive literature available on TTS, clinicians still face several practical challenges associated with the diagnosis and management of this phenomenon. This potentially results in the underdiagnosis and improper management of TTS in clinical practice. The present paper, the first part (part-1) of the consensus report, aims to cover diagnostic and therapeutic challenges associated with TTS along with certain recommendations to combat these challenges.

Takotsubo syndrome (TTS) still remains as an enigmatic phenomenon. In particular, long-term challenges (including clinical recurrence and persistent symptoms) and specific entities in the setting of TTS have been the evolving areas of interest. On the other hand, a significant gap still exists regarding the proper risk-stratification of this phenomenon in the short and long terms. The present paper, the second part (part-2) of the consensus report, aims to discuss less well-known aspects of TTS including specific entities, challenges after recovery and risk-stratification.

Abstract Darknet forums dedicated to child sexual abuse material (CSAM) attract thousands of users interacting with each other through online communications. Given finite resources, law enforcement agencies seek ways to effectively prioritise their investigative efforts by identifying key-players that are central to the forum community. For the identification of such users, law enforcement agencies typically rely on the communication network that can be derived from messages posted on the public part of the forum. Many forums, however, also allow for private communications between members, raising the question to what extent relying on only a single mode of communication biases key-player identification. Using data on both public and private communications on two large-scale darknet CSAM forums, two communication networks are derived and their structures analysed. Measures of centrality robustness are applied to ascertain the level of bias introduced when determining key-players on only one of the available networks. Findings show only a minority of members to participate in forum communication, and limited overlap between participants active in public and private communications. Key-players emerging from combining the public and private communications resemble those from the public network only, suggesting that police prioritisation based on public postings only is still ‘on mark’. Members who are central to the private communications network may nevertheless be of special law enforcement interest.

Abstract Spinal projection neurons (PNs) are defined by long axons that travel from their origin in the spinal cord to the brain where they relay sensory information from the body. The existence and function of a substantial axon collateral network, also arising from PNs and remaining within the spinal cord, is less well appreciated. Here we use a retrograde viral transduction strategy to characterise a novel subpopulation of deep dorsal horn spinoparabrachial neurons. Brainbow assisted analysis confirmed that virally labelled PN cell bodies formed a discrete cell column in the lateral part of Lamina V (LVlat) and the adjoining white matter. These PNs exhibited large dendritic territories biased to regions lateral and ventral to the cell body column and extending considerable rostrocaudal distances. Optogenetic activation of LVLat PNs confirmed this population mediates widespread signalling within spinal cord circuits, including activation in the superficial dorsal horn. This signalling was also demonstrated with patch clamp recordings during LVLat PN photostimulation, with a range of direct and indirect connections identified and evidence of a postsynaptic population of inhibitory interneurons. Together, these findings confirm a substantial role for PNs in local spinal sensory processing, as well as relay of sensory signals to the brain.

Abstract Maternal asthma is associated with increased rates of neonatal lung disease, and fetuses from asthmatic ewes have fewer surfactant‐producing cells and lower surfactant‐protein B gene (SFTPB) expression than controls. Antenatal betamethasone increases lung surfactant production in preterm babies, and we therefore tested this therapy in experimental maternal asthma. Ewes were sensitised to house dust mite allergen, and an asthmatic phenotype induced by fortnightly allergen lung challenges; controls received saline. Pregnant asthmatic ewes were randomised to receive antenatal saline (asthma) or 12 mg intramuscular betamethasone (asthma+beta) at 138 and 139 days of gestation (term = 150 days). Lambs were delivered by Caesarean section at 140 days of gestation and ventilated for 45 min before tissue collection. Lung function and structure were similar in control lambs (n = 16, 11 ewes) and lambs from asthma ewes (n = 14, 9 ewes). Dynamic lung compliance was higher in lambs from asthma+beta ewes (n = 12, 8 ewes) compared to those from controls (P = 0.003) or asthma ewes (P = 0.008). Lung expression of surfactant protein genes SFTPA (P = 0.048) and SFTPB (P

Abstract Spatially resolved molecular assays provide high dimensional genetic, transcriptomic, proteomic, and epigenetic information in situ and at various resolutions. Pairing these data across modalities with histological features enables powerful studies of tissue pathology in the context of an intact microenvironment and tissue structure. Increasing dimensions across molecular analytes and samples require new data science approaches to functionally annotate spatially resolved molecular data. A specific challenge is data-driven cross-sample domain detection that allows for analysis within and between consensus tissue compartments across high volumes of multiplex datasets stemming from tissue atlasing efforts. Here, we present MILWRM (multiplex image labeling with regional morphology)—a Python package for rapid, multi-scale tissue domain detection and annotation at the image- or spot-level. We demonstrate MILWRM’s utility in identifying histologically distinct compartments in human colonic polyps, lymph nodes, mouse kidney, and mouse brain slices through spatially-informed clustering in two different spatial data modalities from different platforms. We used tissue domains detected in human colonic polyps to elucidate the molecular distinction between polyp subtypes, and explored the ability of MILWRM to identify anatomical regions of the brain tissue and their respective distinct molecular profiles.

Abstract Introduction The 2023 nomenclature defined criteria for steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD), alcohol-associated liver disease (ALD), and the overlapping MASLD/ALD (MetALD). We aimed to assess racial and ethnic disparities in the SLD prevalence among United States (US) adults based on this new nomenclature. Methods We undertook a cross-sectional study employing the 2017–2018 National Health and Nutrition Examination Survey (NHANES) database. We identified SLD according to a controlled attenuation parameter ≥288 dB/m, liver stiffness ≥7.2 kPa, or elevated aminotransferase levels. Alcohol use thresholds were established according to the updated SLD definition. We estimated prevalences using the complex design of the NHANES survey. Multivariable logistic regressions with complex design weights were employed. Results A total of 5532 individuals are included. The mean age is 45.4 years, and 50.9% are women. The adjusted estimated prevalence of MASLD is 42.4% (95% CI: 41.1–43.8%), MetALD 1.7% (95% CI: 1.3–2.0%), and ALD 0.6% (95% CI: 0.3–0.8%). Hispanics exhibit a higher prevalence of SLD, but there are no significant differences in advanced fibrosis prevalence due to SLD among racial/ethnic groups. In MASLD, men, individuals aged 40–64 and ≥65 years, Hispanics, those with health insurance, higher BMI, diabetes, hypertension, hypertriglyceridemia, and low high-density lipoprotein (HDL) cholesterol or use of lipid-lowering agents are independently associated with a higher risk, while Blacks have the lowest risk. In MetALD, men and higher BMI are independently associated with a higher risk of MetALD in adjusted multivariable analysis. In ALD, the adjusted multivariable analysis shows that only health insurance is independently associated with a lower ALD risk. Conclusions MASLD prevalence is high in the US, especially in men, older individuals, and Hispanics. MetALD and ALD prevalence was substantial but could be underestimated.

Abstract Introduction Cardiac amyloidosis is a rarely reported and potentially fatal variant of the systemic disease. Its early diagnosis could potentially lead to significantly improved clinical outcomes. Case presentation A 56-year-old female presented with dyspnea and palpitations. Her physical exam and non-invasive evaluation with cardiac magnetic resonance imaging (CMRI) revealed restrictive cardiomyopathy, and the bone marrow biopsy results showed systemic amyloidosis. Discussion The diagnosis of cardiac amyloidosis is not always straightforward, and delay can cause the progression of the disease and an increased risk of morbidity and mortality. Electrocardiograms, echocardiograms, cardiac magnetic resonance imaging, and histopathologic evaluation are the main methods for diagnosing cardiac amyloidosis. The treatment consists of controlling heart failure symptoms and disease-modifying interventions, including medical and surgical therapeutic methods. Clinical learning point (conclusion) Cardiac involvement is the main cause of death in systemic amyloidosis. Early suspicion, diagnosis, and treatment are crucial in improving patients’ survival. CMRI can play an essential role in the diagnosis of cardiac Amyloidosis. A graphical abstract is provided for visual summary. Graphical Abstract

Abstract Providing a better understanding of what makes a compound a successful drug candidate is crucial for reducing the high attrition rates in drug discovery. Analyses of the differences between active compounds, clinical candidates and drugs require high-quality datasets. However, most datasets of drug discovery programs are not openly available. This work introduces a dataset of compound-target pairs extracted from the open-source bioactivity database ChEMBL (release 32). Compound-target pairs in the dataset either have at least one measured activity or are part of the manually curated set of known interactions in ChEMBL. Known interactions between drugs or clinical candidates and targets are specifically annotated to facilitate analyses of differences between drugs, clinical candidates, and other active compounds. In total, the dataset comprises 614,594 compound-target pairs, 5,109 (3,932) of which are known interactions between drugs (clinical candidates) and targets. The extraction is performed in an automated manner and fully reproducible. We are providing not only the datasets but also the code to rerun the analyses with other ChEMBL releases.

Abstract Cancer is caused by an accumulation of somatic mutations and copy number alterations (CNAs). Besides mutations, these copy number changes are key characteristics of cancer development. Nonetheless, some tumors show hardly any CNAs, a remarkable phenomenon in oncogenesis. Head and neck squamous cell carcinomas (HNSCCs) arise by either exposure to carcinogens, or infection with the human papillomavirus (HPV). HPV-negative HNSCCs are generally characterized by many CNAs and frequent mutations in CDKN2A, TP53, FAT1, and NOTCH1. Here, we present the hallmarks of the distinct subgroup of HPV-negative HNSCC with no or few CNAs (CNA-quiet) by genetic profiling of 802 oral cavity squamous cell carcinomas (OCSCCs). In total, 73 OCSCC (9.1%) are classified as CNA-quiet and 729 as CNA-other. The CNA-quiet group is characterized by wild-type TP53, frequent CASP8 and HRAS mutations, and a less immunosuppressed tumor immune microenvironment with lower density of regulatory T cells. Patients with CNA-quiet OCSCC are older, more often women, less frequently current smokers, and have a better 5-year overall survival compared to CNA-other OCSCC. This study demonstrates that CNA-quiet OCSCC should be considered as a distinct, clinically relevant subclass. Given the clinical characteristics, the patient group with these tumors will rapidly increase in the aging population.

Abstract The understanding of recent climate extremes and the characterization of climate risk require examining these extremes within a historical context. However, the existing datasets of observed extremes generally exhibit spatial gaps and inaccuracies due to inadequate spatial extrapolation. This problem arises from traditional statistical methods used to account for the lack of measurements, particularly prevalent before the mid-20th century. In this work, we use artificial intelligence to reconstruct observations of European climate extremes (warm and cold days and nights) by leveraging Earth system model data from CMIP6 through transfer learning. Our method surpasses conventional statistical techniques and diffusion models, showcasing its ability to reconstruct past extreme events and reveal spatial trends across an extensive time span (1901-2018) that is not covered by most reanalysis datasets. Providing our dataset to the climate community will improve the characterization of climate extremes, resulting in better risk management and policies.

Abstract Background Radiopharmaceutical therapy (RPT) uses radionuclides that decay via one of three therapeutically relevant decay modes (alpha, beta, and internal conversion (IC) / Auger electron (AE) emission) to deliver short range, highly damaging radiation inside of diseased cells, maintaining localized dose distribution and sparing healthy cells. Antimony-119 (119Sb, t1/2 = 38.19 h, EC = 100%) is one such IC/AE emitting radionuclide, previously limited to in silico computational investigation due to barriers in production, chemical separation, and chelation. A theranostic (therapeutic/diagnostic) pair can be formed with 119Sb’s radioisotopic imaging analogue 117Sb (t1/2 = 2.80 h, Eγ = 158.6 keV, Iγ = 85.9%, β+ = 262.4 keV, Iβ+ = 1.81%). Results Within, we report techniques for sustainable and cost-effective production of pre-clinical quality and quantity, radionuclidically pure 119Sb and 117Sb, novel low energy photon measurement techniques for 119Sb activity determination, and physical yields for various tin target isotopic enrichments and thicknesses using (p, n) and (d, n) nuclear reactions. Additionally, we present a two-column separation providing a radioantimony yield of 73.1% ± 6.9% (N = 3) and tin separation factor of (6.8 ± 5.5) x 105 (N = 3). Apparent molar activity measurements for deuteron produced 117Sb using the chelator TREN-CAM were measured at 42.4 ± 25 MBq 117Sb/µmol (1.14 ± 0.68 mCi/µmol), and we recovered enriched 119Sn target material at a recycling efficiency of 80.2% ± 5.5% (N = 6) with losses of 11.6 mg ± 0.8 mg (N = 6) per production. Conclusion We report significant steps in overcoming barriers in 119Sb production, chemical isolation and purification, enriched target material recycling, and chelation, helping promote accessibility and application of this promising therapeutic radionuclide. We describe a method for 119Sb activity measurement using its low energy gamma (23.87 keV), negating the need for attenuation correction. Finally, we report the largest yet-measured 119Sb production yields using proton and deuteron irradiation of natural and enriched targets and radioisotopic purity > 99.8% at end of purification.

Abstract Background Missing data in confounding variables present a frequent challenge in generating evidence using real-world data, including electronic health records (EHR). Our objective was to apply a recently published toolkit for characterizing missing data patterns and based on the toolkit results about likely missingness mechanisms, illustrate the decision-making process for analyses in an empirical case example. Methods We utilized the Structural Missing Data Investigations (SMDI) toolkit to characterize missing data patterns in the context of a pharmacoepidemiology study comparing cardiovascular outcomes of initiating sodium-glucose-cotransporter-2 inhibitors (SGLT2i) and dipeptidyl peptidase‐4 inhibitors (DPP‐4i) among older adults. The study used a linked EHR-Medicare claims dataset from Duke Health patients (2015–2017), focusing on partially observed confounders from EHR data (HbA1c lab and body mass index [BMI] values). Our analysis incorporated SMDI's descriptive functions and diagnostic tests to explore missingness patterns and determine missingness mitigation approaches. We used findings from these investigations to inform estimation of adjusted hazard ratios comparing the two classes of medications. Results High levels of missingness were noted for important confounding variables including HbA1c (63.6%) and BMI (16.5%). Diagnostic tests resulted in output that described: 1) the distributions of patient characteristics, exposure, and outcome between patients with or without an observed value of the partially observed covariate, 2) the ability to predict missingness based on observed covariates, and 3) estimate if the missingness of a partially observed covariate is differential with respect to the outcome. There was evidence that missingness could be sufficiently described using observed data, which allowed multiple imputation by chained equations using random forests to address missing confounder data in estimating treatment effects. Multiple imputation resulted in improved alignment of effect estimates with previous studies. Conclusions We were able to demonstrate the practical application of the SMDI toolkit in a real-world setting. Application of the SMDI toolkit and the resulting insights of potential missingness patterns can inform the choice of appropriate analytic methods and increase transparency of research methods in handling missing data. This type of approach can inform analytic decision making and may increase our ability to generate evidence from real-world data.

Abstract The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90’s interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.

Abstract Background Lung cancer screening (LCS) can reduce lung cancer mortality but has potential harms for patients. A shared decision-making (SDM) conversation about LCS is required by the Centers for Medicare & Medicaid Services (CMS) for LCS reimbursement. To overcome barriers to SDM in primary care, this protocol describes a telehealth decision coaching and navigation intervention for LCS in primary care clinics delivered by patient navigators. The objective of the study is to evaluate the effectiveness of the intervention and its implementation potential, compared with an enhanced usual care (EUC) arm. Methods Patients (n = 420) of primary care clinicians (n = 120) are being recruited to a cluster randomized controlled trial. Clinicians are randomly assigned to 1) TELESCOPE intervention: prior to an upcoming non-acute clinic visit, patients participate in a telehealth decision coaching and navigation session about LCS delivered by trained patient navigators and nurse navigators place a low-dose CT scan (LDCT) order for each TELESCOPE patient wanting LCS, or 2) EUC: patients receive enhanced usual care from a clinician. Usual care is enhanced by providing clinicians in both arms with access to a Continuing Medical Education (CME) webinar about LCS and an LCS discussion guide. Patients complete surveys at baseline and 1-week after the scheduled clinic visit to assess quality of the SDM process. Re-navigation is attempted with TELESCOPE patients who have not completed the LDCT within 3 months. One month before being due for an annual screening, TELESCOPE patients whose initial LCS showed low-risk findings are randomly assigned to receive a telehealth decision coaching booster session with a navigator or no booster. Electronic health records are abstracted at 6, 12 and 18 months after the initial decision coaching session (TELESCOPE) or clinic visit (EUC) to assess initial and annual LCS uptake, imaging results, follow-up testing for abnormal findings, cancer diagnoses, treatment, and tobacco treatment referrals. This study will evaluate factors that facilitate or interfere with program implementation using mixed methods. Discussion We will assess whether a decision coaching and patient navigation intervention can feasibly and effectively support high-quality SDM for LCS and guideline-concordant LCS uptake for patients in busy primary care practices serving diverse patient populations. Trial registration This study was registered at ClinicalTrials.gov (NCT05491213) on August 4, 2022. Protocol version Version 1, April 10, 2024.

Abstract Voxelotor is a small molecule that reduces the polymerization of sickle hemoglobin by increasing its affinity for oxygen. In patients with sickle cell anemia, it has been postulated that increasing hemoglobin‐oxygen affinity could limit oxygen offloading from hemoglobin, causing an increase in cerebral metabolic stress. To investigate this hypothetical concern, we used multimodal brain imaging to define the effects of voxelotor on cerebral blood flow and oxygen extraction. We followed four patients for 2–5 months during and/or after voxelotor therapy. This study showed no observable increase in cerebral blood flow or oxygen extraction fraction during treatment.

Abstract Objectives To analyse the presentation, management and long‐term outcomes of renal transplant patients who formed kidney stones in their allograft. The secondary aim was to identify risk factors for stone formation in this cohort. Materials and Methods Patient information from an institutional renal transplant database was used to identify individuals who both did and did not form kidney stones following renal transplantation. Computerized tomography (CT) imaging was used to make the diagnosis of kidney stones and measure stone size. Age‐ and gender‐matched controls never forming a stone in their allograft were used for comparative analysis to identify risk factors for stone formation in transplant patients. Results A total of 8835 transplant patients were included in the study, of which 128 (1.4%) formed a kidney stone in their allograft after surgery. The mean time to kidney stone identification was 6.2 years, and the mean number of stones formed was 1.7, with a mean maximum size dimension on a CT scan of 5.7 mm per stone. A total of 26 patients were subjected to stone‐removing procedures, the most common being ureteroscopy (42.3%). The primary intervention failed in eight patients requiring a secondary intervention, and percutaneous nephrolithotomy (PCNL) had the lowest success rate (60%). A total of 164 controls were identified. In comparison to controls, stone formers had lower serum calcium (p = 0.008), lower estimated glomerular filtration rates (p = 0.019), higher lymphocyte counts (p = 0.021) and greater rate of urinary tract infection (p = 0.003). Graft failure rates were the same (p = 0.524), but time to graft failure was significantly longer in stone patients compared with controls (p = 0.008). Conclusions The rate of stone formation is low in transplant patients. Success rates for stone treatment vary based on the surgery selected, with PCNL being the worst. Graft survival rates were equivocal, but survival time was better in stone patients. Our analysis calls for further investigation of this important topic.

Abstract Background Positron emission tomography/computed tomography (PET/CT) using prostate-specific membrane antigen (PSMA)-targeted radiotracers labeled with zirconium-89 (89Zr; half-life ~ 78.41 h) showed promise in localizing biochemical recurrence of prostate cancer (BCR) in pilot studies. Methods Retrospective analysis of 38 consecutive men with BCR (median [minimum–maximum] prostate-specific antigen 0.52 (0.12–2.50 ng/mL) undergoing [89Zr]Zr-PSMA-617 PET/CT post-negative [68Ga]Ga-PSMA-11 PET/CT. PET/CT acquisition 1-h, 24-h, and 48-h post-injection of a median (minimum–maximum) [89Zr]Zr-PSMA-617 tracer activity of 123 (84–166) MBq. Results [89Zr]Zr-PSMA-617 PET/CT detected altogether 57 lesions: 18 local recurrences, 33 lymph node metastases, 6 bone metastases in 30/38 men with BCR (78%) and prior negative conventional PSMA PET/CT. Lesion uptake significantly increased from 1-h to 24-h and, in a majority of cases, from 24-h to 48-h. Tumor-to-background ratios significantly increased over time, with absolute increases of 100 or more. No side effects were noted. After [89Zr]Zr-PSMA-617 PET/CT-based treatment, prostate-specific antigen concentration decreased in all patients, becoming undetectable in a third of patients. Limitations: retrospective, single center design; infrequent histopathological and imaging verification. Conclusion This large series provides further evidence that [89Zr]Zr-PSMA-617 PET/CT is a beneficial imaging modality to localize early BCR. A remarkable increase in tumor-to-background ratio over time allows localization of tumor unidentified on conventional PSMA PET/CT.

Abstract Background The worldwide number of adults aged 60 years and older is expected to double from 1 billion in 2019 to 2.1 billion by 2050. As the population lives longer, the rising incidence of chronic diseases, cognitive disorders, and behavioral health issues threaten older adults’ health span. Exercising, getting sufficient sleep, and staying mentally and socially active can improve quality of life, increase independence, and potentially lower the risk for Alzheimer’s disease or other dementias. Nonpharmacological approaches might help promote such behaviors. Indoor lighting may impact sleep quality, physical activity, and cognitive function. Dynamically changing indoor lighting brightness and color throughout the day has positive effects on sleep, cognitive function, and physical activity of its occupants. The aim of this study is to investigate how different indoor lighting conditions affect such health measures to promote healthier aging. Methods This protocol is a randomized, cross-over, single-site trial followed by an exploratory third intervention. Up to 70 older adults in independent living residences at a senior living facility will be recruited. During this 16-week study, participants will experience three lighting conditions. Two cohorts will first experience a static and a dynamic lighting condition in a cluster-randomized cross-over design. The static condition lighting will have fixed brightness and color to match lighting typically provided in the facility. For the dynamic condition, brightness and color will change throughout the day with increased brightness in the morning. After the cross-over, both cohorts will experience another dynamic lighting condition with increased morning brightness to determine if there is a saturation effect between light exposure and health-related measures. Light intake, sleep quality, and physical activity will be measured using wearable devices. Sleep, cognitive function, mood, and social engagement will be assessed using surveys and cognitive assessments. Discussion We hypothesize participants will have better sleep quality and greater physical activity during the dynamic lighting compared to the static lighting condition. Additionally, we hypothesize there is a maximal threshold at which health-outcomes improve based on light exposure. Study findings may identify optimal indoor lighting solutions to promote healthy aging for older adults. Trial registration ClinicalTrials.gov Identifier: NCT05978934.

Abstract Background Higher educational attainment is important for economic wellbeing and associated with better health and longevity. Previous research focused on intelligence, socioeconomic status and mental health or individual risk behaviours as predictors of educational attainment, but the role of multiple domains of adolescent risk behaviours is less clear. This study examined the association between multiple domains of risk behaviour in adolescence and educational attainment by 22 years-of-age. Methods Young people (Generation 2, Gen2) and their parents (Generation 1, Gen1) participating in the Raine Study completed questionnaires at years 1, 5, 8, 10 (Gen1 only), 14, 17 (both) and 22 (Gen2 only). The Raine Study is an ongoing longitudinal study initiated in Perth, Western Australia, between 1989 and 1991. The 1,102 Gen2 participants who responded to questions about highest educational attainment were included in this study. The association between Gen2 self-reported risk behaviours (including age at commencement of drinking alcohol, smoking, sexual intercourse and drug use) and educational attainment (defined as self-reported years of completed high school: ≤10, 11, 12 or tertiary education (> 12)) at year 22, after adjusting for mother’s age and combined parental education level, participant sex, and family income, educational performance and adolescent mental health, was explored using ordinal regression models and presented as odds ratios (OR) with 95% confidence intervals (CI). Results Ordinal models suggested that never smoking or starting older than 18 compared with smoking before age 15 (OR 2.02, 95%CI: 1.28–2.14); first drinking alcohol between 15 and 17 years compared with younger than 15 (OR 1.52, 95%CI: 1.08–2.14); and, first sexual intercourse aged ≥ 18 years compared with under 15 (OR 1.67, 95%CI: 1.08–2.57) were associated with higher levels of educational attainment at 22-year follow-up. Additionally, lower (“better”) behavioural scores increased the odds of higher levels of attainment. Conclusions Absence of health risk behaviours at a younger age or later commencement was associated with higher educational attainment. Evidence-based interventions that address the societal influences underpinning risk behaviours in adolescents may support longer school retention.

Abstract Background Glucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer’s disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters. Methods The Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models. Results EQW affected FCN2 (Cohen’s d -0.019), PAI-1 (Cohen’s d -0.033), sVCAM-1 (Cohen’s d 0.035) and a cytokine-cytokine cluster (Cohen’s d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65. Conclusions EQW treatment was associated with significant change in inflammatory proteins associated with AD. Trial Registration EXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010.

Abstract Mental health issues have increased substantially since the onset of the COVID-19 pandemic. However, health policymakers do not have adequate data and tools to predict mental health demand, especially amid a crisis. Using time-series data collected in Singapore, this study examines if and how algorithmically measured emotion indicators from Twitter posts can help forecast emergency mental health needs. We measured the mental health needs during 549 days from 1 July 2020 to 31 December 2021 using the public’s daily visits to the emergency room of the country’s largest psychiatric hospital and the number of users with “crisis” state assessed through a government-initiated online mental health self-help portal. Pairwise Granger-causality tests covering lag length from 1 day to 5 days indicated that forecast models using Twitter joy, anger and sadness emotions as predictors perform significantly better than baseline models using past mental health needs data alone (e.g., Joy Intensity on IMH Visits, χ2 = 14·9, P < ·001***; Sadness Count on Mindline Crisis, χ2 = 4·6, P = ·031*, with a one-day lag length). The findings highlight the potential of new early indicators for tracking emerging public mental health needs.

Abstract Most albumin in blood plasma is thought to be monomeric with some 5% covalently dimerized. However, many reports in the recent biophysics literature find that albumin is reversibly dimerized or even oligomerized. We review data on this from X‐ray crystallography and diverse biophysical techniques. The number‐average molecular weight of albumin would be increased by dimerization, affecting size‐dependent filtration processes of albumin such as at the glycocalyx of the capillary endothelium and the podocyte slit‐diaphragm of the renal glomerulus. If correct, and depending on characteristics of the process, such as Kd, reversible dimerization of albumin in plasma would have major implications for normal physiology and medicine. We present quantitative models of the impact of dimerization on albumin molecular forms, on the number‐average molecular weight of albumin, and estimate the effect on the colloid osmotic pressure of albumin. Dimerization reduces colloid osmotic pressure as total albumin concentration increases below that expected in the absence of dimerization. Current models of albumin filtration by the renal glomerulus would need revision to account for the dynamic size of albumin molecules filtered. More robust biophysical data are needed to give a definitive answer to the questions posed and we suggest possible approaches to this.

Abstract Aims The objective of this study was to examine associations between elevated depressive symptoms and increased risk of adverse clinical events patients with heart failure and reduced ejection fraction (HFrEF), as well as the potential contribution of health behaviours. Methods and results One hundred forty‐two men and women with HFrEF were enrolled through heart failure (HF) clinics and followed over time. At baseline and 6 months, depressive symptoms were assessed by the Beck Depression Inventory‐II (BDI‐II) and HFrEF disease activity by B‐type natriuretic peptide (BNP). The Self‐Care of Heart Failure Index (SCHFI) was used to assess HF self‐care behaviours. Proportional hazards regression models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. Over a median follow‐up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10‐point higher baseline BDI‐II score was associated with a 35% greater risk of death or cardiovascular hospitalization. Higher baseline BDI‐II scores were associated with poorer HF self‐care maintenance behaviours (R = −0.30, P

Abstract Aims Clinical trials in heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) commonly have detailed eligibility criteria. This may contribute to challenges with efficient enrolment and questions regarding the generalizability of trial findings. Methods and results Patients with HFmrEF/HFpEF from a large US healthcare system were identified through a computable phenotype applied in linked imaging and electronic health record databases. We evaluated shared eligibility criteria from five recent/ongoing HFmrEF/HFpEF trials (PARAGON‐HF, EMPEROR‐Preserved, DELIVER, FINE‐ARTS, and SPIRRIT‐HFpEF) and compared clinical and echocardiographic features as well as outcomes between trial‐eligible and trial‐ineligible patients. Among 5552 patients with HFpEF/HFmrEF, 792 (14%) were eligible for trial consideration, having met all criteria assessed. Causes of ineligibility included lack of recent loop diuretics (37%), significant pulmonary disease (24%), reduced estimated glomerular filtration rate (17%), recent stroke/transient ischaemic attack (13%), or low natriuretic peptides (12%); 53% of ineligible patients had >1 reason for exclusion. Compared with eligible patients, ineligible patients were younger (age 71 vs. 75 years, P

Abstract Emergent phases often appear when the electronic kinetic energy is comparable to the Coulomb interactions. One approach to seek material systems as hosts of such emergent phases is to realize localization of electronic wavefunctions due to the geometric frustration inherent in the crystal structure, resulting in flat electronic bands. Recently, such efforts have found a wide range of exotic phases in the two-dimensional kagome lattice, including magnetic order, time-reversal symmetry breaking charge order, nematicity, and superconductivity. However, the interlayer coupling of the kagome layers disrupts the destructive interference needed to completely quench the kinetic energy. Here we demonstrate that an interwoven kagome network—a pyrochlore lattice—can host a three dimensional (3D) localization of electron wavefunctions. Meanwhile, the nonsymmorphic symmetry of the pyrochlore lattice guarantees all band crossings at the Brillouin zone X point to be 3D gapless Dirac points, which was predicted theoretically but never yet observed experimentally. Through a combination of angle-resolved photoemission spectroscopy, fundamental lattice model and density functional theory calculations, we investigate the novel electronic structure of a Laves phase superconductor with a pyrochlore sublattice, CeRu2. We observe evidence of flat bands originating from the Ce 4f orbitals as well as flat bands from the 3D destructive interference of the Ru 4d orbitals. We further observe the nonsymmorphic symmetry-protected 3D gapless Dirac cone at the X point. Our work establishes the pyrochlore structure as a promising lattice platform to realize and tune novel emergent phases intertwining topology and many-body interactions.

Abstract X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy. Most (80%) children with XLMTM have profound muscle weakness and hypotonia at birth resulting in severe respiratory insufficiency, the inability to sit up, stand or walk, and early mortality. At birth, 85–90% of children with XLMTM require mechanical ventilation, with more than half requiring invasive ventilator support. Historically, ventilator-dependent children with neuromuscular-derived respiratory failure of this degree and nature, static or progressive, are not expected to achieve complete independence from mechanical ventilator support. In the ASPIRO clinical trial (NCT03199469), participants receiving a single intravenous dose of an investigational gene therapy (resamirigene bilparvovec) started showing significant improvements in daily hours of ventilation support compared with controls by 24 weeks post-dosing, and 16 of 24 dosed participants achieved ventilator independence between 14 and 97 weeks after dosing. At the time, there was no precedent or published guidance for weaning chronically ventilated children with congenital neuromuscular diseases off mechanical ventilation. When the first ASPIRO participants started showing dramatically improved respiratory function, the investigators initiated efforts to safely wean them off ventilator support, in parallel with primary protocol respiratory outcome measures. A group of experts in respiratory care and physiology and management of children with XLMTM developed an algorithm to safely wean children in the ASPIRO trial off mechanical ventilation as their respiratory muscle strength increased. The algorithm developed for this trial provides recommendations for assessing weaning readiness, a stepwise approach to weaning, and monitoring of children during and after the weaning process.

Abstract Under predicted future ocean conditions, corals will experience frequent and intense thermal stress events while simultaneously being exposed to chronic ocean acidification. Yet, some corals will likely be more resistant and/or resilient to these predicted conditions than others and may be critical to reef persistence in the future. Following natural thermal stress in two consecutive years (2014 and 2015), we evaluated the effects of feeding and simulated ocean acidification on the physiological recovery of Montipora capitata and Porites compressa sourced from Kāneʻohe Bay and Waimānalo Bay, Hawaiʻi. Following the 2014 thermal stress event, simulated ocean acidification did not slow recovery of the holobiont and feeding enhanced recovery. However, feeding did not decrease susceptibility to the 2015 thermal stress event, and simulated ocean acidification did not increase susceptibility. Recovery strategies employed between species and between sites clearly differed, highlighting that coral reef restoration and management should consider species-level and site-specific vulnerabilities. Overall, our findings call attention to the immediate threat which ocean warming presents, the lack of additional stress to the holobiont from ocean acidification, the importance of heterotrophy in coral resilience, and the potential significance of additional local biotic stressors (i.e., predator outbreaks) for coral resiliency under annual thermal stress.

Abstract We revisit the existence of monotonic quantities along renormalization group flows using only the Null Energy Condition and the Ryu-Takayanagi formula for the entanglement entropy of field theories with anti-de Sitter gravity duals. In particular, we consider flows within the same dimension and holographically reprove the c-, F -, and a-theorems in dimensions two, three, and four. We focus on the family of maximally spherical entangling surfaces, define a quasi-constant of motion corresponding to the breaking of conformal invariance, and use a properly defined distance between minimal surfaces to construct a holographic c-function that is monotonic along the flow. We then apply our method to the case of flows across dimensions: there, we reprove the monotonicity of flows from AdS D+1 to AdS3 and prove the novel case of flows from AdS5 to AdS4.

Abstract The precise classification of copy number variants (CNVs) presents a significant challenge in genomic medicine, primarily due to the complex nature of CNVs and their diverse impact on rare genetic diseases (RGDs). This complexity is compounded by the limitations of existing methods in accurately distinguishing between benign, uncertain, and pathogenic CNVs. Addressing this gap, we introduce CNVoyant, a machine learning-based multi-class framework designed to enhance the clinical significance classification of CNVs. Trained on a comprehensive dataset of 52,176 ClinVar entries across pathogenic, uncertain, and benign classifications, CNVoyant incorporates a broad spectrum of genomic features, including genome position, disease-gene annotations, dosage sensitivity, and conservation scores. Models to predict the clinical significance of copy number gains and losses were trained independently. Final models were selected after testing 29 machine learning architectures and 10,000 hyperparameter combinations each for deletions and duplications via fivefold cross-validation. We validate the performance of CNVoyant by leveraging a comprehensive set of 21,574 CNVs from the DECIPHER database, a highly regarded resource known for its extensive catalog of chromosomal imbalances linked to clinical outcomes. Compared to alternative approaches, CNVoyant shows marked improvements in precision-recall and ROC AUC metrics for binary pathogenic classifications while going one step further, offering multi-classification of clinical significance and corresponding SHAP explainability plots. Additionally, when provided germline CNV calls from real-world RGD cases with diagnostic CNV(s), CNVoyant correctly classified all diagnostic CNVs as having pathogenic significance with high confidence. This large-scale validation demonstrates CNVoyant’s superior accuracy and underscores its potential to aid genomic researchers and clinical geneticists in interpreting the clinical implications of real CNVs.

Abstract Background Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p

Abstract Background The relationship between the quality of inpatient versus outpatient obstetric postpartum recovery is under-explored. We examined the association between inpatient reported quality of recovery with outpatient global recovery, pain severity, pain interference, anxiety, and depression screening scores postpartum. Methods We conducted a multicenter observational cohort study of women in labor who underwent vaginal, operative vaginal, or intrapartum cesarean birth. Subjects completed baseline assessments of pain, social support, anxiety, and depression in early labor. We assessed the Obstetric Quality of Recovery-10 (ObsQoR-10) on the day of discharge and the ObsQoR-10, Global Health Scale (GHVAS; 0–100), Brief Pain Inventory (BPI), and the Edinburgh Postnatal Depression Scale (EPDS) on postpartum day seven. We hypothesized that the ObsQoR-10 scores at discharge would be useful in predicting postpartum day seven measures of recovery and postpartum depression screening scores. Results We consented 558 subjects, 551/558(98%) completed baseline assessments, 400/551(72%) completed the ObsQoR-10 tool, and 344/551(62%) completed an EPDS assessment. Median (1st, 3rd quartile) ObsQoR-10 scores were 78 (63, 90) at discharge and 85 (68,93) on postpartum day seven, (difference of 7 [99% CI 2 to 13], P 86 at discharge had a RR of 1.5 [95% CI 1.2 to 1.8], P