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IntroductionGlaucoma, optic neuritis (ON), and non-arteritic anterior ischemic optic neuropathy (NAION) produce distinct patterns of retinal ganglion cell (RGC) damage. We propose a booster Variational Autoencoder (bVAE) to capture spatial variations in RGC loss and generate latent space (LS) montage maps that visualize different degrees and spatial patterns of optic nerve bundle injury. Furthermore, the bVAE model is capable of tracking the spatial pattern of RGC thinning over time and classifying the underlying cause.MethodsThe bVAE model consists of an encoder, a display decoder, and a booster decoder. The encoder decomposes input ganglion cell layer (GCL) thickness maps into two display latent variables (dLVs) and eight booster latent variables (bLVs). The dLVs capture primary spatial patterns of RGC thinning, while the display decoder reconstructs the GCL map and creates the LS montage map. The bLVs add finer spatial details, improving reconstruction accuracy. XGBoost was used to analyze the dLVs and bLVs, estimating normal/abnormal GCL thinning and classifying diseases (glaucoma, ON, and NAION). A total of 10,701 OCT macular scans from 822 subjects were included in this study.ResultsIncorporating bLVs improved reconstruction accuracy, with the image-based root-mean-square error (RMSE) between input and reconstructed GCL thickness maps decreasing from 5.55 ± 2.29 µm (two dLVs only) to 4.02 ± 1.61 µm (two dLVs and eight bLVs). However, the image-based structural similarity index (SSIM) remained similar (0.91 ± 0.04), indicating that just two dLVs effectively capture the main GCL spatial patterns. For classification, the XGBoost model achieved an AUC of 0.98 for identifying abnormal spatial patterns of GCL thinning over time using the dLVs. Disease classification yielded AUCs of 0.95 for glaucoma, 0.84 for ON, and 0.93 for NAION, with bLVs further increasing the AUCs to 0.96 for glaucoma, 0.93 for ON, and 0.99 for NAION.ConclusionThis study presents a novel approach to visualizing and quantifying GCL thinning patterns in optic neuropathies using the bVAE model. The combination of dLVs and bLVs enhances the model’s ability to capture key spatial features and predict disease progression. Future work will focus on integrating additional image modalities to further refine the model’s diagnostic capabilities.

Background. Hepatocellular carcinoma (HCC) has a rising incidence and mortality in North America. Liver transplantation (LT) with adjunctive therapies offers excellent outcomes. However, HCC recurrences are associated with high mortality. We investigate whether adjuvant systemic therapy can reduce recurrence, as shown with other malignancies. Methods. Medical records of patients undergoing LT for HCC at a single center between January 2016 and December 2022 were retrospectively reviewed. Patients were stratified into 3 groups: (1) recipients of adjuvant sorafenib, (2) nonrecipients at high recurrence risk, and (3) nonrecipients at low risk by explant pathology features. The outcomes were overall survival (OS) and recurrence-free survival (RFS). Adjuvant sorafenib recipients were also propensity score matched 1:2 to nonadjuvant recipients based on recurrence risk features. Results. During the study period, 273 patients with HCC underwent LT and 16 (5.9%) received adjuvant sorafenib therapy. Adjuvant sorafenib recipients were demographically similar to nonrecipients and, on explant pathology, had greater tumor burden, lymphovascular invasion, and poorer differentiation (all P

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response.CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts.Our GWAS identified two genome-wide significant (P

Background: Unhealthy alcohol use is a leading cause of preventable mortality and a risk factor for an array of social and health problems. The Intervention in Small primary care Practices to Implement Reduction in unhealthy alcohol use (INSPIRE) study is part of a nationwide campaign to improve the identification and treatment of patients engaging in unhealthy alcohol use. Methods: We conducted a single arm, pragmatic study consisting of seventeen primary care practices in the Chicago metropolitan area, Wisconsin, and California across two waves with a 6-month latent period, a 12-month intervention period, followed by a 6-month sustainability period. Enrolled practices were independent, Federally Qualified Health Centers, network-based, and academic health centers. INSPIRE utilized the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework to examine implementation feasibility, fidelity, and performance of clinicians on practice adoption of screening, brief intervention, referral to treatment (SBIRT) and medication for unhealthy alcohol use (MAUD) activities in primary care clinics. Results: Seventeen eligible primary care practices were enrolled over the course of 21 months beginning in March of 2020 through December of 2021. There was a pause in recruitment from March of 2020 through July of 2020 due to the Covid-19 pandemic. The majority of enrolled practices were small (

Tobacco smoking is increasing in many low-and-middle-income countries, but data about initiation and cessation patterns are sparse, particularly in rural areas. We investigated changes in smoking status and their determinants in rural South Africa. Participants enrolled in the Vukuzazi population cohort in rural KwaZulu-Natal, South Africa completed a baseline tobacco behavioural survey during 1 May 2018 to 31 March 2020. A follow-up survey was conducted during 4 May 2021 to 18 November 2022 among all participants aged ≥15 years who reported current and former smoking at baseline (to detect cessation and relapse) and in a random selection of participants aged 15-29 years who reported never smoking at baseline (to detect initiation). We fit regression models to estimate smoking initiation (from never to current or former smoking), cessation (from current to former smoking) and relapse (from former to current smoking) between baseline and follow-up, and to investigate the sociodemographic and behavioural variables associated with each outcome. Of those recruited, 52% (754/1448) participated in the follow-up survey, which occurred a median of 3.0 years (IQR: 2.6-3.2) from baseline. Initiation, cessation and relapse occurrence was 12.0% (95% CI: 8.4-16.8), 12.9% (95% CI: 10.0-16.5) and 10.9% (95% CI: 4.4-24.2), respectively. Males had significantly higher odds of initiation than females (adjusted odds ratio [AOR] 12.81, 95% confidence interval [CI]: 3.54-46.36). Moderate/heavy smoking (≥10 products per day; AOR 0.27, 95% CI: 0.08-0.93 relative to light smoking

Honey bees balance colony populations against available food resources by adjusting brood rearing during nutritionally-stressed periods. Workers limit colony populations primarily through brood cannibalism of eggs and young larvae but often resume brood rearing when conditions improve. However, extended brood cannibalism reduces brood and removes brood signals that mediate brood rearing, such as E-β-ocimene, a volatile pheromone produced by eggs, young larvae, prepupae and ovipositing queens. We examined the effects of pollen supplementation on ocimene signaling in nutritionally-stressed colonies. Pollen-deprived colonies showed declines in ocimene emissions that coincided with sustained brood cannibalism of pheromone-producing brood. In contrast, pollen-supplemented colonies reared more brood and released more ocimene. Twelve day old workers that completed adult development in pollen-deprived colonies had less well developed hypopharyngeal glands and fat bodies than workers that matured in pollen-supplemented colonies. Given that ocimene emissions increased once brood rearing resumed, we considered the possibility that ocimene may help suppress brood cannibalism and support egg retention in nutritionally stressed nuc colonies. Broodless nucleus frames were treated with synthetic ocimene releases equivalent to 3,744 L2-L3 larvae. All ocimene-supplemented nucs retained large numbers of eggs and young larvae four days after initial treatment. By contrast, half of the unsupplemented nucs cannibalized all of their eggs and L1 larvae. Most of the remaining unsupplemented nuc colonies retained fewer eggs and L1 larvae than ocimene supplemented nuc colonies. E-B-ocimene may prime nutritionally stressed workers to increase brood rearing during dearth periods by projecting the presence of healthy eggs and young larvae.

Agronomic and weed management practices employed by growers in the production of snap bean (Phaseolus vulgaris) for the processing industry are poorly characterized. To address this knowledge gap, records of agronomic and weed management practices from 358 snap bean fields were obtained from collaborating processors. These fields encompassed three production regions in the United States: the Northwest (NW), Midwest (MW), and Northeast (NE). The obtained records were formatted to be more suitable for presentation or analysis. Forty cultivars were used across all three regions, primarily of green round podded type (∼90% of all fields). However, it was common for only relatively few cultivars to be widespread in each region. Seeding rates were substantially higher (by more than 100,000 plants/ha on average) in the NW region. Crop row widths were also narrower in the NW region compared with other regions. Planting and harvest occurred across a wide range of dates in all three production regions, with the NW having a delay of ∼10 days. The most common crop in rotation with snap bean was usually some type of corn, although the NW region had more variability in crop rotation. Spring tillage and irrigation were commonly used practices across all regions. Weed management was dominated by the use of interrow cultivation and a narrow spectrum of preemergence and postemergence herbicides. However, interrow cultivation was not used as much in the NW compared with the other two regions. Snap bean grown in the NW production region showed a departure in agronomic and weed management practices compared with the MW and NE production regions.

The DAF-2/insulin/insulin-like growth factor signaling (IIS) pathway plays an evolutionarily conserved role in regulating reproductive development, life span, and stress resistance. In Caenorhabditis elegans, DAF-2/IIS signaling is modulated by an extensive array of insulin-like peptides (ILPs) with diverse spatial and temporal expression patterns. However, the release dynamics and specific functions of these ILPs in adapting to different environmental conditions remain poorly understood. Here, we show that the ILP, insulin-3 (INS-3), plays a crucial role in modulating the response to various environmental stressors in C. elegans. ins-3 mutants display increased resistance to heat, oxidative stress, and starvation; however, this advantage is countered by slower reproductive development under favorable conditions. We find that ins-3 expression is downregulated in response to environmental stressors, whereas, the neurohormone tyramine, which is released during the acute flight response, increases ins-3 expression. We show that tyramine induces intestinal calcium (Ca2+) transients through the activation of the TYRA-3 receptor. Our data support a model in which tyramine negatively impacts environmental stress resistance by stimulating the release of INS-3 from the intestine via the activation of a TYRA-3-Gαq-IP3 pathway. The release of INS-3 systemically activates the DAF-2 pathway, resulting in the inhibition of cytoprotective mechanisms mediated by DAF-16/FOXO. These studies offer mechanistic insights into a brain-gut communication pathway that weighs adaptive strategies to respond to acute and long-term stressors.

IntroductionHaemodynamic atrioventricular delay (AVD) optimisation has primarily focussed on signals that are not easy to acquire from a pacing system itself, such as invasive left ventricular catheterisation or arterial blood pressure (ABP). In this study, standard clinical central venous pressure (CVP) signals are tested as a potential alternative.MethodsSixteen patients with a temporary pacemaker after cardiac surgery were studied. AV delay optimisation was performed by alternating between a reference AVD of 120ms and tested settings ranging from 40 to 280ms, with 8 replicates for each setting. Alongside (a) the raw data, three methods of correcting for respiration were tested: (b) limiting analysis to a respiratory cycle, (c) asymmetric least squares (ALS) and (d) discrete wavelet transform (DWT). The utility of a quality control step was tested.ResultsCVP signals were a mirror image of the systolic ABP signals: The four R values were -0.674, -0.692, -0.631, -0.671 respectively (all pConclusionsCentral venous pressure signals could be used to optimise AVD, because they have a reliable inverse relationship with ABP when pacemaker settings undergo protocolised testing. However, protocols need careful design to circumvent spontaneous biological variability.

Cognitive flexibility requires both the encoding of task-relevant and the ignoring of task-irrelevant stimuli. While the neural coding of task-relevant stimuli is increasingly well understood, the mechanisms for ignoring task-irrelevant stimuli remain poorly understood. Here, we study how task performance and biological constraints jointly determine the coding of relevant and irrelevant stimuli in neural circuits. Using mathematical analyses and task-optimized recurrent neural networks, we show that neural circuits can exhibit a range of representational geometries depending on the strength of neural noise and metabolic cost. By comparing these results with recordings from primate prefrontal cortex (PFC) over the course of learning, we show that neural activity in PFC changes in line with a minimal representational strategy. Specifically, our analyses reveal that the suppression of dynamically irrelevant stimuli is achieved by activity-silent, sub-threshold dynamics. Our results provide a normative explanation as to why PFC implements an adaptive, minimal representational strategy.

ObjectiveTo assess the burden of dietary iron deficiency in the Middle East and North Africa (MENA) region, focusing on prevalence and years lived with disability (YLD) in 2021 and their changes since 1990.MethodsData from the Global Burden of Disease (GBD) 2021 study were utilised to report counts and age-standardised rates for prevalence and YLD related to dietary iron deficiency. All estimates were accompanied by 95% uncertainty intervals (UIs).ResultsIn 2021, the age-standardised prevalence of dietary iron deficiency in the MENA region was 14368.2 per 100,000, representing a 26% decline since 1990. The highest age-standardised prevalence rates were observed in Yemen (30146.5), Sudan (19296.9), and Morocco (15,303) per 100,000 population. Prevalence was notably highest among children under 5 years old and women of reproductive age, with a gradual decline in older age groups. The greatest reductions in prevalence were seen among older age groups, indicating an age-related downward trend from 1990 to 2021.ConclusionDespite some improvements, dietary iron deficiency remains a significant public health concern in the MENA region, particularly in countries with lower socio-demographic indices (SDI). Targeted interventions are essential, especially for vulnerable groups such as children and women.

Hypereutrophic Grand Lake St Marys (GLSM) is a large (52 km2), shallow (mean depth ~ 1.5 m) reservoir in an agricultural watershed of western Ohio (USA). GLSM suffers from extensive cyanobacterial harmful algal blooms (cHABs) that persist much of the year, resulting in total microcystin concentrations that are often above safe contact levels. Over two summers (2020 and 2021), two phosphorus (P) binding agents (alum and lanthanum/bentonite clay Phoslock, respectively), in conjunction with a P-binding algaecide (SeClear) in 2021, were applied to a 3.24-ha enclosure to mitigate cHAB activity and create a ‘safe’ recreational space for the public. We evaluated these applications by comparing total phosphorus (TP), total microcystin, total chlorophyll, and phycocyanin concentrations within the enclosure and the adjacent lake. Some evidence for short-term reductions in TP, microcystin, chlorophyll, and phycocyanin concentrations were observed following each P binding treatment, but all parameters rapidly returned to or exceeded pre-application levels within 2–3 weeks after treatment. These results suggest that in-lake chemical treatments to mitigate cHABs are unlikely to provide long-lasting benefits in these semi-enclosed areas of large, shallow, hypereutrophic systems, and resources may be better applied toward reducing external nutrient loads (P and nitrogen) from the watershed.

Levayer and colleagues assessed integrity issues in randomized controlled trials (RCTs) in four spine journals using baseline p-values from categorical variables, concluding that there was no evidence of ‘systemic fraudulent behaviour’. We used their published dataset to assess the accuracy of reported p-values and whether observed and expected distributions of frequency counts and p-values were consistent. In 51 out of 929 (5.5%) baseline variables, the sum of frequencies did not agree with the reported number of participants. For one-third of reported p-values (172 out of 522), we could not calculate a matching p-value using a range of statistical tests. Sparse data were common: for 22% (74 out of 332) of variables in which the reported p-value matched the p-value calculated from a chi-square test, the expected cells were smaller than recommended for the use of chi-square tests. There were 20–25% more two-arm trials with differences in frequency counts of 1 or 2 between-groups than expected. There were small differences between observed and expected distributions of baseline p-values, but these depended on analysis methods. In summary, incorrectly reported p-values and incorrect statistical test usage were common, and there were differences between observed and expected distributions of baseline p-values and frequency counts, raising questions about the integrity of some RCTs in these journals.

This proof-of-concept study evaluated an optimization strategy for the Community Case Detection Tool (CCDT) aimed at improving community-level mental health detection and help-seeking among children aged 6–18 years. The optimization strategy, CCDT+, combined data-driven supervision with motivational interviewing techniques and behavioural nudges for community gatekeepers using the CCDT. This mixed-methods study was conducted from January to May 2023 in Palorinya refugee settlement in Uganda. We evaluated (1) the added value of the CCDT+ in improving the accuracy of detection and mental health service utilization compared to standard CCDT, and (2) implementation outcomes of the CCDT+. Of the 1026 children detected, 801 (78%) sought help, with 656 needing mental health care (PPV = 0.82; 95% CI: 0.79, 0.84). The CCDT+ significantly increased detection accuracy, with 2.34 times higher odds compared to standard CCDT (95% CI: 1.41, 3.83). Additionally, areas using the CCDT+ had a 2.05-fold increase in mental health service utilization (95% CI: 1.09, 3.83). The CCDT+ shows promise as an embedded quality-optimization process for the detection of mental health problems among children and enhance help-seeking, potentially leading to more efficient use of mental health care resources.

In recent years the evidence base for psychological interventions in low- and -middle-income countries (LMIC) has rapidly accrued, demonstrating that task-shifting models result in desired outcomes. Next, it is important to look at how this evidence translates into practice. In doing so, this paper argues that the field of global mental health might benefit from applying a system theory or system science perspective. Systems thinking aims to understand how different components are connected and interdependent within a larger emergent entity. At present much of the research efforts into psychological interventions in LMIC are focusing on single interventions, with little focus on how these interventions sit in, or influence, a larger system. Adopting systems theory and system dynamics tools can help in; (i) better analyzing and understanding the key drivers of mental health problems and services, (ii) optimizing mental health services; and (iii) understanding the organization of people, institutions and resources required for rolling out and scaling-up mental health services. This paper reflects on some of these merits of a systems perspective, as well as provides some examples.

Background Gait analysis is traditionally conducted using marker-based methods yet markerless motion capture is emerging as an alternative. Initial studies have begun to evaluate the reliability of markerless motion capture yet the evaluation of different clothing conditions across sessions and complete evaluation of the lower limb and pelvis reliability have yet to be considered. The aim of this study was to evaluate the inter-trial, inter-session and inter-session-clothing variation and root mean square differences between tight- or loose-fitting clothing during walking. Method Twenty-two healthy adult participants walked along an indoor walkway whilst eight video cameras recorded their gait in either tight- or loose-fitting clothing. A commercial markerless motion capture system (Theia3D) provided gait kinematics for evaluation. Results Reliability results showed average inter-trial variation of

BackgroundCampylobacter is associated with environmental enteric dysfunction (EED) and malnutrition in children. Campylobacter infection could be a linchpin between livestock fecal exposure and health outcomes in low-resource smallholder settings.MethodsWe followed a birth cohort of 106 infants in rural smallholder households in eastern Ethiopia up to 13 months of age. We measured anthropometry, surveyed sociodemographic determinants, and collected stool and urine samples. A short survey was conducted during monthly visits, infant stool samples were collected, and Campylobacter spp. was quantified using genus-specific qPCR. In month 13, we collected stool and urine samples to assay for EED biomarkers. We employed regression analyses to assess the associations of household determinants with Campylobacter colonization, EED, and growth faltering.ResultsThe Campylobacter load in infant stools increased with age. The mean length-for-age Z-score (LAZ) decreased from −0.45 at 3–4 months of age to −2.06 at 13 months, while the prevalence of stunting increased from 3 to 51%. The prevalence of EED at 13 months of age was 56%. A higher Campylobacter load was associated with more frequent diarrhea. Prelacteal feeding significantly increased Campylobacter load in the first month of life. Over the whole follow-up period, Campylobacter load was increased by keeping chickens unconfined at home and unsanitary disposal of infant stools while decreased by mothers’ handwashing with soap. Longitudinally, Campylobacter load was positively associated with food insecurity, introduction of complementary foods, and raw milk consumption. There were no significant associations between Campylobacter load, EED, and LAZ.ConclusionThis study found that most determinants associated with increased Campylobacter infection were related to suboptimal feeding practices and hygiene. The findings related to livestock-associated risks were inconclusive. Although stunting, EED, and Campylobacter prevalence rates all increased to high levels by the end of the first year of life, no significant association between them was identified. While additional research is needed to investigate whether findings from this study are replicable in other populations, community efforts to improve infant and young child feeding practices and food hygiene, and water, sanitation, and hygiene (WaSH) at the household level, could reduce (cross-)contamination at the point of exposure.

Objectives Platform trials were used successfully in adult populations during the COVID-19 pandemic. By testing multiple treatments within a single trial, platform trials can help identify the most effective treatments (and any interactions between treatments) for patients more quickly and with less burden for patients and their families. The aim of this qualitative research was to inform the design of the first adaptive platform trial for paediatric intensive care in the UK with young people, parents/carers and paediatric intensive care unit (PICU) staff.Design Qualitative semistructured focus group study. Data were analysed using reflexive thematic analysis.Participants Young people, parents/carers, and PICU medical, nursing and research staff.Setting The UK.Results A total of 86 participants (18 young people; 15 parents/carers; 53 PICU staff) took part in 1 of 10 focus groups between May and September 2023. Participants viewed the proposed PICU platform trial and use of research without prior consent to be acceptable. Findings provide insight into how the PICU platform trial should be designed and operationalised, including having a broad and inclusive population eligible for inclusion onto the platform trial, with different inclusion and exclusion criteria for each domain; starting the trial with no more than three domains and prioritising the outcomes of Child quality of life and Survival (all participants). Optimal governance structure and suggestions about how any challenges to the success of the full trial can be overcome are also presented.Conclusions Young people, parents/carers and PICU staff viewed the proposed PICU platform trial to be acceptable. These key stakeholders supported us with the design of an adaptive platform trial for PICU that has a rigorous methodology, yet can be operationalised in a family-centred way, to provide high-quality evidence that can support clinical decision-making and guide the treatment of critically ill children. Our findings have informed the PICU platform trial protocol.

Obtaining diagnostic-quality magnetic resonance imaging (MRI) of the abdomen in critically ill patients can be difficult due to challenges with breath-holding and the inability to follow technologist instructions. Protocols that harness advances in commercially available MRI techniques provide a potential solution, particularly using the golden radial angle sparse parallel (GRASP) technique for dynamic post-contrast T1-weighted imaging. The GRASP technique uses a combination of free-breathing, a stack-of-stars radial acquisition, and compressed sensing reconstruction acquired over several minutes to produce motion-free images at time points defined by the user; these include the non-contrast, arterial, venous, and delayed images, which are typical of abdominal MRI protocols. The three cases discussed herein illustrate the use of this technique in providing both exquisite image quality and diagnostic value in the care of critically ill patients with hepatopancreaticobiliary diseases. Our work aims to raise awareness of this technique and its utility in imaging patients who cannot hold their breath for dynamic T1-weighted post-contrast imaging.

Abstract The cytogenetic abnormality inv(2)(p23q13) in acute myeloid leukemia (AML) results in a fusion of RANBP2 with ALK. This fusion makes ALK constitutively active and acts as a driver for the proliferation of AML cell lines. Gilteritinib, a FLT3 inhibitor approved in AML, also can inhibit ALK among other receptor tyrosine kinases. A 75-year-old-woman with a history of essential thrombocythemia (ET) and a presumed germline DDX41 mutation developed ALK-fusion positive AML and despite standard therapies was transfusion-dependent and globally declining. The patient has been on gilteritinib with an ongoing response of more than one year with near normal blood counts and no evidence of AML. The fact that she was found to harbor a presumed germline DDX41 alteration may account for why she developed, and yet survived, two myeloid neoplasms (ET and AML). Additionally, this demonstrates that gilteritinib is clinically active as an ALK inhibitor, and could be considered for use in any AML patient presenting with an inv(2(p23q13)) translocation. Finally, it is an example of using a disease-agnostic, precision medicine approach to arrive at a beneficial treatment.

Abstract Background Treatment decisions for persons with relapsing–remitting multiple sclerosis (RRMS) rely on clinical and radiological disease activity, the benefit-harm profile of drug therapy, and preferences of patients and physicians. However, there is limited evidence to support evidence-based personalized decision-making on how to adapt disease-modifying therapy treatments targeting no evidence of disease activity, while achieving better patient-relevant outcomes, fewer adverse events, and improved care. Serum neurofilament light chain (sNfL) is a sensitive measure of disease activity that captures and prognosticates disease worsening in RRMS. sNfL might therefore be instrumental for a patient-tailored treatment adaptation. We aim to assess whether 6-monthly sNfL monitoring in addition to usual care improves patient-relevant outcomes compared to usual care alone. Methods Pragmatic multicenter, 1:1 randomized, platform trial embedded in the Swiss Multiple Sclerosis Cohort (SMSC). All patients with RRMS in the SMSC for ≥ 1 year are eligible. We plan to include 915 patients with RRMS, randomly allocated to two groups with different care strategies, one of them new (group A) and one of them usual care (group B). In group A, 6-monthly monitoring of sNfL will together with information on relapses, disability, and magnetic resonance imaging (MRI) inform personalized treatment decisions (e.g., escalation or de-escalation) supported by pre-specified algorithms. In group B, patients will receive usual care with their usual 6- or 12-monthly visits. Two primary outcomes will be used: (1) evidence of disease activity (EDA3: occurrence of relapses, disability worsening, or MRI activity) and (2) quality of life (MQoL-54) using 24-month follow-up. The new treatment strategy with sNfL will be considered superior to usual care if either more patients have no EDA3, or their health-related quality of life increases. Data collection will be embedded within the SMSC using established trial-level quality procedures. Discussion MultiSCRIPT aims to be a platform where research and care are optimally combined to generate evidence to inform personalized decision-making in usual care. This approach aims to foster better personalized treatment and care strategies, at low cost and with rapid translation to clinical practice. Trial registration ClinicalTrials.gov NCT06095271. Registered on October 23, 2023

Gene mutations linked to diseases like cancer may be caused by exposure to environmental chemicals. The X-linked phosphatidylinositol glycan class A (PIG-A) gene, required for glycosylphosphatidylinositol (GPI) anchor biosynthesis, is a key target locus for in vitro genetic toxicity assays. Various organisms and cell lines may respond differently to genotoxic agents. Here, we compared the mutagenic potential of directly genotoxic ethyl methane sulfonate (EMS) to metabolically activated pro-mutagenic polycyclic aromatic hydrocarbons (PAHs). The two classes of mutagens were compared in an in vitro PIG-A gene mutation test using the metabolically active murine hepatoma Hepa1c1c7 cell line and the human TK6 cell line, which has limited metabolic capability. Determination of cell viability is required for quantifying mutagenicity. Two common cell viability tests, the MTT assay and propidium iodide (PI) staining measured by flow cytometry, were evaluated. The MTT assay overestimated cell viability in adherent cells at high benzo[a]pyrene (B[a]P) exposure concentrations, so PI-based cytotoxicity was used in calculations. The spontaneous mutation rates for TK6 and Hepa1c1c7 cells were 1.87 and 1.57 per million cells per cell cycle, respectively. TK6 cells exposed to 600 µM and 800 µM EMS showed significantly higher mutation frequencies (36 and 47 per million cells per cell cycle, respectively). Exposure to the pro-mutagen benzo[a]pyrene (B[a]P, 10 µM) did not increase mutation frequency in TK6 cells. In Hepa1c1c7 cells, mutation frequencies varied across exposure groups (50, 50, 29, and 81 per million cells per cell cycle when exposed to 10 µM B[a]P, 5-methylcholanthrene (5-MC), chrysene, or 16,000 µM EMS, respectively). We demonstrate that the choice of cytotoxicity assay and cell line can determine the outcome of the Pig-A mutagenesis assay when assessing a specific mutagen.

Abstract In this study, we report a biological temperature-sensing electrical regulator in the cytochrome c oxidase of the Devil Worm, Halicephalobus mephisto. This extremophile metazoan was isolated 1.3 km underground in a South African goldmine, where it adapted to heat and potentially to hypoxia, making its mitochondrial sequence a likely target of adaptational change. We obtained the complete mitochondrial genome sequence of this organism and show through dN/dS analysis evidence of positive selection in H. mephisto cytochrome c oxidase subunits. Seventeen of these positively selected amino acid substitutions were located in proximity to the H- and K-pathway proton channels of the complex. Surprisingly, the H. mephisto cytochrome c oxidase completely shuts down at low temperatures (20 °C), leading to a 4.8-fold reduction in the transmembrane proton gradient (ΔΨ m ) compared to optimal temperature (37 °C). Direct measurement of oxygen consumption found a corresponding 4.6-fold drop at 20 °C compared to 37 °C. Correspondingly, the lifecycle of H. mephisto takes four times longer at low temperature than at higher. This elegant evolutionary adaptation creates a finely-tuned mitochondrial temperature sensor, allowing this ectothermic organism to maximize its reproductive success across varying environmental temperatures.

Abstract A genomic database of all Earth’s eukaryotic species could contribute to many scientific discoveries; however, only a tiny fraction of species have genomic information available. In 2018, scientists across the world united under the Earth BioGenome Project (EBP), aiming to produce a database of high-quality reference genomes containing all ~1.5 million recognized eukaryotic species. As the European node of the EBP, the European Reference Genome Atlas (ERGA) sought to implement a new decentralised, equitable and inclusive model for producing reference genomes. For this, ERGA launched a Pilot Project establishing the first distributed reference genome production infrastructure and testing it on 98 eukaryotic species from 33 European countries. Here we outline the infrastructure and explore its effectiveness for scaling high-quality reference genome production, whilst considering equity and inclusion. The outcomes and lessons learned provide a solid foundation for ERGA while offering key learnings to other transnational, national genomic resource projects and the EBP.

Abstract 1q jumping translocation (JT) is rare and its molecular profiles in myeloid malignancies are not well-known. This study evaluated gene mutations in 1q-JT cohorts (0.38%) from hematological malignant specimens that underwent genetic analysis at the Johns Hopkins Hospital (n = 11,908) and the MD Anderson Cancer Center. 1q-JT had frequent mutations in eleven genes, most of which are associated with worse prognosis. BCOR mutations significantly co-occurred with others. Patients tended to have mutations in DNA-repair, spliceosome, and epigenetic modification pathways, though genes utilized within each of these pathways were not randomly distributed. Multi-, albeit overlapping, pathway interruptions tended to manifest in mutations of two gene sets. One gene set consisted of SF3B1 (spliceosome) and TET2 (epigenetic modification), while the other consisted of STAG2 (DNA repair), SRSF2, U2AF (spliceosome), ASXL1, KMT2D (epigenetic modification), BCOR, and GATA2 (transcription factors). An “intermediate” JT-like rearrangement may represent an early sign of occurring 1q-JT. Treatments (hypomethylating agents) and unique structures of the short arms of acrocentric chromosomes may contribute to 1q-JT formation in myeloid malignancies. The median overall survival after identification of a JT was 10 months (95% confidence interval, 5–15 months). Our cohort represents the largest number of myeloid malignancies from multi-centers with before and after the 1q-JT event analyzed to date. Overall, this study identified specific molecular profiles that are associated with 1q-JT in myeloid malignancies. 1q-JT could serve as a poor prognosis biomarker in myeloid malignancies, which could be important in making well-informed clinical decisions and treatment strategies.

Abstract Background The burden of hypertension among people with HIV is high, particularly in low-and middle-income countries, yet gaps in hypertension screening and care in these settings persist. This study aimed to identify facilitators of and barriers to hypertension screening, treatment, and management among people with HIV in primary care clinics in Johannesburg, South Africa. Additionally, different stakeholder groups were included to identify discordant perceptions. Methods Using a cross-sectional study design, data were collected via interviews (n = 53) with people with HIV and hypertension and clinic managers and focus group discussions (n = 9) with clinic staff. A qualitative framework analysis approach guided by COM-B and the Theoretical Domains Framework were used to identify and compare determinants of hypertension care across stakeholder groups. Results Data from clinic staff and managers generated three themes characterizing facilitators of and barriers to the adoption and implementation of hypertension screening and treatment: 1) clinics have limited structural and operational capacity to support the implementation of integrated care models, 2) education and training on chronic care guidelines is inconsistent and often lacking across clinics, and 3) clinicians have the goal of enhancing chronic care within their clinics but first need to advocate for health system characteristics that will sustainably support integrated care. Patient data generated three themes characterizing existing facilitators of and barriers to clinic attendance and chronic disease self-management: 1) the threat of hypertension-related morbidity and mortality as a motivator for lifestyle change, 2) the emotional toll of clinic’s logistical, staff, and resource challenges, and 3) hypertension self-management as a patchwork of informational and support sources. The main barriers to hypertension screening, treatment, and management were related to environmental resources and context (i.e., lack of enabling resources and siloed flow of clinic operations) and patients’ knowledge and emotions (i.e., lack of awareness about hypertension risk, fear, and frustration). Clinical actors and patients differed in perceived need to prioritize HIV versus hypertension care. Conclusions The convergence of multi-stakeholder data highlight key areas for improvement, where tailored implementation strategies targeting motivations of clinic staff and capacity of patients may address challenges to hypertension screening, treatment, and management recognized across groups.

Abstract Background Antigen removal is a cornerstone of treatment of hypersensitivity pneumonitis (HP), but its association with transplant-free survival remains unclear. Further, HP guidelines conflict as to whether antigen removal is a recommended diagnostic test in patients with suspected HP. Objective The purpose of this study is to (1) evaluate the impact of antigen removal on transplant-free survival and (2) to describe the impact of antigen removal on pulmonary function testing and imaging in a retrospective cohort of patients with HP. Methods We retrospectively identified HP patients evaluated between 2011 and 2020. Demographic, physiologic, radiographic, and pathologic data were recorded. Results 212 patients were included in the cohort. Patients who identified and removed antigen had a better transplant-free survival than patients who did not identify antigen and patients who identified but did not remove antigen. Antigen removal was associated with improvement in FVC by 10% predicted in 16.9% of patients with fibrotic HP and 56.7% of patients with nonfibrotic HP. Discussion Our results suggest that over 50% of nonfibrotic HP patients and 16.9% of fibrotic HP patients improve with exposure removal. In addition, antigen removal, rather than antigen identification, is associated with transplant-free survival in HP.

Abstract Background Antimicrobial resistance (AMR) constitutes a major threat to global health. While antimicrobial misuse or overuse is one of the main drivers for AMR, little is known about the extent to which antibiotic misuse is due to a lack of national government-led efforts to enforce rational use in low and middle-income countries (LMICs). Methods To assess antimicrobial stewardship and national implementation measures currently in place for optimizing antimicrobial use and for slowing the spread of AMR, we invited public health experts from 138 LMICs to participate in a Global Survey of Experts on Antimicrobial Resistance (GSEAR). Key coverage measures, as reported by experts, were compared across countries and also juxtaposed with estimates collected in the 2020-21 World Health Organization-organized Tripartite AMR Country Self-Assessment Survey (TrACSS). Results A total of 352 completed surveys from 118 LMICs were analysed. Experts in 67% of the surveyed countries reported a national action plan (NAP) on AMR, 64% reported legislative policies on antimicrobial use, 58% reported national training programs for health professionals, and 10% reported national monitoring systems for antimicrobials. 51% of LMICs had specific targeted policies to limit the sale and use of protected or reserve antibiotics. While 72% of LMICs had prescription requirements for accessing antibiotics, getting antibiotics without a prescription was reported to be possible in practice in 74% of LMICs. On average, country efforts reported in TrACSS were substantially higher than those seen in GSEAR. Conclusions In many LMICs, despite the existence of policies aimed at slowing down the spread of AMR, there are still significant gaps in their implementation and enforcement. Increased national efforts in the areas of enforcement and monitoring of antibiotic use as well as regular monitoring of national efforts are urgently needed to reduce inappropriate antibiotic use in LMICs and to slow the spread of AMR globally.

Abstract The nature of data obtainable from the commercial smartphone – bolstered by a translational model emphasizing the impact of social and physical zeitgebers on circadian rhythms and mood – offers the possibility of scalable and objective vital signs for major depression. Our objective was to explore associations between passively sensed behavioral smartphone data and repeatedly measured depressive symptoms to suggest which features could eventually lead towards vital signs for depression. We collected continuous behavioral data and bi-weekly depressive symptoms (PHQ-8) from 131 psychiatric outpatients with a lifetime DSM-5 diagnosis of depression and/or anxiety over a 16-week period. Using linear mixed-effects models, we related depressive symptoms to concurrent passively sensed behavioral summary features (mean and variability of sleep, activity, and social engagement metrics), considering both between- and within-person associations. Individuals with more variable wake-up times across the study reported higher depressive symptoms relative to individuals with less variable wake-up times (B [95% CI] = 1.53 [0.13, 2.93]). On a given week, having a lower step count (−0.16 [−0.32, −0.01]), slower walking rate (−1.46 [−2.60, −0.32]), lower normalized location entropy (−3.01 [−5.51, −0.52]), more time at home (0.05 [0.00, 0.10]), and lower distances traveled (−0.97 [−1.72, −0.22]), relative to one’s own typical levels, were each associated with higher depressive symptoms. With replication in larger samples and a clear understanding of how these components are best combined, a behavioral composite measure of depression could potentially offer the kinds of vital signs for psychiatric medicine that have proven invaluable to assessment and decision-making in physical medicine. Clinical Trials Registration: The data that form the basis of this report were collected as part of clinical trial number NCT03152864.

Abstract The fine tuning of biological electrical signaling is mediated by variations in the rates of opening and closing of gates that control ion flux through different ion channels. Human ether-a-go-go related gene (HERG) potassium channels have uniquely rapid inactivation kinetics which are critical to the role they play in regulating cardiac electrical activity. Here, we exploit the K+ sensitivity of HERG inactivation to determine structures of both a conductive and non-conductive selectivity filter structure of HERG. The conductive state has a canonical cylindrical shaped selectivity filter. The non-conductive state is characterized by flipping of the selectivity filter valine backbone carbonyls to point away from the central axis. The side chain of S620 on the pore helix plays a central role in this process, by coordinating distinct sets of interactions in the conductive, non-conductive, and transition states. Our model represents a distinct mechanism by which ion channels fine tune their activity and could explain the uniquely rapid inactivation kinetics of HERG.

Abstract Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.

Abstract Background Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance. Methods Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi. Results AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively. Conclusions Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.

The collection and preservation of biological material before DNA analysis is critical for inter alia biomedical research, medical diagnostics, forensics and biodiversity conservation. In this study, we evaluate an in-house formulated buffer called the Forensic DNA Laboratory-buffer (FDL-buffer) for preservation of biological material for long term at room temperature. Human saliva stored in the buffer for 8 years, human blood stored for 3 years and delicate animal tissues from the jellyfish Pelagia noctiluca comb jelly Beroe sp., stored for 4 and 6 years respectively consistently produced high-quality DNA. FDL-buffer exhibited compatibility with standard organic, salting out and spin-column extraction methods, making it versatile and applicable to a wide range of applications, including automation.

Abstract Sea-ice microalgae are a key source of energy and nutrient supply to polar marine food webs, particularly during spring, prior to open-water phytoplankton blooms. The nutritional quality of microalgae as a food source depends on their biomolecular (lipid:protein:carbohydrate) composition. In this study, we used synchrotron-based Fourier transform infra-red microspectroscopy (s-FTIR) to measure the biomolecular content of a dominant sea-ice taxa, Nitzschia frigida, from natural land-fast ice communities throughout the Arctic spring season. Repeated sampling over six weeks from an inner (relatively stable) and an outer (relatively dynamic) fjord site revealed high intra-specific variability in biomolecular content, elucidating the plasticity of N. frigida to adjust to the dynamic sea ice and water conditions. Environmental triggers indicating the end of productivity in the ice and onset of ice melt, including nitrogen limitation and increased water temperature, drove an increase in lipid and fatty acids stores, and a decline in protein and carbohydrate content. In the context of climate change and the predicted Atlantification of the Arctic, dynamic mixing and abrupt warmer water advection could truncate these important end-of-season environmental shifts, causing the algae to be released from the ice prior to adequate lipid storage, influencing carbon transfer through the polar marine system.

Abstract Background Growing evidence suggests that chronic inflammation caused by tuberculosis (TB) may increase the incidence of diabetes. However, the relationship between post-TB pulmonary abnormalities and diabetes has not been well characterized. Methods We analyzed data from a cross-sectional study in KwaZulu-Natal, South Africa, of people 15 years and older who underwent chest X-ray and diabetes screening with hemoglobin A1c testing. The analytic sample was restricted to persons with prior TB, defined by either (1) a self-reported history of TB treatment, (2) radiologist-confirmed prior TB on chest radiography, and (3) a negative sputum culture and GeneXpert. Chest X-rays of all participants were evaluated by the study radiologist to determine the presence of TB lung abnormalities. To assess the relationships between our outcome of interest, prevalent diabetes (HBA1c ≥6.5%), and our exposure of interest, chest X-ray abnormalities, we fitted logistic regression models adjusted for potential clinical and demographic confounders. In secondary analyses, we used the computer-aided detection system CAD4TB, which scores X-rays from 10 to 100 for detection of TB disease, as our exposure interest, and repeated analyses with a comparator group that had no history of TB disease. Results In the analytic cohort of people with prior TB (n = 3,276), approximately two-thirds (64.9%) were women, and the average age was 50.8 years (SD 17.4). The prevalence of diabetes was 10.9%, and 53.0% of people were living with HIV. In univariate analyses, there was no association between diabetes prevalence and radiologist chest X-ray abnormalities (OR 1.23, 95%CI 0.95–1.58). In multivariate analyses, the presence of pulmonary abnormalities was associated with an 29% reduction in the odds of prevalent diabetes (aOR 0.71, 95%CI 0.53–0.97, p = 0.030). A similar inverse relationship was observed for diabetes with each 10-unit increase in the CAD4TB chest X-ray scores among people with prior TB (aOR 0.92, 95%CI 0.87–0.97; p = 0.002), but this relationship was less pronounced in the no TB comparator group (aOR 0.96, 95%CI 0.94–0.99). Conclusions Among people with prior TB, pulmonary abnormalities on digital chest X-ray are inversely associated with prevalent diabetes. The severity of radiographic post-TB lung disease does not appear to be a determinant of diabetes in this South African population.

Abstract Task-specific dystonia leads to loss of sensorimotor control for a particular motor skill. Although focal in nature, it is hugely disabling and can terminate professional careers in musicians. Biomarkers for underlying mechanism and severity are much needed. In this study, we designed a keyboard device that measured the forces generated at all fingertips during individual finger presses. By reliably quantifying overflow to other fingers in the instructed (enslaving) and contralateral hand (mirroring) we explored whether this task could differentiate between musicians with and without dystonia. 20 right-handed professional musicians (11 with dystonia) generated isometric flexion forces with the instructed finger to match 25%, 50% or 75% of maximal voluntary contraction for that finger. Enslaving was estimated as a linear slope of the forces applied across all instructed/uninstructed finger combinations. Musicians with dystonia had a small but robust loss of finger dexterity. There was increased enslaving and mirroring, primarily during use of the symptomatic hand (enslaving p = 0.003; mirroring p = 0.016), and to a lesser extent with the asymptomatic hand (enslaving p = 0.052; mirroring p = 0.062). Increased enslaving and mirroring were seen across all combinations of finger pairs. In addition, enslaving was exaggerated across symptomatic fingers when more than one finger was clinically affected. Task-specific dystonia therefore appears to express along a gradient, most severe in the affected skill with subtle and general motor control dysfunction in the background. Recognition of this provides a more nuanced understanding of the sensorimotor control deficits at play and can inform therapeutic options for this highly disabling disorder.

Abstract Objectives (1) To plot the trajectory of humoral and cellular immune responses to the primary (two‐dose) COVID‐19 mRNA series and the third/booster dose in B‐cell‐depleted multiple sclerosis (MS) patients up to 2 years post‐vaccination; (2) to identify predictors of immune responses to vaccination; and (3) to assess the impact of intercurrent COVID‐19 infections on SARS CoV‐2‐specific immunity. Methods Sixty ocrelizumab‐treated MS patients were enrolled from NYU (New York) and University of Colorado (Anschutz) MS Centers. Samples were collected pre‐vaccination, and then 4, 12, 24, and 48 weeks post‐primary series, and 4, 12, 24, and 48 weeks post‐booster. Binding anti‐Spike antibody responses were assessed with multiplex bead‐based immunoassay (MBI) and electrochemiluminescence (Elecsys®, Roche Diagnostics), and neutralizing antibody responses with live‐virus immunofluorescence‐based microneutralization assay. Spike‐specific cellular responses were assessed with IFNγ/IL‐2 ELISpot (Invitrogen) and, in a subset, by sequencing complementarity determining regions (CDR)‐3 within T‐cell receptors (Adaptive Biotechnologies). A linear mixed‐effect model was used to compare antibody and cytokine levels across time points. Multivariate analyses identified predictors of immune responses. Results The primary vaccination induced an 11‐ to 208‐fold increase in binding and neutralizing antibody levels and a 3‐ to 4‐fold increase in IFNγ/IL‐2 responses, followed by a modest decline in antibody but not cytokine responses. Booster dose induced a further 3‐ to 5‐fold increase in binding antibodies and 4‐ to 5‐fold increase in IFNγ/IL‐2, which were maintained for up to 1 year. Infections had a variable impact on immunity. Interpretation Humoral and cellular benefits of COVID‐19 vaccination in B‐cell‐depleted MS patients were sustained for up to 2 years when booster doses were administered.

Abstract In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae. Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20–5.32) mg/L p

Abstract The population of Russia consists of more than 150 local ethnicities. The ethnic diversity and geographic origins, which extend from eastern Europe to Asia, make the population uniquely positioned to investigate the shared properties of inherited disease risks between European and Asian ancestries. We present the analysis of genetic and phenotypic data from a cohort of 4,145 individuals collected in three metro areas in western Russia. We show the presence of multiple admixed genetic ancestry clusters spanning from primarily European to Asian and high identity-by-descent sharing with the Finnish population. As a result, there was notable enrichment of Finnish-specific variants in Russia. We illustrate the utility of Russian-descent cohorts for discovery of novel population-specific genetic associations, as well as replication of previously identified associations that were thought to be population-specific in other cohorts. Finally, we provide access to a database of allele frequencies and GWAS results for 464 phenotypes.

Abstract A diagnosis of epilepsy has significant consequences for an individual but is often challenging in clinical practice. Novel biomarkers are thus greatly needed. Here, we investigated how common genetic factors (epilepsy polygenic risk scores, [PRSs]) influence epilepsy risk in detailed longitudinal electronic health records (EHRs) of > 700k Finns and Estonians. We found that a high genetic generalized epilepsy PRS (PRSGGE) increased risk for genetic generalized epilepsy (GGE) (hazard ratio [HR] 1.73 per PRSGGE standard deviation [SD]) across lifetime and within 10 years after an unspecified seizure event. The effect of PRSGGE was significantly larger on idiopathic generalized epilepsies, in females and for earlier epilepsy onset. Analogously, we found significant but more modest focal epilepsy PRS burden associated with non-acquired focal epilepsy (NAFE). Here, we outline the potential of epilepsy specific PRSs to serve as biomarkers after a first seizure event.

Abstract The prefusion conformation of human metapneumovirus fusion protein (hMPV Pre-F) is critical for eliciting the most potent neutralizing antibodies and is the preferred immunogen for an efficacious vaccine against hMPV respiratory infections. Here we show that an additional cleavage event in the F protein allows closure and correct folding of the trimer. We therefore engineered the F protein to undergo double cleavage, which enabled screening for Pre-F stabilizing substitutions at the natively folded protomer interfaces. To identify these substitutions, we developed an AI convolutional classifier that successfully predicts complex polar interactions often overlooked by physics-based methods and visual inspection. The combination of additional processing, stabilization of interface regions and stabilization of the membrane-proximal stem, resulted in a Pre-F protein vaccine candidate without the need for a heterologous trimerization domain that exhibited high expression yields and thermostability. Cryo-EM analysis shows the complete ectodomain structure, including the stem, and a specific interaction of the newly identified cleaved C-terminus with the adjacent protomer. Importantly, the protein induces high and cross-neutralizing antibody responses resulting in near complete protection against hMPV challenge in cotton rats, making the highly stable, double-cleaved hMPV Pre-F trimer an attractive vaccine candidate.

Objective: To explore outcomes of anterior cruciate ligament (ACL) reconstructive surgery (ACLR) between individuals using private and public healthcare. Methods: We conducted a cross-sectional study of participants, 9–36 months post-ACLR using public or private healthcare services. Multivariable linear regression assessed the association between healthcare service used (private versus public) with self-reported outcomes (Knee injury and Osteoarthritis Outcome Score (KOOS) subscales of pain, symptoms, sport/recreation, knee-related quality of life (QoL); 0–100 scale), adjusting for potential confounders. Results: A total of 314 participants were included (median age 29 years, 35 ​% female). One hundred and thirty-nine (44 ​%) underwent ACLR using private healthcare. Individuals using private healthcare for ACLR reported better post-ACLR knee-related QoL (mean difference 5.1; 95%CI 0.6 to 9.7) than individuals using public healthcare, when adjusted for available confounders. No other KOOS subscale scores (pain, symptoms, sport/recreation) differed between healthcare groups in our adjusted analysis. Conclusions: Australian young adults who underwent ACLR using private healthcare (compared to public healthcare) services reported better knee-related QoL post-operatively in this cross-sectional cohort. Sociodemographic and socioeconomic factors contributed little to the differences observed. Future research should consider potential disparities in outcomes between participants using differing healthcare services both clinically and when recruiting participants into research studies evaluating outcomes post-ACLR.

Objective: Describe the injury characteristics, game circumstances, and immediate action and management of injuries sustained by boys and girls participating in junior community Australian football. Design: Cohort Study. Methods: All community junior Australian football players from one Victorian-based league were eligible to participate if they were injured during a game and presented to the gameday first aid medics. Injured players were subsequently followed up with a phone call to undertake an injury surveillance survey. The injury surveillance survey gathered information relating to the injury characteristics, game circumstances and management undertaken. Additionally, all players who sustained a head impact were asked about the presence or absence of concussion-related symptoms. Results: 439 players sustained an injury in the 2022 season, with 354 (80.6 ​%) participating in the survey. The head was the most frequently reported injured body region (n ​= ​194, 54.8 ​%), with approximately half (n ​= ​101) being a diagnosed or suspected sports-related concussion. The next three most frequently reported body regions were the ankle (n ​= ​29, 8.2 ​%), knee (n ​= ​24, 6.8 ​%), and shoulder (n ​= ​20, 5.6 ​%). Almost all injuries were acute onset (n ​= ​340, 96.0 ​%) and resulted from a contact-based mechanism (94.9 ​%, n ​= ​222 direct contact, n ​= ​114 indirect contact). Tackling was the most frequently reported game circumstance resulting in an injury (n ​= ​160, 45.2 ​%). Conclusion: The head was the most frequently reported injured body region, with approximately one in every two reported head impacts resulting in a diagnosed/suspected sports-related concussion. Injury prevention strategies that promote safety when tackling and being tackled may reduce the frequency of injury, warranting further investigation.

Background: The association between cardiovascular disease and advanced liver disease is incompletely understood. To explore this interaction, we compared management, clinical outcomes, readmission rates, and resource utilization in ST-elevation myocardial infarction (STEMI) patients with and without liver disease. Methods: The Nationwide Readmissions Database (2016–2020) was queried to identify hospitalizations for STEMI. Cohorts were stratified by presence of liver disease. Liver disease was defined as documented diagnosis of liver cirrhosis or liver failure. Multivariable regression model and propensity score matching was used to compare the risk of outcomes. Results: Among 1,029,608 hospitalizations for STEMI; 45,478 (4.4 %) patients had a history of significant liver disease. Patient with liver disease had higher baseline prevalence of diabetes, chronic kidney disease, anemia, and heart failure. After propensity matching (N = 24,067 in each group), patients with liver disease had higher in-hospital mortality (48.8 % vs 17.3 %, aOR: 6.80 [CI: 6.55–7.06], p

We present a genome assembly from an individual male Ochropleura leucogaster (Freyer, 1831) (Radford's Flame Shoulder; Arthropoda; Insecta; Lepidoptera; Noctuidae). The genome sequence has a total length of 545.70 megabases. Most of the assembly (99.93%) is scaffolded into 31 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 15.37 kilobases in length. Gene annotation of this assembly on Ensembl identified 12,155 protein-coding genes.

ABSTRACT Introduction Functional neurological disorder (FND) and autism spectrum disorder (ASD) are two complex neuropsychiatric conditions that have been historically classified within psychiatric domains, resulting in a lack of extensive research, insufficient clinical recognition, and persistent societal stigma. In recent years, there has been an increasing recognition among professionals and affected individuals of their possible overlap. This review explores the potential clinical and mechanistic overlap between FND and ASD, with particular attention to shared symptoms across sensory, motor, and psychiatric domains. Methods We conducted a narrative analysis utilizing the PubMed, CINAHL, MEDLINE, and ScienceDirect databases from inception to June 2024. The search employed specific MeSH terms related to ASD and FND. Given the limited data availability, we included all relevant articles that explored the potential connections between FND and ASD, focusing on established findings and theoretical hypotheses areas. Results Scientific evidence indicates that FND and ASD may co‐occur more frequently than previously acknowledged and with notable overlaps in their clinical presentations and pathophysiology. Theoretical models that have been applied to FND and ASD, such as the Bayesian brain theory and the tripartite model of autism, may provide valuable insights into the intersection of these conditions. Although much of the current evidence remains speculative, it underscores the need for hypothesis‐driven research to investigate these potential connections further. Conclusion ASD and FND are heterogeneous conditions that appear to co‐occur in a subset of individuals, with overlapping symptomatology and possibly shared underlying mechanisms. This hypothesis‐generating review emphasizes the need for further research to better understand these links, ultimately aiming to improve clinical recognition and develop targeted interventions that enhance the quality of life for affected individuals.

Atrial fibrillation (AF) is a prevalent and clinically significant cardiac arrhythmia, with a growing incidence. The primary objectives in AF management are symptom relief, stroke risk reduction, and prevention of tachycardia-induced cardiomyopathy. Two key strategies for rhythm control include antiarrhythmic drug therapy and pulmonary vein isolation (PVI), with PVI being recommended for selected patients. Even though PVI is effective, post procedural health care utilization is high, contributing to emergency department (ED) overcrowding, which is a global healthcare concern. The use of remote rhythm diagnostics, such as a 1-lead ECG device (KM), may mitigate this issue by reducing ED visits and facilitating more plannable AF care.ObjectiveThis study aimed to assess whether providing AF patients with a 1-lead ECG device for 1 year after PVI would reduce ED utilization compared to standard care. Additionally, the study assessed whether this intervention would render AF care more plannable by reducing the incidence of unplanned cardioversions.MethodsA historically controlled, prospective clinical trial was conducted. The intervention group were patients undergoing PVI for AF between September 2018 and August 2020, all patients in this group received a 1-lead ECG device for 1 year for remote rhythm monitoring. The historical control group were patients undergoing PVI between January 2016 and December 2017; these patients did not receive a 1-lead ECG device. Data on ED visits, planned and unplanned cardioversions, and outpatient contacts in the year after the PVI were collected for both groups.ResultsThe study included 204 patients, 123 in the 1-lead ECG group and 81 in the standard care group. There was no statistically significant difference in the number of all-cause ED visits (63 vs 68 per 100 pts, respectively, p = 0.72), ED visits for possible rhythm disorders, or ED visits for definite rhythm disorders between the two groups. However, the 1-lead ECG group demonstrated a higher proportion of planned cardioversions compared to unplanned ones (odds ratio 4.9 [1.57-15.85], p = 0.007).ConclusionProviding patients with AF following PVI with a 1-lead ECG device did not result in a statistically significant reduction in ED visits during the first year. However, it did improve the management of recurrent AF episodes by substituting unplanned cardioversions with scheduled ones. Clinical Trials Registration Number NCT06283654.

Background: Acute blood loss and transfusion are recognized risks factors of total hip (THA) and total knee arthroplasty (TKA). This study aimed to investigate the clinical value of immediate postoperative hemoglobin and hematocrit (H&H) tests following primary elective THA and TKA. Methods: This retrospective observational study was undertaken at a single academic hospital. Medical records were reviewed for a consecutive series of patients undergoing primary elective THA and TKA over a 12-month period. Patient demographic data; the use of preoperative anticoagulants; preoperative and postoperative blood test results; and the incidence of postoperative allogenic blood transfusion (ABT) were collected. The primary outcome measure was the incidence of postoperative ABT prescribed in response to the immediate postoperative H&H result. Results: Overall, 367 eligible patients were included, with 167 THA (46%) and 200 TKA (54%) cases. Only 3 patients (0.8%) received a postoperative ABT; none on the day of surgery or on postoperative day 1. Immediate postoperative H&H tests were drawn in 246 patients (67%), but it did not influence clinical decision-making with regards to transfusion. No significant differences in ABT were observed in relation to patient age, sex, body mass index, operation (THA or TKA), or the use of preoperative anticoagulation medication. The incidence of ABT was significantly higher in patients with a combined preoperative hemoglobin

Introduction With declining HIV-related mortality, over 20% of people with HIV (PWH) in South Africa are now over age 50 years, and tobacco-related non-communicable disease burden is increasing. We quantified the impact of smoking and smoking cessation on lung cancer and stroke incidence among PWH in South Africa.Methods Using a microsimulation model, we simulated 18 cohorts of initially virologically suppressed PWH over their lifetime, categorised by sex, initial age (35 years/45 years/55 years) and smoking status (current/former/never). Smoking status remains constant throughout the simulation; individuals with former smoking status quit at model start. PWH can disengage from HIV care and experience virological rebound. We modelled the relative risk of lung cancer for females (males) with current versus never smoking status as 16.69 (15.83), and for females (males) with former versus never smoking status as 1.99–8.80 (1.90–6.18), depending on age at cessation. Corresponding modelled relative risks of stroke were 1.79 (1.54) for current versus never smoking, and 1.00–1.29 (1.00–1.12) for former versus never smoking. We varied HIV-related and smoking-related parameters in sensitivity analyses.Results Modelled female (male) PWH who stop smoking at age 45 years experience 61.3% (70.9%) and 35.6% (18.6%) lower cumulative lung cancer and stroke incidence over 25 years compared with people who continue smoking. The proportion alive and lung cancer-free or alive and stroke-free over 25 years would increase by 10.4 (9.5) or 10.5 (8.5) percentage points. In sensitivity analysis, smoking and smoking cessation have a greater impact on lung cancer and stroke cumulative incidence if competing HIV-related mortality risks are lower or if PWH experience higher lung cancer and stroke risk compared with people without HIV apart from smoking.Conclusion Smoking cessation could substantially reduce lung cancer and stroke risk among PWH in South Africa. To reduce the rising non-communicable disease burden among PWH, smoking cessation should become part of routine care of PWH.