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Abstract Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic’s evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate’s contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.4/5] in the COVAIL trial (NCT05289037), titers against 5 strains were assessed as correlates of risk of symptomatic COVID-19 (“COVID-19”) and as correlates of relative (Pfizer-BioNTech Omicron vs. Prototype) booster protection against COVID-19 over 6 months of follow-up during the BA.2-BA.5 Omicron-dominant period. Consistently across the Moderna and Pfizer-BioNTech vaccine platforms and across all variant Spike inserts assessed, both peak and exposure-proximal (“predicted-at-exposure”) titers correlated with lower Omicron COVID-19 risk in individuals previously infected with SARS-CoV-2, albeit significantly less so in naïve individuals [e.g., exposure-proximal hazard ratio per 10-fold increase in BA.1 titer 0.74 (95% CI 0.59, 0.94) for naïve vs. 0.41 (95% CI 0.23, 0.64) for non-naïve; interaction p = 0.013]. Neutralizing antibody titer was a strong inverse correlate of Omicron COVID-19 in non-naïve individuals and a weaker correlate in naïve individuals, posing questions about how prior infection alters the neutralization correlate.

Abstract Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14R117, a critical residue located within a druggable pocket at the FGF14/Nav1.6 PPI interface. We found that 1028 modulates FGF14/Nav1.6 complex assembly and depolarizes the voltage-dependence of Nav1.6 channel inactivation with nanomolar potency by modulating the intramolecular interaction between the III-IV linker and C-terminal domain of the Nav1.6 channel. Consistent with the compound’s effects on Nav1.6 channel inactivation, 1028 enhances MSN excitability ex vivo and accumbal neuron firing rate in vivo in murine models. Systemic administration of 1028 maintains behavioral motivation preferentially during motivationally deficient conditions in murine models. These behavioral effects were abrogated by in vivo gene silencing of Fgf14 in the NAc and were accompanied by a selective reduction in accumbal dopamine levels during reward consumption in murine models. These findings underscore the potential to selectively regulate complex behaviors associated with neuropsychiatric disorders through targeting of PPIs in neurons.

Abstract Neurodevelopmental disorders are thought to arise from intrinsic brain abnormalities. Alternatively, they may arise from disrupted crosstalk among tissues. Here we show the local reduction of two vestibulo-cerebellar lobules, the paraflocculus and flocculus, in mouse models and humans with 22q11.2 deletion syndrome (22q11DS). In mice, this paraflocculus/flocculus dysplasia is associated with haploinsufficiency of the Tbx1 gene. Tbx1 haploinsufficiency also leads to impaired cerebellar synaptic plasticity and motor learning. However, neural cell compositions and neurogenesis are not altered in the dysplastic paraflocculus/flocculus. Interestingly, 22q11DS and Tbx1 +/– mice have malformations of the subarcuate fossa, a part of the petrous temporal bone, which encapsulates the paraflocculus/flocculus. Single-nuclei RNA sequencing reveals that Tbx1 haploinsufficiency leads to precocious differentiation of chondrocytes to osteoblasts in the petrous temporal bone autonomous to paraflocculus/flocculus cell populations. These findings suggest a previously unrecognized pathogenic structure/function relation in 22q11DS in which local skeletal deformity and cerebellar dysplasia result in behavioral deficiencies.

Abstract Glioblastoma (GBM) is a malignant brain tumor with diffuse infiltration. Here, we demonstrate how GBM cells usurp guidance receptor Plexin-B2 for confined migration through restricted space. Using live-cell imaging to track GBM cells negotiating microchannels, we reveal endocytic vesicle accumulation at cell front and filamentous actin assembly at cell rear in a polarized manner. These processes are interconnected and require Plexin-B2 signaling. We further show that Plexin-B2 governs membrane tension and other membrane features such as endocytosis, phospholipid composition, and inner leaflet surface charge, thus providing biophysical mechanisms by which Plexin-B2 promotes GBM invasion. Together, our studies unveil how GBM cells regulate membrane tension and mechano-electrical coupling to adapt to physical constraints and achieve polarized confined migration.

Abstract Large-scale and detailed analyses of activity in the United States (US) remain limited. In this work, we leveraged the comprehensive wearable, demographic, and survey data from the All of Us Research Program, the largest and most diverse population health study in the US to date, to apply and extend the previous global findings on activity inequality within the context of the US. We found that daily steps differed by sex at birth, age, body characteristics, geography, and built environment. Quantifying activity inequality using the modified Gini index, we found a strong correlation with obesity prevalence (R 2 = 0.804) and a moderate correlation with perceived walkability (R 2 = 0.426) and the activity gender gap (R 2 = 0.385). This study demonstrates the value of digital health technologies in exploring and understanding public health practices while highlighting the need to examine complexities, including biopsychosocial factors that may contribute to activity inequality.

Abstract Background TP53 variant classification benefits from the availability of large-scale functional data for missense variants generated using cDNA-based assays. However, absence of comprehensive splicing assay data for TP53 confounds the classification of the subset of predicted missense and synonymous variants that are also predicted to alter splicing. Our study aimed to generate and apply splicing assay data for a prioritised group of 59 TP53 predicted missense or synonymous variants that are also predicted to affect splicing by either SpliceAI or MaxEntScan. Methods We conducted splicing analyses using a minigene construct containing TP53 exons 2 to 9 transfected into human breast cancer SKBR3 cells, and compared results against different splice prediction methods, including correlation with the SpliceAI-10k calculator. We additionally applied the splicing results for TP53 variant classification using an approach consistent with the ClinGen Sequence Variant Interpretation Splicing Subgroup recommendations. Results Aberrant transcript profile consistent with loss of function, and for which a PVS1 (RNA) code would be assigned, was observed for 42 (71%) of prioritised variants, of which aberrant transcript expression was over 50% for 26 variants, and over 80% for 15 variants. Data supported the use of SpliceAI ≥ 0.2 cutoff for predicted splicing impact of TP53 variants. Prediction of aberration types using SpliceAI-10k calculator generally aligned with the corresponding assay results, though maximum SpliceAI score did not accurately predict level of aberrant expression. Application of the observed splicing results was used to reclassify 27/59 (46%) test variants as (likely) pathogenic or (likely) benign. Conclusions In conclusion, this study enhances the integration of splicing predictions and provides splicing assay data for exonic variants to support TP53 germline classification. Graphical abstract

Abstract High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies.

Abstract Background Hypertension is a key risk factor for death and disability, and blood pressure reduction is associated with significant reductions in cardiovascular risk. Large trials have shown that interventions including self-monitoring of blood pressure can reduce blood pressure but real-world data from wider implementation are lacking. Aim The self-monitoring and management service evaluation in primary care (SHIP) study will evaluate a novel digital intervention for hypertension management and medication titration platform (“Hypertension-Plus”) that is currently undergoing initial implementation into primary care in several parts of the UK. Methods and analyses The study will use a mixed methods approach including both quantitative analysis of anonymised electronic health record data and qualitative analyses of interview and customer support log data. Pseudonymised data will be extracted from electronic health records and outcomes compared between those using the digital intervention and their own historical data, as well as to those not registered to the system. The primary outcome will be difference in systolic blood pressure in the 12 months before and after implementation. A further analysis will utilise self-monitored blood pressure data from the Hypertension-Plus system itself. Semi-structured qualitative interviews will be completed with implementation and clinical leads, staff and patients in six general practices located in two different geographical areas in England. Informed by the non-adoption, abandonment, scale-up, spread, and sustainability (NASSS) framework, our analysis will identify the challenges to successful implementation and sustainability of the digital intervention in routine clinical practice and in patients’ homes. Ethics and dissemination The analyses of pseudonymised data were assessed by the sponsor (The University of Oxford) as service evaluation not requiring individual consent and hence did not require ethical approval. Ethics approval for the qualitative analyses was provided by Wales REC 4 (21/WA/0280) and individual written informed consent will be gained for all participants. Results will be published in peer-reviewed journals, presented at national and international conferences and disseminated via patient and health service organisations. Discussion This study will provide an in-depth analysis of the impact and acceptance of initial implementation of a novel digital intervention, enhancing our understanding and supporting more effective implementation of telemonitoring based hypertension management systems for blood pressure control in England.

Abstract Background Although some evidence suggests that alcohol, substance use, and mental health issues diminish adherence to HIV Pre-Exposure Prophylaxis (PrEP) among gay, bisexual, and other men-who-have-sex-with-men (gbMSM), findings are somewhat inconsistent and have primarily derived from studies involving non-random samples. Medical chart extraction can provide unique insight by in part surmounting sampling-related limitations, as data for entire PrEP clinic populations can be examined. Our investigation entailed comprehensive chart extraction to assess the extent to which chart-reported alcohol, substance use, and mental health issues were associated with chart-reported PrEP nonadherence. Methods Data from medical charts of gbMSM at two PrEP clinics in Toronto, Canada were extracted for a retrospective 12-month period (02/2018-01/2019). Charts were reviewed for all patients who were 1) ≥ 18 years old; 2) gbMSM; 3) prescribed PrEP ≥ 3 months, and 4) not in a PrEP-related drug trial. Information regarding PrEP, alcohol, substance use, mental health, and sexual behavior was extracted. PrEP adherence was classified in terms of (1) any reported nonadherence, and (2) ‘suboptimal adherence,’ reflecting nonadherence patterns indicative of insufficient pharmacological protection from HIV. Multivariate logistic regression was employed to identify factors associated with adherence outcomes. Results Data were extracted from 4,292 clinic visits among 501 eligible patients (age: M = 39.1; duration on PrEP: M = 17.4 months; daily PrEP regimen = 93.8%). Hazardous/harmful drinking, club drug use, and mental health issues were reported among 8.8%, 22.2%, and 26.1% of patients, respectively. Any nonadherence and suboptimal adherence were reported among 37.5% and 12.4% of patients, respectively. Factors significantly associated with any nonadherence included age

In the last century, global pandemics have been primarily driven by respiratory infections, which consistently rank among the top 20 causes of death worldwide. The coronavirus disease 2019 (COVID-19) pandemic has underscored the intricate nature of managing multiple health crises simultaneously. In recent years, climate change has emerged as a major biosafety and population health challenge. Global warming and extreme weather events have intensified outbreaks of climate-sensitive infectious diseases, especially respiratory diseases. Influenza and COVID-19 have emerged as two of the most significant respiratory pandemics, each with unique epidemic characteristics and far-reaching consequences. Our comparative analysis reveals that while both diseases exhibit high transmission rates, COVID-19′s longer incubation period and higher severity have led to more profound and prolonged socioeconomic disruptions than influenza. Both pandemics have highlighted the exacerbating effects of climate change, with extreme weather events intensifying the spread and impact of these diseases. The COVID-19 pandemic exposed vulnerabilities in global healthcare systems and economies on an unprecedented scale, outstripping the strain caused by influenza outbreaks. Importantly, the COVID-19 pandemic has not only reshaped global public health strategies but also significantly impacted the epidemiology of influenza. Despite these differences and associations, both diseases underscore the urgent need for robust pandemic preparedness and adaptable public health strategies. This review delineates the overlaps and distinctions between influenza and COVID-19, offering insights into future challenges and the critical steps needed to enhance healthcare system resilience and improve global responses to pandemics.

Abstract Background Carpal tunnel syndrome (CTS) is a prevalent cumulative strain injury associated with occupational risk factors such as vibration, repetitive and forceful wrist movements, and awkward wrist postures. This study aimed to identify Ontario workers at elevated risk for CTS and to explore sex differences in CTS risk among workers. Methods The Occupational Disease Surveillance System (ODSS) links accepted lost time compensation claims to health administrative databases. CTS cases were identified from physician billing (Ontario Health Insurance Plan) records and defined as at least one record for CTS surgery (fee code N290) between 2002 and 2020. A 3-year washout period and restricted follow-up period of 3 years were applied. A total of 792,769 workers were included in the analytical cohort. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for CTS by occupation and industry, adjusted for age and birth year, stratified by sex. Results A total of 3,224 CTS cases among females (f) and 2,992 cases among males (m) were identified in the cohort. We observed elevated risks of CTS in many occupations requiring repetitive and forceful manual work: slaughtering and meat cutting, canning, curing and packing (HRf = 2.28, 95%CI = 1.42–3.68; HRm = 1.95, 95%CI = 1.33–2.85); welding and flame cutting (HRf = 1.83, 95%CI = 1.01–3.32; HRm = 1.65, 95%CI = 1.35–2.01); motor vehicle fabricating and assembling (HRf = 2.14, 95%CI = 1.74–2.62; HRm = 2.43, 95%CI = 2.04–2.89); and packaging (HRf = 2.06, 95%CI = 1.43–2.97; HRm = 1.82, 95%CI = 1.12–2.98). Elevated risks were observed among males employed as nursing aides and orderlies (HRm = 1.72, 95%CI = 1.13–2.62), in mining (HRm = 1.57, 95%CI = 1.01–2.45), and in construction (HRm = 1.32, 95%CI = 1.19–1.47). Elevated risks were observed among females in mineral, metal, chemical processing (HRf = 1.58, 95%CI = 1.27–1.97), textile processing (HRf = 1.89, 95%CI = 1.22–2.94), wood machining (HRf = 2.84, 95%CI = 1.47–5.45), and females employed as janitors, charworkers and cleaners (HRf = 1.50, 95%CI = 1.32–1.71). Findings by industry were consistent with occupation results. Conclusion The risk of CTS varied by occupation, industry, and sex in this large cohort. Workers engaged in highly repetitive and forceful manual work were at elevated CTS risk, highlighting the need to further understand and reduce ergonomic hazards among identified groups. Future studies should also explore CTS risk by sex, with a focus on female workers.

Abstract A long-standing goal of neuroimaging is the non-invasive volumetric assessment of whole brain function and structure at high spatial and temporal resolutions. Functional ultrasound (fUS) and ultrasound localization microscopy (ULM) are rapidly emerging techniques that promise to bring advanced brain imaging and therapy to the clinic with the safety and low-cost advantages associated with ultrasound. fUS has been used to study cerebral hemodynamics at high temporal resolutions while ULM has been used to study cerebral microvascular structure at high spatial resolutions. These two methods have complementary spatio-temporal characteristics, making them ideally suited for multimodal imaging, but both suffer from limitations associated with transcranial ultrasound imaging. Here, these two methods are combined on the same data acquisition, completely non-invasively, using contrast-enhancements, which solves the dual challenges of sensitivity during transcranial imaging and the ability to implement super-resolution. From this combined approach, the cerebral blood flow, activated brain region, brain connectivity, vessel diameter, and vessel velocity were all calculated from the same data acquisition. During stimulation periods, there was a statistically significant (p

Abstract Impaired mucociliary transport is a distinguishing sign of cystic fibrosis, but current methods of evaluation are invasive or expose young patients to ionizing radiation. Contrast-enhanced ultrasound imaging may provide a feasible alternative. We formulated a cationic microbubble ultrasound contrast agent, to optimize adhesion to the respiratory mucus layer when inhaled. Potential toxicity was evaluated in human bronchial epithelial cell (hBEC) cultures following a 24-hour exposure, compared to positive and negative control conditions. In vivo tolerability and pulmonary image enhancement feasibility were evaluated in mice, comparing oropharyngeal administration of contrast agent to saline control. When induced to flow across mucus plated on microscope slides, cationic microbubbles demonstrated greater affinity for target samples than standard microbubbles. Cationic microbubbles elicited no proinflammatory or cytotoxic response in hBECs, nor were any cross-links to the cilia observed. Unlike standard microbubbles, cationic microbubbles mixed into the mucus layer, without epithelial absorption, and were observed to move with the mucus layer by the action of mucociliary transport. When administered to mice, cationic microbubbles enhanced sonographic visualization of the trachea, and were well-tolerated with no adverse effects. This developmental work supports the safety and feasibility of a mucus-targeting contrast agent that may be useful for pulmonary ultrasound applications.

Abstract Recent laboratory tests and large-scale observations have revealed the complex interplays between aseismic and seismic deformation, as well as the progressive localization of the rock failure process. To investigate these processes, we conducted triaxial tests that combined distributed strain sensing (DSS) with acoustic emission (AE) sensors. Progressive strain localization was detected by DSS at 80% of the peak stress but did not produce measurable AEs. Closer to the peak stress, regions exhibiting strain localizations began to show clusters of AEs. This reveals that DSS measurements are more informative during the preparatory stage of brittle rock failure. The frequency-magnitude distribution of the AEs showed an inverse correlation with the volumetric deformation rate a few seconds preceding catastrophic failure. Our results are consistent with recent large-scale observations and offer crucial insights into progressive failure assessment.

Abstract Background Immunotherapy has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with immunotherapy naïve and exposed primary ccRCC tumors to better understand immunotherapy resistance. Results Spatial molecular imaging of tumor and adjacent stroma samples from 21 tumors suggests that viable tumors following immunotherapy harbor more stromal CD8 + T cells and neutrophils than immunotherapy naïve tumors. YES1 is significantly upregulated in immunotherapy exposed tumor cells. Spatial GSEA shows that the epithelial-mesenchymal transition pathway is spatially enriched and the associated ligand-receptor transcript pair COL4A1-ITGAV has significantly higher autocorrelation in the stroma after exposure to immunotherapy. More integrin αV + cells are observed in immunotherapy exposed stroma on multiplex immunofluorescence validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. Assessing bulk RNA expression and proteomic correlates in CPTAC databases reveals that collagen IV protein is more abundant in advanced stages of disease. Conclusions Spatial transcriptomics of samples of 3 patient cohorts with cRCC tumors indicates that COL4A1 and ITGAV are more autocorrelated in immunotherapy-exposed stroma compared to immunotherapy-naïve tumors, with high expression among fibroblasts, tumor cells, and endothelium. Further research is needed to understand changes in the ccRCC tumor immune microenvironment and explore potential therapeutic role of integrin after immunotherapy treatment.

Abstract Earth’s obliquity and eccentricity cycles are strongly imprinted on Earth’s climate and widely used to measure geological time. However, the record of these imprints on the oxygen isotope record in deep-sea benthic foraminifera (δ18Ob) shows contradictory signals that violate isotopic principles and cause controversy over climate-ice sheet interactions. Here, we present a δ18Ob record of high fidelity from International Ocean Drilling Program (IODP) Site U1406 in the northwest Atlantic Ocean. We compare our record to other records for the time interval between 28 and 20 million years ago, when Earth was warmer than today, and only Antarctic ice sheets existed. The imprint of eccentricity on δ18Ob is remarkably consistent globally whereas the obliquity signal is inconsistent between sites, indicating that eccentricity was the primary pacemaker of land ice volume. The larger eccentricity-paced early Antarctic ice ages were vulnerable to rapid termination. These findings imply that the self-stabilizing hysteresis effects of large land-based early Antarctic ice sheets were strong enough to maintain ice growth despite consecutive insolation-induced polar warming episodes. However, rapid ice age terminations indicate that resistance to melting was weaker than simulated by numerical models and regularly overpowered, sometimes abruptly.

Background: This study characterized the risk of new-onset asthma among workers in Manitoba, Canada. Methods: Accepted time loss claims from the Workers' Compensation Board of Manitoba from 2006 to 2019, containing workers' occupations and industries, were linked with administrative health data from 1996 to 2020. After restricting the cohort to the first claim per person in an occupation and applying age and coverage exclusions, the cohort comprised 142,588 person–occupation combinations. Asthma cases were identified if workers had at least two medical records for asthma (International Classification of Diseases, Ninth Revision, 493) within a 12-month period, within the 2 years before 3 years after cohort entry. New-onset asthma was identified using a 3-year washout period. Asthma hazard ratios by occupation and industry were estimated using Cox proportional hazard models, adjusted for age, and stratified by sex. Results: Increased asthma risk was observed among workers with known asthmagen exposure, including male veterinary and animal health technologists and technicians (hazard ratio 3.97, 95% CI 1.78–8.86), male fish processing workers (3.40, 1.53–7.57), and male machining tool operators (2.91, 1.72–4.92). Increases were also observed for occupations with unknown or suspected allergens, including gas station attendants, drivers, mail/postal and related workers, public works and maintenance laborers, mine laborers and crane operators, and some indoor worker groups. Decreased risks were observed among nurses and residential and commercial installer and servicers. Conclusion: This database linkage study successfully identified occupations and industries with known sensitizing agents or irritants, and several occupation and industries not typically associated with work-related asthma, warranting further investigation.

Objective: To investigate the cost-effectiveness of using artificial intelligence (AI) to screen for low ejection fraction (EF) in routine clinical practice using a pragmatic randomized controlled trial (RCT). Patients and Methods: In a post hoc analysis of the electrocardiogram (ECG) AI-guided screening for low ejection fraction trial, we developed a decision analytic model for patients aged 18 years and older without previously diagnosed heart failure and underwent a clinically indicated ECG between August 5, 2019, and March 31, 2020. In the previously published RCT, the intervention arm underwent an AI-guided targeted screening program for low EF with a workflow embedded into routine clinical practice—AI was applied to the ECG to identify patients at high-risk and recommended clinicians to order an ECG and the control arm received usual care without the screening program. We used results from the RCT for rates of low EF diagnosis and a lifetime Markov model to project the long-term outcomes. Quality-adjusted life years (QALYs), costs of intervention and treatment, disease event costs, incremental cost-effectiveness ratio (ICER), and cost for the number needed to screen. Multiple scenario and sensitivity analyses were performed. Results: Compared with usual care, AI-integrated ECG was cost effective, with an incremental cost-effectiveness ratio of $27,858/QALY. The program remained cost effective even with a change in patient age and follow-up time duration, although the specific ICER values varied for these parameters. The program was more cost effective in outpatient settings (ICER $1651/QALY) than in inpatient or emergency room settings. Conclusion: Implementing AI-guided targeted screening for low EF in routine clinical practice was cost effective.

Indigenous-driven and community-partnered research projects seeking to develop salient, legitimate, and credible knowledge bases for environmental decision-making require a multiple knowledge systems approach. When involving partners in addition to communities, diverging perspectives and priorities may arise, making the pathways to engaging in principled research while generating actionable knowledge unclear to disciplinarily-trained natural science researchers. Here, we share insights from the Eeyou Coastal Habitat Comprehensive Research Project (CHCRP), an interdisciplinary, Cree-driven community-academic partnership. This project brought together Cree community members, regional organizations, industry (Hydro-Québec), and academics from seven universities across Canada to address the unprecedented loss of seagrass Zostera marina (eelgrass), the concurrent decline in migratory Canada geese and its impact on fall goose harvest activities in Eeyou Istchee. After describing the history and context of the project, we discuss the challenges, complexities, and benefits of the collaborative approach balancing saliency, legitimacy, and credibility of the knowledge produced. We suggest the paper may be of use to researchers and partners seeking to engage in principled and actionable research related to environmental change including impacts of past development.

Detecting cracks in cylinder heads traditionally relies on manual inspection, which is time-consuming and susceptible to human error. As an alternative, automated object detection utilizing computer vision and machine learning models has been explored. However, these methods often face challenges due to a lack of sufficiently annotated training data, limited image diversity, and the inherently small size of cracks. Addressing these constraints, this paper introduces a novel automated crack-detection method that enhances data availability through a synthetic data generation technique. Unlike general data augmentation practices, our method involves copying cracks from one location to another, guided by both random and informed engineering decisions about likely crack formations due to cyclic thermomechanical loads. The innovative aspect of our approach lies in the integration of domain-specific engineering knowledge into the synthetic generation process, which substantially improves detection accuracy. We evaluate our method’s effectiveness using two metrics: the F2 score, which emphasizes recall to prioritize detecting all potential cracks, and mean average precision (MAP), a standard measure in object detection. Experimental results demonstrate that, without engineering insights, our method increases the F2 score from 0.40 to 0.65, while maintaining a stable MAP. Incorporating detailed engineering knowledge further enhances the F2 score to 0.70 and improves MAP to 0.57, representing increases of 63% and 43%, respectively. These results confirm that our approach not only mitigates the limitations of traditional data augmentation but also significantly advances the reliability and precision of crack detection in industrial settings.

Abstract Background The COVID-19 pandemic has served as a catalyst for recognizing the challenging environments in which healthcare workers operate, underscoring the urgent need to enhance their wellness to better support themselves and others. The implementation of a culture of wellness within the context of healthcare education, with a particular emphasis on individual-level strategies, allows for the realization of its intrinsic value and significance as a foundation for broader organizational strategies. This approach facilitates the establishment of a sustainable culture of wellness that benefits both current and subsequent generations of healthcare professionals. Methods We implemented our wellness program using a pragmatic pre-post study design for different settings. Our wellness intervention program was tested in three ways by creating combinations of different intensities (high, moderate, or low), delivery methods (face-to-face vs. virtual), different motivations (incentive, mandatory, or volunteer participation), and different timings (during medical programs or before entering into healthcare programs) among medical and nursing students. The effects of the wellness program were measured on quality of life, emotional intelligence, and efficacy scores among healthcare students. Statistical methods included repeated measures analysis of variance and paired t-tests. Results A total of 224 students (13 in high, 145 in moderate, and 66 in low-dose interventions) participated in our study program. Most scores were significantly improved except for a few factors in the high-dose face-to-face Well-Teach intervention cohort. Among quality of life components, the average psychological scores were markedly increased after high (13.2 vs. 14.7, p = .018), moderate (13.9 vs. 14.8, p

Abstract Feline hyperthyroidism (FHT) is a debilitating disease affecting > 10% of elderly cats. It is generally characterised by chronic elevation of thyroid hormone in the absence of circulating TSH. Understanding of the molecular pathogenesis of FHT is currently limited. However, FHT shares clinical and histopathological similarities with human toxic multinodular goitre, which has been associated with activating mutations in TSH receptor (TSHR) and Gsα encoding genes. Using RNA-seq transcriptomic analysis of thyroid tissue from hyperthyroid and euthyroid cats, we identified differentially expressed genes and dysregulated pathways in FHT, many of which are downstream of TSHR. In addition, we detected missense variants in thyroid RNA-seq reads that alter the structure of both TSHR and Gsα. All FHT-associated mutations were absent in germline sequence from paired blood samples. Only a small number of hyperthyroid cats demonstrated TSHR variation, however all thyroids from advanced cases of FHT carried at least one missense variant affecting Gsα. The activating nature of the acquired Gsα mutations was demonstrated by increased cAMP production in vitro. These data indicate that constitutive activation of signalling downstream of TSHR is central to the TSH-independent production of thyroid hormone in FHT, offering a novel therapeutic target pathway in this common disease.

Abstract Aspects of the Quaternary sedimentary geology of South-East Asia have proven problematic in terms of interpretation as to the origins and relationships of the surface sediment layers. The MIS 20 large meteorite impact (c., 788 to 785 ka) occurred within mainland South-East Asia, evident from the well-researched ‘Australasian Tektite Strewn Field’ which extends over at least one tenth of the surface of the Earth. Key questions include: 1) whether the sedimentary impact signature is preserved in the Quaternary sediment cover of the region and 2) whether stratigraphic indicators and dating methods can discriminate meteorite impact-related associations of sedimentary strata, despite subsequent reworking and diagenesis. The importance of the questions raised relate to the search for the impact site, which has not been located conclusively. Moreover, the sedimentary signatures of meteorite impacts are not well known and the descriptions in this study should aid the recognition of impact signatures elsewhere in the world. An hypothesis was developed: Surface Quaternary sediments across a wide area of mainland South-East Asia represent the effects of a regionally significant meteorite impact. Over one hundred sedimentary sections were logged across five countries in mainland South-East Asia. Methods used, defining the stratigraphy and sedimentology, include computed tomography and X-ray scanning, geochemistry, magnetic susceptibility, and environmental luminescence as well as conventional grain size analyses. Luminescence analyses were applied to samples from key strata to provide age constraints and indications of reworking through dose distributional analysis of quartz fractions. The results of the investigation explain the nature of the stratigraphy and relate it specifically to the meteorite impact. In this manner, the strata and sedimentary signatures of the ejecta from a large cosmic impact are defined across a broad region, rather than being described at singular and isolated sections. The novelty is the spatial scale of the investigation which nevertheless remains detailed. A summary model of impact stratigraphy is presented that applies to the regional ejecta blanket covering at least 300,000 km2. Tektites were co-deposited with the ejecta and not introduced by surface processes reworking the deposits. Similar models may be applicable outside of mainland South-East Asia, wherever other large impacts are suspected to have occurred.

Thromboembolism in blood vessels poses a serious risk of stroke, heart attack, and even sudden death if not properly managed. Sonothrombolysis combined with ultrasound contrast agents has emerged as a promising approach for the effective treatment of thromboembolism. Recent reports have highlighted the potential of intravascular sonothrombolysis as a safe and effective treatment modality for deep vein thrombosis (DVT). However, its efficiency has not been validated through in vivo testing of retracted clots. This study aimed to develop a miniaturized multidirectional transducer featuring two 4-layer lead zirconate titanate (PZT-5A) stacks with an aperture size of 1.4 mm × 1.4 mm, enabling both forward- and side-looking treatment. Integrated into a custom two-lumen 10-French (Fr) catheter, the capability of this device for intravascular sonothrombolysis was validated both in vitro and in vivo. With low-dose tissue plasminogen activators and nanodroplets, the rotational multidirectional transducer reduced the retracted clot mass (800 mg) by an average of 52% within 30 min during in vitro testing. The lysis rate was significantly higher by 37% than that in a forward-viewing transducer without rotation. This improvement was particularly noteworthy in the treatment of retracted clots. Notably, a long-retracted clot (> 10 cm) was successfully treated within 40 min in vivo by creating a flow channel with a diameter > 4 mm in a porcine DVT model. In conclusion, these findings strongly suggest the potential of this technique for clinical applications in sonothrombolysis, offering a feasible solution for effectively treating thromboembolism, particularly in challenging cases involving retracted clots.

Abstract SARS-CoV-2 continues to be a public health burden, driven in-part by its continued antigenic diversification and resulting emergence of new variants. By increasing herd immunity, current vaccines have improved infection outcomes for many. However, prophylactic and treatment interventions that are not compromised by viral evolution of the Spike protein are still needed. Using a differential staining strategy with a rationally designed SARS-CoV-2 Receptor Binding Domain (RBD) – ACE2 fusion protein and a native Omicron RBD protein, we developed a recombinant human monoclonal antibody (hmAb) from a convalescent individual following SARS-CoV-2 Omicron infection. The resulting hmAb, 1301B7 potently neutralized a wide range of SARS-CoV-2 variants including the original Wuhan-1, the more recent Omicron JN.1 strain, and SARS-CoV. 1301B7 contacts the ACE2 binding site of RBD exclusively through its VH1-69 heavy chain. Broad specificity is achieved through 1301B7 binding to many conserved residues of Omicron variants including Y501 and H505. Consistent with its extensive binding epitope, 1301B7 is able to potently diminish viral burden in the upper and lower respiratory tract and protect mice from challenge with Omicron XBB1.5 and Omicron JN.1 viruses. These results suggest 1301B7 has broad potential to prevent or treat clinical SARS-CoV-2 infections and to guide development of RBD-based universal SARS-CoV-2 prophylactic vaccines and therapeutic approaches.

Abstract The remobilization of stored assimilates from stems to seeds plays a pivotal role in augmenting barley yield, particularly under water stress conditions. This study examines the molecular mechanisms underlying stem reserve utilization by conducting a comparative analysis of the proteome and metabolome across three barley contrasting genotypes: Yousef, Morocco, and PBYT17. Evaluations were performed at 21 and 28 days after anthesis (DAA) under both water stress and control conditions. The results indicate that the Yousef genotype exhibits superior remobilization of stem reserves, thereby demonstrating its potential to thrive even in adverse environmental conditions. Utilizing advanced quantitative proteomics and targeted metabolomics, this investigation identified a significant number of metabolites and proteins exhibiting differential accumulation across the genotypes. Specifically, 17 metabolites and 1580 proteins were catalogued, highlighting the intricate biochemical responses to water stress. Noteworthy enzymes such as sucrose synthase, inositol monophosphatase 3, and galactokinase were found to be closely associated with remobilization efficiency. In the drought-tolerant genotype, these enzymes maintained stable levels, in stark contrast to the decline observed in the susceptible genotype. This stability is crucial for promoting seed development through ascorbic acid synthesis and for mitigating oxidative stress, which is exacerbated by drought conditions. The elevated levels of certain metabolites, including glucose 6-phosphate, and UDP-glucose, in the drought-tolerant genotype suggest a robust mechanism for maintaining signalling molecules for carbon availability, which is then instrumental in regulating plant growth and seed size development. The findings from this study strongly imply that the drought-tolerant genotype, through enhanced antioxidant capacity, can effectively produce energy-rich storage compounds, thereby optimizing carbon allocation under water stress. Such insights are invaluable for future breeding strategies aimed at improving barley resilience in the face of climate variability.

Abstract Cervical pedicle screws (CPS) provide biomechanically superior fixation compared to other techniques but are technically more demanding. Navigated CPS placement has been increasingly reported as a safe and accurate technique, yet there are few studies comparing different combinations of imaging and navigation systems under comparable conditions. With this study, we aimed to compare different imaging and navigation systems for CPS placement in terms of accuracy, screw placement time and applied radiation dose. For this experimental study, navigated CPS placement was performed at levels C2 to C7 in 24 identical radiopaque artificial spine models by two surgeons with different levels of experience using three different combinations of intraoperative 3D imaging devices and navigation systems. Accuracy, time and radiation dose were compared between the groups. In total, 288 screws were placed. Accuracy was > 98% in all groups with no significant differences between groups or between surgeons (P = 0.30 and P = 0.31, respectively), but the inexperienced surgeon required significantly more time (P 98% were achieved for navigated CPS placement regardless of the imaging modality or navigation system used. Radiation doses were significantly lower for CBCT compared to iCT guidance.

Abstract We have previously engineered E. coli transketolase (TK) enzyme variants that accept new substrates such as aliphatic or aromatic aldehydes, and also with improved thermal stability. Irreversible aggregation is the primary mechanism of deactivation for TK in the buffers used for biocatalysis, and so we were interested in determining the extent to which this remains true in more complex media, crude cell lysates or even in vivo. Such understanding would better guide future protein engineering efforts. NMR offers a potential approach to probe protein structure changes, aggregation, and diffusion, and19F-labelled amino acids are a useful NMR probe for complex systems with little or no background signal from the rest of the protein or their environment. Here we labelled E. coli TK with two different19F probes, trifluoromethyl-L-phenylalanine (tfm-Phe), and 4-fluoro phenylalanine (4 F-Phe), through site specific non-natural amino acid incorporation. We targeted them to residue K316, a highly solvent exposed site located at the furthest point from the enzyme active sites. Characterisation of the19F-labelled TK variants revealed surprising effects of these mutations on stability, and to some extent on activity. While variant TK-tfm-Phe led to a 7.5 °C increase in the thermal transition midpoint (T m) for denaturation, the TK-4 F-Phe variant largely abolished the aggregation of the enzyme when incubated at 50 °C19. F-NMR revealed different behaviours in response to temperature increases for the two TK variants, displaying opposite temperature gradient chemical shifts, and diverging motion regimes, suggesting that the mutations affected differently both the local environment at this site, and its temperature-induced dynamics. A similar incubation of TK at 40–55 °C is also known to induce higher cofactor-binding affinities, leading to an apparent heat activation under low cofactor concentration conditions. We have hypothesised previously that a heat-inducible conformational change in TK leads to this effect1. H-NMR revealed a temperature-dependent re-structuring of methyl groups, also at 30–50 °C, which may be linked to the heat activation. While our kinetic studies were not expected to observe the heat activation event due to the high cofactor concentrations used, this was not the case for TK-4 F-Phe, which did appear to heat activate slightly at 45 °C. This implied that the mutations at K316 could influence cofactor-binding, despite their location at 47 Å from either active site. Such long-distance effects of mutations are not unprecedented, and indeed we have previously shown how distant mutations can influence active-site loop stability and function in TK, mediated via dynamically coupled networks of residues. Molecular dynamics simulations of the two19F containing variants similarly revealed networks of residues that could couple the changes in dynamics at residue K316, through to changes in active site dynamics. These results independently highlight the sensitivity of active-site function to distant mutations coupled through correlated dynamic networks of residues. They also highlight the potential influence of surface-incorporated probes on protein stability and function, and the need to characterise them well prior to further studies.

Abstract Amblyomma maculatum sensu lato (s.l.) is an ixodid tick found in the semi-arid southwestern United States and northern Mexico where it is a parasite of medical and veterinary significance, including as a vector for Rickettsia parkeri, a cause of spotted fever rickettsiosis in the Americas. To describe the comprehensive natural history of this tick, monthly small mammal trapping and avian mist netting sessions were conducted at sites in Cochise County Arizona, within the Madrean Archipelago region where human cases of R. parkeri rickettsiosis and adult stages of A. maculatum s.l. were previously documented. A total of 1949 larvae and nymphs were removed from nine taxonomic groups of rodents and ten species of birds and were used in combination with records for adult stages collected both from vegetation and hunter-harvested animals to model seasonal activity patterns. A univoltine phenology was observed, initiated by the onset of the annual North American monsoon and ceasing during the hot, dry conditions preceding the following monsoon season. Cotton rats (Sigmodon spp.) were significantly more likely to be infested than other rodent taxa and carried the highest tick loads, reflecting a mutual affinity of host and ectoparasite for microhabitats dominated by grass.

Abstract Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.S vaccination as correlates of risk and of protection against severe-critical COVID-19 through 220 days post-vaccination in the ENSEMBLE trial (NCT04505722), constituting ~4.5 months longer follow-up than our previous correlates analysis and enabling inclusion of 42 severe-critical vaccine-breakthrough cases. Neutralizing antibody titer is a strong inverse correlate of severe-critical COVID-19, with estimated hazard ratio (HR) per 10-fold increase 0.35 (95% CI: 0.13, 0.90). In a multivariable model, HRs are 0.31 (0.11, 0.89) for neutralizing antibody titer and 1.22 (0.49, 3.02) for anti-Spike binding antibody concentration. VE against severe-critical COVID-19 rises with neutralizing antibody titer: 63.1% (95% CI: 40.0%, 77.3%) at unquantifiable [

Abstract Introduction Data on the resumption of sporting activity (return-to-sport, RTS) after traumatic spine injuries are mainly available for elite athletes. This study aimed to determine the RTS rate in amateurs after spine injury and to identify factors possibly influencing RTS. Methods First, a retrospective analysis of clinical data of patients with traumatic spine injuries receiving inpatient treatment at a national trauma center from 2016 to 2020 was performed. Patients up to the age of 60 who were active in sports before the injury were included. Patients with the following relevant concomitant injuries were excluded: spinal cord injury, pelvic injury, extremity injuries, as well as craniocerebral trauma grade 2 or higher. A telephone interview on participants’ RTS within the first year after the injury was conducted. Participants with early and those with late or no RTS were compared in univariate analysis regarding potential influencing factors. The level of significance was set to p

Abstract Background Dissemination and implementation science is an evolving field that focuses on the strategies and mechanisms by which scientific evidence is adopted, used, and sustained in clinical and community practice. Main body Implementation scientists are confronted by the challenge to balance rigor and generalizability in their work while also attempting to speed the translation of evidence into clinical and community practice. Hybrid Effectiveness-Implementation studies and the RE-AIM framework were conceptualized to address these challenges. Hybrid Effectiveness-Implementation (HEI) studies provide methods of examining the effectiveness of health promoting interventions while concurrently assessing the utility of dissemination and implementation strategies designed to enhance the application of evidence-based principles in practice. RE-AIM provides a set of planning and evaluation dimensions that can be assessed with a goal to balance internal and external validity. The purpose of this commentary is to provide clarity on definitions of each approach and how to effectively use them together to answer research questions that will advance dissemination and implementation science for health promotion. Conclusions We provide examples of concerted use of RE-AIM within HEI studies from the literature and focus on language to provide a clarity and consistency across research questions, designs, and settings. We share how to operationalize RE-AIM dimensions in HEI studies for both dissemination and implementation strategies. Future directions include refining, defining, and evaluating each RE-AIM dimension within hybrid studies.

Abstract The Arctic-Boreal region is projected to experience spatially divergent trends in snow depth following climate change. However, the impact of these spatial trends has remained largely unexplored, despite potentially large consequences for the carbon cycle. To address this knowledge gap, we forced a customised arctic version of the dynamic vegetation model LPJ-GUESS with daily CMIP6 outputs from a global climate model (MRI-ESM2-0) under three climate scenarios. We find that snow depths increased the most in the coldest, northernmost regions, insulating the soil, which led to increased heterotrophic respiration and reduced carbon residence times. We emphasise the need for improved projections of future snow depth - in particular diverging trends across landscapes - to more accurately simulate the strength of Arctic-Boreal carbon feedbacks and their impact on global climate.

Abstract Background Compared to the general population, people who inject drugs have poor health and wellbeing. Longitudinal studies can provide insight into factors driving these worse health outcomes but are subject to methodological challenges, such as cohort attrition. The aim of this study was to assess and characterise attrition in a prospective cohort of people who inject drugs in Victoria, Australia. Methods Using annually collected self-reported data from The Melbourne Injecting Drug User Cohort Study (SuperMIX) from September 2008 to January 2021, we estimated the incidence of participants being lost-to-follow-up (LTFU), with an episode of being LTFU defined as participants not undertaking a follow-up interview within two years of their last interview. We utilised a multiple event discrete-time survival analysis on participant period-observation data to estimate the associations between key factors and LTFU. Key areas of exposure measurement in analyses were sociodemographic, drug use and mental health. Results A total of n = 1328 SuperMIX participants completed a baseline interview, with n = 489 (36.8%) LTFU, i.e. not completing a follow-up interview in the following two years. Increased attrition was observed among SuperMIX participants who were: born outside Australia, younger than 30 years, reporting having completed fewer years of education, not residing in stable accommodation, not in stable employment and not on opioid agonist therapy (OAT). Conclusions The attrition rate of the SuperMIX cohort has largely been stable throughout the duration of the study. Higher attrition rates among individuals at greater sociodemographic disadvantage and not on OAT suggest that additional efforts are required to retain these participants. Findings also suggest that SuperMIX might not be capturing data on adverse health and wellbeing outcomes among subpopulations at high risk of harm.

Background: The Vienna Prediction Model (VPM) identifies patients with a first unprovoked deep vein thrombosis of the leg and/or pulmonary embolism who have a low recurrence risk and may, therefore, not benefit from extended-phase anticoagulation. Objectives: The aim of this study was to evaluate patients with a predicted high risk of recurrent venous thromboembolism (VTE). Methods and Results: We prospectively followed 266 patients in whom the VPM had predicted a recurrence risk of more than 5.5% at 1 year for a median of 13.5 months. Their median age was 56 years, and 96% were men. After the VPM risk assessment, 196 patients restarted anticoagulation. While on anticoagulation, none of the patients experienced recurrent VTE, whereas 4 patients had nonmajor clinically relevant bleeding (absolute bleeding rate, 1.8 [95% CI, 0.5-4.5] events per 100 patient-years). Seventy patients were left untreated after VPM risk assessment for various reasons. Among patients not using anticoagulation, 15 had recurrence (absolute recurrence rate, 18.1 [95% CI, 10.1, 29.9] events per 100 person-years). According to the extended Kaplan–Meier analysis, the probability of VTE recurrence in patients not on anticoagulation was 10.1% and 17.9% at 6 and 12 months after VPM risk assessment, respectively. Conclusion: Anticoagulant therapy is effective and safe in patients with an unprovoked VTE, in whom the VPM had predicted a high risk of recurrent VTE. If these patients are left untreated, the risk of recurrence is high.

Objective: Despite advances in artificial intelligence (AI) in glaucoma prediction, most works lack multicenter focus and do not consider fairness concerning sex, race, or ethnicity. This study aims to examine the impact of these sensitive attributes on developing fair AI models that predict glaucoma progression to necessitating incisional glaucoma surgery. Design: Database study. Participants: Thirty-nine thousand ninety patients with glaucoma, as identified by International Classification of Disease codes from 7 academic eye centers participating in the Sight OUtcomes Research Collaborative. Methods: We developed XGBoost models using 3 approaches: (1) excluding sensitive attributes as input features, (2) including them explicitly as input features, and (3) training separate models for each group. Model input features included demographic details, diagnosis codes, medications, and clinical information (intraocular pressure, visual acuity, etc.), from electronic health records. The models were trained on patients from 5 sites (N = 27 999) and evaluated on a held-out internal test set (N = 3499) and 2 external test sets consisting of N = 1550 and N = 2542 patients. Main Outcomes and Measures: Area under the receiver operating characteristic curve (AUROC) and equalized odds on the test set and external sites. Results: Six thousand six hundred eighty-two (17.1%) of 39 090 patients underwent glaucoma surgery with a mean age of 70.1 (standard deviation 14.6) years, 54.5% female, 62.3% White, 22.1% Black, and 4.7% Latinx/Hispanic. We found that not including the sensitive attributes led to better classification performance (AUROC: 0.77–0.82) but worsened fairness when evaluated on the internal test set. However, on external test sites, the opposite was true: including sensitive attributes resulted in better classification performance (AUROC: external #1 - [0.73–0.81], external #2 - [0.67–0.70]), but varying degrees of fairness for sex and race as measured by equalized odds. Conclusions: Artificial intelligence models predicting whether patients with glaucoma progress to surgery demonstrated bias with respect to sex, race, and ethnicity. The effect of sensitive attribute inclusion and exclusion on fairness and performance varied based on internal versus external test sets. Prior to deployment, AI models should be evaluated for fairness on the target population. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Objectives: Despite evidence of praziquantel's (PZQ) safety for treating schistosomiasis in pregnancy, many countries withhold treatment. Only two randomized controlled trials have investigated PZQ in pregnancy, none involving Schistosoma haematobium. Methods: Pregnant women during the second trimester in Lambaréné (Gabon) were screened for S. haematobium infection using urine microscopy and circulating anodic antigen detection. Participants positive for either test were randomized (3:1) to single-dose PZQ 40 mg/kg during pregnancy versus no treatment during pregnancy. Investigators were blinded for allocation. Primary outcomes were reduction of egg (egg reduction rate [ERR]) and antigen production (infection reduction rate [IRR]) while explorative outcomes included assessment of cure rate, adverse events, maternal hemoglobin levels, maternal anemia prevalence at delivery, pregnancy outcomes, and newborn anthropometric parameters. Results: Of 761 women screened 165 were eligible and randomized (intervention n = 124, control n = 41). Of them, 124 completed the study (n = 90 and n = 34, respectively). Treatment led to a significantly higher ERR (95.0% [91-97%] vs 27.0% [−42-63%]) and IRR (95% [91-97%] vs 56% [14-78%]). Common adverse events were dizziness, nausea, and vomiting. Maternal anemia at delivery was significantly lower in the intervention group (odds ratio: 0.40 [0.16;0.96], P = 0.04). No increased risk for adverse pregnancy outcomes was observed. Conclusions: This first randomized controlled trial investigating PZQ in pregnant women with S. haematobium found PZQ to be safe, effective, and reducing maternal anemia. We recommend treating confirmed infections to prevent morbidity in pregnant women.

Abstract Aims Heart failure (HF) is a clinical syndrome with no definitive diagnostic tests. HF registries are often based on manual reviews of medical records of hospitalized HF patients identified using International Classification of Diseases (ICD) codes. However, most HF patients are not hospitalized, and manual review of big electronic health record (EHR) data is not practical. The US Department of Veterans Affairs (VA) has the largest integrated healthcare system in the nation, and an estimated 1.5 million patients have ICD codes for HF (HF ICD‐code universe) in their VA EHR. The objective of our study was to develop artificial intelligence (AI) models to phenotype HF in these patients. Methods and results The model development cohort (n = 20 000: training, 16 000; validation 2000; testing, 2000) included 10 000 patients with HF and 10 000 without HF who were matched by age, sex, race, inpatient/outpatient status, hospital, and encounter date (within 60 days). HF status was ascertained by manual chart reviews in VA's External Peer Review Program for HF (EPRP‐HF) and non‐HF status was ascertained by the absence of ICD codes for HF in VA EHR. Two clinicians annotated 1000 random snippets with HF‐related keywords and labelled 436 as HF, which was then used to train and test a natural language processing (NLP) model to classify HF (positive predictive value or PPV, 0.81; sensitivity, 0.77). A machine learning (ML) model using linear support vector machine architecture was trained and tested to classify HF using EPRP‐HF as cases (PPV, 0.86; sensitivity, 0.86). From the ‘HF ICD‐code universe’, we randomly selected 200 patients (gold standard cohort) and two clinicians manually adjudicated HF (gold standard HF) in 145 of those patients by chart reviews. We calculated NLP, ML, and NLP + ML scores and used weighted F scores to derive their optimal threshold values for HF classification, which resulted in PPVs of 0.83, 0.77, and 0.85 and sensitivities of 0.86, 0.88, and 0.83, respectively. HF patients classified by the NLP + ML model were characteristically and prognostically similar to those with gold standard HF. All three models performed better than ICD code approaches: one principal hospital discharge diagnosis code for HF (PPV, 0.97; sensitivity, 0.21) or two primary outpatient encounter diagnosis codes for HF (PPV, 0.88; sensitivity, 0.54). Conclusions These findings suggest that NLP and ML models are efficient AI tools to phenotype HF in big EHR data to create contemporary HF registries for clinical studies of effectiveness, quality improvement, and hypothesis generation.

Abstract Aberrant caspase recruitment domain family member 14 (CARD14) signaling has been strongly associated with inflammatory skin conditions. CARD14 acts as a scaffold protein, ultimately activating the transcription factor NF-KB. Although primarily studied in the context of inflammation, recent research has suggested its potential implications in tumorigenesis. In this study, we gathered The Cancer Genome Atlas (TCGA) tumor data to gauge the involvement of CARD14 in cancer, including genetic alterations, expression patterns, survival correlations, immune cell infiltration and functional interactions across diverse cancer types. We found heightened CARD14 expression in most tumors and there was a significant correlation between CARD14 expression and the prognosis of patients for certain tumors. For instance, patients with higher CARD14 expression had a better prognosis in sarcoma, lung, cervix and head and neck cancers. Moreover, CARD14 expression positively correlated with neutrophil infiltration in most of the cancer types analyzed. Finally, enrichment analysis showed that epithelial development and differentiation pathways were involved in the functional mechanism of CARD14. Our results show that CARD14 may have the potential to become a prognostic biomarker in several cancers, hence, further prospective studies will be required for its validation.

Abstract Background Cigarette smoking prevalence is higher for rural than urban adults, yet digital access to cessation programming is reduced. We aim to investigate digital access interventions to promote engagement with an online evidence-based cessation treatment (EBCT) program among rural adults. Methods This pilot trial used a pragmatic, three-arm, randomized, parallel-group design (ClinicalTrials.gov: NCT05209451). Inclusion criteria included being aged ≥18, Mayo Clinic Midwest patient, rural residency, and currently smokes cigarettes. All participants received an online, 12-week EBCT program and were randomized to receive one of three digital access interventions: print materials (control, n = 30); print materials + loaner iPad device with data plan coverage (n = 30); or print materials + loaner device + up to six, 15–20-minute motivational interviewing-based coaching calls to support technology needs (n = 30). A composite score of trial engagement (primary outcome) and self-reported smoking abstinence and use of EBCT resources (secondary outcomes) were assessed online at 4 and 12 weeks. Qualitative interviews were used to assess patient experience. Neither participants nor outcome assessors were blinded to group assignment. Results Results are reported for all 30 participants in each group. The average age of participants is 51.0 years and 61% are women. We show no significant arm differences for the trial engagement composite score (p = 0.30). We also find coaching support is significantly (p

Abstract Our affective states can influence whether we help others and after helping we often experience improved affect. One important factor determining whether we help, is the amount of effort involved. Using an ecological momentary assessment approach across two measurement bursts (N = 803; N = 303), we investigated the affective antecedents and consequences of everyday helping in terms of participants’ self-reported momentary stress and mood valence, with a specific focus on the perceived amount of effort involved. Regardless of the amount of effort involved in helping, participants reported more positive mood valence after helping across both measurement bursts. In burst 2, this mood boosting effect of helping was strongest in those reporting lower mood prior to helping. In burst 1, we found a bidirectional relationship between stress and helping effort: the greater the effort involved in helping, the greater the perceived stress both before and after helping. Contrary to our preregistered hypotheses, changes in stress or mood valence did not precede helping regardless of the amount of effort involved. Our results support previous work linking helping to enhanced mood but suggest that when helping is more effortful it is both preceded and followed by greater stress. These findings have important implications for fostering and sustaining prosocial behaviours, especially when effort is involved.

Abstract Promiscuous enzymes often serve as the starting point for the evolution of novel functions. Yet, the extent to which the promiscuity of an individual enzyme can be harnessed several times independently for different purposes during evolution is poorly reported. Here, we present a case study illustrating how NAD(P)+-dependent succinate semialdehyde dehydrogenase of Escherichia coli (Sad) is independently recruited through various evolutionary mechanisms for distinct metabolic demands, in particular vitamin biosynthesis and central carbon metabolism. Using adaptive laboratory evolution (ALE), we show that Sad can substitute for the roles of erythrose 4-phosphate dehydrogenase in pyridoxal 5’-phosphate (PLP) biosynthesis and glyceraldehyde 3-phosphate dehydrogenase in glycolysis. To recruit Sad for PLP biosynthesis and glycolysis, ALE employs various mechanisms, including active site mutation, copy number amplification, and (de)regulation of gene expression. Our study traces down these different evolutionary trajectories, reports on the surprising active site plasticity of Sad, identifies regulatory links in amino acid metabolism, and highlights the potential of an ordinary enzyme as innovation reservoir for evolution.

Abstract Volcano monitoring is constrained by the distribution of sensors that record activity. Here, we explore the role of crowdsourcing to broaden acoustic monitoring records by surveying people across Aotearoa New Zealand about the sounds they heard following the 2022 climactic eruption of Hunga volcano in Tonga. We compare the 1930 survey responses to geophysical records of the pressure waves and find that they align well, both recording ~5-7 audible signals of varying amplitude with a peak of 60-80 decibels, arriving in two 30-minute phases ~3 hours post-eruption, travelling North-to-South. The crowdsourced observations fill instrumental gaps regarding the wave’s audible frequencies and contribute insights into interactions between the far-field acoustic wave and the social and built environment. Descriptions of short-lived impacts reveal that pressure waves are capable of substantial disturbances thousands of kilometers from the vent. We demonstrate that crowdsourcing can support traditional monitoring as a reliable low-cost method to capture perishable data.

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.

Purpose: Diabetic macular edema (DME), a leading cause of visual impairment, can occur regardless of diabetic retinopathy (DR) stage. Poor metabolic control is hypothesized to contribute to DME development, although large-scale studies have yet to identify such an association. This study aims to determine whether measurable markers of dysmetabolism are associated with DME development in persons with diabetes. Design: Retrospective cohort study. Participants: Using data from the Sight Outcomes Research Collaborative (SOURCE) repository, patients with diabetes mellitus and no preexisting DME were identified and followed over time to see what factors associated with DME development. Methods: Cox proportional hazard modeling was used to assess the relationship between demographic variables, diabetes type, smoking history, baseline DR status, blood pressure (BP), lipid profile, body mass index (BMI), hemoglobin A1C (HbA1C), and new onset of DME. Main Outcome Measures: Adjusted hazard ratio (HR) of developing DME with 95% confidence intervals (CIs). Results: Of 47 509 eligible patients from 10 SOURCE sites (mean age 63 ± 12 years, 58% female sex, 48% White race), 3633 (7.6%) developed DME in the study period. The mean ± standard deviation time to DME was 875 ± 684 days (∼2.4 years) with those with baseline nonproliferative DR (HR 3.67, 95% CI: 3.41–3.95) and proliferative DR (HR 5.19, 95% CI: 4.61–5.85) more likely to develop DME. There was no difference in DME risk between type 1 and type 2 patients; however, Black race was associated with a 40% increase in DME risk (HR 1.40, 95% CI: 1.30–1.51). Every 1 unit increase in HbA1C had a 15% increased risk of DME (HR 1.15, 95% CI: 1.13–1.17), and each 10 mmHg increase in systolic BP was associated with a 6% increased DME risk (HR 1.06, 95% CI: 1.02–1.09). No association was identified between DME development and BMI, triglyceride levels, or high-density lipoprotein levels. Conclusions: These findings suggest that in patients with diabetes modifiable risk factors such as elevated HbA1C and BP confer a higher risk of DME development; however, other modifiable systemic markers of dysmetabolism such as obesity and dyslipidemia did not. Further work is needed to identify the underlying contributions of race in DME. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

In education testing, the items that examinees receive may be selected for a variety of reasons, resulting in missing data for items that were not selected. Item selection is internal when based on prior performance on the test, such as in adaptive testing designs or for branching items. Item selection is external when based on an auxiliary variable collected independently to performance on the test, such as education level in a targeting testing design or geographical location in a nonequivalent anchor test equating design. This paper describes the implications of this distinction for Item Response Theory (IRT) estimation, drawing upon missing-data theory (e.g., Mislevy & Sheehan, 1989, https://doi.org/10.1007/BF02296402; Rubin, 1976, https://doi.org/10.1093/biomet/63.3.581), and selection theory (Meredith, 1993, https://doi.org/10.1007/BF02294825). Through mathematical analyses and simulations, we demonstrate that this internal versus external item selection framework provides a general guide in applying missing-data and selection theory to choose a valid analysis model for datasets with missing data.

3D electron diffraction (3DED) is increasingly employed to determine molecular and crystal structures from micro-crystals. Indomethacin is a well known, marketed, small-molecule non-steroidal anti-inflammatory drug with eight known polymorphic forms, of which four structures have been elucidated to date. Using 3DED, we determined the structure of a new ninth polymorph, σ, found within an amorphous solid dispersion, a product formulation sometimes used for active pharmaceutical ingredients with poor aqueous solubility. Subsequently, we found that σ indomethacin can be produced from direct solvent evaporation using dichloromethane. These results demonstrate the relevance of 3DED within drug development to directly probe product formulations.