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Communicating risks and mitigation benefits associated with natural hazards such as wind to the general public is challenging given the location-dependency of parameters and the complexity of the problem. Web tools play a crucial role in educating residents, decision-makers, and stakeholders regarding potential wind hazard losses to, for example, residential buildings.However, a notable gap exists on the practical incorporation of mitigation actions within these tools. This gap hampers the collective awareness and understanding among stakeholders, communities, and citizens regarding the tangible advantages of mitigation strategies in reducing wind-related risks. Furthermore, there exists a need to elucidate the functionality and objectives of these tools in a more accessible manner. This study aims to present and outline the wind risk and mitigation calculator tool (WRMCT) within the Hazardaware platform, which is an address-based risk assessment tool. This tool, developed for 196 counties in the Gulf of Mexico coastal area, facilitates users' education of potential risks and benefits associated with mitigation strategies. WRMCT enables users to access location-specific wind risk and interactively suggests potential mitigation actions along with economic savings to support informed decisions and residential risk reduction. WRMCT intends to enhance users’ ability to make informed decisions, take proactive measures in mitigating wind hazards, and contribute to the development of resilient, residential communities.

Abstract Internal tandem duplications (ITD) in fms-like tyrosine kinase 3 (FLT3) represent the most common genetic alteration in de novo acute myeloid leukemia (AML). Here, we identify ribosomal protein s6 kinase a1 (RSK1) as a core dependency in FLT3-ITD AML and unveil the existence of crucial bi-directional regulation. RSK1 perturbation resulted in marked apoptosis and abrogated phosphorylation of FLT3 and associated downstream signaling cascades in FLT3-ITD AML cell lines. Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Importantly, multivariate analysis revealed heightened expression of RPS6KA1 and USP1 to be associated with poor patient prognosis, and these effectors may serve as biomarkers predictive of patient survival and therapeutic response to FLT3-ITD inhibitors. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic Flt3 ITD Tet2 KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia.

Abstract Background Biological evidence suggests ursodeoxycholic acid (UDCA)—a common treatment of cholestatic liver disease—may prevent severe COVID-19 outcomes. We aimed to compare the hazard of COVID-19 hospitalisation or death between UDCA users versus non-users in a population with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). Methods With the approval of NHS England, we conducted a population-based cohort study using primary care records between 1 March 2020 and 31 December 2022, linked to death registration data and hospital records through the OpenSAFELY-TPP platform. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between time-varying UDCA exposure and COVID-19 related hospitalisation or death, stratified by geographical region and considering models unadjusted and fully adjusted for pre-specified confounders. Results We identify 11,305 eligible individuals, 640 were hospitalised or died with COVID-19 during follow-up, 400 (63%) events among UDCA users. After confounder adjustment, UDCA is associated with a 21% relative reduction in the hazard of COVID-19 hospitalisation or death (HR 0.79, 95% CI 0.67–0.93), consistent with an absolute risk reduction of 1.35% (95% CI 1.07%–1.69%). Conclusions We found evidence that UDCA is associated with a lower hazard of COVID-19 related hospitalisation and death, support calls for clinical trials investigating UDCA as a preventative measure for severe COVID-19 outcomes.

Abstract Acute mountain sickness (AMS) is a well‐studied illness defined by clinical features (e.g., headache and nausea), as assessed by the Lake Louise score (LLS). Although obvious in its severe form, early stages of AMS are poorly defined and easily confused with common travel‐related conditions. Measurement of hypoxaemia, the cause of AMS, should be helpful, yet to date its utility for identifying AMS susceptibility remains unclear. This study quantified altitude‐induced hypoxaemia in individuals during an ascent to 4800 m to determine the utility of nocturnal pulse oximetry measurements for prediction of AMS. Eighteen individuals (36 ± 16 years of age) ascended to 4800 m over 12 days. Symptomology of AMS was assessed each morning via LLS criteria, with participants categorized as either AMS‐positive (LLS ≥ 3 with headache) or AMS‐negative. Overnight peripheral oxygen saturations (ov‐SpO2) were recorded continuously (1 Hz) using portable oximeters. Derivatives of these recordings were compared between AMS‐positive and ‐negative subjects (Mann–Whitney U‐test). Exploratory analyses (Pearson's) were conducted to investigate relationships between overnight parameters and AMS severity. Overnight derivatives, including ov‐SpO2, heart rate/ov‐SpO2, variance, oxygen desaturation index, hypoxic burden and total sleep time at

Objectives: Hybrid stage I palliation has been used in many clinical scenarios including initial palliation in single ventricle heart disease, a bridge to biventricular repair, a bridge to transplant, and as a destination therapy. There is considerable hybrid stage I palliation practice variation, which we aimed to better understand in this study. Methods: Survey-based assessment of practice variation related to hybrid stage I palliation was sent to congenital heart centers across the United States and Canada. Results: Of the 106 centers surveyed, responses were received from 54 centers (50.9%). Of respondents, 45 centers perform hybrid stage I palliation. Centers most commonly (97.7%) perform hybrid stage I palliation on “high-risk” patients with single ventricle heart disease. Regarding the technical aspects of hybrid stage I palliation, most centers (95.3%) accomplish restrictive pulmonary blood flow using pulmonary artery bands and primarily use changes in oxygen saturation (34.1%) to identify appropriate restriction. Ductal stents are most often used (67.4%) to maintain ductal patency. Only 10 centers (23.3%) routinely enlarge the atrial septal defect. Indications for atrial septal defect intervention varied widely. Most centers (71.9%) discharge patients home to follow with a formal “interstage” program. Conclusions: There is significant variation in practice patterns for hybrid stage I palliation indications, technical aspects, and postoperative care. Therefore, generalizability of single-center studies on outcomes after hybrid stage I palliation is limited. Future multicenter studies are needed to best delineate which patients benefit most from hybrid stage I palliation and to further define optimal approaches to caring for these patients.

Abstract Surveys often estimate vaccination intentions using dichotomous ("Yes"/"No") or trichotomous ("Yes," "Unsure," "No") response options presented in different orders. Do survey results depend on these variations? This controlled experiment randomized participants to dichotomous or trichotomous measures of vaccine intentions (with “Yes” and “No” options presented in different orders). Intentions were measured separately for COVID-19, its booster, and influenza vaccines. Among a sample of U.S. adults (N = 4,764), estimates of vaccine intention varied as much as 37.5 ± 17.4 percentage points as a function of the dichotomous or trichotomous response set. Among participants who had not received the COVID-19 vaccine, the “Unsure” option was more likely to reduce the share of “No” (versus “Yes”) responses, whereas among participants who had received the COVID-19 vaccine, the “Unsure” option was more likely to reduce the share of “Yes” (versus “No”) responses. The “Unsure” category may increase doubt and decrease reliance on past vaccination behavior when forming intentions. The order of “Yes” and “No” responses had no significant effect. Future research is needed to further evaluate why the effects of including the “Unsure” option vary in direction and magnitude.

Abstract The use of acute carbon monoxide inhalation (COi) and hot water immersion (HWI) are of growing interest as interventions to stimulate erythropoietin (EPO) production. However, whether EPO production is further augmented when combining these stressors and whether there are sex differences in this response are poorly understood. Therefore, we measured circulating EPO concentration in response to acute COi and HWI independently and in combination and determined whether the responses were altered by sex. Participants completed three study visits—COi, HWI, and combined COi and HWI—separated by 1 week in a randomized, balanced, crossover design. Renal blood velocity was measured during all interventions, and carboxyhaemoglobin was measured during and after COi. Serum samples were analysed every hour for 6 h post‐intervention for EPO concentration. HWI decreased renal blood velocity (46.2 cm/s to 36.2 cm/s) (P

Abstract Neonatal dilated cardiomyopathy (DCM) is a poorly understood muscular disease of the heart. Several homozygous biallelic variants in LMOD2, the gene encoding the actin-binding protein Leiomodin 2, have been identified to result in severe DCM. Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death. Thus, it is evident that Lmod2 is essential to normal human cardiac muscle function. This study aimed to understand the underlying pathophysiology and signaling pathways related to the first reported LMOD2 variant (c.1193 G > A, p.Trp398*). Using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model harboring the homologous mutation to the patient, we discovered dysregulated actin-thin filament lengths, altered contractility and calcium handling properties, as well as alterations in the serum response factor (SRF)-dependent signaling pathway. These findings reveal that LMOD2 may be regulating SRF activity in an actin-dependent manner and provide a potential new strategy for the development of biologically active molecules to target LMOD2-related cardiomyopathies.

The Holocene La Taza andesitic volcano is one of over 1000 volcanic centers located within the Michoacán-Guanajuato Volcanic Field (MGVF) in central-western Mexico. La Taza (~8500–8200 yr BP) represents one possible eruption style within the field, with deposits indicating Strombolian activity followed by a series of lava flows. In our study, we reconstruct the eruption of La Taza through a combination of LiDAR mapping and petrological and geochemical analyses. LiDAR mapping combined with ground- truthing in the field allowed us to differentiate and determine the sequence of the volcano’s lava flows, revealing seven lava flows with a volume of ~0.6 km3. This morphological information was paired with geothermobarometers to estimate lava flow viscosities, mean effusion rates, and emplacement times, showing a likely duration of 1.1–4.3 years. Recreating this eruption contributes to the understanding of potential durations and lava flow rheology of future MGVF eruptions, crucial characteristics for hazard planning and mitigation.

To assess the current real-world applications of machine learning (ML) and artificial intelligence (AI) as functionality of digital behavior change interventions (DBCIs) that influence patient or consumer health behaviors. A scoping review was done across the EMBASE, PsycInfo, PsycNet, PubMed, and Web of Science databases using search terms related to ML/AI, behavioral science, and digital health to find live DBCIs using ML or AI to influence real-world health behaviors in patients or consumers. A total of 32 articles met inclusion criteria. Evidence regarding behavioral domains, target real-world behaviors, and type and purpose of ML and AI used were extracted. The types and quality of research evaluations done on the DBCIs and limitations of the research were also reviewed. Research occurred between October 9, 2023, and January 20, 2024. Twenty-three DBCIs used AI to influence real-world health behaviors. Most common domains were cardiometabolic health (n=5, 21.7%) and lifestyle interventions (n=4, 17.4%). The most common types of ML and AI used were classical ML algorithms (n=10, 43.5%), reinforcement learning (n=8, 34.8%), natural language understanding (n=8, 34.8%), and conversational AI (n=5, 21.7%). Evidence was generally positive, but had limitations such as inability to detect causation, low generalizability, or insufficient study duration to understand long-term outcomes. Despite evidence gaps related to the novelty of the technology, research supports the promise of using AI in DBCIs to manage complex input data and offer personalized, contextualized support for people changing real-world behaviors. Key opportunities are standardizing terminology and improving understanding of what ML and AI are.

Abstract Introduction Psoriatic arthritis (PsA) is a chronic inflammatory disease requiring long-term treatment. Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated tolerability and sustained clinical efficacy for up to 1 year for patients with PsA. Here, we report the longer-‍term safety and efficacy of bimekizumab up to 2 years. Methods BE OPTIMAL (biologic disease-modifying antirheumatic drug [bDMARD]-naïve) and BE COMPLETE (prior inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi-IR]) assessed subcutaneous bimekizumab 160 mg every 4 weeks in patients with PsA. BE OPTIMAL included a reference arm (adalimumab 40 mg every 2 weeks); patients switched to bimekizumab at week 52 with no washout between treatments. BE OPTIMAL week 52 and BE COMPLETE week 16 completers were eligible for the BE VITAL open-label extension. Efficacy outcomes are reported to week 104/100 (BE OPTIMAL/BE COMPLETE). Results A total of 710/852 (83.3%) bDMARD-naïve and 322/400 (80.5%) TNFi-IR patients completed week 104/100. Up to 104 weeks, patients treated with bimekizumab in BE OPTIMAL and BE COMPLETE had treatment-emergent adverse event incidence rates (exposure-adjusted incidence rate/100 patient-years) of 179.9 (95% CI 166.9, 193.7) and 100.3 (89.2, ‍112.4), respectively. The proportion of patients achieving efficacy outcomes (≥ 50% improvement from baseline in American College of Rheumatology [ACR] response criteria, 100% improvement from baseline in Psorisis Area and Severity Index [PASI], minimal disease activity [MDA]) was sustained in all patients from week 52 to week 104/100. Conclusions Bimekizumab was well tolerated for up to 2 years of treatment and no new safety signals were observed. Sustained clinical efficacy was observed up to 2 years in bDMARD-naïve and TNFi-IR patients with active PsA. Patients switching from adalimumab to bimekizumab demonstrated further improvement in skin and nail symptoms, and sustained efficacy in joint symptoms. Trial Registration BE OPTIMAL (NCT03895203), BE COMPLETE (NCT03896581), BE VITAL (NCT04009499).

Abstract Physical neuromorphic computing, exploiting the complex dynamics of physical systems, has seen rapid advancements in sophistication and performance. Physical reservoir computing, a subset of neuromorphic computing, faces limitations due to its reliance on single systems. This constrains output dimensionality and dynamic range, limiting performance to a narrow range of tasks. Here, we engineer a suite of nanomagnetic array physical reservoirs and interconnect them in parallel and series to create a multilayer neural network architecture. The output of one reservoir is recorded, scaled and virtually fed as input to the next reservoir. This networked approach increases output dimensionality, internal dynamics and computational performance. We demonstrate that a physical neuromorphic system can achieve an overparameterised state, facilitating meta-learning on small training sets and yielding strong performance across a wide range of tasks. Our approach’s efficacy is further demonstrated through few-shot learning, where the system rapidly adapts to new tasks.

Abstract Global demand for food is expected to nearly double by 2050. Alternative proteins (AP) have been proposed as a sustainable solution to provide food security as natural resources become more depleted. However, the growth and consumer intake of AP remains limited. This review aims to better understand the challenges and environmental impacts of four main AP categories: plant-based, insect-based, microbe-derived, and cultured meat and seafood. The environmental benefits of plant-based and insect-based proteins have been documented but the impacts of microbe-derived proteins and cultured meat have not been fully assessed. The development of alternative products with nutritional and sensory profiles similar to their conventional counterparts remains highly challenging. Furthermore, incomplete safety assessments and a lack of clear regulatory guidelines confuse the food industry and hamper progress. Much still needs to be done to fully support AP utilization within the context of supporting the drive to make the global food system sustainable.

Objective: We examined the effect of frailty on in-hospital mortality, readmission rates, and hospitalization costs after transcatheter and surgical aortic valve replacement in a population-level cohort. Methods: The Nationwide Readmissions Database was queried for patients who underwent transcatheter or surgical aortic valve replacement during 2016-2018. Multivariate logistic regression was used to discern independent effects of frailty on outcomes. Kaplan–Meier time-to-event analysis was used to evaluate the effect of frailty on freedom from readmission. Results: A total of 243,619 patients underwent aortic valve replacement: 142,786 (58.6%) transcatheter aortic valve replacements and 100,833 (41.4%) surgical aortic valve replacements. Frail patients constituted 16,388 (11.5%) and 7251 (7.2%) in the transcatheter aortic valve replacement and surgical aortic valve replacement cohorts, respectively. Compared with nonfrail patients, frail patients had greater in-hospital mortality (transcatheter aortic valve replacement: 3.2% vs 1.1%; surgical aortic valve replacement: 6.1% vs 2.0%; both P

Abstract Methods to quantify cortical hyperexcitability are of enormous interest for mapping epileptic networks in patients with focal epilepsy. We hypothesize that, in the resting state, cortical hyperexcitability increases firing-rate correlations between neuronal populations within seizure onset zones (SOZs). This hypothesis predicts that in the gamma frequency band (40–200 Hz), amplitude envelope correlations (AECs), a relatively straightforward measure of functional connectivity, should be elevated within SOZs compared to other areas. To test this prediction, we analyzed archived samples of interictal electrocorticographic (ECoG) signals recorded from patients who became seizure-free after surgery targeting SOZs identified by multiday intracranial recordings. We show that in the gamma band, AECs between nodes within SOZs are markedly elevated relative to those elsewhere. AEC-based node strength, eigencentrality, and clustering coefficient are also robustly increased within the SOZ with maxima in the low-gamma band (permutation test Z-scores > 8) and yield moderate discriminability of the SOZ using ROC analysis (maximal mean AUC ~ 0.73). By contrast to AECs, phase locking values (PLVs), a measure of narrow-band phase coupling across sites, and PLV-based graph metrics discriminate the seizure onset nodes weakly. Our results suggest that gamma band AECs may provide a clinically useful marker of cortical hyperexcitability in focal epilepsy.

Abstract Cerebral dopamine neurotrophic factor (CDNF) and its close structural relative, mesencephalic astrocyte-derived neurotrophic factor (MANF), are proteins with neurotrophic properties. CDNF protects and restores the function of dopamine (DA) neurons in rodent and non-human primate (NHP) toxin models of Parkinson’s disease (PD) and therefore shows promise as a drug candidate for disease-modifying treatment of PD. Moreover, CDNF was found to be safe and to have some therapeutic effects on PD patients in phase 1/2 clinical trials. However, the mechanism underlying the neurotrophic activity of CDNF is unknown. In this study, we delivered human CDNF (hCDNF) to the brain using an adeno-associated viral (AAV) vector and demonstrated the neurotrophic effect of AAV-hCDNF in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. AAV-hCDNF resulted in the expression of hCDNF in the striatum (STR) and substantia nigra (SN), and no toxic effects on the nigrostriatal pathway were observed. Intrastriatal injection of AAV-hCDNF reduced motor impairment and partially alleviated gait dysfunction in the acute MPTP mouse model. In addition, gene therapy with AAV-hCDNF had significant neuroprotective effects on the nigrostriatal pathway and decreased the levels of interleukin 1beta (IL-1β) and complement 3 (C3) in glial cells in the acute MPTP mouse model. Moreover, AAV-hCDNF reduced C/EBP homologous protein (CHOP) and glucose regulatory protein 78 (GRP78) expression in astroglia. These results suggest that the neuroprotective effects of CDNF may be mediated at least in part through the regulation of neuroinflammation and the UPR pathway in a mouse MPTP model of PD in vivo.

Abstract Commensal relationships between wild plants and their dispersers play a key ecological and evolutionary role in community structure and function. While non-human dispersers are often considered critical to plant recruitment, human dispersers have received much less attention, especially when it comes to non-domesticated plants. Australia, as a continent historically characterized by economies reliant on non-domesticated plants, is thus a key system for exploring the ecological role of people as seed dispersers in the absence of agriculture. Here, we utilize a controlled observation research design, employing ecological surveys and ethnographic observations to examine how seed dispersal and landscape burning by Martu Aboriginal people affects the distribution of three preferred plants and one (edible, but non-preferred) control species. Using an information theoretic approach, we find that the three preferred plants show evidence of human dispersal, with the strongest evidence supporting anthropogenic dispersal for the wild bush tomato, Solanum diversiflorum.

Here, the novel technique of extended-range high-energy-resolution fluorescence detection (XR-HERFD) has successfully observed the n = 2 satellite in manganese to a high accuracy. The significance of the satellite signature presented is many hundreds of standard errors and well beyond typical discovery levels of three to six standard errors. This satellite is a sensitive indicator for all manganese-containing materials in condensed matter. The uncertainty in the measurements has been defined, which clearly observes multiple peaks and structure indicative of complex physical quantum-mechanical processes. Theoretical calculations of energy eigenvalues, shake-off probability and Auger rates are also presented, which explain the origin of the satellite from physical n = 2 shake-off processes. The evolution in the intensity of this satellite is measured relative to the full Kα spectrum of manganese to investigate satellite structure, and therefore many-body processes, as a function of incident energy. Results demonstrate that the many-body reduction factor S02 should not be modelled with a constant value as is currently done. This work makes a significant contribution to the challenge of understanding many-body processes and interpreting HERFD or resonant inelastic X-ray scattering spectra in a quantitative manner.

Background: Patients with partial thickness rotator cuff tears (PTRCTs) often present with concurrent pathology of the long head of the biceps tendon (LHBT). To address both conditions simultaneously, long head of the biceps (LHB) tenotomy or tenodesis can be performed at the time of arthroscopic rotator cuff repair (RCR). This study aims to compare postoperative shoulder active range of motion (AROM) and complications following transtendinous RCR with concurrent LHB tenodesis or tenotomy. Methods: A total of 90 patients with PTRCTs met inclusion criteria for this study. Patients who underwent tear-completion-and-repair, revision surgery, or open repair of the LHB tendon were excluded. Patients were stratified into tenotomy, arthroscopic suprapectoral tenodesis, or no biceps operation cohorts and were propensity matched 1:1:1 on age, sex, body mass index, and smoking status. Primary outcome measures included AROM in forward flexion, abduction, external rotation, and internal rotation at 6 weeks, 3 months, and 6 months postoperatively. The development of severe stiffness and rates of rotator cuff retear at final follow-up were recorded as secondary outcomes. Results: When comparing the tenotomy and tenodesis cohorts, tenotomy patients were found to have increased AROM at 3 months in forward flexion (153.2° vs. 130.1°, P = .004), abduction (138.6° vs. 114.2°, P = .019), and external rotation (60.4° vs. 43.8°, P = .014), with differences in forward flexion remaining significant at 6 months (162.4° vs. 149.4°, P = .009). There were no significant differences in interval rates of recovery in any plane between cohorts. Additionally, there were no significant differences in rates of symptomatic retears between groups (P = .458). Rates of severe postoperative stiffness approached but did not achieve statistical significance between tenotomy (4.2%) and tenodesis (29.2%) cohorts (P = .066). Smoking status was a significant predictor of severe stiffness (odds ratio, 13.69; P = .010). Conclusion: Despite significant differences in absolute AROM between cohorts, the decision to perform tenotomy or tenodesis was not found to differentially affect rates of AROM recovery for patients undergoing arthroscopic transtendinous RCR for PTRCT. Notably, however, transient stiffness complications were more commonly observed in smokers, and data trends suggested an increased risk of stiffness for patients undergoing LHB tenodesis. Overall, postoperative stiffness is likely multifactorial and attributable to both patient- and procedure-specific factors, and LHB tenotomy may be more appropriate for patients with risk factors for developing stiffness postoperatively.

Background: The ligamentous and osseous structures of the elbow joint are the major contributors to its inherent stability and damage to any of these structures can result in elbow instability. The aim of this study is to present objective and subjective outcomes following ligament repairs and/or reconstructions for acute elbow instability and chronic elbow instability. Methods: This study included patients who underwent an elbow ligament repair and/or reconstruction for acute or chronic elbow instability. We performed a comprehensive retrospective data analysis of the patient's files, followed by a clinical examination and X-ray of these patients. Results: We identified 12 acute stabilizations and 22 stabilizations for chronic instability. Patients who underwent stabilization for chronic instability had statistically significant improvements in their preoperative flexion and extension; 14.8 ± 6.4° and 5.9 ± 2.5°. Patients with chronic instability achieved better extension-flexion and pronation-supination arcs compared with their acute instability counterparts and this reached statistical significance. When the elbow pain and function scores were compared, we found stabilizations in the acute setting had better outcomes. There were two cases of postoperative instability, one in the acute instability group and one in the chronic instability group. Conclusion: This study provides evidence for elbow ligament repairs and reconstructions in both acute and chronic settings. It is an effective way of stabilizing the elbow joint in chronic instability patients, and results in an improvement in their overall range of motion. These patients achieved a greater range of motions compared with their acute instability counterparts.

On March 11th 2020, the World Health Organization characterised COVID-19 as a pandemic. Responses to containing the spread of the virus have relied heavily on policies involving restricting contact between people. Evolving policies regarding shielding and individual choices about restricting social contact will rely heavily on perceived risk of poor outcomes from COVID-19. In order to make informed decisions, both individual and collective, good predictive models are required. For outcomes related to an infectious disease, the performance of any risk prediction model will depend heavily on the underlying prevalence of infection in the population of interest. Incorporating measures of how this changes over time may result in important improvements in prediction model performance. This protocol reports details of a planned study to explore the extent to which incorporating time-varying measures of infection burden over time improves the quality of risk prediction models for COVID-19 death in a large population of adult patients in England. To achieve this aim, we will compare the performance of different modelling approaches to risk prediction, including static cohort approaches typically used in chronic disease settings and landmarking approaches incorporating time-varying measures of infection prevalence and policy change, using COVID-19 related deaths data linked to longitudinal primary care electronic health records data within the OpenSAFELY secure analytics platform.

Introduction: Left-sided gallbladder (LSG) is a rare anatomic variant in the pediatric population where the gallbladder lies to the left of the round ligament. The diagnosis of LSG is often made intraoperatively as preoperative imaging has poor sensitivity for detection. As LSG is also associated with biliary and vascular anatomic variation, lack of familiarity with these anatomic variants can lead to higher rates of bleeding and bile duct injury. Case presentation: A 17-year-old previously healthy male with history of scoliosis and sickle cell trait was referred for surgical management of symptomatic cholelithiasis. The patient had presented with multiple transient episodes of severe epigastric pain and nausea with ultrasound findings of cholelithiasis. There was no comment on the ultrasound report of any anatomic variation or abnormal location of the gallbladder. However, review of the imaging demonstrated a gallbladder that was situated on the left side of the liver and medial to ligamentum teres hepatis (round ligament). During the laparoscopic cholecystectomy, we confirmed that the gallbladder was located to the left of the round ligament and inferior to segment III of the liver. A retrograde top-down approach was utilized to clearly delineate the cystic artery and duct. The cystic artery was identified by its entry point into the gallbladder crossing anterior to the common bile duct in a right-to-left fashion. The cystic duct was identified and noted to drain into the right-side of the common hepatic duct. Due to clear delineation of the gallbladder anatomy with this approach, intraoperative cholangiography or fluorescence cholangiography were not utilized. He was discharged on postoperative day one without any complications. Conclusion: LSG is associated with biliary and vascular anomalies, which may lead to intraoperative complications. Therefore, the biliary anatomy should be clearly elucidated prior to proceeding with cholecystectomy in cases of LSG.

IntroductionIn the biological sciences, many areas of uncertainty exist regarding the factors that contribute to success within the faculty job market. Earlier work from our group reported that beyond certain thresholds, academic and career metrics like the number of publications, fellowships or career transition awards, and years of experience did not separate applicants who received job offers from those who did not. Questions still exist regarding how academic and professional achievements influence job offers and if candidate demographics differentially influence outcomes.MethodsTo continue addressing these gaps, we initiated surveys collecting data from faculty applicants in the biological sciences field for three hiring cycles in North America (Fall 2019 to the end of May 2022), a total of 449 respondents were included in our analysis.Results and discussionThese responses highlight the interplay between various scholarly metrics, extensive demographic information, and hiring outcomes, and for the first time, allowed us to look at persons historically excluded due to ethnicity or race (PEER) status in the context of the faculty job market. Between 2019 and 2022, we found that the number of applications submitted, position seniority, and identifying as a women or transgender were positively correlated with a faculty job offer. Applicant age, residence, first generation status, and number of postdocs, however, were negatively correlated with receiving a faculty job offer. Our data are consistent with other surveys that also highlight the influence of achievements and other factors in hiring processes. Providing baseline comparative data for job seekers can support their informed decision-making in the market and is a first step toward demystifying the faculty job market.

Abstract Understanding the interaction between Mars and the solar wind is crucial for comprehending the atmospheric evolution and climate change on Mars. To gain a comprehensive understanding of the Martian plasma environment, global numerical simulations are essential in addition to spacecraft observations. However, there are still discrepancies among different simulation models. This study investigates how these discrepancies stem from the considered physical processes and numerical implementations. We compare two global multispecies MHD models: the “Sun model” based on the BATS‐R‐US code and the “Sakata model” based on a newly developed multifluid model MAESTRO. By employing the same typical upstream conditions and the same neutral atmosphere for current Mars, along with similar numerical implementations such as inner boundary conditions, we obtain simulation results that exhibit unprecedented agreement between the two models. The dayside results are nearly identical, especially along the subsolar line, indicating the robustness of MHD models to predict dayside interaction under given upstream conditions and ionosphere assumptions. The escape rates of planetary ions are also in good agreement. However, discrepancies remain in the terminator and nightside regions. Detailed numerical implementations, including inner boundary conditions, magnetic field divergence control methods, and radial resolutions, are shown to influence certain aspects of the results greatly, such as magnetotail configuration and ion diffusion.

Mitochondrial membranes are defined by their diverse functions, complex geometries, and unique lipidomes. In the inner mitochondrial membrane, highly curved membrane folds known as cristae house the electron transport chain and are the primary sites of cellular energy production. The outer mitochondrial membrane is flat by contrast, but is critical for the initiation and mediation of processes key to mitochondrial physiology: mitophagy, interorganelle contacts, fission and fusion dynamics, and metabolite transport. While the lipid composition of both the inner mitochondrial membrane and outer mitochondrial membrane have been characterized across a variety of cell types, a mechanistic understanding for how individual lipid classes contribute to mitochondrial structure and function remains nebulous. In this review, we address the biophysical properties of mitochondrial lipids and their related functional roles. We highlight the intrinsic curvature of the bulk mitochondrial phospholipid pool, with an emphasis on the nuances surrounding the mitochondrially-synthesized cardiolipin. We also outline emerging questions about other lipid classes — ether lipids, and sterols — with potential roles in mitochondrial physiology. We propose that further investigation is warranted to elucidate the specific properties of these lipids and their influence on mitochondrial architecture and function.

Abstract Little is known about the catastrophic bushfire from a micro‐pollution point of view, and there is also very limited understanding of the emerging contamination of microplastics and nanoplastics. Upon exposure to fire, plastic items, such as water tanks, may release a substantial quantity of microplastics and nanoplastics, as characterized in this study through the analysis of residual debris. Using Raman imaging with the scanning pixel size down to 100 nm × 100 nm, we over‐scan the sample surface to collect a hyperspectral matrix. In order to map and convert the scanning hyperspectral matrix to an image, we compare and advance the chemometrics of algorithms, including logic and principal component analysis (PCA), to extract the weak signal of microplastics and particularly nanoplastics, which enables us to directly visualize the different degrees of burning. By doing so, we can identify the microplastics and nanoplastics down to ˜100 nm, which means that we can break through the diffraction limit of the laser which is ˜296 nm (λ/2NA) to capture nanoplastics. Using statistical analysis, we estimate that 1.4–4.7 million micro‐ and nanoplastics per cm2 can be left behind by the mimicked‐bushfire‐burned plastic tank. This study suggests that bushfire can accelerate the release of micro‐ and nanoplastics in the environment. This study not only contributes essential insights into the micro‐pollution consequences of fire burning but also underscores the urgency of addressing this understudied aspect to inform environmental conservation strategies and public health measures.

Abstract During the COVID-19 pandemic, the Province of Ontario, Canada, launched a wastewater surveillance program to monitor SARS-CoV-2, inspired by the early work and successful forecasts of COVID-19 waves in the city of Ottawa, Ontario. This manuscript presents a dataset from January 1, 2021, to March 31, 2023, with RT-qPCR results for SARS-CoV-2 genes and PMMoV from 107 sites across all 34 public health units in Ontario, covering 72% of the province’s and 26.2% of Canada’s population. Sampling occurred 2–7 times weekly, including geographical coordinates, serviced populations, physico-chemical water characteristics, and flowrates. In doing so, this manuscript ensures data availability and metadata preservation to support future research and epidemic preparedness through detailed analyses and modeling. The dataset has been crucial for public health in tracking disease locally, especially with the rise of the Omicron variant and the decline in clinical testing, highlighting wastewater-based surveillance’s role in estimating disease incidence in Ontario.

Abstract Introduction There has been a rapid expansion in the use of point-of-care ultrasonography (POCUS) by emergency medical services (EMS). However, less than a third of UK EMS utilise imaging archiving for POCUS, and fewer review saved images as part of a clinical governance structure. This paper describes the implementation of a novel image archiving system and a robust clinical governance framework in our UK physician-paramedic staffed helicopter emergency medical service (HEMS). Methods A retrospective database review was conducted of all patients attended by East Anglian Air Ambulance (EAAA) between the introduction of a new POCUS device and image archiving system on 1 December 2020 to 31 January 2024. All patients with recorded POCUS examinations were included. Images from POCUS examinations at EAAA are archived on a cloud-based server, and retrospectively reviewed within 24 h by an EAAA POCUS supervisor. Image quality is graded using a 5-point Likert-type scale, agreement between reviewer and clinician is recorded and feedback is provided on scanning technique. T-tests were used to assess the difference in image quality between physicians and paramedics. Inter-rater reliability between reviewers and clinicians was assessed using Cohen’s kappa (κ). Results During the study period, 5913 patients were attended by EAAA. Of these, 1097 patients had POCUS images recorded. The prevalence of POCUS during the study period was 18.6%. 1061 patient examinations underwent quality assurance (96.7%). The most common POCUS examination was echocardiography (60%), predominantly during cardiac arrest. The primary scanning clinician was a paramedic in 25.4% of POCUS examinations. Across all examination types; image quality was not significantly different between physicians and paramedics and agreement between reviewers and clinicians was strong (κ > 0.85). Conclusions In this service evaluation study, we have described outcomes following the introduction of a new POCUS device, image archiving system and governance framework in our HEMS. Paramedics were the primary scanning clinician in a quarter of scans, with image quality comparable to physicians. Almost all scans underwent quality assurance and inter-rater reliability was strong between clinicians and reviewers. Further research is required to investigate the diagnostic accuracy of POCUS and to demonstrate the effect of utilising prehospital POCUS to refine diagnosis on clinical outcomes.

Adult-onset diabetes increases one’s risk of neurodegenerative disease including Alzheimer’s disease (AD); however, the risk associated with youth-onset diabetes (Y-DM) remains underexplored. We quantified plasma biomarkers of neurodegeneration and AD in participants with Y-DM from the SEARCH cohort at adolescence and young adulthood (Type 1, n = 25; Type 2, n = 25; 59% female; adolescence, age = 15 y/o [2.6]; adulthood, age = 27.4 y/o [2.2]), comparing them with controls (adolescence, n = 25, age = 14.8 y/o [2.7]; adulthood, n = 21, age = 24.9 y/o [2.8]). Plasma biomarkers, including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), and amyloid beta (Aβ40, Aβ42), were measured via Simoa. A subset of participants (n = 7; age = 27.5 y/o [5.7]) and six controls (age = 25.1 y/o [4.5]) underwent PET scans to quantify brain amyloid and tau densities in AD sensitive brain regions. Y-DM adolescents exhibited lower plasma levels of Aβ40, Aβ42, and GFAP, and higher pTau181 compared to controls (p < 0.05), a pattern persisting into adulthood (p < 0.001). All biomarkers showed significant increases from adolescence to adulthood in Y-DM (p < 0.01), though no significant differences in brain amyloid or tau were noted between Y-DM and controls in adulthood. Preliminary evidence suggests that preclinical AD neuropathology is present in young people with Y-DM, indicating a potential increased risk of neurodegenerative diseases.

Abstract Background Tumor necrosis factor inhibitors (TNFi) are frequently chosen as the first biologic for patients with psoriatic arthritis (PsA). Given that many patients with PsA are TNFi inadequate responders (TNF-IR; either inadequate efficacy or intolerance), treatments utilizing alternative mechanisms of action are needed. In phase 3 studies, the fully human interleukin (IL)-23p19 subunit-inhibitor, guselkumab, was efficacious in patients with active PsA, including TNFi-IR. Efficacy was generally consistent between TNFi-naïve and TNFi-experienced cohorts; however, in the latter, higher response rates have been observed with the Q4W dosing regimen relative to the Q8W dosing regimen for some endpoints, suggesting the need to evaluate whether more frequent dosing may provide an incremental clinical benefit for TNFi-IR patients. Methods The phase 3b SOLSTICE study will assess guselkumab efficacy and safety in TNFi-IR PsA patients. Eligibility criteria include a PsA diagnosis for ≥ 6 months; active disease (≥ 3 swollen, ≥ 3 tender joints, C-reactive protein ≥ 0.3 mg/dL); and inadequate efficacy with, and/or intolerance to, one prior TNFi. Participants will be randomized 1:1:1 to guselkumab Q4W or Q8W or placebo→guselkumab Q4W (at Week 24). The primary endpoint is the proportion of patients achieving ≥ 20% improvement in the American College of Rheumatology criteria (ACR20) at Week 24. Major secondary endpoints include ACR50, ACR70; an Investigator’s Global Assessment (IGA) of psoriasis score of 0/1 plus ≥ 2-grade reduction and ≥ 90% improvement in Psoriasis Area and Severity Index (both among patients with ≥ 3% body surface area affected by psoriasis and baseline IGA ≥ 2); minimal/very low disease activity; and changes from baseline in Health Assessment Questionnaire-Disability Index, the 36-item Short-Form Health Survey Physical Component Summary, and Functional Assessment of Chronic Illness Therapy-Fatigue scores. The target sample size (N = 450) is estimated to provide > 90% power in detecting differences between each guselkumab group and the placebo group for the primary endpoint assuming a 2-sided α = 0.05. Cochran-Mantel–Haenszel testing and analyses of covariance will be used to compare efficacy for binary and continuous endpoints, respectively. Discussion Findings from the phase 3b SOLSTICE study, the design of which was informed by results from previously conducted phase 3 studies, is expected to provide important efficacy and safety information on guselkumab therapy in TNFi-IR patients with PsA. Trial registration This trial was registered at ClinicalTrials.gov, NCT04936308, on 23 June 2021.

Abstract Neuroferritinopathy is a disorder of neurodegeneration with brain iron accumulation that has no proven disease‐modifying treatments. Clinical trials require biomarkers of iron deposition. We examined brain iron accumulation in one presymptomatic FTL mutation carrier, two individuals with neuroferritinopathy and one healthy control using ultra‐high‐field 7T MRI. There was increased magnetic susceptibility, suggestive of iron deposition, in superficial and deep gray matter in both presymptomatic and symptomatic neuroferritinopathy. Cavitation of the putamen and globus pallidus increased with disease stage and at follow up. The widespread brain iron deposition in presymptomatic and early disease provides an opportunity for monitoring disease‐modifying intervention.

An X-ray absorption spectroscopy (XAS) electrochemical cell was used to collect high-quality XAS measurements of N-truncated Cu:amyloid-β (Cu:Aβ) samples under near-physiological conditions. N-truncated Cu:Aβ peptide complexes contribute to oxidative stress and neurotoxicity in Alzheimer's patients' brains. However, the redox properties of copper in different Aβ peptide sequences are inconsistent. Therefore, the geometry of binding sites for the copper binding in Aβ4–8/12/16 was determined using novel advanced extended X-ray absorption fine structure (EXAFS) analysis. This enables these peptides to perform redox cycles in a manner that might produce toxicity in human brains. Fluorescence XAS measurements were corrected for systematic errors including defective-pixel data, monochromator glitches and dispersion of pixel spectra. Experimental uncertainties at each data point were measured explicitly from the point-wise variance of corrected pixel measurements. The copper-binding environments of Aβ4–8/12/16 were precisely determined by fitting XAS measurements with propagated experimental uncertainties, advanced analysis and hypothesis testing, providing a mechanism to pursue many similarly complex questions in bioscience. The low-temperature XAS measurements here determine that CuII is bound to the first amino acids in the high-affinity amino-terminal copper and nickel (ATCUN) binding motif with an oxygen in a tetragonal pyramid geometry in the Aβ4–8/12/16 peptides. Room-temperature XAS electrochemical-cell measurements observe metal reduction in the Aβ4–16 peptide. Robust investigations of XAS provide structural details of CuII binding with a very different bis-His motif and a water oxygen in a quasi-tetrahedral geometry. Oxidized XAS measurements of Aβ4–12/16 imply that both CuII and CuIII are accommodated in an ATCUN-like binding site. Hypotheses for these CuI, CuII and CuIII geometries were proven and disproven using the novel data and statistical analysis including F tests. Structural parameters were determined with an accuracy some tenfold better than literature claims of past work. A new protocol was also developed using EXAFS data analysis for monitoring radiation damage. This gives a template for advanced analysis of complex biosystems.

Abstract Despite decades of research, the influence of climate on the export of dissolved organic carbon (DOC) from soil remains poorly constrained, adding uncertainty to global carbon models. The limited temporal range of contemporary monitoring data, ongoing climate reorganisation and confounding anthropogenic activities muddy the waters further. Here, we reconstruct DOC leaching over the last ~14,000 years using alpine environmental archives (two speleothems and one lake sediment core) across 4° of latitude from Te Waipounamu/South Island of Aotearoa New Zealand. We selected broadly comparable palaeoenvironmental archives in mountainous catchments, free of anthropogenically-induced landscape changes prior to ~1200 C.E. We show that warmer temperatures resulted in increased allochthonous DOC export through the Holocene, most notably during the Holocene Climatic Optimum (HCO), which was some 1.5–2.5 °C warmer than the late pre-industrial period—then decreased during the cooler mid-Holocene. We propose that temperature exerted the key control on the observed doubling to tripling of soil DOC export during the HCO, presumably via temperature-mediated changes in vegetative soil C inputs and microbial degradation rates. Future warming may accelerate DOC export from mountainous catchments, with implications for the global carbon cycle and water quality.

Abstract Background Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also important for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. Results We have generated high-resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma. This analysis has detected single-nucleosome repositioning at key regulatory regions in a patient-specific manner and common cancer-specific patterns across patients. The nucleosomes gained in tumour versus normal tissue were particularly informative of cancer pathways, with ~ 20-fold enrichment at CpG islands, a large fraction of which marked promoters of genes encoding DNA-binding proteins. The tumour tissues were characterised by a 5–10 bp decrease in the average distance between nucleosomes (nucleosome repeat length, NRL), which is qualitatively similar to the differences between pluripotent and differentiated cells. This effect was correlated with gene activity, differential DNA methylation and changes in local occupancy of linker histone variants H1.4 and H1X. Conclusions Our study offers a novel resource of high-resolution nucleosome maps in breast cancer patients and reports for the first time the effect of systematic decrease of NRL in paired tumour versus normal breast tissues from the same patient. Our findings provide a new mechanistic understanding of nucleosome repositioning in tumour tissues that can be valuable for patient diagnostics, stratification and monitoring.

Dishevelled 2 (Dvl2) is a key mediator of the Wingless/Wnt signaling pathway that regulates cell proliferation, migration, and immune function. However, little is known about the role of macrophage Dvl2 in modulating NOD1-mediated pyroptosis and hepatocyte death in oxidative stress-induced inflammatory liver injury. In a mouse model of oxidative stress-induced liver inflammation, mice with myeloid-specific Dvl2 knockout (Dvl2M−KO) displayed exacerbated ischemia/reperfusion (IR) stress-induced hepatocellular damage with increased serum ALT levels, oxidative stress, and proinflammatory mediators. Unlike in Dvl2FL/FL controls, Dvl2M−KO enhanced NOD1, caspase-1, GSDMD, and NF-κB activation in liver macrophages after IR. Interestingly, IR stress enhanced YAP colocalized with HSF1 in Dvl2FL/FL macrophages, while macrophage Dvl2 deficiency reduced YAP and HSF1 colocalization in the nucleus under inflammatory conditions. Importantly, Dvl2 deletion diminished nuclear YAP interacted with HSF1 and augmented NOD1/caspase-1 and GSDMD activation in response to inflammatory stimulation. However, Dvl2 activation increased YAP interaction with HSF1 and activated HSF1 target gene eEF2, inhibiting NOD1/caspase-1, GSDMD, and NF-κB activity. Moreover, macrophage eEF2 deletion increased the NOD1-caspase-1 interaction, GSDMD activation, HMGB1 release, and hepatocyte LDH release after macrophage/hepatocyte co-culture. Adoptive transfer of eEF2-expressing macrophages in Dvl2M−KO mice alleviated IR-triggered liver inflammation and hepatocellular damage. Therefore, macrophage Dvl2 deficiency promotes NOD1-mediated pyroptosis and exacerbates IR-induced hepatocellular death by disrupting the YAP-HSF1 axis. eEF2 is crucial for modulating NOD1-driven pyroptosis, inflammatory response, and hepatocyte death. Our findings underscore a novel role of macrophage Dvl2 in modulating liver inflammatory injury and imply the therapeutic potential in organ IRI and transplant recipients.