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Abstract Background Plasmodium falciparum (P. falciparum) remains a significant public health challenge globally, especially in sub-Saharan Africa (SSA), where it accounts for 99% of all malaria infections. The outcomes of P. falciparum infection vary, ranging from asymptomatic to severe, and are associated with factors such as host immunity, parasite genetic diversity, and multiplicity of infection (MOI). Using seven neutral microsatellite markers, the current study investigated P. falciparum genetic diversity and MOI in both asymptomatic and symptomatic malaria individuals in Uganda. Methods This cross-sectional study analyzed 225 P. falciparum isolates from both asymptomatic and symptomatic malaria patients, ranging in age from 6 months to ≥ 18 years. P. falciparum genetic diversity, MOI, and multi-locus linkage disequilibrium (LD) were assessed through genotyping of seven neutral microsatellite markers: Poly-α, TA1, TA109, PfPK2, 2490, C2M34–313, and C3M69–383. Genetic data analysis was performed using appropriate genetic analysis software. Results P. falciparum infections exhibited high genetic diversity in both asymptomatic and symptomatic individuals. The mean expected heterozygosity (He) ranged from 0.79 in symptomatic uncomplicated malaria cases to 0.81 in asymptomatic individuals. There was no significant difference (p = 0.33) in MOI between individuals with asymptomatic and symptomatic infections, with the mean MOI ranging from 1.92 in symptomatic complicated cases to 2.10 in asymptomatic individuals. Polyclonal infections were prevalent, varying from 58.5% in symptomatic complicated malaria to 63% in symptomatic uncomplicated malaria cases. A significant linkage disequilibrium (LD) was observed between asymptomatic and symptomatic uncomplicated/complicated infections (p

Abstract Despite a rapid expansion of Porcine reproductive and respiratory syndrome virus (PRRSV) sublineage 8.7 over recent years, very little is known about the patterns of virus evolution, dispersal, and the factors influencing this dispersal. Relying on a national PRRSV surveillance project established over 20 years ago, we expand the available genomic data of sublineage 8.7 from China. We perform independent interlineage and intralineage recombination analyses for the entire study period, which showed a heterogeneous recombination pattern. A series of Bayesian phylogeographic analyses uncover the role of Guangdong as an important infection hub within Asia. The spatial spread of PRRSV is highly linked with a composite of human activities and the heterogeneous provincial distribution of the swine industry, largely propelled by the smaller-scale Chinese rural farming systems in the past years. We sequence all four available modified live vaccines (MLVs) and perform genomic analyses with publicly available data, of which our results suggest a key “leaky” period spanning 2011–2017 with two concurrent amino acid mutations in ORF1a 957 and ORF2 250. Overall, our study provides an in-depth overview of the evolution, transmission dynamics, and potential leaky status of HP-PRRS MLVs, providing critical insights into new MLV development.

Abstract We investigate the emergence, mutation profile, and dissemination of SARS-CoV-2 lineage B.1.214.2, first identified in Belgium in January 2021. This variant, featuring a 3-amino acid insertion in the spike protein similar to the Omicron variant, was speculated to enhance transmissibility or immune evasion. Initially detected in international travelers, it substantially transmitted in Central Africa, Belgium, Switzerland, and France, peaking in April 2021. Our travel-aware phylogeographic analysis, incorporating travel history, estimated the origin to the Republic of the Congo, with primary European entry through France and Belgium, and multiple smaller introductions during the epidemic. We correlate its spread with human travel patterns and air passenger data. Further, upon reviewing national reports of SARS-CoV-2 outbreaks in Belgian nursing homes, we found this strain caused moderately severe outcomes (8.7% case fatality ratio). A distinct nasopharyngeal immune response was observed in elderly patients, characterized by 80% unique signatures, higher B- and T-cell activation, increased type I IFN signaling, and reduced NK, Th17, and complement system activation, compared to similar outbreaks. This unique immune response may explain the variant's epidemiological behavior and underscores the need for nasal vaccine strategies against emerging variants.

Abstract Religious characteristics are predictive of Americans’ skepticism toward climate-related science and policy. Though attributable to a variety of interrelated factors, we propose specific religious beliefs help explain the dynamic in part. Specifically, we theorize that belief in divine (versus human) control over Earth’s climate likely engenders skepticism toward scientific claims that human behavior is leading Earth toward environmental crisis. Regression analyses with national survey data (N = 5321) demonstrate that believing “God would not allow humans to destroy the Earth” is associated with lower concern about climate change. Next, a pre-registered survey experiment (N = 3345) finds that manipulating belief in God’s—vis-à-vis humans’—control of Earth’s climate reduced the perceived severity of climate change and need for policy intervention. Our manipulation also reduced demand for climate-related information from the National Oceanic and Atmospheric Association. These results establish an important causal link between a religious belief and climate change attitudes in the U.S. public.

Abstract In 2016, a new, improved and modern intensive care unit was constructed at Kamuzu Central Hospital in Lilongwe, Malawi. Having been operational for about 4 years, there has not been a systematic audit to gauge its performance. Therefore, this quantitative retrospective cohort study aimed at investigating the performance of the intensive care unit at Kamuzu Central Hospital in Lilongwe, Malawi. We analysed the patterns of admission through 250 clinical cases and their respective outcomes spanning from 1st January 2019 to 31st December 2019 using STATA. Descriptive and inferential statistics were computed. We also had a follow-up discussion with the Head of the unit to better understand the unit’s functioning. Out of the 250 admissions, we evaluated 249 case files. About 30.8% of all patients were referred from the main operating theatre, and 20.7% from the casualty (emergency medicine). Head injury (26.7%) and peritonitis (15.7%) were the commonest causes of admission. The overall mortality was 52.2% with more females (57.5%) dying than males (47.9%). Head injury and peritonitis had the highest contribution to the mortality accounting for 25.3% and 16.9% of all deaths respectively. In conclusion, despite the new unit registering an improved performance compared to the old unit’s 2012 mortality of 60.9%, the current mortality rate of 52.2% generally reflects a suboptimal performance. The intensive care unit is still grappling with a number of challenges that need immediate attention including few working beds, shortage of critical care specialists and nursing staff and lack of standard admission criteria.

Abstract The performance of superconducting qubits is degraded by a poorly characterized set of energy sources breaking the Cooper pairs responsible for superconductivity, creating a condition often called “quasiparticle poisoning”. Both superconducting qubits and low threshold dark matter calorimeters have observed excess bursts of quasiparticles or phonons that decrease in rate with time. Here, we show that a silicon crystal glued to its holder exhibits a rate of low-energy phonon events that is more than two orders of magnitude larger than in a functionally identical crystal suspended from its holder in a low-stress state. The excess phonon event rate in the glued crystal decreases with time since cooldown, consistent with a source of phonon bursts which contributes to quasiparticle poisoning in quantum circuits and the low-energy events observed in cryogenic calorimeters. We argue that relaxation of thermally induced stress between the glue and crystal is the source of these events.

Background: Medical school clerkship grades are used to evaluate orthopedic surgery residency applicants, however, high interinstitutional variability in grade distribution calls into question the utility of clerkship grades when evaluating applicants from different medical schools. This study aims to evaluate the variability in grade distribution among medical schools and look for trends in grade distribution over recent years. Methods: Applications submitted to Rush University's orthopedic surgery residency program from 2015, 2019, and 2022 were collected from the Electronic Residency Application Service. Applications from the top 100 schools according to the 2023–2024 U.S. News and World Report Research Rankings were reviewed. The percentage of “honors” grades awarded by medical schools for the surgery and internal medicine clerkships were extracted from applicants' Medical Student Performance Evaluation letters. Results: The median percentage of honors given in 2022 was 36.0 % (range 10.0–82.0) for the surgery clerkship and 33.0 % (range 6.7–80.0) for the internal medicine clerkship. Honors were given 6.6 % more in the surgery clerkship in 2022 compared to 2015. There was a negative correlation between a higher (worse) U.S. News and World Report research ranking and the percentage of honors awarded in 2022 for the surgery and internal medicine clerkships. Conclusion: There is substantial interinstitutional variability in the rate that medical schools award an “honors” grade with evidence of grade inflation in the surgery clerkship. Residency programs using clerkship grades to compare applicants should do so cautiously provided the variability demonstrated in this study.

ABSTRACT E.PathDash facilitates re-analysis of gene expression data from pathogens clinically relevant to chronic respiratory diseases, including a total of 48 studies, 548 samples, and 404 unique treatment comparisons. The application enables users to assess broad biological stress responses at the KEGG pathway or gene ontology level and also provides data for individual genes. E.PathDash reduces the time required to gain access to data from multiple hours per data set to seconds. Users can download high-quality images such as volcano plots and boxplots, differential gene expression results, and raw count data, making it fully interoperable with other tools. Importantly, users can rapidly toggle between experimental comparisons and different studies of the same phenomenon, enabling them to judge the extent to which observed responses are reproducible. As a proof of principle, we invited two cystic fibrosis scientists to use the application to explore scientific questions relevant to their specific research areas. Reassuringly, pathway activation analysis recapitulated results reported in original publications, but it also yielded new insights into pathogen responses to changes in their environments, validating the utility of the application. All software and data are freely accessible, and the application is available at scangeo.dartmouth.edu/EPathDash.IMPORTANCEChronic respiratory illnesses impose a high disease burden on our communities and people with respiratory diseases are susceptible to robust bacterial infections from pathogens, including Pseudomonas aeruginosa and Staphylococcus aureus, that contribute to morbidity and mortality. Public gene expression datasets generated from these and other pathogens are abundantly available and an important resource for synthesizing existing pathogenic research, leading to interventions that improve patient outcomes. However, it can take many hours or weeks to render publicly available datasets usable; significant time and skills are needed to clean, standardize, and apply reproducible and robust bioinformatic pipelines to the data. Through collaboration with two microbiologists, we have shown that E.PathDash addresses this problem, enabling them to elucidate pathogen responses to a variety of over 400 experimental conditions and generate mechanistic hypotheses for cell-level behavior in response to disease-relevant exposures, all in a fraction of the time.

An environment interacting with a quantum system can enhance transport through the suppression of quantum effects responsible for localization. In this paper, we study the interplay between bulk dephasing and a linear potential in a boundary-driven tight-binding chain. A linear potential induces Wannier-Stark localization in the absence of noise, while dephasing induces diffusive transport in the absence of a tilt. We derive an approximate expression for the steady-state current as a function of both dephasing and tilt which closely matches the exact solution for a wide range of parameters. From it, we find that the maximum current occurs for a dephasing rate equal to the period of Bloch oscillations in the Wannier-Stark localized system. We also find that the current displays a maximum as a function of the system size, provided that the total potential tilt across the chain remains constant. Our results can be verified in current experimental platforms and represents a step forward in analytical studies of environment-assisted transport.

Introduction: Malawi is one of the countries enduring an enormous burden of cervical cancer. Human Papillomavirus (HPV) vaccination offers a feasible and effective tool for reducing the burden. Such a prospect however, is being impeded by low uptake rates of the HPV vaccine in the country. This study, therefore, sought to identify barriers to caregiver acceptance of the HPV vaccine for their female children in Chileka, Blantyre, Malawi and to establish the consequential willingness to vaccinate their children. Methodology: A cross-sectional study was conducted using qualitative methods. We conducted 6 Focus Group Discussions (FGDs) with 4 groups of women and 2 groups of men in 4 villages located in a semi-urban area, Chileka, Blantyre. The guiding questionnaire was designed to draw out two main outcomes: barriers to caregiver acceptance of the HPV vaccine and willingness to vaccinate children. The data was analysed by thematic analysis by an inductive approach using NVivo software version 11. Results: Lack of knowledge on cervical cancer and HPV vaccination coupled with numerous misconceptions are the main barriers discouraging the population from accepting the HPV vaccine. Consequently, there was little desire to get their children vaccinated against HPV. Though responsibility to get the children vaccinated was mainly attributed to women, men argued that they need to have a final say in their children’s vaccination. Conclusion: In the wake of the revealed barriers and low acceptance of the HPV vaccine, it is imperative to organize effective and sustainable awareness programmes for the improvement of the HPV vaccine’s uptake.

Abstract Excitons in two-dimensional (2D) semiconductors have offered an attractive platform for optoelectronic and valleytronic devices. Further realizations of correlated phases of excitons promise device concepts not possible in the single particle picture. Here we report tunable exciton “spin” orders in WSe2/WS2 moiré superlattices. We find evidence of an in-plane (xy) order of exciton “spin”—here, valley pseudospin—around exciton filling v ex = 1, which strongly suppresses the out-of-plane “spin” polarization. Upon increasing v ex or applying a small magnetic field of ~10 mT, it transitions into an out-of-plane ferromagnetic (FM-z) spin order that spontaneously enhances the “spin” polarization, i.e., the circular helicity of emission light is higher than the excitation. The phase diagram is qualitatively captured by a spin-1/2 Bose–Hubbard model and is distinct from the fermion case. Our study paves the way for engineering exotic phases of matter from correlated spinor bosons, opening the door to a host of unconventional quantum devices.

Abstract Background In sub-Saharan Africa (SSA), Plasmodium falciparum causes most of the malaria cases. Despite its crucial roles in disease severity and drug resistance, comprehensive data on Plasmodium falciparum genetic diversity and multiplicity of infection (MOI) are sparse in SSA. This study summarizes available information on genetic diversity and MOI, focusing on key markers (msp-1, msp-2, glurp, and microsatellites). The systematic review aimed to evaluate their influence on malaria transmission dynamics and offer insights for enhancing malaria control measures in SSA. Methods The review was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Two reviewers conducted article screening, assessed the risk of bias (RoB), and performed data abstraction. Meta-analysis was performed using the random-effects model in STATA version 17. Results The review included 52 articles: 39 cross-sectional studies and 13 Randomized Controlled Trial (RCT)/cohort studies, involving 11,640 genotyped parasite isolates from 23 SSA countries. The overall pooled mean expected heterozygosity was 0.65 (95% CI: 0.51–0.78). Regionally, values varied: East (0.58), Central (0.84), Southern (0.74), and West Africa (0.69). Overall pooled allele frequencies of msp-1 alleles K1, MAD20, and RO33 were 61%, 44%, and 40%, respectively, while msp-2 I/C 3D7 and FC27 alleles were 61% and 55%. Central Africa reported higher frequencies (K1: 74%, MAD20: 51%, RO33: 48%) than East Africa (K1: 46%, MAD20: 42%, RO33: 31%). For msp-2, East Africa had 60% and 55% for I/C 3D7 and FC27 alleles, while West Africa had 62% and 50%, respectively. The pooled allele frequency for glurp was 66%. The overall pooled mean MOI was 2.09 (95% CI: 1.88–2.30), with regional variations: East (2.05), Central (2.37), Southern (2.16), and West Africa (1.96). The overall prevalence of polyclonal Plasmodium falciparum infections was 63% (95% CI: 56–70), with regional prevalences as follows: East (62%), West (61%), Central (65%), and South Africa (71%). Conclusion The study shows substantial regional variation in Plasmodium falciparum parasite genetic diversity and MOI in SSA. These findings suggest a need for malaria control strategies and surveillance efforts considering regional-specific factors underlying Plasmodium falciparum infection.

Abstract Oral drug absorption kinetics are usually established in populations with a properly functioning gastrointestinal tract. However, many diseases and therapeutics can alter gastrointestinal physiology and cause diarrhea. The extent of diarrhea‐associated impact on drug pharmacokinetics has not been quantitatively described. To address this knowledge gap, we used a population pharmacokinetic modeling approach with data collected in a phase IIa study of matched human immunodeficiency virus (HIV)–infected adults with/without cryptosporidiosis and diarrhea to examine diarrhea‐associated impact on oral clofazimine pharmacokinetics. A population pharmacokinetic model was developed with 428 plasma samples from 23 HIV‐infected adults with/without Cryptosporidium infection using nonlinear mixed‐effects modeling. Covariates describing cryptosporidiosis‐associated diarrhea severity (e.g., number of diarrhea episodes, diarrhea grade) or HIV infection (e.g., viral load, CD4+ T cell count) were evaluated. A two‐compartment model with lag time and first‐order absorption and elimination best fit the data. Maximum diarrhea grade over the study duration was found to be associated with a more than sixfold reduction in clofazimine bioavailability. Apparent clofazimine clearance, intercompartmental clearance, central volume of distribution, and peripheral volume of distribution were 3.71 L/h, 18.2 L/h (interindividual variability [IIV] 45.0%), 473 L (IIV 3.46%), and 3434 L, respectively. The absorption rate constant was 0.625 h−1 (IIV 149%) and absorption lag time was 1.83 h. In conclusion, the maximum diarrhea grade observed for the duration of oral clofazimine administration was associated with a significant reduction in clofazimine bioavailability. Our results highlight the importance of studying disease impacts on oral therapeutic pharmacokinetics to inform dose optimization and maximize the chance of treatment success.

Introduction: Image-based machine learning holds great promise for facilitating clinical care; however, the datasets often used for model training differ from the interventional clinical trial-based findings frequently used to inform treatment guidelines. Here, we draw on longitudinal imaging of psoriasis patients undergoing treatment in the Ultima 2 clinical trial (NCT02684357), including 2,700 body images with psoriasis area severity index (PASI) annotations by uniformly trained dermatologists. Methods: An image-processing workflow integrating clinical photos of multiple body regions into one model pipeline was developed, which we refer to as the “One-Step PASI” framework due to its simultaneous body detection, lesion detection, and lesion severity classification. Group-stratified cross-validation was performed with 145 deep convolutional neural network models combined in an ensemble learning architecture. Results: The highest-performing model demonstrated a mean absolute error of 3.3, Lin’s concordance correlation coefficient of 0.86, and Pearson correlation coefficient of 0.90 across a wide range of PASI scores comprising disease classifications of clear skin, mild, and moderate-to-severe disease. Within-person, time-series analysis of model performance demonstrated that PASI predictions closely tracked the trajectory of physician scores from severe to clear skin without systematically over- or underestimating PASI scores or percent changes from baseline. Conclusion: This study demonstrates the potential of image processing and deep learning to translate otherwise inaccessible clinical trial data into accurate, extensible machine learning models to assess therapeutic efficacy.

People with disabilities (PWD) face elevated mental health concerns and are more likely to utilize mental health services compared to their nondisabled counterparts, yet they also report higher unmet mental health service needs due to myriad attitudinal and environmental barriers to accessing care. Despite these well-documented disparities, little research has examined the nuanced lived experiences of PWD who receive mental health services. Drawing upon semi-structured interviews with 20 U.S. adults with disabilities who were diverse in race/ethnicity, sexual orientation, and gender identity, the present research examined the various structural and interpersonal processes through which ableism undermines the perceived effectiveness and relevance of mental health services. Reflexive thematic analysis identified six themes that characterized participants' ableism experiences in mental healthcare settings, including misplaced assumptions about the impact of disability on mental health, medical trauma and gaslighting, interpersonal ableism, lack of disability knowledge, accessibility challenges, and systematic ableism. These findings highlight the importance of centering PWD's voices in disability-affirmative mental health research and underscore important clinical considerations for fostering accessible and inclusive mental health services.

Vaccination is one of the greatest public health achievements of the 20th century, with a tremendous impact in the prevention and control of diseases. However, the recent reemergence of vaccine-preventable diseases calls for a need to evaluate current vaccination practices and disparities in vaccination between high-income countries and low-and-middle-income countries. There are massive deficits in vaccine availability and coverage in resource-constrained settings. Therefore, this perspective seeks to highlight the reemergence of vaccine-preventable diseases in Africa within the lens of health equity and offer recommendations on how the continent should be prepared to deal with the myriad of its health systems challenges. Among the notable factors contributing to the reemergence, stand health inequities affecting vaccine availability and the dynamic vaccine hesitancy. Strengthening health systems and addressing health inequities could prove useful in halting the reemergence of vaccine-preventable diseases.

IntroductionGlobal shipping has accelerated the spread of non-native species. Factors such as environmental filtering and interactions with local biota can affect invasion likelihood, yet their relative contribution to predicting invasion risk remains unresolved. To test how abiotic filters and an experimentally-derived measure of biotic resistance interact with propagule pressure, we developed an integrated model to evaluate their relative effects on invasion risk of marine biofouling organisms to different focal port regions. We predicted that environmental filtering impacts invasion risk when fewer but stronger connections are part of the network. Further, predation is a mechanism of biotic resistance, which can reduce invasion risk, with most pronounced effects predicted in the tropics that decline at higher latitudes.MethodsWe examined shipping traffic and predation impact at three coastal bioregions spanning 47-degrees of latitude al range in the Northeast Pacific (Alaska, California, and Panama). We used vessel traffic databases to characterize propagule pressure and construct a worldwide port network of marine shipping routes and ports. Environmental resistance was estimated using temperature and salinity data from donor and recipient regions. We further used standardized predator exposure experiments to quantify predation impact on fouling community biomass as an estimate of potential for biotic resistance. We then expanded on existing models of relative invasion risk to incorporate the probability that propagules will survive predation by local predators and overcome environmental filtering to generate a predicted invasion risk for each port.ResultsEnvironmental filtering in all regions and predation pressure in the tropics worked to reduce the invasion risk, resulting in markedly different cumulative risk profiles over time among regions.DiscussionIn an increasingly connected world with more vessel traffic, our results highlight that while the number and distribution of shipping routes are important to understand risk, abiotic and biotic filters can modify model predictions.

IntroductionMany military service members and civilians suffer from lower extremity trauma. Despite recent advancements in lower limb bracing technology, it remains unclear whether these newer advanced braces offer improved comfort and functionality compared to conventional options. The IDEO (Intrepid Dynamic Exoskeletal Orthosis), a type of “advanced” orthosis was developed to assist in maintaining high functional performance in patients who have experienced high-energy lower extremity trauma and underwent limb salvage surgeries.MethodsA cross-sector multi-site initiative was completed to study the efficacy of advanced ankle foot orthoses (AFO) for lower limb trauma and injury compared to a conventional AFO. Following fitting, training, and accommodation, the subjects were assessed in each AFO system for mobility, self-reported function, safety and pain, and preference.ResultsThey preferred the advanced over the conventional AFO and the mobility and exertion perception improved with the advanced AFO with no difference in pain or overall health status scores.DiscussionThus, an advanced AFO is an option for trauma affecting the lower limb. Long-term studies are required to better understand the accommodation and learning process of using an advanced AFO.

Abstract Background Deep‐learning (DL) methods are rapidly changing the way researchers classify neurological disorders. For example, combining functional magnetic resonance imaging (fMRI) and DL has helped researchers identify functional biomarkers of neurological disorders (e.g., brain activation and connectivity) and pilot innovative diagnostic models. However, the knowledge required to perform DL analyses is often domain‐specific and is not widely taught in the brain sciences (e.g., psychology, neuroscience, and cognitive science). Conversely, neurological diagnoses and neuroimaging training (e.g., fMRI) are largely restricted to the brain and medical sciences. In turn, these disciplinary knowledge barriers and distinct specializations can act as hurdles that prevent the combination of fMRI and DL pipelines. The complexity of fMRI and DL methods also hinders their clinical adoption and generalization to real‐world diagnoses. For example, most current models are not designed for clinical settings or use by nonspecialized populations such as students, clinicians, and healthcare workers. Accordingly, there is a growing area of assistive tools (e.g., software and programming packages) that aim to streamline and increase the accessibility of fMRI and DL pipelines for the diagnoses of neurological disorders. Objectives and Methods In this study, we present an introductory guide to some popular DL and fMRI assistive tools. We also create an example autism spectrum disorder (ASD) classification model using assistive tools (e.g., Optuna, GIFT, and the ABIDE preprocessed repository), fMRI, and a convolutional neural network. Results In turn, we provide researchers with a guide to assistive tools and give an example of a streamlined fMRI and DL pipeline. Conclusions We are confident that this study can help more researchers enter the field and create accessible fMRI and deep‐learning diagnostic models for neurological disorders.

IntroductionPostoperative urinary retention (POUR) is the inability to urinate after a surgical procedure despite having a full bladder. It is a common complication following lumbar spine surgery which has been extensively linked to increased patient morbidity and hospital costs. This study hopes to development and validate a predictive model for POUR following lumbar spine surgery using patient demographics, surgical and anesthesia variables.MethodsThis is a retrospective observational cohort study of 903 patients who underwent lumbar spine surgery over the period of June 2017 to June 2019 in a tertiary academic medical center. Four hundred and nineteen variables were collected including patient demographics, ICD-10 codes, and intraoperative factors. Least absolute shrinkage and selection operation (LASSO) regression and logistic regression models were compared. A decision tree model was fitted to the optimal model to classify each patient’s risk of developing POUR as high, intermediate, or low risk. Predictive performance of POUR was assessed by area under the receiver operating characteristic curve (AUC-ROC).Results903 patients were included with average age 60 ± 15 years, body mass index of 30.5 ± 6.4 kg/m2, 476 (53%) male, 785 (87%) white, 446 (49%) involving fusions, with average 2.1 ± 2.0 levels. The incidence of POUR was 235 (26%) with 63 (7%) requiring indwelling catheter placement. A decision tree was constructed with an accuracy of 87.8%.ConclusionWe present a highly accurate and easy to implement decision tree model which predicts POUR following lumbar spine surgery using preoperative and intraoperative variables.

Summary: The chaperonin CCT mediates folding of many cytosolic proteins, including G protein β subunits (Gβs). Here, we present a protocol for isolating Gβ5 bound to CCT and its co-chaperone PhLP1 and determining the CCT-mediated folding trajectory of Gβ5 using single-particle cryoelectron microscopy (cryo-EM) techniques. We describe steps for purifying CCT-Gβ5-PhLP1 from human cells, stabilizing the closed CCT conformation, preparing and imaging cryo-EM specimens, and processing data to recover multiple Gβ5 folding intermediates. This protocol permits visualization of protein folding by CCT.For complete details on the use and execution of this protocol, please refer to Sass et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Previous studies suggest that meridional migrations of the Antarctic Circumpolar Current may have altered wind-driven upwelling and carbon dioxide degassing in the Southern Ocean during past climate transitions. Here, we report a quantitative and continuous record of the Antarctic Circumpolar Current latitude over the last glacial-interglacial cycle, using biomarker-based reconstructions of surface layer temperature gradient in the southern Indian Ocean. The results show that the Antarctic Circumpolar Current was more equatorward during the ice ages and shifted ~6° poleward at the end of glacial terminations, consistent with Antarctic Circumpolar Current migration playing a role in glacial-interglacial atmospheric carbon dioxide change. Comparing the temporal evolution of the Antarctic Circumpolar Current mean latitude with other observations provides evidence that Earth’s axial tilt affects the strength and latitude range of Southern Ocean wind-driven upwelling, which may explain previously noted deviations in atmospheric carbon dioxide concentration from a simple correlation with Antarctic climate.

Abstract Exciton polaritons are quasiparticles of photons coupled strongly to bound electron-hole pairs, manifesting as an anti-crossing light dispersion near an exciton resonance. Highly anisotropic semiconductors with opposite-signed permittivities along different crystal axes are predicted to host exotic modes inside the anti-crossing called hyperbolic exciton polaritons (HEPs), which confine light subdiffractionally with enhanced density of states. Here, we show observational evidence of steady-state HEPs in the van der Waals magnet chromium sulfide bromide (CrSBr) using a cryogenic near-infrared near-field microscope. At low temperatures, in the magnetically-ordered state, anisotropic exciton resonances sharpen, driving the permittivity negative along one crystal axis and enabling HEP propagation. We characterize HEP momentum and losses in CrSBr, also demonstrating coupling to excitonic sidebands and enhancement by magnetic order: which boosts exciton spectral weight via wavefunction delocalization. Our findings open new pathways to nanoscale manipulation of excitons and light, including routes to magnetic, nonlocal, and quantum polaritonics.

Abstract Background There are more than 18 million cancer survivors in the United States. Yet, survivors of color remain under-represented in cancer survivorship research (Saltzman et al. in Contemp Clin Trials Commun 29:100986, 2022; Pang et al. in J Clin Oncol 34:3992–3999, 2016; Lythgoe et al. in Prostate Cancer Prostatic Dis 24:1208–1211, 2021). Our long-term goal is to enroll and follow a cohort of historically under-represented cancer survivors, to better understand modifiable risk factors that influence clinical and quality of life outcomes in these populations. Towards that goal, we describe herein how we applied community-based participatory research approaches to develop inclusive study materials for enrolling such a cohort. Methods We implemented community engagement strategies to inform and enhance the study website and recruitment materials for this cohort including: hiring a dedicated engagement coordinator/community health educator as a member of our team; working with the Helen Diller Family Comprehensive Cancer Center Office of Community Engagement (OCE) and Community Advisory Board members; presenting our educational, research, and study recruitment materials at community events; and establishing a community advisory group specifically for the study (4 individuals). In parallel with these efforts, 20 semi-structured user testing interviews were conducted with diverse cancer survivors to inform the look, feel, and usability of the study website. Results Engagement with community members was a powerful and important approach for this study’s development. Feedback was solicited and used to inform decisions regarding the study name (eat move sleep, EMOVES), logo, study website content and imagery, and recruitment materials. Based on community feedback, we developed additional educational materials on healthy groceries and portion size in multiple languages and created a study video. Conclusions Including an engagement coordinator as a permanent team member, partnering with the institutional community outreach and engagement resources (i.e., OCE), and allocating dedicated time and financial support for cultivating relationships with stakeholders outside the university were critical to the development of the study website and materials. Our community guided strategies will be tested as we conduct enrollment through community advisor networks and via the state cancer registry.

Abstract Background This study examines how leadership is provided at the operational level of a health system in a protracted crisis context. Despite advances in medical science and technology, health systems in low- and middle-income countries struggle to deliver quality care to all their citizens. The role of leadership in fostering resilience and positive transformation of a health system is established. However, there is little literature on this issue in Democratic Republic of the Congo (DRC). This study describes leadership as experienced and perceived by health managers in crisis affected health districts in Eastern DRC. Methods A qualitative cross-sectional study was conducted in eight rural health districts (corresponding to health zones, in DRC’s health system organization), in 2021. Data were collected through in-depth interviews and non-participatory observations. Participants were key health actors in each district. The study deductively explored six themes related to leadership, using an adapted version of the Leadership Framework conceptual approach to leadership from the United Kingdom National Health Service’s Leadership Academy. From these themes, a secondary analysis extracted emerging subthemes. Results The study has revealed deficiencies regarding management and organization of the health zones, internal collaboration within their management teams as well as collaboration between these teams and the health zone’s external partners. Communication and clinical and managerial capacities were identified as key factors to be strengthened in improving leadership within the districts. The findings have also highlighted the detrimental influence of vertical interventions from external partners and hierarchical supervisors in health zones on planning, human resource management and decision-making autonomy of district leaders, weakening their leadership. Conclusions Despite their decentralized basic operating structure, which has withstood decades of crisis and insufficient government investment in healthcare, the districts still struggle to assert their leadership and autonomy. The authors suggest greater support for personal and professional development of the health workforce, coupled with increased government investment, to further strengthen health system capacities in these settings.

ABSTRACTMARCKS is an actin and PIP2-binding protein that plays an essential role in neutrophil migration and adhesion; however, the molecular details regarding MARCKS function in these processes remains unclear. Neutrophil adhesion and migration also require the cell surface receptors β2-integrins. We hypothesized that MARCKS inhibition would alter neutrophil β2-integrin activation and signaling. We utilized a MARCKS-targeting peptide to inhibit MARCKS in inside-out and outside-in β2-integrin activation in neutrophils. MANS-mediated MARCKS inhibition had no significant effect on inside-out β2-integrin activation. MANS treatment significantly attenuated ICAM-1/Mn2+-stimulated static adhesion, cell spreading and β2-integrin clustering, suggesting a role for MARCKS function in outside-in β2-integrin activation. Additional work is needed to better understand the molecular mechanisms of MARCKS role in outside-in β2-integrin activation and signaling.

Antimicrobial photodynamic inactivation (aPDI) offers a promising alternative to combat drug-resistant bacteria. This study explores the potential of lapachol, a natural naphthoquinone derived from Tabebuia avellanedae, as a photosensitizer (PS) for aPDI. Lapachol’s photosensitizing properties were evaluated using Staphylococcus aureus and Escherichia coli strains under blue LED light (450 nm). UV-vis spectroscopy confirmed lapachol’s absorption peak at 482 nm, aligning with effective excitation wavelengths for phototherapy. Photoinactivation assays demonstrated significant bacterial growth inhibition, achieving complete eradication of S. aureus at 25 µg·mL−1 under light exposure. Scanning electron microscopy (SEM) revealed morphological damage in irradiated bacterial cells, confirming lapachol’s bactericidal effect. This research underscores lapachol’s potential as a novel photosensitizer in antimicrobial photodynamic therapy, addressing a critical need in combating antibiotic resistance.

Melanoma, a deadly form of skin cancer, has seen improved survival rates due to advances in diagnosis and treatment, yet the need for further improvement remains critical. Tumor-associated antigens, such as PRAME (Preferentially Expressed Antigen in Melanoma), offer promising avenues for enhanced diagnostic precision, prognostic assessment, and targeted immunotherapy. PRAME, a cancer testis antigen, is selectively expressed in various cancers, including melanoma, and plays a key role in promoting tumorigenesis through inhibition of retinoic acid signaling, epithelial-to-mesenchymal transition, and immune evasion. This review explores the diagnostic utility of PRAME in distinguishing melanoma from benign nevi, its prognostic value in aggressive melanoma subtypes, and its potential as a therapeutic target in cancer vaccines and adoptive T-cell therapies. While PRAME-targeted therapies face challenges such as tumor heterogeneity and immune suppression, ongoing research aims to overcome these barriers, offering hope for more effective melanoma treatments.

Biunivalent holomorphic functions form an interesting class in geometric function theory and are connected with special functions and solutions of complex differential equations. This class has been investigated by many authors, mainly to find the coefficient estimates. The assumption of biunivalence is rigid; this rigidity means that, for example, only the initial Taylor coefficients have been estimated. The aim of this paper is to develop a variational technique for biunivalent functions, which provides a power tool for solving the general extremal problems on the classes of such functions. It involves quasiconformal analysis.

Summary: Implantable electrode arrays are powerful tools for directly interrogating neural circuitry in the brain, but implementing this technology in the spinal cord in behaving animals has been challenging due to the spinal cord’s significant motion with respect to the vertebral column during behavior. Consequently, the individual and ensemble activity of spinal neurons processing motor commands remains poorly understood. Here, we demonstrate that custom ultraflexible 1-μm-thick polyimide nanoelectronic threads can conduct laminar recordings of many neuronal units within the lumbar spinal cord of unrestrained, freely moving mice. The extracellular action potentials have high signal-to-noise ratio, exhibit well-isolated feature clusters, and reveal diverse patterns of activity during locomotion. Furthermore, chronic recordings demonstrate the stable tracking of single units and their functional tuning over multiple days. This technology provides a path for elucidating how spinal circuits compute motor actions.

Abstract Background Financial toxicity of bladder cancer care may influence how patients utilize healthcare resources, from emergency department (ED) encounters to office visits. We aim to examine whether greater household net worth (HHNW) confers differential access to healthcare resources after radical cystectomy (RC). Methods This population‐based cohort study examined the association between HHNW and healthcare utilization costs in the 90 days post‐RC in commercially insured patients with bladder cancer. Costs accrued from the index hospitalization to 90 days after including health plan costs (HPC) and out‐of‐pocket costs (OPC). Multivariable logistic regression models were generated by encounter (acute inpatient, ED, outpatient, and office visit). Results A total of 141,903 patients were identified with HHNW categories near evenly distributed. Acute inpatient encounters incurred the greatest HPC and OPC. Office visits conferred the lowest HPC while ED visits had the lowest OPC. Black patients harbored increased odds of an acute inpatient encounter (OR 1.22, 95% CI 1.16–1.29) and ED encounter (OR 1.20, 95% CI 1.14–1.27) while Asian (OR 0.76, 95% CI 0.69–0.85) and Hispanic (OR 0.74, 95% CI 0.69–0.78, p

ABSTRACTChronic Pseudomonas aeruginosa lung infections are a feature of cystic fibrosis (CF) that many patients experience even with the advent of highly effective modulator therapies. Identifying factors that impact P. aeruginosa in the CF lung could yield novel strategies to eradicate infection or otherwise improve outcomes. To complement published P. aeruginosa studies using laboratory models or RNA isolated from sputum, we analyzed transcripts of strain PAO1 after incubation in sputum from different CF donors prior to RNA extraction. We compared PAO1 gene expression in this “spike-in” sputum model to that for P. aeruginosa grown in synthetic cystic fibrosis sputum medium to determine key genes, which are among the most differentially expressed or most highly expressed. Using the key genes, gene sets with correlated expression were determined using the gene expression analysis tool eADAGE. Gene sets were used to analyze the activity of specific pathways in P. aeruginosa grown in sputum from different individuals. Gene sets that we found to be more active in sputum showed similar activation in published data that included P. aeruginosa RNA isolated from sputum relative to corresponding in vitro reference cultures. In the ex vivo samples, P. aeruginosa had increased levels of genes related to zinc and iron acquisition which were suppressed by metal amendment of sputum. We also found a significant correlation between expression of the H1-type VI secretion system and CFTR corrector use by the sputum donor. An ex vivo sputum model or synthetic sputum medium formulation that imposes metal restriction may enhance future CF-related studies.IMPORTANCEIdentifying the gene expression programs used by Pseudomonas aeruginosa to colonize the lungs of people with cystic fibrosis (CF) will illuminate new therapeutic strategies. To capture these transcriptional programs, we cultured the common P. aeruginosa laboratory strain PAO1 in expectorated sputum from CF patient donors. Through bioinformatic analysis, we defined sets of genes that are more transcriptionally active in real CF sputum compared to a synthetic cystic fibrosis sputum medium. Many of the most differentially active gene sets contained genes related to metal acquisition, suggesting that these gene sets play an active role in scavenging for metals in the CF lung environment which may be inadequately represented in some models. Future studies of P. aeruginosa transcript abundance in CF may benefit from the use of an expectorated sputum model or media supplemented with factors that induce metal restriction.

Amid national trends in postponed parenthood and more diverse family structures, the fatherhood identity may be important to men’s sexual behaviors. This study examined factors associated with reports of consistent contraceptive use and multiple sexual partners across fatherhood status. Using public data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), Wave V (2016–2018), two sexual behaviors were examined among 1,163 men aged 32 to 42 years. Outcomes were two binary indicators: consistent contraceptive use with partner and having multiple (≥2) sexual partners in the past year. Fatherhood status was categorized as nonfather, resident father, and nonresident father. Demographic (e.g., race/ethnicity, education, income, and relationship type) and health-related (e.g., drinking, perceived stress, depressive symptoms, and insurance status) factors were considered. Logistic regression analysis produced odds ratios and 95% confidence intervals and were stratified by fatherhood categories. In the sample, 72% of men were resident fathers, 10% were nonresident fathers, and 18% were nonfathers; 28% reported consistent contraceptive use and 16% reported multiple sexual partners. For nonfathers, relationship type and race were associated with reporting multiple sexual partners. For resident fathers, relationship type was the crucial factor associated with consistent contraceptive use and reporting multiple sexual partners. In nonresident fathers, relationship type, education, and income were important factors to consistent contraceptive use and reporting multiple sexual partners. Key findings suggest that relationship type, income, and education are crucial factors to men’s sexual behavior. Heterogeneous effects were observed across fatherhood status. This study adds to limited research on fatherhood and sexual behavior among men transitioning from young adulthood to middle age.

Background Paediatric HIV data shows a variable and sometimes catastrophic response in the initial stage of ART regimen administration. The burden of disease that affects children in their first year of treatment is not comprehensively available. Objective Objective of our study was to describe patterns of admission in children; before ART initiation, within the first six months, and post-six months of ART between 2001 and 2016. Methods Principal caregivers of 260 children (45.7% females 54.2% males, all

Summary: Here, we present a protocol for single-molecule super-resolution imaging of the nuclear export of pre-ribosomal subunits pre-40S and pre-60S through nuclear pore complexes. We describe steps for plating cells and co-transfecting cells. We then detail steps for using single-point edge-excitation sub-diffraction microscopy, allowing visualization of real-time dynamics of the pre-ribosomal subunits.For complete details on the use and execution of this protocol, please refer to Junod et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background: Glenohumeral instability is a challenging problem in children and adolescents. For patients with anterior glenoid bone loss, the Latarjet procedure is an effective treatment option. However, concerns about coracoid size and morphology may limit its utilization within this patient population. The purpose of this study was to establish normative data on coracoid and glenoid size and morphology among a large cohort of adolescent patients and describe the anatomic relationships with demographic factors. Methods: This is a retrospective cross-sectional study of a consecutive series of 584 patients aged 12-21 years after a chest computed tomography scan for non-shoulder related trauma at a single level I trauma center. Demographic characteristics were collected from the electronic medical record, and the following coracoid anatomic measurements were obtained from computed tomography scans: coracoid length, coracoid thickness, coracoid width, glenoid height, and glenoid width. The ratio of coracoid thickness to glenoid width was calculated to estimate the percent bone loss that could be addressed with a traditional Latarjet coracoid transfer. To ensure reliability among 3 reviewers, all measured the same 25 scans and inter-rater reliability was excellent with all Kappa coefficients >0.81. The remaining scans were divided equally and assessed separately by these reviewers. Correlation coefficients were used to quantify the relationships between all anatomic measures and the age, weight, and height of individuals. Growth curves for each measurement were modeled using quantile regression with height and height∗height as predictors. Additionally, we stratified the growth curves by sex, when significant. Of the 584 subjects, 55% were male, and average age was 19 years (range 12, 21). Results: All growth curves illustrated increase anatomic size across the height range of 145-190 cm. The growth curve including all patients (Fig. 1) illustrated that the 50% percentile of median coracoid length increased from approximately 28 to 32 mm. In addition to height, sex was a significant predictor for coracoid width and glenoid width. The median coracoid width increased from approximately 9.5 to 10.2 mm for females compared to an increased width from approximately 10 to 11 mm for males. The median glenoid width for females increased from approximately 21 to 25 mm and for males the median glenoid width increased from just under 22 to 25.5 mm. Conclusions: Among children and adolescents, coracoid and glenoid size are correlated with patient height. These data can help guide patient selection for the Latarjet procedure.

Abstract Objective: The current study presents results of a midpoint analysis of an ongoing natural experiment evaluating the diet-related effects of the Minneapolis Minimum Wage Ordinance, which incrementally increases the minimum wage to $15/h. Design: A difference-in-difference (DiD) analysis of measures collected among low-wage workers in two U.S. cities (one city with a wage increase policy and one comparison city). Measures included employment-related variables (hourly wage, hours worked and non-employment assessed by survey questions with wages verified by paystubs), BMI measured by study scales and stadiometers and diet-related mediators (food insecurity, Supplemental Nutrition Assistance Program (SNAP) participation and daily servings of fruits and vegetables, whole-grain rich foods and foods high in added sugars measured by survey questions). Setting: Minneapolis, Minnesota and Raleigh, North Carolina. Participants: A cohort of 580 low-wage workers (268 in Minneapolis and 312 in Raleigh) who completed three annual study visits between 2018 and 2020. Results: In DiD models adjusted for time-varying and non-time-varying confounders, there were no statistically significant differences in variables of interest in Minneapolis compared with Raleigh. Trends across both cities were evident, showing a steady increase in hourly wage, stable BMI, an overall decrease in food insecurity and non-linear trends in employment, hours worked, SNAP participation and dietary outcomes. Conclusion: There was no evidence of a beneficial or adverse effect of the Minimum Wage Ordinance on health-related variables during a period of economic and social change. The COVID-19 pandemic and other contextual factors likely contributed to the observed trends in both cities.

Purpose: Contemporary treatment strategies for localized prostate cancer (PCa) have been evolved over time. However, there is little data regarding survival outcomes based on initial treatment by risk group in this new era. This study aims to evaluate survival outcomes among men who underwent observation, radiotherapy, or radical prostatectomy for localized PCa using a population-based cohort. Materials and Methods: The Surveillance, Epidemiology, and End Results (SEER) prostate with watchful waiting dataset (2010– 2016) was used. We included men diagnosed with localized PCa and clinical stage T1c-2cN0M0. Other inclusion criteria were age 50–79 years, prostate-specific antigen (PSA) ≤50 ng/mL, and initial treatment with observation (active surveillance/ watchful waiting), radiotherapy, or radical prostatectomy. PCa risk was assessed using the D’Amico classification. The primary endpoint was overall survival. Secondary endpoints included PCa-specific survival. Inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazard regression and competing risk analysis were performed to assess outcomes. Results: After IPTW-adjusting, pseudo-population comprised 521,656 men (observation: 170,428, radiotherapy: 175,628, radical prostatectomy: 175,600) at a median 36.5 month follow-up. Observation demonstrated the lowest 5-year overall survival rate (91.6%) after IPTW-adjusting in comparison to radiotherapy (92.4%) and radical prostatectomy (96.1%, p

Abstract Introduction We aim to characterize the magnitude of the work burden (weeks off from work) associated with prostate cancer (PCa) treatment over a 10‐year period after PCa diagnosis and identify those at greatest risk. Materials and Methods We identified men diagnosed with PCa treated with radical prostatectomy, radiation therapy, or active surveillance/watchful waiting within CaPSURE. Patients self‐reported work burden and SF36 general health scores via surveys before and 1,3,5, and 10 years after treatment. Using multivariate repeated measures generalized estimating equation modeling we examined the association between primary treatment with risk of any work weeks lost due to care. Results In total, 6693 men were included. The majority were White (81%, 5% Black, and 14% Other) with CAPRA low‐ (60%) or intermediate‐risk (32%) disease and underwent surgery (62%) compared to 29% radiation and 9% active surveillance. Compared to other treatments, surgical patients were more likely to report greater than 7 days off work in the first year, with relatively less time off over time. Black men (RR 0.64, 95% CI 0.54–0.77) and those undergoing radiation (vs. surgery, RR 0.46, 95% CI 0.41–0.51) were less likely to report time off from work over time. Mean baseline GH score (73 [SD 18]) was similar between race and treatment groups, and stable over time. Conclusions The work burden of cancer care continued up to 10 years after treatment and varied across racial groups and primary treatment groups, highlighting the multifactorial nature of this issue and the call to leverage greater resources for those at greatest risk.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a global pandemic of coronavirus disease 2019 (COVID-19). Early in the pandemic, efforts were made to test the SARS-CoV-2 antiviral efficacy of repurposed medications that were already approved and available for other indications, including hydroxychloroquine (HCQ) and azithromycin (AZI). To reduce the risk of SARS-CoV-2 exposure for clinical-trial study participants and to conform with lockdowns and social distancing guidelines, biospecimen collection for HCQ and AZI included at-home dried blood spot (DBS) collection rather than standard venipuncture by trained clinicians. In this study, we developed and validated the first sensitive and selective simultaneous LC–MS/MS method to accurately quantitate the concentration of HCQ, HCQ metabolites (Desethylchloroquine [DCQ], Bisdesethylchloroquine [BDCQ], Monodesethylhydroxychloroquine [DHCQ]) and AZI extracted from DBS. The validated method was successfully applied for the quantification of over 2000 DBS specimens to evaluate the pharmacokinetic profile of AZI, HQC, and its metabolites. This new method has a small sample volume requirement (~ 10 µL), results in high sensitivity (1 ng/mL), and would facilitate remotely conducted therapeutic drug monitoring.

Univalent functions with asymptotically conformal extension to the boundary form a subclass of functions with quasiconformal extension with rather special features. Such functions arise in various questions of geometric function theory and Teichmüller space theory and have important applications involving conformal and quasiconformal maps. The paper provides an approximative characterization of local conformality and its connection with univalent polynomials. Also, some other quantitative applications of this connection are given.

Abstract Although there are several decision aids for the treatment of localized prostate cancer (PCa), there are limitations in the consistency and certainty of the information provided. We aimed to better understand the treatment decision process and develop a decision-predicting model considering oncologic, demographic, socioeconomic, and geographic factors. Men newly diagnosed with localized PCa between 2010 and 2015 from the Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting database were included (n = 255,837). We designed two prediction models: (1) Active surveillance/watchful waiting (AS/WW), radical prostatectomy (RP), and radiation therapy (RT) decision prediction in the entire cohort. (2) Prediction of AS/WW decisions in the low-risk cohort. The discrimination of the model was evaluated using the multiclass area under the curve (AUC). A plausible Shapley additive explanations value was used to explain the model’s prediction results. Oncological variables affected the RP decisions most, whereas RT was highly affected by geographic factors. The dependence plot depicted the feature interactions in reaching a treatment decision. The decision predicting model achieved an overall multiclass AUC of 0.77, whereas 0.74 was confirmed for the low-risk model. Using a large population-based real-world database, we unraveled the complex decision-making process and visualized nonlinear feature interactions in localized PCa.

Abstract Hydroxychloroquine (HCQ) is Food and Drug Administration (FDA)‐approved for malaria, systemic and chronic discoid lupus erythematosus, and rheumatoid arthritis. Because HCQ has a proposed multimodal mechanism of action and a well‐established safety profile, it is often investigated as a repurposed therapeutic for a range of indications. There is a large degree of uncertainty in HCQ pharmacokinetic (PK) parameters which complicates dose selection when investigating its use in new disease states. Complications with HCQ dose selection emerged as multiple clinical trials investigated HCQ as a potential therapeutic in the early stages of the COVID‐19 pandemic. In addition to uncertainty in baseline HCQ PK parameters, it was not clear if disease‐related consequences of SARS‐CoV‐2 infection/COVID‐19 would be expected to impact the PK of HCQ and its primary metabolite desethylhydroxychloroquine (DHCQ). To address the question whether SARS‐CoV‐2 infection/COVID‐19 impacted HCQ and DHCQ PK, dried blood spot samples were collected from SARS‐CoV‐2(−)/(+) participants administered HCQ. When a previously published physiologically based pharmacokinetic (PBPK) model was used to fit the data, the variability in exposure of HCQ and DHCQ was not adequately captured and DHCQ concentrations were overestimated. Improvements to the previous PBPK model were made by incorporating the known range of blood to plasma concentration ratios (B/P) for each compound, adjusting HCQ and DHCQ distribution settings, and optimizing DHCQ clearance. The final PBPK model adequately captured the HCQ and DHCQ concentrations observed in SARS‐CoV‐2(−)/(+)participants, and incorporating COVID‐19‐associated changes in cytochrome P450 activity did not further improve model performance for the SARS‐CoV‐2(+) population.

Abstract Changes in ocean ventilation have been pivotal in regulating carbon sequestration and release on centennial to millennial timescales. However, paleoceanographic reconstructions documenting changes in deep-ocean ventilation using 14C dating, may bear multidimensional explanations, obfuscating the roles of ocean ventilation played on climate evolution. Here, we show that previously inferred poorly ventilated conditions in the North Atlantic were linked to enhanced pre-aged organic carbon (OC) input during Heinrich Stadial 1 (HS1). The 14C age of sedimentary OC was approximately 13,345 ± 692 years older than the coeval foraminifera in the central North Atlantic during HS1, which is coupled to a ventilation age of 5,169 ± 660 years. Old OC was mainly of terrigenous origin and exported to the North Atlantic by ice-rafting. Remineralization of old terrigenous OC in the ocean may have contributed to, at least in part, the anomalously old ventilation ages reported for the high-latitude North Atlantic during HS1.

Abstract Many current statistical and machine learning methods have been used to explore Alzheimer’s disease (AD) and its associated patterns that contribute to the disease. However, there has been limited success in understanding the relationship between cognitive tests, biomarker data, and patient AD category progressions. In this work, we perform exploratory data analysis of AD health record data by analyzing various learned lower dimensional manifolds to separate early-stage AD categories further. Specifically, we used Spectral embedding, Multidimensional scaling, Isomap, t-Distributed Stochastic Neighbour Embedding, Uniform Manifold Approximation and Projection, and sparse denoising autoencoder based manifolds on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. We then determine the clustering potential of the learned embeddings and then determine if category sub-groupings or sub-categories can be found. We then used a Kruskal–sWallis H test to determine the statistical significance of the discovered AD subcategories. Our results show that the existing AD categories do exhibit sub-groupings, especially in mild cognitive impairment transitions in many of the tested manifolds, showing there may be a need for further subcategories to describe AD progression.

Abstract Rhythmic neural network activity has been broadly linked to behavior. However, it is unclear how membrane potentials of individual neurons track behavioral rhythms, even though many neurons exhibit pace-making properties in isolated brain circuits. To examine whether single-cell voltage rhythmicity is coupled to behavioral rhythms, we focused on delta-frequencies (1–4 Hz) that are known to occur at both the neural network and behavioral levels. We performed membrane voltage imaging of individual striatal neurons simultaneously with network-level local field potential recordings in mice during voluntary movement. We report sustained delta oscillations in the membrane potentials of many striatal neurons, particularly cholinergic interneurons, which organize spikes and network oscillations at beta-frequencies (20–40 Hz) associated with locomotion. Furthermore, the delta-frequency patterned cellular dynamics are coupled to animals’ stepping cycles. Thus, delta-rhythmic cellular dynamics in cholinergic interneurons, known for their autonomous pace-making capabilities, play an important role in regulating network rhythmicity and movement patterning.

Abstract Airborne mineral dust is sensitive to climatic changes, but its response to orbital forcing is still not fully understood. Here, we present a reconstruction of dust input to the Subarctic Pacific Ocean covering the past 190 kyr. The dust composition record is indicative of source moisture conditions, which were dominated by precessional variations. In contrast, the dust flux record is dominated by obliquity variations and displays an out‐of‐phase relationship with a dust record from the mid‐latitude North Pacific Ocean. Climate model simulations suggest precession likely drove changes in the aridity and extent of dust source regions. Additionally, the obliquity variations in dust flux can be explained by meridional shifts in the North Pacific westerly jet, driven by changes in the meridional atmospheric temperature gradient. Overall, our findings suggest that North Pacific dust input was primarily modulated by orbital‐controlled source aridity and the strength and position of the westerly winds.

Abstract Subduction zones are fundamental features of Earth's mantle convection and plate tectonics, but mantle flow and pressure around slabs are poorly understood because of the lack of direct observational constraints on subsurface flow. To characterize the linkages between slabs and mantle flow, we integrate high‐resolution representations of Earth's lithosphere and slabs into a suite of global mantle convection models to produce physically plausible present‐day flow fields for Earth's mantle. We find that subduction zones containing wide, thick, and long slabs dominate regional mantle flow in the neighboring regions and this flow conforms to patterns predicted by simpler regional subduction models. These subduction zones, such as Kuril‐Japan‐Izu‐Bonin‐Mariana, feature prismatic poloidal flow coupled to the downgoing slab that rotates toward toroidal slab‐parallel flow near the slab edge. However, other subduction zones, such as Sumatra, deviate from this pattern because of the competing influence of other slabs or longer‐wavelength mantle flow, showing that upper mantle flow can link separate subduction zones and how flow at subduction zones is influenced by broader scale mantle flow. We find that the non‐linear dislocation creep reduces the coupling between slab motion and asthenospheric flow and increases the occurrence of non‐ideal flow, in line with inferences derived from seismological constraints on mantle anisotropy.

Abstract Introduction Rhinoplasty is one of the most common cosmetic surgical procedures performed globally. Twitter, also known as “X,” is used by both patients and physicians and has been studied as a useful tool for analyzing trends in healthcare. The public social media discourse of rhinoplasty has not been previously reported in the field of otolaryngology. The goal of this study was to characterize the most common user type, sentiment, and temporal trends in the discussion of rhinoplasty on Twitter to guide facial plastic surgeons in their clinical and social media practices. Methods A total of 1,427,015 tweets published from 2015 to 2020 containing the keywords “rhinoplasty” or “nose job” were extracted using Twitter Academic API. Tweets were standardized and filtered for spam and duplication. Natural language processing (NLP) algorithms and data visualization techniques were applied to characterize tweets. Results Significantly more “nose job” tweets (80.8%) were published compared with “rhinoplasty” (19.2%). Annual tweet frequency increased over the 5 years, with “rhinoplasty” tweets peaking in January and “nose job” tweets peaking in the summer and winter months. Most “rhinoplasty” tweets were linked to a surgeon or medical practice source, while most “nose job” tweets were from isolated laypersons. While discussion was positive in sentiment overall (M = +0.08), “nose job” tweets had lower average sentiment scores (P