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All people have a fingerprint that is unique to them and persistent throughout life. Similarly, we propose that people have a gaitprint, a persistent walking pattern that contains unique information about an individual. To provide evidence of a unique gaitprint, we aimed to identify individuals based on basic spatiotemporal variables. 81 adults were recruited to walk overground on an indoor track at their own pace for four minutes wearing inertial measurement units. A total of 18 trials per participant were completed between two days, one week apart. Four methods of pattern analysis, a) Euclidean distance, b) cosine similarity, c) random forest, and d) support vector machine, were applied to our basic spatiotemporal variables such as step and stride lengths to accurately identify people. Our best accuracy (98.63%) was achieved by random forest, followed by support vector machine (98.40%), and the top 10 most similar trials from cosine similarity (98.40%). Our results clearly demonstrate a persistent walking pattern with sufficient information about the individual to make them identifiable, suggesting the existence of a gaitprint.

Abstract The COVID-19 pandemic has emphasised the importance of vaccines and preparedness against viral threats crossing species barriers. In response, a worldwide vaccination campaign targeting SARS-CoV-2 was implemented, which provides some cross-protective immunological memory to other coronavirus species with zoonotic potential. Following a vaccination regimen against SARS-CoV-2 spike in a preclinical mouse model, we were able to demonstrate the induction of neutralizing antibodies towards multiple human ACE2 (hACE2)-binding Sarbecovirus spikes. Importantly, compared to vaccines based on the SARS-CoV-2 Reference strain, vaccines based on Omicron spike sequences induced drastically less broadly cross-protective neutralizing antibodies against other hACE2-binding sarbecoviruses. This observation remained true whether the vaccination regimens were based on protein subunit or mRNA / LNP vaccines. Overall, while it may be necessary to update vaccine antigens to combat the evolving SARS-CoV-2 virus for enhanced protection from COVID-19, Reference-based vaccines may be a more valuable tool to protect against novel coronavirus zoonoses.

Abstract Base excision repair is the main pathway involved in active DNA demethylation. 5-formylcytosine and 5-carboxylcytosine, two oxidized moieties of methylated cytosine, are recognized and removed by thymine DNA glycosylase (TDG) to generate an abasic site. Using single molecule fluorescence experiments, we study TDG in the presence and absence of 5-formylcytosine. TDG exhibits multiple modes of linear diffusion, including hopping and sliding, in search of base modifications. TDG active site variants and truncated N-terminus, reveals these variants alter base modification search and recognition mechanism of TDG. On DNA containing an undamaged nucleosome, TDG is found to either bypass, colocalize with, or encounter but not bypass the nucleosome. Truncating the N-terminus reduces the number of interactions with the nucleosome. Our findings provide mechanistic insights into how TDG searches for modified DNA bases in chromatin.

Objective: Cardiac surgeons experience unpredictable overnight operative responsibilities, with variable rest before same-day, first-start scheduled cases. This study evaluated the frequency and associated impact of a surgeon's overnight operative workload on the outcomes of their same-day, first-start operations. Methods: A statewide cardiac surgery quality database was queried for adult cardiac surgical operations between July 1, 2011, and March 1, 2021. Nonemergency, first-start, Society of Thoracic Surgeons predicted risk of mortality operations were stratified by whether or not the surgeon performed an overnight operation that ended after midnight. A generalized mixed effect model was used to evaluate the effect of overnight operations on a Society of Thoracic Surgeons composite outcome (5 major morbidities or operative mortality) of the first-start operation. Results: Of all first-start operations, 0.4% (239/56,272) had a preceding operation ending after midnight. The Society of Thoracic Surgeons predicted risk of morbidity and mortality was similar for first-start operations whether preceded by an overnight operation or not (overnight operation: 11.3%; no overnight operation: 11.7%, P = .42). Unadjusted rates of the primary outcome were not significantly different after an overnight operation (overnight operation: 13.4%; no overnight operation: 12.3%, P = .59). After adjustment, overnight operations did not significantly impact the risk of major morbidity or mortality for first-start operations (adjusted odds ratio, 1.1, P = .70). Conclusions: First-start cardiac operations performed after an overnight operation represent a small subset of all first-start Society of Thoracic Surgeons predicted risk operations. Overnight operations do not significantly influence the risk of major morbidity or mortality of first-start operations, which suggests that surgeons exercise proper judgment in determining appropriate workloads.

Abstract Clinical success with poly (ADP-ribose) polymerase inhibitors (PARPi) is impeded by inevitable resistance and associated cytotoxicity. Depletion of Amplified in Liver Cancer 1 (ALC1), a chromatin-remodeling enzyme, can overcome these limitations by hypersensitizing BReast CAncer genes 1/2 (BRCA1/2) mutant cells to PARPi. Here, we demonstrate that PARPi hypersensitivity upon ALC1 loss is reliant on its role in promoting the repair of chromatin buried abasic sites. We show that ALC1 enhances the ability of the abasic site processing enzyme, Apurinic/Apyrimidinic endonuclease 1 (APE1) to cleave nucleosome-occluded abasic sites. However, unrepaired abasic sites in ALC1-deficient cells are readily accessed by APE1 at the nucleosome-free replication forks. APE1 cleavage leads to fork breakage and trapping of PARP1/2 upon PARPi treatment, resulting in hypersensitivity. Collectively, our studies reveal how cells overcome the chromatin barrier to repair abasic lesions and uncover cleavage of abasic sites as a mechanism to overcome limitations of PARPi.

Abstract Background High b-value diffusion-weighted images (DWI) are used for detection of clinically significant prostate cancer (csPCa). This study qualitatively and quantitatively compares synthesized DWI (sDWI) to acquired (aDWI) for detection of csPCa. Methods One hundred fifty-one consecutive patients who underwent prostate MRI and biopsy were included in the study. Axial DWI with b = 0, 500, 1000, and 2000 s/mm2 using a 3T clinical scanner using a 32-channel phased-array body coil were acquired. We retrospectively synthesized DWI for b = 2000 s/mm2 via extrapolation based on mono-exponential decay, using b = 0 and b = 500 s/mm2 (sDWI500) and b = 0, b = 500 s/mm2, and b = 1000 s/mm2 (sDWI1000). Differences in signal intensity between sDWI and aDWI were evaluated within different regions of interest (prostate alone, prostate plus 5 mm, 30 mm and 70 mm margin and full field of view). The maximum DWI value within each ROI was evaluated for prediction of csPCa. Classification accuracy was compared to Restriction Spectrum Imaging restriction score (RSIrs), a previously validated biomarker based on multi-exponential DWI. Discrimination of csPCa was evaluated via area under the receiver operating characteristic curve (AUC). Results Within the prostate, mean ± standard deviation of percent mean differences between sDWI and aDWI signal were -46 ± 35% for sDWI1000 and -67 ± 24% for sDWI500. AUC for aDWI, sDWI500, sDWI1000, and RSIrs within the prostate 0.62[95% confidence interval: 0.53, 0.71], 0.63[0.54, 0.72], 0.65[0.56, 0.73] and 0.78[0.71, 0.86], respectively. Conclusion sDWI is qualitatively comparable to aDWI within the prostate. However, hyperintense artifacts are introduced with sDWI in the surrounding pelvic tissue that interfere with quantitative cancer detection and might mask metastases. In the prostate, RSIrs yields superior quantitative csPCa detection than sDWI or aDWI.

Background & Aims: Patients with β-catenin (encoded by CTNNB1)-mutated hepatocellular carcinoma (HCC) demonstrate heterogenous responses to first-line immune checkpoint inhibitors (ICIs). Precision-medicine based treatments for this subclass are currently in clinical development. Here, we report derivation of the Mutated β-catenin Gene Signature (MBGS) to predict CTNNB1-mutational status in patients with HCC for future application in personalized medicine treatment regimens. Methods: Co-expression of mutant-Nrf2 and hMet ± mutant-β-catenin in murine livers in mice led to HCC development. The MBGS was derived using bulk RNA-seq and intersectional transcriptomic analysis of β-catenin-mutated and non-mutated HCC models. Integrated RNA/whole-exome-sequencing and spatial transcriptomic data from multiple cohorts of patients with HCC was assessed to address the ability of MBGS to detect CTNNB1 mutation, the tumor immune microenvironment, and/or predict therapeutic responses. Results: Bulk RNA-seq comparing HCC specimens in mutant β-catenin-Nrf2, β-catenin-Met and β-catenin-Nrf2-Met to Nrf2-Met HCC model yielded 95 common upregulated genes. In The Cancer Genome Atlas (TCGA)-LIHC dataset, differential gene expression analysis with false discovery rate (FDR) = 0.05 and log2(fold change) >1.5 on the 95 common genes comparing CTNNB1-mutated vs. wild-type patients narrowed the gene panel to a 13-gene MBGS. MBGS predicted CTNNB1-mutations in TCGA (n = 374) and French (n = 398) patient cohorts with AUCs of 0.90 and 0.94, respectively. Additionally, a higher MBGS expression score was associated with lack of significant improvement in overall survival or progression-free survival in the atezolizumab-bevacizumab arm vs. the sorafenib arm in the IMbrave150 cohort. MBGS performed comparable or superior to other CTNNB1-mutant classifiers. MBGS overlapped with Hoshida S3, Boyault G5/G6, and Chiang CTNNB1 subclass tumors in TCGA and in HCC spatial transcriptomic datasets visually depicting these tumors to be situated in an immune excluded tumor microenvironment. Conclusions: MBGS will aid in patient stratification to guide precision medicine therapeutics for CTNNB1-mutated HCC subclass as a companion diagnostic, as anti-β-catenin therapies become available. Impact and implications:: As precision medicine for liver cancer treatment becomes a reality, diagnostic tools are needed to help classify patients into groups for the best treatment choices. We have developed a molecular signature that could serve as a companion diagnostic and uses bulk or spatial transcriptomic data to identify a unique subclass of liver tumors. This subgroup of liver cancer patients derive limited benefit from the current standard of care and are expected to benefit from specialized directed therapies that are on the horizon.

Abstract Colour polymorphic species often exhibit variation in morphology, physiology, and behaviour among morphs. In particular, dominance status may be signalled by the interaction between behaviour and colour morph. Behavioural traits associated with dominance include boldness, exploration, and aggression, which influence access to preferred habitat, territorial defence, and mate acquisition. In ectotherms, the social structure associated with morphs may result in the exploitation of structural niches differing in thermal quality. Hence, social interactions among morphs may generate concordant variation in thermal preference and environmental temperature. However, few studies have assessed thermal preference variation in colour polymorphic species and its covariation with behaviour. Doing so can provide insight into niche specialization and the maintenance of colour polymorphism in populations. Here, we investigated the patterns of covariation in boldness behaviour, exploratory behaviour, and thermal preference in the tree lizard, Urosaurus ornatus. We assessed trait variation between territorial and non‐territorial male morphs and between orange and yellow female morphs. Boldness and exploratory behaviour were repeatable in male U. ornatus and bolder individuals were significantly more likely to incur tail loss, a potential consequence of bold behaviour. Territorial male morphs were significantly bolder and more exploratory and preferred higher body temperatures with a narrower T set than non‐territorial morphs. Female morphs did not vary in behavioural or thermal traits. This study highlights behavioural mechanisms that underly ecological niche segregation and variable habitat use between morphs in a colour polymorphic species.

Lavandula angustifolia Mill., lavender, is an aromatic plant in the Lamiaceae family. Lavender is an important economic plant that is cultivated throughout the world. Previous studies have shown that the primary pollinators of lavender in Europe and North Africa are bee species, specifically Bombus spp. However, similar studies have not been previously performed in North America. The current study, on cultivated population lavender (grown from seed) in Utah (USA), found a diverse community of bees visiting lavender over a 4-week sequential and successive blooming period. The observed and identified bees were distinguished across 8 genera and 12 species, of which 3 were species not native to North America. The most observed bees were Apis mellifera (88.3%), Bombus fervidus (4.2%), and B. huntii (3.7%). To investigate seed production and viability, lavender plants were either caged off and their access withheld from pollinators, or selectively granted access to various pollinators, to determine (1) if lavender is capable of self-pollination, (2) if pollination increases both the seed production rates and seed viability of lavender, and (3) which bee species are the most efficient pollinators of lavender. The findings from this study demonstrate the ecological interactions between pollinators both native and non-native to North America on lavender, a plant native to the Mediterranean region.

Abstract Continued spread of chronic wasting disease (CWD) through wild cervid herds negatively impacts populations, erodes wildlife conservation, drains resource dollars, and challenges wildlife management agencies. Risk factors for CWD have been investigated at state scales, but a regional model to predict locations of new infections can guide increasingly efficient surveillance efforts. We predicted CWD incidence by county using CWD surveillance data depicting white-tailed deer (Odocoileus virginianus) in 16 eastern and midwestern US states. We predicted the binary outcome of CWD-status using four machine learning models, utilized five-fold cross-validation and grid search to pinpoint the best model, then compared model predictions against the subsequent year of surveillance data. Cross validation revealed that the Light Boosting Gradient model was the most reliable predictor given the regional data. The predictive model could be helpful for surveillance planning. Predictions of false positives emphasize areas that warrant targeted CWD surveillance because of similar conditions with counties known to harbor CWD. However, disagreements in positives and negatives between the CWD Prediction Web App predictions and the on-the-ground surveillance data one year later underscore the need for state wildlife agency professionals to use a layered modeling approach to ensure robust surveillance planning. The CWD Prediction Web App is at https://cwd-predict.streamlit.app/ .

Abstract Introduction Although prostate magnetic resonance imaging (MRI) is commonly used in the diagnosis, staging and active surveillance of prostate cancer, little is known about patient perspectives on MRI. Methods We performed a qualitative study consisting of in‐depth, semi‐structured interviews of patients with low‐ and intermediate‐risk prostate cancer managed with active surveillance. Interviews focused on experiences with and knowledge of prostate MRI and MRI‐ultrasound fusion biopsy during active surveillance. We purposively sampled patients who received prostate MRI as part of their clinical care, conducted interviews until reaching thematic saturation and performed conventional content analysis to analyse data. Results Twenty patients aged 51–79 years (mean = 68 years) participated in the study. At diagnosis, 17 (85%) had a Gleason grade group 1, and three (15%) had a grade group 2 tumour. Overall, participants viewed prostate MRI as a valuable tool that accurately localizes and monitors prostate cancer over time, and they considered prostate MRI central to active surveillance monitoring. We identified five thematic categories related to MRI use: (1) the experiential aspects of undergoing an MRI scan; (2) the experience of visualizing one's own prostate and prostate cancer; (3) adequacy of provider explanations of MRI results; (4) confidence in prostate MRI in decision‐making; and (5) the role of prostate MRI in longitudinal follow‐up, including an interest in using MRI to modify the timing of, or replace, prostate biopsy. Conclusion Patients value prostate MRI as a tool that enhances their confidence in the initial diagnosis and monitoring of prostate cancer. This work can inform future studies to optimize patient experience, education and counselling during active surveillance for prostate cancer.

Objective: Donor hearts procured after circulatory death (DCD) may significantly increase the number of hearts available for transplantation. The purpose of this study was to analyze current DCD and brain-dead donor (DBD) heart transplantation rates and characterize organ refusal using the most up-to-date United Network for Organ Sharing (UNOS) and Organ Procurement and Transplantation Network data. Methods: We analyzed UNOS and Organ Procurement and Transplantation Network DBD and DCD candidate, transplantation, and demographic data from 2020 through 2022 and 2022 refusal code data to characterize DCD heart use and refusal. Subanalyses were performed to characterize DCD donor demographics and regional transplantation rate variance. Results: DCD hearts were declined 3.37 times more often than DBD hearts. The most frequently used code for DCD refusal was neurologic function, related to concerns of a prolonged dying process and organ preservation. In 2022, 92% (1329/1452) of all DCD refusals were attributed to neurologic function. When compared with DBD, DCD donor hearts were more frequently declined as the result of prolonged warm ischemic time (odds ratio, 5.65; 95% confidence interval, 4.07-7.86) and other concerns over organ preservation (odds ratio, 4.06; 95% confidence interval, 3.33-4.94). Transplantation rate variation was observed between demographic groups and UNOS regions. DCD transplantation rates are currently experiencing second order polynomial growth. Conclusions: DCD donor hearts are declined more frequently than DBD. DCD heart refusals result from concerns over a prolonged dying process and organ preservation. Heart transplantation rates may be substantially improved by ex situ hemodynamic assessment, adoption of normothermic regional perfusion guidelines, and quality initiatives.

IntroductionAlthough psychotic behaviors can be difficult to assess in children, early identification of children at high risk for the emergence of psychotic symptoms may facilitate the prevention of related disorders. Psychotic-like experiences (PLEs), or subthreshold thought and perceptual disturbances, could be early manifestations of psychosis that may predict a future diagnosis of a psychosis-related disorder or nonspecific correlates of a wide range of psychological problems. Additional research is needed regarding how PLEs map onto dimensions of psychopathology in children.MethodsIn the present study, we examined the association between PLEs and general and specific dimensions of psychological problems in a sample of 10,692 children from the Adolescent Brain Cognitive Development Study (ABCD Study).ResultsThe results of this study showed that self-reported PLEs were associated with a general psychopathology factor and an ADHD factor, which were defined in hierarchical models of parent-rated psychological problems.DiscussionThese findings suggest that PLEs are broadly associated with a wide range of psychological problems through the general psychopathology factor even before psychotic disorders typically manifest. This study supports the need for longitudinal analyses of future waves of the ABCD Study to determine if PLEs can detect children at high risk for serious psychological problems in adulthood.

Abstract About 15–40% of patients with schizophrenia are treatment resistance (TR) and require clozapine. Identifying individuals who have higher risk of development of TR early in the course of illness is important to provide personalized intervention. A total of 1400 patients with FEP enrolled in the early intervention for psychosis service or receiving the standard psychiatric service between July 1, 1998, and June 30, 2003, for the first time were included. Clozapine prescriptions until June 2015, as a proxy of TR, were obtained. Premorbid information, baseline characteristics, and monthly clinical information were retrieved systematically from the electronic clinical management system (CMS). Training and testing samples were established with random subsampling. An automated machine learning (autoML) approach was used to optimize the ML algorithm and hyperparameters selection to establish four probabilistic classification models (baseline, 12-month, 24-month, and 36-month information) of TR development. This study found 191 FEP patients (13.7%) who had ever been prescribed clozapine over the follow-up periods. The ML pipelines identified with autoML had an area under the receiver operating characteristic curve ranging from 0.676 (baseline information) to 0.774 (36-month information) in predicting future TR. Features of baseline information, including schizophrenia diagnosis and age of onset, and longitudinal clinical information including symptoms variability, relapse, and use of antipsychotics and anticholinergic medications were important predictors and were included in the risk calculator. The risk calculator for future TR development in FEP patients (TRipCal) developed in this study could support the continuous development of data-driven clinical tools to assist personalized interventions to prevent or postpone TR development in the early course of illness and reduce delay in clozapine initiation.

Abstract Background Tissue‐based gene expression (genomic) tests provide estimates of prostate cancer aggressiveness and are increasingly used for patients considering or engaged in active surveillance. However, little is known about patient experiences with genomic testing and its role in their decision‐making. Methods We performed a qualitative study consisting of in‐depth, semi‐structured interviews of patients with low‐ or favourable‐intermediate‐risk prostate cancer managed with active surveillance. We purposively sampled to include patients who received biopsy‐based genomic testing as part of clinical care. The interview guide focused on experiences with genomic testing during patients' decision‐making for prostate cancer management and understanding of genomic test results. We continued interviews until thematic saturation was reached, iteratively created a code key and used conventional content analysis to analyse data. Results Participants' (n = 20) mean age was 68 years (range 51–79). At initial biopsy, 17 (85%) had a Gleason grade group 1, and 3 (15%) had a grade group 2 prostate cancer. The decision to undergo genomic testing was driven by both participants and physicians' recommendations; however, some participants were unaware that testing had occurred. Overall, participants understood the role of genomic testing in estimating their prostate cancer risk, and the test results increased their confidence in the decision for active surveillance. Participants had some misconceptions about the difference between tissue‐based gene expression tests and germline genetic tests and commonly believed that tissue‐based tests measured hereditary cancer risk. While some participants expressed satisfaction with their physicians' explanations, others felt that communication was limited and lacked sufficient detail. Conclusion Patients interact with and are influenced by the results of biopsy‐based genomic testing during active surveillance for prostate cancer, despite gaps in understanding about test results. Our findings indicate areas for improvement in patient counselling in order to increase patient knowledge and comfort with genomic testing.

Deafness-causing deficiencies in otoferlin (OTOF) have been addressed preclinically using dual adeno-associated virus (AAV)-based approaches. However, timing of transduction, recombination of mRNA, and protein expression with dual hybrid AAV methods methods have not previously been characterized. Here, we have established an ex vivo assay to determine the kinetics of dual-AAV mediated expression of OTOF in hair cells of the mouse utricle. We utilized two different recombinant vectors that comprise DB-OTO, one containing the 5′ portion of OTOF under the control of the hair cell-specific Myo15 promoter, and the other the 3′ portion of OTOF. We explored specificity of the Myo15 promoter in hair cells of the mouse utricle, established dose response characteristics of DB-OTO ex vivo in an OTOF-deficient mouse model, and demonstrated tolerability of AAV1 in utricular hair cells. Furthermore, we established deviations from a one-to-one ratio of 5′ to 3′ vectors with little impact on recombined OTOF. Finally, we established a plateau in quantity of recombined OTOF mRNA and protein expression by 14 to 21 days ex vivo with comparable recovery timing to that in vivo model. These findings demonstrate the utility of an ex vivo model system for exploring expression kinetics and establish in vivo and ex vivo recovery timing of dual AAV-mediated OTOF expression.

The current study investigates the valorization of waste wood from a tropical hardwood found in Guyana (Greenheart – Chlorocardium rodiei) to high surface area activated carbons (AC). We subsequently deployed these adsorbents to sequester Mn 2+, Fe3+, and Al3+ from the acidic waters of a recreational bauxite pit-lake. We studied the impact of activation parameters such as temperature, impregnation ratio and acid concentration on the texture and surface chemistry of ACs and demonstrate that optimized low pH at point-of-zero charge (pHpzc) ACs are efficient adsorbents for the target ions. A mesoporous AC with specific surface area of 2208 m2/g, 11 % surface oxygen and pHpzc of 1.98 was produced under optimized conditions. ACs removed 93–100 % of target ions from pit-lake waters at a native pH of 3.1. Al3+ exerted an antagonistic effect on Mn2+ adsorption in synthetic binary ion systems reducing adsorption by as much as 56 %. The Sips Model fitted the adsorption data best predicting maximum adsorption capacities for Mn2+, Fe3+ and Al3+ of 17.8 mg/g, 23.7 mg/g, and 6.12 mg/g for these low pHpzc optimized materials. These materials show great promise in removing heavy metals from acidic waters.

The current study is concerned with how HIV is spatialized, or emplaced in everyday life, and therefore how prevention, Queer identity, and the virus itself are given meaning. Employing a transdisciplinary methodology based in Critical Discourse Studies and critical human geography, this study provides a geosemiotic analysis of an HIV prevention social marketing effort called the Little Prick campaign. Findings showed that space was constructed through multiple competing dynamics across professionals and citizens, as well as amidst contested notions of risk and branding in the epidemic. The analysis illuminates the discursive relationship amongst Queer, HIV, and prevention. Equally, this study counters the biased notion that “prevention fatigue” in high-risk populations hampers professional labor by, instead, exposing a semiotic fatigue in the HIV epidemic and prevention efforts.

Background: The US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk. Patients and Methods: Participants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models. Results and Interpretation: On univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00–1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91–1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79–1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04–1.09,

Summary: Recurrent Clostridioides difficile infection (CDI) results in significant morbidity and mortality. We previously established that CDI in mice does not protect against reinfection and is associated with poor pathogen-specific B cell memory (Bmem), recapitulating our observations with human Bmem. Here, we demonstrate that the secreted toxin TcdB2 is responsible for subversion of Bmem responses. TcdB2 from an endemic C. difficile strain delayed immunoglobulin G (IgG) class switch following vaccination, attenuated IgG recall to a vaccine booster, and prevented germinal center formation. The mechanism of TcdB2 action included increased B cell CXCR4 expression and responsiveness to its ligand CXCL12, accounting for altered cell migration and a failure of germinal center-dependent Bmem. These results were reproduced in a C. difficile infection model, and a US Food and Drug Administration (FDA)-approved CXCR4-blocking drug rescued germinal center formation. We therefore provide mechanistic insights into C. difficile-associated pathogenesis and illuminate a target for clinical intervention to limit recurrent disease.

Childhood environments are critical in shaping cognitive neurodevelopment. With the increasing availability of large-scale neuroimaging datasets with deep phenotyping of childhood environments, we can now build upon prior studies that have considered relationships between one or a handful of environmental and neuroimaging features at a time. Here, we characterize the combined effects of hundreds of inter-connected and co-occurring features of a child’s environment (“exposome”) and investigate associations with each child’s unique, multidimensional pattern of functional brain network organization (“functional topography”) and cognition. We apply data-driven computational models to measure the exposome and define personalized functional brain networks in pre-registered analyses. Across matched discovery (n=5139, 48.5% female) and replication (n=5137, 47.1% female) samples from the Adolescent Brain Cognitive Development study, the exposome was associated with current (ages 9–10) and future (ages 11–12) cognition. Changes in the exposome were also associated with changes in cognition after accounting for baseline scores. Cross-validated ridge regressions revealed that the exposome is reflected in functional topography and can predict performance across cognitive domains. Importantly, a single measure capturing a child’s exposome could more accurately and parsimoniously predict cognition than a wealth of personalized neuroimaging data, highlighting the importance of children’s complex, multidimensional environments in cognitive neurodevelopment.

Brain networks are continuously modified throughout development, yet this plasticity can also make functional networks vulnerable to early life stress. Little is currently known about the effect of early life stress on the functional organization of the brain. The current study investigated the association between environmental stressors and network topology using data from the Adolescent Brain Cognitive DevelopmentSM (ABCD®) Study. Hierarchical modeling identified a general factor of environmental stress, representing the common variance across multiple stressors, as well as four subfactors including familial dynamics, interpersonal support, neighborhood SES deprivation, and urbanicity. Functional network topology metrics were obtained using graph theory at rest and during tasks of reward processing, inhibition, and affective working memory. The general factor of environmental stress was associated with less specialization of networks, represented by lower modularity at rest. Local metrics indicated that general environmental stress was also associated with less efficiency in the subcortical-cerebellar and visual networks while showing greater efficiency in the default mode network at rest. Subfactors of environmental stress were associated with differences in specialization and efficiency in select networks. The current study illustrates that a wide range of stressors in a child’s environment are associated with differences in brain network topology.

Objective: This study evaluated interhospital variability and determinants of failure-to-rescue for patients undergoing surgical aortic valve replacement. Methods: An observational study was conducted among 28,842 patients undergoing aortic valve replacement with or without coronary artery bypass grafting between July 2011 and June 2017 across 90 hospitals participating in the Society of Thoracic Surgeons Adult Cardiac Surgery Database. Postoperative complications were defined as major (stroke, renal failure, reoperation, prolonged ventilation, sternal infection) and overall (major plus 14 other morbidities). Hospital terciles of observed to expected (O/E) mortality were compared on crude rates of major and overall complications, operative mortality, and failure to rescue (among major and overall complications). The correlation between hospital observed and expected failure-to-rescue rates was assessed. Results: Median Society of Thoracic Surgeons Adult Cardiac Surgery Database predicted mortality risk was similar across hospital O:E mortality terciles (P = .10). As expected, mortality rates significantly increased across terciles (low O/E tercile: 1.6%, high O/E tercile: 4.7%; P

Abstract An ongoing thrust of research focused on human gait pertains to identifying individuals based on gait patterns. However, no existing gait database supports modeling efforts to assess gait patterns unique to individuals. Hence, we introduce the Nonlinear Analysis Core (NONAN) GaitPrint database containing whole body kinematics and foot placement during self-paced overground walking on a 200-meter looping indoor track. Noraxon Ultium MotionTM inertial measurement unit (IMU) sensors sampled the motion of 35 healthy young adults (19–35 years old; 18 men and 17 women; mean ± 1 s.d. age: 24.6 ± 2.7 years; height: 1.73 ± 0.78 m; body mass: 72.44 ± 15.04 kg) over 18 4-min trials across two days. Continuous variables include acceleration, velocity, position, and the acceleration, velocity, position, orientation, and rotational velocity of each corresponding body segment, and the angle of each respective joint. The discrete variables include an exhaustive set of gait parameters derived from the spatiotemporal dynamics of foot placement. We technically validate our data using continuous relative phase, Lyapunov exponent, and Hurst exponent—nonlinear metrics quantifying different aspects of healthy human gait.

Abstract Background In a recent phase III randomized control trial, delivering a focal radiotherapy (RT) boost to tumors visible on MRI was shown to improve disease-free survival and regional/distant metastasis-free survival for patients with prostate cancer—without increasing toxicity. The aim of this study was to assess how widely this technique is being applied in current practice, as well as physicians’ perceived barriers toward its implementation. Methods We invited radiation oncologists to complete an online questionnaire assessing their use of intraprostatic focal boost in December 2022 and February 2023. To include perspectives from a broad range of practice settings, the invitation was distributed to radiation oncologists worldwide via email list, group text platform, and social media. Results 263 radiation oncologist participants responded. The highest-represented countries were the United States (42%), Mexico (13%), and the United Kingdom (8%). The majority of participants worked at an academic medical center (52%) and considered their practice to be at least partially genitourinary (GU)-subspecialized (74%). Overall, 43% of participants reported routinely using intraprostatic focal boost. Complete GU-subspecialists were more likely to implement focal boost, with 61% reporting routine use. In both high-income and low-to-middle-income countries, less than half of participants routinely use focal boost. The most cited barriers were concerns about registration accuracy between MRI and CT (37%), concerns about risk of additional toxicity (35%), and challenges to accessing high-quality MRI (29%). Conclusions Two years following publication of a randomized trial of patient benefit without increased toxicity, almost half of the radiation oncologists surveyed are now routinely offering focal RT boost. Further adoption of this technique might be aided by increased access to high-quality MRI, better registration algorithms of MRI to CT simulation images, physician education on benefit-to-harm ratio, and training on contouring prostate lesions on MRI.

Abstract Background As the COVID-19 pandemic continues to evolve, novel vaccines need to be developed that are readily manufacturable and provide clinical efficacy against emerging SARS-CoV-2 variants. Virus-like particles (VLPs) presenting the spike antigen at their surface offer remarkable benefits over other vaccine antigen formats; however, current SARS-CoV-2 VLP vaccines candidates in clinical development suffer from challenges including low volumetric productivity, poor spike antigen density, expression platform-driven divergent protein glycosylation and complex upstream/downstream processing requirements. Despite their extensive use for therapeutic protein manufacturing and proven ability to produce enveloped VLPs, Chinese Hamster Ovary (CHO) cells are rarely used for the commercial production of VLP-based vaccines. Methods Using CHO cells, we aimed to produce VLPs displaying the full-length SARS-CoV-2 spike. Affinity chromatography was used to capture VLPs released in the culture medium from engineered CHO cells expressing spike. The structure, protein content, and glycosylation of spikes in VLPs were characterized by several biochemical and biophysical methods. In vivo, the generation of neutralizing antibodies and protection against SARS-CoV-2 infection was tested in mouse and hamster models. Results We demonstrate that spike overexpression in CHO cells is sufficient by itself to generate high VLP titers. These VLPs are evocative of the native virus but with at least three-fold higher spike density. In vivo, purified VLPs elicit strong humoral and cellular immunity at nanogram dose levels which grant protection against SARS-CoV-2 infection. Conclusions Our results show that CHO cells are amenable to efficient manufacturing of high titers of a potently immunogenic spike protein-based VLP vaccine antigen.

The lymphatic vasculature regulates lung homeostasis through drainage of fluid and trafficking of immune cells and plays a key role in the response to lung injury in several disease states. We have previously shown that lymphatic dysfunction occurs early in the pathogenesis of chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) and that this is associated with increased thrombin and fibrin clots in lung lymph. However, the direct effects of CS and thrombin on lymphatic endothelial cells (LECs) in COPD are not entirely clear. Studies of the blood vasculature have shown that COPD is associated with increased thrombin after CS exposure that causes endothelial dysfunction characterized by changes in the expression of coagulation factors and leukocyte adhesion proteins. Here, we determined whether similar changes occur in LECs. We used an in vitro cell culture system and treated human lung microvascular lymphatic endothelial cells with cigarette smoke extract (CSE) and/or thrombin. We found that CSE treatment led to decreased fibrinolytic activity in LECs, which was associated with increased expression of plasminogen activator inhibitor 1 (PAI-1). LECs treated with both CSE and thrombin together had a decreased expression of tissue factor pathway inhibitor (TFPI) and increased expression of adhesion molecules. RNA sequencing of lung LECs isolated from mice exposed to CS also showed upregulation of prothrombotic and inflammatory pathways at both acute and chronic exposure time points. Analysis of publicly available single-cell RNA sequencing of LECs as well as immunohistochemical staining of lung tissue from COPD patients supported these data and showed increased expression of inflammatory markers in LECs from COPD patients compared to those from controls. These studies suggest that in parallel with blood vessels, the lymphatic endothelium undergoes inflammatory changes associated with CS exposure and increased thrombin in COPD. Further research is needed to unravel the mechanisms by which these changes affect lymphatic function and drive tissue injury in COPD.

Hydrologic reconstructions from North America are largely unknown for the Middle Miocene. Examination of fungal palynomorph assemblages coupled with traditional plant-based palynology permits delineation of local, as opposed to regional, climate signals and provides a baseline for study of ancient fungas. Here, the Fungi in a Warmer World project presents paleoecology and paleoclimatology of 351 fungal morphotypes from 3 sites in the United States: the Clarkia Konservat-Lagerstätte site (Idaho), the Alum Bluff site (Florida), and the Bouie River site (Mississippi). Of these, 83 fungi are identified as extant taxa and 41 are newly reported from the Miocene. Combining new plant-based paleoclimatic reconstructions with funga-based paleoclimate reconstructions, we demonstrate cooling and hydrologic changes from the Miocene climate optimum to the Serravallian. In the southeastern United States, this is comparable to that reconstructed with pollen and paleobotany alone. In the northwestern United States, cooling is greater than indicated by other reconstructions and hydrology shifts seasonally, from no dry season to a dry summer season. Our results demonstrate the utility of fossil fungi as paleoecologic and paleoclimatic proxies and that warmer than modern geological time intervals do not match the “wet gets wetter, dry gets drier” paradigm. Instead, both plants and fungi show an invigorated hydrological cycle across mid-latitude North America.

Shortening analgesic onset has been researched and it has been documented that prewarming epidural medications to body temperature (37°C) prior to administration increases medication efficacy. Our double-blind randomized controlled trial was designed to investigate if a lower degree of prewarming in providers' pockets could achieve similar results without the need of a bedside incubator. A total of 136 parturients were randomized into either the pocket-warmed group or the room temperature group to receive 10 mL of 0.125% bupivacaine with 2 μg/mL fentanyl epidural bolus at either the 27.8 ±1.7°C or 22.1 ±1.0°C temperatures, respectively. Primary outcome, time to analgesic onset (verbal rating scale pain score ≤ 3) was recorded in 0-, 5-, 10-, 15-, 20-, 30-, and 60-minutes intervals. It was observed that the pocket-warming group (n = 64) and room temperature group (n = 72) had no significant difference of analgesic onset time (median 8 vs. 6.2 minutes; p = 0.322). The incidence of adverse events such as hypotension, fever (≥ 38°C), nausea, vomiting, and number of top-off epidural boluses, as well as patient satisfaction rates and mode of delivery, were not significantly different between the groups as well. Further research is warranted to confirm these findings and explore the impact of different temperatures on analgesic onset time as well as the logistical issues associated with their clinical implementations.

We assess the composition and geometry of four individual rock glaciers in Alaska, Wyoming and Colorado by measuring their radio wave speed and applying these results to ground-penetrating radar depth corrections and dielectric mixing models. Our method includes a correction for subsurface reflector dip angle, which we show can lead to an incorrect determination of wave speeds using common midpoint configurations. By observing the radar properties of the rock glaciers and their supraglacial debris, we find that some of the sites exhibit nearly pure ice cores, and all of the sites indicate volumetric ice fractions >50%. These results have implications for terrestrial glaciology and hydrology because the present ice volume is connected to past ice accumulation and subsurface ice preservation, which may affect the future availability of alpine water resources. An understanding of the processes that govern rock glacier evolution over a wide range of latitudes and elevations will also contribute to the exploration of planetary surfaces such as Mars, which hosts a significant population of debris-covered glaciers. Our subsurface composition and geometry estimates will inform simulations of rock glacier formation and evolution to test hypothesized ice origin mechanisms along with the preservation of climate signals.

Abstract Snakes are difficult to study due to their cryptic coloration, minimal movements, and use of inaccessible habitats. Although well‐timed surveys during a species' active season can result in higher detection rates and conserve survey resources (i.e., time and money), survey effort may not ensure the detection of rare and cryptic species. Thus, in such instances, a strategic species‐specific sampling design is needed. The Kirtland's snake (Clonophis kirtlandii) is a rare, cryptic species assumed to be experiencing range‐wide declines. Naturalists have noted the disappearance of Kirtland's snakes from various habitats since the early 1970s. The primary objective of our study was to determine detection of Kirtland's snakes and the environmental and temporal factors influencing detection. We calculated the effort needed to detect individuals at sites by estimating detection probabilities of 3 known Kirtland's snake populations in Illinois from 2019 to 2021. Based on 77 Kirtland's snake detections over 226 site visits (34.1%) across 3 study sites, we found that high cloud cover, moderate air temperature, and low relative humidity enhanced the detection probability of this species. The middle of May to the beginning of July was the best time to conduct surveys when detection rates were highest. As our results suggested, it is imperative to establish strategic monitoring programs maximizing conservation resources to document populations for conservation action and range shifts for species of conservation concern, such as Kirtland's snakes.

Summary: During adolescence, the brain undergoes extensive changes in white matter structure that support cognition. Data-driven approaches applied to cortical surface properties have led the field to understand brain development as a spatially and temporally coordinated mechanism that follows hierarchically organized gradients of change. Although white matter development also appears asynchronous, previous studies have relied largely on anatomical tract-based atlases, precluding a direct assessment of how white matter structure is spatially and temporally coordinated. Harnessing advances in diffusion modeling and machine learning, we identified 14 data-driven patterns of covarying white matter structure in a large sample of youth. Fiber covariance networks aligned with known major tracts, while also capturing distinct patterns of spatial covariance across distributed white matter locations. Most networks showed age-related increases in fiber network properties, which were also related to developmental changes in executive function. This study delineates data-driven patterns of white matter development that support cognition.

Background: Impairment in intrinsic motivation (IM), the drive to satisfy internal desires like mastery, may play a key role in disability in psychosis. However, we have limited knowledge regarding relative impairments in IM compared to extrinsic motivation (EM) or general motivation (GM), in part due to limitations in existing measures. Methods: Here we address this gap using a novel Trait Intrinsic and Extrinsic Motivation self-report scale in a sample of n = 243 participants including those with schizophrenia, psychosis-risk, and healthy controls. Each of the 7 IM and 6 EM items used a 7-point Likert scale assessing endorsement of dispositional statements. Bifactor analyses of these items yielded distinct IM, EM, and GM factor scores. Convergent and discriminant validity were examined in relation to General Causality Orientation Scale (GCOS-CP) and Quality of Life 3-item IM measure (QLS-IM). Utility was assessed in relation to psychosis-spectrum (PS) status and CAINS clinical amotivation. Results: IM and EM showed acceptable inter-item consistency (IM: α = 0.88; EM: α = 0.66); the bifactor model exhibited fit that varied from good to borderline to inadequate depending on the specific fit metric (SRMR = 0.038, CFI = 0.94, RMSEA = 0.106 ± 0.014). IM scores correlated with established IM measures: GCOS-CP Autonomy (rho = 0.38, p 0.05). Two-year stability in an available longitudinal subset (n = 35) was strong (IM: rho = 0.64, p

Abstract Background Little is known about the transformer stage of the parasitic lampreys, a brief but critical period that encompasses juvenile out-migration from rivers to lakes or oceans to begin parasitic feeding. Information about this life stage could have significant conservation implications for both imperiled and invasive lampreys. We investigated tag retention, survival, wound healing, and swim performance of newly transformed sea lamprey (Petromyzon marinus) implanted with a new micro-acoustic transmitter, the eel–lamprey acoustic transmitter (ELAT), in a controlled laboratory environment. Results The 61-day survival of our tagged subjects was 71%, within the range reported in similar studies of juvenile lampreys. However, survival was significantly lower in the tagged animals (vs control), with no effect statistically attributable to measures of animal length, mass, condition, or population of origin (Great Lakes vs. Atlantic drainage). Mortality in tagged fish was concentrated in the first four days post-surgery, suggesting injury from the surgical process. An unusually long recovery time from anesthesia may have contributed to the increased mortality. In a simple burst swim assay, tagged animals swam significantly slower (− 22.5%) than untagged animals, but were not significantly different in endurance swim tests. A composite wound healing score at day four was a significant predictor of maximum burst swim speed at day 20, and wound condition was related to animal mass, but not length, at the time of tagging. Conclusions Impairments to survival and swim performance of juvenile sea lamprey implanted with the ELAT transmitter were within currently reported ranges for telemetry studies with small, difficult to observe fishes. Our results could be improved with more refined anesthesia and surgical techniques. The ability to track migratory movements of imperiled and pest populations of parasitic lampreys will improve our ability to estimate vital rates that underlie recruitment to the adult population (growth, survival) and to investigate the environmental factors that regulate the timing and rates of movement, in wild populations.

Antiretroviral APOBEC3 may contribute to HIV-1 latency. In this study, Ajoge and Renner et al. identify a previously undescribed function of human APOBEC3 proteins in redirecting integrations of HIV-1 DNA into more transcriptionally inactive regions of the genome.

Diagnosis of bile duct cancer often occur in advanced stages, leading to poor survival. Here, the authors combine light scattering and diffuse reflectance spectroscopies in a minimally invasive endoscopic technique for directly assessing the malignant potential of the bile duct lining, and demonstrate 97% detection accuracy.

Abstract Background Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. Men of African ancestry are at an increased risk of PrCa; however, current polygenic risk score (PRS) models are based on European ancestry groups and may not be broadly applicable. The objective of this study was to construct an African ancestry-specific PrCa PRS (PRState) and evaluate its performance. Methods African ancestry group of 4,533 individuals in ELLIPSE consortium was used for discovery of African ancestry-specific PrCa SNPs. PRState was constructed as weighted sum of genotypes and effect sizes from genome-wide association study (GWAS) of PrCa in African ancestry group. Performance was evaluated using ROC-AUC analysis. Results We identified African ancestry-specific PrCa risk loci on chromosomes 3, 8, and 11 and constructed a polygenic risk score (PRS) from 10 African ancestry-specific PrCa risk SNPs, achieving an AUC of 0.61 [0.60–0.63] and 0.65 [0.64–0.67], when combined with age and family history. Performance dropped significantly when using ancestry-mismatched PRS models but remained comparable when using trans-ancestry models. Importantly, we validated the PRState score in the Million Veteran Program (MVP), demonstrating improved prediction of PrCa and metastatic PrCa in individuals of African ancestry. Conclusions African ancestry-specific PRState improves PrCa prediction in African ancestry groups in ELLIPSE consortium and MVP. This study underscores the need for inclusion of individuals of African ancestry in gene variant discovery to optimize PRSs and identifies African ancestry-specific variants for use in future studies.

Abstract Using our strongly immunogenic SmT1 SARS-CoV-2 spike antigen platform, we developed antigens based on the Beta & Delta variants of concern (VOC). These antigens elicited higher neutralizing antibody activity to the corresponding variant than comparable vaccine formulations based on the original reference strain, while a multivalent vaccine generated cross-neutralizing activity in all three variants. This suggests that while current vaccines may be effective at reducing severe disease to existing VOC, variant-specific antigens, whether in a mono- or multivalent vaccine, may be required to induce optimal immune responses and reduce infection against arising variants.