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Abstract Background With more than 15,000 annual deaths from head and neck cancer (HNC), an important aspect of end-of-life care for these patients is place of death. Recent evidence suggests an increasing preference for home/hospice at end of life; however, it is unclear whether there is variation in home/hospice use based on region or urban status. We described differences in the place of death of HNC patients based on their region and urban status. Methods Using the CDC WONDER (Wide-Ranging Online Data for Epidemiologic Research) database for HNC mortality (1999 to 2019), place of death was dichotomized as home/hospice vs. other, by Health and Human Services (HHS) region (Regions 1-10), and by urbanization status. Multivariable logistic regression analyses estimated odds of place of death being home/hospice, and being urban/metro, adjusting for both clinical and nonclinical variables. Results Over the study period, there were 260,630 deaths, 47.4% of which were at home or hospice. Compared to patients in New England/Region 1 (CT, ME, MA, NH, RI, and VT), HNC patients were more likely to die at home/hospice in the Pacific Northwest/Region 10 (AK, ID, OR, WA) (aOR (1.73; 95% CI: 1.64, 1.83) and less likely in the Eastern Section/Region 2 (NJ, NY, PR, VI) (aOR 0.93; 95% CI: 0.89, 0.97). Further, large central metro areas had significantly lower rates of dying at home/hospice than did all other settings. Conclusion Patients in moderately urban areas were reported to have the greatest use of hospice services and at-home death; patients in the HHS Region representing Alaska, Idaho, Oregon, and Washington were also found to have the highest rates of use. These differences in hospice care should be considered when clinicians counsel patients on their end-of-life options.

Abstract Haplotype information is crucial for biomedical and population genetics research. However, current strategies to produce de novo haplotype-resolved assemblies often require either difficult-to-acquire parental data or an intermediate haplotype-collapsed assembly. Here, we present Graphasing, a workflow which synthesizes the global phase signal of Strand-seq with assembly graph topology to produce chromosome-scale de novo haplotypes for diploid genomes. Graphasing readily integrates with any assembly workflow that both outputs an assembly graph and has a haplotype assembly mode. Graphasing performs comparably to trio phasing in contiguity, phasing accuracy, and assembly quality, outperforms Hi-C in phasing accuracy, and generates human assemblies with over 18 chromosome-spanning haplotypes.

Abstract Racial and ethnic minorities bear a disproportionate burden of type 2 diabetes (T2D) and its complications, with social determinants of health (SDoH) recognized as key drivers of these disparities. Implementing efficient and effective social needs management strategies is crucial. We propose a machine learning analytic pipeline to calculate the individualized polysocial risk score (iPsRS), which can identify T2D patients at high social risk for hospitalization, incorporating explainable AI techniques and algorithmic fairness optimization. We use electronic health records (EHR) data from T2D patients in the University of Florida Health Integrated Data Repository, incorporating both contextual SDoH (e.g., neighborhood deprivation) and person-level SDoH (e.g., housing instability). After fairness optimization across racial and ethnic groups, the iPsRS achieved a C statistic of 0.71 in predicting 1-year hospitalization. Our iPsRS can fairly and accurately screen patients with T2D who are at increased social risk for hospitalization.

Abstract Aims Interatrial shunts are under evaluation as a treatment for heart failure (HF); however, their in vivo flow performance has not been quantitatively studied. We aimed to investigate the fluid dynamics properties of the 0.51 cm orifice diameter Ventura shunt and assess its lumen integrity with serial transesophageal echocardiography (TEE). Methods and results Computational fluid dynamics (CFD) and bench flow tests were used to establish the flow‐pressure relationship of the shunt. Open‐label patients from the RELIEVE‐HF trial underwent TEE at shunt implant and at 6 and 12 month follow‐up. Shunt effective diameter (Deff) was derived from the vena contracta, and flow was determined by the continuity equation. CFD and bench studies independently validated that the shunt's discharge coefficient was 0.88 to 0.89. The device was successfully implanted in all 97 enrolled patients; mean age was 70 ± 11 years, 97% were NYHA class III, and 51% had LVEF ≤40%. Patency was confirmed in all instances, except for one stenotic shunt at 6 months. Deff remained unchanged from baseline at 12 months (0.47 ± 0.01 cm, P = 0.376), as did the trans‐shunt mean pressure gradient (5.1 ± 3.9 mmHg, P = 0.316) and flow (1137 ± 463 mL/min, P = 0.384). TEE measured flow versus pressure closely correlated (R2 ≥ 0.98) with a fluid dynamics model. At 12 months, the pulmonary/systemic flow Qp/Qs ratio was 1.22 ± 0.12. Conclusions When implanted in patients with advanced HF, this small interatrial shunt demonstrated predictable and durable patency and performance.

Abstract Oral fluids provide ready detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host responses. This study sought to evaluate relationships between oral virus, oral and systemic anti-SARS-CoV-2-specific antibodies, and symptoms. Oral fluids (saliva/throat wash (saliva/TW)) and serum were collected from asymptomatic and symptomatic, nasopharyngeal (NP) SARS-CoV-2 RT-qPCR+ human participants (n = 45). SARS-CoV-2 RT-qPCR and N-antigen detection by immunoblot and lateral flow assay (LFA) were performed. RT-qPCR for subgenomic RNA (sgRNA) was sequence confirmed. SARS-CoV-2-anti-S protein RBD LFA and ELISA assessed IgM and IgG responses. Structural analysis identified host salivary molecules analogous to SARS-CoV-2-N-antigen. At time of enrollment (baseline, BL), LFA-detected N-antigen in 86% of TW and was immunoblot-confirmed. However, only 3/17 were saliva/TW qPCR+ . Sixty percent of saliva and 83% of TW demonstrated persistent N-antigen at 4 weeks. N-antigen LFA signal in three anti-spike sero-negative participants suggested potential cross-detection of 4 structurally analogous salivary RNA binding proteins (alignment 19–29aa, RMSD 1–1.5 Angstroms). At enrollment, symptomatic participants demonstrated replication-associated sgRNA junctions, were IgG+ (94%/100% in saliva/TW), and IgM+ (63%/54%). At 4 weeks, SARS-CoV-2 IgG (100%/83%) and IgM (80%/67%) persisted. Oral and serum IgG correlated 100% with NP+ PCR status. Cough and fatigue severity (p = 0.010 and 0.018 respectively), and presence of weakness, nausea, and composite upper respiratory symptoms (p = 0.037, 0.005, and 0.017, respectively) were negatively associated with saliva IgM but not TW or serum IgM. Throat wash IgM levels were higher in women compared to men, although the association did not reach statistical significance (median: 290 (female) versus 0.697, p = 0.056). Important to transmission and disease course, oral viral replication and persistence showed clear relationships with select symptoms and early oral IgM responses during early infection. N-antigen cross-reactivity may reflect mimicry of structurally analogous host proteins.

Tom MacDonald’s success in the music industry can provide valuable insights for leaders and founders, particularly in the context of high-reliability organization (HRO) theory—MacDonald’s approach to music challenges conventional wisdom and societal norms, promoting open communication and adaptability. HROs should prioritize open channels, invest in training, and support continuous learning. Clear communication is crucial for employees to understand the organization’s roles, responsibilities, and goals, facilitating collaboration and problem-solving. It also helps manage change and prevents crises. Investing in communication skills and practices is essential for driving organizational success and resilience in today’s fast-paced business environment.

Abstract Relationships between adult females are fundamental to understanding diversity in animal social systems. While cooperative relationships between kin are known to promote fitness benefits, the proximate mechanisms underlying this are not well understood. Here we show that when related female house mice (Mus musculus domesticus) cooperate to rear young communally, those with higher endogenous oxytocin levels have more egalitarian and successful cooperative relationships. Sisters with higher oxytocin concentrations in the paraventricular nucleus (PVN) of the hypothalamus weaned significantly more offspring, had lower reproductive skew and spent more equal proportions of time in the nest. By contrast, PVN oxytocin was unrelated to the number of weaned offspring produced in the absence of cooperation, and did not vary in response to manipulation of nest site availability or social cues of outgroup competition. By linking fitness consequences of cooperation with oxytocin, our findings have broad implications for understanding the evolution of egalitarian social relationships.

Abstract Genome-scale metabolic models (GEMs) can facilitate metabolism-focused multi-omics integrative analysis. Since Yeast8, the yeast-GEM of Saccharomyces cerevisiae, published in 2019, has been continuously updated by the community. This has increased the quality and scope of the model, culminating now in Yeast9. To evaluate its predictive performance, we generated 163 condition-specific GEMs constrained by single-cell transcriptomics from osmotic pressure or reference conditions. Comparative flux analysis showed that yeast adapting to high osmotic pressure benefits from upregulating fluxes through central carbon metabolism. Furthermore, combining Yeast9 with proteomics revealed metabolic rewiring underlying its preference for nitrogen sources. Lastly, we created strain-specific GEMs (ssGEMs) constrained by transcriptomics for 1229 mutant strains. Well able to predict the strains’ growth rates, fluxomics from those large-scale ssGEMs outperformed transcriptomics in predicting functional categories for all studied genes in machine learning models. Based on those findings we anticipate that Yeast9 will continue to empower systems biology studies of yeast metabolism.

Abstract Purpose To evaluate the relationship between delivered radiation (RT) and post-RT inversion-recovery ultrashort-echo-time (IR-UTE) MRI signal-intensity (SI) in gynecologic cancer patients treated with high-dose-rate (HDR) brachytherapy (BT). Methods Seven patients underwent whole-pelvis RT (WPRT) followed by BT to the high-risk clinical target volume (HR-CTV). MR images were acquired at three time-points; pre-RT, post-WPRT/pre-BT, and 3–6 months post-BT. Diffuse-fibrosis (FDiffuse) was imaged with a non-contrast dual-echo IR (inversion time [TI] = 60 ms) UTE research application, with image-subtraction of the later echo, only retaining the ultrashort-echo SI. Dense-fibrosis (FDense) imaging utilized single-echo Late-Gadolinium-Enhanced IR-UTE, acquired ∼ 15 min post-Gadavist injection. Resulting FDiffuse and FDense SI were normalized to the corresponding gluteal-muscle SI. Images were deformably registered between time-points based on normal tissue anatomy. The remnant tumor at both time-points was segmented using multi-parametric MRI. Contours corresponding to the 50%, 100%, 150%, and 200% isodose lines (IDLs) of the prescription BT-dose were created. Mean FDiffuse and FDense SI within (i) each IDL contour and (ii) the remnant tumor were calculated. Post-BT FDiffuse and FDense SI were correlated with prescribed BT-dose. To determine the relationship between BT-dose and IR-UTE SI, the differences in the post-BT FDense across IDLs was determined using paired t-tests with Bonferroni correction. Results FDense was higher in regions of higher dose for 6/7 patients, with mean ± SD values of 357 ± 103% and 331 ± 97% (p = .03) in the 100% and 50% IDL, respectively. FDense was higher in regions of higher dose in the responsive regions with mean ± SD values of 380 ± 122% and 356 ± 135% (p = .03) in the 150% and 50% IDL, respectively. Within the segmented remnant tumor, an increase in prescribed dose correlated with an increase in FDense post-BT (n = 5, r = .89, p = .04). Post-BT FDiffuse inversely correlated (n = 7, r = -.83, p = .02) with prescribed BT-dose within the 100% IDL. Conclusions Results suggest that FDense SI 3–6 months post-BT is a sensitive measure of tissue response to heterogeneous BT radiation-dose. Future studies will validate whether FDiffuse and FDense are accurate biomarkers of fibrotic radiation response.

Abstract Epiphytic microbes are those that live for some or all of their life cycle on the surface of plant leaves. Leaf surfaces are a topologically complex, physicochemically heterogeneous habitat that is home to extensive, mixed communities of resident and transient inhabitants from all three domains of life. In this review, we discuss the origins of leaf surface microbes and how different biotic and abiotic factors shape their communities. We discuss the leaf surface as a habitat and microbial adaptations which allow some species to thrive there, with particular emphasis on microbes that occupy the continuum between epiphytic specialists and phytopathogens, groups which have considerable overlap in terms of adapting to the leaf surface and between which a single virulence determinant can move a microbial strain. Finally, we discuss the recent findings that the wheat pathogenic fungus Zymoseptoria tritici spends a considerable amount of time on the leaf surface, and ask what insights other epiphytic organisms might provide into this pathogen, as well as how Z. tritici might serve as a model system for investigating plant–microbe-microbe interactions on the leaf surface.

Abstract Skeletal muscle responds for most of the insulin-stimulated glucose disposal at postprandial state, impacting glucose homeostasis. Polyphenols were shown to prevent obesity-associated glucose intolerance and peripheral insulin resistance in animal models, but the implication of skeletal muscle to these effects is unclear. We investigated the role of polyphenolic extracts from jaboticaba (Plinia jaboticaba (Vell.) Berg) (PEJ), a Brazilian native species, on skeletal muscle insulin resistance in diet-induced obese mice. PEJ administration was associated with an increase in skeletal muscle protein content of glucose transporter-4 (GLUT-4) and AMP-activated protein kinase (AMPK) phosphorylated at Thr172. PEJ also reduced skeletal muscle mRNA levels of inflammatory genes nuclear factor-ҡB (NF-κB), tumoral necrose factor-α (TNF-α), interleukin 1β (IL-1β), and c-Jun N-terminal kinase (JNK). This study demonstrates that polyphenols from jaboticaba may be a valuable therapeutic agent in the management and prevention of obesity-associated metabolic disorders by reducing skeletal muscle obesity-associated insulin resistance and inflammation. Graphical Abstract

Healthcare professionals experience negative behaviors such as incivility from various sources within the hospital environment. However, little is known regarding the experience of unlicensed assistive personnel with these behaviors. Using a cross-sectional survey design, the research team aimed to examine the presence, sources, and impact of negative behaviors among registered nurses and unlicensed assistive personnel within a US hospital. Descriptive and inferential statistics were used to analyze quantitative data, while thematic analysis was used to analyze the qualitative responses. A total of 309 participants completed the survey, and 135 participants responded to three qualitative questions. Most respondents identified inadequate staffing/resources to handle workload (87%) and job stress leading to loss of control over behavior as contributing factors to lateral/vertical aggression in the work environment (71%). Impacts of negative behavior on job performance were related to both personal well-being and the work environment. Demoralization was identified as a common consequence of negative behaviors for individuals and within the work environment. The results suggested that registered nurses, unlicensed assistive personnel, and nursing leadership may benefit from system-wide approaches addressing negative behaviors such as incivility within the clinical environment. Specifically, efforts and policies aimed at aiding clinicians in responding to negative behaviors could potentially improve the clinical environment.

Abstract Human iPSC-derived cardiomyocytes (hiPSC-CMs) have proven invaluable for cardiac disease modeling and regeneration. Challenges with quality, inter-batch consistency, cryopreservation and scale remain, reducing experimental reproducibility and clinical translation. Here, we report a robust stirred suspension cardiac differentiation protocol, and we perform extensive morphological and functional characterization of the resulting bioreactor-differentiated iPSC-CMs (bCMs). Across multiple different iPSC lines, the protocol produces 1.2E6/mL bCMs with ~94% purity. bCMs have high viability after cryo-recovery (>90%) and predominantly ventricular identity. Compared to standard monolayer-differentiated CMs, bCMs are more reproducible across batches and have more mature functional properties. The protocol also works with magnetically stirred spinner flasks, which are more economical and scalable than bioreactors. Minor protocol modifications generate cardiac organoids fully in suspension culture. These reproducible, scalable, and resource-efficient approaches to generate iPSC-CMs and organoids will expand their applications, and our benchmark data will enable comparison to cells produced by other cardiac differentiation protocols.

Abstract We construct classical curvature spinors in topologically massive gauge theory and topologically massive gravity, expressed in terms of massive three-particle amplitudes. We show that when the amplitudes double copy, the curvature spinors associated with particular solutions satisfy the Cotton double copy, the three-dimensional cousin of the Weyl double copy. Furthermore, we show that under certain circumstances the Cotton double copy can be derived via a dimensional reduction of the Weyl double copy.

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 Peripheral artery disease (PAD) is characterized by varying severity of arterial stenosis, exercise induced claudication, malperfused tissue precluding normal healing and skeletal muscle dysfunction. Revascularization interventions improve circulation, but post-reperfusion changes within the skeletal muscle are not well characterized. This study investigates if revascularization enhanced hemodynamics increases walking performance with concurrent improvement of mitochondrial function and reverses abnormal skeletal muscle morphological features that develop with PAD. Fifty-eight patients completed walking performance testing and muscle biopsy before and 6 months after revascularization procedures. Muscle fiber morphology, desmin structure, and mitochondria respiration assessments before and after the revascularization were evaluated. Revascularization improved limb hemodynamics, walking function, and muscle morphology. Qualitatively not all participants recovered normal structural architecture of desmin in the myopathic myofibers after revascularization. Heterogenous responses in the recovery of desmin structure following revascularization may be caused by other underlying factors not reversed with hemodynamic improvements. Revascularization interventions clinically improve patient walking ability and can reverse the multiple subcellular functional and structural abnormalities in muscle cells. Further study is needed to characterize desmin structural remodeling with improvements in skeletal muscle morphology and function.

ABSTRACT Grapes have been cultivated for wine production for millennia. Wine production involves a complex biochemical process where sugars in grape must are converted into alcohol and other compounds by microbial fermentation, primarily by the yeast Saccharomyces cerevisiae. Commercially available S. cerevisiae strains are often used in winemaking, but indigenous (native) strains are gaining attention for their potential to contribute unique flavors. Recent advancements in high-throughput DNA sequencing have revolutionized our understanding of microbial communities during wine fermentation. Indeed, transcriptomic analysis of S. cerevisiae during wine fermentation has revealed a core gene expression program and provided insights into how this yeast adapts to fermentation conditions. Here, we assessed how the age of vines impacts the grape fungal microbiome and used transcriptomics to characterize microbial functions in grape must fermented with commercial and native S. cerevisiae. We discovered that ~130-year-old Zinfandel vines harbor higher fungal loads on their grapes compared to 20-year-old Zinfandel vines, but fungal diversity is similar. Additionally, a comparison of inoculated and uninoculated fermentations showed distinct fungal dynamics, with uninoculated fermentations harboring the yeasts Metschnikowia and Pichia. Transcriptomic analysis revealed significant differences in gene expression between fermentations inoculated and not inoculated with a commercial S. cerevisiae strain. Genes related to metabolism, stress response, and cell adhesion were differentially expressed, indicating varied functionality of S. cerevisiae in these fermentations. These findings provide insights into S. cerevisiae function during fermentation and highlight the potential for indigenous yeast to contribute to wine diversity.IMPORTANCEUnderstanding microbial functions during wine fermentation, particularly the role of Saccharomyces cerevisiae, is crucial for enhancing wine quality. While commercially available S. cerevisiae strains are commonly used, indigenous strains can offer unique flavors, potentially reflecting vineyard terroir. By leveraging high-throughput DNA sequencing and transcriptomic analysis, we explored the impact of vine age on the grape mycobiome and characterized microbial functions during grape fermentation. Our findings revealed that older vines harbor higher fungal loads, but fungal diversity remains similar across vine ages. Additionally, uninoculated fermentations exhibited diverse fungal dynamics, including the beneficial wine yeasts Metschnikowia and Pichia. Transcriptomic analysis uncovered significant differences in S. cerevisiae gene expression between inoculated and uninoculated fermentations, highlighting the potential of indigenous yeast to enhance wine diversity and inform winemaking practices.

Abstract Natural selection favors individuals with the highest inclusive fitness (i.e., total number of descendants). In cases where one sex is more productive, one or both parents may maximize their inclusive fitness by investing in the offspring of the more prolific sex. Such preferential production can lead to skewed sex ratios at various life history stages, including at birth, resulting in secondary sex ratio bias. Several competing hypotheses have been proposed to explain observed variation in secondary sex ratios including Fisher's frequency dependence and two hypotheses related to maternal condition: Trivers–Willard and the local resource hypotheses. Although it has been shown that maternal condition can influence the number of offspring produced in white‐tailed deer, there is no consensus as to which of the hypotheses drives sex ratio bias in wild populations. Using a spatiotemporally extensive dataset of pregnant white‐tailed deer from Mississippi, USA, we examined fetal sex ratio in relation to the Fisherian frequency‐dependence hypothesis and hypotheses related to maternal condition. While there was a male‐sex ratio bias in pregnant females that reduced in intensity with the number of offspring, there was no support for condition‐related hypotheses. Instead, secondary sex ratios for white‐tailed deer in Mississippi were nearly consistent with Fisherian frequency dependence. Our findings add to the body of literature on secondary sex biases in white‐tailed deer and help inform sex bias ratios for a southern population of a cervid of management importance in the US.

Background: Charles Bonnet syndrome (CBS) is a condition in which people with vision loss experience complex visual hallucinations. These complex visual hallucinations may be caused by increased excitability in the visual cortex that are present in some people with vision loss but not others. Objectives: We aimed to evaluate the association between γ-aminobutyric acid (GABA) in the visual cortex and CBS. We also tested the relationship among visually evoked responses, functional connectivity, and CBS. Design: This is a prospective, case-controlled, cross-sectional observational study. Methods: We applied 3-Tesla magnetic resonance spectroscopy, as well as task-based and resting state (RS) connectivity functional magnetic resonance imaging in six participants with CBS and six controls without CBS. GABA+ was measured in the early visual cortex (EVC) and in the lateral occipital cortex (LOC). Participants also completed visual acuity and cognitive tests, and the North-East Visual Hallucinations Interview. Results: The two groups were well-matched for age, gender, visual acuity and cognitive scores. There was no difference in GABA+ levels between groups in the visual cortex. Most participants showed the expected blood oxygenation level dependent (BOLD) activation to images of objects and the phase-scrambled control. Using a fixed effects analysis, we found that BOLD activation was greater in participants with CBS compared to controls. Analysis of RS connectivity with LOC and EVC showed little difference between groups. A fixed effects analysis showed a correlation between the extent of functional connectivity with LOC and hallucination strength. Conclusion: Overall, our results provide no strong evidence for an association between GABAergic inhibition in the visual cortex and CBS. We only found subtle differences in visual function and connectivity between groups. These findings suggest that the neurochemistry and visual connectivity for people with Charles Bonnet hallucinations are comparable to a sight loss population. Differences between groups may emerge when investigating subtle and transient changes that occur at the time of visual hallucinations.

IntroductionMany youth with pain lack access to pediatric pain expertise. There is a critical shortage of pediatric pain physicians, due partly to a paucity of training programs in Pediatric Pain Medicine. Pain fellowships are Anesthesiology-based and there is no pathway to fellowship training or Pain Medicine board certification for pediatricians. This workforce assessment sought to examine the current state of Pediatric Pain Medicine in the United States and future interest in pursuing Pain Medicine among pediatricians.MethodsA multidisciplinary working group of Pain Medicine clinicians designed three surveys to examine pediatric comprehensive pain programs in the US, practice patterns of pediatricians and their motivations and opinions regarding Pain Medicine board certification, and current residents’ exposure to and interest in Pediatric Pain Medicine.ResultsWait times for initial evaluations are two months or longer for two-thirds of responding centers, and barriers to increase staff size and resources were reported, including an inadequate number of trained or available physicians. Pediatricians expressed interest in earning board certification in Pain Medicine, given the opportunity. Additionally, there is interest among pediatric residents in pursuing Pediatric Pain Medicine, and qualitative data highlight information residents perceived needing in order to pursue a career in the field.DiscussionResults demonstrate the need for increased training opportunities in pediatric pain medicine. A formal pathway to Pain Medicine for Pediatricians should be developed to increase the potential workforce and to address the lack of trained pediatric pain specialists, thereby improving access to care for youth with pain.

ABSTRACT Selenium is a trace element that plays critical roles in redox biology; it is typically incorporated into “selenoproteins” as the 21st amino acid selenocysteine. Additionally, selenium exists as a labile non-selenocysteine cofactor in a small subset of selenoproteins known as selenium-dependent molybdenum hydroxylases (SDMHs). In purinolytic clostridia, SDMHs are implicated in the degradation of hypoxanthine, xanthine, and uric acid for carbon and nitrogen. While SDMHs have been biochemically analyzed, the genes responsible for the insertion and maturation of the selenium cofactor lack characterization. In this study, we utilized the nosocomial pathogen Clostridioides difficile as a genetic model to begin characterizing this poorly understood selenium utilization pathway and its role in the catabolism of host-derived purines. We first observed that C. difficile could utilize hypoxanthine, xanthine, or uric acid to overcome a growth defect in a minimal medium devoid of glycine and threonine. However, strains lacking selenophosphate synthetase (selD mutants) still grew poorly in the presence of xanthine and uric acid, suggesting a selenium-dependent purinolytic process. Previous computational studies have identified yqeB and yqeC as potential candidates for cofactor maturation, so we subsequently deleted each gene using CRISPR-Cas9 technology. We surprisingly found that the growth of the ΔyqeB mutant in response to each purine was similar to the behavior of the selD mutants, while the ΔyqeC mutant exhibited no obvious phenotype. Our results suggest an important role for YqeB in selenium-dependent purine catabolism and also showcase C. difficile as an appropriate model organism to study the biological use of selenium.IMPORTANCEThe apparent modification of bacterial molybdenum hydroxylases with a catalytically essential selenium cofactor is the least understood mechanism of selenium incorporation. Selenium-dependent molybdenum hydroxylases play an important role in scavenging carbon and nitrogen from purines for purinolytic clostridia. Here, we used Clostridioides difficile as a genetic platform to begin dissecting the selenium cofactor trait and found genetic evidence for a selenium-dependent purinolytic pathway. The absence of selD or yqeB—a predicted genetic marker for the selenium cofactor trait—resulted in impaired growth on xanthine and uric acid, known substrates for selenium-dependent molybdenum hydroxylases. Our findings provide a genetic foundation for future research of this pathway and suggest a novel metabolic strategy for C. difficile to scavenge host-derived purines from the gut.

Introduction Diabetes disparities exist based on socioeconomic status, race, and ethnicity. The aim of this study is to compare two cohorts with diabetes from California and Florida to better elucidate how health outcomes are stratified within underserved communities according to state location, race, and ethnicity.Research design and methods Two cohorts were recruited for comparison from 20 Federally Qualified Health Centers as part of a larger ECHO Diabetes program. Participant-level data included surveys and HbA1c collection. Center-level data included Healthcare Effectiveness Data and Information Set metrics. Demographic characteristics were summarized overall and stratified by state (frequencies, percentages, means (95% CIs)). Generalized linear mixed models were used to compute and compare model-estimated rates and means.Results Participant-level cohort: 582 adults with diabetes were recruited (33.0% type 1 diabetes (T1D), 67.0% type 2 diabetes (T2D)). Mean age was 51.1 years (95% CI 49.5, 52.6); 80.7% publicly insured or uninsured; 43.7% non-Hispanic white (NHW), 31.6% Hispanic, 7.9% non-Hispanic black (NHB) and 16.8% other. Center-level cohort: 32 796 adults with diabetes were represented (3.4% with T1D, 96.6% with T2D; 72.7% publicly insured or uninsured). Florida had higher rates of uninsured (p9% HbA1c (p

Ethyl carbamate (EC) is a process contaminant found in fermented foods and alcoholic beverages. Metabolic conversion of ethyl carbamate generates vinyl carbamate (VC), a carcinogenic metabolite. EC, as a Group 2A probable human carcinogen, and the more potent VC, are known to cause tumors in rodents. However, their effects on the kidney are unknown and were explored here. Female A/J inbred mice received an intraperitoneal injection of vehicle or VC. Beginning 5 weeks after VC injection, mice showed signs of moribund state. Mouse necropsies revealed renal glomerular injury that histopathologically recapitulated human membranoproliferative glomerulonephritis (MPGN), as evidenced by light microscopy, immunostaining for immunoglobulins and complements, and electron microscopy. To determine the molecular pathomechanisms, a post-hoc analysis was performed on a publicly available RNA-Seq transcriptome of kidneys from control rats and rats treated with fermented wine containing high concentrations of EC. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the differentially expressed genes revealed that the complement and coagulation cascades were a top predicted biological process involved. Furthermore, pathway-based data integration and visualization revealed that key regulators of complement activation were altered by high EC treatment. Among these, complement factors (CF) D and H, critical positive and negative regulators of the alternative pathway, respectively, were most affected, with CFD induced by 3.49-fold and CFH repressed by 5.9-fold, underscoring a hyperactive alternative pathway. Consistently, exposure of primary glomerular endothelial cells to EC or VC resulted in induction of CFD and repression of CFH, accompanied by increased fixation of C3 and C5b9. This effect seems to be mediated by Ras, one of the top genes that interact with both EC and VC, as identified by analyzing the chemical-gene/protein interactions database. Indeed, EC or VC-elicited complement activation was associated with activation of Ras signaling, but was abolished by the Ras inhibitor farnesyl thiosalicylic acid. Collectively, our findings suggest that VC, a metabolite of EC, induces glomerular injury in mice akin to human MPGN, possibly via perturbing the expression of complement regulators, resulting in an effect that favors activation of the alternative complement pathway.

Landslides are destructive geohazards to people and infrastructure, resulting in hundreds of deaths and billions of dollars of damage every year. Therefore, mapping the rate of deformation of such geohazards and understanding their mechanics is of paramount importance to mitigate the resulting impacts and properly manage the associated risks. In this paper, the main outcomes relevant to the joint European Space Agency (ESA) and the Chinese Ministry of Science and Technology (MOST) Dragon-5 initiative cooperation project ID 59,339 “Earth observation for seismic hazard assessment and landslide early warning system” are reported. The primary goals of the project are to further develop advanced SAR/InSAR and optical techniques to investigate seismic hazards and risks, detect potential landslides in wide regions, and demonstrate EO-based landslide early warning system over selected landslides. This work only focuses on the landslide hazard content of the project, and thus, in order to achieve these objectives, the following tasks were developed up to now: a) a procedure for phase unwrapping errors and tropospheric delay correction; b) an improvement of a cross-platform SAR offset tracking method for the retrieval of long-term ground displacements; c) the application of polarimetric SAR interferometry (PolInSAR) to increase the number and quality of monitoring points in landslide-prone areas; d) the semiautomatic mapping and preliminary classification of active displacement areas on wide regions; e) the modeling and identification of landslides in order to identify triggering factors or predict future displacements; and f) the application of an InSAR-based landslide early warning system on a selected site. The achieved results, which mainly focus on specific sensitive regions, provide essential assets for planning present and future scientific activities devoted to identifying, mapping, characterizing, monitoring and predicting landslides, as well as for the implementation of early warning systems.

The smoking rate is high in patients with schizophrenia. Brain stimulation targeting conventional brain circuits associated with nicotine addiction has also yielded mixed results. We aimed to identify alternative circuitries associated with nicotine addiction in both the general population and schizophrenia, and then test whether modulation of such circuitries may alter nicotine addiction behaviors in schizophrenia. In Study I of 40 schizophrenia smokers and 51 non-psychiatric smokers, cross-sectional neuroimaging analysis identified resting state functional connectivity (rsFC) between the dorsomedial prefrontal cortex (dmPFC) and multiple extended amygdala regions to be most robustly associated with nicotine addiction severity in healthy controls and schizophrenia patients (p = 0.006 to 0.07). In Study II with another 30 patient smokers, a proof-of-concept, patient- and rater-blind, randomized, sham-controlled rTMS design was used to test whether targeting the newly identified dmPFC location may causally enhance the rsFC and reduce nicotine addiction in schizophrenia. Although significant interactions were not observed, exploratory analyses showed that this dmPFC–extended amygdala rsFC was enhanced by 4-week active 10Hz rTMS (p = 0.05) compared to baseline; the severity of nicotine addiction showed trends of reduction after 3 and 4 weeks (p ≤ 0.05) of active rTMS compared to sham; Increased rsFC by active rTMS predicted reduction of cigarettes/day (R = −0.56, p = 0.025 uncorrected) and morning smoking severity (R = −0.59, p = 0.016 uncorrected). These results suggest that the dmPFC–extended amygdala circuit may be linked to nicotine addiction in schizophrenia and healthy individuals, and future efforts targeting its underlying pathophysiological mechanisms may yield more effective treatment for nicotine addiction.

The relationship between many viruses and cellular autophagy is complex; autophagy is a useful mechanism of membrane rearrangement and trafficking, but autophagosomes can degrade virus components and newly formed virions. Picornaviruses, whose relationship to autophagy has been studied for almost thirty years, cause a range of diseases, from mild respiratory illnesses such as the common cold to major paralysis syndromes such as poliomyelitis and acute flaccid myelitis. Like most viruses with RNA genomes, picornaviruses translate, replicate, and package their genome in the cytosol, often in association with membranes. Early in picornavirus infections, there is an extensive rearrangement of intracellular membranes to form a replication platform, the cytosolic surface of which serves as the site for viral RNA replication. Later in infection, autophagosome-like vesicles bud from the replication organelle and are used to traffic viruses to the cell surface, releasing virus packets surrounded by the former inner membrane of the double-membrane autophagosome-like vesicles. Thus, picornaviruses must inhibit the degradative aspects of the pathway to prevent viral proteins or even newly formed virions from being consumed in autolysosomes. With this in mind, we recently described the dual-natured role of host TFEB (transcription factor EB), in the picornavirus virus cycle. TFEB is required for early infection, but cleaved by a viral protease late in infection as part of a viral strategy to subvert the autophagy machinery to remodel membranes while inhibiting degradative autophagy. This is a story out of Shakespeare, in which viruses betray a cellular ally in a manner worthy of Brutus; first usurping the function of TFEB, then cleaving that same protein when the needs of the virus change late in infection.

Multiligament knee reconstruction surgery is technically challenging, requiring careful planning and execution. Accurate placement of bone tunnels is important for graft function and there is an inherent risk of tunnel collision, which can compromise graft integrity. In this proof-of-concept study, we present a technique using computer navigation to help optimize tunnel placement and to avoid collision during multiligament knee reconstruction. A computed tomography (CT)-based navigation system was used to plan and execute femoral tunnel placement on a Sawbones model, for a Schenck KD-IV multiligament knee reconstruction. After CT scanning of the Sawbones model, commercially available software was used to plan tunnel trajectories for reconstruction of the posterolateral corner, medial ligament complex, and both cruciate ligaments. Tunnel entry points and trajectories were based on bony landmarks as identified on CT. The model was successfully registered with an accuracy of

Background Data on the benefits of cardiac resynchronization therapy (CRT) in patients with severe heart failure symptoms are limited. We investigated the relative effects of CRT in patients with ambulatory New York Heart Association (NYHA) IV versus III functional class at the time of device implantation. Methods and Results In this meta‐analysis, we pooled patient‐level data from the MIRACLE (Multicenter InSync Randomized Clinical Evaluation), MIRACLE‐ICD (Multicenter InSync Implantable Cardioversion Defibrillation Randomized Clinical Evaluation), and COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trials. Outcomes evaluated were time to the composite end point of the first heart failure hospitalization or all‐cause mortality, and time to all‐cause mortality alone. The association between CRT and outcomes was evaluated using a Bayesian hierarchical Weibull survival regression model. We assessed if this association differed between NYHA III and IV groups by adding an interaction term between CRT and NYHA class as a random effect. A sensitivity analysis was performed by including data from RAFT (Resynchronization‐Defibrillation for Ambulatory Heart Failure). Our pooled analysis included 2309 patients. Overall, CRT was associated with a longer time to heart failure hospitalization or all‐cause mortality (adjusted hazard ratio [aHR], 0.79 [95% credible interval [CI], 0.64–0.99]; posterior probability or P=0.044), with a similar association with time to all‐cause mortality (aHR, 0.78 [95% CI, 0.59–1.03]; P=0.083). Associations of CRT with outcomes were not significantly different for those in NYHA III and IV classes (ratio of aHR, 0.72 [95% CI, 0.30–1.27]; P=0.23 for heart failure hospitalization/mortality; ratio of aHR, 0.70 [95% CI, 0.35–1.34]; P=0.27 for all‐cause mortality alone). The sensitivity analysis, including RAFT data, did not show a significant relative CRT benefit between NYHA III and IV classes. Conclusions Overall, there was no significant difference in the association of CRT with either outcome for patients in NYHA functional class III compared with functional class IV.

The intracellular symbiont Wolbachia pipientis evolved after the divergence of arthropods and nematodes, but it reached high prevalence in many of these taxa through its abilities to infect new hosts and their germlines. Some strains exhibit long-term patterns of co-evolution with their hosts, while other strains are capable of switching hosts. This makes strain selection an important factor in symbiont-based biological control. However, little is known about the ecological and evolutionary interactions that occur when a promiscuous strain colonizes an infected host. Here, we study what occurs when two strains come into contact in host cells following horizontal transmission and infection. We focus on the faithful wMel strain from Drosophila melanogaster and the promiscuous wRi strain from Drosophila simulans using an in vitro cell culture system with multiple host cell types and combinatorial infection states. Mixing D. melanogaster cell lines stably infected with wMel and wRi revealed that wMel outcompetes wRi quickly and reproducibly. Furthermore, wMel was able to competitively exclude wRi even from minuscule starting quantities, indicating that this is a nearly deterministic outcome, independent of the starting infection frequency. This competitive advantage was not exclusive to wMel's native D. melanogaster cell background, as wMel also outgrew wRi in D. simulans cells. Overall, wRi is less adept at in vitro growth and survival than wMel and its in vivo state, revealing differences between the two strains in cellular and humoral regulation. These attributes may underlie the observed low rate of mixed infections in nature and the relatively rare rate of host-switching in most strains. Our in vitro experimental framework for estimating cellular growth dynamics of Wolbachia strains in different host species and cell types provides the first strategy for parameterizing endosymbiont and host cell biology at high resolution. This toolset will be crucial to our application of these bacteria as biological control agents in novel hosts and ecosystems.

Spontaneous intracerebral hemorrhage (sICH) is associated with significant morbidity and mortality, with subsequent hematoma expansion (HE) linked to worse neurologic outcomes. Accurate, real-time predictions of the risk of HE could enable tailoring management—including blood pressure control or surgery—based on individual patient risk. Although multiple radiographic markers of HE have been proposed based on standard imaging, their clinical utility remains limited by a reliance on subjective interpretation of often ambiguous findings and a poor overall predictive power. Radiomics refers to the quantitative analysis of medical images that can be combined with machine-learning algorithms to identify predictive features for a chosen clinical outcome with a granularity beyond human limitations. Emerging data have supported the potential utility of radiomics in the prediction of HE after sICH. In this review, we discuss the current clinical management of sICH, the impact of HE and standard imaging predictors, and finally, the current data and potential future role of radiomics in HE prediction and management of patients with sICH.

Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUVmax) was measured for all lesions, and PSMA response was defined as the percent change in SUVmax of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUVmax), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months (P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population. Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

Objective: In recent years, frailty has been reported to be an important predictive factor associated with worse outcomes in neurosurgical patients. The purpose of the present systematic review was to analyze the impact of frailty on outcomes of chronic subdural hematoma (cSDH) patients. Methods: We performed a systematic review of literature using the PubMed, Cochrane library, Wiley online library, and Web of Science databases following PRISMA guidelines of studies evaluating the effect of frailty on outcomes of cSDH published until January 31, 2023. Results: A comprehensive literature search of databases yielded a total of 471 studies. Six studies with 4085 patients were included in our final qualitative systematic review. We found that frailty was associated with inferior outcomes (including mortality, complications, recurrence, and discharge disposition) in cSDH patients. Despite varying frailty scales/indices used across studies, negative outcomes occurred more frequently in patients that were frail than those who were not. Conclusions: While the small number of available studies, and heterogenous methodology and reporting parameters precluded us from conducting a pooled analysis, the results of the present systematic review identify frailty as a robust predictor of worse outcomes in cSDH patients. Future studies with a larger sample size and consistent frailty scales/indices are warranted to strengthen the available evidence. The results of this work suggest a strong case for using frailty as a pre-operative risk stratification measure in cSDH patients.

Abstract We combined two climate‐based distribution models with three finer‐scale suitability models to identify habitat for pronghorn recovery in California now and into the future. We used a consensus approach to identify areas of suitable climate now and future for pronghorn in California. We compared the results of climate models from two separate hypotheses about their historical ecology in the state. Under the migration hypothesis, pronghorn were expected to be limited climatically by extreme cold in winter and extreme heat in summer; under the niche reduction hypothesis, historical pronghorn of distribution would have better represented the climatic limitations of the species. We combined occurrences from GPS collars distributed across three populations of pronghorn in the state to create three distinct habitat suitability models: (1) an ensemble model using random forests, Maxent, classification and regression Trees, and a generalized linear model; (2) a step selection function; and (3) an expert‐driven model. We evaluated consensus among both the climate models and the suitability models to prioritize areas for, and evaluate the prospects of, pronghorn recovery. Climate suitability for pronghorn in the future depends heavily on model assumptions. Under the migration hypothesis, our model predicted that there will be no suitable climate in California in the future. Under the niche reduction hypothesis, by contrast, suitable climate will expand. Habitat suitability also depended on the methods used, but areas of consensus among all three models exist in large patches throughout the state. Identifying habitat for a species which has undergone extreme range collapse, and which has very fine scale habitat needs, presents novel challenges for spatial ecologists. Our multimethod, multihypothesis approach can allow habitat modelers to identify areas of consensus and, perhaps more importantly, fill critical knowledge gaps that could resolve disagreements among the models. For pronghorn, a better understanding of their upper thermal tolerances and whether historical populations migrated will be crucial to their potential recovery in California and throughout the arid Southwest.

Abstract Increases in wildfire activity and rainfall intensification are driving more postfire debris flows (PFDF) in many regions around the world. PFDFs are most common in the first postfire year and may even occur before a fire is fully controlled. This underscores the importance of assessing postfire hazards before a fire starts. Evaluation of PFDF hazards prior to fire can help strategize interventions lessening the negative effects of future fires. However, debris‐flow runout and inundation analyses are not routine in PFDF hazard assessments, partially due to time constraints and substantial uncertainties in boundary conditions. Here, we propose a prefire PFDF inundation assessment framework using a debris‐flow runout model based on the Herschel‐Bulkley (HB) rheology (HEC‐RAS v6.1). We constrain model inputs and parameters using Bayesian posterior analysis, rainfall‐runoff simulations, and a debris‐flow volume model. We use observations from recent PFDF incidents in northern Arizona, USA, to calibrate model components and then apply our prefire inundation assessment framework in a nearby unburned area. Specifically, we (a) identify yield stress as the most influential factor on inundation extent and arrival time in a HB model, (b) establish posterior distributions for model parameters suitable for forward modeling by leveraging uncertainties in field observations, and (c) implement a predictive forward analysis in an area that has not burned recently to evaluate PFDF inundation under several future fire scenarios. This study improves our ability to assess postfire debris‐flow hazards before a fire begins and provides guidance for future applications of single‐phase rheological models when assessing PFDF hazards.

Introduction The underdevelopment of preterm infants can lead to delayed progression through key early milestones. Demonstration of safe oral feeding skills, constituting proper suck-swallow reflex are requirements for discharge from the neonatal intensive care unit (NICU) to ensure adequate nutrition acquisition. Helping an infant develop these skills can be draining and emotional for both families and healthcare staff involved in the care of preterm infants with feeding difficulties. Currently, there are no systematic reviews evaluating both family and healthcare team perspectives on aspects of oral feeding. Thus, we first aim to evaluate the current knowledge surrounding the perceptions, experiences and needs of families with preterm babies in the context of oral feeding in the NICU. Second, we aim to evaluate the current knowledge surrounding the perceptions, experiences and needs of healthcare providers (physicians, advanced practice providers, nurses, dietitians, speech-language pathologists and occupational therapists) in the context of oral feeding in the NICU.Methods and analysis A literature search will be conducted in multiple electronic databases from their inception, including PubMed, CINHAL, Embase, the Cochrane Central Register for Controlled Trials and PsycINFO. No restrictions will be applied based on language or data of publication. Two authors will screen the titles and abstracts and then review the full text for the studies’ inclusion in the review. The data will be extracted into a pilot-tested data collection sheet by three independent authors. To evaluate the quality, reliability and relevance of the included studies, the Critical Appraisal Skills Programme checklist will be used. The overall evidence will be assessed using the Grading of Recommendation Assessment, Development and Evaluation criteria. We will report the results of the systematic review by following the Enhancing Transparency in Reporting the synthesis of Qualitative research checklist.Ethics and dissemination Ethical approval of this project is not required as this is a systematic review using published and publicly available data and will not involve contact with human subjects. Findings will be published in a peer-reviewed journal.PROSPERO registration number CRD42023479288.

The paradigm of centralised water and wastewater services is coming under significant pressure from multiple global factors. Therefore, there is a need to consider the challenges and opportunities for decentralised water and wastewater technologies and systems. This search is particularly relevant within the context of Scotland, where a proportion of the population uses existing decentralised technologies. The Scottish context shows that those using decentralised services struggle to manage their water and wastewater services without appropriate support. However, the global goals of universal access to safe water and adequate sanitation, a just transition to net-zero and community empowerment, provide opportunities and policy pathways towards the implementation and improvement of decentralised technologies and systems. HIGHLIGHTS Decentralised water and wastewater systems provide an alternative to traditional carbon-intensive centralised infrastructure.; Challenges with existing decentralised systems in Scotland are a rural issue due to historical factors.; Opportunities for improvements to the management of decentralised systems are universal access to water and sanitation, a just transition to net-zero and community empowerment.;

Abstract Background Multicenter trials in orthopedic trauma are costly, yet crucial to advance the science behind clinical care. The number of sites is a key cost determinant. Each site has a fixed overhead cost, so more sites cost more to the study. However, more sites can reduce total costs by shortening the study duration. We propose to determine the optimal number of sites based on known costs and predictable site enrollment. Methods This retrospective marginal analysis utilized administrative and financial data from 12 trials completed by the Major Extremity Trauma Research Consortium. The studies varied in size, design, and clinical focus. Enrollment across the studies ranged from 1054 to 33 patients. Design ranged from an observational study with light data collection to a placebo-controlled, double-blinded, randomized controlled trial. Initial modeling identified the optimal number of sites for each study and sensitivity analyses determined the sensitivity of the model to variation in fixed overhead costs. Results No study was optimized in terms of the number of participating sites. Excess sites ranged from 2 to 39. Excess costs associated with extra sites ranged from $17K to $330K with a median excess cost of $96K. Excess costs were, on average, 7% of the total study budget. Sensitivity analyses demonstrated that studies with higher overhead costs require more sites to complete the study as quickly as possible. Conclusions Our data support that this model may be used by clinical researchers to achieve future study goals in a more cost-effective manner. Trial registration Please see Table 1 for individual trial registration numbers and dates of registration.

Path planning for a point-mass robot moving in a cluttered two-dimensional environment is a well studied but non-trivial problem. In this paper we propose a novel computationally efficient and resolution-complete path generation method based on electrostatics. The proposed scheme comprises two stages. First, an auxiliary electrostatic problem is formulated where the boundary conditions of the Laplace equation are specified based on the map of the original path planning problem and is solved to obtain a map-specific electrostatic potential. Second, feasible paths are constructed by following any equipotential curve whose potential value is different from those of obstacles and boundaries. The electrostatic potential in the proposed method differs from the celebrated repulsive/attractive force-based potential field by its non-vanishing gradient, based on which the resolution-completeness is established. The computational efficiency of the proposed method arises from a novel electrostatic solver based on complex analysis, and on an original collision-checking algorithm inspired by the Residue theorem. Extensive numerical examples are provided to demonstrate the effectiveness and limitations of the proposed method. We believe this work provides an unconventional strategy for quantitatively encoding global map information and can play a role complementary to prevailing path planning methods.

Traumatic brain injuries (TBIs) and concussions are prevalent in collision sports, and there is evidence that levels of exposure to such sports may increase the risk of neurological abnormalities. Elevated levels of fluid-based biomarkers have been observed after concussions or among athletes with a history of participating in collision sports, and certain biomarkers exhibit sensitivity toward neurodegeneration. This study investigated a cohort of 28 male amateur athletes competing in ?Masters? competitions for persons >35 years of age. The primary objective of this study was to compare the levels of blood and saliva biomarkers associated with brain injury, inflammation, aging, and neurodegeneration between athletes with an extensive history of collision sport participation (i.e., median?=?27 years; interquartile range?=?18?44, minimum?=?8) and those with no history. Plasma proteins associated with neural damage and neurodegeneration were measured using Simoa? assays, and saliva was analyzed for markers associated with inflammation and telomere length using quantitative real-time polymerase chain reaction. There were no significant differences between collision and non-collision sport athletes for plasma levels of glial fibrillary acidic protein, neurofilament light, ubiquitin C-terminal hydrolase L1, tau, tau phosphorylated at threonine 181, and brain-derived neurotrophic factor. Moreover, salivary levels of genes associated with inflammation and telomere length were similar between groups. There were no significant differences between groups in symptom frequency or severity on the Sport Concussion Assessment Tool?5th Edition. Overall, these findings provide preliminary evidence that biomarkers associated with neural tissue damage, neurodegeneration, and inflammation may not exhibit significant alterations in asymptomatic amateur athletes with an extensive history of amateur collision sport participation.

Abstract Objective Magnetic resonance (MR) measures of muscle quality are highly sensitive to disease progression and predictive of meaningful functional milestones in Duchenne muscular dystrophy (DMD). This investigation aimed to establish the reproducibility, responsiveness to disease progression, and minimum clinically important difference (MCID) for multiple MR biomarkers at different disease stages in DMD using a large natural history dataset. Methods Longitudinal MR imaging and spectroscopy outcomes and ambulatory function were measured in 180 individuals with DMD at three sites, including repeated measurements on two separate days (within 1 week) in 111 participants. These data were used to calculate day‐to‐day reproducibility, responsiveness (standardized response mean, SRM), minimum detectable change, and MCID. A survey of experts was also performed. Results MR spectroscopy fat fraction (FF), as well as MR imaging transverse relaxation time (MRI‐T2), measures performed in multiple leg muscles, and had high reproducibility (Pearson's R > 0.95). Responsiveness to disease progression varied by disease stage across muscles. The average FF from upper and lower leg muscles was highly responsive (SRM > 0.9) in both ambulatory and nonambulatory individuals. MCID estimated from the distribution of scores, by anchoring to function, and via expert opinion was between 0.01 and 0.05 for FF and between 0.8 and 3.7 ms for MRI‐T2. Interpretation MR measures of FF and MRI T2 are reliable and highly responsive to disease progression. The MCID for MR measures is less than or equal to the typical annualized change. These results confirm the suitability of these measures for use in DMD and potentially other muscular dystrophies.

Abstract Background Health care routinely fails Indigenous peoples and anti-Indigenous racism is common in clinical encounters. Clinical training programs aimed to enhance Indigenous cultural safety (ICS) rely on learner reported impact assessment even though clinician self-assessment is poorly correlated with observational or patient outcome reporting. We aimed to compare the clinical impacts of intensive and brief ICS training to control, and to assess the feasibility of ICS training evaluation tools, including unannounced Indigenous standardized patient (UISP) visits. Method Using a prospective parallel group three-arm randomized controlled trial design and masked standardized patients, we compared the clinical impacts of the intensive interactive, professionally facilitated, 8- to10-h Sanyas ICS training; a brief 1-h anti-bias training adapted to address anti-Indigenous bias; and control continuing medical education time-attention matched to the intensive training. Participants included 58 non-Indigenous staff physicians, resident physicians and nurse practitioners from family practice clinics, and one emergency department across four teaching hospitals in Toronto, Canada. Main outcome measures were the quality of care provided during UISP visits including adjusted odds that clinician would be recommended by the UISP to a friend or family member; mean item scores on patient experience of care measure; and clinical practice guideline adherence for NSAID renewal and pain assessment. Results Clinicians in the intensive or brief ICS groups had higher adjusted odds of being highly recommended to friends and family by standardized patients (OR 6.88, 95% CI 1.17 to 40.45 and OR 7.78, 95% CI 1.05 to 58.03, respectively). Adjusted mean item patient experience scores were 46% (95% CI 12% to 80%) and 40% (95% CI 2% to 78%) higher for clinicians enrolled in the intensive and brief training programs, respectively, compared to control. Small sample size precluded detection of training impacts on clinical practice guideline adherence; 100% of UISP visits were undetected by participating clinicians. Conclusions Patient-oriented evaluation design and tools including UISPs were demonstrated as feasible and effective. Results show potential impact of cultural safety training on patient recommendation of clinician and improved patient experience. A larger trial to further ascertain impact on clinical practice is needed. Trial registration Clinicaltrials.org NCT05890144. Retrospectively registered on June 5, 2023.

Objectives: Cardiac surgery using cardiopulmonary bypass contributes to a robust systemic inflammatory process. Local intrapericardial postsurgical inflammation is believed to trigger important clinical implications, such as postoperative atrial fibrillation and postsurgical intrathoracic adhesions. Immune mediators in the pericardial space may underlie such complications. Methods: In this prospective pilot clinical study, 12 patients undergoing isolated coronary artery bypass graft surgery were enrolled. Native pericardial fluid and venous blood samples (baseline) were collected immediately after pericardiotomy. Postoperative pericardial fluid and venous blood samples were collected 48-hours after cardiopulmonary bypass and compared with baseline. Flow cytometry determined proportions of specific immune cells, whereas multiplex analysis probed for inflammatory mediators. Results: Neutrophils are the predominant cells in both the pericardial space and peripheral blood postoperatively. There are significantly more CD163lo macrophages in blood compared with pericardial effluent after surgery. Although there are significantly more CD163hi macrophages in native pericardial fluid compared with baseline blood, after surgery there are significantly fewer of these cells present in the pericardial space compared with blood. Postoperatively, concentration of interleukin receptor antagonist 6, and interleukin 8 were significantly higher in the pericardial space compared with blood. After surgery, compared with blood, the pericardial space has a significantly higher concentration of matrix metalloproteinase 3, matrix metalloproteinase 8, and matrix metalloproteinase 9. The same trend was observed with transformational growth factor β. Conclusions: Cardiac surgery elicits an inflammatory response in the pericardial space, which differs from systemic inflammatory responses. Future work should determine whether or not this distinct local inflammatory response contributes to postsurgical complications and could be modified to influence clinical outcomes.

Abstract Predicting insect responses to climate change is essential for preserving ecosystem services and biodiversity. Due to high daytime temperatures and low humidity levels, nocturnal insects are expected to have lower heat and desiccation tolerance compared to diurnal species. We estimated the lower (CTMin) and upper (CTMax) thermal limits of Megalopta, a group of neotropical, forest-dwelling bees. We calculated warming tolerance (WT) as a metric to assess vulnerability to global warming and measured survival rates during simulated heatwaves and desiccation stress events. We also assessed the impact of body size and reproductive status (ovary area) on bees’ thermal limits. Megalopta displayed lower CTMin, CTMax, and WTs than diurnal bees (stingless bees, orchid bees, and carpenter bees), but exhibited similar mortality during simulated heatwave and higher desiccation tolerance. CTMin increased with increasing body size across all bees but decreased with increasing body size and ovary area in Megalopta, suggesting a reproductive cost or differences in thermal environments. CTMax did not increase with increasing body size or ovary area. These results indicate a greater sensitivity of Megalopta to temperature than humidity and reinforce the idea that nocturnal insects are thermally constrained, which might threaten pollination services in nocturnal contexts during global warming.

Western Monarch butterflies (Danaus plexippus) migrate from inland breeding ranges to coastal overwintering grounds in California. Given that migratory individuals may make multi-scale habitat selection decisions, we considered a multi-scale species distribution model (SDM) using range-wide climatic and local landscape-level predictors of migratory and overwintering habitat and community-science presence data. The range-wide model output was included as a predictor in the local-scale model, generating multi-scale habitat suitability. The top range-wide predictor was the minimum temperature in December, contributing 83.7% to the model, and was positively associated with presence. At the local scale, the strongest predictors of presence were the range-wide output and percent coverage of low and medium levels of development, contributing > 95%, with 61–63% from the range-wide output, with local-scale suitability coinciding with the California coastal zones. Development’s positive association with overwintering monarch presence was counterintuitive. It is likely that our local-scale model is overfit to these development zones, but it is unclear whether this overfitting resulted from modeler choices, monarchs overwintering close to human development, biased detection near human development, or a combination of these factors. Therefore, alternative approaches to collecting local-scale attribute data are suggested while recognizing the primacy of climate in restricting overwinter sites.

Immunotherapy represents a transformative shift in cancer treatment. Among myriad immune-based approaches, chimeric antigen receptor (CAR) T-cell therapy has shown promising results in treating hematological malignancies. Despite aggressive treatment options, the prognosis for patients with malignant brain tumors remains poor. Research leveraging CAR T-cell therapy for brain tumors has surged in recent years. Pre-clinical models are crucial in evaluating the safety and efficacy of these therapies before they advance to clinical trials. However, current models recapitulate the human tumor environment to varying degrees. Novel in vitro and in vivo techniques offer the opportunity to validate CAR T-cell therapies but also have limitations. By evaluating the strengths and weaknesses of various pre-clinical glioma models, this review aims to provide a roadmap for the development and pre-clinical testing of CAR T-cell therapies for brain tumors.

BackgroundWhen research evidence is limited, inconsistent, or absent, healthcare decisions and policies need to be based on consensus amongst interested stakeholders. In these processes, the knowledge, experience, and expertise of health professionals, researchers, policymakers, and the public are systematically collected and synthesised to reach agreed clinical recommendations and/or priorities. However, despite the influence of consensus exercises, the methods used to achieve agreement are often poorly reported. The ACCORD (ACcurate COnsensus Reporting Document) guideline was developed to help report any consensus methods used in biomedical research, regardless of the health field, techniques used, or application. This explanatory document facilitates the use of the ACCORD checklist.Methods and findingsThis paper was built collaboratively based on classic and contemporary literature on consensus methods and publications reporting their use. For each ACCORD checklist item, this explanation and elaboration document unpacks the pieces of information that should be reported and provides a rationale on why it is essential to describe them in detail. Furthermore, this document offers a glossary of terms used in consensus exercises to clarify the meaning of common terms used across consensus methods, to promote uniformity, and to support understanding for consumers who read consensus statements, position statements, or clinical practice guidelines. The items are followed by examples of reporting items from the ACCORD guideline, in text, tables and figures.ConclusionsThe ACCORD materials - including the reporting guideline and this explanation and elaboration document - can be used by anyone reporting a consensus exercise used in the context of health research. As a reporting guideline, ACCORD helps researchers to be transparent about the materials, resources (both human and financial), and procedures used in their investigations so readers can judge the trustworthiness and applicability of their results/recommendations.

Microorganisms are a valuable source of pharmaceutically active chemicals, serving as scaffolds for synthesis as well as lead structures. Investigating novel biomes frequently yields intriguing chemistry; the Atacama Desert in Chile is one such example. This study reports the isolation of a new reduced anthracycline-related compound from the Atacama Desert-derived bacterium Saccharothrix S26. Structural characterisation was achieved by one-dimensional and two-dimensional NMR, HR-LCMS, and X-ray crystallography. The compound was tested against the ESKAPE pathogens, bovine mastitis-related pathogens, and the fungal strain Cryptococcus neoformans, but no antimicrobial activity was observed.

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In this white paper, we describe the founding of a new ELIXIR Community - the Systems Biology Community - and its proposed future contributions to both ELIXIR and the broader community of systems biologists in Europe and worldwide. The Community believes that the infrastructure aspects of systems biology - databases, (modelling) tools and standards development, as well as training and access to cloud infrastructure - are not only appropriate components of the ELIXIR infrastructure, but will prove key components of ELIXIR’s future support of advanced biological applications and personalised medicine. By way of a series of meetings, the Community identified seven key areas for its future activities, reflecting both future needs and previous and current activities within ELIXIR Platforms and Communities. These are: overcoming barriers to the wider uptake of systems biology; linking new and existing data to systems biology models; interoperability of systems biology resources; further development and embedding of systems medicine; provisioning of modelling as a service; building and coordinating capacity building and training resources; and supporting industrial embedding of systems biology. A set of objectives for the Community has been identified under four main headline areas: Standardisation and Interoperability, Technology, Capacity Building and Training, and Industrial Embedding. These are grouped into short-term (3-year), mid-term (6-year) and long-term (10-year) objectives.

For social groups to form and be stable over time, animals must develop strategies to cope with conflict among group members. Animals may behave submissively either by fleeing from an aggressor, or by signalling submission. The use of these two submissive responses may vary depending on the social and ecological context. Group size is a key aspect of social context for group living animals, as individuals in smaller groups may respond to aggression differently than those from larger groups. Here, we examine the relationship between group size and submissive behaviour in a cooperatively breeding fish, the daffodil cichlid (Neolamprologus pulcher). We found that subordinate fish showed similar levels of submission signals in response to dominant aggression in larger and smaller groups, however, subordinates from larger groups were less likely to flee from dominant aggression than those in smaller groups. Subordinates in larger groups also showed more digging behaviour which may be also used to avoid conflict with the dominant group members. Our data show that social context affects submissive behaviour in a cooperatively breeding fish.