Minibox: Custom solo or semi-group housing chambers for long term housing of rats with miniscopes.

In this detailed procedure, we include open-source methodologies using 'solidworks' designs for creating solo or semi-group housing units for rats wearing miniscopes for long periods of time. Builds are optimized to preserve rat health and prevent hardware destruction. We include all prices and suggestions for purchasing strategies to reduce overall build-costs.•Chambers are optimized for long-term housing to protect rats wearing delicate headstages (e.g., miniscopes).•Designed to be low-cost, efficient supplement to operant chambers and provides numerous benefits to long-term miniscope imaging. The housing chambers can be augmented by installing cameras, commutators, or different types of floor grids depending on experimental conditions.•The chambers can also be secured to one another to create "rat-duplexes", allowing experimenters to control the degree of social isolation.

The development and validation of a survey to measure fecal-oral child exposure to zoonotic enteropathogens: The FECEZ Enteropathogens Index.

Child exposure to animal feces and associated enteropathogens contribute to a significant burden of disease in low- and middle-income countries. However, there are no standardized, validated survey-based approaches to enable accurate assessment of child exposure to zoonotic enteropathogens. We developed and validated a survey-based measure of exposure, the fecal-oral child exposure to zoonotic enteropathogens Index (the FECEZ Enteropathogens Index). First, we identified critical attributes of child exposure through in-depth interviews (IDIs) in Ecuador among individuals who care for animals (n = 29) and mothers of children under two years old (n = 58), and through a systematic review of existing exposure measures. Second, based on these findings, we developed a 105-question survey and administered it to 297 mothers with children under age five. Third, we refined the survey, using principal component analysis to determine the optimal number of components. The final index consisted of 34 items across two sub-domains: the child Environment and child Behavior. Lastly, we compared index scores to two commonly used, unvalidated measures of child exposure-maternal reported household animal ownership and presence of animal feces. Using the FECEZ Enteropathogens Index revealed varying degrees of exposure in our study population, with only two children having no exposure. In contrast, if we had used animal ownership or the presence of animal feces as a measure of exposure, 44% and 33% of children would have been classified as having no exposure, respectively. These common binary exposure measures may be inadequate because they do not provide sufficient information to identify the relative risk of zoonotic pathogen exposure. The FECEZ Enteropathogens Index overcomes this limitation, advancing our ability to assess exposure by quantifying the multiple components of child exposure to zoonotic enteropathogens with higher resolution. Additional testing and evaluation of the index is needed to ensure its reliability, validity, and cross-cultural equivalence in other contexts.

Effects of Sotagliflozin on Health Status in Patients With Worsening Heart Failure: Results From SOLOIST-WHF.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve health status in heart failure (HF) across the left ejection fraction ejection spectrum. However, the effects of SGLT1 and SGLT2 inhibition on health status are unknown. OBJECTIVES: These prespecified analyses of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial examined the effects of sotagliflozin vs placebo on HF-related health status. METHODS: SOLOIST-WHF randomized patients hospitalized or recently discharged after a worsening HF episode to receive sotagliflozin or placebo. The primary endpoint was total number of HF hospitalizations, urgent HF visits, and cardiovascular death. Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score was a prespecified secondary endpoint. This analysis evaluated change in the KCCQ-12 score from baseline to month 4. RESULTS: Of 1,222 patients randomized, 1,113 (91%) had complete KCCQ-12 data at baseline and 4 months. The baseline KCCQ-12 score was low overall (median: 41.7; Q1-Q3: 27.1-58.3) and improved by 4 months in both groups. Sotagliflozin vs placebo reduced the risk of the primary endpoint consistently across KCCQ-12 tertiles (Ptrend = 0.54). Sotagliflozin-treated patients vs those receiving placebo experienced modest improvement in KCCQ-12 at 4 months (adjusted mean change: 4.1 points; 95% CI: 1.3-7.0 points; P = 0.005). KCCQ-12 improvements were consistent across prespecified subgroups, including left ventricular ejection fraction <50% or ≥50%. More patients receiving sotagliflozin vs those receiving placebo had at least small (≥5 points) improvements in KCCQ-12 at 4 months (OR: 1.38; 95% CI: 1.06-1.80; P = 0.017). CONCLUSIONS: Sotagliflozin improved symptoms, physical limitations, and quality of life within 4 months after worsening HF, with consistent benefits across baseline demographic and clinical characteristics. (Effect of Sotagliflozin on Cardiovascular Events in Participants With Type 2 Diabetes Post Worsening Heart Failure [SOLOIST-WHF]; NCT03521934).

Chemotactic signaling pathways in prostate cancer: Implications in the tumor microenvironment and as potential therapeutic targets.

Prostate cancer (PCa) stands as a significant global health concern, ranking among the leading causes of cancer deaths in men. While there are several treatment modalities for localized PCa, metastatic castration-resistant PCa (mCRPC) remains incurable. Despite therapeutic advancements showing promise in mCRPC, their impact on overall survival has been limited. This chapter explores the process by which tumors form, reviews our current understanding of PCa progression to mCRPC, and addresses the challenges of boosting anti-tumor immune responses in these tumors. It specifically discusses how chemotactic signaling affects the tumor microenvironment and its role in immune evasion and cancer progression. The chapter further examines the rationale of directly or indirectly targeting these pathways as adjuvant therapies for mCRPC, highlighting recent pre-clinical and clinical studies currently underway. The discussion emphasizes the potential of targeting specific chemokines and chemokine receptors as combination therapies with mainstream treatments for PCa and mCRPC to maximize long-term survival for this deadly disease.

LACK OF AGREEMENT BETWEEN A POINT-OF-CARE BLOOD URIC ACID METER AND A BENCHTOP CHEMISTRY ANALYZER IN EASTERN BOX TURTLES (TERRAPENE CAROLINA CAROLINA).

Uric acid (UA) is excreted as an end product of protein metabolism in many reptiles, including some chelonians. Elevated plasma UA concentrations can occur due to many physiologic and pathologic changes, and determining plasma UA concentrations is part of a complete general health assessment in this taxon. UA concentrations are typically measured using benchtop chemistry analyzers, but point-of-care (POC) UA meters have also been developed for human use. However, these POC UA meters have not been investigated for use in any reptile species. The purpose of this study was to assess agreement between UA measurements produced by a standard benchtop chemistry analyzer and a POC UA meter in free-living eastern box turtles (Terrapene carolina carolina). UA concentrations were measured with a POC meter using fresh whole blood and frozen-thawed plasma and with a standard benchtop chemistry analyzer using frozen-thawed plasma. Poor-to-moderate agreement was present between each of the three methods as evidenced by mixed models, Passing-Bablok regression, Bland-Altman plots, and Cohen's κ. Differences between methods fell outside of clinically acceptable limits, indicating that the POC UA meter should not be used in eastern box turtles.

HEALTH ASSESSMENT OF SPOTTED (CLEMMYS GUTTATA) AND PAINTED (CHRYSEMYS PICTA) TURTLES IN CAPE COD, MASSACHUSETTS, U.S.A, WITH DETECTION OF A NOVEL ADENOVIRUS.

Freshwater turtles face numerous anthropogenic threats worldwide. Health assessments are a key component of chelonian population assessment and monitoring but are under reported in many species. The purpose of this study was to characterize the health of spotted turtles (Clemmys guttata; n = 30) and painted turtles (Chrysemys picta; n = 24) at Camp Edwards, a military base in Cape Cod, Massachusetts, using physical examinations, hematology, plasma heavy metal analyses, and pathogen surveillance via PCR. Spotted turtles had a high prevalence of carapace (n = 27, 90%) and plastron (n = 14, 46.7%) lesions, and a previously undescribed adenovirus was detected in three animals (proposed as Clemmys adenovirus-1). Female painted turtles had lower plasma copper (p = 0.012) and higher strontium (p = 0.0003) than males, and appeared to be in a similar plane of health to previous reports. This initial health assessment effort provides useful baseline data for future comparison in these species. Conservation efforts on Camp Edwards should incorporate continued health surveillance of these populations to identify intervention opportunities and determine the conservation threats, if any, of the novel adenovirus.

Descriptive analysis of recommendations made by county-level overdose fatality review teams in indiana to combat the opioid epidemic.

Overdose fatality review teams (OFRTs) are becoming more common across U.S. communities as a means of addressing the overdose epidemic and improving local overdose prevention strategies; however, empirical examinations of the work of OFRTs are lacking. The current study seeks to characterize recommendations for local overdose prevention strategies made by county-level OFRTs across Indiana in order to understand their practices. METHODS: A qualitative descriptive content analysis was conducted on recommendations made by 19 county-level OFRTs across Indiana in 2022. RESULTS: OFRTs generated 1512 recommendations during 2022 based on case reviews of 291 overdose deaths occurring across 19 Indiana counties; of those, 26.8 % (n=405) were specific to the case reviewed, rather than relevant to the broader community, and were not further coded. The remaining 1109 recommendations were coded according to their overall scope, recommendation strategy, and target agency. The most common recommendations addressed substance use more broadly (e.g., improving substance use screening/assessment in healthcare settings), followed by recommendations directly addressing overdose risk (e.g., naloxone distribution, increasing harm reduction programs). Other common recommendations related to mental health, OFRT practices, and addressing social determinants of health. Common recommendation strategies were to implement new services or service improvements. CONCLUSION: Results highlight the extent of further efforts needed to improve overdose prevention and the need for further research and support of OFRTs across the United States.

How we Solved the Shortage of Cardiothoracic Surgeons: Train More or Work Longer.

BACKGROUND: In the early 2000s, a significant shortage of cardiothoracic surgeons was predicted. We sought to evaluate our specialty's progress and update the predicted needs of cardiothoracic surgeons in the coming decades. METHODS: To assess the supply of cardiothoracic surgeons, the evolution of cardiothoracic surgery training was reviewed. The cardiothoracic surgery workforce and future supply and demand were obtained from the National Center for Health Workforce Analysis. Based on these data, predictions from the early 2000s were compared to the current status, and future supply of cardiothoracic surgeons was modeled. RESULTS: The number of cardiothoracic surgery trainees increased from 230 in 2008-2009 to 519 in 2022-2023. In 2022-2023, 174 trainees underwent the American Board of Thoacic Surgery Certification Exam with 129 certificates awarded. From 2005 to 2021, the total number of practicing cardiothoracic surgeons in the United States increased from 4000 to 5200, which contradicts all projections from the early 2000s. The average attrition of 31 cardiothoracic surgeons per year was significantly less than predictive models from the early 2000s. Predictive models project a need of 7000 cardiothoracic surgeons by 2050 - which can be met if we continue to fill our available training spots with 173 graduates-per-year. CONCLUSIONS: The predicted shortage of cardiothoracic surgeons by mid-century has been overcome by training more cardiothoracic surgeons as well as a reduction in cardiothoracic surgeon attrition. Future increasing demand can be met by filling our available training positions. Continual assessment of cardiothoracic surgeon supply and demand will help achieve the optimal number of cardiothoracic surgery training positions.

Gut Analysis Toolbox: Automating quantitative analysis of enteric neurons.

The enteric nervous system (ENS) consists of an extensive network of neurons and glial cells embedded within the wall of the gastrointestinal (GI) tract. Alterations in neuronal distribution and function are strongly associated with GI dysfunction. Current methods for assessing neuronal distribution suffer from undersampling, partly due to challenges associated with imaging and analyzing large tissue areas, and operator bias due to manual analysis. We present the Gut Analysis Toolbox (GAT), an image analysis tool designed for characterization of enteric neurons and their neurochemical coding using 2D images of GI wholemount preparations. It is developed in Fiji, has a user-friendly interface and offers rapid and accurate segmentation via custom deep learning (DL) based cell segmentation models developed using StarDist, and a ganglion segmentation model in deepImageJ. We use proximal neighbor-based spatial analysis to reveal differences in cellular distribution across gut regions using a public dataset. In summary, GAT provides an easy-to-use toolbox to streamline routine image analysis tasks in ENS research. GAT enhances throughput allowing unbiased analysis of larger tissue areas, multiple neuronal markers and numerous samples rapidly.

Primate superior colliculus is causally engaged in abstract higher-order cognition.

The superior colliculus is an evolutionarily conserved midbrain region that is thought to mediate spatial orienting, including saccadic eye movements and covert spatial attention. Here, we reveal a role for the superior colliculus in higher-order cognition, independent of its role in spatial orienting. We trained rhesus macaques to perform an abstract visual categorization task that involved neither instructed eye movements nor differences in covert attention. We compared neural activity in the superior colliculus and the posterior parietal cortex, a region previously shown to causally contribute to abstract category decisions. The superior colliculus exhibits robust encoding of learned visual categories, which is stronger than in the posterior parietal cortex and arises at a similar latency in the two areas. Moreover, inactivation of the superior colliculus markedly impaired animals' category decisions. These results demonstrate that the primate superior colliculus mediates abstract, higher-order cognitive processes that have traditionally been attributed to the neocortex.

Dynamic chromatin architecture identifies new autoimmune-associated enhancers for IL2 and novel genes regulating CD4+ T cell activation.

Genome-wide association studies (GWAS) have identified hundreds of genetic signals associated with autoimmune disease. The majority of these signals are located in non-coding regions and likely impact cis-regulatory elements (cRE). Because cRE function is dynamic across cell types and states, profiling the epigenetic status of cRE across physiological processes is necessary to characterize the molecular mechanisms by which autoimmune variants contribute to disease risk. We localized risk variants from 15 autoimmune GWAS to cRE active during TCR-CD28 co-stimulation of naïve human CD4+ T cells. To characterize how dynamic changes in gene expression correlate with cRE activity, we measured transcript levels, chromatin accessibility, and promoter-cRE contacts across three phases of naive CD4+ T cell activation using RNA-seq, ATAC-seq, and HiC. We identified ~1200 protein-coding genes physically connected to accessible disease-associated variants at 423 GWAS signals, at least one-third of which are dynamically regulated by activation. From these maps, we functionally validated a novel stretch of evolutionarily conserved intergenic enhancers whose activity is required for activation-induced IL2 gene expression in human and mouse, and is influenced by autoimmune-associated genetic variation. The set of genes implicated by this approach are enriched for genes controlling CD4+ T cell function and genes involved in human inborn errors of immunity, and we pharmacologically validated eight implicated genes as novel regulators of T cell activation. These studies directly show how autoimmune variants and the genes they regulate influence processes involved in CD4+ T cell proliferation and activation.

Flexor tendon rupture following repeated corticosteroid injections for carpal tunnel syndrome: A case report.

INTRODUCTION: Corticosteroid injection (CSI) for carpal tunnel syndrome is a common diagnostic and therapeutic procedure. Adverse effects of corticosteroid injections are infrequent, though rare cases of flexor tendon rupture have been documented. PRESENTATION OF CASE: We present a case of a 67-year-old female with acute loss of left index finger flexion due to rupture of the left index flexor digitorum profundus (FDP) and the flexor digitorum superficialis (FDS) tendons and left long finger FDS tendon following numerous carpal tunnel corticosteroid injections. Intraoperatively, she was also found to have a complete rupture of the long finger FDS and partial rupture of the long finger FDP. Side-to-side tendon transfers were performed to restore the flexor tendon function. DISCUSSION: The overall incidence of serious adverse effects in patients receiving CSIs for carpal tunnel syndrome, including flexor tendon rupture, intraneural injection or gangrene, is extremely low. Only three cases of flexor tendon ruptures following CSI for carpal tunnel syndrome have been reported in the literature. Given our patient's multiple CSIs per year over the course of 6 years, she may have been at increased risk of spontaneous tendon rupture given extra-articular CSIs can result in tendon rupture as a rare, but serious complication. CONCLUSION: This case demonstrates that flexor tendon ruptures are a possible, although rare, complication following steroid injections for carpal tunnel syndrome. Proper injection techniques should be used to minimize adverse effects.

Long-term Risk of Right Coronary Artery Injury Following Catheter Ablation of Cavotricuspid Isthmus-dependent Flutter.

BACKGROUND: Radiofrequency ablation (RFA) of cavotricuspid isthmus (CTI)-dependent atrial flutter requires ablation of the tricuspid annulus overlying the right coronary artery (RCA). While considered safe, reports of acute and subacute RCA injury in human and animal studies raise the possibility of late RCA stenosis. OBJECTIVE: To compare the incidence and severity of angiographic RCA stenoses in patients who have undergone CTI RFA to a control group to assess the long-term risk of RCA damage. METHODS: A two-center retrospective case-cohort study was performed including all patients from 2002-2018 undergoing atrial fibrillation (AF) with CTI ablation (CTI+AF) or AF ablation alone with subsequent coronary angiography (CAG). The AF alone group served as controls due to anticipated similarity of baseline characteristics. Coronary arteries that are anatomically remote to the CTI were examined as prespecified falsification endpoints. CAG was scored by a blinded observer. RESULTS: 156 patients who underwent PVI with subsequent CAG (CTI+AF, n=81; AF alone, n=75) had no difference in baseline characteristics including age, sex, comorbidities, and medications. Mean time from ablation to CAG was similar (CTI+AF 5.0±3.7 years vs AF alone 5.4 ±3.9 years, p=0.5). The mid and distal RCA showed no difference in the average number of angiographic stenoses or lesion severity. In regression analysis, CTI ablation was not a predictor of RCA stenosis severity (p=0.6). There was no difference in coronary disease at sites remote to the CTI ablation (p=NS for all). CONCLUSION: There was no observed relationship between CTI RFA and the number or severity of angiographically apparent RCA stenoses in long-term follow up.

Establishing human microbial observatory programs in low- and middle-income countries.

Studies of the human microbiome are progressing rapidly but have largely focused on populations living in high-income countries. With increasing evidence that the microbiome contributes to the pathogenesis of diseases that affect infants, children, and adults in low- and middle-income countries (LMICs), and with profound and rapid ongoing changes occurring in our lifestyles and biosphere, understanding the origins of and developing microbiome-directed therapeutics for treating a number of global health challenges requires the development of programs for studying human microbial ecology in LMICs. Here, we discuss how the establishment of long-term human microbial observatory programs in selected LMICs could provide one timely approach.

Acute Cardiovascular Responses to the 100-Mile Western States Endurance Run.

Ultramarathon participation is growing in popularity and exposes runners to unique stressors including extreme temperatures, high altitude, and exceedingly long exercise duration. However, the acute effects of ultramarathon participation on the cardiovascular system are not well understood. PURPOSE: To determine the acute effects of trail ultramarathon participation on central artery stiffness and hemodynamics. METHODS: Forty-one participants (9F, 32M) participating in the 2023 Western States Endurance Run underwent measures of carotid-femoral pulse wave velocity (cf-PWV) and pulse wave analysis pre- and <1h post-race. Subendocardial viability ratio (SEVR) was calculated from central blood pressure (BP) waveforms. Serum was analyzed for creatine kinase (CK) activity as a measure of muscle damage. Normally distributed data are presented as mean±SD and non-normally distributed data are presented as median (interquartile range). RESULTS: Runners were middle-aged and generally lean (age=44±9 y, BMI=22.7±1.8 kg●m-2). There was no difference in cf-PWV from pre- to post-race (pre=6.4±1.0, post=6.2±0.85 m/s, p=0.104), a finding that persisted after adjusting for mean arterial pressure (p=0.563). Systolic and diastolic BP were lower post-race (pre=129/77±9/7, post=122/74±10/8 mmHg, ps<0.001). Augmentation index (AIx; pre=17.3±12.2, post=6.0±13.7%, p<0.001), AIx normalized to a heart rate of 75bpm (p=0.043), reflection magnitude (pre=55.5(49.0-60.8), post=45.5(41.8-48.8) %, p<0.001), and SEVR (pre=173.0(158.0-190.0), post=127.5(116.5-145.8) %, p<0.001) were reduced post-race. CK increased markedly from pre- to post-race (pre=111(85-162), post=11,973(5,049-17,954) U/L, p<0.001). CONCLUSIONS: Completing a 161-km trail ultramarathon does not affect central arterial stiffness and acutely reduces BP despite eliciting profound muscle damage. However, the reduced post-race SEVR suggests a short-term mismatch between myocardial work and coronary artery perfusion.

Multilevel factors drive child exposure to enteric pathogens in animal feces: A qualitative study in northwestern coastal Ecuador.

Exposure to animal feces and associated enteric pathogens poses significant risks to child health. However, public health strategies to mitigate enteric infections among children largely aim to reduce exposure to human feces, overlooking transmission pathways related to animal feces. In this study we examine if and how children are exposed to enteric pathogens in animal feces in northwestern coastal Ecuador. We conducted qualitative interviews with mothers of children aged 10-18 months that owned (n = 32) and did not own (n = 26) animals in urban and rural communities. Using thematic analysis, we identified community, household, and child behavioral factors that influence exposure. We also compared child exposure by household animal ownership. Our findings revealed myriad opportunities for young children to be exposed to enteric pathogens in many locations and from multiple animal sources, regardless of household animal ownership. Animal feces management practices (AFM) used by mothers, such as rinsing feces into ditches and throwing feces into surrounding areas, may increase environmental contamination outside their homes and in their communities. Unsafe AFM practices were similar to unsafe child feces management practices reported in other studies, including practices related to defecation location, feces removal and disposal, environmental contamination cleaning, and handwashing. Findings suggest that animal feces may contaminate the environment along similar pathways as human feces. Identification and incorporation of safe AFM practices, similar to those developed for child feces management, would 1) mitigate child exposure to enteric pathogens by reducing animal feces contamination in domestic and public spaces; and 2) enable an integrated approach to address enteric pathogen exposure pathways related to animal and child feces.

NCI's Proteomic Data Commons: A Cloud-Based Proteomics Repository Empowering Comprehensive Cancer Analysis through Cross-Referencing with Genomic and Imaging Data.

Proteomics has emerged as a powerful tool for studying cancer biology, developing diagnostics, and therapies. With the continuous improvement and widespread availability of high-throughput proteomic technologies, the generation of large-scale proteomic data has become more common in cancer research, and there is a growing need for resources that support the sharing and integration of multi-omics datasets. Such datasets require extensive metadata including clinical, biospecimen, and experimental and workflow annotations that are crucial for data interpretation and reanalysis. The need to integrate, analyze, and share these data has led to the development of NCI's Proteomic Data Commons (PDC), accessible at https://pdc.cancer.gov. As a specialized repository within the NCI Cancer Research Data Commons (CRDC), PDC enables researchers to locate and analyze proteomic data from various cancer types and connect with genomic and imaging data available for the same samples in other CRDC nodes. Presently, PDC houses annotated data from more than 160 datasets across 19 cancer types, generated by several large-scale cancer research programs with cohort sizes exceeding 100 samples (tumor and associated normal when available). In this article, we review the current state of PDC in cancer research, discuss the opportunities and challenges associated with data sharing in proteomics, and propose future directions for the resource. SIGNIFICANCE: The Proteomic Data Commons (PDC) plays a crucial role in advancing cancer research by providing a centralized repository of high-quality cancer proteomic data, enriched with extensive clinical annotations. By integrating and cross-referencing with complementary genomic and imaging data, the PDC facilitates multi-omics analyses, driving comprehensive insights, and accelerating discoveries across various cancer types.

Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone.

Heart failure is a leading cause of morbidity and mortality1,2. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion3-8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect9,10. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.