Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 months of an ongoing randomized phase 3 trial.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol /0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month, double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The co-primary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy versus placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% versus 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% versus 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was < 1% and was attenuated compared with bone loss observed with elagolix monotherapy.

Predicting the Collapse of Pain Medicine Using the Economic Recession of 2008 as a Comparator: Lessons Remain Unlearned.

The last decade has seen a boom in pain medicine, basic science and interventional pain management. Concomitantly, there is a need to educate trainees, young attendings, and seasoned attendings on these innovations. There has been a growth in the number of societies that represent pain medicine physicians, each with its own philosophy and guiding principles. The variety of thought within pain management, within the various groups that practice this field, and amongst the societies which protect those missions inherently creates divergence and isolation within these different communities. There is the enormous opportunity for our field to grow, but we need the voices of all different specialties and sub-specialties which practice pain medicine to collectively design the future of our emerging field. The explosion of revolutionary percutaneous surgeries, medications, psychotherapy, and research and development in our field has outpaced the ability of payers to fully embrace them. There is an increased number of pain practitioners using novel therapies, postgraduate training programs do not adequately train users in these techniques thereby creating a potential for sub-optimal outcomes. In part, this is a reason why payers for many of our more novel treatments have decreased patient access or eliminated remuneration for some of them. We believe that society-based collaborative regulation of education, research, and treatment guidelines is needed to improve visibility for payers and end users who provide these treatments. Furthermore, postgraduate chronic pain fellowship education has been deemed by many to be insufficient to educate on all of the necessary requirements needed for the independent practice of pain medicine, especially the consummation of newer technologies. Here, we draw comparison with this tenuous stage in pain management history with the last United States recession to remind us of how poor institutional regulation and neglect for long-term growth hampers a community.

Advancing Medical Imaging Research Through Standardization: The Path to Rapid Development, Rigorous Validation, and Robust Reproducibility.

ABSTRACT: Artificial intelligence (AI) has made significant advances in radiology. Nonetheless, challenges in AI development, validation, and reproducibility persist, primarily due to the lack of high-quality, large-scale, standardized data across the world. Addressing these challenges requires comprehensive standardization of medical imaging data and seamless integration with structured medical data.Developed by the Observational Health Data Sciences and Informatics community, the OMOP Common Data Model enables large-scale international collaborations with structured medical data. It ensures syntactic and semantic interoperability, while supporting the privacy-protected distribution of research across borders. The recently proposed Medical Imaging Common Data Model is designed to encompass all DICOM-formatted medical imaging data and integrate imaging-derived features with clinical data, ensuring their provenance.The harmonization of medical imaging data and its seamless integration with structured clinical data at a global scale will pave the way for advanced AI research in radiology. This standardization will enable federated learning, ensuring privacy-preserving collaboration across institutions and promoting equitable AI through the inclusion of diverse patient populations. Moreover, it will facilitate the development of foundation models trained on large-scale, multimodal datasets, serving as powerful starting points for specialized AI applications. Objective and transparent algorithm validation on a standardized data infrastructure will enhance reproducibility and interoperability of AI systems, driving innovation and reliability in clinical applications.

Defining a screening tool for post-traumatic stress disorder in East Africa: a penalized regression approach.

Background: Scalable PTSD screening strategies must be brief, accurate and capable of administration by a non-specialized workforce. Methods: We used PTSD as determined by the structured clinical interview as our gold standard and considered predictors sets of (a) Posttraumatic Stress Checklist-5 (PCL-5), (b) Primary Care PTSD Screen for the DSM-5 (PC-PTSD) and, (c) PCL-5 and PC-PTSD questions to identify the optimal items for PTSD screening for public sector settings in Kenya. A logistic regression model using LASSO was fit by minimizing the average squared error in the validation data. Area under the receiver operating characteristic curve (AUROC) measured discrimination performance. Results: Penalized regression analysis suggested a screening tool that sums the Likert scale values of two PCL-5 questions-intrusive thoughts of the stressful experience (#1) and insomnia (#21). This had an AUROC of 0.85 (using hold-out test data) for predicting PTSD as evaluated by the MINI, which outperformed the PC-PTSD. The AUROC was similar in subgroups defined by age, sex, and number of categories of trauma experienced (all AUROCs>0.83) except those with no trauma history- AUROC was 0.78. Conclusion: In some East African settings, a 2-item PTSD screening tool may outperform longer screeners and is easily scaled by a non-specialist workforce.

Twin-based Mendelian Randomization Analyses Highlight Smoking's Effects on Blood DNA Methylation, with Putative Reverse Causation.

Epigenome-wide association studies (EWAS) aim to identify differentially methylated loci associated with complex traits and disorders. EWAS of cigarette smoking shows some of the most widespread DNA methylation (DNAm) associations in blood. However, traditional EWAS cannot differentiate between causation and confounding, leading to ambiguity in etiological interpretations. Here, we apply an integrated approach combining Mendelian Randomization and twin-based Direction-of-Causation analyses (MR-DoC) to examine causality underlying smoking-associated blood DNAm changes in the Netherlands Twin Register (N=2577). Evidence across models suggests that current smoking's causal effects on DNAm likely drive many of the previous EWAS findings, implicating functional pathways relevant to several adverse health outcomes of smoking, including hemopoiesis, cell- and neuro-development, and immune regulation. Additionally, we find evidence of potential reverse causal influences at some DNAm sites, with 17 of these sites enriched for gene regulatory functional elements in the brain. The top three sites with evidence of DNAm's effects on smoking annotate to genes involved in G protein-coupled receptor signaling (GNG7, RGS3) and innate immune response (SLC15A4), elucidating potential biological risk factors for smoking. This study highlights the utility of integrating genotypic and DNAm measures in twin cohorts to clarify the causal relationships between health behaviors and blood DNAm.

Three Pillars of Support for Orphan Drug Programs: Individual Valuations, Societal Valuations, and Anonymous Altruism.

OBJECTIVES: To identify and describe potential societal and individual sources of support for orphan drug programs. METHODS: The generalized risk-adjusted cost-effectiveness (GRACE) method shows that acute illness and disability severity increase individuals' willingness to pay (WTP) for health gains. We develop a social welfare function (SWF) that incorporates individuals' own values, combined with politically- or ethically determined weights. We introduce the concept of horizontal equity-that individuals in similar situations should be treated similarly-into the SWF. Finally, we introduce anonymous altruism into individuals' utility functions-the desire to help others, without knowing their identity. RESULTS: Combined with the empirical link between disease severity and rarity, GRACE demonstrates heightened WTP for health gains, leading rational individuals to support orphan drug programs, our first pillar of support. Adding horizontal equity to the SWF further increases societal support for orphan drug programs. Anonymous altruism, focusing most strongly on those in the most-dire circumstances, leads to altruistic support for those with severe disorders. Because innovators' economic incentives lead them to focus on larger markets, anonymous altruistic individuals to specifically support orphan drug programs. The presence of free-rider problems translates this into public program support. CONCLUSIONS: We identify supporting three pillars for orphan drug programs: (1) individuals' desire for treatments to treat rare disease that are often severe and life-threatening; (2) the concept of horizontal equity in our SWF: (3) anonymous altruism, the desire to people, even when unknown, in dire circumstances.

Direct-Acting Oral Anticoagulants and Antiseizure Medications for Atrial Fibrillation and Epilepsy and Risk of Thromboembolic Events.

Importance: Direct-acting oral anticoagulants (DOACs) are commonly prescribed with antiseizure medications (ASMs) due to concurrency of and the association between atrial fibrillation (AF) and epilepsy. However, enzyme-inducing (EI) ASMs may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk. Objective: To assess the rates of thromboembolic and major bleeding events in adults with AF and epilepsy dispensed DOACs and EI ASMs vs DOACs with non-EI ASMs. Design, Setting, and Participants: This active-comparator, new-user cohort study included US health care data from the Clinformatics Data Mart database from October 2010 to September 2021 for a nationally representative population of adults with AF and epilepsy. Exposure: Evaluations included episodes of contiguous coadministration of DOACs for AF with EI ASMs (exposed) or non-EI ASMs (referent) for epilepsy. Main Outcomes and Measures: Thromboembolic events (primary outcome) and major bleeding events (secondary outcome) were identified based on a series of validated, diagnosis-based coding algorithms. Data-adaptive, high-dimensional propensity score matching was used to control for observed confounders and proxies for unobserved confounders. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regression models with robust variance estimators to account for clustering within matched pairs. Results: This study included 14 078 episodes (median age, 74 [IQR, 67-81]; 52.4% female) and 14 158 episodes (median age, 74 [IQR, 67-81]; 52.4% female) of incident DOAC and ASM use that met eligibility criteria for assessment of thromboembolic and major bleeding outcomes, respectively. Incidence was 88.5 per 1000 person-years for thromboembolic events and 68.3 per 1000 person-years for bleeding events. Compared with use of non-EI ASMs, use of EI ASMs with DOACs was not associated with a difference in risk of thromboembolic events (AHR, 1.10; 95% CI, 0.82-1.46) but was associated with a reduction in risk of major bleeding events (AHR, 0.63; 95% CI, 0.44-0.89). Conclusions and Relevance: In this cohort study, EI ASMs were not associated with alteration in DOAC efficacy. Further research is needed on the reduction in bleeding risk associated with EI ASMs, as this may suggest that pharmacokinetic interactions are associated with lowering DOAC levels without negating therapeutic effects.

The Most Cited Publications in Abdominal Wall Reconstruction-A Bibliometric Analysis.

BACKGROUND: Abdominal wall reconstruction (AWR) is a treatment option for structural defects of the abdominal wall. The most frequently cited publications related to AWR have not been quantitatively or qualitatively assessed. This bibliometric analysis characterizes and assesses the most frequently cited AWR publications, to identify trends, gaps, and guide future efforts for the international research community. METHODS: The 100 most cited publications in AWR were identified on Web of Science, across all available journal years (from May 1964 to December 2023). Study details, including the citation count, main content focus, and outcome measures, were extracted and tabulated from each publication. Oxford Centre for Evidence-Based Medicine levels of evidence (LOE) of each study were also assessed. RESULTS: The 100 most cited publications in AWR were cited by a total of 9674 publications. Citations per publication ranged from 43 to 414 (mean 96.7 ± 52.48). Most publications were LOE 3 (n = 60), representative of the large number of retrospective cohort studies. The number of publications for LOE 5, 4, 3, 2, and 1 was 21, 2, 60, 2, and 12, respectively. The main content focus was surgical technique in 44 publications followed by outcomes in 38 publications. Patient-reported outcome measures were used in 3 publications, and no publications reported validated esthetic outcome measures. CONCLUSIONS: Overall, 3 was the LOE for most frequently cited AWR publications, with more publications below LOE 3 than above LOE 3. Validated outcome measures and patient-reported outcome measures were infrequently incorporated in the studies evaluated.

Clinical, Cultural, Computational, and Regulatory Considerations to Deploy AI in Radiology: Perspectives of RSNA and MICCAI Experts.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. The Radiological Society of North of America (RSNA) and the Medical Image Computing and Computer Assisted Intervention (MICCAI) Society have led a series of joint panels and seminars focused on the present impact and future directions of artificial intelligence (AI) in radiology. These conversations have collected viewpoints from multidisciplinary experts in radiology, medical imaging, and machine learning on the current clinical penetration of AI technology in radiology, and how it is impacted by trust, reproducibility, explainability, and accountability. The collective points-both practical and philosophical-define the cultural changes for radiologists and AI scientists working together and describe the challenges ahead for AI technologies to meet broad approval. This article presents the perspectives of experts from MICCAI and RSNA on the clinical, cultural, computational, and regulatory considerations-coupled with recommended reading materials-essential to adopt AI technology successfully in radiology and more generally in clinical practice. The report emphasizes the importance of collaboration to improve clinical deployment and highlights the need to integrate clinical and medical imaging data and introduces strategies to ensure smooth and incentivized integration. ©RSNA, 2024.

Decoding the Mastectomy SKIN Score: An Evaluation of Its Predictive Performance in Immediate Breast Reconstruction.

BACKGROUND: The skin ischemia and necrosis (SKIN) score was introduced to standardize the assessment of mastectomy skin flap necrosis (MSFN) severity and the need for reoperation. The authors evaluated the association between the SKIN score and the long-term postoperative outcomes of MSFN after mastectomy and immediate breast reconstruction. METHODS: The authors conducted a retrospective cohort study of consecutive patients who developed MSFN after mastectomy and immediate breast reconstruction from January of 2001 to January of 2021. The primary outcome was breast-related complications after MSFN. Secondary outcomes were 30-day readmission, operating room (OR) débridement, and reoperation. Study outcomes were correlated with the SKIN composite score. RESULTS: The authors identified 299 reconstructions in 273 consecutive patients with mean follow-up time of 111.8 ± 3.9 months. Most patients had a composite SKIN score of B2 (25.0%, n = 13), followed by D2 (17.3%) and C2 (15.4%). We found no significant difference in rates of OR débridement ( P = 0.347), 30-day readmission ( P = 0.167), any complication ( P = 0.492), or reoperation for a complication ( P = 0.189) based on the SKIN composite score. The composite skin score was a poor predictor of reoperation, with an area under the curve of 0.56. A subgroup analysis in patients who underwent implant-based reconstruction revealed no difference in rates of OR débridement ( P = 0.986), 30-day readmission ( P = 0.530), any complication ( P = 0.492), or reoperation for a complication ( P = 0.655) based on the SKIN composite score. CONCLUSIONS: The SKIN score was a poor predictor for postoperative MSFN outcomes and reoperation. An individualized risk-assessment tool that incorporates the anatomic appearance of the breast, imaging data, and patient-level risk factors is needed. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV.

Smartphone usage during walking decreases the positive persistency in gait cycle variability.

Gait cycle variability during steady walking, described by the stride interval time series, has been used as a gait-stability-related measure. In particular, the positive persistency in the stride intervals with 1/f-like fluctuation and reduction of the persistency are the well-documented metrics that can characterize gait patterns of healthy young adults and elderly including patients with neurological diseases, respectively. Here, we examined effects of a dual task on gait cycle variability in healthy young adults, based on the mean and standard deviation statistics as well as the positive persistency of the stride intervals during steady walking on a treadmill. Specifically, three gait conditions were examined: control condition, non-cognitive task with holding a smartphone in front of the chest using their dominant hand and looking fixedly at a blank screen of the smartphone, and cognitive motor task with holding a smartphone as in the non-cognitive task and playing a puzzle game displayed on the smartphone by one-thumb operation. We showed that only the positive persistency, not the mean and standard deviation statistics, was affected by the cognitive and motor load of smartphone usage in the cognitive condition. More specifically, the positive persistency exhibited in the control and the non-cognitive conditions was significantly reduced in the cognitive condition. Our results suggest that the decrease in the positive persistency during the cognitive task, which might represent the deterioration of healthy gait pattern, is caused endogenously by the cognitive and motor load, not necessarily by the reduction of visual field as often hypothesized.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers for Advanced Chronic Kidney Disease : A Systematic Review and Retrospective Individual Participant-Level Meta-analysis of Clinical Trials.

BACKGROUND: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. PURPOSE: To examine the association of ACEi or ARB treatment initiation, relative to a non-ACEi or ARB comparator, with rates of KFRT and death. DATA SOURCES: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. STUDY SELECTION: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. DATA EXTRACTION: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m2), albuminuria (urine albumin-creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. DATA SYNTHESIS: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m2, of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). LIMITATION: Individual participant-level data for hyperkalemia or acute kidney injury were not available. CONCLUSION: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. PRIMARY FUNDING SOURCE: National Institutes of Health. (PROSPERO: CRD42022307589).

Clinical and imaging findings associated with preservation of knee joint health over 8 years in individuals aged 65 and over: data from the OAI.

OBJECTIVE: While risk factors for osteoarthritis (OA) are well known, it is not well understood why certain individuals maintain high mobility and joint health throughout their life while others demonstrate OA at older ages. The purpose of this study was to assess which demographic, clinical and MRI quantitative and semi-quantitative factors are associated with preserving healthy knees in older individuals. METHODS: This study analyzed data from the OA Initiative (OAI) cohort of individuals at the age of 65 years or above. Participants without OA at baseline (BL) (Kellgren-Lawrence (KL) ≤ 1) were followed and classified as incident cases (KL ≥ 2 during follow-up; n = 115) and as non-incident (KL ≤ 1 over 96-month; n = 391). Associations between the predictor-variables sex, age, BMI, race, clinical scoring systems, T2 relaxation times and Whole-Organ Magnetic Resonance Imaging-Score (WORMS) readings at BL and the preservation of healthy knees (KL ≤ 1) during a 96-month follow-up period were assessed using logistic regression models. RESULTS: Obesity and presence of pain showed a significant inverse association with maintaining radiographically normal joints in patients aged 65 and above. T2 relaxation times of the lateral femur and tibia as well as the medial femur were also significantly associated with maintaining radiographically normal knee joints. Additionally, absence of lesions of the lateral meniscus and absence of cartilage lesions in the medial and patellofemoral compartments were significantly associated with maintaining healthy knee joints. CONCLUSION: Overall, this study provides protective clinical parameters as well as quantitative and semi-quantitative MR-imaging parameters associated with maintaining radiographically normal knee joints in an older population over 8 years.

A Camelid-Derived STAT-Specific Nanobody Inhibits Neuroinflammation and Ameliorates Experimental Autoimmune Encephalomyelitis (EAE).

Proinflammatory T-lymphocytes recruited into the brain and spinal cord mediate multiple sclerosis (MS) and currently there is no cure for MS. IFN-γ-producing Th1 cells induce ascending paralysis in the spinal cord while IL-17-producing Th17 cells mediate cerebellar ataxia. STAT1 and STAT3 are required for Th1 and Th17 development, respectively, and the simultaneous targeting of STAT1 and STAT3 pathways is therefore a potential therapeutic strategy for suppressing disease in the spinal cord and brain. However, the pharmacological targeting of STAT1 and STAT3 presents significant challenges because of their intracellular localization. We have developed a STAT-specific single-domain nanobody (SBT-100) derived from camelids that targets conserved residues in Src homolog 2 (SH2) domains of STAT1 and STAT3. This study investigated whether SBT-100 could suppress experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We show that SBT-100 ameliorates encephalomyelitis through suppressing the expansion of Th17 and Th1 cells in the brain and spinal cord. Adoptive transfer experiments revealed that lymphocytes from SBT-100-treated EAE mice have reduced capacity to induce EAE, indicating that the immunosuppressive effects derived from the direct suppression of encephalitogenic T-cells. The small size of SBT-100 makes this STAT-specific nanobody a promising immunotherapy for CNS autoimmune diseases, including multiple sclerosis.

Factors influencing canine rabies vaccination among dog-owning households in Nigeria.

Rabies perpetuates in Nigeria despite initiatives like the Regional Disease Surveillance System Enhancement Project, with evidence indicating suboptimal canine vaccination rates as a contributing factor. To inform effective planning of mass dog vaccination campaigns, it is crucial to understand the factors associated with variation in canine vaccination rates. We conducted a cross-sectional study in 2022 to understand factors associated with canine vaccination. We used stratified random sampling of the streets and dog-owning households to survey 4162 households from three states and the Federal Capital Territory (FCT). We then built a joint probabilistic model to understand factors associated with dog vaccination and non-vaccination. First, we modelled rabies knowledge as a latent variable indirectly measured with several targeted survey questions. This method allowed a respondent's unobserved understanding of rabies to be estimated using their responses to a collection of survey questions that targeted different aspects of rabies epidemiology and took various possible response distributions (i.e., ordinal, categorical, binary). Second, we modelled factors influencing pet owners' decisions to vaccinate their dogs against rabies and barriers to dog vaccination among dog owners whose dogs were not vaccinated against rabies. Posterior distributions revealed that the probability of dog vaccination was positively associated with the owner's latent knowledge of rabies, civil servant service employment, residence in the FCT, ownership of a single dog, providing care to dogs, and a preference for contemporary treatment following a dog bite. Conversely, non-vaccination was positively associated with private employment, residing in Anambra and Enugu states, owning multiple dogs, allowing dogs to search for leftovers, and a preference for traditional treatment after a dog bite. Cost was the primary barrier against vaccination for dog owners in Anambra and Enugu, while mistrust posed a major challenge for those in the FCT. Owners in areas with veterinary establishments cited cost as a barrier, while those without a veterinary establishment cited access as the primary barrier. Our study underscores the need to enhance rabies knowledge, tailor vaccination campaigns to specific demographics, address financial and access barriers, and combat hesitancy to improve rabies vaccination rates in Nigeria.

The tumour suppressor Fat1 is dispensable for normal murine hematopoiesis.

Loss and overexpression of FAT1 occurs among different cancers with these divergent states equated with tumor suppressor and oncogene activity, respectively. Regarding the latter, FAT1 is highly expressed in a high proportion of human acute leukemias relative to normal blood cells, with evidence pointing to an oncogenic role. We hypothesized that this occurrence represents legacy expression of FAT1 in undefined hematopoietic precursor subsets that is sustained following transformation, predicating a role for FAT1 during normal hematopoiesis. We explored this concept by using the Vav-iCre strain to construct conditional knockout (cKO) mice where Fat1 expression was deleted at the hematopoietic stem cell stage. Extensive analysis of precursor and mature blood populations using multi-panel flow cytometry revealed no ostensible differences between Fat1 cKO mice and normal littermates. Further functional comparisons involving colony forming unit and competitive bone marrow transplantation assays support the conclusion that Fat1 is dispensable for normal murine hematopoiesis.

Weight training and risk of all-cause, cardiovascular disease and cancer mortality among older adults.

BACKGROUND: While previous studies indicate muscle-strengthening exercises may reduce mortality risk, further research is needed to increase certainty of the evidence. We investigated overall and dose-response associations between weight training and the risks of all-cause, cardiovascular disease (CVD) and cancer mortality in a large cohort of older adults with long follow-up time and a large number of deaths. We also investigated the joint associations of weight training and aerobic exercise with mortality risk. METHODS: Weight training was assessed via self-report in 2004-05 in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study (USA; n = 216 339), with follow-up to 2019. Cox regression estimated the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between weight training and mortality, after adjusting for confounders including aerobic exercise. RESULTS: Around 25% of participants [mean age = 69.9 years (standard deviation = 5.4), 58% men] reported engaging in weight training over the past year, and there were 79 107 (37%) deaths. Engaging in any weight training (vs none) was associated with lower risks of all-cause (HR = 0.94; 95% CI = 0.93-0.96), CVD (HR = 0.92; 95% CI = 0.90-0.95) and cancer mortality (HR = 0.95; 95% CI = 0.92-0.98). More time spent in weight training was associated with only marginally greater risk reductions. Larger risk reductions were observed among women than men. Performing both aerobic exercise and weight training conferred the greatest mortality risk reduction; weight training was not associated with mortality risk among participants who did no aerobic exercise. CONCLUSION: Performing any amount of weight training lowered mortality risk.

TRPV4-Expressing Tissue-Resident Macrophages Regulate the Function of Collecting Lymphatic Vessels via Thromboxane A2 Receptors in Lymphatic Muscle Cells.

Rationale: TRPV4 channels are critical regulators of blood vascular function and have been shown to be dysregulated in many disease conditions in association with inflammation and tissue fibrosis. These are key features in the pathophysiology of lymphatic system diseases, including lymphedema and lipedema; however, the role of TRPV4 channels in the lymphatic system remains largely unexplored. TRPV4 channels are calcium permeable, non-selective cation channels that are activated by diverse stimuli, including shear stress, stretch, temperature, and cell metabolites, which may regulate lymphatic contractile function. Objective: To characterize the expression of TRPV4 channels in collecting lymphatic vessels and to determine the extent to which these channels regulate the contractile function of lymphatics. Methods and Results: Pressure myography on intact, isolated, and cannulated lymphatic vessels showed that pharmacological activation of TRPV4 channels with GSK1016790A (GSK101) led to contractile dysregulation. The response to GSK101 was multiphasic and included, 1) initial robust constriction that was sustained for ≥1 minute and in some instances remained for ≥4 minutes; and 2) subsequent vasodilation and partial or complete inhibition of lymphatic contractions associated with release of nitric oxide. The functional response to activation of TRPV4 channels displayed differences across lymphatics from four anatomical regions, but these differences were consistent across different species (mouse, rat, and non-human primate). Importantly, similar responses were observed following activation of TRPV4 channels in arterioles. The initial and sustained constriction was prevented with the COX inhibitor, indomethacin. We generated a controlled and spatially defined single-cell RNA sequencing (scRNAseq) dataset from intact and microdissected collecting lymphatic vessels. Our data uncovered a subset of macrophages displaying the highest expression of Trpv4 compared to other cell types within and surrounding the lymphatic vessel wall. These macrophages displayed a transcriptomic profile consistent with that of tissue-resident macrophages (TRMs), including differential expression of Lyve1 , Cd163 , Folr2 , Mrc1 , Ccl8 , Apoe , Cd209f , Cd209d , and Cd209g ; and at least half of these macrophages also expressed Timd4. This subset of macrophages also highly expressed Txa2s , which encodes the thromboxane A2 (TXA2) synthase. Inhibition of TXA2 receptors (TXA2Rs) prevented TRPV4-mediated contractile dysregulation. TXA2R activation on LMCs caused an increase in mobilization of calcium from intracellular stores through Ip3 receptors which promoted store operated calcium entry and vasoconstriction. Conclusions: Clinical studies have linked cancer-related lymphedema with an increased infiltration of macrophages. While these macrophages have known anti-inflammatory and pro-lymphangiogenic roles, as well as promote tissue repair, our results point to detrimental effects to the pumping capacity of collecting lymphatic vessels mediated by activation of TRPV4 channels in macrophages. Pharmacological targeting of TRPV4 channels in LYVE1-expressing macrophages or pharmacological targeting of TXA2Rs may offer novel therapeutic strategies to improve lymphatic pumping function and lymph transport in lymphedema.

How Shape Perception Works, in Two Dimensions and Three Dimensions.

The ventral visual pathway transforms retinal images into neural representations that support object understanding, including exquisite appreciation of precise 2D pattern shape and 3D volumetric shape. We articulate a framework for understanding the goals of this transformation and how they are achieved by neural coding at successive ventral pathway stages. The critical goals are (a) radical compression to make shape information communicable across axonal bundles and storable in memory, (b) explicit coding to make shape information easily readable by the rest of the brain and thus accessible for cognition and behavioral control, and (c) representational stability to maintain consistent perception across highly variable viewing conditions. We describe how each transformational step in ventral pathway vision serves one or more of these goals. This three-goal framework unifies discoveries about ventral shape processing into a neural explanation for our remarkable experience of shape as a vivid, richly detailed aspect of the natural world.