Targeting NGF but not VEGFR1 or BDNF signaling reduces endometriosis-associated pain in mice.

INTRODUCTION: Endometriosis is a chronic inflammatory disease that affects âˆ¼10 % of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis. OBJECTIVES: We aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice. METHODS: Peritoneal fluid was collected from endometriosis patients undergoing surgery and the levels of NGF and VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA. VEGFR1 regulator concentrations were used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibodies, and pharmacological approaches to specifically block neurotrophic ligands (NGF or BDNF) or receptors (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was measured using von Frey filaments, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Disease parameters were evaluated by lesion size and prevalence. To evaluate potential toxicity, we measured the effect of entrectinib dose and schedule on body weight, liver and kidney function, and bone structure (via micro-CT). RESULTS: We found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though calculated receptor occupancy revealed that VEGFR1 agonist levels are sufficient to support signaling, blocking VEGFR1 via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. Notably, changing dosing schedule to once weekly eliminated entrectinib-induced bone-loss without decreasing efficacy against pain. CONCLUSIONS: This suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment.

Consensus Statement: Technical Standards for Thoracoabdominal Normothermic Regional Perfusion.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a powerful technique for optimizing organ procurement from donation after circulatory death donors. Despite its rapid adoption, standardized guidelines for TA-NRP implementation are lacking, prompting the need for consensus recommendations to ensure safe and effective utilization of this technique. METHODS: A working group composed of members from The American Society of Transplant Surgeons, The International Society of Heart and Lung Transplantation, The Society of Thoracic Surgeons, and The American Association for Thoracic Surgery was convened to develop technical guidelines for TA-NRP. The group systematically reviewed existing literature, consensus statements, and expert opinions to identify key areas requiring standardization, including predonation evaluation, intraoperative management, postdonation procedures, and future research directions. RESULTS: The working group formulated recommendations encompassing donor evaluation and selection criteria, premortem testing and therapeutic interventions, communication protocols, and procedural guidelines for TA-NRP implementation. These recommendations aim to facilitate coordination among transplant teams, minimize variability in practice, and promote transparency and accountability throughout the TA-NRP process. CONCLUSIONS: The consensus guidelines presented herein serve as a comprehensive framework for the successful and ethical implementation of TA-NRP programs in organ procurement from donation after circulatory death donors. By providing standardized recommendations and addressing areas of uncertainty, these guidelines aim to enhance the quality, safety, and efficiency of TA-NRP procedures, ultimately contributing to improved outcomes for transplant recipients.

Cost-Effectiveness of HIV Screening in Emergency Departments: Results From the Pragmatic Randomized HIV Testing Using Enhanced Screening Techniques in Emergency Departments Trial.

STUDY OBJECTIVE: Identification of HIV remains a critical health priority for which emergency departments (EDs) are a central focus. The comparative cost-effectiveness of various HIV screening strategies in EDs remains largely unknown. The goal of this study was to compare programmatic costs and cost-effectiveness of nontargeted and 2 forms of targeted opt-out HIV screening in EDs using results from a multicenter, pragmatic randomized clinical trial. METHODS: This economic evaluation was nested in the HIV Testing Using Enhanced Screening Techniques in Emergency Departments (TESTED) trial, a multicenter pragmatic clinical trial of different ED-based HIV screening strategies conducted from April 2014 through January 2016. Patients aged 16 years or older, with normal mental status and not critically ill, or not known to be living with HIV were randomized to 1 of 3 HIV opt-out screening approaches, including nontargeted, enhanced targeted, or traditional targeted, across 4 urban EDs in the United States. Each screening method was fully integrated into routine emergency care. Direct programmatic costs were determined using actual trial results, and time-motion assessment was used to estimate personnel activity costs. The primary outcome was newly diagnosed HIV. Total annualized ED programmatic costs by screening approach were calculated using dollars adjusted to 2023 as were costs per patient newly diagnosed with HIV. One-way and multiway sensitivity analyses were performed. RESULTS: The trial randomized 76,561 patient visits, resulting in 14,405 completed HIV tests, and 24 (0.2%) new diagnoses. Total annualized new diagnoses were 12.9, and total annualized costs for nontargeted, enhanced targeted, and traditional targeted screening were $111,861, $88,629, and $70,599, respectively. Within screening methods, costs per new HIV diagnoses were $20,809, $23,554, and $18,762, respectively. Enhanced targeted screening incurred higher costs but with similar annualized new cases detected compared with traditional targeted screening. Nontargeted screening yielded an incremental cost-effectiveness ratio of $25,586 when compared with traditional targeted screening. Results were most sensitive to HIV prevalence and costs of HIV tests. CONCLUSION: Nontargeted HIV screening was more costly than targeted screening largely due to an increased number of HIV tests performed. Each HIV screening strategy had similar within-strategy costs per new HIV diagnosis with traditional targeted screening yielding the lowest cost per new diagnosis. For settings with budget constraints or very low HIV prevalences, the traditional targeted approach may be preferred; however, given only a slightly higher cost per new HIV diagnosis, ED settings looking to detect the most new cases may prefer nontargeted screening.

Modified Delphi panel consensus recommendations for management of severe aplastic anemia.

ABSTRACT: Severe aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 experts on adult and pediatric aplastic anemia was assembled and, using the RAND/University of California, Los Angeles modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here, we present the panel's recommendations to rule out inherited bone marrow failure syndromes, on supportive care before and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant vs medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA.

Ethnic Differences in Survival among Brazilian Modern-era Olympic Medalists from 1920 to 1992: A Cohort Study. / Diferenças Étnicas na Sobrevida entre Medalhistas Olímpicos Brasileiros da Era Moderna de 1920 a 1992: Um Estudo de Coorte.

BACKGROUND: Disparities in health outcomes among racial groups warrant investigation, even among elite athletes. Therefore, understanding the impact of race upon post-medal survival in Brazilian Olympians becomes essential. OBJECTIVE: To compare post-medal survival between white and non-white Brazilian Olympic medalists from 1920 to 1992. METHODS: This study used publicly available data for a retrospective cohort study on all Brazilian Olympic medalists from 1920 to 1992 (males only). Athletes were classified into white and non-white groups using structured ethnicity determination. Kaplan-Meier analyses computed the restricted mean survival time (RMST) for each ethnic group. A Cox proportional hazards analysis assessed ethnicity-based survival differences, adjusting for medal-winning age and birth year (p<0.05). RESULTS: Among 123 athletes (73.9% white), the mean age of medal achievement was 25.03±4.8 years. During the study, 18.7% of white and 37.5% of non-white athletes died (p=0.031). White athletes had a mean age at death of 75.10±18.01 years, while non-white athletes had an age of 67.13±14.90 years (p=0.109). The RMST for white athletes was 51.59 (95% CI 49.79-53.39) years, while for non-white athletes, it was 45.026 (95% CI 41.31-48.74) years, resulting in a ΔRMST of 6.56 (95% CI 2.43-10.70; p=0.0018). Multivariate analysis showed that non-white athletes had a higher mortality risk than did white athletes (HR 5.58; 95% CI, 2.18-14.31). CONCLUSION: Following their first medal, white Brazilian Olympians typically enjoy a six-year longer lifespan than their non-white counterparts, illustrating a marked mortality gap and health disparities among healthy individuals in Brazil.

FUNDAMENTO: As disparidades nos resultados de saúde entre grupos raciais merecem investigação, mesmo em atletas de elite. Portanto, compreender o impacto da raça na sobrevida pós-medalha em atletas olímpicos brasileiros torna-se essencial. OBJETIVO: Comparar a sobrevida pós-medalha entre medalhistas olímpicos brasileiros brancos e não brancos de 1920 a 1992. MÉTODOS: Utilizamos dados disponíveis publicamente para um estudo de coorte retrospectivo de todos os medalhistas olímpicos brasileiros de 1920 a 1992 (somente homens). Os atletas foram classificados nos grupos brancos e não brancos usando determinação estruturada de etnia. As análises de Kaplan-Meier calcularam o tempo médio de sobrevida restrito (TMSR) para cada grupo étnico. Uma análise de riscos proporcionais de Cox avaliou as diferenças de sobrevida baseadas na etnia, ajustando para a idade da conquista da medalha e ano de nascimento (p<0,05). RESULTADOS: Entre 123 atletas (73,9% brancos), a idade média da conquista de medalhas foi de 25,03 ± 4,8 anos. Durante o estudo, 18,7% dos atletas brancos e 37,5% dos atletas não brancos morreram (p=0,031). Os atletas brancos tiveram média de idade ao óbito de 75,10 ± 18,01 anos, enquanto os atletas não brancos tiveram idade média de 67,13 ± 14,90 anos (p=0,109). O TMSR para atletas brancos foi de 51,59 (IC 95%, 49,79 - 53,39) anos, e para atletas não brancos foi de 45,026 (IC 95%, 41,31 - 48,74) anos, resultando em um ΔTMSR de 6,56 (IC 95%, 2,43 - 10,70; p=0,0018). A análise multivariada mostrou que atletas não brancos apresentavam maior risco de mortalidade do que atletas brancos (RC 5,58; IC 95%, 2,18 - 14,31). CONCLUSÃO: Após a primeira medalha, os atletas olímpicos brasileiros brancos normalmente desfrutam de uma expectativa de vida seis anos mais longa do que seus colegas não brancos, ilustrando uma acentuada diferença de mortalidade e disparidades de saúde entre indivíduos saudáveis no Brasil.

The Xpert® MTB/RIF cycle threshold value predicts M. tuberculosis transmission to close contacts in a Brazilian prospective multicenter cohort.

BACKGROUND: The Xpert® MTB/RIF rapid molecular test provides a quantitative measure of Mycobacterium tuberculosis (Mtb) DNA in the form of cycle threshold (Ct) values. This information can be translated into mycobacterial load and used as a potential risk measure of bacterial spread for tuberculosis cases, which can impact infection control. However, the role of Ct values in assessing Mtb transmission to close contacts has not yet been demonstrated. METHODS: A prospective study was performed to investigate the association between Xpert® MTB/RIF Ct values and Mtb transmission to close contacts of patients with culture-confirmed pulmonary TB in a multi-center Brazilian cohort. We evaluated clinical and laboratory data, such as age, sex, race, smoking habits, drug use, alcohol use, chest radiograph, Xpert® MTB/RIF results among pulmonary tuberculosis cases, and QuantiFERON(QFT)-Plus results at baseline and after six months for close contacts who had a negative result at baseline. RESULTS: A total of 1,055 close contacts of 382 pulmonary tuberculosis cases were included in the study. The median Ct values from pulmonary tuberculosis cases of QFT-Plus positive (at baseline or six months) close contacts were lower compared with those who were QFT-Plus negative. An adjusted logistic regression demonstrated that reduced Ct values from the index cases were independently associated with QFT-Plus conversion from negative to positive (OR: 1.61, 95% CI: 1.12-2.32) after adjusting for clinical characteristics. CONCLUSION: Close contacts of pulmonary TB index cases exhibiting low Xpert MTB/RIF Ct values displayed higher rates of TB infection, reflecting Mtb transmission.

Ecological modeling, biogeography, and phenotypic analyses setting the tiger cats' hyperdimensional niches reveal a new species.

Recently, the tiger-cat species complex was split into Leopardus tigrinus and Leopardus guttulus, along with other proposed schemes. We performed a detailed analysis integrating ecological modeling, biogeography, and phenotype of the four originally recognized subspecies-tigrinus, oncilla, pardinoides, guttulus-and presented a new multidimensional niche depiction of the species. Species distribution models used > 1400 records from museums and photographs, all checked for species accuracy. Morphological data were obtained from institutional/personal archives. Spotting patterns were established by integrating museum and photographic/camera-trap records. Principal component analysis showed three clearly distinct groups, with the Central American specimens (oncilla) clustering entirely within those of the Andes, namely the pardinoides group of the cloud forests of the southern Central-American and Andean mountain chains (clouded tiger-cat); the tigrinus group of the savannas of the Guiana Shield and central/northeastern Brazil (savanna tiger-cat); and the guttulus group in the lowland forests of the Atlantic Forest domain (Atlantic Forest tiger-cat). This scheme is supported by recent genetic analyses. All species displayed different spotting patterns, with some significant differences in body measurements/proportions. The new distribution presented alarming reductions from the historic range of - 50.4% to - 68.2%. This multidimensional approach revealed a new species of the elusive and threatened tiger-cat complex.

Efficacy and Safety of a Polypill to Reduce Cardiovascular Events: A Review of Clinical Trials.

ABSTRACT: Cardiovascular disease continues to be the leading cause of mortality globally. Modifiable risk factors, such as hypertension and dyslipidemia, can be managed through lifestyle and pharmacotherapy treatments to reduce the risk of primary and secondary major cardiovascular events in patients with elevated risk. Despite effective and available medications to manage and mitigate cardiovascular risk factors, control rates of hypertension and dyslipidemia are suboptimal, and greater efforts are needed to reduce cardiovascular event rates worldwide. A polypill containing several classes of medications proven to lower cardiovascular risk in a single-dose form has been associated with improved medication adherence over multiple single-ingredient medications and may lead to reduced cardiovascular events. The goal of this article is to review available data from clinical trials assessing the efficacy and safety of polypills compared with placebo or usual care for cardiovascular risk reduction. Three databases were searched (PubMed/MEDLINE, CINAHL, and ScienceDirect) for randomized trials that compared a single polypill with usual care or placebo and reported major adverse cardiovascular events for each study group. A total of 6 trials were selected for inclusion. Several polypill formulations were compared with placebo or usual care with multiple single-ingredient medications in study populations consisting of both primary and secondary prevention patients. Overall, the polypill seems to be associated with reduced major adverse cardiovascular event and comparable safety with usual care treatment with an added benefit of improved adherence over multiple single-ingredient medications. The polypill has potential to be a cost-effective intervention to reduce the global burden of cardiovascular disease.

Social Media and Digital Footprints in Orthopaedic Trauma: An Analysis of 1465 Orthopaedic Trauma Association Members.

OBJECTIVES: The purpose of this study was to quantify social media usage among Orthopaedic Trauma Association (OTA) members. METHODS: All active OTA members were searched for involvement among common social media platforms. Surgeons were then classified as "active" on any given social media site if they posted within the past 6 months. Surgeons were also identified by the region they practiced in, sex, and their practice setting (academic vs. private). Finally, a surgeon's score and number of reviews from common physician review websites were examined. RESULTS: A total of 1465 OTA members were included in the analysis. Most surgeons were male (89.1% [n = 1305]) and practiced in a private setting (54.5% [n = 799]). A total of 590 surgeons (40.3%) had at least one form of social media account. Social media sites most used were LinkedIn with 48.7% (n = 713) and ResearchGate with 29.2% (n = 428). Academic surgeons were more likely to have a ResearchGate, LinkedIn, and Twitter account while private surgeons were more likely to have a personal website ( P < 0.05). Finally, there was no correlation between surgeons more active on social media and average scores on Vitals.com or Healthgrade.com ( P > 0.05). CONCLUSIONS: Most orthopaedic trauma surgeons do not have professional social media accounts. Although social media may help spread scholarship, having a professional social media account does not correlate with better online physician reviews or increased online reviews among orthopaedic trauma surgeons.

Diferenças Étnicas na Sobrevida entre Medalhistas Olímpicos Brasileiros da Era Moderna de 1920 a 1992: Um Estudo de Coorte / Ethnic Differences in Survival among Brazilian Modern-era Olympic Medalists from 1920 to 1992: A Cohort Study

Resumo Fundamento: As disparidades nos resultados de saúde entre grupos raciais merecem investigação, mesmo em atletas de elite. Portanto, compreender o impacto da raça na sobrevida pós-medalha em atletas olímpicos brasileiros torna-se essencial. Objetivo: Comparar a sobrevida pós-medalha entre medalhistas olímpicos brasileiros brancos e não brancos de 1920 a 1992. Métodos: Utilizamos dados disponíveis publicamente para um estudo de coorte retrospectivo de todos os medalhistas olímpicos brasileiros de 1920 a 1992 (somente homens). Os atletas foram classificados nos grupos brancos e não brancos usando determinação estruturada de etnia. As análises de Kaplan-Meier calcularam o tempo médio de sobrevida restrito (TMSR) para cada grupo étnico. Uma análise de riscos proporcionais de Cox avaliou as diferenças de sobrevida baseadas na etnia, ajustando para a idade da conquista da medalha e ano de nascimento (p<0,05). Resultados: Entre 123 atletas (73,9% brancos), a idade média da conquista de medalhas foi de 25,03 ± 4,8 anos. Durante o estudo, 18,7% dos atletas brancos e 37,5% dos atletas não brancos morreram (p=0,031). Os atletas brancos tiveram média de idade ao óbito de 75,10 ± 18,01 anos, enquanto os atletas não brancos tiveram idade média de 67,13 ± 14,90 anos (p=0,109). O TMSR para atletas brancos foi de 51,59 (IC 95%, 49,79 - 53,39) anos, e para atletas não brancos foi de 45,026 (IC 95%, 41,31 - 48,74) anos, resultando em um ΔTMSR de 6,56 (IC 95%, 2,43 - 10,70; p=0,0018). A análise multivariada mostrou que atletas não brancos apresentavam maior risco de mortalidade do que atletas brancos (RC 5,58; IC 95%, 2,18 - 14,31). Conclusão: Após a primeira medalha, os atletas olímpicos brasileiros brancos normalmente desfrutam de uma expectativa de vida seis anos mais longa do que seus colegas não brancos, ilustrando uma acentuada diferença de mortalidade e disparidades de saúde entre indivíduos saudáveis no Brasil.

Abstract Background: Disparities in health outcomes among racial groups warrant investigation, even among elite athletes. Therefore, understanding the impact of race upon post-medal survival in Brazilian Olympians becomes essential. Objective: To compare post-medal survival between white and non-white Brazilian Olympic medalists from 1920 to 1992. Methods: This study used publicly available data for a retrospective cohort study on all Brazilian Olympic medalists from 1920 to 1992 (males only). Athletes were classified into white and non-white groups using structured ethnicity determination. Kaplan-Meier analyses computed the restricted mean survival time (RMST) for each ethnic group. A Cox proportional hazards analysis assessed ethnicity-based survival differences, adjusting for medal-winning age and birth year (p<0.05) Results: Among 123 athletes (73.9% white), the mean age of medal achievement was 25.03±4.8 years. During the study, 18.7% of white and 37.5% of non-white athletes died (p=0.031). White athletes had a mean age at death of 75.10±18.01 years, while non-white athletes had an age of 67.13±14.90 years (p=0.109). The RMST for white athletes was 51.59 (95% CI 49.79-53.39) years, while for non-white athletes, it was 45.026 (95% CI 41.31-48.74) years, resulting in a ΔRMST of 6.56 (95% CI 2.43-10.70; p=0.0018). Multivariate analysis showed that non-white athletes had a higher mortality risk than did white athletes (HR 5.58; 95% CI, 2.18-14.31). Conclusion: Following their first medal, white Brazilian Olympians typically enjoy a six-year longer lifespan than their non-white counterparts, illustrating a marked mortality gap and health disparities among healthy individuals in Brazil.

Faster rehabilitation weight gain during childhood is associated with risk of non-communicable disease in adult survivors of severe acute malnutrition.

Nutritional rehabilitation during severe acute malnutrition (SAM) aims to quickly restore body size and minimize poor short-term outcomes. We hypothesized that faster weight gain during treatment is associated with greater cardiometabolic risk in adult life. Anthropometry, body composition (DEXA), blood pressure, blood glucose, insulin and lipids were measured in a cohort of adults who were hospitalized as children for SAM between 1963 and 1993. Weight and height measured during hospitalization and at one year post-recovery were abstracted from hospital records. Childhood weight gain during nutritional rehabilitation and weight and height gain one year post-recovery were analysed as continuous variables, quintiles and latent classes in age, sex and minimum weight-for-age z-scores-adjusted regression models against adult measurements. Data for 278 adult SAM survivors who had childhood admission records were analysed. Of these adults, 85 also had data collected 1 year post-hospitalisation. Sixty percent of participants were male, mean (SD) age was 28.2 (7.7) years, mean (SD) BMI was 23.6 (5.2) kg/m2. Mean admission age for SAM was 10.9 months (range 0.3-36.3 months), 77% were wasted (weight-for-height z-scores<-2). Mean rehabilitation weight gain (SD) was 10.1 (3.8) g/kg/day and 61.6 (25.3) g/day. Rehabilitation weight gain > 12.9 g/kg/day was associated with higher adult BMI (difference = 0.5 kg/m2, 95% CI: 0.1-0.9, p = 0.02), waist circumference (difference = 1.4 cm, 95% CI: 0.4-2.4, p = 0.005), fat mass (difference = 1.1 kg, 95% CI: 0.2-2, p = 0.02), fat mass index (difference = 0.32kg/m2, 95% CI: -0.0001-0.6, p = 0.05), and android fat mass (difference = 0.09 kg, 95% CI: 0.01-0.2, p = 0.03). Post-recovery weight gain (g/kg/month) was associated with lean mass (difference = 1.3 kg, 95% CI: 0.3-2.4, p = 0.015) and inversely associated with android-gynoid fat ratio (difference = -0.03, 95% CI: -0.07to-0.001 p = 0.045). Rehabilitation weight gain exceeding 13g/kg/day was associated with adult adiposity in young, normal-weight adult SAM survivors. This challenges existing guidelines for treating malnutrition and warrants further studies aiming at optimising these targets.

Does depth divide? Variable genetic connectivity patterns among shallow and mesophotic Montastraea cavernosa coral populations across the Gulf of Mexico and western Caribbean.

Despite general declines in coral reef ecosystems in the tropical western Atlantic, some reefs, including mesophotic reefs (30-150 m), are hypothesized to function as coral refugia due to their relative isolation from anthropogenic stressors. Understanding the connectivity dynamics among these putative refugia and more degraded reefs is critical to develop effective management strategies that promote coral metapopulation persistence and recovery. This study presents a geographically broad assessment of shallow (<30 m) and mesophotic (>30 m) connectivity dynamics of the depth-generalist coral species Montastraea cavernosa. Over 750 coral genets were collected across the Northwest and Southern Gulf of Mexico, Florida, Cuba, and Belize, and ~5000 SNP loci were generated to quantify high-resolution genetic structure and connectivity among these populations. Generally, shallow and mesophotic populations demonstrated higher connectivity to distant populations within the same depth zone than to adjacent populations across depth zones. However, exceptions to this pattern include the Northwest Gulf of Mexico and the Florida Keys which exhibited relatively high vertical genetic connectivity. Furthermore, estimates of recent gene flow emphasize that mesophotic M. cavernosa populations are not significant sources for their local shallow counterparts, except for the Northwest Gulf of Mexico populations. Location-based differences in vertical connectivity are likely a result of diverse oceanographic and environmental conditions that may drive variation in gene flow and depth-dependent selection. These results highlight the need to evaluate connectivity dynamics and refugia potential of mesophotic coral species on a population-by-population basis and to identify stepping-stone populations that warrant incorporation in future international management approaches.

MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy.

BACKGROUND: Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy. METHODS: We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes Mybpc3 (cardiac myosin binding protein C3) or Myh6 (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms. RESULTS: We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models. CONCLUSIONS: Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment.

Neuromuscular ultrasound in leprosy: A scanning protocol.

The diagnosis of leprosy neuropathies has been traditionally based on clinical findings and electrodiagnostic studies, but ultrasound has emerged as a new tool for use in clinical practice. We conducted a literature search on the subject and developed a pragmatic ultrasound scanning protocol for patients with confirmed or suspected leprosy neuropathy. We suggest scanning the ulnar, median, superficial radial, common fibular and sural nerves at specific sites and assessing cross-sectional area, vascularity, and epineural thickness. Our protocol is potentially useful in differentiating leprosy neuropathies from other demyelinating neuropathies, but its applicability and accuracy must be evaluated in different centers.

Fungal Duel between Penicillium brasilianum and Aspergillus nomius Results in Dual Induction of Miktospiromide A and Kitrinomycin A.

Cocultivation of the fungi Penicillium brasilianum MST-FP1927 and Aspergillus nomius MST-FP2004 resulted in the reciprocal induction of two new compounds, miktospiromide A (1) from A. nomius and kitrinomycin A (2) from P. brasilianum. A third new compound, kitrinomycin B (3), was also identified from an axenic culture of P. brasilianum, along with the previously reported compounds austalide K (4), 17S-dihydroaustalide K (5), verruculogen (6), and fumitremorgin B (7). The structures of 1-3 were elucidated by detailed spectroscopic analysis and DFT calculations, while 4-7 were identified by comparison to authentic standards. The genome of A. nomius MST-FP2004 was sequenced, and a putative biosynthetic gene cluster for 1 was identified. Compound 2 showed activity against murine melanoma NS-1 cells (LD99 7.8 µM) and the bovine parasite Tritrichomonas foetus (LD99 4.8 µM).

Entry receptor LDLRAD3 is required for Venezuelan equine encephalitis virus peripheral infection and neurotropism leading to pathogenesis in mice.

Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus responsible for epidemics of neurological disease across the Americas. Low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3) is a recently reported entry receptor for VEEV. Here, using wild-type and Ldlrad3-deficient mice, we define a critical role for LDLRAD3 in controlling steps in VEEV infection, pathogenesis, and neurotropism. Our analysis shows that LDLRAD3 is required for efficient VEEV infection and pathogenesis prior to and after central nervous system invasion. Ldlrad3-deficient mice survive intranasal and intracranial VEEV inoculation and show reduced infection of neurons in different brain regions. As LDLRAD3 is a determinant of pathogenesis and an entry receptor required for VEEV infection of neurons of the brain, receptor-targeted therapies may hold promise as countermeasures.

A Resident-Led Firearm Curriculum for Pediatrics Residents Improves Safe Storage Counseling.

OBJECTIVE: To develop and implement a resident-led firearm safety curriculum, delivered to pediatrics residents, and to evaluate outcomes. STUDY DESIGN: A firearm safety curriculum was developed in 2019-2020 at a single academic center, using Kern's framework and cognitive load theory. The curriculum was organized using the "Be SMART" firearm safety model. Sessions were led by resident peers. The content included workshops on firearm safety counseling, advocacy training, and a gun lock program in collaboration with the local police department. Content was integrated into existing residency didactic curriculum. Impact was measured by a pre/posttest knowledge assessment and a systematic chart review. RESULTS: The curriculum was provided to 41/66 (62%) pediatrics residents. Knowledge improved (67% to 77% correct) when comparing pre-intervention with post-intervention. A total of 1477 charts were reviewed. Compared with a historical cohort, participants more often asked about presence of a firearm (27% vs 69%, P < .0001) and counseled on firearm safety (9% vs 25%, P < .0001). In the post-intervention timeframe, 25% of eligible families were provided a gun lock. CONCLUSIONS: A firearm safety curriculum designed by pediatrics residents and administered to their peers resulted in a statistically significant improvement in inquiries about firearm ownership and safety counseling in an urban tertiary care continuity clinic. These results demonstrate the promising outcomes of a firearm safety program developed by residents and delivered to peers.

Therapeutic activity of lipoxin A4 in TiO2-induced arthritis in mice: NF-κB and Nrf2 in synovial fluid leukocytes and neuronal TRPV1 mechanisms.

Background: Lipoxin A4 (LXA4) has anti-inflammatory and pro-resolutive roles in inflammation. We evaluated the effects and mechanisms of action of LXA4 in titanium dioxide (TiO2) arthritis, a model of prosthesis-induced joint inflammation and pain. Methods: Mice were stimulated with TiO2 (3mg) in the knee joint followed by LXA4 (0.1, 1, or 10ng/animal) or vehicle (ethanol 3.2% in saline) administration. Pain-like behavior, inflammation, and dosages were performed to assess the effects of LXA4 in vivo. Results: LXA4 reduced mechanical and thermal hyperalgesia, histopathological damage, edema, and recruitment of leukocytes without liver, kidney, or stomach toxicity. LXA4 reduced leukocyte migration and modulated cytokine production. These effects were explained by reduced nuclear factor kappa B (NFκB) activation in recruited macrophages. LXA4 improved antioxidant parameters [reduced glutathione (GSH) and 2,2-azino-bis 3-ethylbenzothiazoline-6-sulfonate (ABTS) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and Nrf2 protein expression], reducing reactive oxygen species (ROS) fluorescent detection induced by TiO2 in synovial fluid leukocytes. We observed an increase of lipoxin receptor (ALX/FPR2) in transient receptor potential cation channel subfamily V member 1 (TRPV1)+ DRG nociceptive neurons upon TiO2 inflammation. LXA4 reduced TiO2-induced TRPV1 mRNA expression and protein detection, as well TRPV1 co-staining with p-NFκB, indicating reduction of neuronal activation. LXA4 down-modulated neuronal activation and response to capsaicin (a TRPV1 agonist) and AITC [a transient receptor potential ankyrin 1 (TRPA1) agonist] of DRG neurons. Conclusion: LXA4 might target recruited leukocytes and primary afferent nociceptive neurons to exert analgesic and anti-inflammatory activities in a model resembling what is observed in patients with prosthesis inflammation.