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Background: Chronic pelvic pain remains challenging for physicians to manage due to central and peripheral sensitization and multiple pain generators including the bladder, pelvic floor, and pudendal nerve. Pain management providers have used nerve blocks for years for diagnosis and treatment. We developed a desensitization algorithm that provides a stepwise approach to improve patients pain scores. Methods: This is a prospective observational cohort study of 182 women aged 15-90 years old with chronic pelvic pain using an algorithm from 2016 to 2018. Treatment started with an Anesthetic Challenge Test of the bladder to guide us through a protocol of intravesical therapy and/or pudendal nerve blocks as a second step. Results: ACT POSITIVE patients, who received intravesical therapy: 84% had a Visual Analog Score pain improvement of at least 50%, 64% improved at least 80% (41% pain-free). Those desiring additional relief that received further Pudendal Blocks: 83% had final improvement of at least 50% (67% pain-free). ACT NEGATIVE patients received Pudendal Blocks with 80% of subjects achieving at least 50% relief, 65% improved at least 80% (35% pain-free). All final groups showed a statistically significance of P < .05% when compared to their initial pain scores. Conclusion: Management of women with chronic pelvic pain would ideally start with treating a specific diagnosis which, in most cases, is difficult to establish since the majority have more than one pain generator. Our algorithm simplified the approach and reduced the severity of pain scores prior to any further necessary surgical interventions.

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Algoritmos , Dolor Crónico , Bloqueo Nervioso , Dimensión del Dolor , Dolor Pélvico , Humanos , Femenino , Dolor Pélvico/terapia , Adulto , Persona de Mediana Edad , Estudios Prospectivos , Dolor Crónico/terapia , Anciano , Adulto Joven , Adolescente , Anciano de 80 o más Años , Bloqueo Nervioso/métodos , Manejo del Dolor/métodos , Fenotipo , Nervio Pudendo

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OBJECTIVES: To assess health status and heat preparation of cyclists at the 2019 Tour Down Under and determine the alignment of heat mitigation strategies with current recommendations. DESIGN: Cohort study. METHODS: Twenty-three (17 % participation rate) male World Tour cyclists from five teams and 10 countries completed a pre-competition questionnaire evaluating exertional heat illness (EHI) history, pre-race health status, and heat mitigation and recovery strategies use. Associations between arrival days pre-competition, years as professional, nationality, team, history of EHI symptoms and diagnosis on heat mitigation and recovery strategy utilisation were assessed. RESULTS: 65 % of cyclists reported previously experiencing one or more EHI symptom (cramping: 48 %) and 22 % a diagnosis of heat stroke. In the 10 days preceding the race, 26 % experienced one or more illness symptoms. 65 % trained in the heat (acclimatisation 8-25 days; acclimation: 3-7 days), which was associated with team (P = 0.047, ϕc = 0.61), nationality (P = 0.009, ϕc = 0.86) and EHI symptoms history (P = 0.058, ϕ = 0.43). All cyclists had a hydration plan, with links to team (0.5-1.0 L·h-1, P = 0.043, ϕc = 0.68) and EHI symptom history (1.0-1.5 L·h-1, P = 0.048, ϕ = 0.476). Most had pre-cooling (87 %) and mid-cooling (83 %) strategies, most commonly cold beverages (75 %) and neck collars (78 %), respectively. All cyclists planned on using at least one recovery strategy (massage: 87 %). CONCLUSIONS: Our data indicate good alignment with current recommendations for competing in the heat, particularly for hydration, cooling and recovery strategies. Whilst the proportion of cyclists engaging in heat acclimation/acclimatisation is encouraging, greater awareness on adapting and implementing heat training is required.

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BACKGROUND: Asthma is a leading cause of children's hospitalizations, emergency department visits, and missed school days. Our school-based asthma intervention has reduced asthma exacerbations for children experiencing health disparities in the Denver Metropolitan Area, due partly to addressing care coordination for asthma and social determinants of health (SDOH), such as access to healthcare and medications. Limited dissemination of school-based asthma programs has occurred in other metropolitan and rural areas of Colorado. We formed and engaged community advisory boards in socioeconomically diverse regions of Colorado to develop two implementation strategy packages for delivering our school-based asthma intervention - now termed "Better Asthma Control for Kids (BACK)" - with tailoring to regional priorities, needs and resources. METHODS: In this proposed type 2 hybrid implementation-effectiveness trial, where the primary goal is equitable reach to families to reduce asthma disparities, we will compare two different packages of implementation strategies to deliver BACK across four Colorado regions. The two implementation packages to be compared are: 1) standard set of implementation strategies including Tailor and Adapt to context, Facilitation and Training termed, BACK-Standard (BACK-S); 2) BACK-S plus an enhanced implementation strategy, that incorporates network weaving with community partners and consumer engagement with school families, termed BACK-Enhanced (BACK-E). Our evaluation will be guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, including its Pragmatic Robust Implementation Sustainability Model (PRISM) determinants of implementation outcomes. Our central hypothesis is that our BACK-E implementation strategy will have significantly greater reach to eligible children/families than BACK-S (primary outcome) and that both BACK-E and BACK-S groups will have significantly reduced asthma exacerbation rates ("attacks") and improved asthma control as compared to usual care. DISCUSSION: We expect both the BACK-S and BACK-E strategy packages will accelerate dissemination of our BACK program across the state - the comparative impact of BACK-S vs. BACK-E on reach and other RE-AIM outcomes may inform strategy selection for scaling BACK and other effective school-based programs to address chronic illness disparities. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT06003569, registered on August 22, 2023, https://classic. CLINICALTRIALS: gov/ct2/show/NCT06003569 .

Asunto(s)

Asma , Servicios de Salud Escolar , Humanos , Asma/terapia , Asma/prevención & control , Niño , Colorado , Servicios de Salud Escolar/organización & administración , Adolescente , Poblaciones Vulnerables , Ciencia de la Implementación , Femenino

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AIM: To assess the effects of a small-molecule nicotinamide N-methyltransferase (NNMT) inhibitor, 5A1MQ, on body composition, metabolic variables, fatty liver pathologies, and circulating biomarkers in diet-induced obese (DIO) mice, and characterize its plasma pharmacokinetics (PK) and tissue distribution in vivo. MATERIALS AND METHODS: DIO mice were administered vehicle or 5A1MQ once daily for 28 days. Longitudinal measures of body composition, blood glucose and plasma insulin levels, and terminal measures of liver histopathology and serum markers, were evaluated. Plasma and tissue PK were established in age- and strain-matched mice after intravenous, oral, and subcutaneous dosing of 5A1MQ. RESULTS: 5A1MQ treatment dose-dependently limited body weight and fat mass gains, improved oral glucose tolerance and insulin sensitivity, and suppressed hyperinsulinaemia in DIO mice. Liver histology from 5A1MQ-treated DIO mice showed attenuated hepatic steatosis and macrophage infiltration, and correspondingly reduced liver weight, size, and triglyceride levels. 5A1MQ treatment normalized circulating levels of alanine transaminase, aspartate transaminase, and ketone bodies, supporting an overall improvement in liver and metabolic functions. The pharmacodynamic effects of 5A1MQ were further corroborated by its high systemic exposure and effective distribution to metabolically active tissues, including adipose, muscle and liver, following subcutaneous dosing of mice. CONCLUSIONS: This work validates NNMT inhibition as a viable pharmacological approach to ameliorate metabolic imbalances and improve liver pathologies that develop with obesity.

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Monocyte-derived macrophages recruited to injured tissues induce a maladaptive fibrotic response characterized by excessive production of collagen by local fibroblasts. Macrophages initiate this programming via paracrine factors, but it is unknown whether reciprocal responses from fibroblasts enhance profibrotic polarization of macrophages. We identify macrophage-fibroblast crosstalk necessary for injury-associated fibrosis, in which macrophages induced interleukin 6 ( IL-6 ) expression in fibroblasts via purinergic receptor P2rx4 signaling, and IL-6, in turn, induced arginase 1 ( Arg1 ) expression in macrophages. Arg1 contributed to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts used as a substrate to synthesize proline, a uniquely abundant constituent of collagen. Imaging of idiopathic pulmonary fibrosis (IPF) lung samples confirmed expression of ARG1 in myeloid cells, and arginase inhibition suppressed collagen expression in cultured precision-cut IPF lung slices. Taken together, we define a circuit between macrophages and fibroblasts that facilitates cross-feeding metabolism necessary for injury-associated fibrosis.

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Transcription factors (TFs) regulate gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Because TF occupancy is driven in part by recognition of DNA sequence, genetic variation can influence TF-DNA associations and gene regulation. To identify variants that impact TF binding in human brain tissues, we assessed allele-specific binding (ASB) at heterozygous variants for 94 TFs in nine brain regions from two donors. Leveraging graph genomes constructed from phased genomic sequence data, we compared ChIP-seq signals between alleles at heterozygous variants within each brain region and identified thousands of variants exhibiting ASB for at least one TF. ASB reproducibility was measured by comparisons between independent experiments both within and between donors. We found that rare alleles in the general population more frequently led to reduced TF binding, whereas common alleles had an equal likelihood of increasing or decreasing binding. Further, for ASB variants in predicted binding motifs, the favored allele tended to be the one with the stronger expected motif match, but this concordance was not observed within highly occupied sites. We also found that neuron-specific cis-regulatory elements (cCREs), in contrast with oligodendrocyte-specific cCREs, showed depletion of ASB variants. We identified 2670 ASB variants associated with evidence for allele-specific gene expression in the brain from GTEx data and observed increasing eQTL effect direction concordance as ASB significance increases. These results provide a valuable and unique resource for mechanistic analysis of cis-regulatory variation in human brain tissue.

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Phase retrieval (PR) is fundamentally important in scientific imaging and is crucial for nanoscale techniques like coherent diffractive imaging (CDI). Low radiation dose imaging is essential for applications involving radiation-sensitive samples. However, most PR methods struggle in low-dose scenarios due to high shot noise. Recent advancements in optical data acquisition setups, such as in-situ CDI, have shown promise for low-dose imaging, but they rely on a time series of measurements, making them unsuitable for single-image applications. Similarly, data-driven phase retrieval techniques are not easily adaptable to data-scarce situations. Zero-shot deep learning methods based on pre-trained and implicit generative priors have been effective in various imaging tasks but have shown limited success in PR. In this work, we propose low-dose deep image prior (LoDIP), which combines in-situ CDI with the power of implicit generative priors to address single-image low-dose phase retrieval. Quantitative evaluations demonstrate LoDIP's superior performance in this task and its applicability to real experimental scenarios.

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OBJECTIVES: This study assessed the state of pediatric medical device (PMD) development by comparing PMD clinical trials to pediatric trials evaluating drugs and biologics, from 1999 to 2022. METHODS: The site www.clinicaltrials.gov was used to identify and quantify both PMD clinical trials and pediatric trials for drugs and biologics. Clinical specialty was also assessed. The institutions included were the 7 children's hospitals primarily affiliated with the Food and Drug Administration (FDA) Pediatric Device Consortia (PDC) grant program between 2018 and 2023. For a national comparison, an additional search assessed PMD trials across all US medical institutions. RESULTS: A total of 243 PMD clinical trials were identified at the FDA-PDC institutions on the basis of the year of initiation; the average number of PMD trials initiated per year per institution was 1.5 from 1999 to 2022. However, PMD trials significantly increased during the period 2014 to 2022 compared with 1999 to 2013 (P < .001); the rate of initiation of drug and biologic pediatric trials demonstrated no significant differences between these time periods. A national survey of all institutions initiating PMD trials, and drugs and biologics trials, identified 1885 PMD trials out of a total 12 943. A comparable trend was noted in the national survey with initiation of PMD trials increasing significantly from 2014 to 2022 (P < .001), compared with 1999 to 2013, whereas the rate of initiation of drug and biologic trials during these periods did not demonstrate a significant change. CONCLUSIONS: Although pediatric clinical trial initiation for drugs and biologics remained stable from 1999 to 2022, the rate of new PMD trials significantly increased during the period 2014 to 2022 at FDA-PDC institutions and nationally.

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Ensayos Clínicos como Asunto , Humanos , Estados Unidos , Niño , Equipos y Suministros , United States Food and Drug Administration , Pediatría , Productos Biológicos/uso terapéutico , Hospitales Pediátricos , Aprobación de Recursos

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Exercise is a potent stimulus for combatting skeletal muscle ageing. To study the effects of exercise on muscle in a preclinical setting, we developed a combined endurance-resistance training stimulus for mice called progressive weighted wheel running (PoWeR). PoWeR improves molecular, biochemical, cellular and functional characteristics of skeletal muscle and promotes aspects of partial epigenetic reprogramming when performed late in life (22-24 months of age). In this investigation, we leveraged pan-mammalian DNA methylome arrays and tandem mass-spectrometry proteomics in skeletal muscle to provide detailed information on late-life PoWeR adaptations in female mice relative to age-matched sedentary controls (n = 7-10 per group). Differential CpG methylation at conserved promoter sites was related to transcriptional regulation genes as well as Nr4a3, Hes1 and Hox genes after PoWeR. Using a holistic method of -omics integration called binding and expression target analysis (BETA), methylome changes were associated with upregulated proteins related to global and mitochondrial translation after PoWeR (P = 0.03). Specifically, BETA implicated methylation control of ribosomal, mitoribosomal, and mitochondrial complex I protein abundance after training. DNA methylation may also influence LACTB, MIB1 and UBR4 protein induction with exercise - all are mechanistically linked to muscle health. Computational cistrome analysis predicted several transcription factors including MYC as regulators of the exercise trained methylome-proteome landscape, corroborating prior late-life PoWeR transcriptome data. Correlating the proteome to muscle mass and fatigue resistance revealed positive relationships with VPS13A and NPL levels, respectively. Our findings expose differential epigenetic and proteomic adaptations associated with translational regulation after PoWeR that could influence skeletal muscle mass and function in aged mice. KEY POINTS: Late-life combined endurance-resistance exercise training from 22-24 months of age in mice is shown to improve molecular, biochemical, cellular and in vivo functional characteristics of skeletal muscle and promote aspects of partial epigenetic reprogramming and epigenetic age mitigation. Integration of DNA CpG 36k methylation arrays using conserved sites (which also contain methylation ageing clock sites) with exploratory proteomics in skeletal muscle extends our prior work and reveals coordinated and widespread regulation of ribosomal, translation initiation, mitochondrial ribosomal (mitoribosomal) and complex I proteins after combined voluntary exercise training in a sizeable cohort of female mice (n = 7-10 per group and analysis). Multi-omics integration predicted epigenetic regulation of serine ß-lactamase-like protein (LACTB - linked to tumour resistance in muscle), mind bomb 1 (MIB1 - linked to satellite cell and type 2 fibre maintenance) and ubiquitin protein ligase E3 component N-recognin 4 (UBR4 - linked to muscle protein quality control) after training. Computational cistrome analysis identified MYC as a regulator of the late-life training proteome, in agreement with prior transcriptional analyses. Vacuolar protein sorting 13 homolog A (VPS13A) was positively correlated to muscle mass, and the glycoprotein/glycolipid associated sialylation enzyme N-acetylneuraminate pyruvate lyase (NPL) was associated to in vivo muscle fatigue resistance.

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BACKGROUND: Outcomes from transcatheter aortic valve replacement (TAVR) in low-surgical risk patients with bicuspid aortic stenosis beyond 2 years are limited. OBJECTIVES: This study aimed to evaluate 3-year clinical and echocardiographic outcomes from the Evolut Low Risk Bicuspid Study. METHODS: The Evolut Low Risk Bicuspid Study is a prospective, multicenter, single-arm study conducted in 25 U.S. CENTERS: Patients with severe aortic stenosis at low surgical risk with bicuspid aortic valve anatomy (all subtypes) underwent TAVR with a self-expanding, supra-annular Evolut R or PRO (Medtronic) bioprosthesis. An independent clinical events committee adjudicated all deaths and endpoint-related adverse events, and a central echocardiographic core laboratory assessed hemodynamic endpoints. RESULTS: An attempted implant was performed in 150 patients from December 2018 to October 2019. The mean age was 70.3 ± 5.5 years, 48% (72/150) of the patients were women, and the mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 1.3% (Q1-Q3: 0.9%-1.7%). Sievers type 1 was the dominant bicuspid morphology (90.7%, 136/150). The Kaplan-Meier rates of all-cause mortality or disabling stroke were 1.3% (95% CI: 0.3%-5.3%) at 1 year, 3.4% (95% CI: 1.4%-8.1%) at 2 years, and 4.1% (95% CI: 1.6%-10.7%) at 3 years. The incidence of new permanent pacemaker implantation was 19.4% (95% CI: 12.4%-29.6%) at 3 years. There were no instances of moderate or severe paravalvular aortic regurgitation at 2 and 3 years after TAVR. CONCLUSIONS: The 3-year results from the Evolut Low Risk Bicuspid Study demonstrate low rates of all-cause mortality or disabling stroke and favorable hemodynamic performance.

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Estenosis de la Válvula Aórtica , Válvula Aórtica , Enfermedad de la Válvula Aórtica Bicúspide , Bioprótesis , Prótesis Valvulares Cardíacas , Hemodinámica , Diseño de Prótesis , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Femenino , Masculino , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/mortalidad , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Reemplazo de la Válvula Aórtica Transcatéter/mortalidad , Reemplazo de la Válvula Aórtica Transcatéter/instrumentación , Anciano , Factores de Riesgo , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Válvula Aórtica/cirugía , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/fisiopatología , Válvula Aórtica/anomalías , Medición de Riesgo , Enfermedad de la Válvula Aórtica Bicúspide/cirugía , Enfermedad de la Válvula Aórtica Bicúspide/fisiopatología , Estados Unidos/epidemiología , Índice de Severidad de la Enfermedad , Complicaciones Posoperatorias/mortalidad , Recuperación de la Función , Anciano de 80 o más Años , Persona de Mediana Edad , Enfermedades de las Válvulas Cardíacas/fisiopatología , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Enfermedades de las Válvulas Cardíacas/cirugía , Enfermedades de las Válvulas Cardíacas/mortalidad

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AIMS: (1) To use intraoperative photographs to visualize and explain pudendal nerve compressions and anatomical variations of compression sites in patients with chronic pelvic pain. (2) To emphasize the diagnostic importance of sensory examination with a safety pin at the six pudendal nerve branches in all patients with chronic pelvic pain; the dorsal nerves (penis or clitoris; the perineal nerves; and the inferior rectal nerves). METHODS: Between 2003 and 2014, "definite" pudendal neuropathy was diagnosed by examination and with two neurophysiologic tests. Neurolysis, via a transgluteal approach, was recommended only after 14 weeks of conservative care failed to adequately improve symptoms and validated symptom scores. Photographs of surgical findings were culled for their educational impact. An illustration of each photo clarifies the surgical anatomy. RESULTS: The transgluteal incision permits access to pudendal anatomy and compression sites from the subpiriformis area through the interligamentary space and the pudendal canal (Alcock canal). Compressions were acquired or congenital and severity varied significantly. Pinprick sensory testing diagnoses pudendal neuropathy in 92% of both genders. Mid-nerve compression occurred commonly between the sacrotuberous and sacrospinous ligaments less frequently in the Alcock canal, but also at aberrant pathways, for example, between layers of the sacrotuberous ligament; a separate inferior rectal nerve passing through the sacrospinous ligament; at an anomalous lateral pathway posterior to the ischial spine. The results of international surgeons are discussed. CONCLUSIONS: Decompression surgery was recommended in approximately 35% of patients in this practice, when pudendal neuropathy (pudendal syndrome), did not respond to two conservative levels of treatment: (1) nerve protection and medications and, (2) a series of three pudendal nerve perineural injections given at 4-week intervals. Significant nerve compression is consistently observed. Pathophysiology includes axonopathy from ischemia and demyelination. Neuropathy is readily diagnosed using a pinprick sensory examination of six pudendal nerve branches. Monitoring with the National Institutes of Health Chronic Prostatitis Symptom Index records cures >13 years.

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Transcriptional profiling has become a common tool for investigating the nervous system. During analysis, differential expression results are often compared to functional ontology databases, which contain curated gene sets representing well-studied pathways. This dependence can cause neuroscience studies to be interpreted in terms of functional pathways documented in better studied tissues (e.g., liver) and topics (e.g., cancer), and systematically emphasizes well-studied genes, leaving other findings in the obscurity of the brain "ignorome". To address this issue, we compiled a curated database of 918 gene sets related to nervous system function, tissue, and cell types ("Brain.GMT") that can be used within common analysis pipelines (GSEA, limma, edgeR) to interpret results from three species (rat, mouse, human). Brain.GMT includes brain-related gene sets curated from the Molecular Signatures Database (MSigDB) and extracted from public databases (GeneWeaver, Gemma, DropViz, BrainInABlender, HippoSeq) and published studies containing differential expression results. Although Brain.GMT is still undergoing development and currently only represents a fraction of available brain gene sets, "brain ignorome" genes are already better represented than in traditional Gene Ontology databases. Moreover, Brain.GMT substantially improves the quantity and quality of gene sets identified as enriched with differential expression in neuroscience studies, enhancing interpretation. •We compiled a curated database of 918 gene sets related to nervous system function, tissue, and cell types ("Brain.GMT").•Brain.GMT can be used within common analysis pipelines (GSEA, limma, edgeR) to interpret neuroscience transcriptional profiling results from three species (rat, mouse, human).•Although Brain.GMT is still undergoing development, it substantially improved the interpretation of differential expression results within our initial use cases.

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Increasing survival rates of children following cancer treatment have resulted in a significant population of adult survivors with the common side effect of infertility. Additionally, the availability of genetic testing has identified Klinefelter syndrome (classic 47,XXY) as the cause of future male infertility for a significant number of prepubertal patients. This study explores new spermatogonia stem cell (SSC)-based fertility therapies to meet the needs of these patients. Testicular cells were isolated from cryopreserved human testes tissue stored from XY and XXY prepubertal patients and propagated in a two-dimensional culture. Cells were then incorporated into a 3D human testicular organoid (HTO) system. During a 3-week culture period, HTOs maintained their structure, viability, and metabolic activity. Cell-specific PCR and flow cytometry markers identified undifferentiated spermatogonia, Sertoli, Leydig, and peritubular cells within the HTOs. Testosterone was produced by the HTOs both with and without hCG stimulation. Upregulation of postmeiotic germ cell markers was detected after 23 days in culture. Fluorescence in situ hybridization (FISH) of chromosomes X, Y, and 18 identified haploid cells in the in vitro differentiated HTOs. Thus, 3D HTOs were successfully generated from isolated immature human testicular cells from both euploid (XY) and Klinefelter (XXY) patients, supporting androgen production and germ cell differentiation in vitro.

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Context: Roux-en-Y gastric bypass (RYGB) has deleterious effects on bone mass, microarchitecture, and strength. Data are lacking on the skeletal effects of sleeve gastrectomy (SG), now the most commonly performed bariatric surgical procedure. Objective: We examined changes in bone turnover, areal and volumetric bone mineral density (aBMD, vBMD), and appendicular bone microarchitecture and estimated strength after SG. We compared the results to those previously reported after RYGB, hypothesizing lesser effects after SG than RYGB. Design Setting Participants: Prospective observational cohort study of 54 adults with obesity undergoing SG at an academic center. Main Outcome Measures: Skeletal characterization with biochemical markers of bone turnover, dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) was performed preoperatively and 6- and 12-months postoperatively. Results: Over 12 months, mean percentage weight loss was 28.8%. Bone turnover marker levels increased, and total hip aBMD decreased -8.0% (95% CI -9.1%, -6.7%, p<0.01). Spinal aBMD and vBMD declines were larger in postmenopausal women than men. Tibial and radial trabecular and cortical microstructure worsened, as did tibial estimated strength, particularly in postmenopausal women. When compared to data from a RYGB cohort with identical design and measurements, some SG biochemical, vBMD, and radial microstructural parameters were smaller, while other changes were not. Conclusions: Bone mass, microstructure, and strength decrease after SG. Some skeletal parameters change less after SG than after RYGB, while for others, we find no evidence for smaller effects after SG. Postmenopausal women may be at highest risk of skeletal consequences after SG.

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Human hallmarks of sarcopenia include muscle weakness and a blunted response to exercise. Nicotinamide N-methyltransferase inhibitors (NNMTis) increase strength and promote the regenerative capacity of aged muscle, thus offering a promising treatment for sarcopenia. Since human hallmarks of sarcopenia are recapitulated in aged (24-month-old) mice, we treated mice from 22 to 24 months of age with NNMTi, intensive exercise, or a combination of both, and compared skeletal muscle adaptations, including grip strength, longitudinal running capacity, plantarflexor peak torque, fatigue, and muscle mass, fiber type, cross-sectional area, and intramyocellular lipid (IMCL) content. Exhaustive proteome and metabolome analyses were completed to identify the molecular mechanisms underlying the measured changes in skeletal muscle pathophysiology. Remarkably, NNMTi-treated aged sedentary mice showed ~ 40% greater grip strength than sedentary controls, while aged exercised mice only showed a 20% increase relative to controls. Importantly, the grip strength improvements resulting from NNMTi treatment and exercise were additive, with NNMTi-treated exercised mice developing a 60% increase in grip strength relative to sedentary controls. NNMTi treatment also promoted quantifiable improvements in IMCL content and, in combination with exercise, significantly increased gastrocnemius fiber CSA. Detailed skeletal muscle proteome and metabolome analyses revealed unique molecular mechanisms associated with NNMTi treatment and distinct molecular mechanisms and cellular processes arising from a combination of NNMTi and exercise relative to those given a single intervention. These studies suggest that NNMTi-based drugs, either alone or combined with exercise, will be beneficial in treating sarcopenia and a wide range of age-related myopathies.

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Envejecimiento , Músculo Esquelético , Nicotinamida N-Metiltransferasa , Condicionamiento Físico Animal , Sarcopenia , Animales , Nicotinamida N-Metiltransferasa/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Ratones , Envejecimiento/fisiología , Sarcopenia/metabolismo , Sarcopenia/tratamiento farmacológico , Masculino , Fuerza Muscular/efectos de los fármacos , Ratones Endogámicos C57BL , Inhibidores Enzimáticos/farmacología

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Antiasmáticos , Asma , Productos Biológicos , Humanos , Asma/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Antiasmáticos/uso terapéutico

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Brain connectome analysis suffers from the high dimensionality of connectivity data, often forcing a reduced representation of the brain at a lower spatial resolution or parcellation. This is particularly true for graph-based representations, which are increasingly used to characterize connectivity gradients, capturing patterns of systematic spatial variation in the functional connectivity structure. However, maintaining a high spatial resolution is crucial for enabling fine-grained topographical analysis and preserving subtle individual differences that might otherwise be lost. Here we introduce a computationally efficient approach to establish spatially fine-grained connectivity gradients. At its core, it leverages a set of landmarks to approximate the underlying connectivity structure at the full spatial resolution without requiring a full-scale vertex-by-vertex connectivity matrix. We show that this approach reduces computational time and memory usage while preserving informative individual features and demonstrate its application in improving brain-behavior predictions. Overall, its efficiency can remove computational barriers and enable the widespread application of connectivity gradients to capture spatial signatures of the connectome. Importantly, maintaining a spatially fine-grained resolution facilitates to characterize the spatial transitions inherent in the core concept of gradients of brain organization.

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Encéfalo , Conectoma , Encéfalo/fisiología , Encéfalo/diagnóstico por imagen , Humanos , Masculino , Femenino , Red Nerviosa/fisiología , Imagen por Resonancia Magnética/métodos , Adulto

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Transcription factors (TFs) orchestrate gene expression programs crucial for brain function, but we lack detailed information about TF binding in human brain tissue. We generated a multiomic resource (ChIP-seq, ATAC-seq, RNA-seq, DNA methylation) on bulk tissues and sorted nuclei from several postmortem brain regions, including binding maps for more than 100 TFs. We demonstrate improved measurements of TF activity, including motif recognition and gene expression modeling, upon identification and removal of high TF occupancy regions. Further, predictive TF binding models demonstrate a bias for these high-occupancy sites. Neuronal TFs SATB2 and TBR1 bind unique regions depleted for such sites and promote neuronal gene expression. Binding sites for TFs, including TBR1 and PKNOX1, are enriched for risk variants associated with neuropsychiatric disorders, predominantly in neurons. This work, titled BrainTF, is a powerful resource for future studies seeking to understand the roles of specific TFs in regulating gene expression in the human brain.

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Encéfalo , Factores de Transcripción , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Encéfalo/metabolismo , Metilación de ADN , Neuronas/metabolismo , Sitios de Unión , Unión Proteica , Secuenciación de Inmunoprecipitación de Cromatina

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BACKGROUND: Permanent pacemaker implantation (PPI) rates following transcatheter aortic valve replacement (TAVR) remain a concern. We assessed the PPI rates over time in patients implanted with an Evolut supra-annular, self-expanding transcatheter valve from the US STS/ACC TVT Registry. METHODS: Patients who underwent TAVR with an Evolut R, Evolut PRO or Evolut PRO+ valve between July 2018 (Q3) and June 2021 (Q2) were included. PPI rates were reported by calendar quarter. In-hospital PPI rates were reported as proportions and 30-day rates as Kaplan-Meier estimates. A Cox regression model was used to determine potential predictors of a new PPI within 30 days of the TAVR procedure. RESULTS: From July 2018 to June 2021, 54,014 TAVR procedures were performed using Evolut valves. Mean age was 79.3 ± 8.8 years and 49.2 % were male. The 30-day PPI rate was 16.6 % in 2018 (Q3) and 10.8 % in 2021 (Q2, 34.9 % decrease, p < 0.001 for trend across all quarters). The in-hospital PPI rate decreased by 40.1 %; from 14.7 % in 2018 (Q3) to 8.8 % in 2021 (Q2) (p < 0.001 for trend across all quarters). Significant predictors of a new PPI within 30 days included a baseline conduction defect, history of atrial fibrillation, home oxygen, and diabetes mellitus. CONCLUSION: From 2018 to 2021, TAVR with an Evolut transcatheter heart valve in over 50,000 patients showed a significant decreasing trend in the rates of in-hospital and 30-day PPI, representing the lowest rate of PPI in any large real-world registry of Evolut. During the same evaluated period, high device success and shorter length of stay was also observed.