Endovascular Ablation of the Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction: The REBALANCE-HF Randomized Clinical Trial.

Importance: Greater splanchnic nerve ablation may improve hemodynamics in patients with heart failure and preserved ejection fraction (HFpEF). Objective: To explore the feasibility and safety of endovascular right-sided splanchnic nerve ablation for volume management (SAVM). Design, Setting, and Participants: This was a phase 2, double-blind, 1:1, sham-controlled, multicenter, randomized clinical trial conducted at 14 centers in the US and 1 center in the Republic of Georgia. Patients with HFpEF, left ventricular ejection fraction of 40% or greater, and invasively measured peak exercise pulmonary capillary wedge pressure (PCWP) of 25 mm Hg or greater were included. Study data were analyzed from May 2023 to June 2024. Intervention: SAVM vs sham control procedure. Main Outcomes and Measures: The primary efficacy end point was a reduction in legs-up and exercise PCWP at 1 month. The primary safety end point was serious device- or procedure-related adverse events at 1 month. Secondary efficacy end points included HF hospitalizations, changes in exercise function and health status through 12 months, and baseline to 1-month change in resting, legs-up, and 20-W exercise PCWP. Results: A total of 90 patients (median [range] age, 71 [47-90] years; 58 female [64.4%]) were randomized at 15 centers (44 SAVM vs 46 sham). There were no differences in adverse events between groups. The primary efficacy end point did not differ between SAVM or sham (mean between-group difference in PCWP, -0.03 mm Hg; 95% CI, -2.5 to 2.5 mm Hg; P = .95). There were also no differences in the secondary efficacy end points. There was no difference in the primary safety end point between the treatment (6.8% [3 of 44]) and sham (2.2% [1 of 46]) groups (difference, 4.6%; 95% CI, -6.1% to 15.4%; P = .36). There was no difference in the incidence of orthostatic hypotension between the treatment (11.4% [5 of 44]) and sham (6.5% [3 of 46]) groups (difference, 4.9%; 95% CI, -9.2% to 18.8%; P = .48). Conclusions and Relevance: Results show that SAVM was safe and technically feasible, but it did not reduce exercise PCWP at 1 month or improve clinical outcomes at 12 months in a broad population of patients with HFpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT04592445.

Viral Determinants of Childhood Asthma Exacerbation Severity and Treatment Response.

BACKGROUND: Although respiratory viruses are common triggers of asthma exacerbations, the influence of viral infection characteristics on exacerbation presentation and treatment response in the pediatric emergency department (ED) is unclear. OBJECTIVE: To assess viral infection characteristics of children experiencing ED asthma exacerbations and to test their associations with severity and treatment response. METHODS: Prospective study of children, 4-18 years, who received standard ED asthma exacerbation treatment with inhaled bronchodilators and systemic corticosteroids. Nasal swabs collected for viral metagenomic analyses determined virus presence, load and species. Outcomes included exacerbation severity (Pediatric Asthma Severity (PAS) score, clinician impression, and vital signs) and treatment response (discharge home without needing additional asthma therapies). RESULTS: Of 107 children, 47% had moderate/severe exacerbations by PAS and 64% demonstrated treatment response. Viral metagenomic analysis on nasal swabs from 73 children detected virus in 86%, with 10 different species identified, primarily rhinovirus A (RV-A), RV-C, and enterovirus D68. Exacerbations involving RV-A were milder (odds ratio [OR]=0.25; 95% CI=0.07-0.83) and tended to be more responsive to treatment compared to non-RV-A infections, whereas exacerbations involving enterovirus D68 were more severe (OR=8.3; 95% CI=1.3-164.7) and had no treatment response association. Viral load was not associated with treatment response but exhibited a strong linear relationship with heart rate (rpartial=0.48), respiratory rate (rpartial=0.25), and oxygen saturation (rpartial=-0.25), indicative of severity. CONCLUSIONS: The majority of ED asthma exacerbations are triggered by respiratory viruses. Viral species are associated with severity and treatment response, suggesting early pathogen detection could inform ED treatment decisions. Additional studies are needed to identify differences in pathobiology underlying exacerbations triggered by different viral species, and how to effectively treat these heterogeneous exacerbations.

How Dermatologic Surgeons Decide to Proceed with Surgery for Nonmelanoma Skin Cancer When Site Identification is Initially Uncertain: A Nationwide, Multicenter, Prospective Study.

BACKGROUND: Few studies show how dermatologic surgeons manage problems with site identification. OBJECTIVE: To estimate frequency and characterize management of skin cancer treated by surgery when the anatomic location of the tumor is in question. METHODS: Nationwide, prospective, multi-site cohort study. RESULTS: Among 17,076 cases at 22 centers, 98 (0.60%) were lesions in question (LIQ) for which site identification was initially uncertain, with these more often in patients who were male, older, and biopsied more than 30 days ago. Surgeons employed on average 5.0 (95% CI: 4.61-5.39) additional techniques to confirm the site location, with common approaches including: re-checking available documentation (90 lesions, 92%); performing an expanded physical examination (89 lesions, 91%); and asking the patient to point using a mirror (61 lesions, 62%). In 15%, photographs were requested from the biopsying provider, and also in 15%, frozen section biopsies were obtained. In 10%, the referring physician was contacted. Eventually, surgeons succeeded in definitively identifying 82% (80/98) of initially uncertain sites, with the remaining 18% (18/98) postponed. Most postponed surgeries were at non-facial sites. LIMITATIONS: Sites were academic centers. CONCLUSIONS: When the anatomic location of the tumor is uncertain, dermatologic surgeons use multiple methods to identify the site, and sometimes cases are postponed.

Health status and heat preparation at a UCI World Tour multistage cycling race.

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.

Effects of COVID-19 related economic threat on political conservatism, xenophobia, and racial bias in the United States.

The uncertainty-threat model of conservatism posits that people turn to political conservatism to protect themselves from perceived threats; indeed, studies show increases in conservative ideology and outgroup bias following threat priming. The COVID-19 pandemic is an unprecedented threat that has had devastating effects on the health and economic lives of Americans. Concerns surrounding the threat of COVID-19 may have secondary effects on other aspects of American life, such as political and anti-Asian racial bias. The current studies explored the effects of COVID-19 related threats on expressed political conservatism, xenophobia, and racial bias under the uncertainty-threat model. Study 1 assessed the effects of priming health or economic risks of COVID-19 (vs. control), and found that economic threat led to increased xenophobia, but had no effects on overall conservatism. Study 2 then investigated whether the effects of COVID-related economic threat prime extended to racial bias, and explored moderators and mediators of effects. Results showed that the economic threat prime increased perceived group-status threat, and indirectly increased conservatism, xenophobia, and racial bias through the mechanism of perceived group-status threat. Effects were greatest for those impacted financially by the pandemic. In general, our studies provide support for the uncertainty-threat model with the novel threat of the COVID-19 pandemic. Implications for understanding potential shifts in conservatism and bias in response to future threats in the United States are discussed.

A Pain Desensitization Algorithm for Phenotyping and Treating Chronic Pelvic Pain.

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.

Reducing asthma attacks in disadvantaged school children with asthma: study protocol for a type 2 hybrid implementation-effectiveness trial (Better Asthma Control for Kids, BACK).

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 .

Allele-specific transcription factor binding across human brain regions offers mechanistic insight into eQTLs.

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.

Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction.

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.

Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading.

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.

Low-Light Phase Retrieval With Implicit Generative Priors.

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.

Resource: A curated database of brain-related functional gene sets (Brain.GMT).

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.

3-Year Outcomes From the Evolut Low Risk TAVR Bicuspid Study.

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.

Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice.

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.

In Vitro Generation of Haploid Germ Cells from Human XY and XXY Immature Testes in a 3D Organoid System.

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.

Pediatric Device Clinical Trials Activity: 1999-2022.

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.

Methylome-proteome integration after late-life voluntary exercise training reveals regulation and target information for improved skeletal muscle health.

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.

The pudendal syndrome: A photo essay of nerve compression damage visualized at neurolysis in patients with chronic neuropathic pelvic pain.

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.