Multidisciplinary lifestyle interventions for neurological disorders during the Silent phase (MINDS) study: a multi-omics randomized controlled trial protocol.

INTRODUCTION: Given the prevalence and staggering cost of neurological disorders, there is dire need for effective early detection and intervention tools. Emerging evidence suggests that multidisciplinary lifestyle interventions (MLI) may mitigate the risk and progression of neurological disorders. The objectives of this protocol are (1) to test the impact of MLI on the progression of neurological disorders and (2) to identify multi-omic biomarkers for early stages of neurological disease and the impact of MLIs on these biomarkers. METHODS AND ANALYSIS: We present the Multidisciplinary lifestyle Interventions for Neurological Disorders during the Silent phase (MINDS) protocol, a randomized controlled trial of MLI in neurologically healthy older adults (≥ 50 years old) exhibiting elevated risk for common neurological disorders: stroke, epilepsy, Parkinson's Disease, or Alzheimer's disease and related dementias. Participants will be randomly assigned to intervention (n = 100) or control (n = 100) groups. The intervention group will receive 3 months of weekly 2-hour sessions on diet education, yoga, music therapy, and cognitive skills training. The participants' neurological health and engagement in relevant lifestyle practices will be assessed at regular intervals for 12 months. Neuroimaging and samples for multi-omic analyses will be collected at baseline, and at 3 months and 12 months after enrollment. Primary outcomes will be signs of progression of the neurological disorder risk that qualified them for study enrollment or a clinical diagnosis of the disorder. Secondary and exploratory outcomes will be based on self-reported health and multi-omic data. Data analysis will include between-group and longitudinal within-group analyses. PERSPECTIVES: The MINDS protocol and trial aims to clarify the impact of MLI on the progression of neurological disorder risk or diagnosis in older adults and to identify biomarkers that can be used to confirm MLI efficacy. The ability to validate the impact of MLI on neurological disorder progression based on biomarker data allows the identification of individuals most likely to benefit from such therapies in the early stages of neurological disease. TRIAL REGISTRATION: The trial is registered on the National Institutes of Health (NIH) ClinicalTrials.gov (NCT05984056) site. It was registered on August 2nd, 2023. The trial has full approval of the Cleveland Clinic Internal Review Board.

Treatment of male stress urinary incontinence at time of inflatable penile prosthesis placement a review of contemporary literature.

Background and Objective: Male stress urinary incontinence (SUI) and erectile dysfunction (ED) are well established diagnoses within Men's Health, often more specifically within the prostate cancer survivorship cohort. Taken individually, well defined treatment algorithms exist with which many surgeons are comfortable; however, treatment of both in a single setting or staged fashion introduces complexity. Emerging treatment options also exist, and there is immature or minimal data when these are combined with inflatable penile prosthesis (IPP) insertion, radiation history, and/or variable degrees of incontinence. Our objective was to describe and summarize the currently available treatment options for SUI particularly at the time of IPP insertion. Methods: A literature review was performed to summarize contemporary treatment of SUI at time of IPP placement. Anecdotal experience was added from high volume, subspecialty trained Men's Health and Reconstructive Urologists. Key Content and Findings: Non-invasive approaches such as pelvic floor muscle training (PFMT), behavioral modification, and external compression devices play some limited role in treatment and/or management of SUI, particularly in the early post operative period, or for those unwilling or unable to undergo more definitive intervention. More invasive options such as artificial urinary sphincter (AUS) implantation, male sling, or other implantable devices are more appropriate for good surgical candidates with higher bother and/or more severe incontinence. These options can be concomitant or staged relative to IPP placement. Climacturia, particularly with mild or no bothersome SUI, can successfully be addressed at the time of penile prosthesis placement with the utilization of the Mini-Jupette suburethral sling. Conclusions: A variety of treatment options exist for concomitant treatment of SUI at time of IPP, and both safety and efficacy have been demonstrated for many in the same operative setting. As with treatment of ED or SUI in isolation, patient selection, careful counseling, and management of expectations can lead to high patient satisfaction.

Child Health Needs and the Pediatric Gastroenterology Workforce: 2020-2040.

This article is part of an American Board of Pediatrics Foundation-sponsored effort to analyze and forecast the pediatric subspecialty workforce between 2020 and 2040. Herein, an overview of the current pediatric gastroenterology workforce is provided, including demographics, work characteristics, and geographic distribution of practitioners. Brief context is provided on the changing nature of current practice models and the increasing prevalence of some commonly seen disorders. On the basis of a rigorous microsimulation workforce projection model, projected changes from 2020 to 2040 in the number of pediatric gastroenterologists and clinical workforce equivalents in the United States are presented. The article closes with a brief discussion of training, clinical practice, policy, and future workforce research implications of the data presented. This data-driven analysis suggests that the field of pediatric gastroenterology will continue to grow in scope and complexity, propelled by scientific advances and the increasing prevalence of many disorders relevant to the discipline. The workforce is projected to double by 2040, a growth rate faster than most other pediatric subspecialties. Disparities in care related to geography, race, and ethnicity are among the most significant challenges for the years ahead. Changes to training and education, incentives to meet the needs of underserved populations, and new multidisciplinary models for health care delivery will be necessary to optimally meet the volume, diversity, and complexity of children with gastroenterological diseases in the years ahead.

Decreased FAM13B Expression Increases Atrial Fibrillation Susceptibility by Regulating Sodium Current and Calcium Handling.

A specific genetic variant associated with atrial fibrillation risk, rs17171731, was identified as a regulatory variant responsible for controlling FAM13B expression. The atrial fibrillation risk allele decreases FAM13B expression, whose knockdown alters the expression of many genes in stem cell-derived cardiomyocytes, including SCN2B, and led to pro-arrhythmogenic changes in the late sodium current and Ca2+ cycling. Fam13b knockout mice had increased P-wave and QT interval duration and were more susceptible to pacing-induced arrhythmias vs control mice. FAM13B expression, its regulation, and downstream effects are potential targets for investigation of patient-specific therapeutics.

Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder.

Inadequate glycogen branching enzyme 1 (GBE1) activity results in different forms of glycogen storage disease type IV, including adult polyglucosan body disorder (APBD). APBD is clinically characterized by adult-onset development of progressive spasticity, neuropathy, and neurogenic bladder and is histologically characterized by the accumulation of structurally abnormal glycogen (polyglucosan bodies) in multiple cell types. How insufficient GBE1 activity causes the disease phenotype of APBD is poorly understood. We hypothesized that proteomic analysis of tissue from GBE1-deficient individuals would provide insights into GBE1-mediated pathobiology. In this discovery study, we utilized label-free LC-MS/MS to quantify the proteomes of lymphoblasts from 3 persons with APBD and 15 age- and gender-matched controls, with validation of the findings by targeted MS. There were 531 differentially expressed proteins out of 3,427 detected between APBD subjects vs. controls, including pronounced deficiency of GBE1. Bioinformatic analyses indicated multiple canonical pathways and protein-protein interaction networks to be statistically markedly enriched in APBD subjects, including: RNA processing/transport/translation, cell cycle control/replication, mTOR signaling, protein ubiquitination, unfolded protein and endoplasmic reticulum stress responses, glycolysis and cell death/apoptosis. Dysregulation of these processes, therefore, are primary or secondary factors in APBD pathobiology in this model system. Our findings further suggest that proteomic analysis of GBE1 mutant lymphoblasts can be leveraged as part of the screening for pharmaceutical agents for the treatment of APBD.

Kynurenine pathway metabolism evolves with development of preclinical and scleroderma-associated pulmonary arterial hypertension.

Understanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2, which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2. Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target.NEW & NOTEWORTHY Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.

Genomics of deletion 7 and 7q in myeloid neoplasm: from pathogenic culprits to potential synthetic lethal therapeutic targets.

Complete or partial deletions of chromosome 7 (-7/del7q) belong to the most frequent chromosomal abnormalities in myeloid neoplasm (MN) and are associated with a poor prognosis. The disease biology of -7/del7q and the genes responsible for the leukemogenic properties have not been completely elucidated. Chromosomal deletions may create clonal vulnerabilities due to haploinsufficient (HI) genes contained in the deleted regions. Therefore, HI genes are potential targets of synthetic lethal strategies. Through the most comprehensive multimodal analysis of more than 600 -7/del7q MN samples, we elucidated the disease biology and qualified a list of most consistently deleted and HI genes. Among them, 27 potentially synthetic lethal target genes were identified with the following properties: (i) unaffected genes by hemizygous/homozygous LOF mutations; (ii) prenatal lethality in knockout mice; and (iii) vulnerability of leukemia cells by CRISPR and shRNA knockout screens. In -7/del7q cells, we also identified 26 up or down-regulated genes mapping on other chromosomes as downstream pathways or compensation mechanisms. Our findings shed light on the pathogenesis of -7/del7q MNs, while 27 potential synthetic lethal target genes and 26 differential expressed genes allow for a therapeutic window of -7/del7q.

Long-term follow-up suggests high satisfaction rates for bulbomembranous radiation-induced urethral stenoses treated with anastomotic urethroplasty.

PURPOSE: To analyze patients who underwent anastomotic urethroplasty for radiationinduced bulbomembranous urethral stricture/stenosis (RIS) due to prostate cancer treatment with up to 19 years of follow-up and assess long-term patient reported outcomes (PROMs). Long-term follow-up with the inclusion of urethroplasty specific PROMs is lacking in the available research. METHODS: Patients who underwent anastomotic urethroplasty for RIS were identified from 2002 to 2020. Inclusion criteria included completion of 4-month post-operative cystoscopy and PROMs including IPSS, SHIM, MSHQ-EF, 6Q-LUTS, and global satisfaction queries at 4 months. PROMs were assessed annually thereafter, and cystoscopy was performed for adverse change in PROMs or worsening uroflow/PVR parameters. PROMs were compared at pre-op, post-op, and most recent follow-up. RESULTS: 23 patients met inclusion criteria. Short-term anatomic success was 95.7%. At a mean follow-up of 73.1 months (9.1-228.9), one late recurrence occurred for an overall success of 91.3%. Significant and sustained objective improvement was identified in voiding scores, quality of life, and urethroplasty specific PROMs. Satisfaction was 91.3% despite sexual side effects, and 95.7% of patients stated they would have surgery again knowing their outcome at a mean of over 6 years' follow up. CONCLUSIONS: RIS are challenging problems, but durable symptomatic relief is achievable in well-selected patients. Patients with bulbomembranous RIS should be appropriately counseled regarding the risk of urinary incontinence and sexual side effects after anastomotic urethroplasty. However, long-term success is high, and overall QoL will have sustained subjective improvement in most cases.

Novel functional atrial fibrillation risk genes and pathways identified from coexpression analyses in human left atria.

BACKGROUND: Genomewide association studies have associated >100 genetic loci with atrial fibrillation (AF), but establishing causal genes contributing to AF remains challenging. OBJECTIVE: The purpose of this study was to determine candidate novel causal genes and mechanistic pathways associated with AF risk loci by incorporating gene expression and coexpression analyses and to provide a resource for functional studies and targeting of AF-associated genes. METHODS: Cis-expression quantitative trait loci were identified for candidate genes near AF risk variants in human left atrial tissues. Coexpression partners were identified for each candidate gene. Weighted gene coexpression network analysis (WGCNA) identified modules and modules with overrepresentation of candidate AF genes. Ingenuity pathway analysis (IPA) was applied to the coexpression partners of each candidate gene. IPA and gene set over representation analysis were applied to each WGCNA module. RESULTS: One hundred sixty-six AF-risk single nucleotide polymorphisms were located in 135 loci. Eighty-one novel genes not previously annotated as putative AF risk genes were identified. IPA identified mitochondrial dysfunction, oxidative stress, epithelial adherens junction signaling, and sirtuin signaling as the most frequent significant pathways. WGCNA characterized 64 modules (candidate AF genes overrepresented in 8), represented by cell injury, death, stress, developmental, metabolic/mitochondrial, transcription/translation, and immune activation/inflammation regulatory pathways. CONCLUSION: Candidate gene coexpression analyses suggest significant roles for cellular stress and remodeling in AF, supporting a dual risk model for AF: Genetic susceptibility to AF may not manifest until later in life, when cellular stressors overwhelm adaptive responses. These analyses also provide a novel resource to guide functional studies on potential causal AF genes.

Metabolomic Differences in Connective Tissue Disease-Associated Versus Idiopathic Pulmonary Arterial Hypertension in the PVDOMICS Cohort.

OBJECTIVE: Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in patients with CTD-PAH versus patients with IPAH that might underlie these observed clinical differences. METHODS: Adult participants with CTD-PAH (n = 141) and IPAH (n = 165) from the Pulmonary Vascular Disease Phenomics (PVDOMICS) study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad-based global metabolomic profiling of plasma samples. Participants were followed prospectively for ascertainment of outcomes. Supervised and unsupervised machine learning algorithms and regression models were used to compare CTD-PAH versus IPAH metabolomic profiles and to measure metabolite-phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 participants. RESULTS: Metabolomic profiles distinguished CTD-PAH from IPAH, with patients with CTD-PAH demonstrating aberrant lipid metabolism with lower circulating levels of sex steroid hormones and higher free fatty acids (FAs) and FA intermediates. Acylcholines were taken up by the right ventricular-pulmonary vascular (RV-PV) circulation, particularly in CTD-PAH, while free FAs and acylcarnitines were released. In both PAH subtypes, dysregulated lipid metabolites, among others, were associated with hemodynamic and RV measurements and with transplant-free survival. CONCLUSIONS: CTD-PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV-PV FA metabolism may imply a reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation.

A multimodal analysis of genomic and RNA splicing features in myeloid malignancies.

RNA splicing dysfunctions are more widespread than what is believed by only estimating the effects resulting by splicing factor mutations (SFMT) in myeloid neoplasia (MN). The genetic complexity of MN is amenable to machine learning (ML) strategies. We applied an integrative ML approach to identify co-varying features by combining genomic lesions (mutations, deletions, and copy number), exon-inclusion ratio as measure of RNA splicing (percent spliced in, PSI), and gene expression (GE) of 1,258 MN and 63 normal controls. We identified 15 clusters based on mutations, GE, and PSI. Different PSI levels were present at various extents regardless of SFMT suggesting that changes in RNA splicing were not strictly related to SFMT. Combination of PSI and GE further distinguished the features and identified PSI similarities and differences, common pathways, and expression signatures across clusters. Thus, multimodal features can resolve the complex architecture of MN and help identifying convergent molecular and transcriptomic pathways amenable to therapies.

Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation.

Effective drugs for atrial fibrillation (AF) are lacking, resulting in significant morbidity and mortality. This study demonstrates that network proximity analysis of differentially expressed genes from atrial tissue to drug targets can help prioritize repurposed drugs for AF. Using enrichment analysis of drug-gene signatures and functional testing in human inducible pluripotent stem cell (iPSC)-derived atrial-like cardiomyocytes, we identify metformin as a top repurposed drug candidate for AF. Using the active compactor, a new design analysis of large-scale longitudinal electronic health record (EHR) data, we determine that metformin use is significantly associated with a reduced risk of AF (odds ratio = 0.48, 95%, confidence interval [CI] 0.36-0.64, p < 0.001) compared with standard treatments for diabetes. This study utilizes network medicine methodologies to identify repurposed drugs for AF treatment and identifies metformin as a candidate drug.

Evaluation of a nitinol stone retrieval basket as an alternative to biopsy forceps for biopsy of suspected upper tract genitourinary malignancies.

Background: The anatomical nature of the ureteroscopic approach for biopsy of upper urothelial tract tumors requires the utilization of small instruments, often limiting biopsy specimen quality. This leads to lower-than-desired tumor grading accuracy and malignancy detection capabilities on the initial evaluation of upper tract tumor specimens. This is problematic because optimal treatment of upper tract urothelial carcinoma (UTUC) depends on early disease detection and subsequent accurate diagnosis. Objective: The objective of our study was to compare the biopsy capabilities of two ureteroscopic biopsy instruments - biopsy forceps and the nitinol stone retrieval basket. Methods: We performed a retrospective analysis of ten patients who underwent biopsy of an upper tract mass with either instrument. Average specimen size, muscularis propria presence, and malignancy detection sensitivity were the variables of interest. Results: The nitinol stone retrieval basket obtained larger biopsy samples than the biopsy forceps, with average biopsy volumes being 0.0674 cm3 and 0.0075 cm3, respectively (P = 0.00017); this was the only statistically significant result of our study. Muscularis propria was present in 31% (4/13) of the biopsies with the nitinol stone retrieval basket, whereas 0% (0/5) of the biopsy forceps biopsies contained muscularis propria (P = 0.2778). Regarding malignancy detection sensitivity, the nitinol stone retrieval basket biopsies identified malignancy in 100% of the specimens that had confirmed malignancy; the biopsy forceps only detected malignancy 40% of the time (P = 0.4134). Conclusion: These findings suggest that the nitinol stone retrieval basket is a useful diagnostic tool for UTUC, although further investigation is warranted to determine its superiority compared to biopsy forceps.

Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease.

BACKGROUND: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification. OBJECTIVES: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort. METHODS: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death. RESULTS: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH. CONCLUSIONS: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS [PVDOMICS]; NCT02980887).

Accounting for population structure in genetic studies of cystic fibrosis.

CFTR F508del (c.1521_1523delCTT, p.Phe508delPhe) is the most common pathogenic allele underlying cystic fibrosis (CF), and its frequency varies in a geographic cline across Europe. We hypothesized that genetic variation associated with this cline is overrepresented in a large cohort (N > 5,000) of persons with CF who underwent whole-genome sequencing and that this pattern could result in spurious associations between variants correlated with both the F508del genotype and CF-related outcomes. Using principal-component (PC) analyses, we showed that variation in the CFTR region disproportionately contributes to a PC explaining a relatively high proportion of genetic variance. Variation near CFTR was correlated with population structure among persons with CF, and this correlation was driven by a subset of the sample inferred to have European ancestry. We performed genome-wide association studies comparing persons with CF with one versus two copies of the F508del allele; this allowed us to identify genetic variation associated with the F508del allele and to determine that standard PC-adjustment strategies eliminated the significant association signals. Our results suggest that PC adjustment can adequately prevent spurious associations between genetic variants and CF-related traits and are therefore effective tools to control for population structure even when population structure is confounded with disease severity and a common pathogenic variant.

Urethral Stricture/Stenosis as a Complication of High Intensity Focused Ultrasound of the Prostate (HIFU): What is the Overall Patient Experience?

OBJECTIVE: To analyze the location and management of urethral stricture/stenosis in patients treated with High-intensity focused ultrasound (HIFU) of the prostate as well as to describe patient reported satisfaction in these men. METHODS: Patients with a history of HIFU requesting consultation for stricture were identified from 2010 to 2020. Demographic and prior treatment data were recorded. Patients who presented for evaluation underwent retrograde cystoscopy, retrograde urethrogram, voiding cystourethrogram, and antegrade cystoscopy through a suprapubic tract. Patients who only had virtual consultation and did not present for in-person evaluation, were followed longitudinally to assess long-term outcomes and quality of life. RESULTS: Over the 10-year study period, 17 patients were identified with a mean age of 65.8 years. Prior to initial consultation, a total of 88% of patients had at least 1 failed surgical intervention at a mean of 45 months post-HIFU. The majority of patients (94%) had strictures that included but were not necessarily limited to the prostatic urethra. Patients underwent various treatments postevaluation, favoring endoscopic therapy (38%), and proximal diversion (20%) at a mean follow-up of 68.2 ± 7.5 months. Only 38% reported satisfaction with urinary symptoms. CONCLUSION: Urethral narrowing post-HIFU appears to overwhelmingly involve the prostatic urethra. Patients usually have a significant treatment burden over a prolonged period and are often managed with repeated endoscopic treatment, extirpative prostatic surgery, or urinary diversion as they have obstruction that is not amendable to urethral reconstruction. Most patients with HIFU strictures experience a diminished QOL due to persistent urinary symptoms.