MINRbase: A Comprehensive Database of Nuclear- and Mitochondrial-Ribosomal-RNA-Derived Fragments (rRFs)

We describe the Mitochondrial and Nuclear rRNA fragment database (MINRbase), a knowledge repository aimed at facilitating the study of ribosomal RNA-derived fragments (rRFs). MINRbase provides interactive access to the profiles of 130 238 expressed rRFs arising from the four human nuclear rRNAs (18S, 5.8S, 28S, 5S), two mitochondrial rRNAs (12S, 16S) or four spacers of 45S pre-rRNA. We compiled these profiles by analyzing 11 632 datasets, including the GEUVADIS and The Cancer Genome Atlas (TCGA) repositories. MINRbase offers a user-friendly interface that lets researchers issue complex queries based on one or more criteria, such as parental rRNA identity, nucleotide sequence, rRF minimum abundance and metadata keywords (e.g. tissue type, disease). A \u27summary\u27 page for each rRF provides a granular breakdown of its expression by tissue type, disease, sex, ancestry and other variables; it also allows users to create publication-ready plots at the click of a button. MINRbase has already allowed us to generate support for three novel observations: the internal spacers of 45S are prolific producers of abundant rRFs; many abundant rRFs straddle the known boundaries of rRNAs; rRF production is regimented and depends on \u27personal attributes\u27 (sex, ancestry) and \u27context\u27 (tissue type, tissue state, disease). MINRbase is available at https://cm.jefferson.edu/MINRbase/

Identifying Opportunities for Prevention of Adverse Outcomes Following Female Genital Fistula Repair: Protocol for a Mixed-Methods Study in Uganda

BACKGROUND: Female genital fistula is a traumatic debilitating injury, frequently caused by prolonged obstructed labor, affecting between 500,000-2 million women in lower-resource settings. Vesicovaginal fistula causes urinary incontinence, and other morbidity may occur during fistula development. Women with fistula are stigmatized, limit social and economic engagement, and experience psychiatric morbidity. Improved surgical access has reduced fistula consequences yet post-repair risks impacting quality of life and well-being include fistula repair breakdown or recurrence and ongoing or changing urine leakage or incontinence. Limited evidence on risk factors contributing to adverse outcomes hinders interventions to mitigate adverse events. This study aims to quantify these adverse risks and inform clinical and counseling interventions to optimize women\u27s health and quality of life following fistula repair through: identifying predictors and characteristics of post-repair fistula breakdown and recurrence (Objective 1) and post-repair incontinence (Objective 2), and to identify feasible and acceptable intervention strategies (Objective 3). METHODS: This mixed-methods study incorporates a prospective cohort of women with successful vesicovaginal fistula repair at approximately 12 fistula repair centers in Uganda (Objectives 1-2) followed by qualitative inquiry among key stakeholders (Objective 3). Cohort participants will have a baseline visit at the time of surgery followed by data collection at 2 weeks, 6 weeks, 3 months and quarterly thereafter for 3 years. Primary predictors to be evaluated include patient-related factors, fistula-related factors, fistula repair-related factors, and post-repair behaviors and exposures, collected via structured questionnaire at all data collection points. Clinical exams will be conducted at baseline, 2 weeks post-surgery, and for outcome confirmation at symptom development. Primary outcomes are fistula repair breakdown or fistula recurrence and post-repair incontinence. In-depth interviews will be conducted with cohort participants (n ~ 40) and other key stakeholders (~ 40 including family, peers, community members and clinical/social service providers) to inform feasibility and acceptability of recommendations. DISCUSSION: Participant recruitment is underway. This study is expected to identify key predictors that can directly improve fistula repair and post-repair programs and women\u27s outcomes, optimizing health and quality of life. Furthermore, our study will create a comprehensive longitudinal dataset capable of supporting broad inquiry into post-fistula repair health. Trial Registration ClinicalTrials.gov Identifier: NCT05437939

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy

Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time in various tissues and disrupt multiple biological systems, including catabolism of other substances, autophagy, and mitochondrial function. These pathological changes ultimately increase oxidative stress and activate innate immunity and inflammation. We have described the pathophysiology of MPS and activated inflammation in this paper, starting with accumulating the primary storage materials, GAGs. At the initial stage of GAG accumulation, affected tissues/cells are reversibly affected but progress irreversibly to: (1) disruption of substrate degradation with pathogenic changes in lysosomal function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), and inflammatory process, and (3) progressive tissue/organ damage and cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current and future treatment, several potential treatments for MPS that can penetrate the blood-brain barrier and bone have been proposed and/or are in clinical trials, including targeting peptides and molecular Trojan horses such as monoclonal antibodies attached to enzymes via receptor-mediated transport. Gene therapy trials with AAV, ex vivo LV, and Sleeping Beauty transposon system for MPS are proposed and/or underway as innovative therapeutic options. In addition, possible immunomodulatory reagents that can suppress MPS symptoms have been summarized in this review

Determining Bystander Motivations and Hesitations to Intervene During an Opioid Overdose Event

Background Harm reduction initiatives have been shown to improve morbidity and mortality of overdose; however, the rate of death due to opioid overdose continues to rise in Philadelphia. One aspect of the overdose scenario that requires more focus is the response of witnesses to overdose.https://jdc.jefferson.edu/aoa_research_symposium_posters/1006/thumbnail.jp

Regulation of the Gut-Brain Axis by Guanylyl Cyclase C

The gut-brain axis is a multi-modal bi-directional communication system integrating gastrointestinal signals into the central nervous system. The gastrointestinal tract relays information about nutritive signals, motility, microbial byproducts, and infection through a host of modalities including hormonal signaling and direct synaptic integration with peripheral neurons. Obesity, visceral pain syndromes, mood disorders, and neurodegenerative diseases have all have links to dysregulation of gut-brain signaling. Identifying molecular targets to repair gut-brain dysbiosis is essential to finding safe and effective treatments for these debilitating diseases. One such target is guanylyl cyclase C (GUCY2C), a transmembrane receptor found on the luminal aspect of the intestinal epithelium, first described for its role in intestinal secretion. GUCY2C is the receptor for two cognate hormones, guanylin (GUCA2A) and uroguanylin (GUCA2B), secreted by the colon and small intestine, respectively. Intriguingly, loss of GUCY2C ligands is associated with both obesity and irritable bowel syndrome, and mouse models deficient in GUCY2C have been shown to be hyperphagic and obese. Reconstituting GUCY2C signaling by oral administration of ligand relieves symptoms of irritable bowel syndrome but has no effect on satiety. Conversely, intravenous infusion of GUCY2C ligand induces satiety, decreasing food intake. Here, we attempt to untangle the multi-modal role of GUCY2C in the gut-brain axis by describing unique anatomical location of GUCY2C in brain and rare intestinal cells. We map GUCY2C protein and mRNA in the brain, demonstrating that GUCY2C is transcribed and translated in the ventral premammillary nucleus (PMV) of the hypothalamus, as well as in dopaminergic nuclei in the midbrain. From these sites, GUCY2C protein is carried to distinct nuclei through axonal projections. Importantly, we find that GUCY2C in the ventral premammillary nucleus is expressed primarily in neurons expressing leptin receptor (LepR), and projects to identical nuclei as LepR+ neurons. These neurons are implicated in feeding regulation and provide one branch of the GUCY2C gut-brain axis where hormonal GUCY2C ligand released post-prandially interacts with hypothalamic GUCY2C to induce satiety. We also find that GUCY2C is most highly expressed in a rare enteroendocrine intestinal cell type called neuropod cells. These cells directly interact with peripheral neurons and are highly reactive to GUCY2C ligand. We find that these cells form another branch of the GUCY2C gut-brain axis, by transducing luminal signals from GUCY2C ligands to dorsal root ganglia neurons, decreasing visceral pain signals to the spinal cord. This affect is unique to neuropod cells, as eliminating GUCY2C only in neuropod cells eliminates analgesic effects of oral GUCY2C ligands. Together, these two branches of the GUCY2C gut-brain axis provide evidence for GUCY2C activity outside of intestinal enterocytes regulating multiple homeostatic signaling mechanisms. The expression of GUCY2C in these newly discovered anatomic locales also provides attractive opportunities for combinatorial therapeutics to enhance the anorexic or analgesic effects of GUCY2C ligands while minimizing the secretory effects of these drugs in intestinal enterocytes

Chlormethine Gel in Combination With Other Therapies for Treatment of Mycosis Fungoides: A Review With Patient Cases

Topical chlormethine gel has been approved as monotherapy for treatment of adult patients with mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma. In clinical practice, chlormethine gel is often combined with other skin-directed or systemic therapies to optimize response and target recalcitrant lesions. Positive outcomes with combination regimens using chlormethine gel and topical corticosteroids, phototherapy, retinoids, methotrexate, or interferon-α have been reported in literature. However, there are no treatment guidelines on the use of combination regimens with chlormethine gel. To provide real-world evidence and guidance on the use of chlormethine gel combination regimens, several cases of patients treated with chlormethine gel combined with phototherapy (n = 5), retinoids (n = 16), or mogamulizumab (n = 3) are presented. These different combination regimens showed promising results. Most patients had a complete or partial response following treatment and the combinations were well-tolerated over extended treatment periods. Patients receiving chlormethine gel with retinoids had long-term periods of remission, even after treatment discontinuation. Durations of response of up to 3 years were observed in these patients. This long-term disease control may be the result of disease-modifying effects of chlormethine. Previous studies have shown targeted reductions in malignant T-cell clones in patients treated with chlormethine gel as well as improved post-treatment responses. Further research is needed to determine the effectiveness and safety of combination treatment regimens with chlormethine gel and to assess the impact chlormethine gel has on disease control

Pharmacotherapy for Primary Biliary Cholangitis: An Assessment of Medication Candidacy and Rates of Treatment

BACKGROUND: Ursodeoxycholic acid is the preferred first-line therapy for primary biliary cholangitis. Alternative therapies, such as obeticholic acid, are recommended for patients who cannot tolerate ursodeoxycholic acid or who have an inadequate response to ursodeoxycholic acid monotherapy. Prior investigations have suggested that as many as 30% of patients with primary biliary cholangitis may have never received treatment with ursodeoxycholic acid. No prior investigations have examined usage rates of obeticholic acid in the treatment of primary biliary cholangitis. METHODS: All patients with an ICD-10 diagnosis of primary biliary cholangitis who had any records within the health system were included. A review of medical records was performed to confirm the diagnosis of primary biliary cholangitis and determine which medications had been prescribed for treatment, as well as candidacy for second-line therapies. RESULTS: A total of 495 patients met inclusion criteria. Notably, 95% of patients were taking ursodeoxycholic acid for treatment of their primary biliary cholangitis, with 67% of patients having disease that was well-controlled on ursodeoxycholic acid monotherapy. In total, 8% of patients were taking obeticholic acid (either as combination or monotherapy). Only 3% would benefit from the addition of a second line therapy but had not yet been offered medication. Only 3% of patients were not on any medication for management of their primary biliary cholangitis. CONCLUSIONS: Ursodeoxycholic acid is a readily available and generally well-tolerated medication that should be offered to all patients with primary biliary cholangitis as first-line therapy. While prior investigations have suggested that up to 30% of patients with primary biliary cholangitis may never have received treatment for the disorder, the present study suggests that patients are generally being managed according to guidelines. Moreover, a significant proportion of patients with primary biliary cholangitis will qualify for second line therapies and prescribers should be aware of the indications to use these medications

Meet an IPE/CP Staff Champion from Thomas Jefferson University

In June 2021, the Integrated Behavioral Health (IBH) team was invited by JCIPE to pilot a new series of interprofessional sessions for primary care teams utilizing the ECHO (Extension for Community Healthcare Outcomes). This model has been utilized and researched worldwide to help with disseminating information across various subject matters within healthcare, with the goal of decreasing health disparities. Through use of subject matter experts, brief didactic education, and case consultations, communities of learners come together to enhance patient care and health outcomes. The IBH team, which consists of clinicians from behavioral health, primary care, nutrition, occupational therapy, psychiatry, pharmacy, and physical therapy, has collaborated with JCIPE to deliver 5 ECHO series on topics including diabetes, insomnia, chronic pain, weight management, mood disorders, and ADHD

Longitudinal Monitoring of Gait Parameters for Lower Limb Prosthetic Users with Physical Therapy Using Video-Based Gait Analysis

Introduction Gait training in physical therapy is a common standard of practice for new lower limb prosthetic users. Progress is typically assessed through functional outcome measures such as the 10-meter or 6-minute walk tests1. While these tests measure walking speed and endurance, they fall short of capturing gait quality or quantifying gait parameters which literature shows to be of therapeutic value 2,3. Routine access to quantitative gait assessment could provide clinicians with benchmarks to optimize treatment interventions. Traditional gait analysis systems require specialized equipment making them very resource-intensive and inconvenient to operate. Using human pose estimation techniques, we have developed and trained a custom gait analysis system that allows us to measure spatiotemporal gait parameters from video4,5. Lower limb prosthetic users were recorded while ambulating during routine physical therapy appointments. Manual annotation of these videos was used to categorize system performance. The goal of the study was to demonstrate if longitudinal tracking of various gait parameters such as cadence and velocity across numerous subjects showed improvements that reflected coinciding functional outcome measures.https://jdc.jefferson.edu/aoa_research_symposium_posters/1004/thumbnail.jp

Post-Capillary Pulmonary Hypertension: Clinical Review

Pulmonary hypertension (PH) caused by left heart disease, also known as post-capillary PH, is the most common etiology of PH. Left heart disease due to systolic dysfunction or heart failure with preserved ejection fraction, valvular heart disease, and left atrial myopathy due to atrial fibrillation are causes of post-capillary PH. Elevated left-sided filling pressures cause pulmonary venous congestion due to backward transmission of pressures and post-capillary PH. In advanced left-sided heart disease or valvular heart disease, chronic uncontrolled venous congestion may lead to remodeling of the pulmonary arterial system, causing combined pre-capillary and post-capillary PH. The hemodynamic definition of post-capillary PH includes a mean pulmonary arterial pressure \u3e 20 mmHg, pulmonary vascular resistance \u3c 3 Wood units, and pulmonary capillary wedge pressure \u3e 15 mmHg. Echocardiography is important in the identification and management of the underlying cause of post-capillary PH. Management of post-capillary PH is focused on the treatment of the underlying condition. Strategies are geared towards pharmacotherapy and guideline-directed medical therapy for heart failure, surgical or percutaneous management of valvular disorders, and control of modifiable risk factors and comorbid conditions. Referral to centers with advanced heart and pulmonary teams has shown to improve morbidity and mortality. There is emerging interest in the use of targeted agents classically used in pulmonary arterial hypertension, but current data remain limited and conflicting. This review aims to serve as a comprehensive summary of postcapillary PH and its etiologies, pathophysiology, diagnosis, and management, particularly as it pertains to advanced heart failure