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

An Exploration and Confirmation of the Measurement of Healthcare Experiences of Children With Autism: Analysis of the 2019 and 2020 National Survey of Children’s Health

Background: Autism spectrum disorders (ASD) are a group of chronic neurodevelopmental disabilities. Due to the complex medical needs of this population, increased morbidity and health resource utilization have been noted, as well as unmet medical needs. Understanding the healthcare experiences could yield improved care. The objective of this study was to determine the underlying structure of patient experience among children and adolescents with ASD.Methods: Data were obtained from the 2019 and 2020 National Survey of Children’s Health (NSCH). Exploratory factor analysis (EFA, 2019 data) and confirmatory factor analysis (CFA, 2020 data) were conducted. The study was limited to caregivers of children between the ages of 0-17 years, who reported children had seen a healthcare provider in the previous 12 months, had an ASD diagnosis, and needed decisions made about healthcare. A total of 419 caregivers in 2019 data and 631 caregivers in 2020 data met the inclusion criteria. Logistic regression was conducted to assess the association between the individual dimensions and healthcare resource utilization metrics (ER visits, hospitalization, mental health treatment visits, and preventive care visits) among respondents to the 2020 NSCH Survey. Results: Three factors emerged for both age groups: family-centered care (FCC), shared decision-making (SDM), and access to healthcare. Increased experiences of SDM were associated with an increased likelihood of experiencing any preventive care visit among children in the previous year. In contrast, access to care was related to mental health visits among children.Conclusions: Components of patient experience are associated with healthcare resource utilization among children with ASD. Further research is warranted to better understand these components and others that may emerge with more comprehensive data

PROJECT PREVENT: A Randomized Controlled Trial of Preoperative Vaginal Metronidazole to Decrease Patient Issues and Infections after Hysterectomy

OBJECTIVES: To evaluate if vaginal metronidazole for 5 days before hysterectomy decreases postoperative infections and patient issues. DESIGN: This randomized trial compared vaginal metronidazole for 5 days before a scheduled hysterectomy to no intervention. Sample size calculation was based on a 20% difference in issues and infection (30% incidence and 10% in the intervention arm) with 80% power and an alpha error of 0.05 and indicated 62 subjects needed in each arm. SETTING: Outpatient gynecology clinics at a single academic institution. PARTICIPANTS: 154 subjects were screened for eligibility between July 2020 and September 2022. 133 underwent hysterectomy including 68 subjects (51.1%) randomized to the metronidazole and 65 (48.9%) controls. Overall, the population was racially and ethnically diverse. There was no significant difference in characteristics between the two groups. INTERVENTIONS: Vaginal metronidazole for 5 days before hysterectomy. MAIN OUTCOME MEASURES: Postoperative patient issues and documented postoperative infections at 4-8 weeks after surgery. RESULTS: There was no difference in the composite rate of patient-reported issues and/or documented postoperative infection (53/133 (39.8%) with no difference between groups (29/68 (42.6%) vs 24/65 (36.9%), p=0.50). There was no difference in patient-reported issues which was 51/133 (38.3%) with no difference between groups (28/68 (41.2%) vs 23/65 (33.8%), p=0.49) or in documented infections with a rate of 25/133 (18.8%) with no significant difference between groups (15/68 (22.0%) vs 10/65 (15.4%), p=0.33). In the intervention arm, the compliance rate was 73.5% for all 5 days of vaginal metronidazole, and a per-protocol analysis was performed which resulted in no significant difference between groups. CONCLUSIONS: There is insufficient evidence to suggest a significant benefit of preoperative vaginal metronidazole to prevent surgical site infections and postoperative patient issues in patients undergoing hysterectomy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT04478617

Comparative Efficacy, Quality of Life, Safety, and Tolerability of Atogepant and Rimegepant in Migraine Prevention: A Matching-Adjusted Indirect Comparison Analysis

BACKGROUND: Comparative evaluations of preventive migraine treatments can help inform clinical decision making for managing migraine in clinical practice. METHODS: An anchored matching-adjusted indirect comparison analysis was conducted using pooled participant-level data from two phase 3 atogepant trials (ADVANCE and PROGRESS) and one phase 2/3 rimegepant trial (BHV3000-305) to evaluate the relative efficacy and safety/tolerability of atogepant and rimegepant as preventive migraine treatments. Participants receiving atogepant 60 mg once daily, rimegepant orally disintegrating tablet 75 mg once every other day, and placebo were included. Only participants meeting the BHV3000-305 inclusion/exclusion criteria were analyzed: ≥6 monthly migraine days and ≤18 monthly headache days at baseline. The primary efficacy assessment of interest was change in monthly migraine days across weeks 1-12. RESULTS: There were 252 participants in the atogepant group and 348 in the rimegepant group. Across weeks 1–12, atogepant 60 mg demonstrated a significantly greater reduction in mean monthly migraine days compared with rimegepant 75 mg (mean difference [95% CI]: −1.65 [−2.49, −0.81]; p \u3c 0.001). Both atogepant and rimegepant demonstrated similar safety/tolerability profiles. CONCLUSION: In this matching-adjusted indirect comparison analysis, oral atogepant 60 mg once daily demonstrated a significantly greater reduction in monthly migraine days compared with rimegepant 75 mg orally disintegrating tablet once every other day

Full Issue: Volume 2, Issue 1 - April 2024

i - Editors’ Note by Ari Clements & Amit Syal ii - Foreword by Dr. Alan Hilibrand 7 - Exploring Approaches to Treatment of Musculoskeletal Injuries by Catherine Alvaro 9 - A Spotlight on the Various Subspecialties of Orthopedic Surgery by Ryan Garemani 14 - Exploring the Importance of Implant Selection in Total Hip Arthroplasty by John Czarnecki 16 - Revolutionizing Orthopaedics: Exploring the Therapeutic Potential of Stem Cells by Harrison Fellheimer 18 - Shoulder Arthroplasty in Patients with Inflammatory Arthritis: Preoperative and Perioperative Management of Disease Modifying Anti-Rheumatic Drug Therapy by Daniel Kwak 22 - The Role of Psychological Readiness in Recovery from ACL Injury in Female Athletes by Samantha Meacock 25 - Examining the Role of Augmented Reality in Total Hip Arthroplasty by Joseph Raphael 28 - The Ins and Outs of Wide-Awake Hand Surgery by Molly Milano 31 - A Review of the Effects of Early Sport Specialization on the Health of Adolescent Baseball Players by Robert C. Juniewicz 34 - Summary of Early Sport Specialization in Baseball by Elijah Hoffma

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

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

Cavernous Wonders: Delving into Cavernous Sinus Syndrome in Neuro-Ophthalmology

Cavernous sinus syndrome (CSS) is any disease process that affects the cavernous sinus. This syndrome is marked by a complex interplay of neurovascular symptoms, primarily due to the compression or dysfunction of the cranial nerves that traverse the cavernous sinus. Understanding the intricate details of this syndrome is critical to providing optimal care and improving patient outcomes

Assessment of OBGYN Department Research Collaboration and Satisfaction

Background There are many simultaneous and similar research projects ongoing within the OB-GYN department, but with little collaboration. Additionally, it can be difficult to identify faculty, residents, and students with similar research interests. Collaboration between residents is shown to improve research productivity (1) and co-residents serve as effective research mentors (2). This project is aimed to assess the department\u27s satisfaction with ongoing research and collaboration and to purpose an intervention for improvement