Faculty Bibliography

NCT06203600.

Brain excitability is dysfunctional in epilepsy and overlapping neuropsychiatric conditions including autism spectrum disorder (ASD). Epilepsy and ASD are often attributed to malfunctioning coordination between synaptic excitation and inhibition. Dravet syndrome (DS) is a severe form of epilepsy arising from haploinsufficiency of the SCN1A gene that encodes the voltage-gated sodium channel Nav1.1. A DS mouse model (Scn1a^+/-) recapitulated essential features of DS and revealed that sodium current density was profoundly reduced in GABAergic inhibitory interneurons while pyramidal cells were spared, suggesting that DS is an "interneuronopathy." Further studies from the Catterall group and others have expanded this picture: DS symptoms, which include recurrent seizures, ataxia, cognitive impairment, ASD, and premature death, could be assigned in part to brain region-specific effects; the Nav1.1 mutations cause dysfunction in some subtypes of interneurons, not others, and are temporally restricted; DS-causing sodium channel mutations were found throughout SCN1A as well as in SCN1B, encoding the β1 subunit. Interest in therapeutic approaches was sparked by preclinical studies of cannabidiol (CBD) that led to the 2018 US Food and Drug Administration approval for treatment of seizures in patients with DS. Independent evidence showed that CBD antagonized GPR55, a G protein-coupled receptor activated by the lipid signaling molecule lysophosphatidylinositol (LPI). We summarized evidence from our group and others that CBD has a dual mechanism of action, targeting both ion channels and GPR55. CBD quells an epileptogenic vicious cycle: seizures strengthen LPI-GPR55 signaling while LPI-GPR55 signaling elevates the synaptic excitatory-inhibitory ratio, thereby promoting further seizures. SIGNIFICANCE STATEMENT: Modern medicine relies on ion channels and G protein-coupled receptors (GPCRs) as key targets. In studies of Dravet syndrome, a devastating genetic disorder with features of epilepsy and autism, William Catterall connected NaV1.1 mutations to deficient excitability of inhibitory neurons. He and his colleagues explored preclinical interventions using cannabidiol (CBD) and clobazam, opening the way to a current understanding of CBD's therapeutic mechanism. CBD affects both ion channels and GPR55, a GPCR activated by lysophosphatidylinositol, an activity-dependent lipid messenger, readjusting the synaptic excitatory-inhibitory ratio.

This document is an update to the 2014 recommendations for optimizing the adequacy of bowel cleansing for colonoscopy from the US Multi-Society Task Force on Colorectal Cancer, which represents the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy. The US Multi-Society Task Force developed consensus statements and key clinical concepts addressing important aspects of bowel preparation for colonoscopy. The majority of consensus statements focus on individuals at average risk for inadequate bowel preparation. However, statements addressing individuals at risk for inadequate bowel preparation quality are also provided. The quality of a bowel preparation is defined as adequate when standard screening or surveillance intervals can be assigned based on the findings of the colonoscopy. We recommend the use of a split-dose bowel preparation regimen and suggest that a 2 L regimen may be sufficient. A same-day regimen is recommended as an acceptable alternative for individuals undergoing afternoon colonoscopy, but we suggest that a same-day regimen is an inferior alternative for individuals undergoing morning colonoscopy. We recommend limiting dietary restrictions to the day before a colonoscopy, relying on either clear liquids or low-fiber/low-residue diets for the early and midday meals. We suggest the adjunctive use of oral simethicone for bowel preparation before colonoscopy. Routine tracking of the rate of adequate bowel preparations at the level of individual endoscopists and at the level of the endoscopy unit is also recommended, with a target of >90% for both rates.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The vaping epidemic is a public health crisis worldwide. E-cigarette, or vaping product, use-associated lung injury (EVALI) was recognised in the summer of 2019 and resulted in more than 2800 hospitalizations and 60 deaths per the Centres for Disease Control and Prevention (CDC). Vaping refers to the use of E-cigarettes, which are electronic nicotine delivery systems (ENDS) and mimic smoking without combustion. Over 40 million people in the United States vape, of which youth and young adults represent over half. We describe the evaluation and pulmonary complications in a large cohort of adolescents and young adults referred to a Pulmonary Complications of Vaping Clinic. METHODS:Youth ages 10-35 with a vaping history and respiratory symptoms underwent a comprehensive diagnostic evaluation. All patients were counselled for vaping cessation. Patients who met criteria for EVALI or probable EVALI with concurrent infection were reported to the Department of Health. RESULTS:One hundred and thirty patients were referred, and 103 patients underwent comprehensive diagnostic evaluation. Eighty-four percent of patients reported vaping both marijuana and nicotine products. Forty-six percent of patients were diagnosed with EVALI or probable EVALI. CONCLUSIONS:The evolving vaping epidemic demonstrates a need for subject matter expertise in the evaluation and diagnosis of youth with vaping-related lung injury, including EVALI. We report a higher number of youth who met criteria for EVALI with the implementation of a standardised vaping questionnaire and evaluation inclusive of outpatients.

BACKGROUND AND AIMS/OBJECTIVE:The COVID-19 pandemic significantly decreased procedural volume in 2020, thus limiting training opportunities. First-year fellows (1YF) are particularly susceptible to reduction in endoscopic volume as they build foundational endoscopic skills. We used an objective validated tool, the Assessment of Competency in Endoscopy (ACE), to determine the effect of the pandemic on endoscopy competency in gastroenterology fellows. METHODS:This was a prospective cohort study conducted across two fellowship programs in New York City. Our primary outcome was the comparison of ACE scores of fellows starting gastroenterology fellowships in 2020 to the scores of those starting in 2016-2018. Our secondary outcome was to compare colonoscopy quality metrics and endoscopy volume between these cohorts. RESULTS:ACE scores were available from 11 pandemic and 10 pre-pandemic 1YFs, and five pandemic and 19 pre-pandemic second (2YF) and third-year fellows (3YF). ACE scores for 1YFs showed significantly higher rating in the pre-pandemic cohort for 4 domains including knowledge of indications and medical issues (p = 0.03), effective and efficient use of air, water, and suction (p = 0.04), pathology identification (p = 0.001), and overall hands-on skills (p = 0.004). 2YFs showed no significant differences. 3YFs showed significantly lower scores in the pandemic cohort in the effective and efficient use of air, water, and suction (p = 0.03), fellows' knowledge of therapeutic tools (p = 0.05), and fellows overall cognitive skills (p = 0.05). There were no significant differences in quality metrics between the cohorts, except longer procedure time for the pandemic cohort (p < 0.01). CONCLUSION/CONCLUSIONS:Following the COVID-19 pandemic, there was a decline in multiple aspects of endoscopic competency both at the beginning and the end of fellowship training. These trends are likely the result of a decrease in overall procedure volume early in training and highlight the need for supplementing trainee education with other modalities.

Natural gene variants of metabotropic glutamate receptor subtype 7 (Grm7), coding for mGluR7, affect individuals' alcohol-drinking preference. Psychopharmacological investigations have suggested that mGluR7 is also involved in responses to cocaine, morphine, and nicotine exposures. We review the pleiotropic effects of Grm7 and the principle of recombinant quantitative trait locus introgression (RQI), which led to the discovery of the first mammalian quantitative gene accounting for alcohol-drinking preference. Grm7/GRM7 can play important roles in mammalian ontogenesis, brain development, and predisposition to addiction. It is also involved in other behavioral phenotypes, including emotion, stress, motivated cognition, defensive behavior, and pain-related symptoms. This review identified pleiotropy and the modulation of neurobehavioral processes by variations in the gene Grm7/GRM7. Patterns of pleiotropic genes can form oligogenic architectures whosecombined additive and interaction effects can significantly predispose individuals to the expressions of disorders. Identifying and characterizing pleiotropic genes are necessary for understanding the expressions of complex traits. This requires tasks, such as discovering and identifying novel genetic elements of the genetic architecture, which are unsuitable for AI but require classical experimental genetics.

Trypanosomatids are parasites of health importance that cause neglected diseases in humans and animals. Chagas' disease, caused by Trypanosoma cruzi, affects 6-7 millions of people worldwide, mostly in Latin America, most of whom do not have access to diagnosis or treatment. Currently, there are no available vaccines, and the antiparasitic drugs used for treatment are often toxic and ineffective for the chronic stage of infection. Therefore, exploration of new therapeutic targets is necessary and highlights the importance of identifying new therapeutic options for the treatment of this disease. Trypanosomatid genes are organized and expressed in a species-specific fashion and many of their regulatory factors remain to be explored, so proteins involved in the regulation of gene expression are interesting candidates as drug targets. Previously, we demonstrated that the TbRRM1 protein from T. brucei is an essential nuclear factor involved in Pol-II transcriptional regulation. TcSR62 is a TbRRM1 orthologous protein in T. cruzi, but little is known about its function. In this study, we used molecular modeling of the RNA-binding domains of the TcSR62 protein and computational molecular docking to identify TcSR62-specific drug candidates. We identified sorafenib tosylate (ST) as a compound with trypanocidal activity. Sorafenib tosylate showed promising half-maximal inhibitory concentration (IC50) for all parasite stages in vitro. Furthermore, overexpression of TcSR62 protein led to ST-resistant parasites, suggesting that the trypanocidal effect might be due to the inhibition of TcSR62 function. These results demonstrate that ST could be repurposed as a novel drug to treat Chagas' disease.

Endometriosis is a common disease, affecting approximately 10% of women of reproductive age. Several intersecting guidelines and consensus statements provide information on imaging diagnosis and surveillance strategies for endometriomas. SRU consensus panel recommendations provide information on initial detection of endometriosis on routine pelvic imaging. Revised American Society of Reproductive Medicine (rASRM) classification, the #ENZIAN classification, and the deep pelvic endometriosis index (dPEI) aim to assess the overall extent of disease and assist in presurgical planning. The Ovarian-Adnexal Reporting and Data System (O-RADS) aims to risk stratify lesions evaluated with US or MR based on their imaging morphology, from typical benign lesions to atypical presentations and malignant transformation. Emerging data shows increased risk of ovarian cancer in patients with endometriosis, especially following menopause and in those patients with long standing endometriosis. (Chen et al. in Front Oncol. 14:1329133, 2024;Streuli et al. in Climacteric. 20:138-143, 2017;Secosan et al. in Diagnostics (Basel). 10:134, 2020;Inceboz in Womens Health (Lond Engl). 11:711-715, 2015;Cassani et al. in Maturitas. 190, 2024;Gemmell et al. in Hum Reprod Update. 23:481-500, 2017;Giannella et al. in Cancers (Basel). 13:4026, 2021;) Current O-RADS guidelines mandate follow-up of endometriomas up to 2 years with further follow-up based on clinical factors. No consensus guidelines exist for imaging surveillance of patients with deep endometriosis from a malignancy standpoint. This review explores the imaging appearance of endometriomas, imaging features of malignant transformation, surveillance strategies and gaps in current literature, and attempts to better understand the risk of malignancy and to encourage further research for long-term imaging surveillance of endometriosis patients.

PURPOSE/OBJECTIVE:We present a novel office-based technique using a 25-gauge needle to reopen closed peripheral iridotomies (PIs) in aphakic eyes filled with silicone oil. METHODS:We use a 25-gauge needle to enter the clear cornea and reopen the closed PI, allowing for aqueous humor and silicone oil to escape and relieve elevated intraocular pressure (IOP). RESULTS:This minimally invasive office-based approach provides immediate relief of elevated IOP due to silicone oil-induced pupillary block, avoiding the need for more invasive surgical intervention. CONCLUSION/CONCLUSIONS:Our technique is a simple, cost-effective, and accessible way to combat silicone-oil induced pupillary block in aphakic patients and may be a good first-line approach for a difficult-to-manage condition.