ChatGPT4 outperforms endoscopists for determination of post-colonoscopy re-screening and surveillance recommendations.

BACKGROUND: Large language models (LLM) including ChatGPT4 improve access to artificial intelligence, but their impact on the clinical practice of gastroenterology is undefined. In this study, we aim to compare the accuracy, concordance and reliability of ChatGPT4 colonoscopy recommendations for colorectal cancer re-screening and surveillance to contemporary guidelines and real-world gastroenterology practice. METHODS: History of present illness, colonoscopy data and pathology reports from patients undergoing procedures at two large academic centers were entered into ChatGPT4 and it was queried for next recommended colonoscopy follow-up interval. Using McNemar's test and inter-rater reliability, we compared the recommendations made by ChatGPT4 with the actual surveillance interval provided in the endoscopist's procedure report (gastroenterology practice) and the appropriate USMSTF guidance. The latter was generated for each case by an expert panel using the clinical information and guideline documents as reference. RESULTS: Text input of de-identified data into ChatGPT4 from 505 consecutive patients undergoing colonoscopy between January 1st and April 30th, 2023 elicited a successful follow-up recommendation in 99.2% of the queries. ChatGPT4 recommendations were in closer agreement with the USMSTF Panel (85.7%) than gastroenterology practice recommendations with the USMSTF Panel (75.4%) (P<.001). Of the 14.3% discordant recommendations between ChatGPT4 and USMSTF Panel, recommendations were for later screening in 26 (5.1%) and earlier screening in 44 (8.7%) cases. The inter-rater reliability was good for ChatGPT4 vs. USMSTF Panel (Fleiss κ: 0.786, CI95%: 0.734-0.838, P<.001). CONCLUSIONS: Initial real-world results suggest that ChatGPT4 can accurately define routine colonoscopy screening intervals based on verbatim input of clinical data. LLM have potential for clinical applications, but further training is needed for broad use.

Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells.

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.

Spontaneous Coronary Artery Dissection in a 19-Year-Old Male Athlete.

We present a 19-year-old male athlete, without cardiovascular risk factors, with anterior ST-segment elevation myocardial infarction caused by left anterior descending artery spontaneous coronary artery dissection. Symptoms began during a swim practice, and patient endorsed using C4 Ripped (Cellucor), a preworkout supplement to enhance athletic performance. We hypothesize that this was the major contributor to presentation. The patient showed improvement after 4 days.

Immune heterogeneity in small-cell lung cancer and vulnerability to immune checkpoint blockade.

Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but high T-effector signals demonstrate longer overall survival with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and high T-effector signal. Our study offers a clinically relevant approach to discriminate SCLC patients likely benefitting most from immunotherapies and highlights the complex mechanisms underlying immunotherapy responses.

Clinical Features and Outcomes of Myxedema Coma in Patients Hospitalized for Hypothyroidism: Analysis of the United States National Inpatient Sample.

Background: Hypothyroidism is a common endocrine condition and chronic thyroid hormone deficiency is associated with adverse effects across multiple organ systems. In compensated hypothyroidism, however, patients remain clinically stable due to gradual physiological adaptation. In contrast, the clinical syndrome of decompensated hypothyroidism referred to as myxedema coma (MC) is an endocrine emergency with high risk of mortality. Because of its rarity, there are currently limited data regarding MC. This study analyzes the clinical features and hospital outcomes of MC compared with hypothyroid patients without MC (nonMChypo) in national United States hospital data. Methods: A retrospective analysis of the National Inpatient Sample, a public database of inpatient admissions to nonfederal hospitals in the United States, 2016-2018, including adult patients with primary diagnosis of MC (International Classification of Diseases 10th Revision [ICD-10]: E03.5) or nonMChypo (E03.0-E03.9, E89.0). Patient demographics, relevant clinical features, mortality, length of stay (LOS), and hospital costs were compared. Results: Of 18,635 patients hospitalized for hypothyroidism, 2495 (13.4%) had a diagnosis of MC. Sex distribution and race/ethnicity were similar between patients with MC and nonMChypo, whereas MC was associated with older patient age (p = 0.02), public insurance (p = 0.01), and unhoused status (p = 0.04). More admissions with MC occurred in winter compared with other seasons (p = 0.01). The overall mortality rate for MC was 6.8% versus 0.7% for nonMChypo (p < 0.001), and MC was independently associated with in-hospital mortality after adjusted regression analysis (adjusted odds ratio = 9.92 [CI 5.69-17.28], p < 0.001). Mean LOS ± standard error was 9.64 ± 0.73 days for MC versus 4.62 ± 0.12 days for nonMChypo (p < 0.001), and total hospital cost for MC was $21,768 ± $1759 versus $8941 ± $276 for nonMChypo (p = 0.07). In linear regression analyses, MC was an independent predictor of both increased LOS and total hospital cost. Conclusions: In summary, MC remains a clinically significant diagnosis in the modern era, independently associated with high mortality and health care costs. This continued burden demonstrates a need for further efforts to prevent, identify, and optimize treatment for patients with MC.

Myocarditis in Athletes: Risk Factors and Relationship with Strenuous Exercise.

Amidst the SARS-CoV-2 pandemic, myocarditis in athletes has demanded increased attention primarily because of the risk of sudden cardiac death. While most athletes who experience myocardial inflammation recover, extensive measures for screening and diagnosis are taken because of the possibility of cardiac necrosis, fibrosis, and remodeling. Several risk factors have been identified that may contribute to the development of this inflammatory response, predominantly a history of viral or bacterial upper-respiratory infections. Recent research suggests new risks specific to athletes remain in question, such as the intensity and longevity of sustained exercise, vaccination status, and genetic and epidemiologic factors. Electrocardiography, echocardiography, and cardiac magnetic resonance imaging are commonly utilized for the diagnosis of myocarditis; however, reference standards are lacking because of the variety of clinical presentations. In this article, we discuss the epidemiology, pathophysiology, and presentation of myocarditis in athletes. We then review the available literature to provide a deeper insight into the diagnostic testing methods available, with the aim of outlining the efficacy and prognostic value. Next, we discuss an algorithmic approach to patient care and treatment based upon hemodynamic stability, symptoms, and findings on testing. Finally, this article reviews the current return to play guidelines and the rationale for revisions to return-to-play protocols.

Increasing Antibiotic-Resistant Infections With Inpatient Endoscopic Retrograde Cholangioscopies (ERCP) Is Associated With Higher Mortality in the United States: A Cross-sectional Cohort Study.

GOALS: This study aims to investigate associated mortality with inpatient endoscopic retrograde cholangiopancreatography (ERCP) with and without resistant infections. The co-primary objective compares frequencies of inpatient ERCP with resistant infections to overall hospitalizations with resistant infections. BACKGROUND: The risks of inpatient antibiotic-resistant organisms are known, but the associated mortality for inpatient ERCP is unknown. We aim to use a national database of hospitalizations and procedures to understand trends and mortality for patients with antibiotic-resistant infections during inpatient ERCP. STUDY: The largest publicly available all-payer inpatient database in the United States (National Inpatient Sample) was used to identify hospitalizations associated with ERCPs and antibiotic-resistant infections for MRSA, VRE, ESBL, and MDRO. National estimates were generated, frequencies were compared across years, and multivariate regression for mortality was performed. RESULTS: From 2017 to 2020, national weighted estimates of 835,540 inpatient ERCPs were generated, and 11,440 ERCPs had coincident resistant infections. Overall resistant infection, MRSA, VRE, and MDRO identified at the same hospitalization of inpatient ERCPs were associated with higher mortality (OR CI(95%): Overall: 2.2(1.77-2.88), MRSA: 1.90 (1.34-2.69), VRE: 3.53 (2.16-5.76), and MDRO: 2.52 (1.39-4.55)). While overall hospitalizations with resistant infections have been decreasing annually, there has been a yearly increase in admissions requiring ERCPs with simultaneous resistant infections ( P =0.001-0.013), as well as infections with VRE, ESBL, and MDRO ( P =0.001-0.016). Required Research Practices for Studies Using the NIS scoring was 0, or the most optimal. CONCLUSIONS: Inpatient ERCPs have increasing coincident resistant infections and are associated with higher mortality. These rising infections during ERCP highlight the importance of endoscopy suite protocols and endoscopic infection control devices.

Generation of antigen-specific mature T cells from RAG1-/-RAG2-/-B2M-/- stem cells by engineering their microenvironment.

Pluripotent stem cells (PSCs) are a promising source of allogeneic T cells for off-the-shelf immunotherapies. However, the process of differentiating genetically engineered PSCs to generate mature T cells requires that the same molecular elements that are crucial for the selection of these cells be removed to prevent alloreactivity. Here we show that antigen-restricted mature T cells can be generated in vitro from PSCs edited via CRISPR to lack endogenous T cell receptors (TCRs) and class I major histocompatibility complexes. Specifically, we used T cell precursors from RAG1-/-RAG2-/-B2M-/- human PSCs expressing a single TCR, and a murine stromal cell line providing the cognate human major histocompatibility complex molecule and other critical signals for T cell maturation. Possibly owing to the absence of TCR mispairing, the generated T cells showed substantially better tumour control in mice than T cells with an intact endogenous TCR. Introducing the T cell selection components into the stromal microenvironment of the PSCs overcomes inherent biological challenges associated with the development of T cell immunotherapies from allogeneic PSCs.

A Preliminary Controlled Trial of Endoscopic Ultrasound-guided Fiducial Markers to Guide Pancreas Surgery.

OBJECTIVE: Endoscopic ultrasound (EUS) is routinely used for fiducial marker placement (FMP) to guide stereotactic radiation of pancreatic tumors, but EUS-FMP explicitly to guide surgery has not been studied in a prospective, controlled manner. Multipurpose EUS systems have been developed that facilitate simultaneous EUS-FMP at the time of biopsy. We aimed to evaluate the feasibility of EUS-FMP to guide pancreatic resection. METHODS: In this prospective trial, we enrolled patients with resectable pancreas masses undergoing tissue sampling and placed preloaded fiducials immediately after biopsy. Intraprocedure confirmation of carcinoma, neuroendocrine, and nonlymphomatous neoplasia by rapid on-site evaluation and lesion size <4 cm was required. The main outcomes were the feasibility and ease of preoperative placement and intraoperative detection of the markers using predefined Likert scales. RESULTS: In 20 patients, EUS-FMP was successful before planned surgery and placement was technically straightforward (Likert Scale: 9.1 ± 1.3; range: 1, most challenging to 10, most facile). Intraoperative detection was feasible and improved when compared with a pre-established comparator of 5 representing an equivalent lesion without a marker (Likert Scale: 7.8 ± 2.2; range: 1, most difficult to 10, most facile; P = 0.011). The mean tumor size on EUS was 1.7 ± 0.9 (range: 0.5 to 3.6) cm. CONCLUSION: EUS-FMP is feasible and safe for resectable pancreatic tumors before surgery and may assist in perioperative detection. Preloaded fiducials may be considered for placement at the time of initial referral for EUS-fine needle biopsy.

Foraminal stenosis and radiculopathy secondary to tophaceous gout: illustrative case.

BACKGROUND: Tophaceous gout is a severe form of gout that results in the formation of large nodules, or tophi, in the affected joints and surrounding tissues. Gouty tophi in the spine have a constellation of presentations that often mimic other pathologies and may not be easily discernable from more common pathologic processes. OBSERVATIONS: A 47-year-old female with a history of chronic renal disease, obesity, gout, inflammatory polyarthritis, and multiple sclerosis presented with 6 months of low-back pain and lumbar radiculopathy affecting the right lower extremity. A lumbar magnetic resonance imaging study revealed right foraminal stenosis and spondylolisthesis at levels L4-5. An intraspinal extradural mass was noted adjacent to the traversing right L5 and exiting right L4 nerve roots. A bilateral decompressive laminectomy, facetectomy, and foraminotomy of L4-5 was performed. A calcific, chalky-white mass was discovered in the foramen, and pathology determined the specimen to be a gout tophus. Postoperatively, the patient endorsed the resolution of her preoperative symptoms, which have not returned on follow-up. LESSONS: Reports of gouty depositions compressing the spinal cord in the current literature are relatively rare. Although the diagnosis of gouty tophi can only be confirmed histologically, patient history may serve as a helpful diagnostic tool.

Development, implementation, and feasibility of site-specific hepatitis C virus treatment workflows for treating vulnerable, high-risk populations: protocol of the Erase Hep C study - a prospective single-arm intervention trial.

BACKGROUND: Hepatitis C virus (HCV) is the leading indication for liver transplantation and liver-related mortality. The development of direct-acting antivirals (DAA) and a simplified treatment algorithm with a > 97% cure rate should make global elimination of HCV an achievable goal. Yet, vulnerable populations with high rates of HCV still have limited access to treatment. By designing locally contextualized site-specific HCV treatment workflows, we aim to cure HCV in vulnerable, high-risk populations, including people experiencing homelessness (PEH) and people who inject drugs (PWID), in Austin, TX, USA. METHODS: Our implementation science study will utilize a qualitative and design thinking approach to characterize patient and systemic barriers and facilitators to HCV treatment in vulnerable, high-risk populations seeking care across seven diverse primary care clinics serving PEHs and PWIDs. Qualitative interviews guided by the Practical, Robust Implementation and Sustainability Model (PRISM) framework will identify barriers and facilitators by leveraging knowledge and experience from both clinic staff and patients. Data synthesized using thematic analysis and design thinking will feed into workshops with clinic stakeholders for idea generation to design site-specific HCV treatment workflows. Providers will be trained on the use of a simplified HCV treatment algorithm with DAAs and clinic staff on the new site-specific HCV treatment workflows. These workflows will be implemented by the seven diverse primary care clinics serving vulnerable, high-risk populations. Implementation and clinical outcomes will be measured using data collected through interviews with staff as well as through medical chart review. DISCUSSION: Our study provides a model of how to contextualize and implement site-specific HCV treatment workflows targeting vulnerable, high-risk populations in other geographic locations. This model can be adopted for future implementation research programs aiming to develop and implement site-specific treatment workflows for vulnerable, high-risk populations and in primary care clinical settings for other disease states beyond just HCV. TRIAL REGISTRATION: Registered on ClinicalTrials.gov on July, 14, 2022. Identifier: NCT05460130 .

Mass Spectrometry-Based Tissue Imaging of the Tumor Microenvironment.

Multiplex ion beam imaging (MIBI) and imaging mass cytometry (IMC) enable highly multiplexed antibody (40+) staining of frozen or formalin fixed, paraffin-embedded (FFPE) human or murine tissues through detection of metal ions liberated from primary antibodies by time-of-flight mass spectrometry (TOF). These methods make detection of more than 50 targets theoretically possible while maintaining spatial orientation. As such, they are ideal tools to identify the multiple immune, epithelial, and stromal cell subsets in the tumor microenvironment and to characterize spatial relationships and tumor-immune status in either murine models or human samples. This chapter summarizes methods for antibody conjugation and validation, staining, and preliminary data collection using IMC or MIBI in both human and mouse pancreatic adenocarcinoma samples. These protocols are intended to facilitate use of these complex platforms in not only tissue-based tumor immunology studies but also tissue-based oncology or immunology studies more broadly.

Delayed Diagnostic Paracentesis Is Associated with Increased Preventable Healthcare Utilization in Disadvantaged Patient Populations with Advanced Liver Disease and Elevated INR.

BACKGROUND: Patients hospitalized with cirrhosis, ascites, and elevated INR often experience delays in timely diagnostic paracentesis. AIMS: Identify whether delays in diagnostic paracentesis were associated with adverse outcomes in a hospital system serving a large disadvantaged population. METHODS: Retrospective cohort analysis of patients admitted from January 2017 to October 2019 with cirrhosis, ascites, and INR ≥ 1.5 across a multi-hospital health system in central Texas. We examined demographic and clinical characteristics of patients with diagnostic paracentesis (1) ≤ 24 h; (2) > 24 h; (3) therapeutic only or no paracentesis. We used logistic regression to examine differences in clinical outcomes controlling for confounders. RESULTS: 479 patients met inclusion criteria. 30.0% (N = 143) were Latino, 6.7% (N = 32) African American, and 67.8% (N = 325) under or uninsured. 54.1% of patients received a diagnostic paracentesis ≤ 24 h of admission and 21.1% did not receive a diagnostic paracentesis during the hospitalization. Undergoing diagnostic paracentesis > 24 h of admission was associated with a 2.3 day increase in length of stay (95% CI 0.8-3.8), and OR 1.7 for an Emergency Room visit within 30 days of discharge (95% CI 1.1-2.7) compared to receiving a diagnostic paracentesis ≤ 24 h. Patients receiving diagnostic paracentesis in radiology were more likely to have a delay in procedure OR 5.8 (95% CI 2.8-8.6). CONCLUSION: Delayed diagnostic paracentesis is associated with increased preventable healthcare utilization compared with timely diagnostic paracentesis. Health systems should support efforts to ensure timely diagnostic paracentesis for patients with advanced liver disease, including performance at the bedside.

Obligate role for Rock1 and Rock2 in adult stem cell viability and function.

The ability of stem cells to rapidly proliferate and differentiate is integral to the steady-state maintenance of tissues with high turnover such as the blood and intestine. Mutations that alter these processes can cause primary immunodeficiencies, malignancies and defects in barrier function. The Rho-kinases, Rock1 and Rock2, regulate cell shape and cytoskeletal rearrangement, activities essential to mitosis. Here, we use inducible gene targeting to ablate Rock1 and Rock2 in adult mice, and identify an obligate requirement for these enzymes in the preservation of the hematopoietic and gastrointestinal systems. Hematopoietic cell progenitors devoid of Rho-kinases display cell cycle arrest, blocking the differentiation to mature blood lineages. Similarly, these mice exhibit impaired epithelial cell renewal in the small intestine, which is ultimately fatal. Our data reveal a novel role for these kinases in the proliferation and viability of stem cells and their progenitors, which is vital to maintaining the steady-state integrity of these organ systems.

Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing.

CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3δ SCID patient's HSPCs resulted in a 71.2% ± 7.85% (n = 3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificial thymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependent functions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversion of the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicating correction of long-term repopulating HSCs. These findings demonstrate the preclinical efficacy of ABE in HSPCs for the treatment of CD3δ SCID, providing a foundation for the development of a one-time treatment for CD3δ SCID patients.

Equitable Implementation of Mailed Stool Test-Based Colorectal Cancer Screening and Patient Navigation in a Safety Net Health System.

BACKGROUND: Mailed stool testing programs increase colorectal cancer (CRC) screening in diverse settings, but whether uptake differs by key demographic characteristics is not well-studied and has health equity implications. OBJECTIVE: To examine the uptake and equity of the first cycle of a mailed stool test program implemented over a 3-year period in a Central Texas Federally Qualified Health Center (FQHC) system. DESIGN: Retrospective cohort study within a single-arm intervention. PARTICIPANTS: Patients in an FQHC aged 50-75 at average CRC risk identified through electronic health records (EHR) as not being up to date with screening. INTERVENTIONS: Mailed outreach in English/Spanish included an introductory letter, free-of-charge fecal immunochemical test (FIT), and lab requisition with postage-paid mailer, simple instructions, and a medical records update postcard. Patients were asked to complete the FIT or postcard reporting recent screening. One text and one letter reminded non-responders. A bilingual patient navigator guided those with positive FIT toward colonoscopy. MAIN MEASURES: Proportions of patients completing mailed FIT in response to initial cycle of outreach and proportion of those with positive FIT completing colonoscopy; comparison of whether proportions varied by demographics and insurance status obtained from the EHR. KEY RESULTS: Over 3 years, 33,606 patients received an initial cycle of outreach. Overall, 19.9% (n = 6672) completed at least one mailed FIT, 5.6% (n = 374) tested positive during that initial cycle, and 72.5% (n = 271 of 374) of those with positive FIT completed a colonoscopy. Hispanic/Latinx, Spanish-speaking, and uninsured patients were more likely to complete mailed FIT compared with white, English-speaking, and commercially insured patients. Spanish-speaking patients were more likely to complete colonoscopy after positive FIT compared with English-speaking patients. CONCLUSIONS: Mailed FIT outreach with patient navigation implemented in an FQHC system was effective in equitably reaching patients not up to date for CRC screening.

Association of Standardized Radiology Reporting and Management of Abdominal CT and MRI With Diagnosis of Pancreatic Cancer.

BACKGROUND & AIMS: Follow-up of abdominal computed tomography (CT) and magnetic resonance imaging (MRI) findings suspicious for pancreatic cancer may be delayed if documentation is unclear. We evaluated whether standardized reporting and follow-up of imaging results reduced time to diagnosis of pancreatic cancer. METHODS: We used a quasi-experimental stepped-wedge cluster design to evaluate the effectiveness of newly implemented radiology reporting system. The system standardizes the reporting of CT and MRI reports using hashtags that classify pancreatic findings. The system also automates referral of patients with findings suspicious for pancreatic cancer to a multidisciplinary care team for rapid review and follow-up. The study examined 318,331 patients who underwent CT or MRI that included the abdomen from 2016 through 2019 who had not had an eligible CT or MRI in the preceding 24 months. We evaluated the association of the intervention with incidence of pancreatic cancer within 60 days and 120 days after imaging. RESULTS: Thirty-eight percent of patients received the intervention, and 1523 patients (0.48%) were diagnosed with pancreatic cancer. In multivariable analysis accounting for age, race/ethnicity, sex, Charlson comorbidity, history of cancer, diabetes, and 4-month calendar period, the intervention was associated with nearly 50% greater odds of diagnosing pancreatic cancer within 60 days (adjusted odds ratio, 1.47; 95% confidence interval, 1.05-2.06) and 120 days (adjusted odds ratio, 1.46; 95% confidence interval, 1.04-2.06). CONCLUSIONS: In this large quasi-experimental, community-based observational study, implementing standardized reporting of abdominal CT and MRI reports with clinical navigation was effective for increasing the detection and diagnosis of pancreatic cancer.