Faculty Bibliography

INTRODUCTION/UNASSIGNED:Patients with Crohn's disease are at increased risk for both colorectal carcinoma and opportunistic infections due to chronic inflammation and long-term immunosuppressive therapy. Fungal infections such as histoplasmosis may mimic malignancy or inflammatory exacerbation, leading to diagnostic delay. CASE PRESENTATION/UNASSIGNED:, confirmed by polymerase chain reaction. The urinary Histoplasma galactomannan antigen test was negative, while serum 1,3 β-D-glucan was positive. The patient was successfully treated with amphotericin B followed by itraconazole, with complete clinical recovery. Retrospective history revealed travel to Ecuador. CONCLUSION/UNASSIGNED:Gastrointestinal histoplasmosis can closely mimic Crohn's flare or malignancy, especially in immunosuppressed patients. Careful histopathologic evaluation and integration of clinical and laboratory findings are essential for timely diagnosis and effective antifungal therapy.

BACKGROUND:Perioperative immune-checkpoint inhibition improves outcomes in muscle-invasive bladder cancer (MIBC). The phase III, randomized CA017-078 (ENERGIZE) trial evaluated perioperative nivolumab plus neoadjuvant gemcitabine-cisplatin (GC) versus neoadjuvant GC alone for previously untreated, resectable MIBC. PATIENTS AND METHODS/METHODS:Adults with previously untreated cT2-T4aN0M0 MIBC eligible for radical cystectomy (RC) and cisplatin were randomized to neoadjuvant nivolumab plus GC followed by RC and adjuvant nivolumab (nivolumab plus GC arm), or neoadjuvant GC followed by RC alone (GC arm). Co-primary endpoints were pathological complete response (pCR; defined as ypT0N0) and event-free survival (EFS). Overall survival (OS) was a secondary endpoint within the prespecified hierarchical testing strategy, and formal testing was contingent on a statistically significant EFS result. RESULTS:At this final analysis with 54.5 months of median follow-up, 325 patients were randomized to the nivolumab plus GC arm, 328 to the GC arm. pCR rates were 39.1% and 29.6%, respectively (adjusted difference 9.5%, 99.91% CI -2.6-21.6). EFS was not improved in the nivolumab plus GC versus GC arm (104 events in each arm; HR 0.94, 95.74% CI 0.71-1.25; P=0.6697). OS was summarized descriptively because EFS did not meet the testing criterion (HR 0.88, 95% CI 0.64-1.21). Grade 3-4 treatment-related adverse events occurred in 50.0% versus 49.5%; one treatment-related death occurred with nivolumab plus GC. Pretreatment ctDNA was positive in 229/416 tested patients (55%) overall, 108/211 (51%) in the GC arm, and 121/205 (59%) in the nivolumab plus GC arm. Clearance by cycle 4 day 1 (C4D1) occurred in 153/199 patients (76.9%) overall, 87/107 (81.3%) with nivolumab plus GC, and 66/92 (71.7%) with GC. ctDNA detection at baseline and at C4D1 was associated with shorter EFS and OS. CONCLUSIONS:The addition of perioperative nivolumab to neoadjuvant GC did not improve outcomes and was associated with predictable toxicity. Exploratory analysis showed ctDNA was strongly prognostic.

IMPORTANCE/UNASSIGNED:Syringe services programs (SSPs) are an evidence-based intervention to reduce bloodborne disease transmission and other risks related to injection drug use; however, SSP access is uneven. State and local syringe distribution laws may influence variation in the presence and number of SSPs across local jurisdictions. OBJECTIVE/UNASSIGNED:To assess the association between state and local syringe distribution laws and presence of publicly listed SSPs in a sample of US cities. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cross-sectional study linked state and local laws with information on publicly reported SSPs in 2024 for the largest US municipalities and census-designated places (localities). The outcomes of policy exposure in SSP presence and total number of SSP locations among localities with at least 1 SSP were estimated using a 2-part negative binomial hurdle model, adjusting for state and local policy and demographic and health characteristics. The study team collected the legal data from January 11, 2023, through May 7, 2024. EXPOSURE/UNASSIGNED:State and local syringe distribution policy environment as of December 31, 2022, categorized from most restrictive (state prohibition) to least restrictive (neither state nor locality prohibits syringe distribution). MAIN OUTCOMES AND MEASURES/UNASSIGNED:Publicly reported SSP presence (binary) and total count of SSP locations within each locality as of February 2024. RESULTS/UNASSIGNED:In this study using data from 482 US localities, there was at least 1 SSP in 181 (37.6%) localities. Localities with the least restrictive legal environment had increased odds of SSP presence (adjusted odds ratio, 16.3; 95% CI, 6.0-44.1) compared with those with the most restrictive legal environment. Among localities with 1 or more SSP, localities in the least restrictive legal environment or a legal environment that exempted SSPs from a syringe distribution prohibition had increased rates of SSPs, relative to the most restrictive legal environment (rate ratio for least restrictive policy environment, 2.7; 95% CI, 1.1-6.4; rate ratio for legal environment that exempts SSPs from prohibition, 2.4; 95% CI, 1.1-5.6). Overall, policies that exempted SSPs from syringe distribution prohibitions and those with no syringe distribution prohibitions had the highest estimated SSP counts (1.9 SSPs; 95% CI, 1.5-2.4; 1.5 SSPs; 95% CI, 1.1-1.9, respectively). CONCLUSIONS AND RELEVANCE/UNASSIGNED:This study found that state and local syringe distribution laws were associated with publicly listed SSP presence. Legal environments that prohibit or restrict syringe distribution may limit the presence and total number of SSPs, highlighting the role of policy context in shaping access to harm-reduction services.

The heart and brain are interconnected, and risk factors that impact the heart can negatively affect the brain and cognition. Among the underlying features that foster both poor brain health and poor heart health are obesity, diabetes, physical inactivity and low sleep quality. Obesity and type 2 diabetes are associated with an increased likelihood of cognitive impairment and dementia. Further, obesity is a causal factor in obstructive sleep apnea, leading to intermittent hypoxemia, neuroinflammation and cognitive dysfunction. Cerebrovascular disease with reduced cerebral blood flow brings on stroke and elevates dementia risk. Like cardiovascular disease, cerebrovascular disease is also accelerated in the setting of obesity, likely through the same mechanisms involving endothelial dysfunction and damage to macrovasculature and microvasculature from hypertension, dyslipidemia and inflammation. Obesity is considered a risk factor for recurrent stroke. The protracted low-grade chronic elevation of inflammatory markers found with excess adiposity leads to oxidative stress and promotes both endothelial dysfunction and a pro-thrombotic state. Greater loss of brain volume has been documented in middle-aged and older adults with obesity compared with young adults with obesity. Obesity poses a threat to the cardiovascular and cerebrovascular health and well-being of individuals worldwide. Unfortunately, treatments directed at reducing caloric intake are of limited effectiveness. This review will focus on the latest research into the link between excess adipose tissue and cardiac and brain health, with attention to dietary and lifestyle interventions that may be protective of the integrity and function of the vasculature and brain.

OBJECTIVE/UNASSIGNED:To study whether microfluidic sperm separation in intracytoplasmic sperm injection cycles provides any benefit over density gradient sperm separation for good-quality embryo formation. DESIGN/UNASSIGNED:Randomized sibling oocyte study. SUBJECTS/UNASSIGNED:Patients undergoing intracytoplasmic sperm injection. INTERVENTION/UNASSIGNED:Microfluidic sperm separation vs. density gradient sperm separation. MAIN OUTCOME MEASURES/UNASSIGNED:Primary outcomes were percentage of good-quality blastocyst formation. Secondary outcomes included sperm parameters after sperm separation, including percent motility, grade of forward progression, fertilization rates, blastocyst formation rates, and ploidy rates in the event that preimplantation testing for aneuploidy was performed. Additionally, subanalysis on those with male factor infertility was performed, evaluating primary and secondary outcomes above. RESULTS/UNASSIGNED:A total of 34 cycles enrolled into the study, yielding 456 oocytes, 231 randomized to microfluidics and 225 to density gradient (DG). Average microfluidic fertilization rate was 76.1% ± 19.2% and 72.4% ± 26.6% for DG. Microfluidic blastocyst formation rate was 58.4% ± 31.9% compared with 58.7% ± 30.5% for DG. Good-quality blastocyst formation rate for microfluidics was 51.4% ± 29.7% and for DG was 51.7% ± 30.9%. Euploid rates were 43.8% ± 35.5% in the microfluidics cohort and 33.7% ± 33.3% in the DG cohort. Subanalysis of cycles with male factor infertility revealed good-quality blastocyst formation rate was 45.9% ± 30.9% after microfluidics and 55.1% ± 29.2% for DG. Subanalysis of cycles with male factor infertility revealed an euploid rate of 50.0% ± 37.6% after microfluidics compared with 18.4% ± 24.5% for DG. CONCLUSION/UNASSIGNED:There were similar rates of good-quality embryo formation after intracytoplasmic sperm injection using sperm separated with microfluidics compared with density gradient; however, subanalysis of the male factor infertility group revealed higher euploid rates with microfluidics. TRIAL REGISTRATION/UNASSIGNED:This trial was registered in clinicaltrials.gov, ID number NCT04818593. URL: https://clinicaltrials.gov/study/NCT04818593. Date of registration: 3/25/2021. Date of first enrollment: 6/18/2021.

BACKGROUND & AIMS/OBJECTIVE:Adherence to guideline-based colonoscopy surveillance intervals remains suboptimal. Large language models show promise for automating interval assignment, but prior studies relied on proprietary models and have variably assessed generalizability. We developed and externally validated a clinical decision-support system that integrates locally deployable, open-source large language model-based variable extraction with a rules engine that encodes the 2020 United States Multi-Society Task Force guidelines. METHODS:We assembled development (n = 256), internal (n = 450), and external validation (n = 415) cohorts of colonoscopy-pathology dyads. We developed a 3-stage clinical decision-support system including: (1) large language model-based extraction of diagnosis-bearing sections from pathology reports; (2) large language model-based extraction of surveillance-relevant variables; and (3) deterministic assignment of surveillance intervals using United States Multi-Society Task Force logic. Seven open-source large language models (3.8-32B parameters) were benchmarked; the highest-performing model by macro-averaged F1 score was locked prior to validation. The primary outcome was guideline-concordant interval assignment (target, 90%); secondary outcomes included extraction performance and hallucination rate. RESULTS:The best-performing open-source model, Gemma-27B-Instruct (macro-averaged F1 score, 0.992), was locked. The clinical decision-support system achieved 94.0% guideline-concordant surveillance interval assignment in internal validation (95% confidence interval, 91.8%-96.0%; κ = 0.92; 95% confidence interval, 0.89-0.95) and 92.8% concordance in external validation (95% confidence interval, 90.1%-95.2%; κ = 0.88; 95% confidence interval, 0.84-0.91). Misclassifications were primarily due to adenoma miscounting and diagnostic biopsies misinterpreted as resections. Hallucination-related errors occurred in fewer than 1% of cases. CONCLUSIONS:We report an externally validated, hybrid large language model rules-based clinical decision-support system for colonoscopy surveillance that achieves >90% concordance while preserving transparency, auditability, and guideline traceability.

PURPOSE/OBJECTIVE:Outpatient specialist palliative care (SPC) referral improves patient outcomes; however, it is unclear whether additional remote monitoring (RM) would provide further benefit. This pilot, parallel-group, single-blind, randomized clinical trial examined the within-group effect of monthly SPC alone or with additional weekly RM on symptom burden in patients with advanced cancer undergoing phase I therapies. METHODS:Eligibility criteria included advanced solid tumor diagnosis and moderate-to-high symptom burden (ie, Edmonton Symptom Assessment System [ESAS] score ≥4/10 for ≥1 symptom and Global Distress Score [GDS] ≥20/90) before starting phase I therapies. Patients were randomly assigned 1:1 to either monthly outpatient SPC visits alone or with additional RM, consisting of weekly phone calls and concurrent electronic ESAS assessments between monthly SPC visits. The primary outcome was within-group change in symptom burden (ESAS-GDS) from baseline to 2 weeks; secondary outcomes included within-group change from baseline in ESAS-GDS and health-related quality of life (HRQOL; measured by Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being [FACIT-Sp]) over 12 weeks. RESULTS:= .02). CONCLUSION/CONCLUSIONS:Incorporating RM into SPC may improve symptoms and HRQOL beyond SPC alone for patients with moderate-to-high symptom burden. Our findings are considered preliminary and larger confirmatory trials are needed.

Achalasia is an uncommon primary esophageal motility disorder characterized by impaired lower esophageal sphincter relaxation and absent esophageal peristalsis. These changes result in progressive esophageal dilation and functional obstruction. Although classically associated with dysphagia and regurgitation, respiratory manifestations may predominate due to chronic aspiration of retained esophageal contents, which can obscure the underlying diagnosis and delay appropriate management. We report the case of a 20-year-old male with a history of asthma, gastroesophageal reflux disease, and gastroparesis who presented with one day of shortness of breath and productive cough, initially treated as an asthma exacerbation. Imaging performed to evaluate new-onset respiratory symptoms for one day prior to admission revealed a markedly dilated, fluid-filled esophagus and radiographic findings consistent with aspiration pneumonia. He was initially treated with one dose of 2 mg IV cefepime, then modified to Unasyn 3 mg and doxycycline 100 mg. Subsequent endoscopic evaluation confirmed severe esophageal dilation with retained food contents, supporting the diagnosis of advanced achalasia. This case highlights how achalasia may present primarily with pulmonary complications in young patients, particularly when coexisting respiratory disease is present. Delayed recognition can result in significant morbidity, including recurrent aspiration, malnutrition, and progressive esophageal dysfunction. Early consideration of esophageal motility disorders in patients with refractory respiratory symptoms and GI history is essential to prevent complications and guide timely therapeutic intervention.

Disseminated cutaneous herpes zoster (DCHZ), defined as lesions involving three or more dermatomes, is strongly associated with immunocompromised states and remains exceptionally rare in young immunocompetent adults. We present a case of DCHZ in a previously healthy 25-year-old male from Guatemala who presented with an eight-day history of a painful vesicular rash involving the right V2/V3, C3-C5, and T2-T3 dermatomes. Comprehensive evaluation for occult immunocompromise, including HIV testing, complete blood count, hemoglobin A1c, and urinalysis, was unrevealing. Treatment with high-dose intravenous acyclovir was complicated by acute kidney injury after four doses, with creatinine rising from 0.80 mg/dL to 2.60 mg/dL. Renal function improved following discontinuation of IV acyclovir and transition to oral valacyclovir. This case highlights the rarity of disseminated zoster in young immunocompetent adults and underscores the importance of targeted evaluation for underlying immunologic vulnerability and thorough investigation of acute kidney injury in the setting of DCHZ.