Chemotherapy, immunotherapy, or combination first-line treatment for metastatic urothelial carcinoma of the bladder: A large real-world experience.

INTRODUCTION: First-line systemic therapy for metastatic urothelial carcinoma of the bladder (mUC) consists of platinum-based chemotherapy in most patients and PD1/L1 inhibitors in selected patients. Multiple combination chemoimmunotherapy trials failed to show a clear benefit over chemotherapy alone. We used real-world data to evaluate clinical and sociodemographic factors associated with receipt of first-line chemotherapy, immunotherapy, or combination chemoimmunotherapy treatment for metastatic bladder cancer and examined differences in overall survival (OS). MATERIALS AND METHODS: We used the National Cancer Database to identify patients with stage IV mUC diagnosed between 2014 and 2018, who were treated with first-line immunotherapy, chemotherapy, or combination treatment. We performed multivariable logistic regression modeling to determine factors associated with treatment receipt Adjusted Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression were used to evaluate the association between treatment and OS. RESULTS: In our cohort of 4,169 patients, multivariable analysis identified increasing age (RRR: 1.07, 95%CI, 1.06-1.08) and comorbidity burden (, as independent predictors of receiving immunotherapy. Treatment at an academic facility was associated with increased likelihood of combination treatment (RRR: 1.29, 95%CI, 1.01-1.65). After IPTW, we found that combination therapy (hazard ratio [HR]: 0.72; 95%CI, 0.62-0.83) was associated with improved survival compared to chemotherapy. CONCLUSIONS: Patients with older age and more comorbidities were more likely to receive immunotherapy than chemotherapy for first-line treatment of metastatic urothelial carcinoma of the bladder. Utilization of chemoimmunotherapy was observed to be higher in academic centers and was associated with improved survival compared to chemotherapy.

Contemporary morbidity and mortality of open versus robotic cystectomy for bladder cancer: An analysis of the National Surgical Quality Improvement Program (NSQIP) procedure targeted cystectomy database.

OBJECTIVES: To evaluate the association between surgical modality (RARC vs. ORC) and the risk of 30-day complications. MATERIALS AND METHODS: We utilized the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) Cystectomy-Targeted database from 2019 to 2021. The primary outcome was a composite of major complications including 30-day mortality, reoperation, cardiac events, and stroke. Secondary outcomes included individual major and cystectomy-specific complications. Propensity score matching (PSM) was employed to minimize inherent differences within our cohort. We performed logistic regression to assess the association between outcomes of interest and operative modality. RESULTS: We found no difference between operative modality and the primary outcome, however, RARC was associated with a 70% lower risk of 30-day mortality (OR 0.30, 95% CI 0.13-0.70) and had favorable outcomes with respect to respiratory, deep venous thrombosis, wound complications, and length of stay. Limitations are related to residual confounding given the observational methodology. CONCLUSIONS: RARC was associated with reduced risk of multiple 30-day complications, including mortality, as well as organ system and cystectomy-specific outcomes. These data support the clinical benefit of increased adoption of RARC.

Comparing Satisfaction Among Providers Treating Both Pediatric and Adult Otolaryngology Patients.

Objective: Although pediatric otolaryngology providers are reported to garner lower patient satisfaction than adults, this difference is not well characterized. This study investigates whether patient satisfaction differences exist in providers who treat both pediatric and adult patients. Study Design: Retrospective review. Setting: Tertiary medical center. Methods: In this cross-sectional study, Press Ganey surveys (PGS) completed by patients or parents on their first-time visit with 5 general otolaryngology providers from July 2014 to March 2022 were analyzed. Surveys were categorized by child (<18 years old) or adult and consisted of 14 items including 6 service domains of access, visit, nursing, provider, personal issues, and assessment. Analysis was performed with Walsh's t test and analysis of variance. Multivariable logistic regression, controlling for wait times and provider, evaluated the likelihood of highest satisfaction scores (HI-SCORES) based on age. Results: A total of 2549 patients (135 pediatric, 2414 adults) completed the PGS on their initial visit. There was no significant difference in the mean overall satisfaction scores between pediatric and adult patients. Further analysis of service domains among pediatric patients found the mean score in the access domain to be higher for the 6- to 11-year-old age group (0-5 years old: 85.5 ± 20.5 [mean ± SD], 6-11 years old: 94.7 ± 11.5, 12-17 years old: 87.3 ± 15.4, P = .03). Pediatric patients did not have a significantly higher likelihood (odds ratio = 1.1, 95% confidence interval: 0.8-1.6, P > .05) of reporting HI-SCORES compared to adults after covariate adjustment. Conclusion: There was no significant difference in patient satisfaction scores for providers who treat pediatric and adult patients utilizing the same facility and scheduling team.

Genomic context sensitizes regulatory elements to genetic disruption.

Genomic context critically modulates regulatory function but is difficult to manipulate systematically. The murine insulin-like growth factor 2 (Igf2)/H19 locus is a paradigmatic model of enhancer selectivity, whereby CTCF occupancy at an imprinting control region directs downstream enhancers to activate either H19 or Igf2. We used synthetic regulatory genomics to repeatedly replace the native locus with 157-kb payloads, and we systematically dissected its architecture. Enhancer deletion and ectopic delivery revealed previously uncharacterized long-range regulatory dependencies at the native locus. Exchanging the H19 enhancer cluster with the Sox2 locus control region (LCR) showed that the H19 enhancers relied on their native surroundings while the Sox2 LCR functioned autonomously. Analysis of regulatory DNA actuation across cell types revealed that these enhancer clusters typify broader classes of context sensitivity genome wide. These results show that unexpected dependencies influence even well-studied loci, and our approach permits large-scale manipulation of complete loci to investigate the relationship between regulatory architecture and function.

Inflammatory bowel disease-associated colorectal cancer negatively affects surgery outcomes and health care costs.

BACKGROUND: Inflammatory bowel disease may affect the pathogenesis and clinicopathologic course of colorectal cancer. We sought to characterize the impact of inflammatory bowel disease on outcomes after colectomy and/or proctectomy for a malignant indication. METHODS: Patients diagnosed with colorectal cancer as well as a pre-existing comorbid diagnosis of Crohn's disease or ulcerative colitis between 2018 and 2021 were identified from Medicare claims data. The postoperative textbook outcome was defined as the absence of complications, as well as no extended hospital stay, 90-day readmission, or mortality. Postdischarge disposition and expenditures were also examined. RESULTS: Among 191,684 patients with colorectal cancer, 4,770 (2.5%) had a pre-existing diagnosis of inflammatory bowel disease. Patients with inflammatory bowel disease-associated colorectal cancer were less likely to undergo surgical resection (no inflammatory bowel disease: 47.6% vs inflammatory bowel disease: 42.1%; P < .001). Among patients who did undergo colorectal surgery, individuals with inflammatory bowel disease were less likely to achieve a textbook outcome (odds ratio 0.64 [95% confidence interval 0.58-0.70]). In particular, patients with inflammatory bowel disease had higher odds of postoperative complications (odds ratio 1.24 [1.12-1.38]), extended hospital stay (odds ratio 1.41 [1.27-1.58]), and readmission within 90 days (odds ratio 1.56 [1.42-1.72]) (all P < .05). Patients with inflammatory bowel disease-associated colorectal cancer were less likely to be discharged to their home under independent care (odds ratio 0.77 [0.68-0.87]) and had 12.2% higher expenditures, which correlated with whether the patient had a postoperative textbook outcome. CONCLUSION: One in 40 patients with colorectal cancer had concomitant inflammatory bowel disease. Inflammatory bowel disease was associated with a lower probability of achieving ideal postoperative outcomes, higher postdischarge expenditure, as well as worse long-term survival after colorectal cancer resection.

Association of county-level food deserts and food swamps on postoperative outcomes among patients undergoing colorectal surgery.

BACKGROUND: Although malnutrition has been linked to worse healthcare outcomes, the broader context of food environments has not been examined relative to surgical outcomes. We sought to define the impact of food environment on postoperative outcomes of patients undergoing resection for colorectal cancer (CRC). METHODS: Patients who underwent surgery for CRC between 2014 and 2020 were identified from the Medicare database. Patient-level data were linked to the United States Department of Agriculture data on food environment. Multivariable regression was used to examine the association between food environment and the likelihood of achieving a textbook outcome (TO). TO was defined as the absence of an extended length of stay (≥75th percentile), postoperative complications, readmission, and mortality within 90 days. RESULTS: A total of 260,813 patients from 3017 counties were included in the study. Patients from unhealthy food environments were more likely to be Black, have a higher Charlson Comorbidity Index, and reside in areas with higher social vulnerability (all P < .01). Patients residing in unhealthy food environments were less likely to achieve a TO than that of patients residing in the healthiest food environments (food swamp: 48.8% vs 52.4%; food desert: 47.9% vs 53.7%; P < .05). On multivariable analysis, individuals residing in the unhealthy food environments had lower odds of achieving a TO than those of patients living in the healthiest food environments (food swamp: OR, 0.86; 95% CI, 0.83-0.90; food desert: OR, 0.79; 95% CI, 0.76-0.82); P < .05). CONCLUSION: The surrounding food environment of patients may serve as a modifiable sociodemographic risk factor that contributes to disparities in postoperative CRC outcomes.

Real-time near infrared artificial intelligence using scalable non-expert crowdsourcing in colorectal surgery.

Surgical artificial intelligence (AI) has the potential to improve patient safety and clinical outcomes. To date, training such AI models to identify tissue anatomy requires annotations by expensive and rate-limiting surgical domain experts. Herein, we demonstrate and validate a methodology to obtain high quality surgical tissue annotations through crowdsourcing of non-experts, and real-time deployment of multimodal surgical anatomy AI model in colorectal surgery.

Membrane-bound O-acyltransferase 7 (MBOAT7) shapes lysosomal lipid homeostasis and function to control alcohol-associated liver injury.

Recent genome-wide association studies (GWAS) have identified a link between single-nucleotide polymorphisms (SNPs) near the MBOAT7 gene and advanced liver diseases. Specifically, the common MBOAT7 variant (rs641738) associated with reduced MBOAT7 expression is implicated in non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis. However, the precise mechanism underlying MBOAT7-driven liver disease progression remains elusive. Previously, we identified MBOAT7-driven acylation of lysophosphatidylinositol lipids as key mechanism suppressing the progression of NAFLD (Gwag et al., 2019). Here, we show that MBOAT7 loss of function promotes ALD via reorganization of lysosomal lipid homeostasis. Circulating levels of MBOAT7 metabolic products are significantly reduced in heavy drinkers compared to healthy controls. Hepatocyte- (Mboat7-HSKO), but not myeloid-specific (Mboat7-MSKO), deletion of Mboat7 exacerbates ethanol-induced liver injury. Lipidomic profiling reveals a reorganization of the hepatic lipidome in Mboat7-HSKO mice, characterized by increased endosomal/lysosomal lipids. Ethanol-exposed Mboat7-HSKO mice exhibit dysregulated autophagic flux and lysosomal biogenesis, associated with impaired transcription factor EB-mediated lysosomal biogenesis and autophagosome accumulation. This study provides mechanistic insights into how MBOAT7 influences ALD progression through dysregulation of lysosomal biogenesis and autophagic flux, highlighting hepatocyte-specific MBOAT7 loss as a key driver of ethanol-induced liver injury.

Proteomics identifies complement protein signatures in patients with alcohol-associated hepatitis.

Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH. Here, we performed a comparative analysis of data derived from human hepatic and serum proteome to identify and characterize complement protein signatures in severe AH (sAH). The quantity of multiple complement proteins was perturbed in liver and serum proteome of patients with sAH. Multiple complement proteins differentiated patients with sAH from those with alcohol cirrhosis (AC) or alcohol use disorder (AUD) and healthy controls (HCs). Serum collectin 11 and C1q binding protein were strongly associated with sAH and exhibited good discriminatory performance among patients with sAH, AC, or AUD and HCs. Furthermore, complement component receptor 1-like protein was negatively associated with pro-inflammatory cytokines. Additionally, lower serum MBL associated serine protease 1 and coagulation factor II independently predicted 90-day mortality. In summary, meta-analysis of proteomic profiles from liver and circulation revealed complement protein signatures of sAH, highlighting a complex perturbation of complement and identifying potential diagnostic and prognostic biomarkers for patients with sAH.

The Utilization of Fine-Needle Vasography to Localize Obstruction of the Male Reproductive Tract.

OBJECTIVE: To report our experience using fine-needle vasography (FNV) to identify a site of obstruction and determine candidacy for reconstructive procedures in patients presenting with suspected obstructive azoospermia (OA) or cryptozoospermia. METHODS: We report a multi-institutional case series of patients with suspected complete or partial OA. Patients that were included had azoospermia or cryptozoospermia, presence of palpable vasa, testicles ≥12 mL, and FSH <7.6 IU/L. All patients underwent testicular biopsy prior to or at the time of FNV to confirm spermatogenesis. FNV was performed using a 25-gauge angiocatheter, with radio-opaque dye visualized under fluoroscopy. Descriptive statistics are reported as median and interquartile range (IQR). RESULTS: A total of 16 patients underwent vasography from 2014 to 2022 with 3 surgeons. Twelve patients presented with azoospermia, and 4 with cryptozoospermia. A total of 7 (44%) men were found to have distal obstruction on FNV. Of the 8 men with prior inguinal hernia repairs, 2 were confirmed to have an obstruction at the level of the inguinal canal. Of the 6 patients with a history of genitourinary infection, 4 had an obstruction at the level of the epididymis (with normal FNV), while 2 had atresia of the vas deferens in the pelvis. CONCLUSION: FNV is an effective, minimally invasive way to identify the site of complete or partial obstruction in patients presenting with suspected OA/cryptozoospermia. It additionally permits identification of men who are candidates for epididymovasostomy reconstruction and helps to differentiate between ejaculatory duct obstruction (EDO) and other causes of blockage.

Systemic Bevacizumab for Recurrent Respiratory Papillomatosis: A Single Institution's Experience.

OBJECTIVES: Medical therapies to limit disease recurrence are critically needed for recurrent respiratory papillomatosis (RRP). Systemic bevacizumab is emerging as an exciting adjuvant therapy toward this end, but uptake has been poor due to the lack of experience and awareness of best prescribing practices. The objective of this study was to describe a single tertiary care academic medical center's experience using systemic bevacizumab for the treatment of RRP. METHODS: A retrospective review was performed to identify patients with RRP on systemic bevacizumab. Demographic and clinical characteristics, findings on imaging reports, and disease response at all anatomic subsites involved in papilloma were documented. RESULTS: Of the 17 RRP patients on systemic bevacizumab, 9 (52.9%) were male, and 12 (70.6%) were diagnosed with juvenile-onset RRP. The total lifetime number of surgeries was high, with more than half (n = 9; 52.9%) undergoing more than 50 surgeries. Following induction of systemic bevacizumab, a significant reduction in patients with laryngeal (n = 15; 94.1% vs. n = 7; 41.2%, p < 0.001) and tracheal (n = 11; 64.7% vs. n = 5; 29.4%, p = 0.04) RRP was noted. Surgical frequency was significantly lower following systemic bevacizumab (2.5 vs. 0.5 surgeries per year; p < 0.001). The most common complications were new-onset hypertension (n = 4; 23.5%) and proteinuria (n = 5; 29.4%). CONCLUSION: Systemic bevacizumab is effective in reducing the number of surgeries needed for RRP while exhibiting a relatively safe complication profile. Papillomas in the larynx and trachea are most responsive to systemic bevacizumab, while pulmonary RRP is most likely to exhibit a partial-to-stable response. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Association of COVID-19 Pandemic with Colorectal Cancer Screening: Impact of Race/Ethnicity and Social Vulnerability.

BACKGROUND: The COVID-19 pandemic disrupted health care delivery, including cancer screening practices. This study sought to determine the impact of the COVID-19 pandemic lockdown on colorectal cancer (CRC) screening relative to social vulnerability. METHODS: Using the Medicare Standard Analytic File, individuals 65 years old or older who were eligible for guideline-concordant CRC screening between 2019 and 2021 were identified. These data were merged with the Center for Disease Control Social Vulnerability Index (SVI) dataset. Changes in county-level monthly screening volumes relative to the start of the COVID-19 pandemic (March 2020) and easing of restrictions (March 2021) were assessed relative to SVI. RESULTS: Among 10,503,180 individuals continuously enrolled in Medicare with no prior diagnosis of CRC, 1,362,457 (12.97%) underwent CRC screening between 2019 and 2021. With the COVID-19 pandemic, CRC screening decreased markedly across the United States (median monthly screening: pre-pandemic [n = 76,444] vs pandemic era [n = 60,826]; median Δn = 15,618; p < 0.001). The 1-year post-pandemic overall CRC screening utilization generally rebounded to pre-COVID-19 levels (monthly median screening volumes: pandemic era [n = 60,826] vs post-pandemic [n = 74,170]; median Δn = 13,344; p < 0.001). Individuals residing in counties with the highest SVI experienced a larger decline in CRC screening odds than individuals residing in low-SVI counties (reference, low SVI: pre-pandemic high SVI [OR, 0.85] vs pandemic high SVI [OR, 0.81] vs post-pandemic high SVI [OR, 0.85]; all p < 0.001). CONCLUSIONS: The COVID-19 pandemic was associated with a decrease in CRC screening volumes. Patients who resided in high social vulnerability areas experienced the greatest pandemic-related decline.

Clinical Utility of Laser Speckle Contrast Imaging and Real-Time Quantification of Bowel Perfusion in Minimally Invasive Left-Sided Colorectal Resections.

BACKGROUND: Left-sided colorectal surgery demonstrates high anastomotic leak rates, with tissue ischemia thought to influence outcomes. Indocyanine green is commonly used for perfusion assessment, but evidence remains mixed for whether it reduces colorectal anastomotic leaks. Laser speckle contrast imaging provides dye-free perfusion assessment in real-time through perfusion heat maps and quantification. OBJECTIVE: This study investigates the efficacy of advanced visualization (indocyanine green versus laser speckle contrast imaging), perfusion assessment, and utility of laser speckle perfusion quantification in determining ischemic margins. DESIGN: Prospective intervention group using advanced visualization with case-matched, retrospective control group. SETTINGS: Single academic medical center. PATIENTS: Forty adult patients undergoing elective, minimally invasive, left-sided colorectal surgery. INTERVENTIONS: Intraoperative perfusion assessment using white light imaging and advanced visualization at 3 time points: T1-proximal colon after devascularization, before transection, T2-proximal/distal colon before anastomosis, and T3-completed anastomosis. MAIN OUTCOME MEASURES: Intraoperative indication of ischemic line of demarcation before resection under each visualization method, surgical decision change using advanced visualization, post hoc laser speckle perfusion quantification of colorectal tissue, and 30-day postoperative outcomes. RESULTS: Advanced visualization changed surgical decision-making in 17.5% of cases. For cases in which surgeons changed a decision, the average discordance between the line of demarcation in white light imaging and advanced visualization was 3.7 cm, compared to 0.41 cm ( p = 0.01) for cases without decision changes. There was no statistical difference between the line of ischemic demarcation using laser speckle versus indocyanine green ( p = 0.16). Laser speckle quantified lower perfusion values for tissues beyond the line of ischemic demarcation while suggesting an additional 1 cm of perfused tissue beyond this line. One (2.5%) anastomotic leak occurred in the intervention group. LIMITATIONS: This study was not powered to detect differences in anastomotic leak rates. CONCLUSIONS: Advanced visualization using laser speckle and indocyanine green provides valuable perfusion information that impacts surgical decision-making in minimally invasive left-sided colorectal surgeries. See Video Abstract . UTILIDAD CLNICA DE LAS IMGENES DE CONTRASTE MOTEADO CON LSER Y LA CUANTIFICACIN EN TIEMPO REAL DE LA PERFUSIN INTESTINAL EN RESECCIONES COLORRECTALES DEL LADO IZQUIERDO MNIMAMENTE INVASIVAS: ANTECEDENTES:La cirugía colorrectal del lado izquierdo demuestra altas tasas de fuga anastomótica, y se cree que la isquemia tisular influye en los resultados. El verde de indocianina se utiliza habitualmente para evaluar la perfusión, pero la evidencia sobre si reduce las fugas anastomóticas colorrectales sigue siendo contradictoria. Las imágenes de contraste moteado con láser proporcionan una evaluación de la perfusión sin colorantes en tiempo real a través de mapas de calor de perfusión y cuantificación.OBJETIVO:Este estudio investiga la eficacia de la evaluación de la perfusión mediante visualización avanzada (verde de indocianina versus imágenes de contraste moteado con láser) y la utilidad de la cuantificación de la perfusión con moteado láser para determinar los márgenes isquémicos.DISEÑO:Grupo de intervención prospectivo que utiliza visualización avanzada con un grupo de control retrospectivo de casos emparejados.LUGARES:Centro médico académico único.PACIENTES:Cuarenta pacientes adultos sometidos a cirugía colorrectal electiva, mínimamente invasiva, del lado izquierdo.INTERVENCIONES:Evaluación de la perfusión intraoperatoria mediante imágenes con luz blanca y visualización avanzada en tres puntos temporales: T1-colon proximal después de la devascularización, antes de la transección; T2-colon proximal/distal antes de la anastomosis; y T3-anastomosis completa.PRINCIPALES MEDIDAS DE VALORACIÓN:Indicación intraoperatoria de la línea de demarcación isquémica antes de la resección bajo cada método de visualización, cambio de decisión quirúrgica mediante visualización avanzada, cuantificación post-hoc de la perfusión con láser moteado del tejido colorrectal y resultados posoperatorios a los 30 días.RESULTADOS:La visualización avanzada cambió la toma de decisiones quirúrgicas en el 17,5% de los casos. Para los casos en los que los cirujanos cambiaron una decisión, la discordancia promedio entre la línea de demarcación en las imágenes con luz blanca y la visualización avanzada fue de 3,7 cm, en comparación con 0,41 cm (p = 0,01) para los casos sin cambios de decisión. No hubo diferencias estadísticas entre la línea de demarcación isquémica utilizando láser moteado versus verde de indocianina (p = 0,16). El moteado con láser cuantificó valores de perfusión más bajos para los tejidos más allá de la línea de demarcación isquémica y al mismo tiempo sugirió 1 cm adicional de tejido perfundido más allá de esta línea. Se produjo una fuga anastomótica (2,5%) en el grupo de intervención.LIMITACIONES:Este estudio no tuvo el poder estadístico suficiente para detectar diferencias en las tasas de fuga anastomótica.CONCLUSIONES:La visualización avanzada utilizando moteado láser y verde de indocianina proporciona información valiosa sobre la perfusión que impacta la toma de decisiones quirúrgicas en cirugías colorrectales mínimamente invasivas del lado izquierdo. (Traducción-Dr. Ingrid Melo).

On the genetic basis of tail-loss evolution in humans and apes.

The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'1-3, with a proposed role in contributing to human bipedalism4-6. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene7-9-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans10. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.

Missing the Match: A National Survey Investigating Education in Renal Donor-Recipient Matching.

PURPOSE: Clinical judgment in renal donor organ and recipient selection is gained through fellowship and mentorship in early career. We aim to understand the past and current state of organ acceptance education. METHODS: We developed and distributed an anonymous, national survey to American Society of Transplant Surgeons faculty members and transplant surgery fellows in 2022. Survey questions explored in detail the evaluation of organ offers, the extent of formal education in organ evaluation, and attitudes regarding training adequacy. FINDINGS: Ninety-eight attending surgeons (65 men, 25 women, and 3 nonbinary) and 38 fellows (25 men, 6 women, and 2 nonbinary) responded. Seventy-eight percent of attending surgeons and 6% of fellows take primary organ offers. Forty-four percent of fellows report no didactic education in donor evaluation and recipient selection. Fellows report that discussion with attending surgeons (37.2%) and independent study of the literature (35.4%) are their primary modes of learning. Fellows call for additional clinical decision-making experience (47.3%), further didactic sessions (44.7%), and additional discussions with faculty (44.7%). Sixty-four percent of fellows and 55% of attendings felt their training provided adequate education about donor selection. CONCLUSION: Our responses suggest gaps in education regarding donor and recipient selection. Increased clinical experience and standardized education at the national level represent opportunities for improvement.

The Social, Mental, and Physical Health Impacts of the COVID-19 Pandemic on People With HIV: Protocol of an Observational International Multisite Study.

ABSTRACT: As the COVID-19 pandemic spread across the world, immunocompromised individuals such as people with HIV (PWH) may have faced a disproportionate impact on their health and HIV outcomes, both from COVID-19 and from the strategies enacted to contain it. Based on the SPIRIT guidelines, we describe the protocol for an international multisite observational study being conducted by The International Nursing Network for HIV Research, with the Coordinating Center based at the University of California, San Francisco (UCSF) School of Nursing. Site Principal Investigators implement a standardized protocol to recruit PWH to complete the study online or in-person. Questions address demographics; HIV continuum of care indicators; mental and social health; COVID-19 and vaccination knowledge, attitudes, behaviors, and fears; and overall outcomes. Results of this study will contribute to knowledge that can inform responses to future public health crises to minimize their impacts on vulnerable populations such as PWH.

Hearing Following Prolonged and Delayed Ganciclovir Treatment in a Murine Cytomegalovirus Model.

OBJECTIVE: Compare hearing outcomes utilizing standard, prolonged and delayed ganciclovir (GCV) therapy in a murine model of cytomegalovirus (CMV). METHODS: BALB/c mice were inoculated with mouse cytomegalovirus (mCMV) or saline via intracerebral injection on postnatal day 3 (p3). Intraperitoneal GCV or saline was administered at 12 h intervals for the duration of the standard (p3-p17), delayed (p30-p44), or prolonged treatment windows (p3-p31). Auditory thresholds were assessed using distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) testing at 4, 6, and 8 weeks of age. Blood and tissue samples were harvested from mice on p17 and p37 one hour after GCV administration, and their concentrations were assessed via liquid chromatography-mass spectrometry. RESULTS: A delayed course of GCV improved ABR but not DPOAE thresholds in mCMV-infected mice. A prolonged course of GCV did not provide better hearing thresholds than those administered standard treatment. The average GCV concentration in all 17-day-old mice tissue was significantly higher than those in older 37-day-old mice. CONCLUSION: Delayed GCV treatment provided a hearing benefit on ABR over untreated mCMV infected mice. Prolonged CGV administration showed no benefit compared to a shorter duration GCV treatment. GCV drug concentrations both systemically and in the cochlea are much lower in older mice. These results have potential implications for the clinical management of cCMV infected children. LEVEL OF EVIDENCE: NA Laryngoscope, 134:433-438, 2024.

Quality of Life and Real-time Patient Experience During Neoadjuvant Therapy: A Prospective Cohort Study.

OBJECTIVE: To use a customized smartphone application to prospectively measure QOL and the real-time patient experience during neoadjuvant therapy (NT). BACKGROUND: NT is increasingly used for patients with localized gastrointestinal (GI) cancers. There is little data assessing patient experience and quality of life (QOL) during NT for GI cancers. METHODS: Patients with GI cancers receiving NT were instructed on using a customized smartphone application through which the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, a validated measure of health-related QOL, was administered at baseline, every 30 days, and at the completion of NT. Participants also tracked their moods and symptoms and used free-text journaling functionalities in the application. Mean overall and subsection health-related QOL scores were calculated during NT. RESULTS: Among 104 enrolled patients, the mean age was 60.5 ± 11.5 years and 55% were males. Common cancer diagnoses were colorectal (40%), pancreatic (37%), and esophageal (15%). Mean overall FACT-G scores did not change during NT ( P = 0.987). While functional well-being scores were consistently the lowest and social well-being scores the highest, FACT subscores similarly did not change during NT (all P > 0.01). The most common symptoms reported during NT were fatigue, insomnia, and anxiety (39.3%, 34.5%, and 28.3% of patient entries, respectively). Qualitative analysis of free-text journaling entries identified anxiety, fear, and frustration as the most common themes, but also the importance of social support systems and confidence in health care providers. CONCLUSIONS: While patient symptom burden remains high, results of this prospective cohort study suggest QOL is maintained during NT for localized GI cancers.

Genomic context sensitizes regulatory elements to genetic disruption.

Enhancer function is frequently investigated piecemeal using truncated reporter assays or single deletion analysis. Thus it remains unclear to what extent enhancer function at native loci relies on surrounding genomic context. Using the Big-IN technology for targeted integration of large DNAs, we analyzed the regulatory architecture of the murine Igf2/H19 locus, a paradigmatic model of enhancer selectivity. We assembled payloads containing a 157-kb functional Igf2/H19 locus and engineered mutations to genetically direct CTCF occupancy at the imprinting control region (ICR) that switches the target gene of the H19 enhancer cluster. Contrasting activity of payloads delivered at the endogenous Igf2/H19 locus or ectopically at Hprt revealed that the Igf2/H19 locus includes additional, previously unknown long-range regulatory elements. Exchanging components of the Igf2/H19 locus with the well-studied Sox2 locus showed that the H19 enhancer cluster functioned poorly out of context, and required its native surroundings to activate Sox2 expression. Conversely, the Sox2 locus control region (LCR) could activate both Igf2 and H19 outside its native context, but its activity was only partially modulated by CTCF occupancy at the ICR. Analysis of regulatory DNA actuation across different cell types revealed that, while the H19 enhancers are tightly coordinated within their native locus, the Sox2 LCR acts more independently. We show that these enhancer clusters typify broader classes of loci genome-wide. Our results show that unexpected dependencies may influence even the most studied functional elements, and our synthetic regulatory genomics approach permits large-scale manipulation of complete loci to investigate the relationship between locus architecture and function.

Membrane Bound O-Acyltransferase 7 (MBOAT7) Shapes Lysosomal Lipid Homeostasis and Function to Control Alcohol-Associated Liver Injury.

Several recent genome-wide association studies (GWAS) have identified single nucleotide polymorphism (SNPs) near the gene encoding membrane-bound O -acyltransferase 7 ( MBOAT7 ) that is associated with advanced liver diseases. In fact, a common MBOAT7 variant (rs641738), which is associated with reduced MBOAT7 expression, confers increased susceptibility to non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis in those chronically infected with hepatitis viruses B and C. The MBOAT7 gene encodes a lysophosphatidylinositol (LPI) acyltransferase enzyme that produces the most abundant form of phosphatidylinositol 38:4 (PI 18:0/20:4). Although these recent genetic studies clearly implicate MBOAT7 function in liver disease progression, the mechanism(s) by which MBOAT7-driven LPI acylation regulates liver disease is currently unknown. Previously we showed that antisense oligonucleotide (ASO)-mediated knockdown of Mboat7 promoted non-alcoholic fatty liver disease (NAFLD) in mice (Helsley et al., 2019). Here, we provide mechanistic insights into how MBOAT7 loss of function promotes alcohol-associated liver disease (ALD). In agreement with GWAS studies, we find that circulating levels of metabolic product of MBOAT7 (PI 38:4) are significantly reduced in heavy drinkers compared to age-matched healthy controls. Hepatocyte specific genetic deletion ( Mboat7 HSKO ), but not myeloid-specific deletion ( Mboat7 MSKO ), of Mboat7 in mice results in enhanced ethanol-induced hepatic steatosis and high concentrations of plasma alanine aminotransferase (ALT). Given MBOAT7 is a lipid metabolic enzyme, we performed comprehensive lipidomic profiling of the liver and identified a striking reorganization of the hepatic lipidome upon ethanol feeding in Mboat7 HSKO mice. Specifically, we observed large increases in the levels of endosomal/lysosomal lipids including bis(monoacylglycero)phosphates (BMP) and phosphatidylglycerols (PGs) in ethanol-exposed Mboat7 HSKO mice. In parallel, ethanol-fed Mboat7 HSKO mice exhibited marked dysregulation of autophagic flux and lysosomal biogenesis when exposed to ethanol. This was associated with impaired transcription factor EB (TFEB)-mediated lysosomal biogenesis and accumulation of autophagosomes. Collectively, this works provides new molecular insights into how genetic variation in MBOAT7 impacts ALD progression in humans and mice. This work is the first to causally link MBOAT7 loss of function in hepatocytes, but not myeloid cells, to ethanol-induced liver injury via dysregulation of lysosomal biogenesis and autophagic flux.