Early host immune responses in a human organoid-derived gallbladder monolayer to Salmonella Typhi strains from patients with acute and chronic infections: a comparative analysis.

Salmonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen, invades the host through the gut to cause typhoid fever. Recent calculations of the typhoid fever burden estimated that more than 10 million new typhoid fever cases occur in low and middle-income countries, resulting in 65,400-187,700 deaths yearly. Interestingly, if not antibiotic-treated, upon the resolution of acute disease, 1%-5% of patients become asymptomatic chronic carriers. Chronically infected hosts are not only critical reservoirs of infection that transmit the disease to naive individuals but are also predisposed to developing gallbladder carcinoma. Nevertheless, the molecular mechanisms involved in the early interactions between gallbladder epithelial cells and S. Typhi remain largely unknown. Based on our previous studies showing that closely related S. Typhi strains elicit distinct innate immune responses, we hypothesized that host molecular pathways activated by S. Typhi strains derived from acutely and chronically infected patients would differ. To test this hypothesis, we used a novel human organoid-derived polarized gallbladder monolayer model, and S. Typhi strains derived from acutely and chronically infected patients. We found that S. Typhi strains derived from acutely and chronically infected patients differentially regulate host mitogen-activated protein kinase (MAPK) and S6 transcription factors. These variations might be attributed to differential cytokine signaling, predominantly via TNF-α and IL-6 production and appear to be influenced by the duration the isolate was subjected to selective pressures in the gallbladder. These findings represent a significant leap in understanding the complexities behind chronic S. Typhi infections in the gallbladder and may uncover potential intervention targets.

Using risk-adjusted cumulative sum to evaluate surgeon, divisional, and institutional outcomes-a feasibility study.

BACKGROUND: Few objective, real-time measurements of surgeon performance exist. The risk-adjusted cumulative sum is a novel method that can track surgeon-level outcomes on a continuous basis. The objective of this study was to demonstrate the feasibility of using risk-adjusted cumulative sum to monitor outcomes after colorectal operations and identify clinically relevant performance variations. METHODS: The National Surgical Quality Improvement Program was queried to obtain patient-level data for 1,603 colorectal operations at a high-volume center from 2011 to 2020. For each case, expected risks of morbidity, mortality, reoperation, readmission, and prolonged length of stay were estimated using the National Surgical Quality Improvement Program risk calculator. Risk-adjusted cumulative sum curves were generated to signal observed-to-expected odds ratios of 1.5 (poor performance) and 0.5 (exceptional performance). Control limits were set based on a false positive rate of 5% (α = 0.05). RESULTS: The cohort included data on 7 surgeons (those with more than 20 cases in the study period). Institutional observed versus expected outcomes were the following: morbidity 12.5% (vs 15.0%), mortality 2.5% (vs 2.0%), prolonged length of stay 19.7% (vs 19.1%), reoperation 11.1% (vs 11.3%), and 30-day readmission 6.1% (vs 4.8%). Risk-adjusted cumulative sum accurately demonstrated within- and between-surgeon performance variations across these metrics and proved effective when considering division-level data. CONCLUSION: Risk-adjusted cumulative sum adjusts for patient-level risk factors to provide real-time data on surgeon-specific outcomes. This approach enables prompt identification of performance outliers and can contribute to quality assurance, root-cause analysis, and incentivization not only at the surgeon level but at divisional and institutional levels as well.

Sex-Based Differences in IBD Surgical Outcomes.

BACKGROUND: Although there are discrepancies in the development and progression of IBD based on biologic sex, little is known about differences in postoperative outcomes between men and women undergoing surgery for this condition. OBJECTIVE: To compare rates of anastomotic leaks, wound complications, and serious adverse events between men and women undergoing surgery for IBD. DESIGN: This was a retrospective cohort study. SETTINGS: Data were obtained from the American College of Surgeons National Surgical Quality Improvement Program IBD Collaborative database, which includes 15 high-volume IBD surgery centers. PATIENTS: All adult patients undergoing surgery for IBD were included. Participants with missing data for exposure or outcome variables were excluded. MAIN OUTCOME MEASURES: Rates of anastomotic leaks, wound complications, and serious adverse events were compared between women and men. RESULTS: A total of 3143 patients were included. There was a significant association between sex and BMI, IBD type, and preoperative medication use. Women had decreased odds of serious adverse events compared to men (OR 0.73; 95% CI, 0.55-0.96), but there was no significant association between sex and anastomotic leaks or wound complications. IBD type was found to be an effect measure modifier of the relationship between sex and serious adverse events. Among patients with ulcerative colitis, women had a 54% decrease in the odds of serious adverse events compared to men, whereas there was no significant difference between women and men with Crohn's disease. LIMITATIONS: This study was limited by capturing only 30 days of postoperative outcomes. CONCLUSIONS: Women undergoing surgery for ulcerative colitis had decreased odds of serious adverse events compared to men. Understanding sex-based differences in outcomes allows clinicians to make patient-centered decisions regarding surgical planning and perioperative management for patients with IBD. See Video Abstract . DIFERENCIAS BASADAS EN EL SEXO EN LOS RESULTADOS QUIRRGICOS DE LA ENFERMEDAD INFLAMATORIA INTESTINAL: ANTECEDENTES:Aunque existen discrepancias en el desarrollo y la progresión de la enfermedad inflamatoria intestinal según el sexo biológico, se sabe poco sobre las diferencias en los resultados postoperatorios entre hombres y mujeres sometidos a cirugía por esta afección.OBJETIVO:Nuestro objetivo fue comparar las tasas de fugas anastomóticas, complicaciones de las heridas y eventos adversos graves entre hombres y mujeres sometidos a cirugía por enfermedad inflamatoria intestinal.DISEÑO:Este fue un estudio de cohorte retrospectivo.AJUSTES:Los datos se obtuvieron de la base de datos del Programa Nacional de Mejora de la Calidad Quirúrgica del Colegio Americano de Cirujanos para la Enfermedad Inflamatoria Intestinal, que incluye 15 centros de cirugía de enfermedad inflamatoria intestinal de alto volumen.PACIENTES:Se incluyeron todos los pacientes adultos sometidos a cirugía por enfermedad inflamatoria intestinal. Se excluyeron los sujetos a los que les faltaban datos sobre exposición o variables de resultado.PRINCIPALES MEDIDAS DE RESULTADO:Se compararon las tasas de fugas anastomóticas, complicaciones de las heridas y eventos adversos graves entre mujeres y hombres.RESULTADOS:Se incluyeron un total de 3.143 pacientes. Hubo una asociación significativa entre el sexo y el índice de masa corporal, el tipo de enfermedad inflamatoria intestinal y el uso de medicación preoperatoria. Las mujeres tuvieron menores probabilidades de sufrir eventos adversos graves en comparación con los hombres (OR = 0,73; IC del 95 %: 0,55 a 0,96), pero no hubo una relacion significativa entre el sexo y las fugas anastomóticas o las complicaciones de las heridas. Se encontró que el tipo de enfermedad inflamatoria intestinal era un modificador de la medida del efecto de la relación entre el sexo y los eventos adversos graves. Entre los pacientes con colitis ulcerosa, las mujeres tuvieron una disminución del 54 % en las probabilidades de sufrir eventos adversos graves en comparación con los hombres, mientras que no hubo diferencias significativas entre mujeres y hombres con enfermedad de Crohn.LIMITACIONES:Este estudio estuvo limitado al capturar solo 30 días de resultados posoperatorios.CONCLUSIONES:Las mujeres sometidas a cirugía por colitis ulcerosa tuvieron menores probabilidades de sufrir eventos adversos graves en comparación con los hombres. Comprender las diferencias en los resultados basadas en el sexo permite a los médicos tomar decisiones centradas en el paciente con respecto a la planificación quirúrgica y el manejo perioperatorio de los pacientes con enfermedad inflamatoria intestinal. (Traducción-Dr Yolanda Colorado).

Monitoring Patients With Inflammatory Bowel Disease at High Risk of Anal Cancer.

Anal cancer is a rare but deadly disease that disproportionately affects patients with inflammatory bowel disease (IBD). Rates of adenocarcinoma and human papillomavirus-related squamous cell carcinoma have been consistently demonstrated to be higher in patients with ulcerative colitis and Crohn's disease. Despite this increased risk, uniform screening, diagnosis, and treatment algorithms are lacking. This review describes the most recent literature surrounding anal cancer in the IBD population as well as the unique challenges inherent in diagnosing and treating this population. We conclude by proposing a new screening motif based off literature review and multidisciplinary clinical experience that aims to increase early detection of anal cancers in the IBD population.

Muscarinic receptor agonist-induced ßPix binding to ß-catenin promotes colon neoplasia.

M3 muscarinic receptors (M3R) modulate ß-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, ßPix, binds to ß-catenin in colon cancer cells, augmenting ß-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M3R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of ßPix and ß-catenin in stem cells overexpressing M3R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M3R agonist-induced cytoplasmic and nuclear association of ßPix with ß-catenin. ßPix knockdown attenuated M3R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing ßPix dose-dependently augmented ß-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of ßPix. Expression levels of ß-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from ßPix-deficient conditional knockout mice. Targeting the M3R/ßPix/ß-catenin axis may have therapeutic potential.

Secretory-IgA binding to intestinal microbiota attenuates inflammatory reactions as the intestinal barrier of preterm infants matures.

Previous work has shown that Secretory-IgA (SIgA) binding to the intestinal microbiota is variable and may regulate host inflammatory bowel responses. Nevertheless, the impact of the SIgA functional binding to the microbiota remains largely unknown in preterm infants whose immature epithelial barriers make them particularly susceptible to inflammation. Here, we investigated SIgA binding to intestinal microbiota isolated from stools of preterm infants <33 weeks gestation with various levels of intestinal permeability. We found that SIgA binding to intestinal microbiota attenuates inflammatory reactions in preterm infants. We also observed a significant correlation between SIgA affinity to the microbiota and the infant's intestinal barrier maturation. Still, SIgA affinity was not associated with developing host defenses, such as the production of mucus and inflammatory calprotectin protein, but it depended on the microbiota shifts as the intestinal barrier matures. In conclusion, we reported an association between the SIgA functional binding to the microbiota and the maturity of the preterm infant's intestinal barrier, indicating that the pattern of SIgA coating is altered as the intestinal barrier matures.

Assessing Content of Accredited Colon and Rectal Surgery Fellowship Websites: Is there Adequate Information for Applicants?

Electronic information is a vital resource used by fellowship applicants. This study aimed to assess the completeness of colon and rectal surgery (CRS) fellowship program online information. Program information on the Association of Program Directors for Colon and Rectal Surgery (APDCRS) website as well as each institutional website was evaluated based on templated criteria. Sixty-eight accredited fellowship programs were identified. Six (9%) programs had complete profiles on the APDCRS platform, with an average of 3.5 details completed per program. Sixty-two (91%) websites were easily accessible. None of these contained all 28 criteria assessed and 47 (69%) contained less than half of assessed content. The most common data point was fellowship program description (96%), while board pass rate (1%) was the least common. Most CRS fellowship websites were grossly incomplete. Electronically available information is vital to fellowship applicants, and programs should try to provide easily accessible information about their program.

Lessons in liability: Examining medical malpractice suits against general surgeons in Maryland.

BACKGROUND: Although medical malpractice lawsuits pose a significant burden, there is a paucity of research on physician-specific characteristics influencing lawsuits against surgeons. Our objective was to identify factors associated with general surgeons being named in malpractice cases. METHODS: This was a cross sectional study of Maryland general surgeons, using malpractice data from a publicly accessible judiciary database. Case number per decade and lifetime lawsuit status were modeled with linear and logistic regression. RESULTS: Male surgeons had a higher average lawsuit volume (p = 0.002) and were more likely to be named in a malpractice case (p < 0.001). In regression analysis, a second graduate degree was a predictor of average cases per 10 years (p = 0.008) and male gender predicted lifetime lawsuit status (OR = 1.73, p = 0.046). CONCLUSIONS: Male gender was associated with increased odds of being named in a malpractice lawsuit. Identifying this difference is a preliminary step in developing interventions to reduce lawsuits amongst surgeons.

Radiation Therapy and Malignant Fistulae of Anorectal Cancers.

PURPOSE: Although fistulization is a well-studied late toxic effect of radiation therapy (RT), anorectal cancers (ARCs) can present with malignant fistulae (MF) and negatively affect quality of life. The effect of RT, often combined with concurrent chemotherapy, on MF needs systematic analysis, because practitioners are concerned that RT may exacerbate MF. We reviewed our institutional series evaluating the hypothesis that RT worsens MF. METHODS AND MATERIALS: A single-institutional retrospective analysis of patients with ARC receiving RT from 2006 to 2019 was performed. These patients were screened for MF. Any MF resected before RT and RT not directed at the site of MF were excluded. Effects were assessed by review of available follow-up documentation and imaging. RESULTS: A total of 639 patients with ARC were reviewed, and 47 had MF (7.4%). With a median follow-up of 22 months (range, 2-133 months), RT improved MF in 17 of 29 evaluable patients (59%), with 9 of 29 (31.0%) having resolution. The median time to improvement was 50 days (range, 25-117 days); the median duration of improvement was 161 days (range, 0-1941 days). Malignant fistulae persisted in 12 of 29 patients (41%), with persistent local disease in all cases; in 2 cases, MF worsened concomitant with local progression. CONCLUSIONS: In all, 7.4% of patients with ARC presented with MF. Radiation therapy led to improvement or resolution in more than half of evaluable patients. Persistence or worsening of MF was only observed in patients with refractory or progressive local disease. Based on our findings, MF is not a contraindication to RT and may be considered as an independent indication for palliative RT.

Impact of Andrographolide and Melatonin Combinatorial Drug Therapy on Metastatic Colon Cancer Cells and Organoids.

BACKGROUND: The death rate (the number of deaths per 100 000 people per year) of colorectal cancer (CRC) has been dropping since 1980 due to increased screening, lifestyle-related risk factors, and improved treatment options; however, CRC is the third leading cause of cancer-related deaths in men and women in the United States. Therefore, successful therapy for CRC is an unmet clinical need. This study aimed to investigate the impacts of andrographolide (AGP) and melatonin (MLT) on CRC and the underlying mechanism. METHODS: To investigate AGP and MLT anticancer effects, a series of metastatic colon cancer cell lines (T84, Colo 205, HT-29, and DLD-1) were selected. In addition, a metastatic patient-derived organoid model (PDOD) was used to monitor the anticancer effects of AGP and MLT. A series of bioassays including 3D organoid cell culture, MTT, colony formation, western blotting, immunofluorescence, and quantitative polymerase chain reaction (qPCR) were performed. RESULTS: The dual therapy significantly promotes CRC cell death, as compared with the normal cells. It also limits CRC colony formation and disrupts the PDOD membrane integrity along with decreased Ki-67 expression. A significantly higher cleaved caspase-3 and the endoplasmic reticulum (ER) stress proteins, IRE-1 and ATF-6 expression, by 48 hours were found. This combinatorial treatment increased reactive oxygen species (ROS) levels. Apoptosis signaling molecules BAX, XBP-1, and CHOP were significantly increased as determined by qPCR. CONCLUSIONS: These findings indicated that AGP and MLT associated ER stress-mediated apoptotic metastatic colorectal cancer (mCRC) cell death through the IRE-1/XBP-1/CHOP signaling pathway. This novel combination could be a potential therapeutic strategy for mCRC cells.

Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience.

PURPOSE: Reirradiation for rectal cancer (RC) after prior pelvic radiation therapy (RT) has been shown to be safe and effective. However, limited data exist for proton therapy (PT), including pencil beam scanning proton therapy (PBS-PT). We hypothesize that PT is safe and feasible for re-treatment and may allow for decreased toxicity and treatment escalation. METHODS AND MATERIALS: A single-institution, retrospective, institutional review board-approved analysis of all patients with RC and prior pelvic RT receiving PBS-PT reirradiation was performed. Data on patient and treatment characteristics and outcomes were collected. Local progression, progression-free survival, overall survival, and late grade >3 toxicity were estimated using the Kaplan-Meier method. RESULTS: Twenty-eight patients (median follow-up: 28.6 months) received PBS-PT reirradiation between 2016 and 2019, including 18 patients with recurrent RC (median prior dose: 54.0 Gy) and 10 patients with de novo RC and variable prior RT. The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 twice daily), and 24 of 28 patients received concurrent chemotherapy. Six underwent surgical resection. Three (10.7%) experienced grade 3 acute toxicities, and 1 did not complete RT owing to toxicity. Four (14.2%) had late grade <3 toxicity, including 1 grade 5 toxicity in a patient with a prior RT-related injury. The 1-year local progression, progression-free survival, and overall survival rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively. CONCLUSIONS: This is the largest series using PT for reirradiation for RC and the first study using PBS-PT. Low acute toxicity rates and acceptable late toxicity support PBS-PT as an option for this high-risk patient population, with a need for continued follow-up.

Postoperative small bowel obstruction secondary to single malformed staple following laparoscopic total abdominal colectomy.

Surgical staplers are ubiquitous in gastrointestinal surgery, especially laparoscopy. Intraperitoneal staples are designed to be inert and are generally regarded as benign; however, complications from primarily malformed staples can rarely occur. Here, we present a case of early mechanical postoperative small bowel obstruction due to a surgical staple following laparoscopic total abdominal colectomy and end ileostomy creation performed for medically refractory ulcerative colitis. Management consisted of diagnostic laparoscopy and careful extraction of a malformed surgical staple tethering a loop of small bowel to the rectal stump. Eight similar cases following gastrointestinal surgery have been identified in the literature, all occurring in the first 2 weeks following laparoscopic appendectomy. To our knowledge, this is the first case described following laparoscopic total abdominal colectomy, with high-grade small bowel obstruction at the level of the rectal stump staple line.

Salmonella enterica serovar Typhi exposure elicits ex vivo cell-type-specific epigenetic changes in human gut cells.

Salmonella enterica serovar Typhi (S. Typhi) causes substantial morbidity and mortality worldwide, particularly among young children. Humans develop an array of mucosal immune responses following S. Typhi infection. Whereas the cellular mechanisms involved in S. Typhi infection have been intensively studied, very little is known about the early chromatin modifications occurring in the human gut microenvironment that influence downstream immune responses. To address this gap in knowledge, cells isolated from human terminal ileum exposed ex vivo to the wild-type S. Typhi strain were stained with a 33-metal-labeled antibody panel for mass cytometry analyses of the early chromatin modifications modulated by S. Typhi. We measured the cellular levels of 6 classes of histone modifications, and 1 histone variant in 11 major cell subsets (i.e., B, CD3 + T, CD4 + T, CD8 + T, NK, TCR-γδ, Mucosal associated invariant (MAIT), and NKT cells as well as monocytes, macrophages, and epithelial cells). We found that arginine methylation might regulate the early-differentiation of effector-memory CD4+ T-cells following exposure to S. Typhi. We also found S. Typhi-induced post-translational modifications in histone methylation and acetylation associated with epithelial cells, NKT, MAIT, TCR-γδ, Monocytes, and CD8 + T-cells that are related to both gene activation and silencing.

Gender differences in urology society award recipients.

BACKGROUND: Approximately 91% of urologists are male and 9% female. We aim to characterize gender differences amongst urology society awardees over the past six decades. METHODS: We queried 16 American urology societies. Inclusion criteria were active membership enrollment, majority urologist members, and awards provided at an annual, biennial or triennial basis. RESULTS: Ten urology societies were included. Between 1963 and 2019, 848 awardees for 34 awards were identified. Men comprised 92.2% and women 7.8% of recipients. The highest percentage of women awardees per year (21.7%) occurred in 2018, increased from 6.5% in 2008 and 0% in 1998. Over the last 11 years, women received 0% of awards offered 61% of the time. CONCLUSIONS: There is an increased trend in the representation of women awardees by urology societies, although the frequency varies widely between societies. This is in keeping with the trend of increasing number of women entering the field of urology.

Limited Role for Routine Restaging After Neoadjuvant Therapy in Locally Advanced Rectal Cancer.

BACKGROUND: Although many patients with locally advanced rectal cancer undergo restaging imaging after neoadjuvant chemoradiotherapy and before surgery, the benefit of this practice is unclear. The purpose of this study was to examine the impact of reimaging on outcomes. MATERIALS AND METHODS: We performed a retrospective analysis of consecutive patients with stage 2 and 3 rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy between May 2005 and April 2018. Patient and disease characteristics, imaging, treatment, and oncologic outcomes were compared between those who underwent restaging and those who went directly to surgery. Predictors of outcomes and cost effectiveness of restaging were determined. RESULTS: Of 224 patients, 146 underwent restaging. Six restaged patients had findings leading to a change in management. There was no difference in freedom from recurrence (P = 0.807) and overall survival (P = 0.684) based on restaging. Pretreatment carcinoembryonic antigen level >3 ng/mL (P = 0.010), clinical T stage 4 (P = 0.016), and pathologic T4 (P = 0.047) and N2 (P = 0.002) disease increased the risk of death, whereas adjuvant chemotherapy decreased the risk of death (P < 0.001) on multivariate analysis. Disease recurrence was lower with pelvic exenteration (P = 0.005) and in females (P = 0.039) and higher with pathologic N2 (P = 0.003) and N3 (P = 0.002) disease. The average cost of reimaging is $40,309 per change in management; however, $45 is saved per patient when downstream surgical costs are considered. CONCLUSIONS: Imaging restaging after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer rarely changes treatment and does not improve survival. In a subset of patients at higher risk for worse outcome, reimaging may be beneficial.

Trends in female surgeon authorship - The role of the middle author.

BACKGROUND: The objective of this study was to compare middle authorships between male and female general surgeons in the United States. METHODS: A stratified random sample of American College of Surgeons general surgery fellows was identified. Relevant author demographic, affiliation, and publication metrics were collected and compared across cohorts to determine which demographics were prognostic for each outcome variable. The primary endpoint was the number of middle author papers between genders. RESULTS: Males were more likely to enter into practice earlier (p<0.001), be fellowship-trained (p<0.001), obtain higher academic rank (p<0.001), and practice at more highly ranked academic institutions (p=0.019). Females had fewer middle author publications (p=0.044) and higher annual rates of first author publications (p=0.020) despite similar rates of total publications. CONCLUSIONS: Female surgeons hold the middle author position less frequently than males despite similar total publication numbers. Reasons for this finding should be the target of future study.