Impact of Adjuvant Chemotherapy on Resected Intraductal Papillary Mucinous Neoplasm-Derived Pancreatic Cancer: Results From an International Multicenter Study.

PURPOSE: The benefit of adjuvant therapy for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) remains unclear because of severely limited evidence. Although biologically distinct entities, adjuvant therapy practices for IPMN-derived PDAC are largely founded on pancreatic intraepithelial neoplasia-derived PDAC. We aimed to evaluate the role of adjuvant chemotherapy in IPMN-derived PDAC. METHODS: This international multicenter retrospective cohort study (2005-2018) was conceived at the Verona Evidence-Based Medicine meeting. Cox regressions were performed to identify risk-adjusted hazard ratios (HR) associated with overall survival (OS). Kaplan-Meier curves and log-rank tests were employed for survival analysis. Logistic regression was performed to identify factors motivating adjuvant chemotherapy administration. A decision tree was proposed and categorized patients into overtreated, undertreated, and optimally treated cohorts. RESULTS: In 1,031 patients from 16 centers, nodal disease (HR, 2.88, P < .001) and elevated (≥37 to <200 µ/mL, HR, 1.44, P = .006) or markedly elevated (≥200 µ/mL, HR, 2.53, P < .001) carbohydrate antigen 19-9 (CA19-9) were associated with worse OS. Node-positive patients with elevated CA19-9 had an associated 34.4-month improvement in median OS (P = .047) after adjuvant chemotherapy while those with positive nodes and markedly elevated CA19-9 had an associated 12.6-month survival benefit (P < .001). Node-negative patients, regardless of CA19-9, did not have an associated benefit from adjuvant chemotherapy (all P > .05). Based on this model, we observed undertreatment in 18.1% and overtreatment in 61.2% of patients. Factors associated with chemotherapy administration included younger age, R1-margin, poorer differentiation, and nodal disease. CONCLUSION: Almost half of patients with resected IPMN-derived PDAC may be overtreated or undertreated. In patients with node-negative disease or normal CA19-9, adjuvant chemotherapy is not associated with a survival benefit, whereas those with node-positive disease and elevated CA19-9 have an associated benefit from adjuvant chemotherapy. A decision tree was proposed. Randomized controlled trials are needed for validation.

Evaluating Receipt of Optimal Medical Therapy Amongst Structurally Disadvantaged Groups Undergoing Amputation.

OBJECTIVES: Optimal medical therapy (OMT) for peripheral artery disease (PAD) is associated with decreased major amputation and mortality. OMT has several components, including antiplatelet and high-intensity statin therapy, blood pressure control, etc. While there are disparities in receipt of OMT among PAD patients, it is unknown if patients from disadvantaged neighborhoods, measured by the area deprivation index (ADI), are less likely to be on OMT. METHODS: We performed a retrospective review of patients that underwent major lower extremity amputation between 2015 and 2019 at two large academic healthcare systems. Primary exposure was high ADI, defined as ADI ≥60th percentile, and secondary exposure was non-Hispanic Black (NHB) race. For each analysis, the primary outcome of interest was receipt of OMT, defined here as at least one antiplatelet agent and a high-intensity statin. The exposure outcome relationship was assessed using multivariable logistic regression. RESULTS: Among 354 patients with median age of 66 (interquartile range [IQR] 58-74), 267 (75.4%) were male, 219 (61.9%) identified as NHB and 116 (32.8%) as non-Hispanic White. Overall, 91 (25.7%) patients were on OMT at time of amputation despite 57.3% of the cohort being established with a vascular surgeon. Compared to those with low ADI, the category high ADI had a higher proportion of NHB patients (48.1% vs 70.3%, p= 0.001) and patients were more often hospitalized at the University-affiliated facilities (47.4% vs 63.0%, p= 0.004). High ADI was not associated with receipt of OMT prior to major amputation (adjusted odds ratio [aOR] 0.72, 95% confidence interval [CI] 0.42-1.24). In secondary analysis, NHB race was not associated with receipt of OMT. Stratification by facility type (Veterans Affairs and University-affiliated facilities) also showed no association between high ADI or race and receipt of OMT. CONCLUSIONS: Neighborhood economic well-being is not associated with receipt of OMT prior to major amputation. While the absence of socioeconomic disparities is notable, the proportion of patients on OMT is suboptimal. Care processes should be critically evaluated and quality measures potentially created to improve the rate of receipt of OMT among patients at risk for amputation.

Comparative Evaluation of Temporomandibular Joint Parameters in Unilateral and Bilateral Cleft Lip and Palate Patients Using Cone-Beam CT: Focus on Growing vs. Non-Growing Subjects.

BACKGROUND: Morphological differences in the temporomandibular joint (TMJ) are crucial for the treatment of patients with cleft lip and palate (CLP). This study aims to evaluate and compare the TMJ parameters in patients with unilateral and bilateral CLP across growing and non-growing age groups using cone-beam computed tomography (CBCT). METHODS: CBCT records from 57 patients (23 males and 34 females) aged 6-50 years with a diagnosed unilateral or bilateral CLP were analyzed. Patients were categorized into four groups: growing unilateral (UGCLP), growing bilateral (BGCLP), non-growing unilateral (UNGCLP), and non-growing bilateral (BNGCLP). Measurements of TMJ parameters, including the mandibular fossa, articular eminence inclination, joint spaces, and roof thickness of the glenoid fossa, were conducted using CBCT images. RESULTS: Significant differences were observed in the anterior joint space (AJS) and the roof of the glenoid fossa (RGF) between growing and non-growing unilateral cleft patients. Additionally, significant discrepancies were found in the articular eminence angle when comparing the cleft and non-cleft sides within the unilateral growing group. No significant differences were observed in TMJ parameters between the right and left sides among bilateral cleft patients. CONCLUSIONS: The study highlights distinct TMJ morphological differences between growing and non-growing patients with CLP, emphasizing the importance of age-specific considerations in the treatment planning and growth monitoring of these patients.

Complication Timing, Failure to Rescue, and Readmission After Inpatient Pediatric Surgery.

BACKGROUND: Complications are associated with postoperative mortality and readmission. However, the timing of complications relative to discharge and the extent to which timing is associated with failure to rescue (FTR) and readmission after pediatric surgery is unknown. Our goal was to describe the timing of complications relative to discharge after inpatient pediatric surgery and determine the association between complication timing, FTR, and unplanned readmission. MATERIALS AND METHODS: National cohort study of patients within the NSQIP-Pediatric database who underwent inpatient surgery (2012-2019). Complications were categorized based on when they occurred relative to discharge: only pre-discharge, only post-discharge, both. The association between perioperative outcomes and the timing of postoperative complications was evaluated with multivariable hierarchical regression. RESULTS: Among 378,551 patients, 30,213 (8.0%) had at least one postoperative complication. Relative to patients with pre-discharge complications, post-discharge complications were associated with significantly decreased odds of FTR (odds ratio 0.21, 95% confidence interval [0.15-0.28]) and significantly increased odds of readmission (odds ratio 19.37 [17.93-20.92]). Odds of FTR and readmission in patients with complications occurring both before and after discharge were similar to that of patients with only post-discharge complications. CONCLUSIONS: FTR and readmission are associated with complications occurring at different times relative to discharge (FTR primarily pre-discharge; readmission primarily post-discharge). This suggests a 'one size fits all' approach to surgical quality improvement may not be effective and different approaches are needed to address different quality indicators.

Top Ten Tips Palliative Care Clinicians Should Know Before Their Patient Undergoes Surgery.

Many seriously ill patients undergo surgical interventions. Palliative care clinicians may not be familiar with the nuances involved in perioperative care, however they can play a valuable role in enabling the delivery of patient-centered and goal-concordant perioperative care. The interval of time surrounding a surgical intervention is fraught with medical, psychosocial, and relational risks, many of which palliative care clinicians may be well-positioned to navigate. A perioperative palliative care consult may involve exploring gaps between clinician and patient expectations, facilitating continuity of symptom management or helping patients to designate a surrogate decision-maker before undergoing anesthesia. Palliative care clinicians may also be called upon to direct discussions around perioperative management of modified code status orders and to engage around the goal-concordance of proposed interventions. This article, written by a team of surgeons and anesthesiologists, many with subspecialty training in palliative medicine and/or ethics, offers ten tips to support palliative care clinicians and facilitate comprehensive discussion as they engage with patients and clinicians considering surgical interventions.

Automated Versus Semi-automated Lab Value Extraction for the VA Cardiac Surgical Quality Improvement Program.

INTRODUCTION: The Veterans Affairs Surgical Quality Improvement Program (VASQIP) trains surgical quality nurses (SQNs) at each Veterans Affairs (VA) hospital to extract or verify 187 variables from the medical record for all cardiac surgical cases. For ten preoperative laboratory values, VASQIP has a semiautomated (SA) system in which local lab values are automatically extracted, verified by SQNs, and lab values recorded at other VA facilities are manually extracted. The objective of this study was to develop and validate a method to automate the extraction of these ten preoperative laboratory values and compare results with the current SA method. MATERIALS AND METHODS: We developed methods to extract ten preoperative laboratory values and measurement dates from the VA Corporate Data Warehouse using Logical Observation Identifiers Names and Codes. Automated (A) versus SA information extraction was compared in terms of agreement, conformance to data definitions, proximity to surgery, and missingness. RESULTS: For surgeries with both A and SA lab values, the intraclass correlation coefficients for the ten variables ranged from 0.90 to 0.98. For several variables, the A method resulted in much lower rates of missing data (e.g., 2.4% versus 22.5% missing data for high-density lipoprotein) and eliminated out-of-date-range entries. CONCLUSIONS: Although SQN-extracted data are widely considered the gold standard within National Surgical Quality Improvement Programs, there may be advantages to fully automating extraction of lab values, including high congruence with SA SQN-extracted or verified values and lower rates of missingness and out-of-date-range data.

Craniofacial and Airway Morphology in Down Syndrome: A Cone Beam Computed Tomography Case Series Evaluation.

Background: Down syndrome (DS) is a genetic condition characterized by an extra copy of chromosome 21, resulting in various physical and cognitive features. This study aimed to comprehensively analyze the dental and craniofacial morphology of individuals with DS using Cone Beam Computed Tomography (CBCT). Methods: Six individuals with DS, comprising five males and one female aged 17 to 35 years, underwent CBCT scanning. Radiographic assessments included dentition, occlusion, paranasal sinuses, airway, skull bones, and suture calcification. Linear and angular cephalometric measurements were performed, and airway analysis was conducted using Dolphin 3D imaging software v.11. Results: The study revealed prognathic maxilla in five patients, prognathic mandible in four, and bimaxillary protrusion in two. Dental findings included microdontia, enamel hypoplasia, and congenitally missing teeth, with maxillary and mandibular third molars most commonly absent. Sinus abnormalities, delayed suture closure, and cervical spine anomalies were also observed. Conclusion: These findings contribute to a deeper understanding of DS-related craniofacial characteristics and emphasize the importance of considering these morphometric features in clinical management strategies for individuals with DS. This study's limited sample size underscores the significance of radiographic assessment in planning interventions such as cosmetic reconstructions, prosthetic rehabilitation, or orthodontic treatment for individuals with DS.

Association between type of index complication and outcomes after noncardiac surgery.

BACKGROUND: Failure to rescue, or the death of a patient after a surgical complication, largely occurs in patients who develop a cascade of postoperative complications. However, it is unclear whether there are specific types of index complications that are more strongly associated with failure to rescue, additional secondary complications, or other types of postoperative outcomes. This is a national cohort study of veterans who underwent noncardiac surgery at Veterans Affairs hospitals using data from the Veterans Affairs Surgical Quality Improvement Program (January 1, 2016 to September 30, 2021). Index complications were grouped into categories (cardiovascular, venous thromboembolism, pulmonary, bleeding/transfusion, renal, central nervous system, wound, sepsis, Clostridium difficile colitis, graft, or minor [defined as complications having an associated mortality rate <1%]). The association between type of index complication and failure to rescue, secondary complications, reoperation, and postoperative length of stay was evaluated with multivariable, hierarchical regression, and risk of death assessed with shared frailty modeling. RESULTS: Among 574,195 patients, 5.3% had at least 1 complication (of which 26.1% had secondary complications, and 8.2% had failure to rescue), and 4.5% had a reoperation. Secondary complication (5.0%-61.4%) and failure to rescue (0.8%-34.2%) rates varied by the type of index complication. Relative to index minor complications, index bleeding was most associated with secondary complication (subdistribution hazard ratio 1.4, 95% confidence interval [1.1-1.8]), index cardiac complications were most associated with failure to rescue (odds ratio 45.4 [34.5-59.7]), index graft complications were most associated with reoperation (odds ratio 96.0 [79.5-115.8]), and index pulmonary complications were associated with 2.6 times longer length of stay (incident rate ratio 2.6 [2.6-2.7]). Index cardiac and central nervous system complications were most strongly associated with risk of death (cardiac-hazard ratio 2.45, 95% confidence interval [2.14-2.81]; central nervous system-hazard ratio 1.84 [1.49-2.27]). CONCLUSION: Different types of index complications are associated with different outcome profiles. This suggests surgical quality improvement efforts should be tailored not only to the type of index complication to be addressed but also to the desired outcome to improve.

Pharmacokinetics and Tolerability of a Single Dose of Apraglutide, a Novel, Long-Acting, Synthetic glucagon-like peptide-2 Analog With a Unique Pharmacologic Profile, in Individuals With Impaired Renal Function.

Renal impairment is a common complication in patients with short bowel syndrome with intestinal failure (SBS-IF). Glucagon-like peptide-2 analogs, such as apraglutide, have been developed as a treatment option for SBS-IF. This study assessed the potential for apraglutide overexposure in individuals with severely impaired renal function versus healthy volunteers with normal renal function. In this phase 1, open-label, multicenter, nonrandomized, parallel-group study, a single dose of apraglutide 5 mg was administered subcutaneously to individuals with severely impaired renal function (<30 mL/min/1.73 m2) and healthy volunteers with normal renal function (≥90 mL/min/1.73 m2). Primary pharmacokinetic endpoints were maximum observed concentration (Cmax) and exposure to apraglutide (area under the curve [AUC] from time 0 to infinity [AUCinf], and AUC from time 0 to the last quantifiable concentration [AUClast]). Each group comprised 8 individuals. Results show that patients with severe renal impairment do not have increased apraglutide exposure. Apraglutide achieved a lower Cmax and AUCinf in individuals with severe renal impairment versus those with normal renal function (Cmax = 36.9 vs 59.5 ng/L; AUCinf = 3100 vs 4470 h · ng/mL, respectively). The respective geometric mean ratios were 0.620 and 0.693 for Cmax and AUCinf, and the upper bound of their 90% confidence intervals were <2, indicating patients with severe renal impairment were not overexposed to apraglutide versus those with normal renal function. Adverse events were mild or moderate in severity. Apraglutide does not require dose reduction for any degree of renal impairment and could be used in a broader patient population of renally impaired patients without dose adjustment.

Outcomes of Women Undergoing Noncardiac Surgery in Veterans Affairs Compared With Non-Veterans Affairs Care Settings.

Importance: Recent legislation facilitates veterans' ability to receive non-Veterans Affairs (VA) surgical care. Although veterans are predominantly male, the number of women receiving care within the VA has nearly doubled to 10% over the past decade and recent data comparing the surgical care of women in VA and non-VA care settings are lacking. Objective: To compare postoperative outcomes among women treated in VA hospitals vs private-sector hospitals. Design, Setting, and Participants: This coarsened exact-matched cohort study across 9 noncardiac specialties in the Veterans Affairs Surgical Quality Improvement Program (VASQIP) and American College of Surgeons National Surgical Quality Improvement Program (NSQIP) took place from January 1, 2016, to December 31, 2019. Multivariable Poisson models with robust standard errors were used to evaluate the association between VA vs private-sector care settings and 30-day mortality. Hospitals participating in American College of Surgeons NSQIP and VASQIP were included. Data analysis was performed in January 2023. Participants included female patients 18 years old or older. Exposures: Surgical care in VA or private-sector hospitals. Main Outcomes and Measures: Postoperative 30-day mortality and failure to rescue (FTR). Results: Among 1 913 033 procedures analyzed, patients in VASQIP were younger (VASQIP: mean age, 49.8 [SD, 13.0] years; NSQIP: mean age, 55.9 [SD, 16.9] years; P < .001) and although most patients in both groups identified as White, there were significantly more Black women in VASQIP compared with NSQIP (29.6% vs 12.7%; P < .001). The mean risk analysis index score was lower in VASQIP (13.9 [SD, 6.4]) compared with NSQIP (16.3 [SD, 7.8]) (P < .001 for both). Patients in the VA were more likely to have a preoperative acute serious condition (2.4% vs 1.8%: P < .001), but cases in NSQIP were more frequently emergent (6.9% vs 2.6%; P < .001). The 30-day mortality, complications, and FTR were 0.2%, 3.2%, and 0.1% in VASQIP (n = 36 762 procedures) as compared with 0.8%, 5.0%, and 0.5% in NSQIP (n = 1 876 271 procedures), respectively (all P < .001). Among 1 763 540 matched women (n = 36 478 procedures in VASQIP; n = 1 727 062 procedures in NSQIP), these rates were 0.3%, 3.7%, and 0.2% in NSQIP and 0.1%, 3.4%, and 0.1% in VASQIP (all P < .01). Relative to private-sector care, VA surgical care was associated with a lower risk of death (adjusted risk ratio [aRR], 0.41; 95% CI, 0.23-0.76). This finding was robust among women undergoing gynecologic surgery, inpatient surgery, and low-physiologic stress procedures. VA surgical care was also associated with lower risk of FTR (aRR, 0.41; 95% CI, 0.18-0.92) for frail or Black women and inpatient and low-physiologic stress procedures. Conclusions and Relevance: Although women comprise the minority of veterans receiving care within the VA, in this study, VA surgical care for women was associated with half the risk of postoperative death and FTR. The VA appears better equipped to meet the unique surgical needs and risk profiles of veterans, regardless of sex and health policy decisions, including funding, should reflect these important outcome differences.

Utility of Hospital Failure to Rescue for Analyzing Variation in Pediatric Postoperative Mortality.

OBJECTIVES: To evaluate the association between pediatric hospital performances in terms of failure to rescue (FTR), defined as postoperative mortality after a surgical complication, and mortality among patients without a surgical complication. DESIGN: Retrospective cohort study. SETTING: Forty-eight academic, pediatric hospitals; data obtained from Pediatric Health Information System database (Child Health Corporation of America, Shawnee Mission, KS) (2012-2020). PATIENTS: Children who underwent at least one of 57 high-risk operations associated with significant postoperative mortality. EXPOSURES: Hospitals were stratified into quintiles of reliability adjusted FTR (lower than average FTR in quintile 1 [Q1], higher than average FTR in quintile 5 [Q5]). Multivariable hierarchical regression was used to evaluate the association between hospital FTR performance and mortality among patients who did not have a surgical complication. MEASUREMENTS AND MAIN RESULTS: Among 203,242 children treated across 48 academic hospitals, the complication and overall postoperative mortality rates were 8.8% and 2.3%, respectively. Among patients who had a complication, the FTR rate was 8.8%. Among patients who did not have a complication, the mortality rate was 1.7%. There was a 6.5-fold increase in reliability adjusted FTR between the lowest and highest performing hospitals (lowest FTR hospital-2.7%; 95% CI [1.6-3.9]; highest FTR hospital-17.8% [16.8-18.8]). Complex chronic conditions were highly prevalent across hospitals (Q1, 72.7%; Q2, 73.8%; Q3, 72.2%; Q4, 74.0%; Q5, 74.8%; trend test p < 0.01). Relative to Q1 hospitals, the odds of mortality in the absence of a postoperative complication significantly increased by 33% at Q5 hospitals (odds ratio 1.33; 95% CI [1.07-1.66]). This association was consistent when limited to patients with a complex chronic condition and neonates. CONCLUSION: FTR may be a useful and valid surgical quality measure for pediatric surgery, even when considering patients without a postoperative complication. These findings suggest practices and processes for preventing FTR at high performing pediatric hospitals might help mitigate the risk of postoperative mortality even in the absence of a postoperative complication.

Hospital Variation in Mortality and Failure to Rescue after Surgery for High-Risk Neonatal Diagnoses.

INTRODUCTION: A large proportion of postoperative mortality after pediatric surgery occurs among neonates with specific high-risk diagnoses. The extent to which there is hospital-level mortality variation among patients with these diagnoses and whether this variation is associated with differences in failure to rescue (FTR) is unclear. METHODS: The Pediatric Health Information System® database (2012-2020) was used to identify patients who underwent surgery for eight high-risk neonatal diagnoses: gastroschisis; volvulus; necrotizing enterocolitis; intestinal atresia; meconium peritonitis; tracheoesophageal fistula; congenital diaphragmatic hernia; and perinatal intestinal perforation. Hospitals were stratified into tertiles of reliability-adjusted inpatient mortality rates (lower than average mortality - tertile 1 [T1]; higher than average mortality - tertile 3 [T3]). Multivariable hierarchical regression was used to evaluate the association between hospital-level, reliability-adjusted mortality and FTR. RESULTS: Overall, 20,838 infants were identified across 48 academic, pediatric hospitals. Adjusted hospital mortality rates ranged from 4.0% (95% CI, 0.0-8.2) to 16.3% (12.2-20.4). Median case volume (range, 80-1,238) and number of NICU beds (range, 24-126) were not significantly different across hospital tertiles. Compared to the hospitals with the lowest postoperative mortality (T1), the odds of FTR were significantly higher in hospitals with the highest (T3) postoperative mortality (odds ratio 1.97 [1.50-2.59]). CONCLUSIONS: Significant variation in neonatal hospital mortality for high-risk diagnoses does not appear to be explained by hospital structural characteristics. Rather, difference in FTR suggests quality improvement interventions targeting early recognition and management of postoperative complications could improve surgical quality and safety for high-risk neonatal care.

Case Sampling for Evaluating Hospital Postoperative Morbidity in US Surgical Quality Improvement Programs.

Importance: US surgical quality improvement (QI) programs use data from a systematic sample of surgical cases, rather than universal review of all cases, to assess and compare risk-adjusted hospital postoperative complication rates. Given decreasing postoperative complication rates over time and the types of cases eligible for abstraction, it is unclear whether case sampling is robust for identifying hospitals with higher than expected complications. Objective: To compare the assessment of hospital 30-day complication rates derived from sampling strategy used by some US surgical QI programs relative to universal review of all cases. Design, Setting, and Participants: This US hospital-level analysis took place from January 1, 2016, through September 30, 2020. Data analysis was performed from July 1, 2022, through December 21, 2022. Quarterly, risk-adjusted, 30-day complication observed to expected (O-E) ratios were calculated for each hospital using the sample (n = 502 730) and universal review (n = 1 725 364). Outlier hospitals (ie, those with higher than expected mortality) were identified using an O-E ratio significantly greater than 1.0. Patients 18 years and older who underwent a noncardiac operation at US Department of Veterans Affairs (VA) hospitals with a record in the VA Surgical Quality Improvement Program (systematic sample) and the VA Corporate Data Warehouse surgical domain (100% of surgical cases) were included. Main Outcome Measure: Thirty-day complications. Results: Most patients in both the representative sample and the universal sample were men (90.2% vs 91.2%) and White (74.7% vs 74.5%). Overall, 30-day complication rates were 7.6% and 5.3% for the sample and universal review cohorts, respectively (P < .001). Over 2145 hospital quarters of data, hospitals were identified as an outlier in 15.0% of quarters using the sample and 18.2% with universal review. Average hospital quarterly complication rates were 4.7%, 7.2%, and 7.4% for outliers identified using the sample only, universal review only, and concurrent identification in both data sources, respectively. For nonsampled cases, average hospital quarterly complication rates were 7.0% at outliers and 4.4% at nonoutliers. Among outlier hospital quarters in the sample, 54.2% were concurrently identified with universal review. For those identified with universal review, 44.6% were concurrently identified using the sample. Conclusion: In this observational study, case sampling identified less than half of hospitals with excess risk-adjusted postoperative complication rates. Future work is needed to ascertain how to best use currently collected data and whether alternative data collection strategies may be needed to better inform local QI efforts.

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.

Case Sampling vs Universal Review for Evaluating Hospital Postoperative Mortality in US Surgical Quality Improvement Programs.

Importance: Representative surgical case sampling, rather than universal review, is used by US Department of Veterans Affairs (VA) and private-sector national surgical quality improvement (QI) programs to assess program performance and to inform local QI and performance improvement efforts. However, it is unclear whether case sampling is robust for identifying hospitals with safety or quality concerns. Objective: To evaluate whether the sampling strategy used by several national surgical QI programs provides hospitals with data that are representative of their overall quality and safety, as measured by 30-day mortality. Design, Setting, and Participants: This comparative effectiveness study was a national, hospital-level analysis of data from adult patients (aged ≥18 years) who underwent noncardiac surgery at a VA hospital between January 1, 2016, and September 30, 2020. Data were obtained from the VA Surgical Quality Improvement Program (representative sample) and the VA Corporate Data Warehouse surgical domain (100% of surgical cases). Data analysis was performed from July 1 to December 21, 2022. Main Outcomes and Measures: The primary outcome was postoperative 30-day mortality. Quarterly, risk-adjusted, 30-day mortality observed-to-expected (O-E) ratios were calculated separately for each hospital using the sample and universal review cohorts. Outlier hospitals (ie, those with higher-than-expected mortality) were identified using an O-E ratio significantly greater than 1.0. Results: In this study of data from 113 US Department of Veterans Affairs hospitals, the sample cohort comprised 502 953 surgical cases and the universal review cohort comprised 1 703 140. The majority of patients in both the representative sample and the universal sample were men (90.2% vs 91.1%) and were White (74.7% vs 74.5%). Overall, 30-day mortality was 0.8% and 0.6% for the sample and universal review cohorts, respectively (P < .001). Over 2145 quarters of data, hospitals were identified as an outlier in 11.7% of quarters with sampling and in 13.2% with universal review. Average hospital quarterly 30-day mortality rates were 0.4%, 0.8%, and 0.9% for outlier hospitals identified using the sample only, universal review only, and concurrent identification in both data sources, respectively. For nonsampled cases, average hospital quarterly 30-day mortality rates were 1.0% at outlier hospitals and 0.5% at nonoutliers. Among outlier hospital quarters in the sample, 47.4% were concurrently identified with universal review. For those identified with universal review, 42.1% were concurrently identified using the sample. Conclusions and Relevance: In this national, hospital-level study, sampling strategies employed by national surgical QI programs identified less than half of hospitals with higher-than-expected perioperative mortality. These findings suggest that sampling may not adequately represent overall surgical program performance or provide stakeholders with the data necessary to inform QI efforts.

Treatment Disparities Partially Mediate Socioeconomic- and Race/Ethnicity-Based Survival Disparities in Stage I-II Hepatocellular Carcinoma.

BACKGROUND: Low socioeconomic status (SES) patients with early-stage hepatocellular carcinoma (HCC) receive procedural treatments less often and have shorter survival. Little is known about the extent to which these survival disparities result from treatment-related disparities versus other causal pathways. We aimed to estimate the proportion of SES-based survival disparities that are mediated by treatment- and facility-related factors among patients with stage I-II HCC. METHODS: We analyzed patients aged 18-75 years diagnosed with stage I-II HCC in 2008-2016 using the National Cancer Database. Inverse odds weighting mediation analysis was used to calculate the proportion mediated by three mediators: procedure type, facility volume, and facility procedural interventions offered. Intersectional analyses were performed to determine whether treatment disparities played a larger role in survival disparities among Black and Hispanic patients. RESULTS: Among 46,003 patients, 15.0% had low SES, 71.6% had middle SES, and 13.4% had high SES. Five-year overall survival was 46.9%, 39.9%, and 35.7% among high, middle, and low SES patients, respectively. Procedure type mediated 45.9% (95% confidence interval [CI] 31.1-60.7%) and 36.7% (95% CI 25.7-47.7%) of overall survival disparities for low and middle SES patients, respectively, which was more than was mediated by the two facility-level mediators. Procedure type mediated a larger proportion of survival disparities among low-middle SES Black (46.6-48.2%) and Hispanic patients (92.9-93.7%) than in White patients (29.5-29.7%). CONCLUSIONS: SES-based disparities in use of procedural interventions mediate a large proportion of survival disparities, particularly among Black and Hispanic patients. Initiatives aimed at attenuating these treatment disparities should be pursued.