Social Vulnerability Index and Survivorship after Colorectal Cancer Resection.

BACKGROUND: Race and socioeconomic status incompletely identify patients with colorectal cancer (CRC) at the highest risk for screening, treatment, and mortality disparities. Social vulnerability index (SVI) was designed to delineate neighborhoods requiring greater support after external health stressors, summarizing socioeconomic, household, and transportation barriers by census tract. SVI is implicated in lower cancer center use and increased complications after colectomy, but its influence on long-term prognosis is unknown. Herein, we characterized relationships between SVI and CRC survival. STUDY DESIGN: Patients undergoing resection of stage I to IV CRC from January 2010 to May 2023 within an academic health system were identified. Clinicopathologic characteristics were abstracted using institutional National Cancer Database and NSQIP. Addresses from electronic health records were geocoded to SVI. Overall survival and cancer-specific survival were compared using Kaplan-Meier and Cox proportional hazards methods. RESULTS: A total of 872 patients were identified, comprising 573 (66%) patients with colon tumor and 299 (34%) with rectal tumor. Patients in the top SVI quartile (32%) were more likely to be Black (41% vs 13%, p < 0.001), carry less private insurance (39% vs 48%, p = 0.02), and experience greater comorbidity (American Society of Anesthesiologists physical status III: 86% vs 71%, p < 0.001), without significant differences by acuity, stage, or CRC therapy. In multivariable analysis, high SVI remained associated with higher all-cause (hazard ratio 1.48, 95% CI 1.12 to 1.96, p < 0.01) and cancer-specific survival mortality (hazard ratio 1.71, 95% CI 1.10 to 2.67, p = 0.02). CONCLUSIONS: High SVI was independently associated with poorer prognosis after CRC resection beyond the perioperative period. Acknowledging needs for multi-institutional evaluation and elaborating causal mechanisms, neighborhood-level vulnerability may inform targeted outreach in CRC care.

Defining the Need for Causal Inference to Understand the Impact of Social Determinants of Health: A Primer on Behalf of the Consortium for the Holistic Assessment of Risk in Transplantation (CHART).

Objective: This study aims to introduce key concepts and methods that inform the design of studies that seek to quantify the causal effect of social determinants of health (SDOH) on access to and outcomes following organ transplant. Background: The causal pathways between SDOH and transplant outcomes are poorly understood. This is partially due to the unstandardized and incomplete capture of the complex interactions between patients, their neighborhood environments, the tertiary care system, and structural factors that impact access and outcomes. Designing studies to quantify the causal impact of these factors on transplant access and outcomes requires an understanding of the fundamental concepts of causal inference. Methods: We present an overview of fundamental concepts in causal inference, including the potential outcomes framework and direct acyclic graphs. We discuss how to conceptualize SDOH in a causal framework and provide applied examples to illustrate how bias is introduced. Results: There is a need for direct measures of SDOH, increased measurement of latent and mediating variables, and multi-level frameworks for research that examine health inequities across multiple health systems to generalize results. We illustrate that biases can arise due to socioeconomic status, race/ethnicity, and incongruencies in language between the patient and clinician. Conclusions: Progress towards an equitable transplant system requires establishing causal pathways between psychosocial risk factors, access, and outcomes. This is predicated on accurate and precise quantification of social risk, best facilitated by improved organization of health system data and multicenter efforts to collect and learn from it in ways relevant to specialties and service lines.

Development of a prospective biliary dashboard to compare performance and surgical cost.

BACKGROUND: Transparency around surgeon level data may align healthcare delivery with quality care for patients. Biliary surgery includes numerous procedures performed by both general surgeons and subspecialists alike. Cholecystectomy is a common surgical procedure and an optimal cohort to measure quality outcomes within a healthcare system. METHODS: Data were collected for 5084 biliary operations performed by 68 surgeons in 11 surgical divisions in a health system including a tertiary academic hospital, two regional community hospitals, and two ambulatory surgery centers. A privacy protected dashboard was developed to compare surgeon performance and cost between July 2018 and June 2022. A sample cohort of patients ≥ 18 years who underwent cholecystectomy were compared by operative time, cost, and 30-day outcomes. RESULTS: Over 4 years, 4568 cholecystectomy procedures were performed by 57 surgeons. Operations were done by 57 surgeons in four divisions and included 3846 (84.2%) laparoscopic cholecystectomies, 601 (13.2%) laparoscopic cholecystectomies with cholangiogram, and 121 (2.6%) open cholecystectomies. Patients were admitted from the emergency room in 2179 (47.7%) cases while 2389 (52.3%) cases were performed in the ambulatory setting. Individual surgeons were compared to peers for volume, intraoperative data, cost, and outcomes. Cost was lowest at ambulatory surgery centers, yet only 4.2% of elective procedures were performed at these facilities. Prepackaged kits with indocyanine green were more expensive than cholangiograms that used iodinated contrast. The rate of emergency department visits was lowest when cases were performed at ambulatory surgery centers. CONCLUSION: Data generated from clinical dashboards can inform surgeons as to how they compare to peers regarding quality metrics such as cost, time, and complications. In turn, this may guide strategies to standardize care, optimize efficiency, provide cost savings, and improve outcomes for cholecystectomy procedures. Future application of clinical dashboards can assist surgeons and administrators to define value-based care.

Development, Deployment, and Implementation of a Machine Learning Surgical Case Length Prediction Model and Prospective Evaluation.

OBJECTIVE: To implement a machine learning model using only the restricted data available at case creation time to predict surgical case length for multiple services at different locations. BACKGROUND: The operating room is one of the most expensive resources in a health system, estimated to cost $22 to $133 per minute and generate about 40% of hospital revenue. Accurate prediction of surgical case length is necessary for efficient scheduling and cost-effective utilization of the operating room and other resources. METHODS: We introduced a similarity cascade to capture the complexity of cases and surgeon influence on the case length and incorporated that into a gradient-boosting machine learning model. The model loss function was customized to improve the balance between over- and under-prediction of the case length. A production pipeline was created to seamlessly deploy and implement the model across our institution. RESULTS: The prospective analysis showed that the model output was gradually adopted by the schedulers and outperformed the scheduler-predicted case length from August to December 2022. In 33,815 surgical cases across outpatient and inpatient platforms, the operational implementation predicted 11.2% fewer underpredicted cases and 5.9% more cases within 20% of the actual case length compared with the schedulers and only overpredicted 5.3% more. The model assisted schedulers to predict 3.4% more cases within 20% of the actual case length and 4.3% fewer underpredicted cases. CONCLUSIONS: We created a unique framework that is being leveraged every day to predict surgical case length more accurately at case posting time and could be potentially utilized to deploy future machine learning models.

Estimation of Surgery Durations Using Machine Learning Methods-A Cross-Country Multi-Site Collaborative Study.

The scheduling of operating room (OR) slots requires the accurate prediction of surgery duration. We evaluated the performance of existing Moving Average (MA) based estimates with novel machine learning (ML)-based models of surgery durations across two sites in the US and Singapore. We used the Duke Protected Analytics Computing Environment (PACE) to facilitate data-sharing and big data analytics across the US and Singapore. Data from all colorectal surgery patients between 1 January 2012 and 31 December 2017 in Singapore and, 1 January 2015 to 31 December 2019 in the US were used, and 7585 cases and 3597 single and multiple procedure cases from Singapore and US were included. The ML models were based on categorical gradient boosting (CatBoost) models trained on common data fields shared by both institutions. The procedure codes were based on the Table of Surgical Procedure (TOSP) (Singapore) and the Current Procedural Terminology (CPT) codes (US). The two types of codes were mapped by surgical experts. The CPT codes were then transformed into the relative value unit (RVU). The ML models outperformed the baseline MA models. The MA, scheduled durations and procedure codes were found to have higher loadings as compared to surgeon factors. We further demonstrated the use of the Duke PACE in facilitating data-sharing and big data analytics.

Development and Performance of a Clinical Decision Support Tool to Inform Resource Utilization for Elective Operations.

Importance: Hospitals ceased most elective procedures during the height of coronavirus disease 2019 (COVID-19) infections. As hospitals begin to recommence elective procedures, it is necessary to have a means to assess how resource intensive a given case may be. Objective: To evaluate the development and performance of a clinical decision support tool to inform resource utilization for elective procedures. Design, Setting, and Participants: In this prognostic study, predictive modeling was used on retrospective electronic health records data from a large academic health system comprising 1 tertiary care hospital and 2 community hospitals of patients undergoing scheduled elective procedures from January 1, 2017, to March 1, 2020. Electronic health records data on case type, patient demographic characteristics, service utilization history, comorbidities, and medications were and abstracted and analyzed. Data were analyzed from April to June 2020. Main Outcomes and Measures: Predicitons of hospital length of stay, intensive care unit length of stay, need for mechanical ventilation, and need to be discharged to a skilled nursing facility. These predictions were generated using the random forests algorithm. Predicted probabilities were turned into risk classifications designed to give assessments of resource utilization risk. Results: Data from the electronic health records of 42 199 patients from 3 hospitals were abstracted for analysis. The median length of stay was 2.3 days (range, 1.3-4.2 days), 6416 patients (15.2%) were admitted to the intensive care unit, 1624 (3.8%) received mechanical ventilation, and 2843 (6.7%) were discharged to a skilled nursing facility. Predictive performance was strong with an area under the receiver operator characteristic ranging from 0.76 to 0.93. Sensitivity of the high-risk and medium-risk groupings was set at 95%. The negative predictive value of the low-risk grouping was 99%. We integrated the models into a daily refreshing Tableau dashboard to guide decision-making. Conclusions and Relevance: The clinical decision support tool is currently being used by surgical leadership to inform case scheduling. This work shows the importance of a learning health care environment in surgical care, using quantitative modeling to guide decision-making.

Multidisciplinary Approach to Clostridium difficile Infection in Adult Surgical Patients.

BACKGROUND: In 2017, our hospital was identified as a high outlier for postoperative Clostridium difficile infections (CDIs) in the American College of Surgeons NSQIP semi-annual report. The Department of Surgery initiated a CDI task force with representation from Surgery, Infectious Disease, Pharmacy, and Performance Services to analyze available data, identify opportunities for improvement, and implement strategies to reduce CDIs. STUDY DESIGN: Strategies to reduce CDIs were reviewed from the literature and the following multidisciplinary strategies were initiated: antimicrobial stewardship optimization of perioperative order sets to avoid cefoxitin and fluoroquinolone use was completed; penicillin allergy assessment and skin testing were implemented concomitantly; increased use of ultraviolet disinfectant strategies for terminal cleaning of CDI patient rooms; increased hand hygiene and personal protection equipment signage, as well as monitoring in high-risk CDI areas; improved diagnostic stewardship by an electronic best practice advisory to reduce inappropriate CDI testing; education through surgical grand rounds; and routine data feedback via NSQIP and National Healthcare Safety Network CDI reports. RESULTS: The observed rate of CDIs decreased from 1.27% in 2016 to 0.91% in 2017. Cefoxitin and fluoroquinolone use decreased. Clostridium difficile infection testing for patients on laxatives decreased. Terminal cleaning with ultraviolet light increased. Handwashing compliance increased. Data feedback to stakeholders was established. CONCLUSIONS: Our multidisciplinary CDI reduction program has demonstrated significant reductions in CDIs. It is effective, straightforward to implement and monitor, and can be generalized to high-outlier institutions.

Characterization of pathogenesis of and immune response to Burkholderia pseudomallei K96243 using both inhalational and intraperitoneal infection models in BALB/c and C57BL/6 mice.

Burkholderia pseudomallei, the etiologic agent of melioidosis, is a Gram negative bacterium designated as a Tier 1 threat. This bacterium is known to be endemic in Southeast Asia and Northern Australia and can infect humans and animals by several routes. Inhalational melioidosis has been associated with monsoonal rains in endemic areas and is also a significant concern in the biodefense community. There are currently no effective vaccines for B. pseudomallei and antibiotic treatment can be hampered by non-specific symptomology and also the high rate of naturally occurring antibiotic resistant strains. Well-characterized animal models will be essential when selecting novel medical countermeasures for evaluation prior to human clinical trials. Here, we further characterize differences between the responses of BALB/c and C57BL/6 mice when challenged with low doses of a low-passage and well-defined stock of B. pseudomallei K96243 via either intraperitoneal or aerosol routes of exposure. Before challenge, mice were implanted with a transponder to collect body temperature readings, and daily body weights were also recorded. Mice were euthanized on select days for pathological analyses and determination of the bacterial burden in selected tissues (blood, lungs, liver, and spleen). Additionally, spleen homogenate and sera samples were analyzed to better characterize the host immune response after infection with aerosolized bacteria. These clinical, pathological, and immunological data highlighted and confirmed important similarities and differences between these murine models and exposure routes.

A Comparison of the Adaptive Immune Response between Recovered Anthrax Patients and Individuals Receiving Three Different Anthrax Vaccines.

Several different human vaccines are available to protect against anthrax. We compared the human adaptive immune responses generated by three different anthrax vaccines or by previous exposure to cutaneous anthrax. Adaptive immunity was measured by ELISPOT to count cells that produce interferon (IFN)-γ in response to restimulation ex vivo with the anthrax toxin components PA, LF and EF and by measuring circulating IgG specific to these antigens. Neutralising activity of antisera against anthrax toxin was also assayed. We found that the different exposures to anthrax antigens promoted varying immune responses. Cutaneous anthrax promoted strong IFN-γ responses to all three antigens and antibody responses to PA and LF. The American AVA and Russian LAAV vaccines induced antibody responses to PA only. The British AVP vaccine produced IFN-γ responses to EF and antibody responses to all three antigens. Anti-PA (in AVA and LAAV vaccinees) or anti-LF (in AVP vaccinees) antibody titres correlated with toxin neutralisation activities. Our study is the first to compare all three vaccines in humans and show the diversity of responses against anthrax antigens.

A Yersinia pestis YscN ATPase mutant functions as a live attenuated vaccine against bubonic plague in mice.

Yersinia pestis is the causative agent responsible for bubonic and pneumonic plague. The bacterium uses the pLcr plasmid-encoded type III secretion system to deliver virulence factors into host cells. Delivery requires ATP hydrolysis by the YscN ATPase encoded by the yscN gene also on pLcr. A yscN mutant was constructed in the fully virulent CO92 strain containing a nonpolar, in-frame internal deletion within the gene. We demonstrate that CO92 with a yscN mutation was not able to secrete the LcrV protein (V-Antigen) and attenuated in a subcutaneous model of plague demonstrating that the YscN ATPase was essential for virulence. However, if the yscN mutant was complemented with a functional yscN gene in trans, virulence was restored. To evaluate the mutant as a live vaccine, Swiss-Webster mice were vaccinated twice with the ΔyscN mutant at varying doses and were protected against bubonic plague in a dose-dependent manner. Antibodies to F1 capsule but not to LcrV were detected in sera from the vaccinated mice. These preliminary results suggest a proof-of-concept for an attenuated, genetically engineered, live vaccine effective against bubonic plague.

Monoclonal antibodies directed against protective antigen of Bacillus anthracis enhance lethal toxin activity in vivo.

Protective antigen (PA) from Bacillus anthracis binds to cellular receptors, combines with lethal factor (LF) forming lethal toxin (LeTx), and facilitates the translocation of LF into the cytosol. LeTx is cytotoxic for J774A.1 cells, a murine macrophage cell line, and causes death of Fisher 344 rats when injected intravenously. PA is also the major protective component in anthrax vaccines. Antibody-dependent enhancement has been reported for several viral diseases, a bacterial infection, and for B. anthracis LeTx in vitro cytotoxicity. Further screening of our 73 PA monoclonal antibodies (mAbs) identified a total of 17 PA mAbs that enhanced in vitro cytotoxicity at suboptimal concentrations of LeTx. A competitive binding enzyme-linked immunosorbent assay showed that these 17 PA mAbs identified eight different antigenic regions on PA. Eight of the 17 PA mAbs that enhanced LeTx in vitro cytoxicity were examined for their activity in vivo. Of the eight mAbs that were injected intravenously with a sublethal concentration of LeTx into male Fisher 344 rats, four mAbs enhanced the lethality of LeTx and resulted in the death of animals, whereas control animals did not succumb to intoxication. This is the first demonstration that PA mAbs can enhance LeTx intoxication in vivo.

A short course of antibiotic treatment is effective in preventing death from experimental inhalational anthrax after discontinuing antibiotics.

BACKGROUND: Postexposure prophylaxis of inhalational anthrax requires prolonged antibiotic therapy or antibiotics and vaccination. The duration of treatment for established anthrax is controversial, because retained spores may germinate and cause disease after antibiotics are discontinued. Using rhesus macaques, we determined whether a short course of antibiotic treatment, as opposed to prophylaxis, could effectively treat inhalational anthrax and prevent disease caused by the germination of spores after discontinuation of antibiotics. METHODS: Two groups of 10 rhesus macaques were exposed to an aerosol dose of Bacillus anthracis spores. Animals in group 1 received ciprofloxacin prophylaxis beginning 1-2 h after exposure. Those in group 2 began receiving ciprofloxacin after becoming bacteremic, and treatment was continued for 10 days. When each group 2 animal completed 10 days of therapy, the prophylactic antibiotic was discontinued in the paired group 1 animal. RESULTS: In group 1 (prophylaxis), no deaths occurred during antibiotic treatment, but only 2 (20%) of 10 animals survived after antibiotics were discontinued. In contrast, in group 2 (treatment), 3 deaths occurred during antibiotic treatment, but all 7 animals (100%) alive after 10 days of therapy survived when antibiotics were discontinued. CONCLUSIONS: In the treatment of inhalational anthrax, the prolonged course of antibiotics required to achieve prophylaxis may not be necessary to prevent anthrax that results from the germination of retained spores after the discontinuation of antibiotics.

Multiple asparagine deamidation of Bacillus anthracis protective antigen causes charge isoforms whose complexity correlates with reduced biological activity.

Protective antigen is essential for the pathology of Bacillus anthracis and is the proposed immunogen for an improved human anthrax vaccine. Known since discovery to comprise differentially charged isoforms, the cause of heterogeneity has eluded specific structural definition until now. Recombinant protective antigen (rPA) contains similar isoforms that appear early in fermentation and are mostly removed through purification. By liquid chromatography-tandem mass spectrometry sequencing of the entire protein and inspection of spectral data for amino acid modifications, pharmaceutical rPA contained measurable deamidation at seven of its 68 asparagine residues. A direct association between isoform complexity and percent deamidation was observed such that each decreased with purity and increased with protein aging. Position N537 consistently showed the highest level of modification, although its predicted rate of deamidation ranked 10th by theoretical calculation, and other asparagines of higher predicted rates were observed to be unmodified. rPA with more isoforms and greater deamidation displayed lower activities for furin cleavage, heptamerization, and holotoxin formation. Lethal factor-mediated macrophage toxicity correlated inversely with deamidation at residues N466 and N408. The described method measures deamidation without employing theoretical isotopic distributions, comparison between differentially treated samples or computational predictions of reactivity rates, and is broadly applicable to the characterization of other deamidated proteins.

Lateral amygdaloid nucleus expansion in adult rats is associated with exposure to prenatal stress.

Anxiety disorders in humans have been associated with chronic activation of the hypothalamic-pituitary-adrenal axis and changes in the volume of the amygdala. Interest in the etiology of anxiety disorders has led us and others to investigate the effects of prenatal stress on the brain development of adult male rat offspring. Prenatally stressed rats represent a promising animal model for anxiety disorders in that they have already been characterized as having both upregulated corticotropin-releasing factor (CRF) brain biochemistry and altered, more fearful, behaviors. Consistent with this, there is now evidence that prenatal stress also has an impact on the development of CRFergic neurons in the hypothalamic paraventricular nucleus and neurogenesis in the hippocampus. At this time, little information about the impact of prenatal stress on amygdala anatomy has been presented. Here we asked whether prenatal stress also has an impact on the development of the amygdala, because this structure plays a direct role in the emotions of anxiety and fear. Stereological measures of well-defined subregions of amydgdaloid nuclei revealed significantly expanded dimensions of the lateral nucleus in prenatally stressed offspring, due, in part, to more neurons and glia. These data may have direct import for the effect of adverse early life experiences and the etiology of anxiety disorders in humans. They also imply that early experiences may not be "grown out of" with development; in fact, the opposite might be true-adverse early life experiences may set developmental events into motion in the brain that last a lifetime.