Recognition of Refractory Benign Esophageal Strictures at Index Endoscopy: Creation of a Predictive Model.

BACKGROUND AND AIMS: Refractory benign esophageal strictures (RBES) are defined by inadequate response to dilation. Early recognition of RBES allows for earlier initiation of aggressive therapy potentially leading to less morbidity and cost. We sought to establish a predictive model for RBES. METHODS: Patients who underwent esophagogastroduodenoscopy (EGD) with esophageal dilation at Mayo Clinic Rochester were identified. In addition, a cohort of patients from a clinical database of patients with RBES managed with self-dilation was identified. Malignant strictures, Schatzki rings, and previously treated strictures were excluded. RBES was defined by inability to maintain a diameter ≥14mm over 5 dilation sessions. Multivariable logistic regression models were built to predict RBES. RESULTS: 128 patients with index EGD and esophageal dilation were identified, with 25 meeting RBES criteria. An additional 63 RBES patients were identified from the self-dilation cohort for a total of 88 RBES and 103 non-RBES patients. Multivariable analysis yielded a strong predictive model, with a c-statistic of 0.85, identifying stricture length ≥ 2cm, diameter ≤ 7mm and proximal/diffuse stricture location as associated with a higher risk for RBES. Patients without any of these risk factors had a 2% risk of RBES while those with all 3 risk factors had a risk of 73% for RBES. CONCLUSIONS: Risk of RBES can be predicted at index EGD based on stricture features. A predictive model for RBES was created based on readily available risk factors, which may guide an individualized therapeutic approach to patients with benign esophageal stricture, potentially reducing morbidity and cost.

Population Based Time Trends in the Epidemiology and Mortality of Gastroesophageal Junction and Esophageal Adenocarcinoma.

BACKGROUND: Limited data are available on the epidemiology of gastroesophageal junction adenocarcinoma (GEJAC), particularly in comparison to esophageal adenocarcinoma (EAC). With the advent of molecular non-endoscopic Barrett's esophagus (BE) detection tests which sample the esophagus and gastroesophageal junction, early detection of EAC and GEJAC has become a possibility and their epidemiology has gained importance. AIMS: We sought to evaluate time trends in the epidemiology and survival of patients with EAC and GEJAC in a population-based cohort. METHODS: EAC and GEJAC patients from 1976 to 2019 were identified using ICD 9 and 10 diagnostic codes from the Rochester Epidemiology Project (REP). Clinical data and survival status were abstracted. Poisson regression was used to calculate incidence rate ratios (IRR). Survival analysis and Cox proportional models were used to assess predictors of survival. RESULTS: We included 443 patients (287 EAC,156 GEJAC). The incidence of EAC and GEJAC during 1976-2019 was 1.40 (CI 1.1-1.74) and 0.83 (CI 0.61-1.11) per 100,000 people, respectively. There was an increase in the incidence of EAC (IRR = 2.45, p = 0.011) and GEJAC (IRR = 3.17, p = 0.08) from 2000 to 2004 compared to 1995-1999, plateauing in later time periods. Most patients had associated BE and presented at advanced stages, leading to high 5-year mortality rates (66% in EAC and 59% in GEJAC). Age and stage at diagnosis were predictors of mortality. CONCLUSION: The rising incidence of EAC/GEJAC appears to have plateaued somewhat in the last decade. However, both cancers present at advanced stages with persistently poor survival, underscoring the need for early detection.

Innovations in Screening Tools for Barrett's Esophagus and Esophageal Adenocarcinoma.

PURPOSE OF REVIEW: Esophageal adenocarcinoma (EAC) is a lethal disease with rapidly rising incidence. Screening for EAC and its metaplastic precursor, Barrett's esophagus (BE), followed by endoscopic surveillance and endoscopic treatment of dysplasia or early EAC are promising approaches to decreasing EAC incidence and EAC mortality. Historically, screening for EAC has been completed with a traditional per-oral esophagogastroduodenoscopy (EGD); however, this method has limitations including cost, tolerability, and accessibility. For this reason, much effort has been put forward to develop more effective, minimally invasive, and accessible BE and EAC screening tools. The purpose of this review is to describe recent developments of these novel tools. RECENT FINDINGS: While endoscopic alternatives such as transnasal endoscopy are cheaper and well tolerated, they have not gained acceptance. Non-endoscopic modalities namely, swallowable cell collection devices coupled with biomarker analysis have been found to have excellent performance characteristics, tolerability, and cost effectiveness. In this article, we provide an update on innovative developments in EAC/BE screening modalities including transnasal endoscopy, capsule endomicroscopy, swallowable cell collection devices, and exhaled volatile organic compound analyses.

Rapid vaccination using an acetalated dextran microparticulate subunit vaccine confers protection against triplicate challenge by bacillus anthracis.

PURPOSE: A rapid immune response is required to prevent death from Anthrax, caused by Bacillus anthracis. METHOD: We formulated a vaccine carrier comprised of acetalated dextran microparticles encapsulating recombinant protective antigen (rPA) and resiquimod (a toll-like receptor 7/8 agonist). RESULTS: We were able to protect against triplicate lethal challenge by vaccinating twice (Days 0, 7) and then aggressively challenging on Days 14, 21, 28. A significantly higher level of antibodies was generated by day 14 with the encapsulated group compared to the conventional rPA and alum group. Antibodies produced by the co-encapsulated group were only weakly-neutralizing in toxin neutralization; however, survival was not dependent on toxin neutralization, as all vaccine formulations survived all challenges except control groups. Post-mortem culture swabs taken from the hearts of vaccinated groups that did not produce significant neutralizing titers failed to grow B. anthracis. CONCLUSIONS: Results indicate that protective antibodies are not required for rapid protection; indeed, cytokine results indicate that T cell protection may play a role in protection from anthrax. We report the first instance of use of a particulate carrier to generate a rapid protective immunity against anthrax.

COVID-19, the Gut, and Nutritional Implications.

PURPOSE OF REVIEW: Our goal is to provide the most recent and accurate scientific evidence available regarding COVID-19's interaction with the human gut and the role of nutrition/nutritional supplementation in the prevention and treatment of the disease. RECENT FINDINGS: Gastrointestinal symptoms of COVID-19 are common and often persist even after classically defined illness resolution. Nutritional status and content have been shown to impact infection risk and severity. Well-balanced diets are associated with decreased infection risk/severity, and early nutrition is associated with better outcomes in the critically ill. No specific vitamin supplementation regimen has shown consistent benefit for infection treatment or prevention. The impact of COVID-19 extends far past the pulmonary system, and its impact on the gut should not be ignored. For those interested in adopting lifestyle modifications to prevent severe COVID-19 infection/side effects, consideration should be made for adoption of a well-balanced diet (e.g., Mediterranean style), utilization of probiotics, and addressing nutritional/vitamin deficiencies. Future, high-quality research is needed in this arena.

Low Risk for Ross River Virus Infection in Expeditionary Forces Training in Australia Demonstrated by a Serological Survey of Marine Rotational Force-Darwin, 2012-2018.

On an annual basis, approximately 2,500 U.S. Marines and Sailors deploy to Australia on 6-month training rotations. Active duty personnel are generally immunologically naïve to pathogens endemic to tropical Australia, a vulnerability that could significantly impact medical readiness. To estimate risk, we screened 628 post-deployment serum samples by ELISA for serological evidence of infection with Ross River virus (RRV), a mosquito-borne alphavirus endemic to tropical Australia. Samples that tested above the negative cutoff value were paired with their pre-deployment samples to identify deployment-related seroconversion. These paired samples were further investigated with a live virus neutralization assay to assess specificity. There was a single RRV seroconversion and 49 false-positive results. In the context of these analyses (i.e., limited sample numbers collected between the months of March and October), we assess the RRV risk to MRFD as low and encourage strategies such as avoiding and preventing mosquito bites to mitigate the existing risk over widespread vaccination programs, if an FDA-approved vaccine becomes available. The Panbio RRV ELISA lacks the specificity to draw conclusions based on seropositivity from large-scale surveys of U.S. personnel.

Long-Term Outcomes and Risk of Pancreatic Cancer in Intraductal Papillary Mucinous Neoplasms.

Importance: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can give rise to pancreatic cancer (PC). Limited population data exist on their prevalence, natural history, or risk of malignant transformation (IPMN-PC). Objective: To fill knowledge gaps in epidemiology of IPMNs and associated PC risk by estimating population prevalence of IPMNs, associated PC risk, and proportion of IPMN-PC. Design, Setting, and Participants: : This retrospective cohort study was conducted in Olmsted County, Minnesota. Using the Rochester Epidemiology Project (REP), patients aged 50 years and older with abdominal computed tomography (CT) scans between 2000 and 2015 were randomly selected (CT cohort). All patients from the REP with PC between 2000 and 2019 were also selected (PC cohort). Data were analyzed from November 2021 through August 2023. Main outcomes and Measures: CIs for PC incidence estimates were calculated using exact methods with the Poisson distribution. Cox models were used to estimate age, sex, and stage-adjusted hazard ratios for time-to-event end points. Results: The CT cohort included 2114 patients (1140 females [53.9%]; mean [SD] age, 68.6 [12.1] years). IPMNs were identified in 231 patients (10.9%; 95% CI, 9.7%-12.3%), most of which were branch duct (210 branch-duct [90.9%], 16 main-duct [6.9%], and 5 mixed [2.2%] IPMNs). There were 5 Fukuoka high-risk (F-HR) IPMNs (2.2%), 39 worrisome (F-W) IPMNs (16.9%), and 187 negative (F-N) IPMNs (81.0%). After a median (IQR) follow-up of 12.0 (8.1-15.3) years, 4 patients developed PC (2 patients in F-HR and 2 patients in F-N groups). The PC incidence rate per 100 person years for F-HR IPMNs was 34.06 incidents (95% CI, 4.12-123.02 incidents) and not significantly different for patients with F-N IPMNs compared with patients without IPMNs (0.16 patients; 95% CI, 0.02-0.57 patients vs 0.11 patients; 95% CI, 0.06-0.17 patients; P = .62). The PC cohort included 320 patients (155 females [48.4%]; mean [SD] age, 72.0 [12.3] years), and 9.8% (95% CI, 7.0%-13.7%) had IPMN-PC. Compared with 284 patients with non-IPMN PC, 31 patients with IPMN-PC were older (mean [SD] age, 76.9 [9.2] vs 71.3 [12.5] years; P = .02) and more likely to undergo surgical resection (14 patients [45.2%] vs 60 patients [21.1%]; P = .003) and more-frequently had nonmetastatic PC at diagnosis (20 patients [64.5%] vs 130 patients [46.8%]; P = .047). Patients with IPMN-PC had better survival (adjusted hazard ratio, 0.62; 95% CI, 0.40-0.94; P = .03) than patients with non-IPMN PC. Conclusions and Relevance: In this study, CTs identified IPMNs in approximately 10% of patients aged 50 years or older. PC risk in patients with F-N IPMNs was low and not different compared with patients without IPMNs; approximately 10% of patients with PC had IPMN-PC, and they had better survival compared with patients with non-IPMN PC.

Systematic review with meta-analysis: liver transplant provides survival benefit in patients with acute on chronic liver failure.

BACKGROUND: Data on liver transplantation (LT) in acute on chronic liver failure (ACLF) are scanty. AIM: To perform meta-analysis on outcomes after LT for ACLF compared with ACLF patients not receiving LT or with LT recipients for indications other than ACLF. METHODS: We pooled data from 12 studies on LT outcomes among ACLF patients. RESULTS: Among nine studies, 22 238 LT recipients for ACLF vs 30 791 for non-ACLF were younger by 1.1 years, less males (64% vs 66.4%), and higher model for end-stage disease score by 14.5 (14.4-14.6), P < 0.01 for all. Post-transplant patient survival at 30 day, 90 day, 6 months, 1 year and 5 years was lower in ACLF: 96.2% vs 98.1%, 92.6% vs 96.2%, 89.9% vs 94.4%, 86.0% vs 91.9%, 66.9% vs 80.7% respectively, P < 0.01 for all. ACLF patients stayed longer in hospital and ICU by 5.7 and 10.5 days respectively, P < 0.001, with similar post-transplant complications [74.4% vs 55.5%, P = 0.12]. Among three studies, 441 LT recipients for ACLF vs 301 ACLF patients not selected for LT had better 30 day and 1 year survival: 95.2% vs 60% and 85.3% vs 28.2% respectively, P < 0.001. Outcomes were worse in ACLF-3 and better for ACLF-1 and ACLF-2 patients at the time of LT. CONCLUSION: In this pooled analysis with a large sample size across the globe, LT for select patients with ACLF provided survival benefit. However, larger prospective studies are needed to further refine selection criteria, especially for ACLF-3 patients as basis for improving outcomes and optimal utilisation of scarce donor pool.

Serological evidence of Burkholderia pseudomallei infection in U.S. Marines who trained in Australia from 2012-2014: a retrospective analysis of archived samples.

Infection with the gram-negative bacterium Burkholderia pseudomallei can result in a life-threatening disease known as melioidosis. Historically, melioidosis was a common infection in military forces serving in Southeast Asia, and it has the potential to have a serious impact on force health readiness. With the U.S. Department of Defense's increasing strategic and operational focus across the Pacific Theater, melioidosis is an increasingly important issue from a force health protection perspective. U.S. Marines deploy annually to Darwin, Australia, a "hyperendemic" region for B. pseudomallei, to engage in training exercises. In an effort to assess the risk of B. pseudomallei infection to service personnel in Australia, 341 paired samples, representing pre- and post-deployment samples of Marines who trained in Australia, were analyzed for antibodies against B. pseudomallei antigens. Serological evidence of possible deployment-related infection with B. pseudomallei was found in 13 Marines. Future prospective studies are required to further characterize the risk to service members deployed to melioidosis endemic areas.

Acetalated Dextran Microparticulate Vaccine Formulated via Coaxial Electrospray Preserves Toxin Neutralization and Enhances Murine Survival Following Inhalational Bacillus Anthracis Exposure.

Subunit formulations are regarded as the safest type of vaccine, but they often contain a protein-based antigen that can result in significant challenges, such as preserving antigenicity during formulation and administration. Many studies have demonstrated that encapsulation of protein antigens in polymeric microparticles (MPs) via emulsion techniques results in total IgG antibody titers comparable to alum formulations, however, the antibodies themselves are non-neutralizing. To address this issue, a coaxial electrohydrodynamic spraying (electrospray) technique is used to formulate a microparticulate-based subunit anthrax vaccine under conditions that minimize recombinant protective antigen (rPA) exposure to harsh solvents and high shear stress. rPA and the adjuvant resiquimod are encapsulated either in separate or the same acetalated dextran MPs. Using a murine model, the electrospray formulations lead to higher IgG2a subtype titers as well as comparable total IgG antibody titers and toxin neutralization relative to the FDA-approved vaccine (BioThrax). BioThrax provides no protection against a lethal inhalational challenge of the highly virulent Ames Bacillus anthracis anthrax strain, whereas 50% of the mice vaccinated with separately encapsulated electrospray MPs survive. Overall, this study demonstrates the potential use of electrospray for encapsulating protein antigens in polymeric MPs.

Oropharyngeal aspiration of Burkholderia mallei and Burkholderia pseudomallei in BALB/c mice.

Burkholderia mallei and Burkholderia pseudomallei are potentially lethal pathogens categorized as biothreat agents due, in part, to their ability to be disseminated via aerosol. There are no protective vaccines against these pathogens and treatment options are limited and cumbersome. Since disease severity is greatest when these agents are inhaled, efforts to develop pre- or post-exposure prophylaxis focus largely on inhalation models of infection. Here, we demonstrate a non-invasive and technically simple method for affecting the inhalational challenge of BALB/c mice with B. pseudomallei and B. mallei. In this model, two investigators utilized common laboratory tools such as forceps and a micropipette to conduct and characterize an effective and reproducible inhalational challenge of BALB/c mice with B. mallei and B. pseudomallei. Challenge by oropharyngeal aspiration resulted in acute disease. Additionally, 50% endpoints for B. pseudomallei K96243 and B. mallei ATCC 23344 were nearly identical to published aerosol challenge methods. Furthermore, the pathogens disseminated to all major organs typically targeted by these agents where they proliferated. The pro-inflammatory cytokine production in the proximal and peripheral fluids demonstrated a rapid and robust immune response comparable to previously described murine and human studies. These observations demonstrate that OA is a viable alternative to aerosol exposure.

Immune response to two different dosing schedules of the anthrax vaccine precipitated (AVP) vaccine.

A pilot study compared the immune response of regular (0, 3, 6, 32 weeks) and extended (0, 10, 13, 32 weeks) schedules of the UK anthrax vaccine (anthrax vaccine precipitated, AVP). Concentrations of antibodies to protective antigen (PA) were higher (p<0.05) among recipients of the extended (n=7) versus regular schedule (n=6) at week 32, and 2 weeks after the second and third vaccinations. Toxin neutralisation assay levels and anti-lethal factor antibodies followed patterns similar to anti-PA antibodies. Extending the interval between the first two AVP vaccinations may produce a stronger immune response, but persistence of this effect needs further study.