Estimating the Effect of Coronavirus Disease 2019 (COVID-19) Vaccination and Infection Variant on Post-COVID-19 Venous Thrombosis or Embolism Risk.

Background: Previous research has shown that vaccination reduces risk of post-coronavirus disease 2019 (COVID-19) venous thrombosis or embolism (VTE), but the effect of vaccine boosting on post-COVID-19 VTE risk reduction is unclear. We sought to estimate the effect of COVID-19 vaccination on the risk of post-COVID-19 VTE and to examine if the magnitude of this association differed among variant eras. Methods: We performed a case-control study of Military Health System (MHS) beneficiaries who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2020-2022. Cases were defined as those with medically attended VTE within 90 days after their first positive SARS-CoV-2 test; controls were defined as SARS-CoV-2 infections without incident VTE by 90 days. Multivariate logistic regression estimated the odds of post-SARS-CoV-2 VTE based on pre-COVID-19 vaccine status, adjusting for other VTE risk factors. Results: A total of 4646 MHS beneficiaries were included in this analysis; 1370 received a primary vaccine series and a further 790 received at least 1 booster at time of infection; 71 had VTE within 90 days of SARS-CoV-2 infection. Those who were vaccinated had lower odds of VTE (adjusted odds ratio [95% confidence interval]) compared to the unvaccinated following infection (primary series: 0.28 [.13-.62]; booster dose: 0.06 [.01-.46]). Post-COVID-19 VTE risk was lowest during the Omicron era, but VTEs were too rare to examine for an interaction of variant era and vaccine effect. Conclusions: Among MHS beneficiaries, COVID-19 vaccination was associated with a reduced risk of post-COVID-19 VTE diagnosis; estimated risk reduction was larger among those who received a booster.

Cost-Effectiveness Analysis of Current Treatment Options for Eosinophilic Esophagitis.

BACKGROUND AND AIMS: The management strategies for eosinophilic esophagitis (EoE) include proton pump inhibitors (PPI), swallowed topical steroids (tCS), elimination diets, and the biologic agent dupilumab, although there remains little guidance on the selection of initial treament. We performed cost-effectiveness analyses to compare these approaches of first-line therapy. METHODS: A Markov model was constructed from a payer perspective to evaluate the cost-effectiveness of first-line therapies for EoE, including PPI, tCS, and six-food elimination diet (SFED), with.crossover in treatments for primary and secondary non-response. The primary outcome was incremental cost-effectiveness ratio (ICER) at two- and five-year time horizons. Secondary analyses included modeling from a societal perspective that also accounted for patient-specific costs, as well as a separate simplified model comparing dupilumab to tCS and PPI. RESULTS: In the base-case scenario (five-year time horizon), the average costs were SFED:$15,296.81, PPI:$16,153.77, and tCS:$20,975.33 as initial therapy, with SFED being the dominant strategy (more effective/less costly), while PPI offered the lowest cost on a two-year time horizon. From a societal perspective, PPI was the dominant initial strategy on both two- and five-year time horizons. Amongst pharmacologic therapies, PPI was the most cost-effective first-line option. Dupilumab was not cost-effective relative to tCS, unless the quarterly cost is reduced from $7,311 to $2,038.50 per price threshold analysis under permissive modeling conditions. CONCLUSIONS: SFED was the most effective/least costly first-line therapy from payer perspective, while PPI was more cost-effective from societal perspective. PPI is also the most cost-effective pharmacologic strategy. Dupilumab requires substantial cost reductions to be considered cost-effective first-line pharmacotherapy.

Pre-analytic decrease of phenylalanine in plasma of patients with phenylketonuria treated with pegvaliase.

Treatment of phenylketonuria (PKU) has evolved since the initial introduction of a phenylalanine (Phe) restricted diet. The most recent option for adults affected with PKU is treatment with an alternate enzyme, phenylalanine ammonia lyase (PAL), that metabolizes excess Phe. Proper management of all patients with PKU relies on accurate measurement of Phe levels in blood, to comply with guidance intended to minimize the neurological symptoms. Recently, our laboratory was notified of discrepant results for a patient with PKU who is treated with pegvaliase. Two specimens were collected at the same time but yielded unexpectedly different Phe concentrations. After exclusion of specimen mix-ups or analytical errors, we suspected that there was residual pegvaliase activity in the specimens continuing to degrade Phe after collection. To investigate this possibility, we performed spiking studies that showed the degradation of Phe over time at ambient temperatures. Sample preparation by protein crash appears to deactivate pegvaliase and prevents further Phe degradation. However, because pegvaliase deactivation would be required immediately following blood collection, appropriate mitigation measures must be implemented, including stringent pre-analytical requirements, alternate sample matrices such as dried blood spots, or point of care testing. Until then, health care professionals need to be cautious in their interpretation of Phe levels in their patients with PKU that are treated with pegvaliase.

Impact of Body Composition on Esophagogastric Junction Opening Measures: Discordant FLIP and Manometric Findings Are More Common With Increased Body Mass Index.

INTRODUCTION: Increased intra-abdominal pressure in patients with elevated body mass index (BMI) may affect measurements of esophagogastric junction (EGJ) opening. METHODS: Findings from adult patients who underwent both impedance planimetry with functional luminal imaging probe (FLIP) and high-resolution manometry (HRM) were compared by BMI. RESULTS: Among patients with no EGJ outflow obstruction on HRM, abnormal EGJ classifications on FLIP were more common among those with elevated than normal BMI (61.1% vs 31.6%, P = 0.037). DISCUSSION: Discordant results between FLIP and HRM on EGJ opening are more common in patients with elevated BMI. Body composition may impact EGJ function and measures on current testing modalities.

Quantified Metrics of Gastric Emptying Delay by Glucagon-Like Peptide-1 Agonists: A Systematic Review and Meta-Analysis With Insights for Periprocedural Management.

INTRODUCTION: Divergent recommendations for periprocedural management of glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) medications rely on limited evidence. We performed a systematic review and meta-analysis to provide quantitative measures of gastric emptying relevant to mechanisms of weight loss and to periprocedural management of GLP-1 RA. We hypothesized that the magnitude of gastric emptying delay would be low and of limited clinical significance to procedural sedation risks. METHODS: A protocolized search identified studies on GLP-1 RA that quantified gastric emptying measures. Pooled estimates using random effects were presented as a weighted mean difference with 95% confidence intervals (CIs). Univariate meta-regression was performed to assess the influence of GLP-1 RA type, short-acting vs long-acting mechanism of action, and duration of treatment on gastric emptying. RESULTS: Fifteen studies met the inclusion criteria. Five studies (n = 247) utilized gastric emptying scintigraphy. Mean T 1/2 was 138.4 minutes (95% CI 74.5-202.3) for GLP-1 RA vs 95.0 minutes (95% CI 54.9-135.0) for placebo, with a pooled mean difference of 36.0 minutes (95% CI 17.0-55.0, P < 0.01, I2 = 79.4%). Ten studies (n = 411) utilized the acetaminophen absorption test, with no significant delay in gastric emptying measured by T max , area under the curve (AUC) 4hr , and AUC 5hr with GLP-1 RA ( P > 0.05). On meta-regression, the type of GLP-1 RA, mechanism of action, and treatment duration did not impact gastric emptying ( P > 0.05). DISCUSSION: While a gastric emptying delay of ∼36 minutes is quantifiable on GLP-1 RA medications, it is of limited magnitude relative to standard periprocedural fasting periods. There were no substantial differences in gastric emptying on modalities reflective of liquid emptying (acetaminophen absorption test), particularly at time points relevant to periprocedural care.

Centrally Distributed Adiposity as a Modifiable Risk Factor for Fecal Incontinence: United States Population-based Analysis.

BACKGROUND AND AIMS: Fecal incontinence (FI) is highly prevalent with substantial impacts on quality of life and health care utilization. The impact of obesity on FI remains unclear, with differing conclusions using body mass index (BMI) as a risk factor. We aimed to determine the association between obesity and FI, and whether this relationship is dependent on the distribution of adiposity (waist circumference-to-height ratio [WHtR]). METHODS: This was a population-based analysis of the National Health and Nutrition Examination Survey, including participants who responded to the bowel health survey in 2005 to 2010. FI was defined by the accidental bowel leakage of solid stool, liquid, or mucus at least once in the past month. Stepwise multivariable logistic regression models were constructed to assess risk factors for FI. RESULTS: A total of 7606 participants were included, with an overall FI prevalence of 9.2%. When stratified by quartiles of body measurements, FI was increasingly prevalent from the 1st to the 4th quartile for both WHtR (range, 5.3%-12.5%) and BMI (range, 7.1%-10.5%). WHtR was associated with FI and was a stronger predictor than BMI in all quartiles of body measurement. On multivariable analysis, WHtR remained a significant predictor of FI comparing the 4th with the 1st quartile of body measurements (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.11-2.80; P = .017), whereas BMI was not. A WHtR cutoff of >0.592 optimized the Youden index in prediction of FI in the overall sample. CONCLUSION: WHtR was independently associated with increased odds of FI in this nationally representative sample of United States adults, whereas BMI was not consistently correlated. This suggests bowel continence may depend more on how body mass is distributed.

Physiologic measurements of cognitive load in clinical reasoning.

OBJECTIVES: Cognitive load is postulated to be a significant factor in clinical reasoning performance. Monitoring physiologic measures, such as heart rate variability (HRV) may serve as a way to monitor changes in cognitive load. The pathophysiology of why HRV has a relationship to cognitive load is unclear, but it may be related to blood pressure changes that occur in a response to mental stress. METHODS: Fourteen residents and ten attendings from Internal Medicine wore Holter monitors and watched a video depicting a medical encounter before completing a post encounter form used to evaluate their clinical reasoning and standard psychometric measures of cognitive load. Blood pressure was obtained before and after the encounter. Correlation analysis was used to investigate the relationship between HRV, blood pressure, self-reported cognitive load measures, clinical reasoning performance scores, and experience level. RESULTS: Strong positive correlations were found between increasing HRV and increasing mean arterial pressure (MAP) (p=0.01, Cohen's d=1.41). There was a strong positive correlation with increasing MAP and increasing cognitive load (Pearson correlation 0.763; 95 % CI [; 95 % CI [-0.364, 0.983]). Clinical reasoning performance was negatively correlated with increasing MAP (Pearson correlation -0.446; 95 % CI [-0.720, -0.052]). Subjects with increased HRV, MAP and cognitive load were more likely to be a resident (Pearson correlation -0.845; 95 % CI [-0.990, 0.147]). CONCLUSIONS: Evaluating HRV and MAP can help us to understand cognitive load and its implications on trainee and physician clinical reasoning performance, with the intent to utilize this information to improve patient care.

Allergic phenotype identified on allergen testing is associated with proton pump inhibitor nonresponse in eosinophilic esophagitis.

BACKGROUND AND AIM: Food/environmental allergens have been associated with eosinophilic esophagitis (EoE); however, the correlation between allergy profiles and disease responsiveness to proton pump inhibitor (PPI) therapy remains unclear. We aimed to assess the association between food/environmental allergies identified on allergen testing and histologic response to PPI in patients with treatment-naive EoE. METHODS: Adults with newly diagnosed EoE who underwent formal testing for food/environmental allergies at a tertiary center were included. All patients underwent twice-daily PPI for 8 weeks with subsequent repeat endoscopy and biopsy to assess histologic response. Patients with <15 eosinophils/hpf on post-PPI mucosal biopsies were classified as responders (PPI-r-EoE), while those with ≥15 eosinophils/hpf were nonresponders (PPI-nr-EoE). RESULTS: Sixty-one patients met inclusion criteria (21 PPI-r-EoE vs 40 PPI-nr-EoE). Demographic, clinical, and endoscopic finding variables were similar between groups. Positive food allergen test was more prevalent among PPI-nr-EoE patients (82.5% vs 42.9%, P = 0.003). On multivariable analysis, positive food allergen testing remained an independent predictor for PPI nonresponse (aOR 0.15, CI: 0.04-0.58, P = 0.0006). Positive environmental allergen testing was highly prevalent, with no significant differences between groups (77.5% vs 95.2%, P = 0.14). However, higher number of positive environmental allergens (23.3% [≥5 allergens] vs 73.3% [<5 allergens], P = 0.003) and specific aeroallergens correlated with PPI-nr-EoE. CONCLUSION: Positive food allergy testing and increased environmental allergens predicted lower likelihood of histologic response to PPI in EoE. Our findings support an allergic phenotype of EoE that may less likely respond to PPI therapy. Formal allergen testing may play a role in therapy selection and tailored management in EoE.

Decreased Self-reported Physical Fitness Following SARS-CoV-2 Infection and the Impact of Vaccine Boosters in a Cohort Study.

Background: The long-term effects of coronavirus disease 2019 (COVID-19) on physical fitness are unclear, and the impact of vaccination on that relationship is uncertain. Methods: We compared survey responses in a 1-year study of US military service members with (n = 1923) and without (n = 1591) a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We fit Poisson regression models to estimate the association between history of SARS-CoV-2 infection and fitness impairment, adjusting for time since infection, demographics, and baseline health. Results: The participants in this analysis were primarily young adults aged 18-39 years (75%), and 71.5% were male. Participants with a history of SARS-CoV-2 infection were more likely to report difficulty exercising (38.7% vs 18.4%; P < .01), difficulty performing daily activities (30.4% vs 12.7%; P < .01), and decreased fitness test (FT) scores (42.7% vs 26.2%; P < .01) than those without a history of infection. SARS-CoV-2-infected participants were at higher risk of these outcomes after adjusting for other factors (unvaccinated: exercising: adjusted risk ratio [aRR], 3.99; 95% CI, 3.36-4.73; activities: aRR, 5.02; 95% CI, 4.09-6.16; FT affected: aRR, 2.55; 95% CI, 2.19-2.98). Among SARS-CoV-2-positive participants, full vaccination before infection was associated with a lower risk of post-COVID-19 fitness impairment (fully vaccinated: exercise: aRR, 0.81; 95% CI, 0.70-0.95; activities: aRR, 0.76; 95% CI, 0.64-0.91; FT: aRR, 0.87; 95% CI, 0.76-1.00; boosted: exercise: aRR, 0.62; 95% CI, 0.51-0.74; activities: aRR, 0.52; 95% CI, 0.41-0.65; FT: aRR, 0.59; 95% CI, 0.49-0.70). Conclusions: In this study of generally young, healthy military service members, SARS-CoV-2 infection was associated with lower self-reported fitness and exercise capacity; vaccination and boosting were associated with lower risk of self-reported fitness loss.

Pre-Lung transplant reflux testing demonstrates high prevalence of gastroesophageal reflux in cystic fibrosis and reduces chronic rejection risk.

BACKGROUND: Gastroesophageal reflux (GER) has been associated with poor outcomes after lung transplantation for chronic lung disease, including increased risk of chronic rejection. GER is common in cystic fibrosis (CF), but factors influencing the likelihood of pre-transplant pH testing, and the impact of testing on clinical management and transplant outcomes in patients with CF are unknown. AIM: To evaluate the role of pre-transplant reflux testing in the evaluation of lung transplant candidates with CF. METHODS: This was a retrospective study from 2007-2019 at a tertiary medical center that included all patients with CF undergoing lung transplant. Patients with pre-transplant anti-reflux surgery were excluded. Baseline characteristics (age at transplantation, gender, race, body mass index), self-reported GER symptoms prior to transplantation, and pre-transplant cardiopulmonary testing results, were recorded. Reflux testing consisted of either 24-h pH- or combined multichannel intraluminal impedance and pH monitoring. Post-transplant care included a standard immunosuppressive regimen, and regular surveillance bronchoscopy and pulmonary spirometry in accordance with institutional practice as well as in symptomatic patients. The primary outcome of chronic lung allograft dysfunction (CLAD) was defined clinically and histologically per International Society of Heart and Lung Transplantation criteria. Statistical analysis was performed with Fisher's exact test to assess differences between cohorts, and time-to-event Cox proportional hazards modeling. RESULTS: After applying inclusion and exclusion criteria, a total of 60 patients were included in the study. Among all CF patients, 41 (68.3%) completed reflux monitoring as part of pre-lung transplant evaluation. Objective evidence of pathologic reflux, defined as acid exposure time > 4%, was found in 24 subjects, representing 58% of the tested group. CF patients with pre-transplant reflux testing were older (35.8 vs 30.1 years, P = 0.01) and more commonly reported typical esophageal reflux symptoms (53.7% vs 26.3%, P = 0.06) compared to those without reflux testing. Other patient demographics and baseline cardiopulmonary function did not significantly differ between CF subjects with and without pre-transplant reflux testing. Patients with CF were less likely to undergo pre-transplant reflux testing compared to other pulmonary diagnoses (68% vs 85%, P = 0.003). There was a decreased risk of CLAD in patients with CF who underwent reflux testing compared to those who did not, after controlling for confounders (Cox Hazard Ratio 0.26; 95%CI: 0.08-0.92). CONCLUSION: Pre-transplant reflux testing revealed high prevalence of pathologic reflux in CF patients and was associated with decreased risk of CLAD. Systematic reflux testing may enhance outcomes in this patient population.

The effect of geographic origin and destination on congenital heart disease outcomes: a retrospective cohort study.

BACKGROUND: Congenital heart disease (CHD) is a common and significant birth defect, frequently requiring surgical intervention. For beneficiaries of the Department of Defense, a new diagnosis of CHD may occur while living at rural duty stations. Choice of tertiary care center becomes a function of geography, referring provider recommendations, and patient preference. METHODS: Using billing data from the Military Health System over a 5-year period, outcomes for beneficiaries age < 10 years undergoing CHD surgery were compared by patient origin (rural versus urban residence) and the distance to treatment (patient's home and the treating tertiary care center). These beneficiaries include children of active duty, activated reserves, and federally activated National Guard service members. Analysis of the outcomes were adjusted for procedure complexity risk. Treatment centers were further stratified by annual case volume and whether they publicly reported results in the society of thoracic surgery (STS) outcomes database. RESULTS: While increasing distance was associated with the cost of admission, there was no associated risk of inpatient mortality, one year mortality, or increased length of stay. Likewise, rural origination was not significantly associated with target outcomes. Patients traveled farther for STS-reporting centers (STS-pr), particularly high-volume centers. Such high-volume centers (> 50 high complexity cases annually) demonstrated decreased one year mortality, but increased cost and length of stay. CONCLUSIONS: Together, these findings contribute to the national conversation of rural community medicine versus regionalized subspecialty care; separation of patients between rural areas and more urban locations for initial CHD surgical care does not increase their mortality risk. In fact, traveling to high volume centers may have an associated mortality benefit.

Association Between Opioid Use and Outpatient Visits for Dysphagia: An Analysis of the National Ambulatory Medical Care Survey in 2008-2018.

INTRODUCTION: Opioid-induced esophageal dysfunction has been described with characteristic manometric patterns, but the population burden of dysphagia attributable to opioid use remains unclear. METHODS: The National Ambulatory Medical Care Survey from 2008 to 2018 was used to assess the relationship between opioid use and outpatient visits for dysphagia. RESULTS: After controlling for potential confounders, there were no significant difference in ambulatory visits for dysphagia between opioid users and nonusers (adjusted odds ratio = 0.98, confidence interval: 0.59-1.65). DISCUSSION: No correlation between opioid use and ambulatory visits for dysphagia was found in a nationwide sample. Opioid-related manometric changes may be clinically relevant only in a small proportion of patients.

Examining the Nocebo Effect in Trials of Neuromodulators for Use in Disorders of Gut-Brain Interaction.

INTRODUCTION: Nocebo effects are believed to influence the rate of reported adverse events (AE) and subject withdrawal in both the treatment and placebo groups of randomized clinical trials (RCT). Neuromodulators are commonly prescribed to treat disorders of gut-brain interaction (DGBI), but adherence to these medications is often limited by side effects such as headache, dry mouth, fatigue, and altered bowel habits. We performed a systematic review and meta-analysis to assess the proportion and risk difference of patients who experienced side effects leading to withdrawal in the placebo arm vs the treatment arm of RCT of neuromodulators for DGBI. We also sought to estimate the risk of developing any AE in the placebo arm of these studies and the rate of specific individual AEs. METHODS: We searched MEDLINE, Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials Searches to identify RCT that included terms for DGBI and for commonly prescribed neuromodulators. We calculated pooled proportions of patients experiencing an AE leading to withdrawal in the active treatment group vs the placebo group with 95% confidence intervals (CI), the pooled proportions of patients experiencing any AE, the pooled proportions of patients experiencing specific AE such as dizziness and headache, the pooled proportions of patients experiencing severe AE, and corresponding pooled risk differences with 95% CI. RESULTS: There were 30 RCT included representing 2,284 patients with DGBI. Twenty-seven RCT reported data on AE leading to withdrawal. The pooled proportion of total patients with AE leading to withdrawal in the placebo group was 4% (95% CI 0.02-0.04). The pooled proportion of patients with AE leading to withdrawal who received neuromodulators was 9% (95% CI 0.06-0.13). In the 12 studies reporting data on patients experiencing at least 1 AE, the pooled proportion of patients experiencing any AE in the placebo group was 18% (95% CI 0.08-0.30), compared with 43% (95% CI 0.24-0.63) in the neuromodulator group. Thus, approximately 44% of the rate of withdrawal (0.04/0.09) and 42% of the rate reporting any side effects (0.18/0.43) in the neuromodulator group may be attributed to nocebo effects in the right context. Subgroup analysis by sex, medication class, risk of bias, and specific DGBI revealed differing withdrawal rates. There was no statistically significant difference in patients experiencing individual AE of dizziness, headache, or diarrhea. Rates of dry mouth, fatigue, and constipation were higher in treatment groups compared with those in placebo groups. DISCUSSION: Patients with DGBI in RCT randomized to placebo groups frequently experience AE and AE that lead to withdrawal consistent with a strong nocebo effect. Nonspecific AE such as dizziness, headaches, and diarrhea occurred similarly in patients receiving placebo compared with those receiving neuromodulators.

A Nationwide Survey of Gastroenterology Program Leadership Regarding Implementation of the GI Hospitalist Model.

BACKGROUND: Academic gastroenterology (GI) hospitalists are increasing, however the impacts on fellowship training and clinical care are unclear. Motivations for implementation of the GI hospitalist model are uninvestigated. AIMS: We aimed to determine the prevalence of GI hospitalists, explore motivations for and against adoption of a GIH model, and investigate the model's effects on fellowship training. METHODS: Leadership at current general GI fellowships were surveyed about current staffing models, as well as effects and perceptions of the hospitalist model. RESULTS: There was a total of 52 (26%) respondents and 12 (23%) reported having a GI hospitalist at their institution. A majority of respondents stated burnout and reduced time on service for other faculty was a primary reason for hiring a GI hospitalist. DISCUSSION: The largest perceived benefit of a hospitalist is reduced burnout and time on service for outpatient GI faculty. Many respondents also believed a GIH would improve fellowship education and quality of inpatient care.

Utilizing Google Trends to Assess Worldwide Interest in Irritable Bowel Syndrome and Commonly Associated Treatments.

BACKGROUND: Examining the prevalence of irritable bowel syndrome (IBS) across regions has been challenging given significant methodological heterogeneity. AIMS: We aimed to perform a uniform assessment of the global burden of IBS using data from Google Trends, a novel, online tool. METHODS: Google Trends measures popularity of a search term in a given week compared to popularity of all search terms in that week, calculated as relative search volume (RSV). We compiled data on the popularity of IBS and its treatments across 173 countries between 2014 and 2018. We compared Google Trends popularity for IBS with prior epidemiological prevalence data, while controlling for gross domestic product (GDP) per capita and physician density. RESULTS: Of the 173 countries with Google Trends data, 137 countries also had data for GDP per capita and physician density. Worldwide popularity of IBS as a search topic increased from 79 to 89 (13% increase by RSV) over the 5-year period between 2014 and 2018. Country-specific change in IBS RSV ranged from - 35% (Nigeria) to + 64% (Pakistan). There was poor correlation between the Google Trends data and prior epidemiological data (0.08, Pearson correlation, p = 0.64). Popularity of the low-FODMAP diet increased the most among 8 common therapies (RSV 41 to 89, 117% increase). CONCLUSIONS: Google Trends is a novel tool that can complement traditional epidemiological methods in gastrointestinal disease. Future research is needed to assess its utility and accuracy as a measure of disease burden across different gastrointestinal diseases.