Impact of Helicobacter pylori Infection and Treatment on Colorectal Cancer in a Large, Nationwide Cohort.

PURPOSE: Helicobacter pylori is the most common cause of infection-associated cancer worldwide. We aimed to evaluate the impact of H. pylori infection and treatment on colorectal cancer (CRC) incidence and mortality. PATIENTS: US Veterans who completed H. pylori testing between 1999 and 2018. METHODS: We conducted a retrospective cohort analysis among adults within the Veterans Health Administration who completed testing for H. pylori. The primary exposures were (1) H. pylori test result (positive/negative) and (2) H. pylori treatment (untreated/treated) among H. pylori-positive individuals. The primary outcomes were CRC incidence and mortality. Follow-up started at the first H. pylori testing and continued until the earliest of incident or fatal CRC, non-CRC death, or December 31, 2019. RESULTS: Among 812,736 individuals tested for H. pylori, 205,178 (25.2%) tested positive. Being H. pylori-positive versus H. pylori-negative was associated with higher CRC incidence and mortality. H. pylori treatment versus no treatment was associated with lower CRC incidence and mortality (absolute risk reduction 0.23%-0.35%) through 15-year follow-up. Being H. pylori-positive versus H. pylori-negative was associated with an 18% (adjusted hazard ratio [adjusted HR], 1.18 [95% CI, 1.12 to 1.24]) and 12% (adjusted HR, 1.12 [95% CI, 1.03 to 1.21]) higher incident and fatal CRC risk, respectively. Individuals with untreated versus treated H. pylori infection had 23% (adjusted HR, 1.23 [95% CI, 1.13 to 1.34]) and 40% (adjusted HR, 1.40 [95% CI, 1.24 to 1.58]) higher incident and fatal CRC risk, respectively. The results were more pronounced in the analysis restricted to individuals with nonserologic testing. CONCLUSION: H. pylori positivity may be associated with small but statistically significant higher CRC incidence and mortality; untreated individuals, especially those with confirmed active infection, appear to be most at risk.

Helicobacter pylori Burden in the United States According to Individual Demographics and Geography: A Nationwide Analysis of the Veterans Healthcare System.

BACKGROUND & AIMS: There are no contemporary large-scale studies evaluating the burden of Helicobacter pylori in the United States according to detailed demographics. The primary objective was to evaluate H pylori positivity in a large national healthcare system according to individual demographics and geography. METHODS: We conducted a nationwide retrospective analysis of adults in the Veterans Health Administration who completed H pylori testing between 1999 and 2018. The primary outcome was H pylori positivity overall, as well as according to zip code-level geography, race, ethnicity, age, sex, and time period. RESULTS: Among 913,328 individuals (mean, 58.1 years; 90.2% male) included between 1999 and 2018, H pylori was diagnosed in 25.8%. Positivity was highest in non-Hispanic black (median, 40.2%; 95% confidence interval [CI], 40.0%-40.5%) and Hispanic (36.7%; 95% CI, 36.4%-37.1%) individuals and lowest in non-Hispanic white individuals (20.1%; 95% CI, 20.0%-20.2%). Although H pylori positivity declined in all racial and ethnic groups over the timeframe, the disproportionate burden of H pylori in non-Hispanic black and Hispanic compared with non-Hispanic white individuals persisted. Approximately 4.7% of the variation in H pylori positivity was explained by demographics, with race and ethnicity accounting for the vast majority. CONCLUSIONS: The burden of H pylori is substantial in the United States among veterans. These data should (1) motivate research aimed at better understanding why marked demographic differences in H pylori burden persist so that mitigating interventions may be implemented and (2) guide resource allocation to optimize H pylori testing and eradication in high-risk groups.

Bile Acid Sequestrant Use and Gastric Cancer: A National Retrospective Cohort Analysis.

INTRODUCTION: Bile acids have been implicated in gastric carcinogenesis. We hypothesized that bile acid sequestrant medication (BAM) use is associated with a lower gastric cancer (GC) incidence. METHODS: We assembled a cohort of veterans receiving longitudinal care within the Veterans Health Administration between 2000 and 2020 who completed testing for Helicobacterpylori . The index date was the date of completed H. pylori testing. The primary exposure was the number of filled BAM prescription(s) in the 5 years before the index date. The primary outcome was incident GC, stratified by anatomic subsite. Follow-up began at the index date and ended at the earliest of GC, death, after 2 years of follow-up, or the study end (May 31, 2020). We used Kaplan-Meier curves to visualize differences in GC incidence by exposure group and multivariable Cox proportional hazards models to estimate the association between BAM exposure and anatomic site-specific GC. RESULTS: Among 417,239 individuals (89% male, mean age 54 years, 63% non-Hispanic White), 4,916 (1.2%) filled at least one BAM prescription, 2,623 of whom filled ≥4. Compared with unexposed individuals, those with ≥4 BAM fills before entry had a lower incidence (adjusted hazard ratio 0.71; 95% confidence interval, 0.37-1.36) of GC, but confidence intervals were wide. Results were consistent irrespective of GC anatomic site. DISCUSSION: BAMs may have a protective effect against both cardia and noncardia GC. Further research and external validation are needed to confirm these findings.

Validation of an algorithm to identify fractures among patients within the Veterans Health Administration.

OBJECTIVE: To validate an algorithm that identifies fractures using billing codes from the International Classification of Diseases Ninth Revision (ICD-9) and Tenth Revision (ICD-10) for inpatient, outpatient, and emergency department visits in a population of patients. METHODS: We identified and reviewed a random sample of 543 encounters for adults receiving care within a single Veterans Health Administration healthcare system and had a first fracture episode between 2010 and 2019. To determine if an encounter represented a true incident fracture, we performed chart abstraction and assessed the type of fracture and mechanism. We calculated the positive predictive value (PPV) for the overall algorithm and each component diagnosis code along with 95% confidence intervals. Inverse probabilities of selection sampling weights were used to reflect the underlying study population. RESULTS: The algorithm had an initial PPV of 73.5% (confidence interval [CI] 69.5, 77.1), with low performance when weighted to reflect the full population (PPV 66.3% [CI 58.8, 73.1]). The modified algorithm was restricted to diagnosis codes with PPVs > 50% and outpatient codes were restricted to the first outpatient position, with the exception of one high performing code. The resulting unweighted PPV improved to 90.1% (CI 86.2, 93.0) and weighted PPV of 91.3% (CI 86.8, 94.4). A confirmation sample demonstrated verified performance with PPV of 87.3% (76.0, 93.7). PPVs by location of care (inpatient, emergency department and outpatient) remained greater than 85% in the modified algorithm. CONCLUSIONS: The modified algorithm, which included primary billing codes for inpatient, outpatient, and emergency department visits, demonstrated excellent PPV for identification of fractures among a cohort of patients within the Veterans Health Administration system.

Primary Occurrence of Cardiovascular Events After Adding Sodium-Glucose Cotransporter-2 Inhibitors or Glucagon-like Peptide-1 Receptor Agonists Compared With Dipeptidyl Peptidase-4 Inhibitors: A Cohort Study in Veterans With Diabetes.

BACKGROUND: The effectiveness of glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in preventing major adverse cardiac events (MACE) is uncertain for those without preexisting cardiovascular disease. OBJECTIVE: To test the hypothesis that MACE incidence was lower with the addition of GLP1RA or SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) for primary cardiovascular prevention. DESIGN: Retrospective cohort study of U.S. veterans from 2001 to 2019. SETTING: Veterans aged 18 years or older receiving care from the Veterans Health Administration, with data linkage to Medicare, Medicaid, and the National Death Index. PATIENTS: Veterans adding GLP1RA, SGLT2i, or DPP4i onto metformin, sulfonylurea, or insulin treatment alone or in combination. Episodes were stratified by history of cardiovascular disease. MEASUREMENTS: Study outcomes were MACE (acute myocardial infarction, stroke, or cardiovascular death) and heart failure (HF) hospitalization. Cox models compared the outcome between medication groups using pairwise comparisons in a weighted cohort adjusted for covariates. RESULTS: The cohort included 28 759 GLP1RA versus 28 628 DPP4i weighted pairs and 21 200 SGLT2i versus 21 170 DPP4i weighted pairs. Median age was 67 years, and diabetes duration was 8.5 years. Glucagon-like peptide-1 receptor agonists were associated with lower MACE and HF versus DPP4i (adjusted hazard ratio [aHR], 0.82 [95% CI, 0.72 to 0.94]), yielding an adjusted risk difference (aRD) of 3.2 events (CI, 1.1 to 5.0) per 1000 person-years. Sodium-glucose cotransporter-2 inhibitors were not associated with MACE and HF (aHR, 0.91 [CI, 0.78 to 1.08]; aRD, 1.28 [-1.12 to 3.32]) compared with DPP4i. LIMITATION: Residual confounding; use of DPP4i, GLP1RA, and SGLT2i as first-line therapies were not examined. CONCLUSION: The addition of GLP1RA was associated with primary reductions of MACE and HF hospitalization compared with DPP4i use; SGLT2i addition was not associated with primary MACE prevention. PRIMARY FUNDING SOURCE: VA Clinical Science Research and Development and supported in part by the Centers for Diabetes Translation Research.

Associations Between Gastrointestinal Symptoms and COVID-19 Severity Outcomes Based on a Propensity Score-Weighted Analysis of a Nationwide Cohort.

Background and Aims: Gastrointestinal (GI) symptoms are well-recognized manifestations of coronavirus disease 2019 (COVID-19). Our primary objective was to evaluate the association between GI symptoms and COVID-19 severity. Methods: In this nationwide cohort of US veterans, we evaluated GI symptoms (nausea/vomiting/diarrhea) reported 30 days before and including the date of positive SARS-CoV-2 testing (March 1, 2020, to February 20, 2021). All patients had ≥1 year of prior baseline data and ≥60 days follow-up relative to the test date. We used propensity score (PS)-weighting to balance covariates in patients with vs without GI symptoms. The primary composite outcome was severe COVID-19, defined as hospital admission, intensive care unit admission, mechanical ventilation, or death within 60 days of positive testing. Results: Of 218,045 SARS-CoV-2 positive patients, 29,257 (13.4%) had GI symptoms. After PS weighting, all covariates were balanced. In the PS-weighted cohort, patients with vs without GI symptoms had severe COVID-19 more often (29.0% vs 17.1%; P < .001). When restricted to hospitalized patients (14.9%; n=32,430), patients with GI symptoms had similar frequencies of intensive care unit admission and mechanical ventilation compared with patients without symptoms. There was a significant age interaction; among hospitalized patients aged ≥70 years, lower COVID-19-associated mortality was observed in patients with vs without GI symptoms, even after accounting for COVID-19-specific medical treatments. Conclusion: In the largest integrated US health care system, SARS-CoV-2-positive patients with GI symptoms experienced severe COVID-19 outcomes more often than those without symptoms. Additional research on COVID-19-associated GI symptoms may inform preventive efforts and interventions to reduce severe COVID-19.

Factors Associated With Parental COVID-19 Vaccination Acceptance.

As the coronavirus pandemic continues to impact families and children, understanding parental attitudes and likely acceptance of the COVID-19 vaccine is essential. We conducted a statewide survey with a representative sample of parents in Tennessee focused on COVID-19 and influenza vaccine acceptance and perspectives. Data from 1066 parents were analyzed using weighted survey methods to generalize results to the state of Tennessee. About 53% of parents reported a likelihood to vaccinate their children against COVID-19, and 45% were likely to vaccinate their child against COVID-19 and influenza. Female parents were less likely to vaccinate their children against COVID-19, but the strongest predictor of likely COVID-19 vaccine acceptance was influenza vaccine acceptance (adjusted odds ratio = 5.46; 95% confidence interval: 3.20-9.30). Parental acceptance of COVID-19 vaccines for children is closely tied to influenza vaccine acceptance. Public health approaches to maximize vaccine uptake could focus on children who have not been receiving influenza vaccines.

Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis.

Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori-infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori-infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori-induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein-coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori-induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.

Impact of stigmatizing language describing opioid-exposed mother infant dyads: A randomized case vignette study.

Background: Existing literature suggests that using stigmatizing language may promote negative attitudes and result in more punitive views toward individuals with addiction. It is unclear how the commonly used colloquial terms to describe opioid-exposed mother infant dyads impacts public opinion of pregnant women with opioid use disorder (OUD). We sought to examine the extent to which language such as "opioid addict" and "born addicted" influences the perception of pregnant women with OUD. Methods: We conducted a randomized case-based vignette study using a population-weighted sample of parents living in Tennessee, varying in the language used to describe an opioid-exposed mother infant dyad. Participant demographics, views on opioid prescribing, and opinions on criminal justice and child welfare responses following delivery were obtained. Ordinal logistic regression was used to examine the association between vignette type and punitive responses. Results: Eleven hundred participants completed the survey. Overall, 30.6% felt the mother should be arrested and 68.6% felt the mother should lose custody of her infant. There was insufficient evidence to suggest a difference in punitive response selection based on the vignette language (p = 0.27). In the adjusted model, the odds of answering a more punitive response among parents who received non-stigmatizing language was 0.8 (95% CI 0.59-1.08) compared to parents who received stigmatizing language in the vignette. Conclusions: Many parents hold punitive views toward mothers receiving OUD treatment that was not altered by using less value-laden language. Broader stigma-reduction interventions may be more effective.

Comparison of family health history in surveys vs electronic health record data mapped to the observational medical outcomes partnership data model in the All of Us Research Program.

OBJECTIVE: Family health history is important to clinical care and precision medicine. Prior studies show gaps in data collected from patient surveys and electronic health records (EHRs). The All of Us Research Program collects family history from participants via surveys and EHRs. This Demonstration Project aims to evaluate availability of family health history information within the publicly available data from All of Us and to characterize the data from both sources. MATERIALS AND METHODS: Surveys were completed by participants on an electronic portal. EHR data was mapped to the Observational Medical Outcomes Partnership data model. We used descriptive statistics to perform exploratory analysis of the data, including evaluating a list of medically actionable genetic disorders. We performed a subanalysis on participants who had both survey and EHR data. RESULTS: There were 54 872 participants with family history data. Of those, 26% had EHR data only, 63% had survey only, and 10.5% had data from both sources. There were 35 217 participants with reported family history of a medically actionable genetic disorder (9% from EHR only, 89% from surveys, and 2% from both). In the subanalysis, we found inconsistencies between the surveys and EHRs. More details came from surveys. When both mentioned a similar disease, the source of truth was unclear. CONCLUSIONS: Compiling data from both surveys and EHR can provide a more comprehensive source for family health history, but informatics challenges and opportunities exist. Access to more complete understanding of a person's family health history may provide opportunities for precision medicine.

Lenalidomide consolidation benefits patients with CLL receiving chemoimmunotherapy: results for CALGB 10404 (Alliance).

Prior to novel targeted agents for chronic lymphocytic leukemia (CLL), the best chemoimmunotherapy regimen in patients with non-del(11q) disease was unclear. The role of lenalidomide was also not defined. This phase 2 study randomized 342 untreated patients with non-del(11q) CLL requiring therapy to fludarabine plus rituximab (FR; n = 123), FR plus lenalidomide consolidation (FR+L; n = 109), or FR plus cyclophosphamide (FCR; n = 110) and compared 2-year progression-free survival (PFS) rates of each to the historical control rate with FC (60%). Patients with del(11q) in at least 20% of pretreatment cells continued with FCR (n = 27) or were reassigned to FCR+L (n = 31) and excluded from the primary analysis. Among non-del(11q) patients, 2-year PFS rates were 64% (90% confidence interval [CI], 57-71; FR), 72% (90% CI, 65-79; FR+L), and 74% (90% CI, 66-80; FCR); FR+L and FCR had rates significantly greater than historical control. Median PFS was significantly shorter with FR compared with FR+L (P = .04) and FCR (P < .001): 43 (95% CI, 33-50), 61 (95% CI, 45-71), and 97 (95% CI, 61 to not reached) months, respectively. Median follow-up was 73 months and median overall survival (OS) was only reached with FCR (101 months; 95% CI, 96 to not reached). With FR+L, the risk of death decreased over time and was lower than with FR at later time points (P = .01), but not significantly different from FCR (P = .21). Future studies incorporating short courses of lenalidomide into other novel treatment regimens are justified.

MYD88 mutation status does not impact overall survival in Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is an immunoglobulin M-associated lymphoma, with majority of cases demonstrating MYD88 locus alteration, most commonly, MYD88L265P . Owing to low prevalence of the wild-type (WT) MYD88 genotype in WM, clinically relevant data in this patient population are sparse, with one study showing nearly a 10-fold increased risk of mortality in this subgroup compared to patients with MYD88L265P mutation. We studied a large cohort of patients with MYD88L265P and MYD88WT WM, evaluated at Mayo Clinic, Rochester, between 1995 and 2016, to specifically assess the impact of these genotypes on clinical course. Of 557 patients, MYD88L265P mutation status, as determined by allele-specific polymerase chain reaction, was known in 219, and 174 (79%) of those exhibited MYD88L265P , 157 of 174 patients had active disease. Of 45 (21%) patients with MYD88WT genotype, 44 had active disease. The estimated median follow-up was 7.0 years; median overall survival was 10.2 years (95% CI: 8.4-16.5) for MYD88L265P versus 13.9 years (95% CI: 6.4-29.3) for the MYD88WT (P = 0.86). The time-to-next therapy from frontline treatment and the presenting features were similar in the two patient populations. For patients with smoldering WM at diagnosis, the median time-to-progression to active disease was 2.8 years (95% CI: 2.2-3.8) in the MYD88L265P cohort and 1.9 years (95% CI: 0.7-3.1) in the MYD88WT cohort (P = 0.21). The frequency of transformation to high-grade lymphoma, or the development of therapy-elated myelodysplastic syndrome was higher in the MYD88WT cohort (16% versus 4% in the MYD88L265P , P = 0.009). In conclusion, MYD88L265P mutation does not appear to be a determinant of outcome, and its presence may not be a disease-defining feature in WM. Our findings warrant external validation, preferably through prospective studies.

Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma.

This phase 1/2 trial evaluated the maximum tolerated doses, safety, and efficacy of pomalidomide, bortezomib, and dexamethasone (PVD) combination in patients with relapsed lenalidomide-refractory multiple myeloma (MM). In phase 1, dose level 1 consisted of pomalidomide (4 mg by mouth on days 1 to 21), IV or subcutaneous bortezomib (1.0 mg/m2 on days 1, 8, 15, and 22), and dexamethasone (40 mg by mouth on days 1, 8, 15, and 22) given every 28 days. Bortezomib was increased to 1.3 mg/m2 for dose level 2 and adopted in the phase 2 expansion cohort. We describe the results of 50 patients. Objective response rate was 86% (95% confidence interval [CI], 73-94) among all evaluable patients (stringent complete response, 12%; complete response, 10%; very good partial response, 28%; and partial response, 36%) and 100% among high-risk patients. Within a median follow-up of 42 months, 20% remain progression free, 66% are alive, and 4% remain on treatment. Median progression-free survival was 13.7 months (95% CI, 9.6-17.7). The most common toxicities were neutropenia (96%), leukopenia (84%), thrombocytopenia (82%), anemia (74%), and fatigue (72%); however, the majority of these were grade 1 or 2. The most common grade ≥3 toxicities included neutropenia (70%), leukopenia (36%), and lymphopenia (20%). Deep vein thrombosis occurred in 5 patients. In conclusion, PVD is a highly effective combination in lenalidomide-refractory MM patients. Weekly administration of bortezomib enhanced tolerability and convenience. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy. This trial was registered at www.clinicaltrials.gov as #NCT01212952.

Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib.

Proteasome inhibitors have become an integral part of myeloma therapy. Considerable efforts have gone into optimizing this therapeutic approach to obtain maximal proteasome inhibition with least toxicity. Ixazomib is the first oral proteasome inhibitor to enter the clinic and has been studied as a single agent as well as in various combinations. The current trial was designed to examine the efficacy and toxicity of combining 2 different doses of ixazomib (4 mg and 5.5 mg given weekly for 3 of 4 weeks) with 40 mg weekly of dexamethasone, in relapsed myeloma. Seventy patients were enrolled, 35 patients randomly assigned to each ixazomib dose. Overall, 30 (43%; 95% confidence interval, 31-55) of the patients achieved a confirmed partial response or better, with 31% achieving a response with 4 mg and 54% with 5.5 mg of ixazomib. The median event-free survival (EFS) for the entire study population was 8.4 months; 1-year overall survival was 96%. The EFS was 5.7 months for patients with prior bortezomib exposure and 11.0 months for bortezomib-naïve patients. A grade 3 or 4 adverse event considered at least possibly related to treatment was seen in 11 (32%) patients at 4 mg and in 21 (60%) at 5.5 mg. Dose reductions were more frequent with 5.5 mg dose. Overall, the ixazomib with dexamethasone has good efficacy in relapsed myeloma, is well-tolerated and with higher response rate at 5.5 mg, albeit with more toxicity. This study was registered at www.clinicaltrials.gov as #NCT01415882.