Clinical Characteristics and Patterns of Immune Responses in COVID-19 Patients From a Rural Community Hospital.

Background Although demographic and clinical factors such as age, certain comorbidities, and sex have been associated with COVID-19 outcomes, these studies were largely conducted in urban populations affiliated with large academic medical centers. There have been very few studies focusing on rural populations that also characterize broader changes in inflammatory cytokines and chemokines. Methodology A single-center study was conducted between June 2020 and March 2021 in Abilene, Texas, USA. Patients were included if they presented to the hospital for treatment of COVID-19, had extra biological materials from routine care available, and were between the ages of 0 to 110 years. There were no exclusion criteria. Patient characteristics, symptom presentation, and clinical laboratory results were extracted from electronic health records. Blood specimens were analyzed by protein microarray to quantitate 40 immunological biomarkers. Results A total of 122 patients were enrolled, of whom 81 (66%) were admitted to the general non-critical inpatient unit, 37 (30%) were admitted to the intensive or critical care units, and four (3.2%) were treated outpatient. Most hospitalized COVID-19 patients in this rural population were elderly, male, obese, and retired individuals. Predominant symptoms for non-critical patients were shortness of breath, fever, and fatigue. Ferritin levels for outpatient patients were lower on average than those in an inpatient setting and lactate dehydrogenase (LDH) levels were noted to be lower in non-critical and outpatient than those in the intensive care unit setting. Inflammatory biomarkers were positively correlated and consistent with inflammatory cascade. Interleukin (IL)-10 was positively correlated while platelet-derived growth factor was negatively correlated with inflammatory biomarkers. Patients ≥65 years had significantly higher levels of LDH and seven cytokines/chemokines (granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin IL-1b, IL-6, IL-10, IL-11, macrophage inflammatory protein (MIP)-1d, and IL-8) while levels of five other immune molecules (intercellular adhesion molecule 1 (ICAM-1), monocyte chemoattractant protein 1 (MCP-1), tissue inhibitor of metalloproteinase 2 (TIMP-2), IL-2, and IL-4) were significantly lower compared to those <65 years. Females had significantly higher levels of LDH and 10 cytokines/chemokines (GM-CSF, IL-1b, IL-6, IL-10, IL-11, IL-15, IL-16, MIP-1a, MIP-1d, and IL-8) while levels of TIMP-2 and IL-4 were significantly lower than male patients. Conclusions The clinical characteristics of this rural cohort of hospitalized patients differed somewhat from nationally reported data. The contributions of social, environmental, and healthcare access factors should be investigated. We identified age and sex-associated differences in immunological response markers that warrant further investigation to identify the underlying molecular mechanisms and impact on COVID-19 pathogenesis.

Pathways Linking Post-Traumatic Stress Disorder to Incident Ischemic Heart Disease in Women: Call to Action.

Background: Post-traumatic stress disorder (PTSD) is associated with increased rates of incident ischemic heart disease (IHD) in women. Objectives: The purpose of this study was to determine mechanisms of the PTSD-IHD association in women. Methods: In this retrospective longitudinal cohort study, data were obtained from electronic health records of all U.S. women veterans who were enrolled in Veterans Health Administration care from January 1, 2000 to December 31, 2017. Propensity score matching was used to match women with PTSD to women without PTSD on age, number of prior Veterans Health Administration visits, and presence of various traditional and nontraditional cardiovascular risk factors at index visit. Cox regression was used to model time until incident IHD diagnosis (ie, coronary artery disease, angina, or myocardial infarction) as a function of PTSD and potential mediating risk factors. Diagnoses of IHD, PTSD, and risk factors were defined by International Classification of Diseases-9th or -10th Revision, and/or Current Procedural Terminology codes. Results: PTSD was associated with elevated rates of developing each risk factor. Traditional risk factors (hypertension, hyperlipidemia, smoking, diabetes) accounted for 24.2% of the PTSD-IHD association, psychiatric risk factors (eg, depression, anxiety, substance use disorders) accounted for 33.8% of the association, and all 13 risk factors accounted for 48.5% of the association. Conclusions: Traditional IHD risk factors explained a quarter of the PTSD-IHD association in women veterans, and over half of the risk of IHD associated with PTSD remained unexplained even when adjusting for a wide range of risk factors. To be actionable, factors underlying the remaining PTSD-IHD association warrant timely investigation.

Association of statins with nonalcoholic fatty liver disease in patients with diabetes.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in patients with diabetes; limited data suggested that statins may reduce the risk of NAFLD progression. This study aimed to examine the association between statins and the development or progression of NAFLD in veterans with diabetes. In a new-user negative control design, we conducted a retrospective propensity score (PS)-matched cohort study of patients with diabetes between 2003 and 2015. After excluding patients with other causes of liver disease, we formed PS using 85 characteristics. The primary outcome was a composite NAFLD progression outcome. Primary analysis examined odds of outcome in PS-matched cohort. Post-hoc analysis included a PS-matched cohort of statin users with intensive lowering of low-density lipoprotein-cholesterol (LDL-C) vs low-intensity lowering. We matched 34,102 pairs from 300,739 statin users and 38,038 non-users. The composite outcome occurred in 8.8% of statin users and 8.6% of non-users (odds ratio (OR) 1.02, 95% confidence interval (95% CI) 0.97-1.08). In the post-hoc analysis, intensive lowering of LDL-C compared to low-intensity showed increased NAFLD progression (OR 1.21, 95% CI 1.13-1.30). This study showed that statin use in patients with diabetes was not associated with decreased or increased risk of NAFLD progression. Intensive LDL-C lowering, compared to low-intensity LDL-C lowering, was associated with an increased risk of NAFLD progression.

Effect of pregabalin initiation on diuretic requirements in patients with chronic heart failure.

BACKGROUND: Literature on pregabalin use in patients with heart failure is largely limited to patient case reports and cohort studies. OBJECTIVE: This study aimed to evaluate the effect of pregabalin initiation on diuretic requirements in patients with heart failure. METHODS: A retrospective analysis of patients with heart failure who were started on pregabalin between January 1, 2014, and September 1, 2021, at the Veterans Affairs North Texas Health Care System was used. The primary objective was to determine the median change in loop diuretic dose, in furosemide dose equivalents, 6 months after pregabalin initiation. RESULTS: Of 58 patients analyzed, there was no statistically significant difference in the primary outcome (P = 0.162). The secondary outcomes were found to be nonstatistically significant, and there was no correlation between pregabalin dose and outcomes. CONCLUSION: This represents the largest analysis of diuretic dose requirements in patients with heart failure after initiation of pregabalin. Although there was no difference in the median change of diuretic dose prescribed, pregabalin should still be used with caution.

Posttraumatic Stress Disorder Is Associated With Elevated Risk of Incident Stroke and Transient Ischemic Attack in Women Veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with ischemic heart disease in women veterans, but evidence for associations with other cardiovascular disorders remains limited in this population. This retrospective longitudinal cohort study evaluated the association of PTSD with incident stroke/transient ischemic attack (TIA) in women veterans. METHODS AND RESULTS: Veterans Health Administration electronic health records were used to identify women veterans aged ≥18 years engaged with Veterans Health Administration health care from January 1, 2000 to December 31, 2019. We identified women veterans with and without PTSD without a history of stroke or TIA at start of follow-up. Propensity score matching was used to match groups on age, race or ethnicity, traditional cardiovascular risk factors, female-specific risk factors, a range of mental and physical health conditions, and number of prior health care visits. PTSD, stroke, TIA, and risk factors used in propensity score matching were based on diagnostic codes. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for associations of PTSD with an incident stroke/TIA composite. Subanalyses considered stroke and TIA separately, plus age- and race- or ethnicity-stratified analyses were carried out. The analytic sample included 208 092 women veterans (104 046 with and 104 046 without PTSD). PTSD was associated with a greater rate of developing stroke/TIA (HR, 1.33 [95% CI, 1.25-1.42], P<0.001). This elevated risk was especially pronounced in women <50 years old and in Hispanic/Latina women. CONCLUSIONS: Findings indicate a strong association of PTSD with incident stroke/TIA in women veterans. Research is needed to determine whether addressing PTSD and its downstream consequences can offset this risk.

Compliance with recommended pneumococcal vaccination schedule in patients treated for rheumatoid arthritis: A retrospective cohort study in the Veterans Affairs population.

INTRODUCTION: Invasive pneumococcal disease (IPD) is a leading cause of death. Rheumatoid arthritis (RA) patients are at risk of IPD due to immunosuppressant medications. Up until 2022, two pneumococcal vaccines, the 13-valent Pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23), were recommended. Despite the recommendation change to give a single 20-valent PCV vaccine (PCV20), some still require multiple vaccinations. There is a need to identify barriers to vaccine uptake. METHODS: We conducted a retrospective cohort study to assess the on-time vaccination rates for PCV13 and PPSV23 in treated RA patients between 2010 and 2018 using national Veterans Affairs data. Patients > 18 years of age diagnosed with RA and newly initiated on RA treatment were included. Pneumococcal vaccine compliance was assessed by measuring on-time receipt of PCV13 and PPSV23 vaccinations. We identified factors using multivariate logistic regression and described the occurrence of these factors using descriptive statistics. RESULTS: A total of 39,243 patients were included in the study. Most patients were white (75.8 %), male (85.4 %), on methotrexate therapy (41.4 %). The average age was 62.3 years. The proportion of patients considered vaccine compliant is 43.9 %. The primary independent risk factors for vaccine non-compliance were black/African American race (Odds Ratio [OR] 1.26, 95 % Confidence Interval [CI] 1.19-1.34) or missing/unknown race (OR 1.45, 95 % CI 1.31-1.61), missing/unknown ethnicity (OR 1.21, 1.02-1.43), never married (OR 1.10, 95 % CI 1.02-1.19) or widowed (OR 1.23, 95 % CI 1.12-1.34), diagnosed with congestive heart failure (OR 1.10, 95 % CI 1.00-1.22), or dementia (OR 1.48, 95 % CI 1.16-1.91). The proportion of patients who were non-compliant in patients who were vaccine naïve was 32.1 % and the non-compliance rate for non-naïve patients was 65.3 %. CONCLUSIONS: Providers should identify barriers to pneumococcal vaccination in RA patients to improve compliance. Efforts to increase vaccination should be tailored to specific high-risk groups.

Association of Strict Versus Lenient Cholesterol Lowering with Cardiac Outcomes, Diabetes Progression and Complications, and Mortality in Patients with Diabetes Treated with Statins: Is Less More?

INTRODUCTION: Whereas some guidelines recommend statin use to achieve low-density lipoprotein cholesterol (LDL-C) goal < 70 mg/dL for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients at higher risk, others recommend against a target LDL-C level. Achieving a target level < 70 mg/dL commonly requires the use of high intensity statins, which has been associated with higher risk of diabetes progression. The objective of this study is to assess the association of strict (≤ 70 mg/dL) versus lenient (> 70 to100 mg/dL) LDL-C lowering on major adverse cardiovascular events (MACE), diabetes progression, diabetes microvascular complications, and total mortality in patients with diabetes. METHODS: This was a retrospective propensity score (PS)-matched study from a national cohort of, predominantly male, veterans diagnosed with diabetes without prior cardiovascular disease (from fiscal years 2003-2015), who were initiated on a statin. We created PS to match strict (mean LDL-C during follow-up ≤ 70 mg/dL) versus lenient (mean LDL-C during follow up > 70-100 mg/dL) using 65 baseline characteristics including comorbidities, risk scores, medication classes usage, vital signs, and laboratory data. Outcomes included MACE, diabetes progression, microvascular diabetes complications, and total mortality. RESULTS: From 80,110 eligible patients, we PS-matched 21,294 pairs of statin initiators with strict or lenient LDL-C lowering. The mean (SD) age was 64 (9.5) years and mean (SD) duration of follow-up was 6 (3) years. MACE was similar in the PS-matched groups [6.1% in strict versus 5.8% in lenient; odds ratio (OR): 1.06; 95% confidence interval (95% CI) 0.98-1.15, P = 0.17]. Diabetes progression was higher among the strict vs lenient group (66.7% in strict versus 64.1% in lenient; OR 1.12; 95% CI 1.08-1.17, P < 0.001). There was no difference in microvascular diabetes complications (22.3% in strict versus 21.9% in lenient; OR 1.02; 95% CI 0.98-1.07, P = 0.31) and no difference in total mortality (14.6% in strict versus 15% in lenient; OR 0.97; 95% CI 0.92-1.02, P = 0.20). CONCLUSION: Strict compared with lenient lowering of LDL-C with statins in men with diabetes without preexisting ASCVD did not decrease the risk of MACE but was associated with an increased diabetes progression. Clinicians should monitor their patients for diabetes progression upon escalating statins to achieve LDL-C levels ≤ 70 mg/dL.

Trends in Cardiovascular Disease Mortality in US Women Veterans vs Civilians.

Importance: Cardiovascular disease (CVD) remains the leading cause of death in the US. Women veterans have higher rates of CVD compared with civilian US women; however, analyses of recent trends in mortality from cardiac disease for women veterans are lacking. Objective: To investigate trends in cardiac disease mortality among women veterans over approximately the past 2 decades and compare rates with those for civilian women. Design, Setting, and Participants: In this retrospective longitudinal cohort study, US Veterans Health Administration (VHA) electronic health record data, linked with the National Death Index, were analyzed for CVD trends and rates of cardiac disease mortality among women veterans (aged 18 years or older) with VHA health care encounters from January 1, 2000, to December 31, 2017. These data were compared with a national cohort of civilian women (aged 15 years or older) in the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database, which provides cause-of-death data using death certificates for all US residents. The data analysis was performed between March 10, 2021, and November 28, 2022. Exposure: Cardiac disease mortality among women veterans and civilian women. Main Outcomes and Measures: Cardiac disease mortality was based on International Classification of Diseases, Tenth Revision diagnostic codes (I00-I09, I11, I13, and I20-I51 as defined by CDC WONDER). For women veterans and civilian women, crude and age-adjusted cardiac disease mortality rates (per 100 000 life-years) and 95% CIs were calculated, with the 2000 US general population as the reference for age-adjusted rates. Results: From 2000 to 2017, 817 912 women veterans engaged with VHA health care (mean [SD] age, 45.7 [17.1] years), and 19 022 cardiac disease deaths were identified (22.4% of total deaths). The crude and age-adjusted cardiac disease mortality rates, respectively, per 100 000 life-years were 200.2 (95% CI, 181.0-221.0) and 197.6 (95% CI, 175.2-222.0) in 2000 and 196.0 (95% CI, 186.1-206.4) and 208.1 (95% CI, 196.4-220.4) in 2017, reflecting stable crude rates and a 5.3% increase in age-adjusted rates. For civilian women, the crude and age-adjusted rates decreased over time from 320.7 (95% CI, 319.7-321.8) and 268.1 (95% CI, 267.3-269.0) in 2000 to 220.9 (95% CI, 220.1-221.7) and 164.7 (95% CI, 164.1-165.3) in 2017. Conclusions and Relevance: In this cohort study comparing women veterans and civilian women, cardiac disease mortality rates for women veterans did not exhibit the improvements seen for civilian women during the nearly 2-decade study period. Further research and actionable clinical interventions are warranted to improve cardiovascular care for women veterans, who represent the fastest growing group of patients within the VHA health care system.

Association of Thiazide Diuretics With Diabetes Progression, Kidney Disease Progression, Cardiovascular Outcomes, and Death Among Patients With Diabetes Who Initiate Statins.

Statins have been associated with diabetes mellitus (DM) progression but their cardiovascular benefit in patients with DM outweigh the harm. However, the effects of concurrent use of other medications that similarly increase blood glucose level, such as thiazide diuretics, are not well studied. This study aimed to evaluate the association of concurrent use of thiazide diuretics and statins on DM progression, cardiovascular and renal outcomes, and death in patients with DM. This is a retrospective cohort study of Veterans with DM who initiated statins between 2003 and 2015. The cohort comprised thiazide users (concomitantly used thiazides and statins for ≥6 months) and active comparators (concomitantly used calciun channel blockers [CCB] but not thiazides and statins for ≥6 months). We excluded patients who were <18 years old, with chronic kidney disease stage 4 or worse, or used loop diuretics. We propensity-score-matched comparison groups on 99 baseline characteristics including demographics, healthcare utilization, co-morbidities, cardiovascular and co-morbidity scores, vital signs, laboratory data, and medication class usage. Outcomes were: (1) DM progression (new insulin initiation, increase in the number of glucose-lowering medication classes, and hyperglycemic episodes); (2) kidney disease progression (doubling of serum creatinine, incidence of chronic kidney disease stage 5, initiation of renal replacement therapy, and incidence of diabetic nephropathy); (3) cardiovascular outcomes (acute myocardial infarction, stroke, cardiac arrest); and (4) total mortality. From 297,967 statin users (228,509 Thiazide-statin users and 69,458 active comparators), we successfully matched 67,614 pairs. In comparison to active comparators, thiazide-statin users had increased risk of DM progression (65.6% in CCB group vs 68.1% in thiazide group; odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.09 to 1.15), decreased risk of kidney progression (16.9% in CCB group vs 16.5 in thiazide group; OR: 0.97, 95% CI: 0.94 to 0.99), decreased risk of cardiovascular outcomes (15.7% in CCB group vs 14.6% in thiazide group; OR: 0.92, 95% CI: 0.89 to 0.95), and similar risk of total mortality (19.7% in each group; OR: 1.00, 95% CI: 0.98 to 1.03). This study attempted to answer an important clinical question whether thiazide diuretics should be discontinued or substituted upon statin initiation. Our results showed that concurrent use of statin and thiazides in patients with DM was associated with DM progression but with less kidney progression and cardiovascular outcomes and no difference in mortality. Clinicians should closely monitor DM control when thiazides and statins are used concurrently.

Acute and chronic lung inflammation drives changes in epithelial glycans.

Introduction: Asthma is the most common chronic inflammatory disease and it is characterized by leukocyte infiltration and tissue remodeling, with the latter generally referring to collagen deposition and epithelial hyperplasia. Changes in hyaluronin production have also been demonstrated, while mutations in fucosyltransferases reportedly limit asthmatic inflammation. Methods: Given the importance of glycans in cellular communication and to better characterize tissue glycosylation changes associated with asthma, we performed a comparative glycan analysis of normal and inflamed lungs from a selection of murine asthma models. Results: We found that among other changes, the most consistent was an increase in fucose-α1,3-N-acetylglucosamine (Fuc-α1,3-GlcNAc) and fucose-α1,2-galactose (Fuc-α1,2-Gal) motifs. Increases in terminal galactose and N-glycan branching were also seen in some cases, whereas no overall change in O-GalNAc glycans was observed. Increased Muc5AC was found in acute but not chronic models, and only the more human-like triple antigen model yielded increased sulfated galactose motifs. We also found that human A549 airway epithelial cells stimulated in culture showed similar increases in Fuc-α1,2-Gal, terminal galactose (Gal), and sulfated Gal, and this matched transcriptional upregulation of the α1,2-fucosyltransferase Fut2 and the α1,3-fucosyltransferases Fut4 and Fut7. Conclusions: These data suggest that airway epithelial cells directly respond to allergens by increasing glycan fucosylation, a known modification important for the recruitment of eosinophils and neutrophils.

World Federation for Interventional Stroke Treatment (WIST) multispecialty training guidelines for endovascular stroke intervention.

Introduction: Today, endovascular treatment (EVT) is the therapy of choice for strokes due to acute large vessel occlusion, irrespective of prior thrombolysis. This necessitates fast, coordinated multi-specialty collaboration. Currently, in most countries, the number of physicians and centres with expertise in EVT is limited. Thus, only a small proportion of eligible patients receive this potentially life-saving therapy, often after significant delays. Hence, there is an unmet need to train a sufficient number of physicians and centres in acute stroke intervention in order to allow widespread and timely access to EVT. Aim: To provide multi-specialty training guidelines for competency, accreditation and certification of centres and physicians in EVT for acute large vessel occlusion strokes. Material and methods: The World Federation for Interventional Stroke Treatment (WIST) consists of experts in the field of endovascular stroke treatment. This interdisciplinary working group developed competency - rather than time-based - guidelines for operator training, taking into consideration trainees' previous skillsets and experience. Existing training concepts from mostly single specialty organizations were analysed and incorporated. Results: The WIST establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in EVT. WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. Conclusions: WIST multispecialty guidelines outline competency and quality standards for physicians and centres to perform safe and effective EVT. The role of quality control and quality assurance is highlighted.

World Federation for Interventional Stroke Treatment (WIST) Multispecialty Training Guidelines for Endovascular Stroke Intervention.

INTRODUCTION: Today, endovascular treatment (EVT) is the therapy of choice for strokes due to acute large vessel occlusion, irrespective of prior thrombolysis. This necessitates fast, coordinated multi-specialty collaboration. Currently, in most countries, the number of physicians and centres with expertise in EVT is limited. Thus, only a small proportion of eligible patients receive this potentially life-saving therapy, often after significant delays. Hence, there is an unmet need to train a sufficient number of physicians and centres in acute stroke intervention in order to allow widespread and timely access to EVT. AIM: To provide multi-specialty training guidelines for competency, accreditation and certification of centres and physicians in EVT for acute large vessel occlusion strokes. MATERIAL AND METHODS: The World Federation for Interventional Stroke Treatment (WIST) consists of experts in the field of endovascular stroke treatment. This interdisciplinary working group developed competency - rather than time-based - guidelines for operator training, taking into consideration trainees' previous skillsets and experience. Existing training concepts from mostly single specialty organizations were analysed and incorporated. RESULTS: The WIST establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in EVT. WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. CONCLUSIONS: WIST multispecialty guidelines outline competency and quality standards for physicians and centres to perform safe and effective EVT. The role of quality control and quality assurance is highlighted. SUMMARY: The World Federation for Interventional Stroke Treatment (WIST) establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in endovascular treatment (EVT). WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. WIST multispecialty guidelines outline competency and quality standards for physicians and centers to perform safe and effective EVT. The role of quality control and quality assurance is highlighted. SIMULTANEOUS PUBLICATION: The WIST 2023 Guidelines are published simultaneously in Europe (Adv Interv Cardiol 2023).

Controversies in the Prevention and Treatment of Clostridioides difficile Infection in Adults: A Narrative Review.

Clostridioides difficile remains a problematic pathogen resulting in significant morbidity and mortality, especially for high-risk groups that include immunocompromised patients. Both the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America (IDSA/SHEA), as well as the American College of Gastroenterology (ACG) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recently provided guideline updates for C. difficile infection (CDI). In this narrative review, the authors reviewed available literature regarding the prevention or treatment of CDI in adults and focused on disagreements between the IDSA/SHEA and ACG guidelines, as well as articles that have been published since the updates. Several options for primary prophylaxis are available, including probiotics and antibiotics (vancomycin, fidaxomicin). The literature supporting fidaxomicin is currently quite limited. While there are more studies evaluating probiotics and vancomycin, the optimal patient populations and regimens for their use have yet to be defined. While the IDSA/SHEA guidelines discourage metronidazole use for mild CDI episodes, evidence exists that it may remain a reasonable option for these patients. Fidaxomicin has an advantage over vancomycin in reducing recurrences, but its use is limited by cost. Despite this, recent studies suggest fidaxomicin's cost-effectiveness as a first-line therapy, though this is highly dependent on institutional contracts and payment structures. Secondary prophylaxis should focus on non-antimicrobial options to lessen the impact on the microbiome. The oral option of fecal microbiota transplantation (FMT), SER109, and the now FDA-approved RBX2660 represent exciting new options to correct dysbiosis. Bezlotoxumab is another attractive option to prevent recurrences. Further head-to-head studies of newer agents will be needed to guide selection of the optimal therapies for CDI primary and secondary prophylaxis.

Metformin Use Is Associated With Lower Mortality in Veterans With Diabetes Hospitalized With Pneumonia.

BACKGROUND: Recent studies suggest that metformin use may be associated with improved infectious disease-related outcomes, whereas other papers suggest potentially worse outcomes in serious bacterial infections. Our purpose was to examine the association of prior outpatient prescription of metformin on 30- and 90-day mortality for older veterans with pre-existing diabetes hospitalized with pneumonia. METHODS: We conducted a retrospective cohort study using national Department of Veterans Affairs data of patients ≥65 years with a prior history of diabetes who were hospitalized with pneumonia over a 10-year period (fiscal years 2002-2012.) For our primary analysis, we created a propensity score and matched metformin users to nonusers 1:1. RESULTS: We identified 34 759 patients who met the inclusion criteria, 20.3% of whom were prescribed metformin. Unadjusted 30-day mortality was 9.6% for those who received metformin versus 13.9% in nonusers (P < .003), and 90-day mortality was 15.8% for those who received metformin versus 23.0% for nonusers (P < .0001). For the propensity score model, we matched 6899 metformin users to 6899 nonusers. After propensity matching, both 30-day (relative risk [RR]: .86; 95% confidence interval [CI]: .78-.95) and 90-day (RR: .85; 95% CI: .79-.92) mortality was significantly lower for metformin users. CONCLUSIONS: Prior receipt of metformin was associated with significantly lower mortality after adjusting for potential confounders. Additional research is needed to examine the safety and potential benefits of metformin use in patients with respiratory infections.

Association of medical tests use with care continuity in primary care service: evidence from the Department of Veterans Affairs.

BACKGROUND: Continuity of care (CoC) is an important component of health care delivery that can have cost implications and improve patient outcomes. We analysed data obtained from the Department of Veterans Affairs to examine the relationship between CoC and use of image-oriented diagnostic tests in patients with comorbid chronic conditions. METHODS: A longitudinal, retrospective cohort study involving participants ≥18 years old, with comorbid diabetes and chronic kidney disease. We used a multivariate linear regression model to test whether greater care continuity, measured using a care continuity index (CCI), is associated with less frequent use of diagnostic tests. RESULTS: Total of 267,442 patients and 8,142,036 tests were included. Of the diagnostic tests we chose to evaluate, the 4 most frequently ordered tests were X-ray (45.6%), electrocardiogram (EKG, 16.8%), computerized tomography (CT, 13.4%), and magnetic resonance imaging (MRI, 3.4%). Overall, greater CCI was associated with fewer use of tests (P < 0.001). A 1 standard deviation (SD, 0.27) increase in CCI was associated with 4.2% decrease (P < 0.001) in number of tests. But a mixed pattern existed. For X-ray and EKG, greater continuity was associated with less testing, 6.2% (P < 0.001) and 3.3% (P < 0.05) reductions, respectively. Whereas, for CT and MRI, greater continuity was associated with more testing, 2.3% (P < 0.001) and 1.4% increases (P < 0.01), respectively. CONCLUSION: Overall, greater CoC was associated with fewer use of tests, representing a greater presumed efficiency of care. This has implications for designing health care delivery.

Interplay Between the Histone Variant H2A.Z and the Epigenome in Pancreatic Cancer.

BACKGROUND: The oncogenic process is orchestrated by a complex network of chromatin remodeling elements that shape the cancer epigenome. Histone variant H2A.Z regulates DNA control elements such as promoters and enhancers in different types of cancer; however, the interplay between H2A.Z and the pancreatic cancer epigenome is unknown. OBJECTIVE: This study analyzed the role of H2A.Z in different DNA regulatory elements. METHODS: We performed Chromatin Immunoprecipitation Sequencing assays (ChiP-seq) with total H2A.Z and acetylated H2A.Z (acH2A.Z) antibodies and analyzed published data from ChIP-seq, RNA-seq, bromouridine labeling-UV and sequencing (BruUV-seq), Hi-C and ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) in the pancreatic cancer cell line PANC-1. RESULTS: The results indicate that total H2A.Z facilitates the recruitment of RNA polymerase II and transcription factors at promoters and enhancers allowing the expression of pro-oncogenic genes. Interestingly, we demonstrated that H2A.Z is enriched in super-enhancers (SEs) contributing to the transcriptional activation of key genes implicated in tumor development. Importantly, we established that H2A.Z contributes to the three-dimensional (3D) genome organization of pancreatic cancer and that it is a component of the Topological Associated Domains (TADs) boundaries in PANC-1 and that total H2A.Z and acH2A.Z are associated with A and B compartments, respectively. CONCLUSIONS: H2A.Z participates in the biology and development of pancreatic cancer by generating a pro-oncogenic transcriptome through its posttranslational modifications, interactions with different partners, and regulatory elements, contributing to the oncogenic 3D genome organization. These data allow us to understand the molecular mechanisms that promote an oncogenic transcriptome in pancreatic cancer mediated by H2A.Z.

The Risk and Clinical Implications of Antibiotic-Associated Acute Kidney Injury: A Review of the Clinical Data for Agents with Signals from the Food and Drug Administration's Adverse Event Reporting System (FAERS) Database.

Antibiotic-associated acute kidney injury (AA-AKI) is quite common, especially among hospitalized patients; however, little is known about risk factors or mechanisms of why AA-AKI occurs. In this review, the authors have reviewed all available literature prior to 1 June 2022, with a large number of AKI reports. Information regarding risk factors of AA-AKI, mechanisms behind AA-AKI, and treatment/management principles to decrease AA-AKI risk were collected and reviewed. Patients treated in the inpatient setting are at increased risk of AA-AKI due to common risk factors: hypovolemia, concomitant use of other nephrotoxic medications, and exacerbation of comorbid conditions. Clinicians should attempt to correct risk factors for AA-AKI, choose antibiotic therapies with decreased association of AA-AKI to protect their high-risk patients, and narrow, when clinically possible, the use of antibiotics which have decreased incidence of AKI. To treat AKI, it is still recommended to discontinue all offending nephrotoxic agents and to renally adjust all medications according to package insert recommendations to decrease patient harm.

Statins and renal disease progression, ophthalmic manifestations, and neurological manifestations in veterans with diabetes: A retrospective cohort study.

BACKGROUND: Statins increase insulin resistance, which may increase risk of diabetic microvascular complications. Little is known about the impact of statins on renal, ophthalmologic, and neurologic complications of diabetes in practice. The objective of this study was to examine the association of statins with renal disease progression, ophthalmic manifestations, and neurological manifestations in diabetes. METHODS: This is a retrospective cohort study, new-user active comparator design, that included a national Veterans Health Administration (VA) patients with diabetes from 2003 to 2015. Patients were age 30 years or older and were regular users of the VA with data encompassing clinical encounters, demographics, vital signs, laboratory tests, and medications. Patients were divided into statin users or nonusers (active comparators). Statin users initiated statins and nonusers initiated H2-blockers or proton pump-inhibitors (H2-PPI) as an active comparator. Study outcomes were: 1) Composite renal disease progression outcome; 2) Incident diabetes with ophthalmic manifestations; and 3) Incident diabetes with neurological manifestations. RESULTS: Out of 705,774 eligible patients, we propensity score matched 81,146 pairs of statin users and active comparators. Over a mean (standard deviation) of follow up duration of 4.8 (3) years, renal disease progression occurred in 9.5% of statin users vs 8.3% of nonusers (odds ratio [OR]: 1.16; 95% confidence interval [95%CI]: 1.12-1.20), incident ophthalmic manifestations in 2.7% of statin users vs 2.0% of nonusers (OR: 1.35, 95%CI:1.27-1.44), and incident neurological manifestations in 6.7% of statin users vs 5.7% of nonusers (OR: 1.19, 95%CI:1.15-1.25). Secondary, sensitivity, and post-hoc analyses were consistent and demonstrated highest risks among the healthier subgroup and those with intensive lowering of LDL-cholesterol. CONCLUSIONS: Statin use in patients with diabetes was associated with modestly higher risk of renal disease progression, incident ophthalmic, and neurological manifestations. More research is needed to assess the overall harm/benefit balance for statins in the lower risk populations with diabetes and those who receive intensive statin therapy.

Autoantigen characterization in the lower esophageal sphincter muscle of patients with achalasia.

BACKGROUND: Serum anti-myenteric autoantibodies define autoimmune achalasia and tissue MMP-9 activity may locally process autoantigenic proteins in the muscle of the lower esophageal sphincter (LES) of achalasia patients. METHODS: Biopsies of the LES muscle from 36 achalasia patients, 6 esophagogastric junction outflow obstruction (EGJOO) patients, and 16 transplant donors (TD) were compared in a blind cross-sectional study. Histological characteristics such as inflammation, fibrosis, presence of ganglion cells, cells of Cajal, GAD65, PNMA2, S-100, P substance, and MMP-9 proteoforms in tissue were assessed by H&E and Picrosirius Red staining and immunohistochemistry analysis. Anti-neuronal antibodies, onconeural antigens, recoverin, SOX-1, titin, zic4, GAD65, and Tr were evaluated by immunoblot/line assay. KEY RESULTS: Tissue of achalasia patients had heterogeneous inflammatory infiltrates with fibrosis and contrasting higher levels of activated MMP-9, as compared with EGJOO and TD. Moreover, lower ganglion cell percentages and cell of Cajal percentages were determined in esophageal tissues of achalasia patients versus TD. The tissues of achalasia versus EGJOO patients had higher GAD65 and PNMA2 protein expression. Unexpectedly, these proteins were absent in TD tissue. S-100 and P substance had similar expression levels in tissues of achalasia patients versus TD and EGJOO. Most of the achalasia sera had anti-GAD65 (83%) and anti-PNMA2 (90%) autoantibodies versus EGJOO (17% and 33%, respectively) and healthy volunteers (10% and 0%, respectively). CONCLUSIONS AND INFERENCES: Tissue-specific ectopic expression of GAD65 and PNMA/Ta2 and active MMP-9, associated with the presence of specific autoantibodies directed against these proteins, might participate in the pathophysiology of achalasia triggering and/or perpetuating autoimmune disease.

The Risk of Clostridioides difficile Recurrence after Initial Treatment with Vancomycin or Fidaxomicin Utilizing Cerner Health Facts.

(1) Background: Fidaxomicin has been shown to significantly reduce Clostridioides difficile infection (CDI) recurrences rates in randomized, controlled trials. However, national data from the Veterans Affairs has called the real-world applicability of these findings into question. Therefore, we conducted a retrospective cohort study of patients receiving fidaxomicin or vancomycin as initial therapy for an index case of CDI in the hospital to evaluate the relative rates CDI recurrence within 90 days of an index case. (2) Methods: We retrieved patients 18 years and older who were admitted between July 2011 through June 2018 and diagnosed and treated for CDI with vancomycin or fidaxomicin. The first occurrence of CDI with treatment was designated as the index case. Patients with CDI within 1 year prior to index case were excluded. From the remaining index cases (vancomycin = 14,785; fidaxomicin = 889) the primary outcome (a recurrence of CDI within 90 days of the index case) was determined. The CDI recurrence rates for fidaxomicin and vancomyicn were evaluated using a Cox Proportional Hazards model on a propensity score matched cohort. (3) Results: A statistically significantly lower risk of CDI recurrence was observed with fidaxomicin use in the matched cohort (889 patients per treatment) using a Cox Proportional Hazards model (HR 0.67, 95% CI 0.50-0.90). (4) Conclusions: Fidaxomicin was independently associated with a decreased CDI recurrence, as defined by readmission for CDI within 90 days.