General Installation of (4H)-Imidazolone cis-Amide Bioisosteres Along the Peptide Backbone.

Imidazolones represent an important class of heterocycles present in a wide range of pharmaceuticals, metabolites, and bioactive natural products and serve as the active chromophore in green fluorescent protein. Recently, imidazolones have received attention for their ability to act as a nonaromatic amide bond bioisotere which improves pharmacological properties. Herein, we present a tandem amidine installation and cyclization with an adjacent ester to yield (4H)-imidazolone products. Using amino acid building blocks, we can access the first examples of α-chiral imidazolones that have been previously inaccessible. Additionally, our method is amenable to on-resin installation which can be seamlessly integrated into existing solid-phase peptide synthesis protocols. Finally, we show that peptide imidazolones are potent cis-amide bond surrogates that preorganize linear peptides for head-to-tail macrocyclization. This work represents the first general approach to the backbone and side-chain insertion of imidazolone bioisosteres at various positions in linear and cyclic peptides.

Cardiovascular event reduction among a US population eligible for semaglutide per the SELECT trial.

BACKGROUND: Our objective was to determine the number of major cardiovascular events (MACE, nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and deaths from any cause that could be prevented across varying nationwide uptake of semaglutide 2.4 mg SC weekly for the secondary prevention of cardiovascular disease. METHODS: Using a nationally representative cross-sectional study of participants in the 2017-2018 and 2019-March 2020 cycles of the National Health and Nutrition Examination Survey in the U.S. (NHANES), we estimated the number of MACE and deaths from any cause potentially prevented over a four-year period among participants meeting SELECT trial inclusion criteria. RESULTS: In a sample of n = 216 individuals (corresponding to 4,473,681 adults in the U.S. population) potentially eligible for this therapy, a total of 356,329 MACE and 232,808 all-cause mortality events were expected without semaglutide over 4 years and 35,633 MACE and 22,117 all-cause mortality events would be prevented with 50% uptake of semaglutide. CONCLUSIONS: Approximately 4.5 million adults in the U.S. are forecasted to be eligible for semaglutide 2.4mg SC weekly therapy, with substantial impact on CVD and mortality if accessible and broadly used.

Association of allostatic load with overall survival in epithelial ovarian cancer.

OBJECTIVE: Elevated allostatic load (AL), an integrated, cumulative marker of physiologic damage due to socioenvironmental stress, is associated with increased mortality in patients with breast, lung, and other cancers. The relationship between allostatic load and mortality in ovarian cancer patients remains unknown. We examined the relationship between allostatic load and overall survival in ovarian cancer patients. METHODS: This cross-sectional study used data from 201 patients enrolled in a prospective observational ovarian cancer cohort study at a National Cancer Institute-designated Comprehensive Cancer Center from October 2012 through June 2022. All patients underwent debulking surgery and completed a full course of standard-of-care platinum-based chemotherapy. Follow-up was completed through January 2024. Allostatic load was calculated as a summary score by assigning one point to the worst sample quartile for each of ten biomarkers measured within 45 days before the ovarian cancer diagnosis. High allostatic load was defined as having an allostatic load in the top quartile of the summary score. A Cox proportional hazard model with robust variance tested the association between allostatic load and overall survival. RESULTS: There were no associations between allostatic load and ovarian cancer clinical characteristics. After accounting for demographic, clinical, and treatment factors, high allostatic load was associated with a significant increase in mortality (hazard ratio 2.17 [95%CI, 1.13-4.15]; P = 0.02). CONCLUSION: Higher allostatic load is associated with worse survival among ovarian cancer patients. Allostatic load could help identify patients at risk for poorer outcomes who may benefit from greater socioenvironmental support during treatment.

Complementary Strategies for Installation of Thioimidates into Peptide Backbones.

Thioimidates are a precursor and synthetic branch point to access either thioamide or amidine isosteres of the native amide (peptide bond). Previous syntheses of thioimidate-containing peptides were prone to side reactivity and required slow, cumbersome steps that were difficult to monitor. We describe a more efficient approach to directly couple thioimidates onto the growing peptide chain. This work also outlines optimal conditions for thioimidate formation on solid support and identifies potential off-target sites for alkylation that impact the choice of protecting group.

Neuropsychiatric Comorbidities and Psychotropic Medication Use in Medicare Beneficiaries With Dementia by Sex and Race.

BACKGROUND: Neuropsychiatric symptoms affect the majority of dementia patients. Past studies report high rates of potentially inappropriate prescribing of psychotropic medications in this population. We investigate differences in neuropsychiatric diagnoses and psychotropic medication prescribing in a local US cohort by sex and race. METHODS: We utilize Medicare claims and prescription fill records in a cohort of 100% Medicare North and South Carolina beneficiaries ages 50 and above for the year 2017 with a dementia diagnosis. We identify dementia and quantify diagnosis of anxiety, depression and psychosis using validated coding algorithms. We search Medicare claims for antianxiety, antidepressant and antipsychotic medications to determine prescriptions filled. RESULTS: Anxiety and depression were diagnosed at higher rates in White patients; psychosis at higher rates in Black patients. (P < .001) Females were diagnosed with anxiety, depression and psychosis at higher rates than males (P < .001) and filled more antianxiety and antidepressant medications than males. (P < .001) Black and Other race patients filled more antipsychotic medications for anxiety, depression and psychosis than White patients. (P < .001) Antidepressants were prescribed at higher rates than antianxiety or antipsychotic medications across all patients and diagnoses. Of patients with no neuropsychiatric diagnosis, 11.4% were prescribed an antianxiety medication, 22.8% prescribed an antidepressant and 7.6% prescribed an antipsychotic. CONCLUSIONS: The high fill rate of antianxiety (benzodiazepine) medications in dementia patients, especially females is a concern. Patients are prescribed psychotropic medications at high rates. This practice may represent potentially inappropriate prescribing. Patient/caregiver education with innovative community outreach and care delivery models may help decrease medication use.

Association between characteristics of employing healthcare facilities and healthcare worker infection rates and psychosocial experiences during the COVID-19 pandemic.

BACKGROUND: Healthcare facility characteristics, such as ownership, size, and location, have been associated with patient outcomes. However, it is not known whether the outcomes of healthcare workers are associated with the characteristics of their employing healthcare facilities, particularly during the COVID-19 pandemic. METHODS: This was an analysis of a nationwide registry of healthcare workers (the Healthcare Worker Exposure Response and Outcomes (HERO) registry). Participants were surveyed on their personal, employment, and medical characteristics, as well as our primary study outcomes of COVID-19 infection, access to personal protective equipment, and burnout. Participants from healthcare sites with at least ten respondents were included, and these sites were linked to American Hospital Association data to extract information about sites, including number of beds, teaching status, urban/rural location, and for-profit status. Generalized estimating equations were used to estimate linear regression models for the unadjusted and adjusted associations between healthcare facility characteristics and outcomes. RESULTS: A total of 8,941 healthcare workers from 97 clinical sites were included in the study. After adjustment for participant demographics, healthcare role, and medical comorbidities, facility for-profit status was associated with greater odds of COVID-19 diagnosis (aOR 1.76, 95% CI 1.02-3.03, p = .042). Micropolitan location was associated with decreased odds of COVID-19 infection after adjustment (aOR = 0.42, 95% CI 0.24, 0.71, p = .002. For-profit facility status was associated with decreased odds of burnout after adjustment (aOR = 0.53, 95% CI 0.29-0.98), p = .044). CONCLUSIONS: For-profit status of employing healthcare facilities was associated with greater odds of COVID-19 diagnosis but decreased odds of burnout after adjustment for demographics, healthcare role, and medical comorbidities. Future research to understand the relationship between facility ownership status and healthcare outcomes is needed to promote wellbeing in the healthcare workforce. TRIAL REGISTRATION: The registry was prospectively registered: ClinicalTrials.gov Identifier (trial registration number) NCT04342806, submitted April 8, 2020.

Association Between Hospital-Documented Atrial Fibrillation and Central Retinal Artery Occlusion.

BACKGROUND: Carotid stenosis is thought to be the primary risk factor for central retinal artery occlusion (CRAO); however, it is not known whether atrial fibrillation (AF)-a cardiac arrhythmia that underlies over 25% of cerebral ischemic strokes-predisposes patients to CRAO. METHODS: A retrospective, observational, cohort study was performed using data from the State Inpatient Databases and State Emergency Department Databases from New York (2006-2015), California (2003-2011), and Florida (2005-2015) to determine the association between AF and CRAO. The primary exposure was hospital-documented AF. The primary end point was hospital-documented CRAO, defined as having an International Classification of Diseases, Ninth Revision, Clinical Modification, code 362.31 in the primary diagnosis position. Cause-specific hazard models were used to model CRAO-free survival among patients according to hospital-documented AF status. RESULTS: Of 39 834 885 patients included in the study, 2 723 842 (median age, 72.7 years; 48.5% women) had AF documented during the exposure window. The median follow-up duration was 6 years and 1 month. Patients with AF were older, more likely to be of non-Hispanic White race/ethnicity, and had a higher burden of cardiovascular comorbidities compared with patients without AF. The cumulative incidence of CRAO determined prospectively after exclusions was 8.69 per 100 000 at risk in those with AF and 2.39 per 100 000 at risk in those without AF over the study period. Before adjustment, AF was associated with higher risk of CRAO (hazard ratio, 2.55 [95% CI, 2.15-3.03]). However, after adjustment for demographics, state, and cardiovascular comorbidities, there was an inverse association between AF and risk of CRAO (adjusted hazard ratio, 0.72 [95% CI, 0.60-0.87]). These findings were robust in our prespecified sensitivity analyses. By contrast, positive control outcomes of embolic and ischemic stroke showed an expected strong relationship between AF and risk of stroke. CONCLUSIONS: We found an inverse association between AF and CRAO in a large, representative study of hospitalized patients; however, this cohort did not ascertain AF or CRAO occurring outside of hospital or emergency department settings.

Public reporting of black participation in anti-hypertensive drug clinical trials.

BACKGROUND: Non-Hispanic Black people in the United States have the highest prevalence of essential hypertension. Unfortunately, clinical trials often underrepresent Black patients. We aim to understand whether trial sponsorship type is associated with representation of Black participants in anti-hypertensive drug clinical trials. Then, we contextualize our findings amongst current efforts to improve diversity in clinical research populations. METHODS: We searched ClinicalTrials.gov in May 2022 for antihypertensive drug trials. Of n = 408 trials in our initial search, n = 97 (23.77%) met inclusion criteria and were stratified by sponsorship type (industry vs non-industry). Standardized tests of difference were employed to compare characteristics of these trials, and linear regression was used to model change over time. RESULTS: Of 97 trials reporting results from 2010 to 2020, there were minimal differences in the percent of Black patients enrolled in anti-hypertensive clinical trials by sponsorship type. Both industry and non-industry sponsored studies had high rates of non-reporting, with slightly more non-reporting for industry (73.2%) vs non-industry (66.67%) studies. Industry funded studies reported results to ClinicalTrials.gov within 23.3 ± 15.0 months from completing studies, while non-industry funded trials reported within 18.9 ± 10.8 months. CONCLUSIONS: Despite Black Americans carrying the highest burden of disease for essential hypertension, they are underrepresented in anti-hypertension clinical trials and their overall participation has decreased between 2010 and 2020. In addition, there is major underreporting of trial participant race. We implore researchers and funders to establish clear, meaningful targets for anti-hypertensive drug trial diversity, and improve transparency in reporting of study characteristics.

Coordinating Cardiology clinics randomized trial of interventions to improve outcomes (COORDINATE) - Diabetes: rationale and design.

Several medications that are proven to reduce cardiovascular events exist for individuals with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease, however they are substantially underused in clinical practice. Clinician, patient, and system-level barriers all contribute to these gaps in care; yet, there is a paucity of high quality, rigorous studies evaluating the role of interventions to increase utilization. The COORDINATE-Diabetes trial randomized 42 cardiology clinics across the United States to either a multifaceted, site-specific intervention focused on evidence-based care for patients with T2DM or standard of care. The multifaceted intervention comprised the development of an interdisciplinary care pathway for each clinic, audit-and-feedback tools and educational outreach, in addition to patient-facing tools. The primary outcome is the proportion of individuals with T2DM prescribed three key classes of evidence-based medications (high-intensity statin, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and either a sodium/glucose cotransporter-2 inhibitor (SGLT-2i) inhibitor or glucagon-like peptide 1 receptor agonist (GLP-1RA) and will be assessed at least 6 months after participant enrollment. COORDINATE-Diabetes aims to identify strategies that improve the implementation and adoption of evidence-based therapies.

Feasibility of intraoperative injection of radioactive tracer and blue dye for sentinel lymph node biopsy in vulvar cancer.

OBJECTIVE: The objective of this study was to examine the feasibility and success rate of intraoperative injection of radiotracer and blue dye performed by the surgeon without the use of preoperative lymphoscintigraphy for the detection of sentinel lymph nodes in clinically early stage vulvar cancer. METHODS: All patients with clinically early stage vulvar cancer who underwent attempted sentinel lymph node biopsy using intraoperative injection of Technetium-99 m (99mTc) tracer and blue dye performed by the surgeon after induction of anesthesia at single academic institution from 12/2009 to 5/2022 were identified. Demographic and clinicopathologic variables were collected. Data were compared using descriptive statistics. RESULTS: One hundred sixty-four patients (median age 66.4 years) underwent intraoperative injection of radioactive tracer and dye for sentinel lymph node biopsy. Most patients (n = 156, 95.1%) were white. Squamous cell carcinoma accounted for 138 cases (84.1%), melanoma for 10 (6.1%), extra-mammary invasive Paget's disease for 11 (6.7%), and other histologies for 5 (3%). A majority of cases were stage I disease on final pathology (n = 119, 72.6%). Most patients (n = 117, 71%) had tumors located within 2 cm of the midline and underwent planned bilateral groin assessment, while 47 (29%) had well lateralized lesions and underwent unilateral groin assessment. For the patients undergoing unilateral groin assessment, 44 of 47 (93.6%) had successful unilateral mapping. Of the patients who underwent bilateral groin assessment, 87 of 117 (74.4%) had successful bilateral mapping, and 26 of 117 (22.2%) had successful unilateral mapping. Of the 26 patients who underwent bilateral assessment but only had unilateral mapping, 19 had unilateral mapping to ipsilateral groin but failed contralateral mapping, six had midline lesions with successful mapping to one groin but failed mapping to the other groin, and one had unilateral mapping to the contralateral groin but not ipsilateral groin. The total successful sentinel lymph node mapping rate in this cohort was 86.5% (243/281 total sentinel lymph node attempts). CONCLUSION: In this cohort, the overall success rate of sentinel lymph node mapping and biopsy was 86.5%. The high rate of successful sentinel lymph node mapping supports the use of intraoperative radiotracer and blue dye injection by trained providers.

Evaluation of weight change and cardiometabolic risk factors in a real-world population of US adults with overweight or obesity.

Whether individuals in real-world settings are able to lose weight and improve cardiometabolic risk factors over time is unclear. We aimed to determine the management of and degree of body weight change over 2 years among individuals with overweight or obesity, and to assess associated changes in cardiometabolic risk factors and clinical outcomes. Using data from 11 large health systems within the Patient-Centered Outcomes Research Network in the U.S., we collected the following data on adults with a recorded BMI ≥25 kg/m2 between January 1, 2016 and December 31, 2016: body-mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDLC), triglycerides and glycated hemoglobin (HbA1c). We found that among 882,712 individuals with BMI ≥25 kg/m2 (median age 59 years; 56% female), 52% maintained stable weight over 2 years and 1.3% utilized weight loss pharmacotherapy. Weight loss of 10% was associated with small but significant lowering of mean SBP (-2.69 mmHg [95% CI -2.88, -2.50]), DBP (-1.26 mmHg [95% CI -1.35, -1.18]), LDL-C (-2.60 mg/dL [95% CI -3.14, -2.05]), and HbA1c (-0.27% [95% CI -0.35, -0.19]) in the same 12 months. However, these changes were not sustained over the following year. In this study of adults with BMI ≥25 kg/m2, the majority had stable weight over 2 years, pharmacotherapies for weight loss were under-used, and small changes in cardiometabolic risk factors with weight loss were not sustained, possibly due to failure to maintain weight loss.

Dementia and Parkinson's disease diagnoses in electronic health records vs. Medicare claims data: a study of 101,980 linked patients.

BACKGROUND: Medicare claims and electronic health record data are both commonly used for research and clinical practice improvement; however, it is not known how concordant diagnoses of neurodegenerative diseases (NDD, comprising dementia and Parkinson's disease) are in these data types. Therefore, our objective was to determine the sensitivity and specificity of neurodegenerative disease (NDD) diagnoses contained in structured electronic health record (EHR) data compared to Medicare claims data. METHODS: This was a retrospective cohort study of 101,980 unique patients seen at a large North Carolina health system between 2013-2017, which were linked to 100% North and South Carolina Medicare claims data, to evaluate the accuracy of diagnoses of neurodegenerative diseases in EHRs compared to Medicare claims data. Patients age > 50 who were enrolled in fee-for-service Medicare were included in the study. Patients were classified as having or not having NDD based on the presence of validated ICD-CM-9 or ICD-CM-10 codes associated with NDD or claims for prescription drugs used to treat NDD. EHR diagnoses were compared to Medicare claims diagnoses. RESULTS: The specificity of any EHR diagnosis of NDD was 99.0%; sensitivity was 61.3%. Positive predictive value and negative predictive value were 90.8% and 94.1% respectively. Specificity of an EHR diagnosis of dementia was 99.0%, and sensitivity was 56.1%. Specificity of an EHR diagnosis of PD was 99.7%, while sensitivity was 76.1%. CONCLUSIONS: More research is needed to investigate under-documentation of NDD in electronic health records relative to Medicare claims data, which has major implications for clinical practice (particularly patient safety) and research using real-world data.

Amplitude Integrated Electroencephalography: Simulated Assessment of Neonatal Seizure Detection in PICU Patients.

OBJECTIVES: Amplitude integrated electroencephalography (aEEG) is a mainstay of care in neonatal ICUs; however, knowledge gaps exist in relation to its accuracy for identifying seizures in older children. We aimed to review the diagnostic accuracy of existing neonatal seizure detection criteria for seizure detection in older children in hospital. DESIGN: Retrospective study. SETTING: PICU/Neurophysiology Department in Dublin. PATIENTS: One hundred twenty patients (2 mo to 16 yr old) were chosen from a database of formal 10-20 system, 21-lead electroencephalography recordings (2012-2020), comprising 30 studies with seizures, 90 without. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Electroencephalography studies containing electrographic seizures (ESzs) were annotated to describe number, duration, distribution, and spread. Two-channel aEEG (using leads C3-P3, C4-P4) recordings were generated and independently reviewed by a professional specialist in clinical neurophysiology blinded to outcome and without reference to the raw electroencephalography trace. Logistic regression was used to identify factors associated with correct seizure identification on aEEG. Median patient age was 6.1 years. Abnormal recordings featured 123 seizures. Status epilepticus (SE) was evident by electroencephalography in 10 cases. Using neonatal criteria, aEEG had a sensitivity of 70% and negative predictive value of 90% for identifying any ESz. Accurate detection of individual seizures was diminished when seizures were very short or occurred during waking. Sensitivity for individual seizures was 81% when seizures less than 1 minute were excluded. aEEG correctly identified SE in 70% of the 10 cases, although ESz were confirmed to be present in 80% of this subpopulation. CONCLUSIONS: aEEG criteria for neonatal seizure identification can be applied with caution to older children and should be supplemented by formal electroencephalography. Seizure identification is better for longer seizures and those arising from sleep. SE is not always recognized by aEEG among older children.

Racial/ethnic disparities in dementia incidence, outcomes, and health-care utilization.

INTRODUCTION: Racial/ethnic disparities exist in many aspects of health care, but data on racial/ethnic disparities for neurodegenerative diseases (NDDs), such as dementia and Parkinson's disease (PD), are limited. METHODS: We used North and South Carolina Medicare claims from 2013 to 2017 to evaluate disparities in incidence of NDDs and in health-care utilization and outcomes for patients with NDDs. RESULTS: Disparities in incidence of NDD between Black and White beneficiaries narrowed by 0.37 per 100 person-years from 2014 to 2017. After thorough covariate adjustment, Black beneficiaries had a 4% higher risk of all-cause hospitalization, spent 8% more days in skilled nursing facilities and 14% fewer days in hospice facilities, were 38% less likely to receive physical/occupational therapy services, were 8% less likely to receive dementia medications, and were 19% less likely to receive PD medications than White beneficiaries. DISCUSSION: Effective system-level approaches to promote health equity in NDD diagnosis, treatment, and outcomes are clearly needed. HIGHLIGHTS: Racial disparities in neurodegenerative disease incidence narrowed between 2014 and 2017. Black patients were less likely than White patients to receive hospice services. Black patients were less likely than White patients to receive physical therapy. Black patients were less likely than White patients to receive Alzheimer's disease or Parkinson's disease medications. There is a shortage of neurologists in counties with high dementia incidence.

Incorporating SGLT2i and GLP-1RA for Cardiovascular and Kidney Disease Risk Reduction: Call for Action to the Cardiology Community.

Multiple sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to impart significant cardiovascular and kidney benefits, but are underused in clinical practice. Both SGLT-2i and GLP-1RA were first studied as glucose-lowering drugs, which may have impeded uptake by cardiologists in the wake of proven cardiovascular efficacy. Their significant effect on cardiovascular and kidney outcomes, which are largely independent of glucose-lowering effects, must drive a broader use of these drugs. Cardiologists are 3 times more likely than endocrinologists to see patients with both type 2 diabetes and cardiovascular disease, thus they are ideally positioned to share responsibility for SGLT-2i and GLP-1RA treatment with primary care providers. In order to increase adoption, SGLT-2i and GLP-1RA must be reframed as primarily cardiovascular and kidney disease risk-reducing agents with a side effect of glucose-lowering. Coordinated and multifaceted interventions engaging clinicians, patients, payers, professional societies, and health systems must be implemented to incentivize the adoption of these medications as part of routine cardiovascular and kidney care. Greater use of SGLT-2i and GLP-1RA will improve outcomes for patients with type 2 diabetes at high risk for cardiovascular and kidney disease.

A General Strategy to Install Amidine Functional Groups Along the Peptide Backbone.

Amidines are a structural surrogate for peptide bonds, yet have received considerably little attention in peptides due to limitations in existing methods to access them. The synthetic strategy developed in this study represents the first robust and general procedure for the introduction of amidines into the peptide backbone. We exploit and further develop the utility and efficiency of thioimidate protecting groups as a means to side-step reactivity that ultimately renders existing methods unsuitable for the installation of amidines along the main-chain of peptides. This work is significant because it describes a generally applicable path to access unexplored peptide designs and architectures for new therapeutics made possible by the unique properties of amidines.

Association between economic and arrhythmic burden of paroxysmal atrial fibrillation in patients with cardiac implanted electronic devices.

BACKGROUND: As the prevalence of atrial fibrillation (AF) increases, a greater understanding of the costs associated with AF care is required. While individuals with greater arrhythmic burden may interact with the health system more frequently, the relationship between AF burden and costs remains undefined. METHODS: In a longitudinal patient cohort with paroxysmal AF and newly implanted cardiovascular implantable electronic devices (CIED) (2010-2016), we linked CIED remote-monitoring data with Medicare claims to assess the association between the 30-day averaged device-detected daily percentage of time in AF ("AF burden") and healthcare costs. RESULTS: Among 39,345 patients, the mean age was 77.1 ± 8.7 years, 60.7% were male, and the mean CHA2DS2-VASc score was 4.9 ± 1.3. The mean total 1-year costs were $18,668 ± 29,173, driven by hospitalization costs where two-thirds of admissions were due to heart failure. Increasing AF burden was associated with increasing costs: $17,860 ± 28,525 for 0% daily AF burden; $18,840 ± 29,104 for 0-5% daily AF burden; and $20,968 ± 31,228 for 5-98% daily AF burden. There was a linear relationship between AF burden expressed as a continuous variable and 1-year costs (adjusted cost rate ratio 1.031 per 10% daily duration in AF, 95% confidence interval 1.023-1.038; P < .001). CONCLUSIONS: Among older patients with paroxysmal AF and CIEDs, increasing AF burden is associated with higher healthcare costs. As the observational study design is unable to determine causal relationships, prospective study is required to explore the intriguing hypothesis that targeted AF strategies, including comorbidity management, that reduce AF burden may also reduce the high annual costs associated with AF.

Patterns of Potential Moral Injury in Post-9/11 Combat Veterans and COVID-19 Healthcare Workers.

BACKGROUND: Moral injury has primarily been studied in combat veterans but might also affect healthcare workers (HCWs) due to the COVID-19 pandemic. OBJECTIVE: To compare patterns of potential moral injury (PMI) between post-9/11 military combat veterans and healthcare workers (HCWs) surveyed during the COVID-19 pandemic. DESIGN: Cross-sectional surveys of veterans (2015-2019) and HCWs (2020-2021) in the USA. PARTICIPANTS: 618 military veterans who were deployed to a combat zone after September 11, 2001, and 2099 HCWs working in healthcare during the COVID-19 pandemic. MAIN MEASURES: Other-induced PMI (disturbed by others' immoral acts) and self-induced PMI (disturbed by having violated own morals) were the primary outcomes. Sociodemographic variables, combat/COVID-19 experience, depression, quality of life, and burnout were measured as correlates. KEY RESULTS: 46.1% of post-9/11 veterans and 50.7% of HCWs endorsed other-induced PMI, whereas 24.1% of post-9/11 veterans and 18.2% of HCWs endorsed self-induced PMI. Different types of PMI were significantly associated with gender, race, enlisted vs. officer status, and post-battle traumatic experiences among veterans and with age, race, working in a high COVID-19-risk setting, and reported COVID-19 exposure among HCWs. Endorsing either type of PMI was associated with significantly higher depressive symptoms and worse quality of life in both samples and higher burnout among HCWs. CONCLUSIONS: The potential for moral injury is relatively high among combat veterans and COVID-19 HCWs, with deleterious consequences for mental health and burnout. Demographic characteristics suggestive of less social empowerment may increase risk for moral injury. Longitudinal research among COVID-19 HCWs is needed. Moral injury prevention and intervention efforts for HCWs may benefit from consulting models used with veterans.

Glycemic status, non-traditional risk and left ventricular structure and function in the Jackson Heart Study.

BACKGROUND: Left ventricular structure and function abnormalities may be an early marker of cardiomyopathy among African Americans with diabetes (DM) even in the absence of coronary artery disease (CAD), arrhythmia, valvular heart disease and end-stage renal disease (ESRD). This study examined the association of prediabetes (PDM), DM and HbA1c with left ventricular structure and function among Jackson Heart Study (JHS) participants without traditional risk factors. METHODS: Retrospective cross-sectional analyses of the association of PDM, DM and HbA1c with, left ventricular ejection fraction (LV EF), fractional shortening (LV FS), stroke volume index (SVI), cardiac index (CI), left ventricular end diastolic volume index (LVEDVI), left ventricular end systolic volume index (LVESVI), relative wall thickness (RWT), myocardial contraction fraction (MCF) and left ventricular mass index (LVMI). The study was conducted in 2234 adult JHS participants without preexisting CAD, arrhythmia, valvular heart disease or ESRD. Statistical analyses included descriptive, univariate and covariate adjusted linear regression analyses. Sensitivity analyses to explore the impact of hypertension on study outcomes were also carried out. RESULTS: DM compared with no DM was associated with lower, SVI (- 0.96 ml/m2, p = 0.029), LVEDVI (- 1.44 ml/m2 p = 0.015), and MCF (- 1.90% p = 0.007) but higher CI (0.14 L/min/m2, p < 0.001), RWT (0.01 cm, p = 0.002) and LVMI (2.29 g/m2, p = 0.009). After further control for DM duration, only CI remaining significantly higher for DM compared with no DM participants (0.12 L/min/m2, p = 0.009). PDM compared with no PDM was associated with lower, SVI (- 0.87 ml/m2, P = 0.024), LVEDVI (- 1.15 ml/m2 p = 0.003) and LVESVI (- 0.62 ml/m2 p = 0.025). HbA1c ≥ 8.0% compared with HbA1c < 5.7% was associated with lower SVI (- 2.09 ml/m2, p = 0.004), LVEDVI (- 2.11 ml/m2 p = 0.032) and MCF (- 2.94% p = 0.011) but higher CI (0.11 L/min/m2, p = 0.043) and RWT (0.01 cm, p = 0.035). CONCLUSIONS: Glycemic status is associated with important left ventricular structure and function changes among African Americans without prior CAD, arrhythmia, valvular heart disease and ESRD. Longitudinal studies may further elucidate these relationships.

Fitness of real-world data for clinical trial data collection: Results and lessons from a HARMONY Outcomes ancillary study.

BACKGROUND: Despite the extensive use of real-world data for retrospective, observational clinical research, our understanding of how real-world data might increase the efficiency of data collection in patient-level randomized clinical trials is largely unknown. The structure of real-world data is inherently heterogeneous, with each source electronic health record and claims database different from the next. Their fitness-for-use as data sources for multisite trials in the United States has not been established. METHODS: For a subset of participants in the HARMONY Outcomes Trial, we obtained electronic health record data from recruiting sites or Medicare claims data from the Centers for Medicare & Medicaid Services. For baseline characteristics and follow-up events, we assessed the level of agreement between these real-world data and data documented in the trial database. RESULTS: Real-world data-derived demographic information tended to agree with trial-reported demographic information, although real-world data were less accurate in identifying medical history. The ability of real-world data to identify baseline medication usage differed by real-world data source, with claims data demonstrating substantially better performance than electronic health record data. The limited number of lab results in the collected electronic health record data matched closely with values in the trial database. There were not enough follow-up events in the ancillary study population to draw meaningful conclusions about the performance of real-world data for identification of events. Based on the conduct of this ancillary study, the challenges and opportunities of using real-world data within clinical trials are discussed. CONCLUSION: Based on a subset of participants from the HARMONY Outcomes Trial, our results suggest that electronic health record or claims data, as currently available, are unlikely to be a complete substitute for trial data collection of medical history or baseline lab results, but that Medicare claims were able to identify most medications. The limited size of the study population prevents us from drawing strong conclusions based on these results, and other studies are clearly needed to confirm or refute these findings.