Comparative effectiveness of azathioprine and mycophenolate mofetil for myasthenia gravis (PROMISE-MG): a prospective cohort study.

BACKGROUND: Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression, and immunomodulation. In addition to corticosteroids, azathioprine and mycophenolate mofetil are the most frequently used immunosuppressants in North America. We aimed to evaluate the comparative effectiveness of these two drugs, and to assess the effect of the dose and duration of treatment. METHODS: We did a prospective cohort study at 19 academic centres in Canada and the USA. We included patients (aged ≥18 years) with autoimmune myasthenia gravis, who were never treated with immunosuppressants. Treating clinicians determined the choice of medication, dose, follow-up intervals, and drug monitoring. Outcome measures and adverse events were recorded at each visit. We assessed two co-primary outcomes. The first was the patient-reported Myasthenia Gravis-Quality of Life 15-revised (MGQOL-15r) score, measured as the mean change from treatment initiation to the follow-up visit with the lowest score. A clinically meaningful reduction (CMR) in MGQOL-15r was defined as a 5-point decrease. The second was a composite clinical outcome of disease improvement (Myasthenia Gravis Foundation of America Post-Intervention Status Minimal Manifestations or better) and low adverse event burden (defined as grade ≤1 Common Terminology Criteria for Adverse Events). We also compared these outcomes in patients receiving an adequate dose and duration of azathioprine (≥2 mg/kg per day for at least 12 months) or mycophenolate mofetil (≥2 g per day for at least 8 months) and a lower dose or shorter duration of these agents. We used propensity score weighting with generalised linear regression models. This study is registered with ClinicalTrials.gov (NCT03490539). FINDINGS: Between May 1, 2018, and Aug 31, 2020, 167 patients were enrolled; 85 did not receive azathioprine or mycophenolate mofetil and were excluded. Four were excluded from outcome analyses because they had scores of 0 on an outcome measure at treatment initiation. Of the 78 patients included in analyses, 47 received mycophenolate mofetil (median follow-up 25 months [IQR 13·5-31·5]) and 31 received azathioprine (median follow-up 20 months [IQR 13-30]). The mean change in MG-QOL15r was -10·4 (95% CI -18·9 to -1·3) with mycophenolate mofetil and -6·8 (-17·2 to 3·6) with azathioprine (mean difference -3·3, 95% CI -7·7 to 1·2; p=0·15). 38 (81%) of 47 patients receiving mycophenolate mofetil and 18 (57%) of 31 receiving azathioprine had a CMR in MG-QOL15r (risk difference 24·0%; 95% CI -0·2 to 48·0; p=0·052). The clinical composite outcome was achieved in 22 (47·7%) of 47 patients who received mycophenolate mofetil and nine (28·1%) of 31 who received azathioprine (risk difference 19·6%, 95% CI -4·9 to 44·2; p=0·12). Descriptive analysis did not find a difference in the proportion of patients reaching a CMR in MG-QOL15r between the adequate dose and duration group and the lower dose or shorter duration group. Adverse events occurred in 11 (32%) of 34 patients who received azathioprine and nine (19%) of 48 who received mycophenolate mofetil. The most frequent adverse events were hepatotoxicity with azathioprine (five [15%] of 34) and gastrointestinal disturbances (seven [15%] of 48) with mycophenolate mofetil. There were no study-related deaths. INTERPRETATION: More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs. Adverse events associated with azathioprine were potentially more serious than those with mycophenolate mofetil, although mycophenolate mofetil is teratogenic. Lower than recommended doses of azathioprine might be effective, with reduced dose-dependent adverse events. More comparative effectiveness studies are required to inform treatment choices in myasthenia gravis. FUNDING: Patient-Centered Outcomes Research Institute, Myasthenia Gravis Foundation of America.

Post-traumatic stress disorder symptoms among healthcare workers during the COVID-19 pandemic: Analysis of the HERO Registry.

Little is known about the mental health consequences of the COVID-19 pandemic in healthcare workers (HCWs). Past literature has shown that chronic strain caused by pandemics can adversely impact a variety of mental health outcomes in HCWs. There is growing recognition of the risk of stress and loss of resilience to HCWs during the COVID-19 pandemic, although the risk of post-traumatic stress disorder (PTSD) symptoms in HCWs during the COVID-19 pandemic remains poorly understood. We wanted to understand the relationship between the COVID-19 pandemic and the risk of PTDS symptoms in HCWs during the COVID-19 pandemic. We surveyed 2038 health care workers enrolled in the Healthcare Worker Exposure Response & Outcomes (HERO) study, which is a large standardized national registry of health care workers. Participants answered questions about demographics, COVID-19 exposure, job burnout, and PTSD symptoms. We characterize the burden of PTSD symptoms among HCWs, and determined the association between high PTSD symptoms and race, gender, professional role, work setting, and geographic region using multivariable regression. In a fully adjusted model, we found that older HCWs were less likely to report high PTSD symptoms compared with younger HCWs. Additionally, we found that physicians were less likely to report high PTSD symptoms compared with nurses. These data add to the growing literature on increased risks of mental health challenges to healthcare workers during the COVID-19 pandemic.

Addressing substantial covariate imbalance with propensity score stratification and balancing weights: connections and recommendations.

Objectives: Propensity score (PS) weighting methods are commonly used to adjust for confounding in observational treatment comparisons. However, in the setting of substantial covariate imbalance, PS values may approach 0 and 1, yielding extreme weights and inflated variance of the estimated treatment effect. Adaptations of the standard inverse probability of treatment weights (IPTW) can reduce the influence of extremes, including trimming methods that exclude people with PS values near 0 or 1. Alternatively, overlap weighting (OW) optimizes criteria related to bias and variance, and performs well compared to other PS weighting and matching methods. However, it has not been compared to propensity score stratification (PSS). PSS has some of the same potential advantages; being insensitive extreme values. We sought to compare these methods in the setting of substantial covariate imbalance to generate practical recommendations. Methods: Analytical derivations were used to establish connections between methods, and simulation studies were conducted to assess bias and variance of alternative methods. Results: We find that OW is generally superior, particularly as covariate imbalance increases. In addition, a common method for implementing PSS based on Mantel-Haenszel weights (PSS-MH) is equivalent to a coarsened version of OW and can perform nearly as well. Finally, trimming methods increase bias across methods (IPTW, PSS and PSS-MH) unless the PS model is re-fit to the trimmed sample and weights or strata are re-derived. After trimming with re-fitting, all methods perform similarly to OW. Conclusions: These results may guide the selection, implementation and reporting of PS methods for observational studies with substantial covariate imbalance.

Propensity score weighting methods for causal subgroup analysis with time-to-event outcomes.

Evaluating causal effects of an intervention in pre-specified subgroups is a standard goal in comparative effectiveness research. Despite recent advancements in causal subgroup analysis, research on time-to-event outcomes has been lacking. This article investigates the propensity score weighting method for causal subgroup survival analysis. We introduce two causal estimands, the subgroup marginal hazard ratio and subgroup restricted average causal effect, and provide corresponding propensity score weighting estimators. We analytically established that the bias of subgroup-restricted average causal effect is determined by subgroup covariate balance. Using extensive simulations, we compare the performance of various combinations of propensity score models (logistic regression, random forests, least absolute shrinkage and selection operator, and generalized boosted models) and weighting schemes (inverse probability weighting, and overlap weighting) for estimating the causal estimands. We find that the logistic model with subgroup-covariate interactions selected by least absolute shrinkage and selection operator consistently outperforms other propensity score models. Also, overlap weighting generally outperforms inverse probability weighting in terms of balance, bias and variance, and the advantage is particularly pronounced in small subgroups and/or in the presence of poor overlap. We applied the methods to the observational Comparing Options for Management: PAtient-centered REsults for Uterine Fibroids study to evaluate the causal effects of myomectomy versus hysterectomy on the time to disease recurrence in a number of pre-specified subgroups of patients with uterine fibroids.

Gender and intention to leave healthcare during the COVID-19 pandemic among U.S. healthcare workers: A cross sectional analysis of the HERO registry.

IMPORTANCE: The COVID-19 pandemic stressed the healthcare field, resulting in a worker exodus at the onset and throughout the pandemic and straining healthcare systems. Female healthcare workers face unique challenges that may impact job satisfaction and retention. It is important to understand factors related to healthcare workers' intent to leave their current field. OBJECTIVE: To test the hypothesis that female healthcare workers were more likely than male counterparts to report intention to leave. DESIGN: Observational study of healthcare workers enrolled in the Healthcare Worker Exposure Response and Outcomes (HERO) registry. After baseline enrollment, two HERO 'hot topic' survey waves, in May 2021 and December 2021, ascertained intent to leave. Unique participants were included if they responded to at least one of these survey waves. SETTING: HERO registry, a large national registry that captures healthcare worker and community member experiences during the COVID-19 pandemic. PARTICIPANTS: Registry participants self-enrolled online and represent a convenience sample predominantly composed of adult healthcare workers. EXPOSURE(S): Self-reported gender (male, female). MAIN OUTCOME: Primary outcome was intention to leave (ITL), defined as having already left, actively making plans, or considering leaving healthcare or changing current healthcare field but with no active plans. Multivariable logistic regression models were performed to examine the odds of intention to leave with adjustment for key covariates. RESULTS: Among 4165 responses to either May or December surveys, female gender was associated with increased odds of ITL (42.2% males versus 51.4% females reported intent to leave; aOR 1.36 [1.13, 1.63]). Nurses had 74% higher odds of ITL compared to most other health professionals. Among those who expressed ITL, three quarters reported job-related burnout as a contributor, and one third reported experience of moral injury. CONCLUSIONS AND RELEVANCE: Female healthcare workers had higher odds of intent to leave their healthcare field than males. Additional research is needed to examine the role of family-related stressors. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04342806.

Long-term health-related quality of life and symptom severity following hysterectomy, myomectomy, or uterine artery embolization for the treatment of symptomatic uterine fibroids.

BACKGROUND: Few studies have directly compared different surgical procedures for uterine fibroids with respect to long-term health-related quality of life outcomes and symptom improvement. OBJECTIVE: We examined differences in change from baseline to 1-, 2-, and 3-year follow-up in health-related quality of life and symptom severity among patients who underwent abdominal myomectomy, laparoscopic or robotic myomectomy, abdominal hysterectomy, laparoscopic or robotic hysterectomy, or uterine artery embolization. STUDY DESIGN: The COMPARE-UF registry is a multiinstitutional prospective observational cohort study of women undergoing treatment for uterine fibroids. A subset of 1384 women aged 31 to 45 years who underwent either abdominal myomectomy (n=237), laparoscopic myomectomy (n=272), abdominal hysterectomy (n=177), laparoscopic hysterectomy (n=522), or uterine artery embolization (n=176) were included in this analysis. We obtained demographics, fibroid history, and symptoms by questionnaires at enrollment and at 1, 2, and 3 years posttreatment. We used the UFS-QoL (Uterine Fibroid Symptom and Quality of Life) questionnaire to ascertain symptom severity and health-related quality of life scores among participants. To account for potential baseline differences across treatment groups, a propensity score model was used to derive overlap weights and compare total health-related quality of life and symptom severity scores after enrollment with a repeated measures model. For this health-related quality of life tool, a specific minimal clinically important difference has not been determined, but on the basis of previous research, a difference of 10 points was considered as a reasonable estimate. Use of this difference was agreed upon by the Steering Committee at the time when the analysis was planned. RESULTS: At baseline, women undergoing hysterectomy and uterine artery embolization reported the lowest health-related quality of life scores and highest symptom severity scores compared with those undergoing abdominal myomectomy or laparoscopic myomectomy (P<.001). Those undergoing hysterectomy and uterine artery embolization reported the longest duration of fibroid symptoms with a mean of 6.3 years (standard deviation, 6.7; P<.001). The most common fibroid symptoms were menorrhagia (75.3%), bulk symptoms (74.2%), and bloating (73.2%). More than half (54.9%) of participants reported anemia, and 9.4% women reported a history of blood transfusion. Across all modalities, total health-related quality of life and symptom severity score markedly improved from baseline to 1-year with the largest improvement in the laparoscopic hysterectomy group (Uterine Fibroids Symptom and Quality of Life: delta= [+] 49.2; symptom severity: delta= [-] 51.3). Those undergoing abdominal myomectomy, laparoscopic myomectomy, and uterine artery embolization also demonstrated significant improvement in health-related quality of life (delta= [+]43.9, [+]32.9, [+]40.7, respectively) and symptom severity (delta= [-]41.4, [-] 31.5, [-] 38.5, respectively) at 1 year, and the improvement persisted from baseline for uterine-sparing procedures during second (Uterine Fibroids Symptom and Quality of Life: delta= [+]40.7, [+]37.4, [+]39.3 SS: delta= [-] 38.5, [-] 32.0, [-] 37.7 and third year (Uterine Fibroids Symptom and Quality of Life: delta= [+] 40.9, [+]39.9, [+]41.1 and SS: delta= [-] 33.9, [-]36.5, [-] 33.0, respectively), posttreatment intervals, however with a trend toward decline in degree of improvement from years 1 and 2. Differences from baseline were greatest for hysterectomy; however, this may reflect the relative importance of bleeding in the Uterine Fibroids Symptom and Quality of Life, rather than clinically meaningful symptom recurrence among women undergoing uterus-sparing treatments. CONCLUSION: All treatment modalities were associated with significant improvements in health-related quality of life and symptom severity reduction 1-year posttreatment. However, abdominal myomectomy, laparoscopic myomectomy and uterine artery embolization indicated a gradual decline in symptom improvement and health-related quality of life by third year after the procedure.

Dexamethasone for Inpatients With COVID-19 in a National Cohort.

Importance: Limited effective therapeutics are available to hospitalized patients with COVID-19. Clinical trials and observational studies have shown varying effects of systemic corticosteroids, including dexamethasone, in hospitalized patients with COVID-19, with limited descriptions of important patient subgroups. Objective: To examine the clinical use of dexamethasone for hospitalized patients with COVID-19 respiratory illness and to explore the heterogeneity of treatment outcomes across different subgroups. Design, Setting, and Participants: This is a retrospective, propensity score-weighted cohort study of adult patients hospitalized for at least 48 hours for COVID-19 respiratory illness between July 1, 2020, and October 31, 2021, at a large health care network of 156 hospitals across the US. Data analysis was performed from March 2022 to February 2023. Exposures: Systemic dexamethasone administered within 48 hours of either admission or escalation in oxygen support. Main Outcomes and Measures: All-cause in-hospital mortality or discharge to hospice. Results: A total of 80 699 patients who met the eligibility criteria were identified (median [IQR] age, 64 [52-76] years; 37 606 women [46.6%]); 13 230 patients (16.4%) identified as Black, 49 222 (60.9%) as White, 18 247 (22.6%) as other race, and 20 340 (25.2%) as Hispanic ethnicity. Of these patients, 13 040 (16.2%) did not require supplemental oxygen within 48 hours of admission, 56 368 (69.8%) required supplemental oxygen, 7618 (9.4%) required noninvasive positive pressure ventilation (NIPPV), and 3673 (4.6%) required mechanical ventilation (MV) and/or extracorporeal membrane oxygenation (ECMO). After adjustment by propensity score overlap weighting, early use of dexamethasone was associated with reduction in a composite outcome of in-hospital mortality or discharge to hospice for patients receiving supplemental oxygen (aOR, 0.92; 95% CI, 0.86-0.98) and MV and/or ECMO (aOR, 0.82; 95% CI, 0.68-0.99). In contrast, all-cause inpatient mortality or discharge to hospice was not lower for patients who received dexamethasone in the no supplemental oxygen group (aOR, 0.90; 95% CI, 0.78-1.03) and in the NIPPV group (aOR, 0.87; 95% CI, 0.73-1.04). Importantly, patients with more comorbidities had greater benefit from dexamethasone use. Conclusions and Relevance: In this national multicenter cohort study of inpatients with COVID-19, early administration of dexamethasone was associated with significantly reduced odds of mortality or discharge to hospice in those requiring supplemental oxygen or MV and/or ECMO but not in those requiring no supplemental oxygen or NIPPV. These results support the continued use of systemic dexamethasone in patients hospitalized with COVID-19.

A Comparative Analysis of Health-Related Quality of Life 1 Year Following Myomectomy or Uterine Artery Embolization: Findings from the COMPARE-UF Registry.

Objective: To compare 12-month post-treatment health-related quality of life (HR-QoL) and symptom severity (SS) changes among patients with symptomatic uterine fibroids (SUF) not seeking fertility and undergo a hysterectomy, abdominal myomectomy (AM), or uterine artery embolization (UAE). Materials and Methods: The Comparing Options for Management: Patient-Centered Results for Uterine Fibroids (COMPARE-UF) Registry is a multi-institutional prospective observational cohort study of patients treated for SUF. A subset of 1465 women 31-45 years of age, who underwent either hysterectomy (n = 741), AM (n = 446), or UAE (n = 155) were included in this analysis. Demographics, fibroid history, and symptoms were obtained by baseline questionnaires and at 1 year post-treatment. Results were stratified by all treatments and propensity score weighting to adjust for differences in baseline characteristics. Results: Women undergoing UAE reported the lowest baseline HR-QoL and highest SS scores (mean = 40.6 [standard deviation (SD) = 23.8]; 62.3 [SD = 24.2]) followed by hysterectomy (44.3 [24.3]; 59.8 [SD = 24.1]). At 12 months, women who underwent a hysterectomy experienced the largest change in both HR-QoL (48.7 [26.2]) and SS (51.9 [25.6]) followed by other uterine-sparing treatments. Propensity score weighting revealed all treatments produced substantial improvement, with hysterectomy patients reporting the highest HR-QoL score (92.0 [17.8]) compared with myomectomy (86.7 [17.2]) and UAE (82.6 [21.5]) (p < 0.0001). Similarly, hysterectomy patients reported the lowest SS scores (8.2 [15.1]) compared with myomectomy (16.5 [15.1]) and UAE (19.6 [17.5]) (p < 0.0001). Conclusion: All procedures showed improvement in HR-QoL and reduction in SS score at 12 months, hysterectomy showing maximum improvement. Of importance, at 12 months, patients who underwent either a myomectomy or UAE reported comparable symptom relief and HR-QoL. Clinicaltrials.Gov Identifier: NCT02260752.

Experiences of U.S. Nurses Compared With Nonnurses in the First Year of COVID-19: Findings From a National Registry.

BACKGROUND: Nursing professional organizations and media sources indicated early in the pandemic that the physical and psychological effects of COVID-19 might be distinct and possibly greater in nurses than in other types of healthcare workers (HCWs). OBJECTIVES: Based on survey data collected in Healthcare Worker Exposure Response and Outcomes (HERO), a national registry of U.S. HCWs, this study compared the self-reported experiences of nurses with other HCWs during the first 13 months of the pandemic. METHODS: Nurse responses were compared to responses of nonnurse HCWs in terms of viral exposure, testing and infection, access to personal protective equipment (PPE), burnout, and well-being. Logistic regression models were used to examine associations between nurse and nonnurse roles for the binary end points of viral testing and test positivity for COVID-19. We also examined differences by race/ethnicity and high-risk versus low-risk practice settings. RESULTS: Of 24,343 HCWs in the registry, one third self-identified as nurses. Nurses were more likely than other HCWs to report exposure to SARS-CoV-2, problems accessing PPE, and decreased personal well-being, including burnout, feeling tired, stress, trouble sleeping, and worry. In adjusted models, nurses were more likely than nonnurse HCWs to report viral testing and test positivity for COVID-19 infection. Nurses in high-risk settings were more likely to report viral exposure and symptoms related to well-being; nurses in low-risk settings were more likely to report viral testing and test positivity. Black or Hispanic nurses were most likely to report test positivity. DISCUSSION: Differences were identified between nurses and nonnurse HCWs in access to PPE, physical and mental well-being measures, and likelihood of reporting exposure and infection. Among nurses, testing and infection differed based on race and ethnicity, and type of work setting. Our findings suggest further research and policy are needed to elucidate and address social and occupational disparities.

Angiotensin Receptor Neprilysin Inhibition and Associated Outcomes by Race and Ethnicity in Patients With Heart Failure With Reduced Ejection Fraction: Data From CHAMP-HF.

Background There are limited data on the use of angiotensin receptor neprilysin inhibitors (ARNIs) in minority populations with heart failure (HF) with reduced ejection fraction. We used data from the CHAMP-HF (Change the Management of Patients With Heart Failure) registry to evaluate ARNI initiation and associated changes in health status and clinical outcomes across different races and ethnicities. Methods and Results CHAMP-HF was a prospective, observational registry of US outpatients with chronic HF with reduced ejection fraction. We compared patients starting ARNI with patients not starting ARNI using a propensity-matched analysis. Patients were grouped as Hispanic, non-Hispanic Black, non-Hispanic White, or non-Hispanic other individuals, where "non-Hispanic other" consists of all patients who did not identify as Hispanic, Black, or White. Health status was assessed using the 12-item Kansas City Cardiomyopathy Questionnaire. Outcomes were analyzed with multivariable models that included race and ethnicity, ARNI initiation, and an interaction term between race and ethnicity and ARNI initiation. Cox proportional hazards models were used for death/HF hospitalization, and multiple regression was used for change in Kansas City Cardiomyopathy Questionnaire score. The analysis included 1516 patients, with 758 patients in each group (ARNI and no ARNI). Changes in Kansas City Cardiomyopathy Questionnaire score after ARNI initiation were similar among all race and ethnicity groups (mean [SD], non-Hispanic White individuals, 3.5 [19.0]; non-Hispanic Black individuals, 2.0 [17.0]; non-Hispanic other individuals, 5.5 [20.3]; and Hispanic individuals, 3.2 [20.1]), with no statistically significant interaction between race and ethnicity and ARNI initiation (P=0.21). There was similarly no statistically significant interaction between race and ethnicity and ARNI initiation for HF hospitalization (P=0.82) or all-cause mortality (P=0.92). Conclusions In a large registry of outpatients with HF with reduced ejection fraction, the association between ARNI initiation and outcomes did not differ by race and ethnicity. These data support the use of ARNI therapy for chronic HF with reduced ejection fraction irrespective of race and ethnicity.

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial.

Importance: Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). Objective: Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE). Design, Setting, and Participants: In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded. Interventions: Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo. Main Outcomes and Measures: Major or clinically relevant nonmajor (CRNM) bleeding. Results: Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant). Conclusions and Relevance: The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status. Trial Registration: ClinicalTrials.gov Identifier: NCT02415400.

Racial/Ethnic Disparities in Healthcare Worker Experiences During the COVID-19 Pandemic: An Analysis of the HERO Registry.

Background: The extent to which healthcare worker (HCWs) experiences during the COVID-19 pandemic vary by race or ethnicity after adjustment for confounding factors is not currently known. Methods: We performed an observational prospective cohort study of 24,769 healthcare workers from 50 U.S. states and the District of Columbia, enrolled between April 10, 2020 and June 30, 2021, and evaluated participant experiences during the COVID-19 pandemic, including testing, diagnosis with COVID-19, emotional experiences, burnout, and interest in vaccines and vaccine clinical trials. Findings: After adjustment for professional role, medical history, and community characteristics, Black and Asian participants were less likely to receive SARS-CoV-2 viral testing (adjusted odds ratio (aOR) 0·82 [0·70, 0·96], p=0·012 and aOR 0·77 [0·67, 0·89], p<0·001 respectively) than White participants. Hispanic participants were more likely to have evidence of COVID-19 infection (aOR 1·23 (1·00, 1·50, p=0·048). Black and Asian participants were less likely to report interest in a COVID-19 vaccine (aOR 0·11 [0·05, 0·25], p<0·001 and aOR 0·48 [0·27, 0·85] p=0·012). Black participants were less likely to report interest in participating in a COVID-19 vaccine trial (aOR = 0·39 [0·28, 0·54], p<0·001). Black participants were also less likely to report 3 or more daily emotional impacts of COVID-19 (aOR = 0·66 [0·53, 0·82], p=<0·001). Black participants were additionally less likely to report burnout (aOR = 0·66 ([0·49, 0·95], p=0·025). Interpretation: In a large, national study of healthcare workers, after adjustment for individual and community characteristics, race/ethnicity disparities in COVID-19 outcomes persist. Future work is urgently needed to understand precise mechanisms behind these disparities and to develop and implement targeted interventions to improve health equity for healthcare workers. Funding: This work was funded by the Patient-Centered Outcomes Research Institute (PCORI), Contract # COVID-19-2020-001.

Asthma and the Risk of SARS-CoV-2 Infection Among Children and Adolescents.

OBJECTIVES: Over 6 million pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have occurred in the United States, but risk factors for infection remain poorly defined. We sought to evaluate the association between asthma and SARS-CoV-2 infection risk among children. METHODS: We conducted a retrospective cohort study of children 5 to 17 years of age receiving care through the Duke University Health System and who had a Durham County, North Carolina residential address. Children were classified as having asthma using previously validated electronic health record-based definitions. SARS-CoV-2 infections were identified based on positive polymerase chain reaction testing of respiratory samples collected between March 1, 2020, and September 30, 2021. We matched children with asthma 1:1 to children without asthma, using propensity scores and used Poisson regression to evaluate the association between asthma and SARS-CoV-2 infection risk. RESULTS: Of 46 900 children, 6324 (13.5%) met criteria for asthma. Children with asthma were more likely to be tested for SARS-CoV-2 infection than children without asthma (33.0% vs 20.9%, P < .0001). In a propensity score-matched cohort of 12 648 children, 706 (5.6%) children tested positive for SARS-CoV-2 infection, including 350 (2.8%) children with asthma and 356 (2.8%) children without asthma (risk ratio: 0.98, 95% confidence interval: 0.85-1.13. There was no evidence of effect modification of this association by inhaled corticosteroid prescription, history of severe exacerbation, or comorbid atopic diseases. Only 1 child with asthma required hospitalization for SARS-CoV-2 infection. CONCLUSIONS: After controlling for factors associated with SARS-CoV-2 testing, we found that children with asthma have a similar SARS-CoV-2 infection risk as children without asthma.

The association of improvement in left ventricular ejection fraction with outcomes in patients with heart failure with reduced ejection fraction: data from CHAMP-HF.

AIMS: We assessed for an association between improvements in left ventricular ejection fraction (LVEF) and future outcomes, including health status, in routine clinical practice. METHODS AND RESULTS: CHAMP-HF was a registry of outpatients with heart failure (HF) and LVEF ≤40%. Enrolled participants completed the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) at regular intervals and were followed as part of routine care. We assessed for associations between improvements in LVEF (≥10%) over time and concurrent changes in KCCQ-12, as well as the subsequent risk of poor outcomes. We included 2092 participants in the study. They had the following characteristics: median age 67 years (25th-75th percentile 58-75), 29% female, median duration of HF 2.7 years (0.6-6.8), and median baseline LVEF 30% (23-35). Of the study participants, 689 (33%) had a ≥10% absolute improvement in LVEF. Participants with an LVEF improvement also had an improvement in KCCQ-12 overall summary score compared with participants without an LVEF improvement (+7.6 vs. +3.5, adjusted effect estimate +4.01 [95% confidence interval CI 2.3-5.7]). Similarly, subsequent all-cause death or HF hospitalization occurred in 12% in the LVEF improvement group versus 25% in the group without an LVEF improvement (adjusted hazard ratio 0.50, 95% confidence interval 0.41-0.61). CONCLUSION: In a large cohort of outpatients with chronic HF, improvements in LVEF were associated with improved health status and a reduced risk for future clinical events. These data underscore the importance of improvement in LVEF as a treatment target for medical interventions for patients with chronic HF.

Addressing Extreme Propensity Scores in Estimating Counterfactual Survival Functions via the Overlap Weights.

The inverse probability of treatment weighting (IPTW) approach is popular for evaluating causal effects in observational studies, but extreme propensity scores could bias the estimator and induce excessive variance. Recently, the overlap weighting approach has been proposed to alleviate this problem, which smoothly down-weights the subjects with extreme propensity scores. Although advantages of overlap weighting have been extensively demonstrated in literature with continuous and binary outcomes, research on its performance with time-to-event or survival outcomes is limited. In this article, we propose estimators that combine propensity score weighting and inverse probability of censoring weighting to estimate the counterfactual survival functions. These estimators are applicable to the general class of balancing weights, which includes IPTW, trimming, and overlap weighting as special cases. We conduct simulations to examine the empirical performance of these estimators with different propensity score weighting schemes in terms of bias, variance, and 95% confidence interval coverage, under various degrees of covariate overlap between treatment groups and censoring rates. We demonstrate that overlap weighting consistently outperforms IPTW and associated trimming methods in bias, variance, and coverage for time-to-event outcomes, and the advantages increase as the degree of covariate overlap between the treatment groups decreases.

Antithrombotic Therapy in Patients With Atrial Fibrillation After Acute Coronary Syndromes or Percutaneous Intervention.

BACKGROUND: The use of apixaban instead of vitamin K antagonists (VKA) as well as dropping aspirin results in less bleeding and comparable ischemic events in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention treated with a P2Y12 inhibitor. OBJECTIVES: The authors assessed the safety and efficacy of antithrombotic regimens according to HAS-BLED and CHA2DS2-VASc scores in AUGUSTUS (The Open-Label, 2 × 2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention). METHODS: In AUGUSTUS, 4,614 patients were randomized in a 2-by-2 factorial design to open-label apixaban or VKA and blinded aspirin or placebo. The primary endpoint was major or clinically relevant nonmajor bleeding over 6 months of follow-up. Cox proportional hazards models were used to assess treatment effects by baseline HAS-BLED (≤2 vs ≥3) and CHA2DS2-VASc (≤2 vs ≥3) scores. RESULTS: Of 4,386 (95.1%) patients with calculable scores, 66.8% had HAS-BLED ≥3 and 81.7% had CHA2DS2-VASc ≥3. Bleeding rates were lower with apixaban than VKA irrespective of baseline risk (HR: 0.57; 95% CI: 0.41-0.78 [HAS-BLED ≤2]; HR: 0.72; 95% CI: 0.59-0.88 [HAS-BLED ≥3]; interaction P = 0.23). Aspirin increased bleeding irrespective of baseline risk (HR: 1.86; 95% CI: 1.36-2.56 [HAS-BLED ≤2]; HR: 1.81; 95% CI: 1.47-2.23 [HAS-BLED ≥3]; interaction P = 0.88). Apixaban resulted in a lower risk of death or hospitalization than VKA without a significant interaction with baseline stroke risk (HR: 0.92; 95% CI: 0.67-1.25 [CHA2DS2-VASc ≤2]; HR: 0.82; 95% CI: 0.73-0.94 [CHA2DS2-VASc ≥3]; interaction P = 0.53). CONCLUSIONS: Our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for most patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention, irrespective of a patient's baseline bleeding and stroke risk (NCT02415400).

Route of myomectomy and fertility: a prospective cohort study.

OBJECTIVE: To assess prospectively the association between the myomectomy route and fertility. DESIGN: Prospective cohort study. SETTING: The Comparing Treatments Options for Uterine Fibroids (COMPARE-UF) Study is a multisite national registry of eight clinic centers across the United States. PATIENT(S): Reproductive-aged women undergoing surgery for symptomatic uterine fibroids. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): We used life-table methods to estimate cumulative probabilities and 95% confidence intervals (CI) of pregnancy and live birth by the myomectomy route during 12, 24, and 36 months of follow-up (2015-2019). We also conducted 12-month interval-based analyses that used logistic regression to estimate odds ratios and 95% CIs for associations of interest. In all analyses, we used propensity score weighting to adjust for differences across surgical routes. RESULT(S): Among 1,095 women who underwent myomectomy (abdominal = 388, hysteroscopic = 273, and laparoscopic = 434), 202 reported pregnancy and 91 reported live birth during 36 months of follow-up. There was little difference in the 12-month probability of pregnancy or live birth by route of myomectomy overall or among women intending pregnancy. In interval-based analyses, adjusted ORs for pregnancy were 1.28 (95% CI, 0.76-2.14) for hysteroscopic myomectomy and 1.19 (95% CI, 0.76-1.85) for laparoscopic myomectomy compared with abdominal myomectomy. Among women intending pregnancy, adjusted ORs were 1.27 (95% CI, 0.72-2.23) for hysteroscopic myomectomy and 1.26 (95% CI, 0.77-2.04) for laparoscopic myomectomy compared with abdominal myomectomy. Associations were slightly stronger but less precise for live birth. CONCLUSION(S): The probability of conception or live birth did not differ appreciably by the myomectomy route among women observed for 36 months postoperatively. CLINICAL TRIALS REGISTRATION NUMBER: (NCT02260752, clinicaltrials.gov).

Atrial branch coronary artery stenosis as a mechanism for atrial fibrillation.

BACKGROUND: The etiology of atrial fibrillation (AF) is multifactorial and incompletely understood. OBJECTIVE: The purpose of this study was to evaluate the association between coronary artery disease (CAD) affecting atrial tissue and AF. METHODS: Patients from a single center with obstructive CAD during cardiac catheterization (January 1, 2007, through December 1, 2013) were included in a matched case-control analysis on the basis of the presence or absence of new-onset AF within 12 months of catheterization. Quantitative measurements of stenosis severity were performed for the sinoatrial nodal artery, atrioventricular (AV) nodal artery, and right intermediate atrial artery (RIAA) as well as the right coronary, left circumflex, and left anterior descending proximal to the takeoff for each atrial level artery. A multivariable logistic regression model identified factors associated with AF. RESULTS: Of 1794 patients, 115 (6%) developed AF within 1 year of catheterization. The matched cohort included 110 patients with and 110 patients without AF within 12 months of catheterization. Higher odds of AF at 1 year were associated with increasing lesion stenosis severity in the RIAA (odds ratio [OR] 1.41 per 10% increase in lesion severity above 50%; 95% confidence interval [CI] 1.01-1.97; P = .047) and AV nodal artery (OR 1.58 per 10% increase in lesion severity above 50%; 95% CI 1.00-2.49; P = .050). Odds of AF diagnosis during the year after catheterization increased with the number of atrial arteries with >50% lesion (OR 1.53 for each additional artery; 95% CI 1.08-2.15; P = .015). CONCLUSION: In patients with obstructive CAD, disease of the AV nodal artery and RIAA as well as a higher burden of CAD within all arteries supplying blood flow to the atrial myocardium were associated with higher odds of new-onset AF at 1 year.

Racial Disparities in Invasive Management for Patients With Acute Myocardial Infarction With Chronic Kidney Disease.

BACKGROUND: Due to increased risks of contrast nephropathy, chronic kidney disease (CKD) can deter consideration of invasive management for patients with myocardial infarction (MI). Black patients have a higher prevalence of CKD. Whether racial disparities exist in the use of invasive MI management for patients with CKD presenting with MI is unknown. METHODS: We examined 717 012 White and 99 882 Black patients with MI treated from 2008 to 2017 at 914 hospitals in the National Cardiovascular Data Registry Chest Pain-MI Registry. CKD status was defined as estimated glomerular filtration rate (eGFR) ≥90 mL/(min·1.73 m2; no CKD), eGFR <90 but ≥60 (mild), eGFR <60 but ≥30 (moderate), and eGFR <30 or dialysis (severe). We used multivariable logistic regression models to examine the interaction of race and CKD severity in invasive MI management. RESULTS: Among those with MI, Black patients were more likely than White patients to have CKD (eGFR <90; 61.4% versus 58.5%; P<0.001). Among those with MI and CKD, Black patients were more likely than White patients to have severe CKD (21.2% versus 12.4%; P<0.001). Patients with CKD were more likely than those without CKD to have diabetes or heart failure; Black patients with CKD were more likely to have these comorbidities when compared with White patients with CKD (all P<0.0001). Black race and CKD were associated with a lower likelihood of invasive management (adjusted odds ratio, 0.78 [95% CI, 0.75-0.81]; adjusted odds ratio, 0.72 [95% CI, 0.70-0.74]; P<0.001 for both). At eGFR levels ≥10, Black patients were significantly less likely than White patients to undergo invasive management. CONCLUSIONS: Black patients with MI and mild or moderate CKD were less likely to undergo invasive management compared with White patients with similar CKD severity. National efforts are needed to address racial disparities that may remain in the invasive management of MI.

Comparative Effectiveness of Dosing of Medical Therapy for Heart Failure: From the CHAMP-HF Registry.

BACKGROUND: The comparative effectiveness of differing dosages of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) on clinical and patient-reported outcomes in clinical practice in the United States is unknown. This study sought to characterize associations between the dosing of GDMT and outcomes for patients with HFrEF in U.S. clinical practice. METHODS: This analysis included 4832 outpatients who had chronic HFrEF across 150 practices in the U.S. in the Change the Management of Patients with Heart Failure (CHAMP-HF) registry with no contraindication and available dosing data for at least 1 GDMT at baseline. Baseline dosing of angiotensin-converting enzyme (ACEI)/angiotensin II receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA) therapies were examined. For each medication class, multivariable models assessed associations between medication dosing and clinical outcomes over 24 months (all-cause mortality, HF hospitalization) and patient-reported outcomes at 12 months (change in the Kansas City Cardiomyopathy Questionnaire Overall Summary score [KCCQ-OS]). RESULTS: After adjustment, compared with target dosing, lower dosing was associated with higher all-cause mortality for ACEIs/ARBs/ARNIs (50% to < 100% target dosage, HR 1.16 [95% CI 0.87-1.55]; < 50% target dosage, HR 1.37 [95% CI 1.05-1.79]; none, HR 1.75 [95% CI 1.32-2.34; overall P< 0.001) and beta-blockers (50% to < 100% target dosage, HR 1.30 [95% CI 1.00-1.69]; < 50% target dosage, HR 1.41 [95% CI 1.11-1.79; none, HR 1.24 [95% CI 0.92-1.67]; overall P= 0.042). Lower dosing of ACEIs/ARBs/ARNIs was independently associated with higher risk of HF hospitalization (50% to < 100% target dosage, HR 1.08 [95% CI 0.90-1.30]; < 50% target dosage, HR 1.23 [1.04-1.47]; none, HR 1.29 [1.04-1.60]; overall P= 0.046), but beta-blocker dosing was not (overall P= 0.085). Target dosing of MRAs was not associated with risk of mortality or HF hospitalization. For each GDMT, compared with target dosing, lower dosing was not associated with change in the KCCQ-OS at 12 months, with the potential exception of worsening KCCQ-OS scores with lower dosing of ACEIs/ARBs/ARNIs. CONCLUSIONS: In this contemporary U.S. outpatient HFrEF registry, target dosing of ACEI/ARB/ARNI and beta-blocker therapy was associated with reduced mortality and was variably associated with HF hospitalization and patient-reported outcomes. MRA dosing was not associated with outcomes. The totality of these findings support the benefits of target dosing of GDMT in routine practice, as tolerated, with unmeasured differences among patients receiving differing dosages potentially explaining the differing results seen here compared with randomized clinical trials.