Underrepresentation of Women in Reduced Ejection Heart Failure Clinical Trials With Improved Mortality or Hospitalization.

BACKGROUND: There are established sex-specific differences in heart failure with reduced ejection fraction (HFrEF) outcomes. Randomized clinical trials (RCTs) based on cardiovascular outcome benefits, typically either reduced cardiovascular mortality or hospitalization for heart failure (HHF), influence current guidelines for therapy. OBJECTIVES: The authors evaluate the representation of women in HFrEF RCTs that observed reduced all-cause or cardiovascular mortality or HHF. METHODS: We queried Cumulative Index to Nursing and Allied Health Literature, Excerpta Medica dataBASE, Medical Literature Analysis and Retrieval System Online, and PubMed for HFrEF RCTs that reported a statistically significant benefit of intervention resulting in improved mortality or HHF published from 1980 to 2021. We estimated representation using the participation-to-prevalence ratio (PPR). A PPR of 0.8 to 1.2 was considered representative. RESULTS: The final analysis included 33 RCTs. Women represented only 23.2% of all enrolled participants (n = 24,366/104,972), ranging from 11.4% to 40.1% per trial. Overall PPR was 0.58, with per-trial PPR estimates ranging from 0.29 to 1.00. Only 5 trials (15.2%) had a PPR of women representative of the disease population. Representation did not change significantly over time. The proportion of women in North American trials was significantly greater than trials conducted in Europe (P = 0.03). The proportion of women was greater in industry trials compared to government-funded trials (P = 0.05). CONCLUSIONS: Women are underrepresented in HFrEF RCTs that have demonstrated mortality or HHF benefits and influence current guidelines. Representation is key to further delineation of sex-specific differences in major trial results. Sustained efforts are warranted to ensure equitable and appropriate inclusion of women in HFrEF trials.

Predictive Value of Relative Apical Sparing of Longitudinal Strain on Echocardiography for Cardiac Amyloidosis.

Relative apical longitudinal sparing (RALS) on echocardiography has become an increasingly used tool to evaluate for cardiac amyloidosis (CA), but the predictive value of this finding remains unclear. This is a retrospective analysis at a single tertiary care center across 3 years. Patients were included if they had RALS, defined by strain ratio ≥2.0 on echocardiography, and sufficient laboratory, imaging, or histopathologic workup to indicate their likelihood of CA. Patients were stratified by their likelihood of CA, and contributions of other co-morbidities previously shown to be associated with RALS. Of the 220 patients who had adequate workup to determine their likelihood of having CA, 50 (22.7%) had confirmed CA, 35 (15.9%) had suspicious CA, 83 (37.7%) had unlikely CA, and 52 (23.7%) had ruled-out CA. The positive predictive value of RALS for CA was 38.6% for confirmed or suspicious CA. The remaining 61.4% of patients who were unlikely or ruled out for CA had other co-morbidities such as hypertension, chronic kidney disease, malignancy, or aortic stenosis, 17.0% of this group had none of these co-morbidities. In our tertiary care cohort of patients with RALS pattern on echocardiography, we found that fewer than half of patients with RALS were likely to have CA. Given the increasing use of strain technology, further studies are warranted to determine the optimal strategy for assessing CA in a patient with RALS.

Natural language processing to identify reasons for sex disparity in statin prescriptions.

Background: Statins are the cornerstone of treatment of patients with atherosclerotic cardiovascular disease (ASCVD). Despite this, multiple studies have shown that women with ASCVD are less likely to be prescribed statins than men. The objective of this study was to use Natural Language Processing (NLP) to elucidate factors contributing to this disparity. Methods: Our cohort included adult patients with two or more encounters between 2014 and 2021 with an ASCVD diagnosis within a multisite electronic health record (EHR) in Northern California. After reviewing structured EHR prescription data, we used a benchmark deep learning NLP approach, Clinical Bidirectional Encoder Representations from Transformers (BERT), to identify and interpret discussions of statin prescriptions documented in clinical notes. Clinical BERT was evaluated against expert clinician review in 20% test sets. Results: There were 88,913 patients with ASCVD (mean age 67.8±13.1 years) and 35,901 (40.4%) were women. Women with ASCVD were less likely to be prescribed statins compared with men (56.6% vs 67.6%, p <0.001), and, when prescribed, less likely to be prescribed guideline-directed high-intensity dosing (41.4% vs 49.8%, p <0.001). These disparities were more pronounced among younger patients, patients with private insurance, and those for whom English is their preferred language. Among those not prescribed statins, women were less likely than men to have statins mentioned in their clinical notes (16.9% vs 19.1%, p <0.001). Women were less likely than men to have statin use reported in clinical notes despite absence of recorded prescription (32.8% vs 42.6%, p <0.001). Women were slightly more likely than men to have statin intolerance documented in structured data or clinical notes (6.0% vs 5.3%, p=0.003). Conclusions: Women with ASCVD were less likely to be prescribed guideline-directed statins compared with men. NLP identified additional sex-based statin disparities and reasons for statin non-prescription in clinical notes of patients with ASCVD.

Identifying Reasons for Statin Nonuse in Patients With Diabetes Using Deep Learning of Electronic Health Records.

Background Statins are guideline-recommended medications that reduce cardiovascular events in patients with diabetes. Yet, statin use is concerningly low in this high-risk population. Identifying reasons for statin nonuse, which are typically described in unstructured electronic health record data, can inform targeted system interventions to improve statin use. We aimed to leverage a deep learning approach to identify reasons for statin nonuse in patients with diabetes. Methods and Results Adults with diabetes and no statin prescriptions were identified from a multiethnic, multisite Northern California electronic health record cohort from 2014 to 2020. We used a benchmark deep learning natural language processing approach (Clinical Bidirectional Encoder Representations from Transformers) to identify statin nonuse and reasons for statin nonuse from unstructured electronic health record data. Performance was evaluated against expert clinician review from manual annotation of clinical notes and compared with other natural language processing approaches. Of 33 461 patients with diabetes (mean age 59±15 years, 49% women, 36% White patients, 24% Asian patients, and 15% Hispanic patients), 47% (15 580) had no statin prescriptions. From unstructured data, Clinical Bidirectional Encoder Representations from Transformers accurately identified statin nonuse (area under receiver operating characteristic curve [AUC] 0.99 [0.98-1.0]) and key patient (eg, side effects/contraindications), clinician (eg, guideline-discordant practice), and system reasons (eg, clinical inertia) for statin nonuse (AUC 0.90 [0.86-0.93]) and outperformed other natural language processing approaches. Reasons for nonuse varied by clinical and demographic characteristics, including race and ethnicity. Conclusions A deep learning algorithm identified statin nonuse and actionable reasons for statin nonuse in patients with diabetes. Findings may enable targeted interventions to improve guideline-directed statin use and be scaled to other evidence-based therapies.

Treatment Differences in Medical Therapy for Heart Failure With Reduced Ejection Fraction Between Sociodemographic Groups.

BACKGROUND: There are sociodemographic disparities in outcomes of heart failure with reduced ejection fraction (HFrEF), but disparities in guideline-directed medical therapy (GDMT) remain poorly characterized. OBJECTIVES: This study aimed to analyze GDMT treatment rates in eligible patients with recently diagnosed HFrEF, and to determine how rates vary by sociodemographic characteristics. METHODS: This retrospective cohort study included patients diagnosed with HFrEF at Veterans Affairs (VA) hospitals from 2013 to 2019. The authors analyzed GDMT treatment rates and doses, excluding patients with contraindications. Therapies of interest were evidence-based beta-blockers (BBs), renin-angiotensin system inhibitors (RASIs), angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid antagonists (MRAs). The authors compared adjusted treatment rates by race and ethnicity, neighborhood social vulnerability, rurality, distance to medical care, and sex. RESULTS: The cohort comprised 126,670 VA patients with recently diagnosed HFrEF. The study found that racial and ethnic minorities had similar or higher treatment rates than White patients. Patients residing in socially vulnerable neighborhoods had 3.4% lower ARNI (95% CI: 1.9%-5.0%) treatment rates. Patients residing farther from specialty care had similar rates of GDMT therapy overall, but were less likely to be taking at least 50% of the target doses of either BBs (4.0% less likely; 95% CI: 3.1%-5.0%) or RASIs (5.0% less likely; 95% CI: 4.1%-6.0%) compared with those closer to care. CONCLUSIONS: Among VA patients with recently diagnosed HFrEF, the authors did not find that racial and ethnic minority patients were less likely to receive GDMT. However, appropriate dose up-titration may occur less frequently in more remote patients.

Racial Disparity in Referral for Catheter Ablation for Atrial Fibrillation at a Single Integrated Health System.

Background Guidelines recommend catheter ablation of atrial fibrillation (AFCA) as an option for rhythm control. Studies have shown that Black patients are less likely to undergo AFCA compared with White patients. We investigated whether differences in referral patterns play a role in this observed disparity. Methods and Results Using an integrated repository from the electronic medical record at Northwestern Medicine, we conducted a retrospective cohort study of outpatients with newly diagnosed atrial fibrillation. Baseline characteristics by race and ethnicity were compared. Logistic regression models adjusted for socioeconomic and health factors were constructed to determine the association between race and ethnicity and binary dependent variables including referrals and visits to general cardiology and cardiac electrophysiology (EP) and AFCA. Of 5445 patients analyzed, 4652 were non-Hispanic White (NHW) and 793 were non-Hispanic Black (NHB). In adjusted models, NHB patients initially diagnosed with atrial fibrillation in internal medicine and primary care had a significantly greater odds of referral to general cardiology; among all patients in the cohort, there was no significant difference in the odds of referral to EP between NHB and NHW patients; and there were no differences in the odds of completing a visit in general cardiology or EP. Among patients completing an EP visit, NHB patients were less likely to undergo AFCA (odds ratio, 0.63 [95% CI, 0.40-0.98], P=0.040). Conclusions Similar referral rates to general cardiology and EP were observed between NHB and NHW patients. Despite this, NHB patients were less likely to undergo AFCA.

Sepsis Electronic Decision Support Screen in High-Risk Patients Across Age Groups in a Pediatric Emergency Department.

OBJECTIVE: This study aimed to compare the performance of a pediatric decision support algorithm to detect severe sepsis between high-risk pediatric and adult patients in a pediatric emergency department (PED). METHODS: This is a retrospective cohort study of patients presenting from March 2017 to February 2018 to a tertiary care PED. Patients were identified as high risk for sepsis based on a priori defined criteria and were considered adult if 18 years or older. The 2-step decision support algorithm consists of (1) an electronic health record best-practice alert (BPA) with age-adjusted vital sign ranges, and (2) physician screen. The difference in test characteristics of the intervention for the detection of severe sepsis between pediatric and adult patients was assessed at 0.05 statistical significance. RESULTS: The 2358 enrolled subjects included 2125 children (90.1%) and 233 adults (9.9%). The median ages for children and adults were 3.8 (interquartile range, 1.2-8.6) and 20.1 (interquartile range, 18.2-22.0) years, respectively. In adults, compared with children, the BPA alone had significantly higher sensitivity (0.83 [95% confidence interval {CI}, 0.74-0.89] vs 0.72 [95% CI, 0.69-0.75]; P = 0.02) and lower specificity (0.11 [95% CI, 0.07-0.19] vs 0.48 [95% CI, 0.45-0.51; P < 0.001). With the addition of provider screen, sensitivity and specificity were comparable across age groups, with a lower negative predictive value in adults compared with children (0.66 [95% CI, 0.58-0.74] vs 0.77 [95% CI, 0.75-0.79]; P = 0.005). CONCLUSIONS: The BPA was less specific in adults compared with children. With the addition of provider screen, specificity improved; however, the lower negative predictive value suggests that providers may be less likely to suspect sepsis even after automated screen in adult patients. This study invites further research aimed at improving screening algorithms, particularly across the diverse age spectrum presenting to a PED.

Review of Lipid-Lowering Therapy in Women from Reproductive to Postmenopausal Years.

Although cardiovascular disease is the leading cause of death in women, cardiovascular risk factors remain underrecognized and undertreated. Hyperlipidemia is one of the leading modifiable risk factors for CVD. Statins are the mainstay of lipid lowering therapy (LLT), with additional agents such as ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as additive or alternative therapies. Clinical trials have demonstrated that these LLTs are equally efficacious in lipid lowering and cardiovascular risk reduction in women as they are in men. Although the data on statin teratogenicity is evolving, in times of pregnancy or attempted pregnancy, most lipid-lowering agents are generally avoided due to lack of high-quality safety data. This leads to limited treatment options in pregnant women with hyperlipidemia or cardiovascular disease. During the perimenopausal period, the mainstay of lipid management remains consistent with guidelines across all ages. Hormone replacement therapy for cardiovascular risk reduction is not recommended. Future research is warranted to target sex-based disparities in LLT initiation and persistence across the life course.

Invasive pulmonary aspergillosis after treatment with tocilizumab in a patient with COVID-19 ARDS: a case report.

Tocilizumab, an interleukin-6 receptor antagonist, has been used to treat critically ill patients with coronavirus disease-2019. We present the case of a previously immunocompetent man with coronavirus disease-2019 who developed invasive pulmonary aspergillosis after treatment with tocilizumab, illustrating the importance of considering opportunistic infections when providing immune modulating therapy.

Pathophysiology and Treatment of Enteric Hyperoxaluria.

Enteric hyperoxaluria is a distinct entity that can occur as a result of a diverse set of gastrointestinal disorders that promote fat malabsorption. This, in turn, leads to excess absorption of dietary oxalate and increased urinary oxalate excretion. Hyperoxaluria increases the risk of kidney stones and, in more severe cases, CKD and even kidney failure. The prevalence of enteric hyperoxaluria has increased over recent decades, largely because of the increased use of malabsorptive bariatric surgical procedures for medically complicated obesity. This systematic review of enteric hyperoxaluria was completed as part of a Kidney Health Initiative-sponsored project to describe enteric hyperoxaluria pathophysiology, causes, outcomes, and therapies. Current therapeutic options are limited to correcting the underlying gastrointestinal disorder, intensive dietary modifications, and use of calcium salts to bind oxalate in the gut. Evidence for the effect of these treatments on clinically significant outcomes, including kidney stone events or CKD, is currently lacking. Thus, further research is needed to better define the precise factors that influence risk of adverse outcomes, the long-term efficacy of available treatment strategies, and to develop new therapeutic approaches.

Risk factors for severe acute respiratory syndrome coronavirus 2 infection in pregnant women.

Background: Risk factors for severe acute respiratory syndrome coronavirus 2 infection in pregnancy remain poorly understood. Identifying and understanding populations at a heightened risk of acquisition is essential to more effectively target outreach and prevention efforts. Objective: This study aimed to compare sociodemographic and clinical characteristics of pregnant women with and without severe acute respiratory syndrome coronavirus 2 infection and, among those with severe acute respiratory syndrome coronavirus 2, to compare characteristics of those who reported coronavirus disease symptoms and those who were asymptomatic at diagnosis. Study Design: This retrospective cohort study includes pregnant women who delivered or intended to deliver at Northwestern Memorial Hospital after initiation of a universal testing protocol on admission (April 8, 2020-May 31, 2020). Women were dichotomized by whether they had a positive test result for severe acute respiratory syndrome coronavirus 2. Among women with a positive test result, women were further dichotomized by whether they reported symptoms of coronavirus disease 2019. Bivariable analysis and parametric tests of trend were used for analyses. Logistic regression was used to control for potential confounders and to examine effect modification between race and ethnicity and any other identified risk factors. Results: During the study period, 1418 women met inclusion criteria, of whom 101 (7.1%) had a positive test result for severe acute respiratory syndrome coronavirus 2. Of the 101 women who had a positive test result, 77 (76.2%) were symptomatic at the time of diagnosis. Compared with women who had a negative test result for severe acute respiratory syndrome coronavirus 2, those with a positive test result were younger and were more likely to have public insurance, to identify as black or African American or Latina, to be unmarried, to be obese, to have preexisting pulmonary disease, and to have living children. An increasing number of living children was associated with an increasing risk of severe acute respiratory syndrome coronavirus 2 infection, and this finding persisted after controlling for potential confounders. There was no effect modification between race or ethnicity and having living children with regard to the risk of infection. There were no significant differences identified between women who were symptomatic and asymptomatic. Conclusion: Many risk factors for severe acute respiratory syndrome coronavirus 2 infection in pregnancy are similar to the social and structural determinants of health that have been reported in the general population. The observed association between severe acute respiratory syndrome coronavirus 2 infection and having children raises the possibility of children themselves being vectors of viral spread or behavior patterns of parents being mediators of acquisition.

Loss of H3K9me3 Correlates with ATM Activation and Histone H2AX Phosphorylation Deficiencies in Hutchinson-Gilford Progeria Syndrome.

Compelling evidence suggests that defective DNA damage response (DDR) plays a key role in the premature aging phenotypes in Hutchinson-Gilford progeria syndrome (HGPS). Studies document widespread alterations in histone modifications in HGPS cells, especially, the global loss of histone H3 trimethylated on lysine 9 (H3K9me3). In this study, we explore the potential connection(s) between H3K9me3 loss and the impaired DDR in HGPS. When cells are exposed to a DNA-damaging agent Doxorubicin (Dox), double strand breaks (DSBs) are generated that result in the phosphorylation of histone H2A variant H2AX (gammaH2AX) within an hour. We find that the intensities of gammaH2AX foci appear significantly weaker in the G0/G1 phase HGPS cells compared to control cells. This reduction is associated with a delay in the recruitment of essential DDR factors. We further demonstrate that ataxia-telangiectasia mutated (ATM) is responsible for the amplification of gammaH2AX signals at DSBs during G0/G1 phase, and its activation is inhibited in the HGPS cells that display significant loss of H3K9me3. Moreover, methylene (MB) blue treatment, which is known to save heterochromatin loss in HGPS, restores H3K9me3, stimulates ATM activity, increases gammaH2AX signals and rescues deficient DDR. In summary, this study demonstrates an early DDR defect of attenuated gammaH2AX signals in G0/G1 phase HGPS cells and provides a plausible connection between H3K9me3 loss and DDR deficiency.