Designing target trials using electronic health records: A case study of second-line disease-modifying anti-rheumatic drugs and cardiovascular disease outcomes in patients with rheumatoid arthritis.

BACKGROUND: Emulation of the "target trial" (TT), a hypothetical pragmatic randomized controlled trial (RCT), using observational data can be used to mitigate issues commonly encountered in comparative effectiveness research (CER) when randomized trials are not logistically, ethically, or financially feasible. However, cardiovascular (CV) health research has been slow to adopt TT emulation. Here, we demonstrate the design and analysis of a TT emulation using electronic health records to study the comparative effectiveness of the addition of a disease-modifying anti-rheumatic drug (DMARD) to a regimen of methotrexate on CV events among rheumatoid arthritis (RA) patients. METHODS: We used data from an electronic medical records-based cohort of RA patients from Northwestern Medicine to emulate the TT. Follow-up began 3 months after initial prescription of MTX (2000-2020) and included all available follow-up through June 30, 2020. Weighted pooled logistic regression was used to estimate differences in CVD risk and survival. Cloning was used to handle immortal time bias and weights to improve baseline and time-varying covariate imbalance. RESULTS: We identified 659 eligible people with RA with average follow-up of 46 months and 31 MACE events. The month 24 adjusted risk difference for MACE comparing initiation vs non-initiation of a DMARD was -1.47% (95% confidence interval [CI]: -4.74, 1.95%), and the marginal hazard ratio (HR) was 0.72 (95% CI: 0.71, 1.23). In analyses subject to immortal time bias, the HR was 0.62 (95% CI: 0.29-1.44). CONCLUSION: In this sample, we did not observe evidence of differences in risk of MACE, a finding that is compatible with previously published meta-analyses of RCTs. Thoughtful application of the TT framework provides opportunities to conduct CER in observational data. Benchmarking results of observational analyses to previously published RCTs can lend credibility to interpretation.

Eligibility and Projected Benefits of Rapid Initiation of Quadruple Medical Therapy for Newly Diagnosed Heart Failure.

BACKGROUND: U.S. nationwide estimates of the proportion of patients newly diagnosed with heart failure with reduced ejection fraction (HFrEF) eligible for quadruple medical therapy, and the associated benefits of rapid implementation, are not well characterized. OBJECTIVES: This study sought to characterize the degree to which patients newly diagnosed with HFrEF are eligible for quadruple medical therapy, and the projected benefits of in-hospital initiation. METHODS: Among patients hospitalized for newly diagnosed HFrEF in the Get With The Guidelines-Heart Failure registry from 2016 to 2023, eligibility criteria based on regulatory labeling, guidelines, and expert consensus documents were applied for angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor therapies. Of those eligible, the projected effect of quadruple therapy on 12-month mortality was modeled using treatment effects from pivotal clinical trials utilized by the AHA/ACC/HFSA Guideline for the Management of Heart Failure, and compared with observed outcomes among patients treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blockers. RESULTS: Of 33,036 patients newly diagnosed with HFrEF, 27,158 (82%) were eligible for quadruple therapy, and 30,613 (93%) were eligible for ≥3 components. From 2021 to 2023, of patients eligible for quadruple therapy, 15.3% were prescribed quadruple therapy and 41.5% were prescribed triple therapy. Among Medicare beneficiaries eligible for quadruple therapy, 12-month incidence of mortality was 24.7% and HF hospitalization was 22.2%. Applying the relative risk reductions in clinical trials, complete implementation of quadruple therapy by time of discharge was projected to yield absolute risk reductions in 12-month mortality of 10.4% (number needed to treat = 10) compared with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blocker, and 24.8% (number needed to treat = 4) compared with no GDMT. CONCLUSIONS: In this nationwide U.S. cohort of patients hospitalized for newly diagnosed HFrEF, >4 of 5 patients were projected as eligible for quadruple therapy at discharge; yet, <1 in 6 were prescribed it. If clinical trial benefits can be fully realized, in-hospital initiation of quadruple medical therapy for newly diagnosed HFrEF would yield large absolute reductions in mortality.

Dephasingless laser wakefield acceleration in the bubble regime.

Laser wakefield accelerators (LWFAs) have electric fields that are orders of magnitude larger than those of conventional accelerators, promising an attractive, small-scale alternative for next-generation light sources and lepton colliders. The maximum energy gain in a single-stage LWFA is limited by dephasing, which occurs when the trapped particles outrun the accelerating phase of the wakefield. Here, we demonstrate that a single space-time structured laser pulse can be used for ionization injection and electron acceleration over many dephasing lengths in the bubble regime. Simulations of a dephasingless laser wakefield accelerator driven by a 6.2-J laser pulse show 25 pC of injected charge accelerated over 20 dephasing lengths (1.3 cm) to a maximum energy of 2.1 GeV. The space-time structured laser pulse features an ultrashort, programmable-trajectory focus. Accelerating the focus, reducing the focused spot-size variation, and mitigating unwanted self-focusing stabilize the electron acceleration, which improves beam quality and leads to projected energy gains of 125 GeV in a single, sub-meter stage driven by a 500-J pulse.

Comparative Outcomes of Sacubitril/Valsartan Use After Hospitalization for Heart Failure Among Medicare Beneficiaries Naïve to Renin-Angiotensin System Inhibitors.

Sacubitril/valsartan improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with angiotensin-converting enzyme inhibitors (ACEis). However, data on postdischarge outcomes in renin-angiotensin system inhibitor (RASi)-naïve patients are limited. We included Medicare beneficiaries aged ≥65 years who were hospitalized for HFrEF in the Get With The Guidelines-Heart Failure registry between October 2015 and June 2019, had part D prescription coverage, and were not on RASi therapy during the 6 months before hospital admission. We examined the associations between sacubitril/valsartan prescription at hospital discharge and outcomes at 30 days and 1 year after discharge using overlap-weighted median regression and Cox proportional hazards models. The end points included "home time" (defined as days alive and out of any health care institution), mortality, and rehospitalization. Among 3,572 patients with HFrEF and who are naïve to RASi therapy, at discharge, 290 (8.1%) were prescribed sacubitril/valsartan and 1,390 (38.9%) were prescribed ACEis and angiotensin receptor blockers. After adjusting for baseline characteristics, patients prescribed sacubitril/valsartan had a longer median home time (parameter estimate 27.0 days, 95% confidence interval [CI] 12.40 to 41.6, p <0.001) and lower all-cause mortality (hazard ratio [HR] 0.74, 95% CI 0.61 to 0.91, p = 0.004) at 1 year than patients not prescribed sacubitril/valsartan. The prescription of sacubitril/valsartan was not significantly associated with all-cause rehospitalization (HR 0.87, 95% CI 0.74 to 1.03, p = 0.10) or heart failure rehospitalization (HR 0.87, 95% CI 0.70 to 1.07, p = 0.19). In a restricted comparison of patients discharged on sacubitril/valsartan versus ACEis and angiotensin receptor blockers, there were no significant differences in the outcomes. In conclusion, in this contemporary population of RASi-naïve patients with HFrEF from routine clinical practice, compared with not initiating, the initiation of sacubitril/valsartan at discharge was associated with longer home time and improvements in overall survival.

Contemporary Use of Sodium-Glucose Cotransporter-2 Inhibitor Therapy Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction in the US: The Get With The Guidelines-Heart Failure Registry.

Importance: Clinical guidelines for patients with heart failure with reduced ejection fraction (HFrEF) strongly recommend treatment with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) to reduce cardiovascular mortality or HF hospitalization. Nationwide adoption of SGLT2i for HFrEF in the US is unknown. Objective: To characterize patterns of SGLT2i use among eligible US patients hospitalized for HFrEF. Design, Setting, and Participants: This retrospective cohort study analyzed 49 399 patients hospitalized for HFrEF across 489 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry between July 1, 2021, and June 30, 2022. Patients with an estimated glomerular filtration rate less than 20 mL/min/1.73 m2, type 1 diabetes, and previous intolerance to SGLT2i were excluded. Main Outcomes and Measures: Patient-level and hospital-level prescription of SGLT2i at hospital discharge. Results: Of 49 399 included patients, 16 548 (33.5%) were female, and the median (IQR) age was 67 (56-78) years. Overall, 9988 patients (20.2%) were prescribed an SGLT2i. SGLT2i prescription was less likely among patients with chronic kidney disease (CKD; 4550 of 24 437 [18.6%] vs 5438 of 24 962 [21.8%]; P < .001) but more likely among patients with type 2 diabetes (T2D; 5721 of 21 830 [26.2%] vs 4262 of 27 545 [15.5%]; P < .001) and those with both T2D and CKD (2905 of 12 236 [23.7%] vs 7078 vs 37 139 [19.1%]; P < .001). Patients prescribed SGLT2i therapy were more likely to be prescribed background triple therapy with an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, ß-blocker, and mineralocorticoid receptor antagonist (4624 of 9988 [46.3%] vs 10 880 of 39 411 [27.6%]; P < .001), and 4624 of 49 399 total study patients (9.4%) were discharged with prescriptions for quadruple medical therapy including SGLT2i. Among 461 hospitals with 10 or more eligible discharges, 19 hospitals (4.1%) discharged 50% or more of patients with prescriptions for SGLT2i, whereas 344 hospitals (74.6%) discharged less than 25% of patients with prescriptions for SGLT2i (including 29 [6.3%] that discharged zero patients with SGLT2i prescriptions). There was high between-hospital variance in the rate of SGLT2i prescription in unadjusted models (median odds ratio, 2.53; 95% CI, 2.36-2.74) and after adjustment for patient and hospital characteristics (median odds ratio, 2.51; 95% CI, 2.34-2.71). Conclusions and Relevance: In this study, prescription of SGLT2i at hospital discharge among eligible patients with HFrEF was low, including among patients with comorbid CKD and T2D who have multiple indications for therapy, with substantial variation among US hospitals. Further efforts are needed to overcome implementation barriers and improve use of SGLT2i among patients with HFrEF.

Emergomyces pasteurianus in Man Returning to the United States from Liberia and Review of the Literature.

A 65-year-old man with HIV sought treatment for fever, weight loss, and productive cough after returning to the United States from Liberia. Fungal cultures grew Emergomyces pasteurianus, and the patient's health improved after beginning voriconazole. We describe the clinical case and review the literature, treatment, and susceptibilities for E. pasteurianus.

Quality of Care and Outcomes Among Patients Hospitalized for Heart Failure in Rural vs Urban US Hospitals: The Get With The Guidelines-Heart Failure Registry.

Importance: Prior studies have suggested patients with heart failure (HF) from rural areas have worse clinical outcomes. Contemporary differences between rural and urban hospitals in quality of care and clinical outcomes for patients hospitalized for HF remain poorly understood. Objective: To assess quality of care and clinical outcomes for US patients hospitalized for HF at rural vs urban hospitals. Design, Setting, and Participants: This retrospective cohort study analyzed 774 419 patients hospitalized for HF across 569 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry between January 1, 2014, and September 30, 2021. Postdischarge outcomes were assessed in a subset of 161 996 patients linked to Medicare claims. Data were analyzed from August 2022 to January 2023. Main Outcomes and Measures: GWTG-HF quality measures, in-hospital mortality, length of stay, and 30-day mortality and readmission outcomes. Results: This study included 19 832 patients (2.6%) and 754 587 patients (97.4%) hospitalized at 49 rural hospitals (8.6%) and 520 urban hospitals (91.4%), respectively. Of 774 419 included patients, 366 161 (47.3%) were female, and the median (IQR) age was 73 (62-83) years. Compared with patients at urban hospitals, patients at rural hospitals were older (median [IQR] age, 74 [64-84] years vs 73 [61-83] years; standardized difference, 10.63) and more likely to be non-Hispanic White (14 572 [73.5%] vs 498 950 [66.1%]; standardized difference, 34.47). In adjusted models, patients at rural hospitals were less likely to be prescribed cardiac resynchronization therapy (adjusted risk difference [aRD], -13.5%; adjusted odds ratio [aOR], 0.44; 95% CI, 0.22-0.92), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (aRD, -3.7%; aOR, 0.71; 95% CI, 0.53-0.96), and an angiotensin receptor-neprilysin inhibitor (aRD, -5.0%; aOR, 0.68; 95% CI, 0.47-0.98) at discharge. In-hospital mortality was similar between rural and urban hospitals (460 of 19 832 [2.3%] vs 20 529 of 754 587 [2.7%]; aOR, 0.86; 95% CI, 0.70-1.07). Patients at rural hospitals were less likely to have a length of stay of 4 or more days (aOR, 0.75; 95% CI, 0.67-0.85). Among Medicare beneficiaries, there were no significant differences between rural and urban hospitals in 30-day HF readmission (adjusted hazard ratio [aHR], 1.03; 95% CI, 0.90-1.19), all-cause readmission (aHR, 0.97; 95% CI, 0.91-1.04), and all-cause mortality (aHR, 1.05; 95% CI, 0.91-1.21). Conclusions and Relevance: In this large contemporary cohort of US patients hospitalized for HF, care at rural hospitals was independently associated with lower use of some guideline-recommended therapies at discharge and shorter length of stay. In-hospital mortality and 30-day postdischarge outcomes were similar at rural and urban hospitals.

Electronic hand hygiene monitoring systems: Not worth the costs.

Electronic hand hygiene monitoring systems allow the collection of large volumes of data. However, significant resources are required to validate and maintain these systems. Additionally, data are lacking on the correlation with clinically important outcomes. Direct observation of hand hygiene remains the gold standard for monitoring hand hygiene compliance.

Titration of medical therapy and clinical outcomes among patients with heart failure with reduced ejection fraction: Findings from the HF-ACTION trial.

BACKGROUND: Clinical guidelines recommend titration of angiotensin converting enzyme inhibitors (ACEi) and beta-blockers among patients with heart failure with reduced ejection fraction (HFrEF) to maximally tolerated doses. Patient characteristics associated with dose titration and clinical outcomes subsequent to dose titration remain poorly characterized. METHODS: Among 1999 ambulatory patients with chronic HFrEF in the HF-ACTION trial, use and dosing of ACEi and evidence-based beta-blockers were examined at baseline and 6-month follow-up. Multivariable logistic regression models were used to assess factors associated with dose escalation (medication initation or dosing increase) or dose de-escalation (medication discontinuation or dosing decrease). Cox proportional hazard regression models were used to examine associations between dose trajectory group (stable target, stable sub-target, dose escalation, and dose de-escalation) and subsequent mortality and hospitalization outcomes. RESULTS: For both ACEi and beta-blockers, hospitalization for heart failure in the 6 months prior to enrollment (odds ratio [OR] 2.32 [95% confidence interval 1.58-3.42]) for ACEi; 1.42 [1.05-1.9] for beta-blockers) and higher systolic blood pressure (OR 1.01 [1.00-1.03] per 1 mmHg increase for ACEi; 1.01 [1.00-1.02] for beta-blockers) were associated with dose escalation. Hospitalization 6 months prior to enrollment for any cause (including HF or non-HF causes) was associated with dose de-escalation (OR 1.60 [1.14-2.25] for ACEi; 1.67 [1.20-2.33] for beta-blockers). After adjustment for patient characteristics, compared with stable target dosing, dose de-escalation of either medication was associated with greater all-cause mortality (adjusted hazard ratio [aHR] 1.64 [1.11-2.42] for ACEi; 1.62 [1.04-2.53] for beta-blockers). Compared with stable target dosing, both dose de-escalation (aHR 1.98 [1.36-2.87]) and stable sub-target dosing (aHR 1.49 [1.18-1.87]) of beta-blockers were associated with greater cardiovascular mortality or hospitalization for heart failure. CONCLUSIONS: Among outpatients with chronic HFrEF, patient characteristics including recent hospitalization status and blood pressure were associated with odds of subsequent escalation and de-escalation of ACEi and beta-blocker therapy. Compared with patients receiving guildeline-recommended target doses, dose de-escalation of either medication and sub-target dosing of beta-blockers were associated with greater morbidity and mortality over long-term follow-up.

Long Noncoding RNAs as Therapeutic Targets.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of cellular functions including maintenance of cellular homeostasis as well as the onset and progression of disease. LncRNAs often exhibit cell-, tissue-, and disease-specific expression patterns, making them desirable therapeutic targets. LncRNAs are commonly targeted using oligonucleotide therapeutics, and advances in oligonucleotide chemistry including C2 ribose sugar modifications such as 2'-fluoro, 2'-O-methyl, and 2-O-methoxyethyl modifications; 2'4'-constrained nucleotides such as locked nucleic acids and constrained 2'-O-ethyl (cEt) nucleotides; and phosphorothioate bonds have dramatically improved efficacy of oligonucleotide therapies. Novel delivery platforms such as viral vectors and nanoparticles have also improved pharmacokinetic properties of oligonucleotides targeting lncRNAs. Accumulating pre-clinical studies have utilized these strategies to therapeutically target lncRNAs and alter progression of many different disease states including Snhg12 and Chast in cardiovascular disease, Mirt2 and HOTTIP in sepsis and autoimmune disease, and Malat1 and HOXB-AS3 in cancer. Emerging oligonucleotide conjugation methods including the use of peptide nucleic acids hold promise to facilitate targeting to specific tissue types. Here, we review recent advances in lncRNA therapeutics and provide examples of how lncRNAs have been successfully targeted in pre-clinical models of disease. Finally, we detail remaining challenges facing the lncRNA field and how advances in delivery platforms and oligonucleotide chemistry might help overcome these barriers to catalyze the translation of pre-clinical studies to successful pharmaceutical development.

COVID-19 and antimicrobial stewardship: lessons learned, best practices, and future implications.

The coronavirus disease 2019 (COVID-19) pandemic has had a profound and often devastating impact on global healthcare systems. Healthcare systems have had to repurpose programs and staff as part of COVID-19 relief efforts. The infrastructure and skilled personnel of antimicrobial stewardship programs (ASPs) have been utilized in new ways as part of COVID-19 pandemic response efforts. A critical focus of ASPs both before and during the pandemic has been on limiting the development of antimicrobial resistance. Fortunately, existing data indicate that rates of bacterial co-infection are relatively low and ASPs should continue aggressive efforts to limit unnecessary antimicrobial use. ASPs have taken a lead role in COVID-19 focused guideline creation and curation, as well as in helping to steward access to potential novel therapeutic agents. Disparities in ASP program resources and personnel exist, and ASP activities focused on the COVID-19 response should be tailored to individual settings. There is an urgent need for research to help inform ASP best practices within pandemic response efforts that take into account local resources. Investment in infrastructure and personnel is urgently needed both in the context of current relief efforts and to prepare for future pandemics.