Pragmatic Trial of Messaging to Providers About Treatment of Hyperlipidemia (PROMPT-LIPID): A Randomized Clinical Trial.

BACKGROUND: Lipid-lowering therapy (LLT) is underutilized for very high-risk atherosclerotic cardiovascular disease. PROMPT-LIPID (PRagmatic Trial of Messaging to Providers about Treatment of HyperLIPIDemia) sought to determine whether electronic health record (EHR) alerts improve 90-day LLT intensification in patients with very high-risk atherosclerotic cardiovascular disease. METHODS: PROMPT-LIPID was a pragmatic trial in which cardiovascular and internal medicine clinicians within Yale New Haven Health (New Haven, CT) were cluster-randomized to receive an EHR alert with individualized LLT recommendations or no alert for outpatients with very high-risk atherosclerotic cardiovascular disease and LDL-C (low-density lipoprotein cholesterol), ≥70 mg/dL. The primary outcome was 90-day LLT intensification (change to high-intensity statin and addition of ezetimibe or PCSK9i [proprotein subtilisin/kexin type 9 inhibitors]). Secondary outcomes included LDL-C level, proportion of patients with LDL-C of <70 or < 55 mg/dL, rate of major adverse cardiovascular events, ED visit incidence, and 6-month mortality. Results were analyzed using logistic and linear regression clustered at the provider level. RESULTS: The no-alert group included 47 clinicians and 1370 patients (median age, 71 years; 50.1% female, median LDL-C, 93 mg/dL); the alert group included 49 clinicians and 1130 patients (median age, 72 years; 47% female, median LDL-C 91, mg/dL). The primary outcome was observed in 14.1% of patients in the alert group as compared with 10.4% in the no-alert group. There were no differences in any secondary outcomes at 6 months. Among 542 patients whose clinicians (n=46) did not dismiss the EHR alert recommendations, LLT intensification was significantly greater (21.2% versus 10.4%, odds ratio, 2.33 [95% CI, 1.48-3.66]). CONCLUSIONS: With a real-time, targeted, individualized EHR alert as compared with usual care, the proportion of patients with atherosclerotic cardiovascular disease with LLT intensification was numerically higher but not statistically significant. Among clinicians who did not dismiss the alert, there was a > 2-fold increase in LLT intensification. EHR alerts, coupled with strategies to reduce clinician dismissal, may help address persistent gaps in LDL-C management. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04394715, https://www.clinicaltrials.gov/ct2/show/study/NCT04394715.

Differences in Mortality Among Patients With Asthma and COPD Hospitalized With COVID-19.

BACKGROUND: It remains unclear whether patients with asthma and/or chronic obstructive pulmonary disease (COPD) are at increased risk for severe coronavirus disease 2019 (COVID-19). OBJECTIVE: Compare in-hospital COVID-19 outcomes among patients with asthma, COPD, and no airway disease. METHODS: A retrospective cohort study was conducted on 8,395 patients admitted with COVID-19 between March 2020 and April 2021. Airway disease diagnoses were defined using International Classification of Diseases, 10th Revision codes. Mortality and sequential organ failure assessment (SOFA) scores were compared among groups. Logistic regression analysis was used to identify and adjust for confounding clinical features associated with mortality. RESULTS: The median SOFA score in patients without airway disease was 0.32 and mortality was 11%. In comparison, asthma patients had lower SOFA scores (median 0.15; P < .01) and decreased mortality, even after adjusting for age, diabetes, and other confounders (odds ratio 0.65; P = .01). Patients with COPD had higher SOFA scores (median 0.86; P < .01) and increased adjusted odds of mortality (odds ratio 1.40; P < .01). Blood eosinophil count of 200 cells/µL or greater, a marker of type 2 inflammation, was associated with lower mortality across all groups. Importantly, patients with asthma showed improved outcomes even after adjusting for eosinophilia, indicating that noneosinophilic asthma was associated with protection as well. CONCLUSIONS: COVID-19 severity was increased in patients with COPD and decreased in those with asthma, eosinophilia, and noneosinophilic asthma, independent of clinical confounders. These findings suggest that COVID-19 severity may be influenced by intrinsic immunological factors in patients with airway diseases, such as type 2 inflammation.

Risk of COVID-19 breakthrough infection and hospitalization in individuals with comorbidities.

BACKGROUND: The successful development of multiple COVID-19 vaccines has led to a global vaccination effort to reduce severe COVID-19 infection and mortality. However, the effectiveness of the COVID-19 vaccines wane over time leading to breakthrough infections where vaccinated individuals experience a COVID-19 infection. Here we estimate the risks of breakthrough infection and subsequent hospitalization in individuals with common comorbidities who had completed an initial vaccination series. METHODS: Our study population included vaccinated patients between January 1, 2021 to March 31, 2022 who are present in the Truveta patient population. Models were developed to describe 1) time from completing primary vaccination series till breakthrough infection; and 2) if a patient was hospitalized within 14 days of breakthrough infection. We adjusted for age, race, ethnicity, sex, and year-month of vaccination. RESULTS: Of 1,218,630 patients in the Truveta Platform who had completed an initial vaccination sequence between January 1, 2021 and March 31, 2022, 2.85, 3.42, 2.75, and 2.88 percent of patients with CKD, chronic lung disease, diabetes, or are in an immunocompromised state experienced breakthrough infection, respectively, compared to 1.46 percent of the population without any of these four comorbidities. We found an increased risk of breakthrough infection and subsequent hospitalization in individuals with any of the four comorbidities when compared to individuals without these four comorbidities. CONCLUSIONS: Vaccinated individuals with any of the studied comorbidities experienced an increased risk of breakthrough COVID-19 infection and subsequent hospitalizations compared to the people without any of the studied comorbidities. Individuals with immunocompromising conditions and chronic lung disease were most at risk of breakthrough infection, while people with CKD were most at risk of hospitalization following breakthrough infection. Patients with multiple comorbidities have an even greater risk of breakthrough infection or hospitalization compared to patients with none of the studied comorbidities. Individuals with common comorbidities should remain vigilant against infection even if vaccinated.

Effect of intravenous antihypertensives on outcomes of severe hypertension in hospitalized patients without acute target organ damage.

BACKGROUND: Treatment of severe inpatient hypertension (HTN) that develops during hospitalization is not informed by guidelines. Intravenous (i.v.) antihypertensives are used to manage severe HTN even in the absence of acute target organ damage; however they may result in unpredictable blood pressure (BP) reduction and cardiovascular events. Our goal was to assess the association between i.v. antihypertensives and clinical outcomes in this population. METHODS: This is a multihospital retrospective study of adults admitted for reasons other than HTN who develop severe HTN during hospitalization without acute target end organ damage. We defined severe HTN as BP elevation of systolic >180 or diastolic >110 mmHg. Treatment was defined as receiving i.v. antihypertensives within 3 h of BP elevation. We used overlap propensity score weighted Cox models to study the association between treatment and clinical outcomes during index hospitalization. RESULTS: Of 224 265 unique, nonintensive care unit hospitalizations, 20 383 (9%) developed severe HTN, of which 5% received i.v. antihypertensives and 79% were untreated within 3 h of severe BP elevation. In the overlap propensity weighted population, patients who received i.v. antihypertensives were more likely to develop myocardial injury (5.9% in treated versus 3.6% in untreated; hazard ratio [HR]: 1.6 [1.13, 2.24]). Treatment was not associated with increased risk of stroke (HR: 0.7 [0.3, 1.62]), acute kidney injury (HR: 0.97 [0.81, 1.17]), or death (HR: 0.86 [0.49, 1.51]). CONCLUSIONS: Intravenous antihypertensives were associated with increased risk of myocardial injury in patients who develop severe HTN during hospitalization. These results suggest that i.v. antihypertensives should be used with caution in patients without acute target organ damage.

Effect of Androgen-Androgen Receptor Directed Therapy on COVID-19 Outcome in Prostate Cancer Patients.

TMPRSS2 is utilized by SARS-CoV-2 for cellular entry. Androgen-Androgen receptor directed therapy (A/ARDT) downregulates expression of TMPRSS2. We hypothesized A/ARDT might protect prostate cancer (PCa) patients from poor COVID-19 outcome. A retrospective analysis of PCa patients with COVID-19 infection was performed. 146 PCa cases were identified, 17% were on A/ARDT. Hospitalization rates were same 52% (OR = 0.99, 0.41-2.24). Mean hospitalization was 9.2 (Range: 1-25) and 14.9 (Range: 2-47) days in A/ARDT and non-A/ARDT groups, respectively. While definitive conclusions cannot be made regarding outcome differences between groups due to lack of statistical significance, these data generate hypothesis that A/ARDT might shorten hospitalization stay.

Alerting Clinicians to 1-Year Mortality Risk in Patients Hospitalized With Heart Failure: The REVEAL-HF Randomized Clinical Trial.

Importance: Heart failure is a major cause of morbidity and mortality worldwide. The use of risk scores has the potential to improve targeted use of interventions by clinicians that improve patient outcomes, but this hypothesis has not been tested in a randomized trial. Objective: To evaluate whether prognostic information in heart failure translates into improved decisions about initiation and intensity of treatment, more appropriate end-of-life care, and a subsequent reduction in rates of hospitalization or death. Design, Setting, and Participants: This was a pragmatic, multicenter, electronic health record-based, randomized clinical trial across the Yale New Haven Health System, comprising small community hospitals and large tertiary care centers. Patients hospitalized for heart failure who had N-terminal pro-brain natriuretic peptide (NT-proBNP) levels of greater than 500 pg/mL and received intravenous diuretics within 24 hours of admission were automatically randomly assigned to the alert (intervention) or usual-care groups. Interventions: The alert group had their risk of 1-year mortality calculated using an algorithm that was derived and validated using similar historic patients in the electronic health record. This estimate, including a categorical risk assessment, was presented to clinicians while they were interacting with a patient's electronic health record. Main Outcomes and Measures: The primary outcome was a composite of 30-day hospital readmissions and all-cause mortality at 1 year. Results: Between November 27, 2019, through March 7, 2021, 3124 patients were randomly assigned to the alert (1590 [50.9%]) or usual-care (1534 [49.1%]) group. The alert group had a median (IQR) age of 76.5 (65-86) years, and 796 were female patients (50.1%). Patients from the following race and ethnicity groups were included: 13 Asian (0.8%), 324 Black (20.4%), 136 Hispanic (8.6%), 1448 non-Hispanic (91.1%), 1126 White (70.8%), 6 other ethnicity (0.4%), and 127 other race (8.0%). The usual-care group had a median (IQR) age of 77 (65-86) years, and 788 were female patients (51.4%). Patients from the following race and ethnicity groups were included: 11 Asian (1.4%), 298 Black (19.4%), 162 Hispanic (10.6%), 1359 non-Hispanic (88.6%), 1077 White (70.2%), 13 other ethnicity (0.9%), and 137 other race (8.9%). Median (IQR) NT-proBNP levels were 3826 (1692-8241) pg/mL in the alert group and 3867 (1663-8917) pg/mL in the usual-care group. A total of 284 patients (17.9%) and 270 patients (17.6%) were admitted to the intensive care unit in the alert and usual-care groups, respectively. A total of 367 patients (23.1%) and 359 patients (23.4%) had a left ventricular ejection fraction of 40% or less in the alert and usual-care groups, respectively. The model achieved an area under the curve of 0.74 in the trial population. The primary outcome occurred in 619 patients (38.9%) in the alert group and 603 patients (39.3%) in the usual-care group (P = .89). There were no significant differences between study groups in the prescription of heart failure medications at discharge, the placement of an implantable cardioverter-defibrillator, or referral to palliative care. Conclusions and Relevance: Provision of 1-year mortality estimates during heart failure hospitalization did not affect hospitalization or mortality, nor did it affect clinical decision-making. Trial Registration: ClinicalTrials.gov Identifier NCT03845660.

Pragmatic randomized trial assessing the impact of digital health technology on quality of life in patients with heart failure: Design, rationale and implementation.

BACKGROUND: Self-care and patient engagement are important elements of heart failure (HF) care, endorsed in the guidelines. Digital health tools may improve quality of life (QOL) in HF patients by promoting care, knowledge, and engagement. This manuscript describes the rationale and challenges of the design and implementation of a pragmatic randomized controlled trial to evaluate the efficacy of three digital health technologies in improving QOL for patients with HF. HYPOTHESIS: We hypothesize that digital health interventions will improve QOL of HF patients through the early detection of warning signs of disease exacerbation, the opportunity of self-tracking symptoms, and the education provided, which enhances patient empowerment. METHODS: Using a fully electronic enrollment and consent platform, the trial will randomize 200 patients across HF clinics in the Yale New Haven Health system to receive either usual care or one of three digital technologies designed to promote self-management and provide critical data to clinicians. The primary outcome is the change in QOL as assessed by the Kansas City Cardiomyopathy Questionnaire at 3 months. RESULTS: First enrollment occurred in September 2021. Recruitment was anticipated to last 6-8 months and participants were followed for 6 months after randomization. Our recruitment efforts have highlighted the large digital divide in our population of interest. CONCLUSION: Assessing clinical outcomes, patient usability, and ease of clinical integration of digital technologies will be beneficial in determining the feasibility of the integration of such technologies into the healthcare system.

Rationale and design of a pragmatic trial aimed at improving treatment of hyperlipidemia in outpatients with very high risk atherosclerotic cardiovascular disease: A pragmatic trial of messaging to providers about treatment of hyperlipidemia (PROMPT-LIPID).

BACKGROUND: Despite guideline recommendations to optimize low-density lipoprotein cholesterol (LDL-C) reduction with intensification of lipid-lowering therapy (LLT) in patients with atherosclerotic cardiovascular disease (ASCVD), few of these patients achieve LDL-C < 70 mg/dL in practice. PURPOSE: We developed a real-time, targeted electronic health record (EHR) alert with embedded ordering capability to promote intensification of evidence based LLT in outpatients with very high risk ASCVD. METHODS: We designed a pragmatic, multicenter, single-blind, cluster randomized trial to test the effectiveness of an EHR-based LLT intensification alert. The study will enroll about 100 providers who will be randomized to either receive the alert or undergo usual care for outpatients with high risk ASCVD with LDL-C > 70 mg/dL. Total enrollment will include 2,500 patients. The primary outcome will be the proportion of patients with LLT intensification at 90 days. Secondary outcomes include achieved LDL-C at 6 months and the proportion of patients with LDL-C < 70 mg/dL or < 55 mg/dL at 6 months. RESULTS: Enrollment of 1,250 patients (50% of goal) was reached within 47 days (50% women, mean age 72, median LDL-C 91). At baseline, 71%, 9%, and 3% were on statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 inhibitors, respectively. CONCLUSIONS: PRagmatic Trial of Messaging to Providers about Treatment of HyperLIPIDemia has rapidly reached 50% enrollment of patients with very high risk ASCVD, demonstrating low baseline LLT utilization. This pragmatic, EHR-based trial will determine the effectiveness of a real-time, targeted EHR alert with embedded ordering capability to promote LLT intensification. Findings from this low-cost, widely scalable intervention to improve LDL-C may have important public health implications. TRIAL REGISTRATION: clinicaltrials.gov NCT04394715.

Associations between hospitalist physician workload, length of stay, and return to the hospital.

BACKGROUND: Hospitalist physicians' workload-the total number of patients they care for daily-is rising in the U.S. Hospitalists report that increased workload negatively affects patients care. OBJECTIVE: Measure the associations between hospitalist physicians' workload and clinical outcomes. DESIGN, SETTINGS, AND PARTICIPANTS: Observational study, using electronic health record (EHR) data, of adults hospitalized on the hospitalist service at Yale-New Haven Hospital from 2015-2018. MAIN OUTCOME AND MEASURES: We defined hospitalists' workload as the number of patients they cared for on the first full hospital day of a given patient's encounter. We used multilevel Poisson and logistic regression to examine associations between workload and length of stay (LOS), return to the Emergency Department (ED), and readmission. We adjusted for sociodemographic factors, patient complexity and severity of illness, and weekend admission (for LOS) or discharge (for ED visits or readmission). RESULTS: We analyzed 38,141 hospitalizations. Median patient age was 64 years (IQR 51-78 years), 53% were female, and 34% were nonwhite. Mean workload was 15 patients (SD 3 patients; range 10-34 patients). LOS was prolonged by 0.05 days (95% CI 0.02, 0.08; p(0.001) when comparing the 75th workload percentile (16 patients) to the 25th workload percentile (13 patients). There were no associations between workload and ED visits or readmission within 7 and 30 days. CONCLUSIONS: There was a statistically significant but modest relationship between workload and LOS; workload was not associated with ED visits or readmissions.Given clinical reports of the deleterious effects of increased hospitalist workload, there is a need for prospective research assessing a range of outcomes, beyond those measurable in contemporary EHR data.

Blood pressure response to commonly administered antihypertensives for severe inpatient hypertension.

BACKGROUND: Blood pressure (BP) elevations are commonly treated in hospitalized patients; however, treatment is not guideline directed. Our objective was to assess BP response to commonly prescribed antihypertensives after the development of severe inpatient hypertension (HTN). METHODS: This is a cohort study of adults, excluding intensive care unit patients, within a single healthcare system admitted for reasons other than HTN who developed severe HTN (systolic BP>180 or diastolic BP >110 mmHg at least 1 hour after admission). We identified the most commonly administered antihypertensives given within 6 hours of severe HTN (given to >10% of treated patients). We studied the association of treatment with each antihypertensive vs. no treatment on BP change in the 6 hours following severe HTN development using mixed-effects model after adjusting for demographics and clinical characteristics. RESULTS: Among 23,147 patients who developed severe HTN, 9,166 received antihypertensive treatment. The most common antihypertensives given were oral metoprolol (n = 1991), oral amlodipine (n = 1812), oral carvedilol (n = 1116), IV hydralazine (n = 1069) and oral hydralazine (n = 953). In the fully adjusted model, treatment with IV hydralazine led to 13 [-15.9, -10.1], 18 [-22.2, -14] and 11 [-14.1, -8.3] mmHg lower MAP, SBP, and DBP in the 6 hours following severe HTN development compared to no treatment. Treatment with oral hydralazine and oral carvedilol also resulted in significantly lower BPs in the 6 hours following severe HTN development (6 [-9.1, -2.1 and -7 [-9.1, -4.2] lower MAP, respectively) compared to no treatment. Receiving metoprolol and amlodipine did not result in a drop in BP compared to no treatment. CONCLUSION: Among commonly used antihypertensives, IV hydralazine resulted in the most significant drop in BP following severe HTN, while metoprolol and amlodipine did not lower BP. Further research to assess the effect of treatment on clinical outcomes and if needed which antihypertensives to administer are necessary.

Electronic Alerts to Improve Heart Failure Therapy in Outpatient Practice: A Cluster Randomized Trial.

BACKGROUND: The use of guideline-directed medical therapy (GDMT) is underprescribed in patients with heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study sought to examine whether targeted and tailored electronic health record (EHR) alerts recommending GDMT in eligible patients with HFrEF improves GDMT use. METHODS: PROMPT-HF (PRagmatic trial Of Messaging to Providers about Treatment of Heart Failure) was a pragmatic, EHR-based, cluster-randomized comparative effectiveness trial. A total of 100 providers caring for patients with HFrEF were randomized to either an alert or usual care. The alert notified providers of individualized GDMT recommendations along with patient characteristics. The primary outcome was an increase in the number of GDMT classes prescribed at 30 days postrandomization. Providers were surveyed on knowledge of guidelines and user experience. RESULTS: The study enrolled 1,310 ambulatory patients with HFrEF from April to October 2021. Median age was 72 years; 31% were female; 18% were Black; and median left ventricular ejection fraction was 32%. At baseline, 84% of participants were receiving ß-blockers, 71% received a renin-angiotensin-aldosterone system inhibitor, 29% received a mineralocorticoid receptor antagonist, and 11% received a sodium-glucose cotransporter-2 inhibitor. The primary outcome occurred in 176 of 685 (26%) participants in the alert arm vs 117 of 625 (19%) in the usual care arm, thus increasing GDMT class prescription by >40% after alert exposure (adjusted relative risk: 1.41; 95% CI: 1.03-1.93; P = 0.03). The number of patients needed to alert to result in an increase in addition of GDMT classes was 14. A total of 79% of alerted providers agreed that the alert was effective at enabling improved prescription of medical therapy for HF. CONCLUSIONS: A real-time, targeted, and tailored EHR-based alerting system for outpatients with HFrEF led to significantly higher rates of GDMT at 30 days when compared with usual care. This low-cost intervention can be rapidly integrated into clinical care and accelerate adoption of high-value therapies in heart failure. (PRagmatic trial Of Messaging to Providers about Treatment of Heart Failure [PROMPT-HF; NCT04514458]).

Mortality after acute kidney injury and acute interstitial nephritis in patients prescribed immune checkpoint inhibitor therapy.

BACKGROUND: In patients receiving immune checkpoint inhibitor (ICI) therapy, acute kidney injury (AKI) is common, and can occur either from kidney injury unrelated to ICI use or from immune activation resulting in acute interstitial nephritis (AIN). In this study, we test the hypothesis that occurrence of AIN indicates a favorable treatment response to ICI therapy and therefore among patients who develop AKI while on ICI therapy, those with AIN will demonstrate greater survival compared with others with AKI. METHODS: In this observational cohort study, we included participants initiated on ICI therapy between 2013 and 2019. We tested the independent association of AKI and estimated AIN (eAIN) with mortality up to 1 year after therapy initiation as compared with those without AKI using time-varying Cox proportional hazard models controlling for demographics, comorbidities, cancer type, stage, and therapy, and baseline laboratory values. We defined eAIN as those with a predicted probability of AIN >90th percentile derived from a recently validated diagnostic model. RESULTS: Of 2207 patients initiated on ICIs, 617 (28%) died at 1 year and 549 (25%) developed AKI. AKI was independently associated with higher mortality (adjusted HR, 2.28 (95% CI 1.90 to 2.72)). Those AKI patients with eAIN had more severe AKI as reflected by a higher peak serum creatinine (3.3 (IQR 2.1-6.1) vs 1.4 (1.2-1.9) mg/dL, p<0.001) but exhibited lower mortality than those without eAIN in univariable analysis (HR 0.43 (95% CI 0.21 to 0.89)) and after adjusting for demographics, comorbidities, and cancer type and severity (adjusted HR 0.44 (95% CI 0.21 to 0.93)). CONCLUSION: In patients treated with ICI, mortality was higher in those with AKI unrelated to ICI but lower in those where the underlying etiology was AIN. Future studies could evaluate the association of biopsy-proven or biomarker-proven AIN with mortality in those receiving ICI therapy.

Association of renalase with clinical outcomes in hospitalized patients with COVID-19.

Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March-June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if <18 years, or opted out of research. The primary composite outcome was intubation or death within 180 days. Secondary outcomes included mortality alone, intensive care unit admission, use of vasopressors, and CPR. Enrolled patients had mean age 64 years (SD±17), were 53% males, and 48% non-whites. Mean renalase levels was 14,108·4 ng/ml (SD±8,137 ng/ml). Compared to patients with high renalase, those with low renalase (< 8,922 ng/ml) were more likely to present with hypoxia, increased ICU admission (54% vs. 33%, p < 0.001), and cardiopulmonary resuscitation (10% vs. 4%, p = 0·023). In Cox proportional hazard model, every 1000 ng/ml increase in renalase decreased the risk of death or intubation by 5% (HR 0·95; 95% CI 0·91-0·98) and increased survival alone by 6% (HR 0·95; CI 0·90-0·98), after adjusting for socio-demographics, initial disease severity, comorbidities and inflammation. Patients with high renalase-low IL-6 levels had the best survival compared to other groups (p = 0·04). Renalase was independently associated with reduced intubation and mortality in hospitalized COVID-19 patients. Future studies should assess the pathophysiological relevance of renalase in COVID-19 disease.

Multiscale PHATE identifies multimodal signatures of COVID-19.

As the biomedical community produces datasets that are increasingly complex and high dimensional, there is a need for more sophisticated computational tools to extract biological insights. We present Multiscale PHATE, a method that sweeps through all levels of data granularity to learn abstracted biological features directly predictive of disease outcome. Built on a coarse-graining process called diffusion condensation, Multiscale PHATE learns a data topology that can be analyzed at coarse resolutions for high-level summarizations of data and at fine resolutions for detailed representations of subsets. We apply Multiscale PHATE to a coronavirus disease 2019 (COVID-19) dataset with 54 million cells from 168 hospitalized patients and find that patients who die show CD16hiCD66blo neutrophil and IFN-γ+ granzyme B+ Th17 cell responses. We also show that population groupings from Multiscale PHATE directly fed into a classifier predict disease outcome more accurately than naive featurizations of the data. Multiscale PHATE is broadly generalizable to different data types, including flow cytometry, single-cell RNA sequencing (scRNA-seq), single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq), and clinical variables.

Severe inpatient hypertension prevalence and blood pressure response to antihypertensive treatment.

Severe hypertension (HTN) that develops during hospitalization is more common than admission for HTN; however, it is poorly studied, and treatment guidelines are lacking. Our goal is to characterize hospitalized patients who develop severe HTN and assess blood pressure (BP) response to treatment. This is a multi-hospital retrospective cohort study of adults admitted for reasons other than HTN who developed severe HTN. The authors defined severe inpatient HTN as the first documented BP elevation (systolic BP > 180 or diastolic BP > 110) at least 1 hour after admission. Treatment was defined as receiving antihypertensives (intravenous [IV] or oral) within 6h of BP elevation. As a measure of possible overtreatment, the authors studied the association between treatment and time to mean arterial pressure (MAP) drop ≥ 30% using the Cox proportional hazards model. Among 224 265 hospitalized adults, 10% developed severe HTN of which 40% were treated. Compared to patients who did not develop severe HTN, those who did were older, more commonly women and black, and had more comorbidities. Incident MAP drop ≥ 30% among treated and untreated patients with severe HTN was 2.2 versus 5.7/1000 person-hours. After adjustment, treated versus. untreated patients had lower rates of MAP drop ≥ 30% (hazard rate [HR]: 0.9 [0.8, 0.99]). However, those receiving only IV treatment versus untreated had greater rates of MAP drop ≥ 30% (1.4 [1.2, 1.7]). Overall, the authors found that clinically significant MAP drop is observed among inpatients with severe HTN irrespective of treatment, with greater rates observed among patients treated only with IV antihypertensives. Further research is needed to phenotype inpatients with severe HTN.

Excessive Blood Pressure Response to Clonidine in Hospitalized Patients With Asymptomatic Severe Hypertension.

BACKGROUND: There are limited and nonconcordant data on the rapidity and safety of blood pressure response to clonidine in the setting of asymptomatic severe hypertension. We evaluated the blood pressure response to clonidine in hospitalized patients with asymptomatic severe hypertension. METHODS: We performed a review of hospitalized, noncritically ill patients receiving clonidine within 6 hours of developing asymptomatic severe hypertension (systolic blood pressure [SBP] >180 or diastolic blood pressure [DBP] >110 mm Hg in the absence of acute hypertension-mediated target organ damage). The incidence of mean arterial pressure (MAP) reduction by ≥30% at 4 hours after clonidine was the primary endpoint. RESULTS: We identified 200 relevant patient encounters (median age 63 years, 48.5% women). Median time to clonidine following asymptomatic severe hypertension was 2.8 hours. A total of 20 (10%) patients had ≥30% MAP reduction within 4 hours after clonidine, and 32 (16%) patients had ≥30% reduction in either SBP, DBP, or MAP. Older age, female sex, and preexisting vascular disease were associated with ≥30% MAP reductions (P < 0.05). Only patient sex and clonidine dose of 0.3 mg were significant in multivariable models. There were 14 adverse events observed within 24 hours of administration of clonidine; most (9) were acute kidney injury. There were no ischemic (myocardial, cerebrovascular) events. CONCLUSIONS: A substantial minority of hospitalized patients with asymptomatic severe hypertension experience precipitous blood pressure decline with clonidine, and though blood pressure declines more precipitously in women and those receiving higher doses (0.3 mg specifically), the response to clonidine is generally not predictable on clinical grounds.

Prognostic Significance of Urinary Biomarkers in Patients Hospitalized With COVID-19.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is common in patients with coronavirus disease 2019 (COVID-19) and associated with poor outcomes. Urinary biomarkers have been associated with adverse kidney outcomes in other settings and may provide additional prognostic information in patients with COVID-19. We investigated the association between urinary biomarkers and adverse kidney outcomes among patients hospitalized with COVID-19. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients hospitalized with COVID-19 (n=153) at 2 academic medical centers between April and June 2020. EXPOSURE: 19 urinary biomarkers of injury, inflammation, and repair. OUTCOME: Composite of KDIGO (Kidney Disease: Improving Global Outcomes) stage 3 AKI, requirement for dialysis, or death within 60 days of hospital admission. We also compared various kidney biomarker levels in the setting of COVID-19 versus other common AKI settings. ANALYTICAL APPROACH: Time-varying Cox proportional hazards regression to associate biomarker level with composite outcome. RESULTS: Out of 153 patients, 24 (15.7%) experienced the primary outcome. Twofold higher levels of neutrophil gelatinase-associated lipocalin (NGAL) (HR, 1.34 [95% CI, 1.14-1.57]), monocyte chemoattractant protein (MCP-1) (HR, 1.42 [95% CI, 1.09-1.84]), and kidney injury molecule 1 (KIM-1) (HR, 2.03 [95% CI, 1.38-2.99]) were associated with highest risk of sustaining primary composite outcome. Higher epidermal growth factor (EGF) levels were associated with a lower risk of the primary outcome (HR, 0.61 [95% CI, 0.47-0.79]). Individual biomarkers provided moderate discrimination and biomarker combinations improved discrimination for the primary outcome. The degree of kidney injury by biomarker level in COVID-19 was comparable to other settings of clinical AKI. There was evidence of subclinical AKI in COVID-19 patients based on elevated injury biomarker level in patients without clinical AKI defined by serum creatinine. LIMITATIONS: Small sample size with low number of composite outcome events. CONCLUSIONS: Urinary biomarkers are associated with adverse kidney outcomes in patients hospitalized with COVID-19 and may provide valuable information to monitor kidney disease progression and recovery.

Rationale and design of a cluster-randomized pragmatic trial aimed at improving use of guideline directed medical therapy in outpatients with heart failure: PRagmatic trial of messaging to providers about treatment of heart failure (PROMPT-HF).

Heart failure with reduced ejection fraction (HFrEF) is one of the most common chronic illnesses in the United States and carries significant risk of morbidity and mortality. Use of guideline-directed medical therapy (GDMT) for patients with HFrEF has been shown to dramatically improve outcomes, but adoption of these treatments remains generally low. Possible explanations for poor GDMT uptake include lack of knowledge about recommended management strategies and provider reluctance due to uncertainties regarding application of said guidelines to real-world practice. One way to overcome these barriers is by harnessing the electronic health record (EHR) to create patient-centered "best practice alerts" (BPAs) that can guide clinicians to prescribe appropriate medical therapies. If found to be effective, these low-cost interventions can be rapidly applied across large integrated healthcare systems. The PRagmatic Trial Of Messaging to Providers about Treatment of Heart Failure (PROMPT-HF) trial is a pragmatic, cluster randomized controlled trial designed to test the hypothesis that tailored and timely alerting of recommended GDMT in heart failure (HF) will result in greater adherence to guidelines when compared with usual care. PROMPT-HF has completed enrollment of 1,310 ambulatory patients with HFrEF cared for by 100 providers who were randomized to receive a BPA vs usual care. The BPA alerted providers to GDMT recommended for their patients and displayed current left ventricular ejection fraction (LVEF) along with the most recent blood pressure, heart rate, serum potassium and creatinine levels, and estimated glomerular filtration rate. It also linked to an order set customized to the patient that suggests medications within each GDMT class not already prescribed. Our goal is to examine whether tailored EHR-based alerting for outpatients with HFrEF will lead to higher rates of GDMT at 30 days post randomization when compared with usual care. Additionally, we are assessing clinical outcomes such as hospital readmissions and death between the alert versus usual care group. Trial Registration: Clinicaltrials.gov NCT04514458.

Development and external validation of a diagnostic model for biopsy-proven acute interstitial nephritis using electronic health record data.

BACKGROUND: Patients with acute interstitial nephritis (AIN) can present without typical clinical features, leading to a delay in diagnosis and treatment. We therefore developed and validated a diagnostic model to identify patients at risk of AIN using variables from the electronic health record. METHODS: In patients who underwent a kidney biopsy at Yale University between 2013 and 2018, we tested the association of >150 variables with AIN, including demographics, comorbidities, vital signs and laboratory tests (training set 70%). We used least absolute shrinkage and selection operator methodology to select prebiopsy features associated with AIN. We performed area under the receiver operating characteristics curve (AUC) analysis with internal (held-out test set 30%) and external validation (Biopsy Biobank Cohort of Indiana). We tested the change in model performance after the addition of urine biomarkers in the Yale AIN study. RESULTS: We included 393 patients (AIN 22%) in the training set, 158 patients (AIN 27%) in the test set, 1118 patients (AIN 11%) in the validation set and 265 patients (AIN 11%) in the Yale AIN study. Variables in the selected model included serum creatinine {adjusted odds ratio [aOR] 2.31 [95% confidence interval (CI) 1.42-3.76]}, blood urea nitrogen:creatinine ratio [aOR 0.40 (95% CI 0.20-0.78)] and urine dipstick specific gravity [aOR 0.95 (95% CI 0.91-0.99)] and protein [aOR 0.39 (95% CI 0.23-0.68)]. This model showed an AUC of 0.73 (95% CI 0.64-0.81) in the test set, which was similar to the AUC in the external validation cohort [0.74 (95% CI 0.69-0.79)]. The AUC improved to 0.84 (95% CI 0.76-0.91) upon the addition of urine interleukin-9 and tumor necrosis factor-α. CONCLUSIONS: We developed and validated a statistical model that showed a modest AUC for AIN diagnosis, which improved upon the addition of urine biomarkers. Future studies could evaluate this model and biomarkers to identify unrecognized cases of AIN.