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BackgroundUnderstanding disease progression, age-specific comorbidities, medical treatment patterns, and unmet needs can help improve the care pathway of individuals with rare genetic epilepsies. A matched longitudinal cohort study has not been performed for these variables from childhood to adolescence across the whole phenome.MethodsWe identified individuals with likely genetic and non-genetic epilepsy syndromes and onset at ages 0-5 years by linkage across the Cleveland Clinic Health System. We used natural language processing to extract medical terms and procedures from longitudinal electronic health records (EHR) and tested for cross-sectional and temporal associations with genetic epilepsies.FindingsWe identified 503 individuals with genetic epilepsy syndromes and matched controls with epilepsy that did not receive genetic testing. The median age at the first encounter was 0·1 years, 7·9 years at the last encounter, and the mean duration of follow-up was 8·2 years. We extracted 188,295 Unified Medical Language System (UMLS) annotations for statistical analysis across 9,659 encounters. Individuals with genetic epilepsy syndromes received an earlier epilepsy diagnosis and had more frequent and complex encounters with the healthcare system. Notably, the highest enrichment of encounters compared to the non-genetic groups was found during the transition from paediatric to adult care. Our computational approach could validate established comorbidities of genetic epilepsies, such as behavioural abnormality and intellectual disability. We also revealed novel associations for genitourinary abnormalities (OR 1·91, 95% CI: 1·66-2·19, p = 2·39×10-19) linked to a spectrum of underrecognized genetic syndromes.InterpretationThis study identified novel features associated with the likelihood of a genetic epilepsy syndrome and quantified the healthcare utilization of genetic epilepsies compared to matched controls with epilepsy who did not receive genetic testing. Our results strongly recommend early genetic testing to stratify individuals into specialized care paths, thus improving the clinical management of people with genetic epilepsies.FundingNot applicable.

Aims Little is known about the impact of weight loss on developing comorbidities in patients with obesity in real-world settings. Understanding health benefits and associated comorbidities with weight loss are critical to addressing the global obesity health epidemic. This study aimed to determine health outcomes associated with weight loss in individuals with obesity, and to better understand the relationship between disease burden (i.e., prior comorbidities, healthcare utilization) and weight loss in individuals with obesity. Electronic health records (EHRs) represent an important resource to investigate these impacts. Materials and methods We conducted a case-control study using deidentified EHR-derived information from 204,921 patients seen at the Cleveland Clinic between 2000-2018. Patients were ≥20 years of age with BMI ≥30 kg/m2 and ≥7 weight measurements, over ≥3 years. Thirty outcomes were investigated, including chronic and acute diseases, as well as psychological and metabolic disorders. Weight change was investigated three, five, and ten years prior to an event. Results Weight loss was associated with reduced incidence of many outcomes (e.g., type 2 diabetes, non-alcoholic steatohepatitis/non-alcoholic fatty liver disease, obstructive sleep apnea, hypertension) (P 10% was associated with increased incidence of certain outcomes including stroke and substance abuse. However, many outcomes that increased with weight loss were attenuated by disease burden adjustments. Conclusions This study provides the most comprehensive real-world evaluation of health impacts of weight change to date. After comorbidity burden and healthcare utilization adjustments, weight loss was associated with an overall reduction in risk of many adverse outcomes. This article is protected by copyright. All rights reserved.

Reports indicate that coronavirus disease 2019 (COVID-19) may impact pancreatic function and increase type 2 diabetes (T2D) risk, although real-world COVID-19 impacts on HbA1c and T2D are unknown. We tested whether COVID-19 increased HbA1c, risk of T2D, or diabetic ketoacidosis (DKA). We compared pre– and post–COVID-19 HbA1c and T2D risk in a large real-world clinical cohort of 8,755 COVID-19(+) patients and 11,998 COVID-19(−) matched control subjects. We investigated whether DKA risk was modified in COVID-19(+) patients with type 1 diabetes (T1D) (N = 701) or T2D (N = 21,830), or by race and sex. We observed a statistically significant, albeit clinically insignificant, HbA1c increase post–COVID-19 (all patients ΔHbA1c = 0.06%; with T2D ΔHbA1c = 0.1%) and no increase among COVID-19(−) patients. COVID-19(+) patients were 40% more likely to be diagnosed with T2D compared with COVID-19(−) patients and 28% more likely for the same HbA1c change as COVID-19(−) patients, indicating that COVID-19–attributed T2D risk may be due to increased recognition during COVID-19 management. DKA in COVID-19(+) patients with T1D was not increased. COVID-19(+) Black patients with T2D displayed disproportionately increased DKA risk (hazard ratio 2.46 [95% CI 1.48–6.09], P = 0.004) compared with White patients, suggesting a need for further clinical awareness and investigation.

The electrocardiography (ECG) has short-term prognostic value in coronavirus disease 2019 (COVID-19), yet its ability to predict long-term mortality is unknown. This study aimed to elucidate the predictive role of initial ECG on long-term all-cause mortality in patients diagnosed with COVID-19.In this prospective cohort study, adults with COVID-19 who underwent ECG testing within a 17-hospital health system in Northeast Ohio and Florida between 03/2020-06/2020 were identified. An expert ECG reader analyzed all studies blinded to patient status. The associations of ECG characteristics with long-term all-cause mortality and intensive care unit (ICU) admission were assessed using Cox proportional hazards regression model and multivariable logistic regression models, respectively. Status of long-term mortality was adjudicated on 01/07/2022.Of 837 patients (median age 65 years, 51% female, 44% Black), 683 (81.6%) were hospitalized, 281 (33.6%) required ICU admission, 67 (8.0%) died in-hospital, and 206 (24.6%) died at final follow-up after a median (IQR) of 21 (9-103) days after ECG. Overall, 179 (20.7%) patients presented with sinus tachycardia, 12 (1.4%) with atrial flutter, and 45 (5.4%) with atrial fibrillation (AF). After multivariable adjustment, sinus tachycardia (E-value for HR=3.09, lower CI=2.2) and AF (E-value for HR=3.13, lower CI=2.03) each independently predicted all-cause mortality. At final follow-up, patients with AF had 64.5% probability of death compared with 20.5% for those with normal sinus rhythm (P.0001).Sinus tachycardia and AF on initial ECG strongly predict long-term all-cause mortality in COVID-19. The ECG can serve as a powerful long-term prognostic tool in COVID-19.

Introduction While sleep disorders are implicated in atrial fibrillation (AF), the interplay and overlap of these disorders in AF risk remains unclear and a risk stratification challenge. Sleep-based clusters associated with AF can account for this complexity and translate to actionable approaches to identify at-risk patients. We hypothesized discrete phenotypes of symptoms and polysomnography (PSG)-based data differ in relation to incident AF. Methods Cleveland Clinic patients (age>18) who underwent PSG 11/27/2004-12/30/2015 were retrospectively examined. Clusters were identified using latent class analysis of 23 symptoms (e.g. related to sleep disordered breathing (SDB), sleepiness, REM intrusion, NREM parasomnias), Epworth Sleepiness Scale (ESS) score, and 24 measures of SDB and sleep architecture from PSG reports. Outcome was 5-year incident AF. Cox-proportional hazards models were adjusted for age, sex, race, body mass index, cardiovascular disease and risk factors, tobacco use, chronic obstructive pulmonary disease, anti-arrhythmic medication use, and positive airway pressure use. Results The sample included 43,433 patients: age 51.8±14.5, 51.9% (n=22,548) male, 74.4% (n=32,313) White, 7.3% (n=3,151) with baseline AF, and 4.3% (n=1,875) developed 5-year incident AF. Five clusters were identified and ranked by strength of AF association: 1) Hypoxemic (n=3,245): highest %time SaO2< 90% (T90), 2) Apneas+Arousals (n=4,592): most witnessed apneas, highest apnea hypopnea index (AHI), highest arousal index, least hypopneas, 3) Short sleep+NREM (n=6,126): shortest sleep time, longest REM latency, lowest %REM, 4) Hypopneas (n=2,661): most hypopneas, 5) Long sleep+REM (n=26,809): longest sleep time, shortest REM latency, highest %REM. Compared to ‘Long sleep+REM’, ‘Hypoxemic’ had 47% higher AF risk (HR=1.47,95%CI=1.27-1.69), and ‘Hypopneas’ did not differ (HR=1.05,95%CI=0.86-1.28). Conclusion Of five clusters identified, the ‘Hypoxemic’ subtype conferred the strongest AF risk with the highest degree of hypoxemia (highest T90, lowest minimum and mean SaO2), maximum end-tidal CO2, heart rate, and ESS score. Consistent with prior evidence of hypoxemia as an AF driver and cardiovascular risk of the sleepy phenotype, this constellation of symptoms and physiologic alterations illustrates risk in the clinical setting, providing potential value as a risk prediction tool. Future investigation should focus on external validation of these findings. Support (if any) Cleveland Clinic Neurological Institute Center for Outcomes Research & Evaluation Pilot Grant, Transformative Research Resource Development Award

IMPORTANCE: Obesity increases the incidence and mortality from some types of cancer, but it remains uncertain whether intentional weight loss can decrease this risk. OBJECTIVE: To investigate whether bariatric surgery is associated with lower cancer risk and mortality in patients with obesity. DESIGN, SETTING, AND PARTICIPANTS: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adult patients with a body mass index of 35 or greater who underwent bariatric surgery at a US health system between 2004 and 2017 were included. Patients who underwent bariatric surgery were matched 1:5 to patients who did not undergo surgery for their obesity, resulting in a total of 30 318 patients. Follow-up ended in February 2021. EXPOSURES: Bariatric surgery (n = 5053), including Roux-en-Y gastric bypass and sleeve gastrectomy, vs nonsurgical care (n = 25 265). MAIN OUTCOMES AND MEASURES: Multivariable Cox regression analysis estimated time to incident obesity-associated cancer (a composite of 13 cancer types as the primary end point) and cancer-related mortality. RESULTS: The study included 30 318 patients (median age, 46 years; median body mass index, 45; 77% female; and 73% White) with a median follow-up of 6.1 years (IQR, 3.8-8.9 years). The mean between-group difference in body weight at 10 years was 24.8 kg (95% CI, 24.6-25.1 kg) or a 19.2% (95% CI, 19.1%-19.4%) greater weight loss in the bariatric surgery group. During follow-up, 96 patients in the bariatric surgery group and 780 patients in the nonsurgical control group had an incident obesity-associated cancer (incidence rate of 3.0 events vs 4.6 events, respectively, per 1000 person-years). The cumulative incidence of the primary end point at 10 years was 2.9% (95% CI, 2.2%-3.6%) in the bariatric surgery group and 4.9% (95% CI, 4.5%-5.3%) in the nonsurgical control group (absolute risk difference, 2.0% [95% CI, 1.2%-2.7%]; adjusted hazard ratio, 0.68 [95% CI, 0.53-0.87], P = .002). Cancer-related mortality occurred in 21 patients in the bariatric surgery group and 205 patients in the nonsurgical control group (incidence rate of 0.6 events vs 1.2 events, respectively, per 1000 person-years). The cumulative incidence of cancer-related mortality at 10 years was 0.8% (95% CI, 0.4%-1.2%) in the bariatric surgery group and 1.4% (95% CI, 1.1%-1.6%) in the nonsurgical control group (absolute risk difference, 0.6% [95% CI, 0.1%-1.0%]; adjusted hazard ratio, 0.52 [95% CI, 0.31-0.88], P = .01). CONCLUSIONS AND RELEVANCE: Among adults with obesity, bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality.

Aims Current guidelines recommend beta‐blocker therapy in chronic heart failure with reduced ejection fraction (HFrEF) titrated according to tolerated target dose. The efficiency of this strategy to obtain adequate heart rate (HR) control remains unclear in clinical practice. The aim of this study was to determine, in a real‐world setting, the proportion of HFrEF patients who fail to achieve beta‐blocker target doses, whether target doses of beta‐blockers have a relationship with the adequacy in reducing resting HR over time. Methods and results Beta‐blocker dose and resting HR of consecutive ambulatory patients with a diagnosis of HFrEF (ejection fraction ≤ 35%) in sinus rhythm were reviewed at the first outpatient contact in the Cleveland Clinic Health System from the year 2000 to 2015. Patients who did not receive beta‐blocker therapy, have congenital heart disease and hypertrophic cardiomyopathy, were not in sinus rhythm, or have a history of heart transplant were excluded. Patients were followed up until their last known visit at the Cleveland Clinic. Median resting HR was 71 b.p.m. [inter‐quartile range (IQR) 60–84 b.p.m.] in 8041 patients (median age 65; 68% male) with 67% on carvedilol, 32% on metoprolol succinate, and 1% on bisoprolol. In 3674 subjects (56%), resting HR was ≥70 b.p.m. At final follow‐up after a median of 21 months (IQR 0.1–7.2 years), resting HR was 72 b.p.m. (IQR 60–84 b.p.m.) in the subset of patients with persistently low ejection fraction ≤ 35%. HR ≥ 70 b.p.m. was observed in 55% of this group. Beta‐blocker target dose was achieved in 19%, 5%, and 15% of those receiving carvedilol, metoprolol succinate, and bisoprolol, respectively. In the subset of patients who experienced beta‐blocker up‐titration, reduced mortality or hospitalization due to heart failure was observed in patients who experienced the lowest HR after titration. Conclusions In our single‐centre experience, the majority of patients with chronic HFrEF treated with beta‐blocker therapy did not achieve target doses over time, and a substantial proportion had inadequate control of resting HR. There was no relationship between achieved beta‐blocker target dose and resting HR control.

OBJECTIVE To assess patient characteristics and treatment factors associated with uncontrolled type 2 diabetes (T2D) and the probability of hemoglobin A1c (A1C) goal attainment. RESEARCH DESIGN AND METHODS This was a retrospective cohort study using the electronic health record at Cleveland Clinic. Patients with uncontrolled T2D (A1C >9%) were identified on the index date of 31 December 2016 (n = 6,973) and grouped by attainment (n = 1,653 [23.7%]) or nonattainment (n = 5,320 [76.3%]) of A1C RESULTS For the entire population, median age at index date was 57.7 years (53.3% male), and the majority were white (67.2%). Median A1C was 10.2%. Obesity (50.6%), cardiovascular disease (46.9%), and psychiatric disease (61.1%) were the most common comorbidities. Metformin (62.7%) and sulfonylureas (38.7%) were the most common antidiabetes medications. Only 1,653 (23.7%) patients achieved an A1C CONCLUSIONS A minority of patients with an A1C >9% achieved an A1C

OBJECTIVE To determine if natural language processing (NLP) improves detection of nonsevere hypoglycemia (NSH) in patients with type 2 diabetes and no NSH documentation by diagnosis codes and to measure if NLP detection improves the prediction of future severe hypoglycemia (SH). RESEARCH DESIGN AND METHODS From 2005 to 2017, we identified NSH events by diagnosis codes and NLP. We then built an SH prediction model. RESULTS There were 204,517 patients with type 2 diabetes and no diagnosis codes for NSH. Evidence of NSH was found in 7,035 (3.4%) of patients using NLP. We reviewed 1,200 of the NLP-detected NSH notes and confirmed 93% to have NSH. The SH prediction model (C-statistic 0.806) showed increased risk with NSH (hazard ratio 4.44; P < 0.001). However, the model with NLP did not improve SH prediction compared with diagnosis code–only NSH. CONCLUSIONS Detection of NSH improved with NLP in patients with type 2 diabetes without improving SH prediction.

Hospital systems, payers, and regulators have focused on reducing length of stay (LOS) and early readmission, with uncertain benefit. Interpretable machine learning (ML) may assist in transparently identifying the risk of important outcomes. We conducted a retrospective cohort study of hospitalizations at a tertiary academic medical center and its branches from January 2011 to May 2018. A consecutive sample of all hospitalizations in the study period were included. Algorithms were trained on medical, sociodemographic, and institutional variables to predict readmission, length of stay (LOS), and death within 48–72 h. Prediction performance was measured by area under the receiver operator characteristic curve (AUC), Brier score loss (BSL), which measures how well predicted probability matches observed probability, and other metrics. Interpretations were generated using multiple feature extraction algorithms. The study cohort included 1,485,880 hospitalizations for 708,089 unique patients (median age of 59 years, first and third quartiles (QI) [39, 73]; 55.6% female; 71% white). There were 211,022 30-day readmissions for an overall readmission rate of 14% (for patients ≥65 years: 16%). Median LOS, including observation and labor and delivery patients, was 2.94 days (QI [1.67, 5.34]), or, if these patients are excluded, 3.71 days (QI [2.15, 6.51]). Predictive performance was as follows: 30-day readmission (AUC 0.76/BSL 0.11); LOS > 5 days (AUC 0.84/BSL 0.15); death within 48–72 h (AUC 0.91/BSL 0.001). Explanatory diagrams showed factors that impacted each prediction.

Summary Objective In shared medical appointments (SMAs), multiple patients with a similar clinical diagnosis are seen by a multidisciplinary team for interactive group sessions. Very few studies have specifically studied SMAs and weight loss in patients with obesity. This study compared weight loss outcomes and anti‐obesity medication (AOM) access between patients with obesity managed through (SMAs) versus individual appointments. Methods Retrospective study of adults seen for obesity between September 2014 and February 2017 at Cleveland Clinic Institute of Endocrinology and Metabolism. Percent weight loss from baseline was compared between two propensity score‐matched populations: patients who attended ≥1 SMA and patients managed with individual medical appointments. Results From all eligible patients identified (n=310 SMA, n=1,993 non‐SMA), 301 matched pairs were evaluated for weight loss. The SMA group (n=301) lost a mean of 4.2%, 5.2% and 3.8% of baseline weight over 6, 12 and 24 months; the non‐SMA group (n=301) lost significantly less weight (1.5%, 1.8% and 1.6%, respectively) (paired t‐test, P

Background: Chronic kidney disease (CKD) poses substantial clinical, economic, and humanistic burden in patients with type 2 diabetes (T2D). Understanding of how to optimize patient care and slow disease progression is warranted.Objective: To compare the prevalence, clinical characteristics, treatment patterns, and healthcare utilization among patients with CKD, T2D, or CKD associated with T2D.Design: Retrospective cross-sectional analysis. Patients: Adult patients with CKD, T2D, or CKD+T2D in the Cleveland Clinic Health System.Main Measures: Clinical characteristics, laboratory measures, medication utilization, cardiometabolic management and healthcare resource utilization.Key Results: In 2019, 122,276 patients were identified as CKD, 63,643 were identified as T2D, and 35,255 were identified as having CKD associated with T2D. Patients with CKD and CKD+T2D were observed to be older than those with T2D alone, 72.6, 72.2, and 63.0 years, respectively. T2D and T2D+CKD cohorts contained a higher percentage of males vs. those with CKD alone, 49.3%, 50.8%, 43.6%, respectively. ACEi/ARB therapy was observed in 27.7%, 42.4%, and 31.5% patients with CKD, T2D+CKD, and T2D, respectively. SGLT-2i therapy was only prescribed to a minority of patients with T2D (5.8%) and T2D+CKD (4.7%). Emergency department visits and hospital admissions were more prevalent in the group with CKD (26.5%, 52.9%) or CKD+T2D (28.8%, 54.9%) vs. T2D alone (18.6%, 41.8%), respectively. The majority of patients with CKD (90.4%), CKD+T2D (60.0%) or T2D (69.1%) did not have an assessment of urine protein.Conclusions: Patients with CKD+T2D or CKD have higher healthcare resource utilization than those with T2D alone. The majority of patients with CKD, CKD+T2D or T2D do not undergo assessment of urine protein and are under prescribed ACEi/ARB therapy. SGLT-2i therapy was prescribed to only a small minority of patients with T2D or CKD+T2D. An opportunity exists to improve the care of patients with CKD, both with and without T2D.

Background Venous thromboembolism (VTE) prophylaxis is recommended for hospitalized medical patients at high risk for VTE. Multiple risk assessment models exist, but few have been compared in large datasets. Methods We constructed a derivation cohort using 6 years of data from 12 hospitals to identify risk factors associated with developing VTE within 14 days of admission. VTE was identified using a complex algorithm combining administrative codes and clinical data. We developed a multivariable prediction model and applied it to three validation cohorts: a temporal cohort, including two additional years, a cross-validation, in which we refit the model excluding one hospital each time, applying the refitted model to the holdout hospital, and an external cohort. Performance was evaluated using the C-statistic. Results The derivation cohort included 155,026 patients with a 14-day VTE rate of 0.68%. The final multivariable model contained 13 patient risk factors. The model had an optimism corrected C-statistic of 0.79 and good calibration. The temporal validation cohort included 53,210 patients, with a VTE rate of 0.64%; the external cohort had 23,413 patients and a rate of 0.49%. Based on the C-statistic, the Cleveland Clinic Model (CCM) outperformed both the Padua (0.76 vs. 0.72, p = 0.002) and IMPROVE (0.68, p Conclusion A new VTE risk assessment model outperformed recommended models.

Type 2 diabetes (T2D) has a strong association with atrial fibrillation (AF) which increases risk of thromboembolic events, heart failure, and frequent hospitalizations. Metformin is the first-line medication for T2D with proposed anti-inflammatory, pro-metabolic, and cardio-protective benefits. Our objective was to investigate if initial therapy with metformin is associated with reduced incidence of AF in comparison to other non-insulin anti-hyperglycemic agents in patients with newly diagnosed T2D.This retrospective cohort analysis included adults with a new diagnosis of T2D who were started on monotherapy (except insulin) between 2007 and 2017, without prior anti-hyperglycemic agent use, history of arrhythmias, or estimated GFR (eGFR) ≤ 30 ml/min. A multivariate analysis was performed using a fine-gray regression competing risk analysis to control for confounding variables after which pooled hazard ratios and 95 % confidence intervals were reported. Patients were followed until the end of study date, development of AF, addition of more anti-hyperglycemic agents, or death, whichever occurred first.Among 4584 metformin initiators compared to 1080 non-metformin monotherapy initiators, 10-year cumulative incidence of AF in metformin group was 5.2 % as compared to 8.1 % with other agents which was not statistically significant. Competing risk analysis did not demonstrate reduced rates of AF with metformin use (HR 0.92, 95 % CI 0.69 to 1.21; P = 0.55). Increased age and the presence of congestive heart failure were associated with significantly higher risk of AF in both groups (HR: 1.29, 95 % CI: 1.21 to 1.37; P ≤ 0.001; HR: 2.73, 95 % CI: 1.62 to 4.61; P ≤ 0.001, respectively).Initiation of metformin as a first line monotherapy for T2D, when compared to other non-insulin monotherapies, was not associated with decreased risk of developing AF in this retrospective observational study.

INTRODUCTION AND OBJECTIVE:The TMPRSS protein serves as a host co-receptor for the SARS-CoV-2 virus that causes COVID-19 and is present in both prostate and lung tissue. This protein is known to be...

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a disproportionately severe effect on men, suggesting that the androgen pathway plays a role in the disease. Studies on the effect of castration and androgen receptor blockade have been mixed, while 5α-reductase inhibitor (5ARI) use in men with COVID-19 (2019 novel coronavirus) have shown potential benefits. We assessed the association of 5ARI use on risk of community acquired SARS-CoV-2 infection.A total of 60,474 males in a prospective registry of people tested for SARS-CoV-2 between March 8, 2020 and February 15, 2021 were included. Using a matched cohort design, men using 5ARIs were matched 1:1 to non5ARI users. Independent analysis using unconditional multivariable logistic regression on the entire unmatched data set was completed for validation. Primary outcome measures were the association of 5ARI use on rates of SARS-Cov-2 positivity and disease severity.Of the men 1,079 (1.8%) reported 5ARI use and 55,100 were available for matching. The final matched cohorts included 944 men each. Mean duration of use was 60.4 months (IQR 17-84 months). Absolute risk for infection was significantly lower in 5ARI users compared to nonusers, 42.3% (399/944) vs 47.2% (446/944), respectively (absolute risk reduction [ARR] 4.9%, OR 0.81, 95% CI 0.67-0.97, p=0.026). Unconditional multivariable logistic regression analysis of the entire study cohort of 55,100 men confirmed the protective association of 5ARI use (ARR 5.3%, OR=0.877, 95% CI 0.774-0.995, p=0.042). Use of 5ARIs was not associated with disease severity.Use of 5ARIs in men without prostate cancer was associated with a reduction in community acquired SARS-CoV-2 infection.

Driven by quality outcomes and economic incentives, predicting 30-day hospital readmissions remains important for healthcare systems. The Cleveland Clinic Health System (CCHS) implemented an internally validated readmission risk score in the electronic medical record (EMR).We evaluated the predictive accuracy of the readmission risk score across CCHS hospitals, across primary discharge diagnosis categories, between surgical/medical specialties, and by race and ethnicity.Retrospective cohort study.Adult patients discharged from a CCHS hospital April 2017-September 2020.Data was obtained from the CCHS EMR and billing databases. All patients discharged from a CCHS hospital were included except those from Oncology and Labor/Delivery, patients with hospice orders, or patients who died during admission. Discharges were categorized as surgical if from a surgical department or surgery was performed. Primary discharge diagnoses were classified per Agency for Healthcare Research and Quality Clinical Classifications Software Level 1 categories. Discrimination performance predicting 30-day readmission is reported using the c-statistic.The final cohort included 600,872 discharges from 11 Northeast Ohio and Florida CCHS hospitals. The readmission risk score for the cohort had a c-statistic of 0.6875 with consistent yearly performance. The c-statistic for hospital sites ranged from 0.6762, CI [0.6634, 0.6876], to 0.7023, CI [0.6903, 0.7132]. Medical and surgical discharges showed consistent performance with c-statistics of 0.6923, CI [0.6807, 0.7045], and 0.6802, CI [0.6681, 0.6925], respectively. Primary discharge diagnosis showed variation, with lower performance for congenital anomalies and neoplasms. COVID-19 had a c-statistic of 0.6387. Subgroup analyses showed c-statistics of0.65 across race and ethnicity categories.The CCHS readmission risk score showed good performance across diverse hospitals, across diagnosis categories, between surgical/medical specialties, and by patient race and ethnicity categories for 3 years after implementation, including during COVID-19. Evaluating clinical decision-making tools post-implementation is crucial to determine their continued relevance, identify opportunities to improve performance, and guide their appropriate use.

This cohort study examines health care utilization patterns for patients with COVID-19 who were enrolled vs not enrolled in a home monitoring program.

The risk of adverse cardiovascular events and mortality associated with testosterone replacement therapy is controversial. The purpose of this report was to evaluate the effect of testosterone replacement therapy (TRT) in men with secondary hypogonadism on the risk of myocardial infarction (MI), stroke (CVA) or all-cause mortality.A retrospective cohort study was conducted using the Cleveland Clinic's electronic health record. Men ≥40 years of age, with at least two testosterone levels 220 ng/dL, with one level obtained between 7 am and 10 am, were identified. Men with primary hypogonadism, secondary hypogonadism related to overt hypothalamic pituitary pathology, human immunodeficiency virus infection, metastatic cancer, and select contraindications to TRT, were excluded. Men exposed to TRT were matched to controls that were not exposed. A survival analysis was performed on the composite outcome of MI, CVA, or all-cause mortality.One hundred sixty-five patients exposed to TRT (treatment group) were matched with 210 not exposed to TRT (comparison group). The prevalence of established cardiovascular disease (CVD) was 20.0% in the treatment group vs. 17.1% in the comparison group (In hypogonadal men with a modest prevalence of established CVD, TRT was not observed to confer a protective or adverse effect on the risk of MI, CVA or all-cause mortality.Le risque d’événements cardiovasculaires indésirables et de mortalité associé au traitement de substitution de la testostérone est controversé. Le but du présent article est d’évaluer chez les hommes qui présentent un hypogonadisme secondaire l’effet du traitement de substitution de la testostérone (TST) sur le risque d’infarctus du myocarde (IM), d’accident cérébrovasculaire (ACV) ou de mortalité toutes causes confondues.Une étude de cohorte rétrospective a été menée en utilisant les dossiers de santé électroniques de la Clinique Cleveland. Ont été identifiés les hommes âgés de plus de 40 ans qui avaient au moins deux dosages de testostérone inférieurs à 220ng/dl, dont l’un obtenu le matin entre 7 et 10 heures. Ont été exclus les hommes qui présentaient un hypogonadisme primaire, un hypogonadisme secondaire lié à une pathologie hypothalamo-hypophysaire évidente, une infection par le virus de l’immunodéficience humaine, un cancer métastatique, et ceux qui présentaient des contrindications déterminées au TST. Les hommes exposés au TST ont été appariés à des témoins non exposés au TST. Une analyse de survie a été réalisée sur le paramètre composite incluant l’IM, l’AVC et la mortalité toutes causes confondues.165 patients exposés au TST (groupe traité) ont été appariés à 210 hommes non exposés au TST (groupe de référence). La prévalence de maladie cardiovasculaire (MCV) établie était de 20.0% dans le groupe traité versus 17.1% dans le groupe de référence (P=0.478). La médiane (écart interquartile (EI)) de l’âge et de l’indice de masse corporelle (IMC) était respectivement de 55 (49, 62) ans et de 35.6 (32.1, 40.1) kg/m2 dans le groupe traité, et respectivement de 55 (49, 61.7) ans et 36.3 (32.1, 40.8) kg/m2 dans le groupe de référence. Il y eut 12 événements indésirables (7.3%) dans le groupe traité, et 16 (7.6%) dans le groupe de référence. La médiane du temps (en années) des événements composites était de 2.1 (EI 0.9, 4.6) et de 1.8 (EI 0.6, 3.4) respectivement pour les groupes traité et de référence. Aucune différence n’a été observée en ce qui concerne le risque cardiovasculaire entre le groupe traité et le groupe de référence, rapport de risque (RR) 0.81 (Intervalle de Confiance à 95% [IC]: 0.38-1.71;Chez les hommes qui présentent un hypogonadisme et une faible prévalence de maladie cardiovasculaire (MCV) établie, le TST n’apparait pas conférer un effet protecteur ou défavorable sur le risque de d’infarctus du myocarde (IM), d’accident cérébrovasculaire (ACV) ou de mortalité toutes causes confondues.Traitement de substitution de la testostérone, Hypogonadisme masculin, Risque cardiovasculaire, Mortalité.

AIMS To assess the effects of 'clinical' and 'intensification inertia' by evaluating the impact of different intensification interventions on the probability of HbA1c goal attainment using real-world data. METHODS Electronic health records (Cleveland Clinic, 2005-2016) were used to identify 7389 people with Type 2 diabetes mellitus and HbA1c ≥53 mmol/mol (≥7.0%), despite a stable regimen of two oral antihyperglycaemic drugs for ≥6 months. The participants were stratified by index HbA1c and analysed over a 6-month period for pharmacological intensification, and then for 12 additional months for HbA1c goal attainment (

Introduction Sleep disruption and sleep architectural changes in relation to migraine are not well characterized. Disruption in sleep may serve as a risk for migraine or result from migraine. We leveraged a large clinical cohort to examine the hypothesis that those with migraine have greater degrees of sleep architectural alterations and sleep disordered breathing (SDB). Methods This was a polysomnogram-based retrospective case (migraine) control (non-migraine) study of patients aged >18 matched 1:3 on age, sex, race, body mass index (BMI), and year of polysomnogram. Two domains were considered: 1)Sleep architecture (arousal index:AI, (primary predictor), total sleep time (TST), percentage of sleep stage time) and 2)SDB (apnea hypopnea index (AHI:primary predictor), mean oxygen saturation) were considered. Comparisons were performed by two-sample t-test or Wilcoxon rank sum test for continuous variables, and chi-square test or Fisher’s exact test for categorical variables. Results 4,783 migraine cases (47.5 ±13.3 years, 76.4% Caucasian, body mass index:BMI 33.7 ±8.6kg/m2) were matched to 14,287 controls. In migraine patients vs those without, TST was lower (359.0[307.0, 421.0] minutes vs 363.0[306.0, 432.5] minutes,p=0.01), percentage of N2 was higher (67.8%[59.6, 75.6] vs 67.0%[58.4, 74.8],p Conclusion In this largest study of its kind, we identify novel associations of migraine in relation to curtailed sleep and sleep architectural alterations, i.e. increase in N2 and reduced REM sleep and lower AI compared to contemporaneously matched controls. Directionality of these relationships requires further elucidation given the cross-sectional nature of this study. Interestingly, we observed lower degree of sleep apnea and hypoxia burden in patients with migraine. As Calcitonin Gene-Related Peptide (CGRP), a neuropeptide increased during and between migraine attacks in migraine patients, and serotonin are implicated in arousals due to apnea-related increases in CO2, there is biologic plausibility for migraines patients to exhibit potential protection from SDB. Further investigation is needed to confirm these findings. Support (If Any)

Introduction Central to the pathophysiology of SARS-CoV-2 is immune dysregulation and systemic inflammation, however, it is yet unknown whether sleep-related hypoxemia--which we have recently noted to be associated with worse COVID-19 clinical outcomes--is mediated by these biomarkers and pathways. Methods Data from patients who tested positive for SARS-CoV-2 and part of the integrated Cleveland Clinic COVID-19 and sleep laboratory registries from March-November 2020 were included. To assess the mediation effect of biomarkers, the relationship between sleep-related hypoxia measures (% sleep time Results The analytic sample included 446 patients hospitalized due to COVID-19: age:63.3.±13.8 years,51.3% female,39% African American with body mass index(BMI)=36.1±9.3kg/m2. Thirty-six percent used supplemental oxygen, 4% used high-flow or non-invasive ventilation,5% required ECMO or mechanical ventilation and 2% died. Hypoxic measures were associated with moderate/severe WHO-7 COVID-19 outcome: T90 median (>1.8%vs.≤1.8%) (OR=2.04, 95%CI:1.28-3.23,p=0.003), 5% increases in both mean SaO2 (OR=0.43, 95%CI: 0.26-0.70,p= Conclusion CRP appears to represent a relevant mediator of sleep-related hypoxia and WHO-7 clinical outcomes. Further investigation is needed to elucidate if treatment of sleep-related hypoxia downregulates biomarkers of systemic inflammation to modify disease course. Support (If Any)

Introduction Although epidemiologic studies have identified associations of architectural disruptions in sleep and atrial fibrillation (AF), inconsistencies in results limit understanding of longitudinal AF and stroke development in clinic-based cohorts. We hypothesize lower arousal index as a biomarker of prolonged respiratory events and objective measures of sleep disruption increase incident AF and stroke. Methods Cleveland Clinic patients (age>18) who underwent polysomnogram (PSG) or split studies 11/27/2004-12/30/2015 were examined. Arousal index, total sleep time (TST,hours), sleep efficiency (SE,%), and wake after sleep onset (WASO,hours) were assessed as predictors of incident AF. Cox proportional hazard models were fit with time from sleep study to AF diagnosis. Secondary analyses were conducted in the subset of patients with baseline AF, with time from sleep study to stroke. Covariates included age, sex, race, body mass index (BMI,kg/m2), cardiovascular risk factors (hypertension, diabetes mellitus, hyperlipidemia), heart failure, coronary artery disease, myocardial infarction, coronary artery bypass grafting, chronic obstructive pulmonary disease, tobacco use, and use of anti-arrhythmic drugs. Data were censored at date of last follow up or the 5-year mark. Results The sample comprised 43,634 patients: age 51.7±14.5, 51.9% male, 74.5% White, and 7.1%(n=3,090) with AF. Of those without baseline AF, 1,176(2.9%) developed 5-year incident AF. Incident AF increased by 9% (HR=1.09, 95%CI=1.04-1.13) for each hour of lost TST. For every 10 percentage point decreased SE, incident AF increased by 7% (HR=1.07, 95%CI=1.04-1.11). For every hour increased WASO, incident AF increased by 14% (HR=1.14, 95%CI=1.07-1.21). Arousal index conferred no statistically detectable change of incident AF. In secondary analyses, any association of arousal index and incident stroke was attenuated after accounting for confounding comorbidities (omnibus p=0.055). Conclusion Objective measures of disrupted sleep architecture predicted incident AF in this clinical cohort. However, arousal index was not associated with AF development, nor stroke development in secondary analyses. Further investigation is needed to elucidate the role of arousal in SDB, perhaps with hierarchal models to clarify the degree to which confounders attenuate or accentuate any relationship. Support (If Any) Cleveland Clinic Neurological Institute Center for Outcomes Research & Education Pilot Grant

Introduction Sleep disordered breathing (SDB) has been implicated in atrial fibrillation (AF) in population-based studies, however, its role remains unclear and inconsistent. We hypothesize greater risk of 5-year incident AF with SDB and sleep-related hypoxia in a clinic-based cohort. Methods Cleveland Clinic patients (age>18) who underwent polysomnogram (PSG) or split studies 11/27/2004-12/30/2015 with >3 hours diagnostic time were examined. Predictors include AHI, % sleep time oxygen saturation Results The sample was comprised of 43,634 patients: age 51.7±14.5, 51.9% male, 74.5% White, and 7.1%(n=3,090) with AF. Of those without AF, 1,176(2.9%) developed 5-year incident AF. For each 10% increase in T90, incident AF increased by 7% (HR=1.07, 95%CI=1.05-1.10). Compared to reference, patients with 25.01-50%, 50.01-75%, and 75.01-100% time T90 had 22% (HR=1.22, 95%CI=1.01-1.46), 49% (HR=1.49, 95%CI=1.20-1.85), and 65% (HR=1.65, 95%CI=1.26-2.15) higher incident AF, respectively. For every 10-unit increase in minSaO2 and meanSaO2, incident AF decreased by 11%(HR=0.89, 95%CI=0.83-0.95) and 23% (HR=0.77, 95%CI=0.68-0.86), respectively. AHI did not demonstrate a statistically significant relationship with incident AF at a significance level of 0.05. Conclusion Sleep-related hypoxemia, defined by cumulative burden below 90% SaO2, demonstrated an association with incident AF in this large clinic-based cohort, even considering confounding factors. On the other hand, SDB severity as defined by AHI did not demonstrate this relationship. These findings are consistent with experimental models that identify intermittent hypoxia and oxidative stress leading to alterations of the cardiac substrate, thus implicating sleep-related hypoxemic mechanisms as a salient driver in the evolution of atrial arrhythmogenesis. Support (If Any) Cleveland Clinic Neurological Institute Center for Outcomes Research & Education Pilot Grant, Neuroscience Transformative Research Resource Development Award

Background Left ventricular non‐compaction remains a poorly described entity, which has led to challenges of overdiagnosis. We aimed to evaluate if the presence of a thin compacted myocardial layer portends poorer outcomes in individuals meeting cardiac magnetic resonance criteria for left ventricular non‐compaction . Methods and Results This was an observational, retrospective cohort study involving individuals selected from the Cleveland Clinic Foundation cardiac magnetic resonance database (N=26 531). Between 2000 and 2018, 328 individuals ≥12 years, with left ventricular non‐compaction or excessive trabeculations based on the cardiac magnetic resonance Petersen criteria were included. The cohort comprised 42% women, mean age 43 years. We assessed the predictive ability of myocardial thinning for the primary composite end point of major adverse cardiac events (composite of all‐cause mortality, heart failure hospitalization, left ventricular assist device implantation/heart transplant, ventricular tachycardia, or ischemic stroke). At mean follow‐up of 3.1 years, major adverse cardiac events occurred in 102 (31%) patients. After adjusting for comorbidities, the risk of major adverse cardiac events was nearly doubled in the presence of significant compacted myocardial thinning (hazard ratio [HR], 1.88 [95% CI, 1.18‒3.00]; P =0.016), tripled in the presence of elevated plasma B‐type natriuretic peptide (HR, 3.29 [95% CI, 1.52‒7.11]; P =0.006), and increased by 5% for every 10‐unit increase in left ventricular end‐systolic volume (HR, 1.01 [95% CI, 1.00‒1.01]; P =0.041). Conclusions The risk of adverse clinical events is increased in the presence of significant compacted myocardial thinning, an elevated B‐type natriuretic peptide or increased left ventricular dimensions. The combination of these markers may enhance risk assessment to minimize left ventricular non‐compaction overdiagnosis whilst facilitating appropriate diagnoses in those with true disease.

Background: Functional mitral regurgitation (MR) grading by echocardiography is often challenging, and cardiac magnetic resonance (CMR) may provide more accurate and reproducible assessment, however optimal CMR thresholds have not been established. We aimed to determine clinically significant thresholds of MR-volume and MR-fraction by CMR in patients with non-ischemic cardiomyopathy (NICM). Methods: All patients having CMR with confirmed NICM between 2001/4/1-2019/3/31 were retrospectively studied. Time to death, heart transplant and/or left ventricular assist device is the primary endpoint, and receiver-operative (ROC) characteristics analyses were used to identify significant cut-points for MR-volume and MR-fraction. Results: Mean MR-volume was 11±12% and MR-fraction 14±13% in 840 NICM patients. C-statistics for the primary endpoint (141 events) were MR-volume 0.629 (95%CI: 0.577-0.691) and MR-fraction 0.594 (95%CI 0.542-0.647). Thresholds of MR-volume≥10mL and MR-fraction≥15% had the highest products of sensitivities and specificities (57.4%, 56.8%; and 54.6%, 63.4% respectively) reflecting elevated risk. MR-volume≥35mL and MR-fraction≥40% were associated the best combination of positive and negative predictive values (40.1%, 84.2%; and 38.4%, 84.6% respectively) representing severe risk. The figure illustrates Kaplan-Meier curves of the primary endpoint, categorized into three subgroups based on aforementioned MR-volume and MR-fraction thresholds. Conclusion: Adverse prognosis are observed when MR-volume≥10mL or MR-fraction≥15%, with increasing risk of adverse outcomes as functional MR severity increased in NICM. The proposed MR thresholds from this study for elevated and severe risk are lower than current valvular regurgitation guidelines, suggesting the need for separate classification schema for functional MR.