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Background: Studies show that digoxin use is declining but is still prevalent. Recent data on digoxin prescription and characteristics of digoxin prescribers are unknown, which can help understand its contemporary use., Methods: Using Medicare Part D data from 2013 to 2019, we studied the change in number and proportion of digoxin prescriptions and digoxin prescribers, overall and by specialty. Using logistic regression, we identified prescriber characteristics associated with digoxin prescription., Results: From 2013 to 2019, total digoxin prescriptions (4.6 to 1.8 million) and proportion of digoxin prescribers decreased (9.1% to 4.3% overall; 26.6% to 11.8% among General Medicine prescribers and 65.4% to 48.9% among Cardiology). Of digoxin prescribers from 2013 practicing in 2019 (91.2% remained active), 59.1% did not prescribe digoxin at all, 31.7% reduced, and 9.2% maintained or increased prescriptions. The proportion of all digoxin prescriptions that were prescribed by General Medicine prescribers declined from 59.7% to 48.2% and increased for Cardiology (29% to 38.5%). Among new prescribers in 2019 ( N = 85,508), only 1.9% prescribed digoxin. Digoxin prescribers when compared to non-digoxin prescribers were more likely male, graduated from medical school earlier, were located in the Midwest or South, and belonged to Cardiology (all P < .001)., Conclusions: Digoxin prescriptions continue to decline with over half of 2013 prescribers no longer prescribing digoxin in 2019. This may be a result of the increasing availability of newer heart failure therapies. The decline in digoxin prescription was greater among general medicine physicians than cardiologists, suggesting a change in digoxin use to a medication prescribed increasingly by specialists., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rohan Khera reports a relationship with NEJM Journal Watch that includes: consulting or advisory. Rohan Khera reports a relationship with Evidence2Health that includes: employment. Rohan Khera has pending Provisional Patent Application No. 63/177,177. Harlan Krumholz reports a relationship with UnitedHealth, Element Science, Aetna, Reality Labs, Tesseract/4Catalyst, F-Prime, the Siegfried and Jensen Law Firm, Arnold and Porter Law Firm, and Martin/Baughman Law Firm that includes: consulting or advisory. Harlan Krumholz reports a relationship with Refactor Health and HugoHealth that includes: employment. Harlan Krumholz reports a relationship with the Centers for Medicare & Medicaid Services and Johnson & Johnson that includes: employment. Yuan Lu reports a relationship with National Heart Lung and Blood Institute that includes: funding grants. Karthik Murugiah reports a relationship with National Heart Lung and Blood Institute that includes: funding grants.

Objective: For comatose survivors of out-of-hospital cardiac arrest (OHCA), current guidelines recommend targeted temperature management (TTM) with a goal temperature of 32 °C-36 °C for at least 24 h. We examined adherence to temperature targets, quantified as time-in-therapeutic range (TTR), and association of TTR with survival and neurologic outcomes., Methods: We conducted a retrospective cohort study of the Resuscitation Outcomes Consortium-Continuous Chest Compressions trial, including adults with OHCA who underwent TTM for >12 h. We imputed continuous temperatures between consecutive temperature measurements using the linear interpolation method and calculated TTR for multiple target temperatures. The association of TTR with survival to hospital discharge and favorable neurological outcome was evaluated using hierarchical regression models., Main Results: Among 2,637 patients (mean age 62.3 years, 29.9 % female), the median duration of TTR for TTM between 32 °C-36 °C was 23 (IQR: 21-24) hours with a median time outside therapeutic range of 0.9 (IQR: 0.0-4.2) hours. In risk-adjusted analyses, there was no association of TTR of 32 °C-36 °C with overall survival (OR 1.00 [95 % CI, 0.90-1.10]) or favorable neurologic outcome (1.02 [95 % CI, 0.90-1.14]). However, in assessments of TTR 33 °C-36 °C, there was a significant association with favorable neurologic survival (OR 1.12 [1.01-1.25]) but not overall survival (OR 1.04 [0.94-1.15])., Conclusions: Among patients with OHCA who underwent TTM, we found variability in adherence to guideline-recommended treatment targets. Higher TTR was not associated with overall survival, but for certain temperature thresholds, TTR was associated with favorable neurologic outcome., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Rapid and irregular ventricular rates (RVR) are an important consequence of atrial fibrillation (AF). Raw accelerometry data in combination with electrocardiogram (ECG) data have the potential to distinguish inappropriate from appropriate tachycardia in AF. This can allow for the development of a just-in-time intervention for clinical treatments of AF events. The objective of this study is to develop a machine learning algorithm that can distinguish episodes of AF with RVR that are associated with low levels of activity., Methods: This study involves 45 patients with persistent or paroxysmal AF. The ECG and accelerometer data were recorded continuously for up to 3 weeks. The prediction of AF episodes with RVR and low activity was achieved using a deterministic probabilistic finite-state automata (DPFA)-based approach. Rapid and irregular ventricular rate (RVR) is defined as having heart rates (HR) greater than 110 beats per minute (BPM) and high activity is defined as greater than 0.75 quantile of the activity level. The AF events were annotated using the FDA-cleared BeatLogic algorithm. Various time intervals prior to the events were used to determine the longest prediction intervals for predicting AF with RVR episodes associated with low levels of activity., Results: Among the 961 annotated AF events, 292 met the criterion for RVR episode. There were 176 and 116 episodes with low and high activity levels respectively. Out of the 961 AF episodes, 770 (80.1%) were used in the training data set and the remaining 191 intervals were held out for testing. The model was able to predict AF with RVR and low activity up to 4.5 min before the events. The mean prediction performance gradually decreased as the time to events increased. The overall Area under the ROC Curve (AUC) for the model lies within the range of 0.67-0.78., Conclusion: The DPFA algorithm can predict AF with RVR associated with low levels of activity up to 4.5 min before the onset of the event. This would enable the development of just-in-time interventions that could reduce the morbidity and mortality associated with AF and other similar arrhythmias., (© 2021. The Author(s).)

Importance: Contemporary national clinical practice guidelines recommend direct-acting oral anticoagulants (DOACs) as the first-line anticoagulant strategy over warfarin for most indications, especially among older individuals with an elevated bleeding risk., Objective: To evaluate anticoagulant prescribing and DOAC uptake by US clinicians in the Medicare population., Design, Setting, and Participants: This retrospective cohort study included all US clinicians with more than 10 Medicare oral anticoagulant prescription claims, who were included in the national Medicare Provider Utilization and Payment Data (2013-2018). Data analyses were conducted between October 2020 and October 2021., Exposures: DOAC prescription in 2013., Main Outcomes and Measures: Clinicians were categorized based on 2013 prescribing as solely prescribing warfarin, DOAC, or both, and their temporal trajectories of proportionate DOAC use were examined., Results: The analysis included 325 666 unique clinicians with more than 10 oral anticoagulant prescriptions between 2013 and 2018 (26 620 [8.2%] cardiologists, 85 563 [26.3%] internal medicine physicians, 84 369 [25.9%] family medicine physicians, and 81 161 [24.9%] advanced practice clinicians, including nurse practitioners and physician assistants). In 2013, among 91 837 prescribers, 54 501 (59.3%) prescribed only warfarin, 1918 (2.1%) prescribed only a DOAC, and 35 418 (38.6%) prescribed both. During the study period, the number of clinicians prescribing DOACs increased, but 19% continued to prescribe only warfarin in 2018. While 359 cardiologists prescribing anticoagulants (1.6%) were warfarin-only prescribers, 10 414 (20.0%) and 6296 (12.6%) of family and internal medicine physicians also prescribed only warfarin, respectively. Clinicians prescribing only warfarin in 2013 had lower proportionate DOAC use throughout the study compared with 2013 DOAC prescribers, which represents a median (IQR) of 41.9% (20.3%-61.9%) of their anticoagulant prescriptions in 2018 vs 67.0% (49.9%-82.8%) for DOAC prescribers., Conclusions and Relevance: Despite the increase in DOAC use among Medicare beneficiaries, many clinicians in this study continued to use warfarin as their predominant or only anticoagulant instead of DOACs. There is a need to address barriers to the uptake of these medications to realize their potential benefits for patients.

Machine learning (ML) algorithms are powerful prediction tools with immense potential in the clinical setting. There are a number of existing clinical tools that use ML, and many more are in development. Physicians are important stakeholders in the health care system, but most are not equipped to make informed decisions regarding deployment and application of ML technologies in patient care. It is of paramount importance that ML concepts are integrated into medical curricula to position physicians to become informed consumers of the emerging tools employing ML. This paradigm shift is similar to the evidence-based medicine (EBM) movement of the 1990s. At that time, EBM was a novel concept; now, EBM is considered an essential component of medical curricula and critical to the provision of high-quality patient care. ML has the potential to have a similar, if not greater, impact on the practice of medicine. As this technology continues its inexorable march forward, educators must continue to evaluate medical curricula to ensure that physicians are trained to be informed stakeholders in the health care of tomorrow., (Copyright © 2021 by the Association of American Medical Colleges.)

Introduction: Little is known about the association of urine metabolites with structural lesions in persons with diabetes., Objectives: We examined the relationship between 12 urine metabolites and kidney structure in American Indians with type 2 diabetes., Methods: Data were from a 6-year clinical trial that assessed renoprotective efficacy of losartan, and included a kidney biopsy at the end of the treatment period. Metabolites were measured in urine samples collected within a median of 6.5 months before the research biopsy. Associations of the creatinine-adjusted urine metabolites with kidney structural variables were examined by Pearson's correlations and multivariable linear regression after adjustment for age, sex, diabetes duration, hemoglobin A 1c , mean arterial pressure, glomerular filtration rate (iothalamate), and losartan treatment., Results: Participants (n = 62, mean age 45 ± 10 years) had mean ± standard deviation glomerular filtration rate of 137 ± 50 ml/min and median (interquartile range) urine albumin:creatinine ratio of 34 (14-85) mg/g near the time of the biopsy. Urine aconitic and glycolic acids correlated positively with glomerular filtration surface density (partial r = 0.29, P = 0.030 and r = 0.50, P < 0.001) and total filtration surface per glomerulus (partial r = 0.32, P = 0.019 and r = 0.43, P = 0.001). 2-ethyl 3-OH propionate correlated positively with the percentage of fenestrated endothelium (partial r = 0.32, P = 0.019). Citric acid correlated negatively with mesangial fractional volume (partial r=-0.36, P = 0.007), and homovanillic acid correlated negatively with podocyte foot process width (partial r=-0.31, P = 0.022)., Conclusions: Alterations of urine metabolites may associate with early glomerular lesions in diabetic kidney disease.

Background: Inflammation linked to diabetic kidney disease (DKD) may affect white blood cell (WBC) counts and differentials. We examined the cross-sectional associations of total WBC count and WBC fractions with structural lesions of DKD in 108 Pima Indians with Type 2 diabetes who underwent research kidney biopsies. We also examined the longitudinal association of these WBC variables with renal function loss (RFL) in 941 Europeans with Type 2 diabetes from the SURDIAGENE study., Methods: Associations of WBC variables with morphometric parameters were assessed by linear regression. RFL was defined as≥40% loss of estimated glomerular filtration rate from baseline. Associations with RFL were evaluated by Cox regression. Hazard ratios (HRs) were reported per standard deviation increment of each WBC variable., Results: After multivariable adjustment, lymphocyte (r  = -0.20, P = 0.043) and eosinophil (r = 0.21, P = 0.032) fractions in the Pima Indians correlated with glomerular basement membrane width. Eosinophil fraction also correlated with glomerular filtration surface density (r  = -0.21, P = 0.031). Lymphocyte fraction (r = 0.25, P = 0.013), neutrophil fraction (r  = -0.23, P = 0.021) and the neutrophil:lymphocyte ratio (r  = -0.22, P = 0.024) correlated with percentage of normally fenestrated endothelial cells. During median follow-up of 4.5 years, 321 SURDIAGENE participants developed RFL. Lower lymphocyte fraction [HR = 0.67, 95% confidence interval (95% CI) 0.60-0.76] and higher neutrophil fraction (HR = 1.35, 95% CI 1.20-1.52), total WBC count (HR = 1.20, 95% CI 1.08-1.35) and neutrophil:lymphocyte ratio (HR = 1.44, 95% CI 1.28-1.62) each predicted RFL in this cohort., Conclusions: WBC fractions associate with morphometric lesions of DKD and predict RFL in individuals with Type 2 diabetes.

Background and Objectives: Most studies describing childhood obesity in the United States are based on cross-sectional surveys and do not include substantial numbers of American Indians (AI). Secular trends in height and weight reflect general health status. This study describes weight trends and transitions among AI children over a 43-year period., Methods: Anthropometric data were obtained from a prospective study conducted in a southwestern US AI population (1965 through 2007). For cross-sectional analysis, 12 377 observations were available from 6529 children across four birth cohorts (1955-1964, 1965-1974, 1975-1984, 1985-1994). Participants were stratified into three age groups: pre- (5-9 years), early (10-13) and late (14-17) adolescence. Longitudinal analyses included 1737 children with one exam in each age group., Results: In early and late adolescence, weight increased across birth cohorts. Prevalence of obesity among pre-adolescents was 17.5% (95% CI, 15.1%-19.9%) in the 1955-1964 cohort and 33.7% (95% CI, 30.1%-36.4%) in the 1985-1994 cohort. 74% of children overweight in pre-adolescence in the 1985-1994 cohort became obese by late adolescence; in the 1955-1964 cohort, only 43% made this transition., Conclusions: This study describes the rising prevalence of childhood obesity. Children obese in pre-adolescence remained obese in late adolescence, stressing the need for early intervention., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Childhood obesity is associated with increased cardiometabolic risk., Objective: To study the relationship between body mass index (BMI) and cardiometabolic risk factors in American Indian children and adolescents., Methods: Differences in metabolic variables by age and sex-specific BMI percentiles (2000 Centers for Disease Control and Prevention Growth Charts) were examined in a cross-sectional analysis of 2977 individuals across three age categories. Children with an exam in two consecutive age categories were included in a longitudinal analysis. Spearman's correlations were used to test the association of BMI percentile with anthropometric and biochemical variables., Results: Body mass index percentile correlated with systolic (r = 0.24 to 0.38) and diastolic (r = 0.13 to 0.22) blood pressure, fasting plasma glucose (r = 0.20 to 0.33), 2-h plasma glucose (r = 0.30 to 0.46), total cholesterol (r = 0.12 to 0.23), serum triglycerides (r = 0.40 to 0.51) and HDL cholesterol (r = -0.36 to -0.43) in each age group (5-9, 10-13 and 14-17 years). Among participants examined in multiple age categories, BMI percentile increased over time. Change in BMI percentile from one age category to the next was associated with an increase in fasting glucose, 2-h glucose and triglycerides and a decrease in HDL cholesterol., Conclusion: Higher BMI was associated with blood pressure elevation, hyperglycaemia and dyslipidaemia in American Indian children and adolescents., (© 2016 World Obesity Federation.)

Objective: To examine the association of bradykinin and related peptides with the development of diabetic nephropathy lesions in 243 participants with type 1 diabetes (T1D) from the Renin-Angiotensin System Study who, at baseline, were normoalbuminuric, normotensive and had normal or increased glomerular filtration rate (GFR)., Design: Plasma concentrations of bradykinin and related peptides were measured at baseline by quantitative mass spectrometry. All participants were randomly assigned at baseline to receive placebo, enalapril or losartan during the 5 years between kidney biopsies. Kidney morphometric data were available from kidney biopsies at baseline and after 5 years. Relationships of peptides with changes in morphometric variables were assessed using multiple linear regression after adjustment for age, sex, diabetes duration, HbA1c, mean arterial pressure, treatment assignment and, for longitudinal analyses, baseline structure., Results: Baseline median albumin excretion rate of study participants was 5.0 μg/min, and mean GFR was 128 mL/min/1.73 m2. After multivariable adjustment, higher plasma concentration of bradykinin (1-8) was associated with greater glomerular volume (partial r = 0.191, P = 0.019) and total filtration surface area (partial r = 0.211, P = 0.010), and higher bradykinin (1-7) and hyp3-bradykinin (1-7) were associated with lower cortical interstitial fractional volume (partial r = -0.189, P = 0.011; partial r = -0.164, P = 0.027 respectively). In longitudinal analyses, higher bradykinin was associated with preservation of surface density of the peripheral glomerular basement membrane (partial r = 0.162, P = 0.013), and for participants randomized to losartan, higher hyp3-bradykinin (1-8) was associated with more limited increase in cortical interstitial fractional volume (partial r = -0.291, P = 0.033)., Conclusions: Higher plasma bradykinin and related peptide concentrations measured before clinical onset of diabetic nephropathy in persons with T1D were associated with preservation of glomerular structures, suggesting that elevations of these kinin concentrations may reflect adaptive responses to early renal structural changes in diabetic nephropathy.

Background: Serum amyloid A (SAA) induces inflammation and apoptosis in kidney cells and is found to be causing the pathologic changes that are associated with diabetic kidney disease (DKD). Higher serum SAA concentrations were previously associated with increased risk of end-stage renal disease (ESRD) and death in persons with type 2 diabetes and advanced DKD. We explored the prognostic value of SAA in American Indians with type 2 diabetes without DKD or with early DKD., Methods: SAA concentration was measured in serum samples obtained at the start of follow-up. Multivariate proportional hazards models were employed to examine the magnitude of the risk of ESRD or death across tertiles of SAA concentration after adjustment for traditional risk factors. The C statistic was used to assess the additional predictive value of SAA relative to traditional risk factors., Results: Of 256 participants (mean ± SD glomerular filtration rate [iothalamate] = 148 ± 45 mL/min, and median [interquartile range] urine albumin/creatinine = 39 [14-221] mg/g), 76 developed ESRD and 125 died during a median follow-up period of 15.2 and 15.7 years, respectively. After multivariable proportional hazards regression, participants in the 2 highest SAA tertiles together exhibited a 53% lower risk of ESRD (hazard ratio [HR] 0.47, 95% CI 0.29-0.78), and a 30% lower risk of death (HR 0.70, 95% CI 0.48-1.02), compared with participants in the lowest SAA tertile, although the lower risk of death was not statistically significant. Addition of SAA to the ESRD model increased the C statistic from 0.814 to 0.815 (p = 0.005)., Conclusions: Higher circulating SAA concentration is associated with a reduced risk of ESRD in American Indians with type 2 diabetes., (© 2017 S. Karger AG, Basel.)

We examined associations of advanced glycation end products (AGEs) with renal function loss (RFL) and its structural determinants in American Indians with type 2 diabetes. Data were from a 6-year clinical trial that assessed renoprotective efficacy of losartan. Participants remained under observation after the trial concluded. Glomerular filtration rate (GFR) was measured annually. Kidney biopsies were performed at the end of the trial. Five AGEs were measured in serum collected at enrollment and at kidney biopsy. RFL was defined as ≥40% decline of measured GFR from baseline. Of 168 participants (mean baseline age 41 years, HbA 1c 9.2%, GFR 164 mL/min, and albumin-to-creatinine ratio 31 mg/g), 104 reached the RFL end point during median follow-up of 8.0 years. After multivariable adjustment, each doubling of carboxyethyl lysine (hazard ratio [HR] 1.60 [95% CI 1.08-2.37]) or methylglyoxal hydroimidazolone (HR 1.30 [95% CI 1.02-1.65]) concentration was associated with RFL. Carboxyethyl lysine, carboxymethyl lysine, and methylglyoxal hydroimidazolone correlated positively with cortical interstitial fractional volume (partial r = 0.23, P = 0.03; partial r = 0.25, P = 0.02; and partial r = 0.31, P = 0.003, respectively). Glyoxyl hydroimidazolone and methylglyoxal hydroimidazolone correlated negatively with total filtration surface per glomerulus (partial r = -0.26, P = 0.01; and partial r = -0.21, P = 0.046, respectively). AGEs improve prediction of RFL and its major structural correlates., (© 2016 by the American Diabetes Association.)

Objective: To determine whether early administration of losartan slows progression of diabetic kidney disease over an extended period., Research Design and Methods: We conducted a 6-year clinical trial in 169 American Indians with type 2 diabetes and urine albumin/creatinine ratio <300 mg/g; 84 participants were randomly assigned to receive losartan and 85 to placebo. Primary outcome was a decline in glomerular filtration rate (GFR; iothalamate) to ≤60 mL/min or to half the baseline value in persons who entered with GFR <120 mL/min. At enrollment, GFR averaged 165 mL/min (interquartile range 49-313 mL/min). During the trial, nine persons reached the primary outcome with a hazard ratio (HR; losartan vs. placebo) of 0.50 (95% CI 0.12-1.99). Participants were then followed posttrial for up to 12 years, with treatment managed outside the study. The effect of losartan on the primary GFR outcome was then reanalyzed for the entire study period, including the clinical trial and posttrial follow-up., Results: After completion of the clinical trial, treatment with renin-angiotensin system inhibitors was equivalent in both groups. During a median of 13.5 years following randomization, 29 participants originally assigned to losartan and 35 to placebo reached the primary GFR outcome with an HR of 0.72 (95% CI 0.44-1.18)., Conclusions: Long-term risk of GFR decline was not significantly different between persons randomized to early treatment with losartan and those randomized to placebo. Accordingly, we found no evidence of an extended benefit of early losartan treatment on slowing GFR decline in persons with type 2 diabetes., (© 2016 by the American Diabetes Association.)

Aims: Cardiovascular autonomic neuropathy (CAN) predicts clinical diabetic nephropathy (DN). We investigated the relationship between DN structural lesions and CAN., Methods: Sixty three Pima Indians with type 2 diabetes underwent kidney biopsies following a 6-year clinical trial testing the renoprotective efficacy of losartan vs. placebo. CAN was assessed a median 9.2years later. CAN variables included expiration/inspiration ratio (E/I), standard deviation of the normal R-R interval (sdNN), and low and high frequency signal power and their ratio (LF, HF, LF/HF); lower values reflect more severe neuropathy. Associations of CAN with renal structural variables were assessed by linear regression adjusted for age, sex, diabetes duration, blood pressure, HbA1c, glomerular filtration rate, and treatment assignment during the trial., Results: Global glomerular sclerosis was negatively associated with sdNN (partial r=-0.35, p=0.01) and LF (r=-0.32, p=0.02); glomerular basement membrane width was negatively associated with all measures of CAN except for LF/HF (r=-0.28 to -0.42, p<0.05); filtration surface density was positively associated with sdNN, LF, and HF (r=0.31 to 0.38, p<0.05); and cortical interstitial fractional volume was negatively associated with HF (r=-0.27, p=0.04)., Conclusions: CAN associates with DN lesions., (Published by Elsevier Inc.)

Context: Data are lacking on how metabolic risk factors during childhood affect the long-term risk of type 2 diabetes., Objectives: Assess four metabolic risk factors as predictors of type 2 diabetes and determine whether the risk differs between younger and older children., Design: In a prospective cohort study conducted between 1965 and 2007, participants were followed for development of diabetes. Baseline measurements included body mass index (BMI), blood pressure, serum cholesterol, and 2-hour plasma glucose after an oral glucose tolerance test. Additional analyses divided subjects into two groups according to baseline age, 5–11 and 12–19 years., Setting: Gila River Indian Community in Arizona., Participants: A total of 5532 nondiabetic Pima Indian children 5–19 years old., Results: A total of 1281 children developed diabetes (median follow-up, 12.4 years). Diabetes incidence was higher in overweight children (BMI ≥ 85th percentile) than in nonoverweight children. Nonoverweight children had the lowest risk of diabetes (20-year cumulative incidence, 9.5%), whereas overweight children with impaired glucose tolerance (2-hour glucose ≥ 140 mg/dL) had the highest (79.0%). The relative risk for children with metabolic abnormalities compared with their healthy counterparts was higher in younger children than in older children early in follow-up. BMI and 2-hour glucose were related to incident diabetes in multivariable models (predicted 15-year cumulative incidence for the highest vs lowest quartile was 3.9 and 1.8 times as high for BMI and 2-hour glucose, respectively; P < .001), whereas blood pressure and cholesterol were not., Conclusions: BMI and impaired glucose tolerance in children are strong predictors of type 2 diabetes. Other components of the “metabolic syndrome” are not.