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Background: Patients with atrial fibrillation and severe chronic kidney disease have higher risks of bleeding, thromboembolism, and mortality. However, optimal anticoagulant choice in these high-risk patients remains unclear., Methods and Results: Using deidentified electronic health records from the Optum Labs Data Warehouse, adults with atrial fibrillation and severe chronic kidney disease (estimated glomerular filtration rate <30 mL/min per 1.73 m 2 ) initiating warfarin, apixaban, or rivaroxaban between 2011 and 2021 were included. Using inverse probability of treatment weighting, adjusted risks of major bleeding, stroke/systemic embolism, and death were compared among agents. A total of 6794 patients were included (mean age, 78.5 years; mean estimated glomerular filtration rate, 24.7 mL/min per 1.73 m 2 ; 51% women). Apixaban versus warfarin was associated with a lower risk of major bleeding (incidence rate, 1.5 versus 2.9 per 100 person-years; subdistribution hazard ratio [sub-HR], 0.53 [95% CI, 0.39-0.70]), and similar risks for stroke/systemic embolism (incidence rate, 1.9 versus 2.4 per 100 person-years; sub-HR, 0.80 [95% CI, 0.59-1.09]) and death (incidence rate, 4.6 versus 4.5 per 100 person-years; HR, 1.03 [95% CI, 0.82-1.29]). Rivaroxaban versus warfarin was associated with a higher risk of major bleeding (incidence rate, 4.9 versus 2.9 per 100 person-years; sub-HR, 1.65 [95% CI, 1.10-2.48]), with no difference in risks for stroke/systemic embolism and death. Apixaban versus rivaroxaban was associated with a lower risk of major bleeding (sub-HR, 0.53 [95% CI, 0.36-0.78])., Conclusions: These real-world findings are consistent with potential safety advantages of apixaban over warfarin and rivaroxaban for patients with atrial fibrillation and severe chronic kidney disease. Further randomized trials comparing individual oral anticoagulants are warranted.

Background The Dietary Approaches to Stop Hypertension (DASH) diet has been shown to reduce biomarkers of cardiovascular disease. We aimed to characterize the time course of change in biomarkers of cardiac injury (high-sensitivity cardiac troponin I), cardiac strain (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and inflammation (hs-CRP [high-sensitivity C-reactive protein]) while consuming the DASH diet. Methods and Results The DASH-Sodium trial was a randomized controlled trial of 412 adults with elevated blood pressure or hypertension. Participants were randomly assigned to 12 weeks of the DASH diet or a typical American diet. Energy intake was adjusted to maintain body weight. Measurements of high-sensitivity cardiac troponin I, NT-proBNP, and hs-CRP were performed in stored serum specimens, collected at baseline and ≈4, 8, and 12 weeks after randomization. In both the control diet and DASH diet, levels of NT-proBNP decreased; however, there was no difference between diets ( P -trend compared with control=0.22). On the DASH diet versus control, levels of high-sensitivity cardiac troponin I decreased progressively during follow-up ( P- trend compared with control=0.025), but a statistically significant between-diet difference in change from baseline levels was not observed until week 12 (% difference, 17.78% [95% CI, -29.51% to -4.09%]). A similar pattern was evident for hs-CRP ( P- trend compared with control=0.01; % difference at week 12, 19.97% [95% CI, -31.94% to -5.89%]). Conclusions In comparison with a typical American diet, the DASH diet reduced high-sensitivity cardiac troponin I and hs-CRP progressively over 12 weeks. These results suggest that the DASH diet has cumulative benefits over time on biomarkers of subclinical cardiac injury and inflammation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000608.

Background Previous studies of worsening chronic kidney disease (CKD) based on declining estimated glomerular filtration rate (eGFR) or increasing urine albumin-creatinine ratio (UACR) are limited to later middle-age and older adults. We examined associations of CKD progression and incident cardiovascular disease (CVD) and mortality in younger adults. Methods and Results We studied 4382 adults in CARDIA (Coronary Artery Risk Development in Young Adults) initially aged 27 to 41 years and prospectively over 20 years. Five-year transition probabilities across CKD risk categories were based on eGFR and UACR measured at each exam. Proportional hazards models predicted incident CVD and all-cause mortality by time-varying CKD risk category, adjusting for demographics and CVD risk factors. Progression of CKD risk categories over 20 years occurred in 28.7% (1256/4382) of participants, driven by increases in UACR, but including 5.8% (n=255) with eGFR<60 mL/min per 1.73 m 2 or UACR ≥300 mg/g. Compared with eGFR ≥60 and UACR <10, demographic and smoking-adjusted hazard ratios for CVD were 1.62 (95% CI, 1.21-2.18) for low CKD risk (eGFR ≥60 with UACR 10-29) and 13.65 (95% CI, 7.52-24.79) for very high CKD risk (eGFR <30 or eGFR 30-44 with UACR 30-299; or eGFR 30-59 with UACR ≥300). Corresponding hazard ratios for all-cause mortality were 1.42 (95% CI, 1.08-1.88) and 14.75 (95% CI, 9.97-21.82). Although CVD associations were attenuated after adjustment for mediating CVD risk factors, all-cause mortality associations remained statistically significant. Conclusions Among young to middle-aged adults, progression to higher CKD risk category was common. Routine monitoring eGFR and UACR holds promise for prevention of CVD and total mortality.

Background Limited data exist on the benefits of lifestyle behavior change delivered using telehealth and web-based applications with varied support on blood pressure (BP). Methods and Results We conducted a 2-site randomized controlled trial at Geisinger (January 2019-March 2021) to compare the efficacy of 2 remotely delivered strategies using web-based applications in participants with 24-hour systolic BP 120-160 mm Hg and body mass index ≥25 kg/m 2 . Both arms received access to web-based applications and the same lifestyle guidance per American Heart Association guidelines. One arm received minimal nonclinical staff support, and the other arm received dietitian support with motivational interviewing during weekly calls. The primary outcome was 12-week change in 24-hour systolic BP. A total of 187 participants were randomly assigned, with 156 (83.4%) completing the trial. In both arms, 24-hour systolic BP was reduced at follow-up, but the difference in BP change was not significant (dietitian-led arm, -6.73 mm Hg [95% CI, -8.64 to -4.82]; minimal-support arm, -4.92 [95% CI, -7.01 to -2.77]; P comparing groups=0.2). The dietitian-support arm had greater 12-week improvements in the secondary outcomes sleep systolic BP (mean, -6.92 versus -1.45; P =0.004), sleep diastolic BP (-3.31 versus 0.73; P =0.001), and self-reported physical activity (866 versus -243 metabolic equivalent task minutes per week; P =0.01) and tended to have improvements in weight loss (-5.11 versus -3.89 kg; P =0.1) and Healthy Eating Index-2015 score (9.23 versus 6.43 units; P =0.09). Conclusions Both the dietitian- and minimal-support interventions reduced 24-hour systolic BP similarly, although the dietitian-led intervention led to greater improvements in several secondary cardiometabolic outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03700710.

Background Diltiazem, a moderate cytochrome P450 3A4 isozyme/P-glycoprotein inhibitor, may potentiate the bleeding risk of direct oral anticoagulants (DOACs) through pharmacokinetic interactions. We evaluated the association between concomitant use of diltiazem with DOACs and bleeding among patients with atrial fibrillation, across varying degrees of kidney function. Methods and Results We identified 4544 patients with atrial fibrillation who were initiated on rivaroxaban (n=1583), apixaban (n=2373), or dabigatran (n=588), between 2010 and 2019 in Geisinger Health, with a mean age of 72 years and an estimated glomerular filtration rate of 70 mL/min per 1.73 m 2 . At the time of DOAC initiation, 15% patients were taking diltiazem and an additional 5% were initiated on diltiazem during follow-up. Among DOAC users, using diltiazem concurrently (versus DOAC alone) was associated with an increased risk of any bleeding-related hospitalization (unadjusted risk difference, 2.4; 95% CI, 0.6-4.2 events per 100 person-years; adjusted hazard ratio, 1.56, 95% CI, 1.15-2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1-2.6 events per 100 person-years]; adjusted hazard ratio, 1.84 [95% CI, 1.18-2.85]). Increased risk of any/major bleeding with diltiazem was observed in both patients with and without CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m 2 ) ( P for interaction=0.524 and 0.629, respectively). Among 13 179 warfarin users (the negative control), concomitant diltiazem use was not associated with bleeding. Conclusions Concomitant use of diltiazem with DOACs was associated with a higher bleeding risk in patients with atrial fibrillation, consistently in both subgroups of chronic kidney disease and non-chronic kidney disease. For DOAC users, concomitant diltiazem should be prescribed only when the benefit outweighs the risk, with close monitoring for signs of bleeding.

Cardiovascular disease surveillance involves quantifying the evolving population-level burden of cardiovascular outcomes and risk factors as a data-driven initial step followed by the implementation of interventional strategies designed to alleviate this burden in the target population. Despite widespread acknowledgement of its potential value, a national surveillance system dedicated specifically to cardiovascular disease does not currently exist in the United States. Routinely collected health care data such as from electronic health records (EHRs) are a possible means of achieving national surveillance. Accordingly, this article elaborates on some key strengths and limitations of using EHR data for establishing a national cardiovascular disease surveillance system. Key strengths discussed include the: (1) ubiquity of EHRs and consequent ability to create a more "national" surveillance system, (2) existence of a common data infrastructure underlying the health care enterprise with respect to data domains and the nomenclature by which these data are expressed, (3) longitudinal length and detail that define EHR data when individuals repeatedly patronize a health care organization, and (4) breadth of outcomes capable of being surveilled with EHRs. Key limitations discussed include the: (1) incomplete ascertainment of health information related to health care-seeking behavior and the disconnect of health care data generated at separate health care organizations, (2) suspect data quality resulting from the default information-gathering processes within the clinical enterprise, (3) questionable ability to surveil patients through EHRs in the absence of documented interactions, and (4) the challenge in interpreting temporal trends in health metrics, which can be obscured by changing clinical and administrative processes.

Background: Concerns about hyperkalemia limit the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium-monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE-I/ARB initiation and developed and validated a hyperkalemia susceptibility score., Methods and Results: We evaluated 69 426 new users of ACE-I/ARB therapy in the Stockholm Creatinine Measurements (SCREAM) project with medication initiation from January 1, 2007 to December 31, 2010, and follow-up for 1 year thereafter. Three fourths (76%) of SCREAM patients had potassium checked within the first year. Potassium >5 and >5.5 mmol/L occurred in 5.6% and 1.7%, respectively. As a comparison, we propensity-matched new ACE-I/ARB users to 20 186 new β-blocker users in SCREAM: 64% had potassium checked. The occurrence of elevated potassium levels was similar between new β-blocker and ACE-I/ARB users without kidney disease; only at estimated glomerular filtration rate <60 mL/min per 1.73 m 2 were risks higher among ACE-I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium-sparing diuretics in new ACE-I/ARB users; this score accurately predicted 1-year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840-0.869) and in a validation cohort from the US-based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794-0.841), with good calibration., Conclusions: Hyperkalemia within the first year of ACE-I/ARB therapy was relatively uncommon among people with estimated glomerular filtration rate >60 mL/min per 1.73 m 2 , but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: As part of its 2020 Impact Goals, the American Heart Association developed the Life's Simple 7 metric for cardiovascular health promotion. The relationship between the Life's Simple 7 metric and incident chronic kidney disease (CKD) is unknown., Methods and Results: We estimated the association between Life's Simple 7 and incident CKD in 14 832 Atherosclerosis Risk in Communities study participants. Ideal levels of Life's Simple 7 health factors were the following: nonsmoker or quit >1 year ago; body mass index <25 kg/m(2); ≥150 minutes/week of physical activity; healthy dietary pattern (high in fruits and vegetables, fish, and fiber-rich whole grains; low in sodium and sugar-sweetened beverages); total cholesterol <200 mg/dL; blood pressure <120/80 mm Hg; and fasting blood glucose <100 mg/dL. At baseline, mean age was 54 years, 55% were women, and 26% were African American. There were 2743 incident CKD cases over a median follow-up of 22 years. Smoking, body mass index, physical activity, blood pressure, and blood glucose were associated with CKD risk (all P<0.01), but diet and blood cholesterol were not. CKD risk was inversely related to the number of ideal health factors (P-trend<0.001). A model containing the Life's Simple 7 health factors was more predictive of CKD risk than the base model including only age, sex, race, and estimated glomerular filtration rate (Life's Simple 7 health factors area under the ROC curve: 0.73, 95% CI: 0.72, 0.74 versus base model area under the ROC curve: 0.68, 95% CI: 0.67, 0.69; P<0.001)., Conclusions: The AHA's Life's Simple 7 metric, developed to measure and promote cardiovascular health, predicts a lower risk of CKD., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Aim: To evaluate the effects of intensive insulin therapy alone and with added pioglitazone on body weight, fat distribution, lean body mass (LBM) and liver fat in type 2 diabetic patients., Methods: Twenty-five insulin-treated, obese patients with type 2 diabetes were randomized to addition of pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12-16 weeks. Dual-energy X-ray absorptiometry/abdominal computed tomography scans were performed before/after treatment. LBM, visceral/subcutaneous adipose tissue (VAT/SAT) and liver/spleen (L/S) attenuation ratios were measured pre-/posttreatment (a ratio <1 represents fatty liver)., Results: Intensive insulin alone and insulin + pioglitazone significantly improved glycaemic control (7.8 ± 0.3 to 7.2 ± 0.3% and 7.6 ± 0.3 to 7.1 ± 0.4%, respectively). Body weight gain was greater with insulin + pioglitazone (4.9 ± 4.5 kg) versus insulin therapy alone (1.7 ± 0.7 kg). SAT increased significantly with pioglitazone + insulin therapy (393.9 ± 48.5 to 443.2 ± 56.7 cm(2) , p < 0.01) compared to a non-significant increase with insulin therapy alone (412.9 ± 42.5 to 420.8 ± 43.8 cm(2) ). VAT decreased non-significantly in both groups (240.3 ± 41.7 to 223.8 ± 38.1 cm(2) with insulin + pioglitazone and 266.6 ± 27.4 to 250.5 ± 22.2 cm(2) with insulin therapy). LBM increased significantly by 1.92 ± 0.74 kg with insulin + pioglitazone treatment. The L/S attenuation ratio in the placebo + insulin group decreased from 1.08 ± 0.1 to 1.04 ± 0.1 (p = ns) and increased from 1.00 ± 0.1 to 1.08 ± 0.05 (p = 0.06) in the pioglitazone + insulin group., Conclusions: Intensification of insulin therapy in type 2 diabetic patients causes modest weight gain and no change in body fat distribution, LBM or liver fat. In contrast, the addition of pioglitazone, at equivalent glycaemia, increases weight gain, fat mass and SAT; increases LBM and tends to decrease liver fat. These changes in fat distribution may contribute to the beneficial effects of pioglitazone, despite greater weight gain., (Published 2011. This article is a US Government work and is in the public domain in the USA.)

Objective: To evaluate the effects of intensive insulin therapy alone or with added pioglitazone on renal salt/water balance and body fluid compartment shifts in type 2 diabetes., Methods: A total of 25 insulin-treated, obese patients with type 2 diabetes were randomized to pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12-16 weeks to achieve equivalent glycaemic control. We measured total body water (TBW) and extracellular/intracellular fluid by bioimpedance analysis; plasma/RBC volume with I(131)albumin; sodium handling by fractional excretion of sodium/lithium (FeNa/FeLi) and other renal/hormonal parameters., Results: Intensification of insulin therapy and the addition of pioglitazone significantly improved glycaemia (HbA1C 7.8-7.2% and 7.6-7.1%) and increased body weight (1.7 and 4.9 kg) respectively. TBW increased 1.7 l with insulin alone (65% intracellular) and 1.6 l with added pioglitazone (75% extracellular) (p = 0.06 and 0.09 respectively). Plasma volume increased 0.2 +/- 0.1 l with insulin alone (p = 0.05) and 0.4 +/- 0.1 l with added pioglitazone (p < 0.05). Extravascular, extracellular (interstitial) fluid increased significantly and more with added pioglitazone (0.8 +/- 0.2 l, p < 0.01) than with insulin alone (0.4 +/- 0.2 l, p = ns). At steady-state, FeLi (marker of proximal-tubular sodium delivery to the distal nephron) increased significantly with added pioglitazone (12.4 +/- 1.3 to 18.0 +/- 3.2%) vs. no significant change with insulin alone (15.4 +/- 1.2 to 14.5 +/- 2.3%). There were no significant changes in the other parameters., Conclusion: In intensively insulin-treated obese type 2 diabetic patients, at equivalent glycaemic control, the addition of pioglitazone causes greater weight gain, but a similar increase in body water that is mainly extracellular and interstitial compared with intracellular increase with insulin therapy alone. Pioglitazone also increases the filtered load of sodium reabsorbed at the distal nephron with no net change in FeNa.

Objective: To compare the prevalence of abnormal Pap smears in patients with systemic lupus erythematosus (SLE) with that in a large group of healthy controls, and to determine whether SLE itself is an independent risk factor. The association of human papillomavirus (HPV) infection and the use of immunosuppressive agents with abnormal Pap smears in SLE was also assessed., Methods: Eighty-five SLE patients participated in this cross-sectional study. A sample of cervical cells was collected from each patient for routine cytologic examination. HPV was typed by restriction and sequencing analysis. A structured questionnaire was administered to the subjects to ascertain the possible behavioral and biologic risk factors associated with cervical atypia. Data on 2,080 healthy female subjects were retrieved for comparison., Results: The mean (+/-SD) age of SLE patients and controls was 42 +/- 9 years and 44 +/- 10 years, respectively. The prevalence of abnormal Pap smears was significantly increased in SLE patients compared with controls (16.5% versus 5.7%). The prevalence of squamous intraepithelial lesions was increased approximately 6-fold in SLE patients (11.8%) compared with controls (2.0%). SLE itself remained an independent risk factor for abnormal Pap smears (odds ratio 3.5, 95% confidence interval 1.8-6.9). The overall prevalence of HPV infection in SLE patients and controls was 11.8% and 7.3%, respectively. However, 10.6% of SLE patients were infected with at least 1 high-risk type of HPV, compared with 4.2% of controls. Multiple infections were also more common in SLE patients than in controls (4.7% versus 1.1%). There were no significant differences in the use of immunosuppressive agents between SLE patients with normal Pap smears and those with abnormal Pap smears., Conclusion: Abnormal Pap smears were more common among SLE patients than controls, even after adjusting for HPV status. SLE-associated immunosuppression increases susceptibility to high-risk HPV infection and multiple HPV infections. The use of immunosuppressant agents was not associated with abnormal Pap smears.

The conclusion arrived at after a review of the relevant literature, coupled with current knowledge of the morphophysiological changes which take place in the transformation zone of the cervix, is that the term cervical erosion is an anachronism. The term should therefore be abandoned. More appropriate terms for the clinical appearance of the cervix are ectropion or ectopy. The metaplastic process and its role in neoplasia is also discussed.

An analysis of a group of predominantly Caucasian women with cervical intraepithelial neoplasia grade 3 lesions seen at the Dunedin Hospital Colposcopy Clinic during a period when it was the only colposcopic service in the region, showed that patients in the lowest socioeconomic class, as judged by two parameters unique in New Zealand were overrepresented. This finding is in agreement with the social class gradient for cervical cancer and precursor lesions observed in other countries. Poverty, more liberal sexual activity and smoking may be factors in the genesis of cervical neoplasia amongst the women studied. In providing cervical smear facilities for at-risk women, special provision should be made for women in the lowest social stratum.

Analysis of 100 paired spatula and Cytobrush cervical smear samples taken and evaluated by one person showed that the combined smear was excellent for sampling the transformation zone and for detecting lesions. However, care in obtaining and evaluating smears are still vital if false-negative smears are to be eliminated. The greater use of the 2-sample smear is advocated.

Observations from a colposcopy clinic from 1982-1985 are presented and show that in women with histologically proven precancerous lesions, those using hormone contraception had a significantly higher infection rate with human papillomavirus (HPV). Hormone contraception was preferred by younger women. Because information relating to sexual behaviour was not available for analysis, the findings in this study need to be interpreted with caution. The association of HPV and cervical cancers is well established. If hormonal contraceptive use and simultaneous HPV infection are associated with cervical neoplasia, and laboratory evidence supports this thesis, then further urgent investigations are needed for the implications are grave.