Publications by authors named "Alvaro Alonso"

547 Publications

Claims-Based Score for the Prediction of Bleeding in a Contemporary Cohort of Patients Receiving Oral Anticoagulation for Venous Thromboembolism.

J Am Heart Assoc 2021 Sep 13:e021227. Epub 2021 Sep 13.

Division of Epidemiology and Community Health School of Public Health University of Minnesota Minneapolis MN.

Background Current scores for bleeding risk assessment in patients with venous thromboembolism (VTE) undergoing oral anticoagulation have limited predictive capacity. We developed and internally validated a bleeding prediction model using healthcare claims data. Methods and Results We selected patients with incident VTE initiating oral anticoagulation in the 2011 to 2017 MarketScan databases. Hospitalized bleeding events were identified using validated algorithms in the 180 days after VTE diagnosis. We evaluated demographic factors, comorbidities, and medication use before oral anticoagulation initiation as potential predictors of bleeding using stepwise selection of variables in Cox models run on 1000 bootstrap samples of the patient population. Variables included in >60% of all models were selected for the final analysis. We internally validated the model using bootstrapping and correcting for optimism. We included 165 434 patients with VTE and initiating oral anticoagulation, of whom 2294 had a bleeding event. After undergoing the variable selection process, the final model included 20 terms (15 main effects and 5 interactions). The c-statistic for the final model was 0.68 (95% CI, 0.67-0.69). The internally validated c-statistic corrected for optimism was 0.68 (95% CI, 0.67-0.69). For comparison, the c-statistic of the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly (>65 Years), Drugs/Alcohol Concomitantly (HAS-BLED) score in this population was 0.62 (95% CI, 0.61-0.63). Conclusions We have developed a novel model for bleeding prediction in VTE using large healthcare claims databases. Performance of the model was moderately good, highlighting the urgent need to identify better predictors of bleeding to inform treatment decisions.
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http://dx.doi.org/10.1161/JAHA.121.021227DOI Listing
September 2021

Association of Longitudinal Changes in Cardiac Biomarkers With Atrial and Ventricular Arrhythmias (from the Atherosclerosis Risk in Communities [ARIC] Study).

Am J Cardiol 2021 Aug 28. Epub 2021 Aug 28.

Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota.

We evaluated the association of longitudinal changes in circulating levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) with the burden of arrhythmias as captured by 2-week ambulatory ECG monitoring. This study included 1,930 Atherosclerosis Risk in Communities Study participants who wore a leadless, ambulatory ECG monitor (Zio XT Patch) at visit 6 (2016 to 2017) and had cardiac biomarkers measured at visit 6 and visit 4 (median of 19 years earlier). The mean age of participants at V6 was 79 ± 5 years, 41% were men, and 22% were black. Adjusting for demographics, body mass index, smoking, diabetes, hypertension, stroke, left ventricular mass, cardiac medications, patch wear time, visit 4 levels of NT-proBNP and hs-cTnT, and relative change in hs-cTnT, each log-transformed unit relative increase in NT-proBNP was associated with a higher likelihood of nonsustained ventricular tachycardia (odds ratio 1.29, 95% confidence interval [CI] 1.12 to 1.48), a higher number of daily atrial tachycardia episodes (geometric mean ratio [GMR] 1.16, 95% CI 1.10 to 1.21), and a higher daily ectopic burden (premature ventricular contractions -GMR 1.42, 95% CI 1.25 to 1.62; premature atrial contractions -GMR 1.40, 95% CI 1.25 to 1.57). In fully adjusted analyses, each log-transformed unit relative increase in hs-cTnT was only found to be weakly associated with a higher daily premature ventricular contraction burden (GMR 1.31, 95% CI 1.01 to 1.70). In conclusion, longitudinal change in NT-proBNP was associated with an increased atrial and ventricular arrhythmia burden.
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http://dx.doi.org/10.1016/j.amjcard.2021.07.043DOI Listing
August 2021

Venous thrombosis recurrence risk according to warfarin versus direct oral anticoagulants for the secondary prevention of venous thrombosis.

Res Pract Thromb Haemost 2021 Aug 17;5(6):e12575. Epub 2021 Aug 17.

Division of Epidemiology and Community Health School of Public Health University of Minnesota Minneapolis Minnesota USA.

Background: Venous thromboembolism (VTE) affects nearly 1 million Americans annually, and many benefit from continued anticoagulation after the initial 3- to 6-month treatment period (secondary prevention).

Objectives: To determine whether warfarin, apixaban, or rivaroxaban is associated with reduced recurrent VTE hospitalization in the secondary prevention of VTE.

Patients/methods: We performed a retrospective cohort study of participants enrolled in the MarketScan Insurance Database between 2013 and 2017 in those with an incident VTE. In those individuals who continued oral anticoagulation (warfarin, apixaban, or rivaroxaban) beyond 6 months, we determined the relative rate of recurrent VTE hospitalization.

Results: Among 119 964 individuals with VTE, 25 419 remained on anticoagulation after 6 months and were matched successfully by age, sex, and date. After adjusting for a propensity score, apixaban versus rivaroxaban (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.45-0.94) and apixaban versus warfarin (HR, 0.68; 95% CI, 0.47-1.00) had a reduced risk of recurrent VTE hospitalization, and rivaroxaban versus warfarin (HR, 1.12; 95% CI, 0.94-1.33) had equivalent rates. For the rivaroxaban versus warfarin comparison there was a significant interaction by renal function ( < .01) where rivaroxaban was associated with a lower risk of recurrent VTE hospitalization (HR, 0.65; 95% CI, 0.41-1.03) in those with kidney disease and increased risk in those without kidney disease (HR, 1.24; 95% CI, 1.02-1.50).

Conclusions: These data suggest that apixaban has a lower recurrent VTE hospitalization rate than rivaroxaban during the secondary prevention of VTE, and further study of diverse patient populations, especially by kidney function, is warranted.
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http://dx.doi.org/10.1002/rth2.12575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371351PMC
August 2021

Research Priorities in the Secondary Prevention of Atrial Fibrillation: A National Heart, Lung, and Blood Institute Virtual Workshop Report.

J Am Heart Assoc 2021 Aug 5;10(16):e021566. Epub 2021 Aug 5.

Division of Research Kaiser Permanente Northern California Oakland CA.

There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF-related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced-based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF-related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team-based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.
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http://dx.doi.org/10.1161/JAHA.121.021566DOI Listing
August 2021

Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.

Circ Genom Precis Med 2021 Aug 28;14(4):e003300. Epub 2021 Jul 28.

Regeneron Genetics Center, Tarrytown, NY. Departments of Medicine, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (S.R.).

Background: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.

Methods: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).

Results: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (, , and ), a controversial monogenic SCD gene (), and novel genes ( and ) involved in cardiac conduction. Loss-of-function and pathogenic variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (=8.4×10). Similar variants in and (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (=4×10), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.

Conclusions: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.
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http://dx.doi.org/10.1161/CIRCGEN.120.003300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373440PMC
August 2021

MI-PACE Home-Based Cardiac Telerehabilitation Program for Heart Attack Survivors: Usability Study.

JMIR Hum Factors 2021 Jul 8;8(3):e18130. Epub 2021 Jul 8.

Division of Cardiology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States.

Background: Cardiac rehabilitation programs, consisting of exercise training and disease management interventions, reduce morbidity and mortality after acute myocardial infarction.

Objective: In this pilot study, we aimed to developed and assess the feasibility of delivering a health watch-informed 12-week cardiac telerehabilitation program to acute myocardial infarction survivors who declined to participate in center-based cardiac rehabilitation.

Methods: We enrolled patients hospitalized after acute myocardial infarction at an academic medical center who were eligible for but declined to participate in center-based cardiac rehabilitation. Each participant underwent a baseline exercise stress test. Participants received a health watch, which monitored heart rate and physical activity, and a tablet computer with an app that displayed progress toward accomplishing weekly walking and exercise goals. Results were transmitted to a cardiac rehabilitation nurse via a secure connection. For 12 weeks, participants exercised at home and also participated in weekly phone counseling sessions with the nurse, who provided personalized cardiac rehabilitation solutions and standard cardiac rehabilitation education. We assessed usability of the system, adherence to weekly exercise and walking goals, counseling session attendance, and disease-specific quality of life.

Results: Of 18 participants (age: mean 59 years, SD 7) who completed the 12-week telerehabilitation program, 6 (33%) were women, and 6 (33%) had ST-elevation myocardial infarction. Participants wore the health watch for a median of 12.7 hours (IQR 11.1, 13.8) per day and completed a median of 86% of exercise goals. Participants, on average, walked 121 minutes per week (SD 175) and spent 189 minutes per week (SD 210) in their target exercise heart rate zone. Overall, participants found the system to be highly usable (System Usability Scale score: median 83, IQR 65, 100).

Conclusions: This pilot study established the feasibility of delivering cardiac telerehabilitation at home to acute myocardial infarction survivors via a health watch-based program and telephone counseling sessions. Usability and adherence to health watch use, exercise recommendations, and counseling sessions were high. Further studies are warranted to compare patient outcomes and health care resource utilization between center-based rehabilitation and telerehabilitation.
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http://dx.doi.org/10.2196/18130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299347PMC
July 2021

Association of heart failure subtypes and atrial fibrillation: Data from the Atherosclerosis Risk in Communities (ARIC) study.

Int J Cardiol 2021 Sep 8;339:47-53. Epub 2021 Jul 8.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA. Electronic address:

Aims: To determine the prevalence and incidence of AF among HF subtypes in a biracial community-based cohort.

Methods: We studied 6496 participants in the Atherosclerosis Risk in Community study (mean age, 75.8 ± 5.3, 59% women, 23% black) who attended the 2011-2013 visit. HF was identified from physician adjudicated diagnosis, hospital discharges, and self-report. HF subtypes were based on echocardiography. A left ventricular ejection fraction <40% represents HF with reduced ejection fraction (HFrEF), 40%-49% for HF with midrange ejection fraction (HFmEF), and ≥ 50% for HF with preserved ejection fraction (HFpEF). AF was ascertained through 2017 from study electrocardiograms, hospital discharges, and death certificates. Confounder-adjusted logistic regression and Cox models were used to estimate associations of HF subtype with prevalent and incident AF.

Results: Among eligible participants, 393 had HF (HFpEF = 232, HFmEF = 41, HFrEF = 35 and unclassified HF = 85) and 735 had AF. Compared to those without HF, all HF subtypes were more likely to have prevalent AF [odds ratio (95% confidence interval (CI)) 7.4 (5.6-9.9) for HFpEF, 8.1 (4.3-15.3) for HFmEF, 10.0 (5.0-20.2) for HFrEF, 8.8 (5.6-14.0) for unclassified HF]. Among participants without AF at baseline (n = 5761), 610 of them developed AF. Prevalent HF was associated with increased risk of AF [hazard ratio (95%CI) 2.3 (1.6-3.2) for HFpEF, 5.0 (2.7-9.3) for HFmEF, 3.5 (1.7-7.6) for HFrEF, 1.9 (0.9-3.7) for unclassified HF].

Conclusion: AF and HF frequently co-occur, with small differences by HF subtype, underscoring the importance of understanding the interplay of these two epidemics and evaluating shared preventive and therapeutic strategies.
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http://dx.doi.org/10.1016/j.ijcard.2021.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419094PMC
September 2021

Associations of anger, vital exhaustion, anti-depressant use, and poor social ties with incident atrial fibrillation: The Atherosclerosis Risk in Communities Study.

Eur J Prev Cardiol 2021 05;28(6):633-640

Department of Epidemiology, Emory University, USA.

Background: We examined the relationships of anger, vital exhaustion, anti-depressant use, and poor social ties with incident atrial fibrillation in a biracial cohort of middle and older-aged adults.

Methods: This analysis included 11,445 Atherosclerosis Risk in Communities Study participants who were free of atrial fibrillation at baseline in 1990-1992. Vital exhaustion was assessed at baseline and defined as a score in the highest quartile on the 21-item Vital Exhaustion Questionnaire. Baseline anti-depressant use was self-reported. The Spielberger Trait Anger Scale to assess anger and both the Interpersonal Support Evaluation List and the Lubben Social Network Scale to assess social ties were also administered at baseline. The primary outcome was incident atrial fibrillation throughout 2016, identified by electrocardiogram, hospital discharge coding of atrial fibrillation, and death certificates.

Results: A total of 2220 incident atrial fibrillation cases were detected over a median follow-up of 23.4 years. After adjusting for age, race-center, sex, education, and height, participants in the 4th Vital Exhaustion Questionnaire quartile (referent = 1st Vital Exhaustion Questionnaire quartile) and those reporting anti-depressant use were at increased risk for atrial fibrillation (hazard ratio = 1.45, 95% confidence interval 1.29-1.64 for Vital Exhaustion Questionnaire; hazard ratio = 1.37, 95% confidence interval 1.11-1.69 for anti-depressant use). The increased atrial fibrillation risk observed for 4th Vital Exhaustion Questionnaire quartile participants remained significant after additional adjustment for relevant comorbidities (hazard ratio = 1.20; confidence interval 1.06-1.35). No significant associations were observed for anger or poor social ties with development of atrial fibrillation.

Conclusions: Vital exhaustion is associated with an increased risk of incident atrial fibrillation.
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http://dx.doi.org/10.1177/2047487319897163DOI Listing
May 2021

Association of arterial stiffness with incident atrial fibrillation: a cohort study.

BMC Cardiovasc Disord 2021 05 20;21(1):247. Epub 2021 May 20.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.

Background: Stiff arteries increase left ventricular (LV) end-systolic workload, leading over time to left atrial and ventricular remodeling, and providing the substrate for atrial fibrillation (AF) development. We investigated if carotid femoral pulse wave velocity (cfPWV), a measure of central arterial stiffness, is associated with incident AF.

Methods: In 2011-2013, cfPWV was measured in 3882 participants of the Atherosclerosis Risk in Communities Cohort Study (ARIC) without prevalent AF. Participants were followed through 2017 for the incidence of AF. Individuals were categorized in cfPWV quartiles based on visit measurements. Multivariable Cox regression models were used to evaluate the association of cfPWV with incident AF.

Results: Mean age was 75 years (SD 5), 60% were female and 20% were African American. Over a median follow-up of 5.5 years we identified 331 incident cases of AF. cfPWV demonstrated U-shaped associations with AF risk. In models adjusted for age, race, center, sex, education levels, and hemodynamic and clinical factors, hazard ratios (HR) of AF for participants in the first, third and fourth quartiles were 1.49 (95% CI 1.06, 2.10), 1.59 (1.14, 2.10), and 1.56(1.10, 2.19), respectively, compared to those in the second quartile.

Conclusion: Among community-dwelling older adults, low and high central arterial stiffness is associated with AF risk.
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http://dx.doi.org/10.1186/s12872-021-02057-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139144PMC
May 2021

Association of Type of Antidepressant Initiation with Bleeding Risk in Atrial Fibrillation Patients Taking Oral Anticoagulants.

Drugs Real World Outcomes 2021 Sep 20;8(3):383-391. Epub 2021 May 20.

Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Rd NE, Atlanta, GA, 30322, USA.

Background: Inconsistent evidence suggests that use of certain antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), in patients using oral anticoagulants (OACs) might be associated with an elevated risk of bleeding.

Objective: This study aims to investigate the risk of bleeding associated with initiation of different types of antidepressants among atrial fibrillation (AF) patients on OAC therapy.

Patients And Methods: A total of 30,336 AF patients (mean age 72.2 years; 54% female) on OAC therapy that started antidepressant treatment were identified from the Truven Health Analytics MarketScan Commercial and Medicare Databases for the period 2007-2015. Exposure was defined as filling a prescription for antidepressant, and categorized as SSRI, serotonin/norepinephrine reuptake inhibitors (SNRIs), serotonin reuptake inhibitors (SRIs), tricyclic antidepressants (TCAs), or other antidepressants. The primary outcome was incident hospitalized bleeding. Associations of antidepressant type with bleeding were assessed calculating hazard ratios (HRs) and 95% confidence intervals (CIs) with adjusted Cox models in pairwise propensity score-matched cohorts.

Results: During a mean follow-up of 21 months, we identified 1612 bleeding episodes. In pairwise comparisons, SSRI use was associated with an increased risk of bleeding when compared to most other antidepressants (HR 1.22, 95% CI 0.96-1.54 vs SNRI; HR 1.10, 95% CI 0.90-1.35 vs SRI; HR 1.03, 95% CI 0.82-1.30 vs TCA). SNRI use was associated with the lowest bleeding risk. Results did not differ by OAC type, age, and sex.

Conclusions: Among AF patients on OAC initiating antidepressants, risk of bleeding varied across antidepressant type. This information can inform treatment choices among patients receiving OAC.
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http://dx.doi.org/10.1007/s40801-021-00258-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324721PMC
September 2021

Impact of oral anticoagulant choice for the secondary prevention of venous thromboembolism on the risk of inpatient bleeding.

Res Pract Thromb Haemost 2021 May 4;5(4):e12514. Epub 2021 May 4.

Division of Epidemiology and Community Health University of Minnesota Minneapolis MN USA.

Background: Randomized trials suggest that direct oral anticoagulants (DOACs) are at least as effective as warfarin for primary treatment of VTE and that bleeding risk may be lower for some DOACs relative to warfarin. However, there is very little information regarding potential bleeding risks for DOACs versus warfarin in secondary prevention of VTE.

Objective: The aim of this study was to compare rates of bleeding events resulting in inpatient admissions between individuals taking apixaban, rivaroxaban, and warfarin for secondary prevention of VTE during the period 2013-2017.

Methods: We used the IBM MarketScan Commercial Claims and Encounters Database and Medicare Supplemental and Coordination of Benefits Database (IBM Watson Health, Ann Arbor, MI) to establish a retrospective cohort. Initial venous thrombolism events were defined from medical claims, and follow-up for this cohort began 6 months after the initial event. Bleeding events resulting in inpatient admission were identified from claims data over the subsequent year of secondary prevention.

Results: A total of 69 264 individuals were identified for the cohort, with 567 bleeding events. The crude rate of bleeding was highest among warfarin users (1.47/100 person-years; 95% confidence interval [CI], 1.24-1.74) and lower among those on either apixaban (1.00/100 person-years; 95% CI, 0.65-1.54) or rivaroxaban (0.84/100 person-years; 95% CI, 0.66-1.08). In multivariable adjusted Cox models, those on apixaban (hazard ratio [HR], 0.80; 95% CI, 0.50-1.29) and rivaroxaban (HR, 0.81; 95% CI, 0.59-1.09) had somewhat lower rates of bleeding events relative to those on warfarin.

Conclusions: We found modest evidence of decreased risk of bleeding for apixaban and rivaroxaban. These estimates were relatively imprecise.
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http://dx.doi.org/10.1002/rth2.12514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105158PMC
May 2021

User-Adapted Web Services by Extending the eIDAS Specification with Functional Attributes.

Int J Environ Res Public Health 2021 04 9;18(8). Epub 2021 Apr 9.

Escuela Técnica Superior de Ingenieros de Telecomunicación, Universidad Politécnica de Madrid, 28040 Madrid, Spain.

To provide web services adapted to the users' functional capabilities, diversity must be considered from the conceptualization and design phases of the services' development. In previous work, we proposed a model that allows the provisioning of adapted interfaces based on users' identity and their functional attributes to facilitate this task for software designers and developers. However, these identities and attributes are self-declared by the users, which may impact reliability and usability. In this work, we propose an extension of our model to resolve these deficiencies by delegating the identity and attributes' provision to external certified entities. The European electronic Identification, Authentication and Trust Services (eIDAS) regulation established a solution to ensure the cross-border mutual recognition of Electronic Identification (eID) mechanisms among the European Member States. This research aims to provide an extension of this regulation mentioned above (eIDAS) to support functional attributes and connect our previously proposed model to this extended eIDAS network. Thanks to this proposal, web services can guarantee adapted and personalized interfaces while improving the functionalities offered without any previous configuration by users and, in a reliable way, since the functional attributes belong to the users' official eID. As the attribute set provided by eIDAS nodes only contains citizens' personal and legal ones, we also propose a mechanism to connect the eIDAS network to external attribute providers that could extend the eIDAS profile of users with their functional attributes. We deployed a pilot to validate the proposed model consisting of an identity provider, an eIDAS node supporting the extended reference code, and an attribute provider supporting functional attributes. We also designed and implemented a simple service that supports eID authentication and serves adapted interfaces based on the retrieved extended eIDAS profile. Finally, we developed an experience for getting feedback from a set of real users with different functional capabilities. According to the results, we concluded that the generalized adoption of the proposed solution in the European digital web services will significantly improve their accessibility in terms of ease of use and adaptability to users' capacities.
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http://dx.doi.org/10.3390/ijerph18083980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070060PMC
April 2021

Association of Carotid Intima-Media Thickness and Other Carotid Ultrasound Features With Incident Dementia in the ARIC-NCS.

J Am Heart Assoc 2021 May 17;10(9):e020489. Epub 2021 Apr 17.

Division of Epidemiology and Community Health School of Public Health University of Minnesota Minneapolis MN.

Background Increased carotid intima-media thickness, interadventitial diameter, presence of carotid plaque, and lower distensibility are predictors for cardiovascular disease. These indices likely relate to cerebrovascular disease, and thus may constitute a form of vascular contributions to dementia and Alzheimer disease-related dementia. Therefore, we assessed the relationship of carotid measurements and arterial stiffness with incident dementia in the ARIC (Atherosclerosis Risk in Communities) study. Methods and Results A total of 12 459 ARIC participants with carotid arterial ultrasounds in 1990 to 1992 were followed through 2017 for dementia. Dementia cases were identified using in-person and phone cognitive status assessments, hospitalization discharge codes, and death certificate codes. Cox proportional hazards models were used to estimate the hazard ratios (HRs) for incident dementia. Participants were aged 57±6 at baseline, 57% were women, and 23% were Black individuals. Over a median follow-up time of 24 years, 2224 dementia events were ascertained. After multivariable adjustments, the highest quintile of carotid intima-media thickness and interadventitial diameter in midlife was associated with increased risk of dementia (HR [95% CIs], 1.25 [1.08-1.45]; and 1.22 [1.04-1.43], respectively) compared with its respective lowest quintile. Presence of carotid plaque did not have a significant association with dementia (HR [95% CI], 1.06 [0.97-1.15]). Higher distensibility was associated with lower risk of dementia (HR [95% CI] highest versus lowest quintile, 0.76 [0.63-0.91]). Conclusions Greater carotid intima-media thickness, interadventitial diameter, and lower carotid distensibility are associated with an increased risk of incident dementia. These findings suggest that both atherosclerosis and carotid stiffness may be implicated in dementia risk.
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http://dx.doi.org/10.1161/JAHA.120.020489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200760PMC
May 2021

Frequent Premature Atrial Contractions Are Associated With Poorer Cognitive Function in the Atherosclerosis Risk in Communities (ARIC) Study.

Mayo Clin Proc 2021 05 9;96(5):1147-1156. Epub 2021 Apr 9.

Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN.

Objective: To evaluate the association of premature atrial contraction (PAC) frequency with cognitive test scores and prevalence of dementia or mild cognitive impairment (MCI).

Materials And Methods: We conducted a cross-sectional analysis using Atherosclerosis Risk in Communities study visit 6 (January 1, 2016, through December 31, 2017) data. We included 2163 participants without atrial fibrillation (AF) (age mean ± SD, 79±4 years; 1273 (58.9%) female; and 604 (27.97.0% Black) who underwent cognitive testing and wore a leadless, ambulatory electrocardiogram monitor for 14 days. We categorized PAC frequency based on the percent of beats: less than 1%, minimal; 1% to <5%, occasional; greater than or equal to 5%, frequent. We derived cognitive domain-specific factor scores (memory, executive function, language, and global z-score). Dementia and MCI were adjudicated.

Results: During a mean analyzable time of 12.6±2.6 days, 339 (15.7%) had occasional PACs and 107 (4.9%) had frequent PACs. Individuals with frequent PACs (vs minimal) had lower executive function factor scores by 0.30 (95% CI, -0.46 to -0.14) and lower global factor scores by 0.20 (95% CI, -0.33 to -0.07) after multivariable adjustment. Individuals with frequent PACs (vs minimal) had higher odds of prevalent dementia or MCI after multivariable adjustment (odds ratio, 1.74; 95% CI, 1.09 to 2.79). These associations were unchanged with additional adjustment for stroke.

Conclusion: In community-dwelling older adults without AF, frequent PACs were cross-sectionally associated with lower executive and global cognitive function and greater prevalence of dementia or MCI, independently of stroke. Our findings lend support to the notion that atrial cardiomyopathy may be a driver of AF-related outcomes. Further research to confirm these associations prospectively and to elucidate underlying mechanisms is warranted.
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http://dx.doi.org/10.1016/j.mayocp.2021.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106627PMC
May 2021

Effects of widespread non-native trees on regulating ecosystem services.

Sci Total Environ 2021 Jul 1;778:146141. Epub 2021 Mar 1.

Department of Life Sciences, University of Alcalá, Ctra. Madrid-Barcelona Km 33.6, E-28805 Alcalá de Henares, Madrid, Spain.

Tree taxa are often planted beyond their native range to increase the provision of some ecosystem services. Yet, they can disrupt ecosystem processes in their new ranges, causing changes in the provision of other services. Here we review the effects of five widespread tree taxa (Acacia, Ailanthus, Eucalyptus, Pinus and Robinia) on six regulating ecosystem services in areas where they are non-native. We conducted a literature search for pair-wise comparisons between sites dominated by any of the selected taxa and sites with native vegetation. An array of variables were used as indicators for each ecosystem service. Data were analysed using multi-level meta-analyses to compare effects of taxa on each ecosystem service, and effects of the same taxa across contexts. We compiled 857 case studies from 107 source papers. Several taxa tended to increase climate regulation, mostly Eucalyptus. Acacia decreased fire risk prevention. Robinia, Acacia and Ailanthus increased soil fertility, while Eucalyptus and Pinus, tended to decrease it. Soil formation was enhanced by Robinia and Ailanthus. Acacia promoted the increase of water in land pools, while Eucalyptus tended to decrease them. All effects show a large heterogeneity across case studies. Part of this heterogeneity could be attributed to gross climatic differences (i.e. biome), to species differences within each genus, to the structure of the recipient ecosystem, and/or to human management. Managers and policy-makers should consider the context-dependency and the potential effects of non-native trees on a wide range of services to ground their decisions. Our analyses also revealed important gaps of knowledge (e.g. on fire risk prevention, erosion control or water cycle regulation) and some potential publication bias. The methodology used here easily allows for future updates as new information will become available.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146141DOI Listing
July 2021

Life's Simple 7 cardiovascular health score and premature atrial contractions: The atherosclerosis risk in communities (ARIC) study.

Int J Cardiol 2021 06 4;332:70-77. Epub 2021 Mar 4.

Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, United States of America.

Background: Premature atrial contractions (PACs) are associated with increased risk of atrial fibrillation (AF) and ischemic stroke. Although lifestyle and risk factor modification reduces AF incidence, their relationship to PACs frequency is unclear. We assessed the association of Life's Simple 7 (LS7) and individual LS7 factors in midlife with PACs frequency in late life in the Atherosclerosis Risk in Communities (ARIC) Study.

Methods: We followed 1924 participants from ARIC clinic Visit 3 (1993--95) to Visit 6 (2016-17) when a 2-week continuous heart rhythm monitor (Zio®XT Patch) was applied. LS7 factors were assessed at Visit 3 and a composite score was calculated. PACs frequency was categorized as minimal (<0.1%), occasional (≥0.1%-5%) and frequent (>5%). Logistic regression was used to evaluate the association of LS7 score and individual factors with PACs frequency.

Results: Each 1-point LS7 score increase was associated with lower odds of frequent PACs vs. no PACs (OR [95% CI]: 0.87 [0.78, 0.98]) and frequent PACs vs. occasional PACs (OR [95% CI]: 0.88 [0.79, 0.98]). Of the individual LS7 factors, compared with ideal physical activity, poor physical activity was associated with 81% higher odds of frequent PACs vs. no PACs. Compared with ideal BMI, poor BMI was associated with 41% higher odds of occasional PACs vs. no PACs.

Conclusion: Lifestyle risk factors, particularly physical activity and BMI, are associated with higher odds of PACs frequency. More research is needed to determine whether modifying these risk factors in midlife would prevent frequent PACs, and thereby prevent AF and stroke in older age.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164708PMC
June 2021

Identification and validation of clinical phenotypes with prognostic implications in patients admitted to hospital with COVID-19: a multicentre cohort study.

Lancet Infect Dis 2021 06 23;21(6):783-792. Epub 2021 Feb 23.

Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Seville, Spain; Departamento de Medicina, Universidad de Sevilla, Seville, Spain; Instituto de Biomedicina de Sevilla, Seville, Spain. Electronic address:

Background: The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality.

Methods: In this study, we used data from two cohorts: the [email protected] cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the [email protected] cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The [email protected] cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The [email protected] cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model.

Findings: Three distinct phenotypes were derived in the derivation cohort (n=2667)-phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])-and reproduced in the internal validation cohort (n=1368)-phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2·5% (95% CI 1·4-4·3) for patients with phenotype A, 30·5% (28·5-32·6) for patients with phenotype B, and 60·7% (53·7-67·2) for patients with phenotype C (log-rank test p<0·0001). The predicted phenotypes in the internal validation cohort and external validation cohort showed similar mortality rates to the assigned phenotypes (internal validation cohort: 5·3% [95% CI 3·4-8·1] for phenotype A, 31·3% [28·5-34·2] for phenotype B, and 59·5% [48·8-69·3] for phenotype C; external validation cohort: 3·7% [2·0-6·4] for phenotype A, 23·7% [21·8-25·7] for phenotype B, and 51·4% [41·9-60·7] for phenotype C).

Interpretation: Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. We developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes. These results might help to better classify patients for clinical management, but the pathophysiological mechanisms of the phenotypes must be investigated.

Funding: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.
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http://dx.doi.org/10.1016/S1473-3099(21)00019-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906623PMC
June 2021

Association of Psychosocial Factors With Short-Term Resting Heart Rate Variability: The Atherosclerosis Risk in Communities Study.

J Am Heart Assoc 2021 02 26;10(5):e017172. Epub 2021 Feb 26.

Department of Medicine School of Medicine Emory University Atlanta GA.

Background Psychosocial factors predict heart disease risk, but our understanding of underlying mechanisms is limited. We sought to evaluate the physiologic correlates of psychosocial factors by measuring their relationships with heart rate variability (HRV), a measure of autonomic health, in the ARIC (Atherosclerosis Risk in Communities) study. We hypothesize that increased psychosocial stress associates with lower HRV. Methods and Results We studied 9331 participants in ARIC with short-term HRV data at visits 2 and 4. The mean (SD) age was 54.4 (5.7) years, 55% were women, and 25% were Black. Psychosocial factors included: (1) vital exhaustion (VE), (2) anger proneness, a personality trait, and (3) perceived social support. Linear models adjusted for sociodemographic and cardiovascular risk factors. Low frequency HRV (ln ms) was significantly lower in the highest versus lowest quartiles of VE (B=-0.14, 95% CI, -0.24 to -0.05). When comparing this effect to age (B=-0.04, 95% CI, -0.05 to -0.04), the difference was equivalent to 3.8 years of accelerated aging. Perceived social support associated with lower time-domain HRV. High VE (versus low VE) also associated with greater decreases in low frequency over time, and both anger and VE associated with greater increases in resting heart rate over time. Survival analyses were performed with Cox models, and no evidence was found that HRV explains the excess risk found with high VE and low perceived social support. Conclusions Vital exhaustion, and to a lesser extent anger and social support, were associated with worse autonomic function and greater adverse changes over time.
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http://dx.doi.org/10.1161/JAHA.120.017172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174247PMC
February 2021

Association of P-Wave Abnormalities With Sudden Cardiac and Cardiovascular Death: The ARIC Study.

Circ Arrhythm Electrophysiol 2021 02 16;14(2):e009314. Epub 2021 Feb 16.

Department of Medicine (L.Y.C.), University of Minnesota, Minneapolis.

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http://dx.doi.org/10.1161/CIRCEP.120.009314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109763PMC
February 2021

Short-term repeatability of the peguero-lo presti electrocardiographic left ventricular hypertrophy criteria.

Ann Noninvasive Electrocardiol 2021 05 16;26(3):e12829. Epub 2021 Feb 16.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: Electrocardiographic left ventricular hypertrophy (ECG-LVH) represents preclinical cardiovascular disease and predicts cardiovascular disease morbidity and mortality. While the newly developed Peguero-Lo Presti ECG-LVH criteria have greater sensitivity for LVH than the Cornell voltage and Sokolow-Lyon criteria, its short-term repeatability is unknown. Therefore, we characterized the short-term repeatability of Peguero-Lo Presti ECG-LVH criteria and evaluate its agreement with Cornell voltage and Sokolow-Lyon ECG-LVH criteria.

Methods: Participants underwent two resting, standard, 12-lead ECGs at each of two visits one week apart (n = 63). We defined a Peguero-Lo Presti index as a sum of the deepest S wave amplitude in any single lead and lead V (i.e., S  + SV ) and defined Peguero-Lo Presti LVH index as ≥ 2,300 µV among women and ≥ 2,800 µV among men. We estimated repeatability as an intraclass correlation coefficient (ICC), agreement as a prevalence-adjusted bias-adjusted kappa coefficient (κ), and precision using 95% confidence intervals (CIs).

Results: The Peguero-Lo Presti index was repeatable: ICC (95% CI) = 0.94 (0.91-0.97). Within-visit agreement of Peguero-Lo Presti LVH was high at the first and second visits: κ (95% CI) = 0.97 (0.91-1.00) and 1.00 (1.00-1.00). Between-visit agreement of the first and second measurements at each visit was comparable: κ (95% CI) = 0.90 (0.80-1.00) and 0.93 (0.85-1.00). Agreement of Peguero-Lo Presti and Cornell or Sokolow-Lyon LVH on any one of the four ECGs was slightly lower: κ (95% CI) = 0.71 (0.54-0.89).

Conclusion: The Peguero-Lo Presti index and LVH have excellent repeatability and agreement, which support their use in clinical and epidemiological studies.
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http://dx.doi.org/10.1111/anec.12829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164147PMC
May 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Periodontal Disease, Atrial Fibrillation and Stroke.

Am Heart J 2021 05 24;235:36-43. Epub 2021 Jan 24.

Department of Periodontology, University of North Carolina, Chapel Hill, NC.

Background: We recently described the association between periodontal disease (PD) and stroke risk.

Purpose: The purpose of this study was to test the association between PD, dental care utilization and incident atrial fibrillation (AF), as well as AF as a mediator to PD- stroke association.

Methods: In dental cohort of the Atherosclerosis Risk in Communities Study (ARIC), participants without prior AF underwent full-mouth periodontal measurements. PD was defined on an ordinal scale as healthy (referent), mild, moderate and severe. In ARIC main cohort, participants were classified as regular or episodic dental care users. These patients were followed for AF, over 17 years. Cox proportional hazards models adjusted for AF risk factors were used to study relationships between PD severity, dental care utilization and AF. Mediation analysis was used to test if AF mediated the PD- stroke association.

Results: In dental ARIC cohort, 5,958 were assessed without prior AF, 754 were found to have AF. Severe PD was associated with AF on both univariable (crude HR, 1.54; 95% CI, 1.26-1.87) and multivariable (adjusted HR, 1.31, 95% CI, 1.06-1.62) analyses. Mediation analysis suggested AF mediates the association between PD and stroke. In the main ARIC cohort, 9,666 participants without prior AF were assessed for dental care use, 1558 were found to have AF. Compared with episodic users, regular users had a lower risk for AF on univariable (crude HR, 0.82, 95% CI, 0.74-0.90) and multivariable (adjusted HR, 0.88, 95% CI, 0.78-0.99) analyses.

Conclusions: PD is associated with AF. The association may explain the PD-stroke risk. Regular users had a lower risk of incident AF compared with episodic users.
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http://dx.doi.org/10.1016/j.ahj.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084947PMC
May 2021

Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association.

Circulation 2021 Feb 27;143(8):e254-e743. Epub 2021 Jan 27.

Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).

Methods: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease.

Results: Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.

Conclusions: The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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http://dx.doi.org/10.1161/CIR.0000000000000950DOI Listing
February 2021

Proton Pump Inhibitor Use, Hypomagnesemia and Risk of Cardiovascular Diseases: The Atherosclerosis Risk in Communities (ARIC) Study.

J Clin Gastroenterol 2021 Sep;55(8):677-683

Division of Epidemiology and Community Health.

Goals: The goal of this study was to evaluate whether proton pump inhibitor (PPI) use is cross-sectionally associated with hypomagnesemia and whether hypomagnesemia mediates the prospective association between PPIs and cardiovascular disease (CVD) risk.

Background: Use of PPIs has been associated with hypomagnesemia, primarily in case reports or within insurance databases. Both PPI use and low serum magnesium (Mg) have been associated with modestly higher CVD risk. Yet, the interrelation between PPI use and Mg in relation to CVD risk is unclear.

Study: The 4436 Atherosclerosis Risk in Communities participants without prevalent CVD at visit 5 (baseline, 2011-2013) were included. Multivariable relative risk regression was used for cross-sectional analyses between PPI and hypomagnesemia prevalence (≤0.75 mmol/L). Incident CVD (defined by atrial fibrillation, coronary heart disease, CVD mortality, heart failure, stroke) was identified through 2017. Multivariable Cox regression was used to examine the PPI-CVD association.

Results: Participants were mean±SD aged 75±5 years; 63% were women, 23% Black, and 24% were PPI users. PPI users had 1.24-fold (95% confidence interval: 1.08-1.44) higher prevalence of hypomagnesemia than nonusers. Over a median 5 years of follow-up, 684 incident CVD events occurred. PPI users had higher CVD risk [hazard ratio (95% confidence interval) 1.31 (1.10-1.57)] than nonusers. The effect estimate was largely unchanged when hypomagnesemia was added to the model as a potential mediator.

Conclusions: In this elderly community-based study, PPI users had a higher prevalence of hypomagnesemia than in nonusers. PPI users also had higher CVD risk than nonusers; however, it appears unlikely that hypomagnesemia explains associations of PPIs with CVD risk.
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http://dx.doi.org/10.1097/MCG.0000000000001420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921206PMC
September 2021

Sphingolipids and physical function in the Atherosclerosis Risk in Communities (ARIC) study.

Sci Rep 2021 01 13;11(1):1169. Epub 2021 Jan 13.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA.

Long-chain sphingomyelins (SMs) may play an important role in the stability of myelin sheath underlying physical function. The objective of this study was to examine the cross-sectional and longitudinal associations of long-chain SMs [SM (41:1), SM (41:2), SM (43:1)] and ceramides [Cer (41:1) and Cer (43:1)] with physical function in the Atherosclerosis Risk in Communities (ARIC) study. Plasma concentrations of SM (41:1), SM (41:2), SM (43:1), Cer (41:1) and Cer (43:1) were measured in 389 ARIC participants in 2011-13. Physical function was assessed by grip strength, Short Physical Performance Battery (SPPB), 4-m walking speed at both 2011-13 and 2016-17, and the modified Rosow-Breslau questionnaire in 2016-2017. Multivariable linear and logistic regression analyses were performed, controlling for demographic and clinical confounders. In cross-sectional analyses, plasma concentrations of SM 41:1 were positively associated with SPPB score (β-coefficients [95% confidence internal]: 0.33 [0.02, 0.63] per 1 standard deviation [SD] increase in log-transformed concentration, p value 0.04), 4-m walking speed (0.042 m/s [0.01, 0.07], p value 0.003), and negatively with self-reported disability (odds ratio = 0.73 [0.65, 0.82], p value < 0.0001). Plasma concentrations of the five metabolites examined were not significantly associated with longitudinal changes in physical function or incidence of poor mobility. In older adults, plasma concentrations of long-chain SM 41:1 were cross-sectionally positively associated with physical function.
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http://dx.doi.org/10.1038/s41598-020-80929-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806657PMC
January 2021

Association of Sickle Cell Trait With Incidence of Coronary Heart Disease Among African American Individuals.

JAMA Netw Open 2021 01 4;4(1):e2030435. Epub 2021 Jan 4.

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.

Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT).

Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals.

Design, Setting, And Participants: This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020.

Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses.

Main Outcomes And Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis).

Results: A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47).

Conclusions And Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.30435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786247PMC
January 2021

Corrigendum to 'Association of sickle cell trait with measures of cognitive function and dementia in African Americans' Vol. 16 (2019), 100,201.

eNeurologicalSci 2020 Dec 12;21:100281. Epub 2020 Oct 12.

Aflac Cancer and Blood Disorder Center of Children's Healthcare of Atlanta, Emory Department of Pediatrics, Atlanta, GA, United States of America.

[This corrects the article DOI: 10.1016/j.ensci.2019.100201.].
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http://dx.doi.org/10.1016/j.ensci.2020.100281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719690PMC
December 2020

Methodology Aspects of Colony Maintain for a Murine Model of Amyotrophic Lateral Sclerosis (ALS) TDP-43 Proteinopathy.

Animals (Basel) 2020 Dec 7;10(12). Epub 2020 Dec 7.

Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45007 Toledo, Spain.

The use of genetically engineered mouse (GEMs) models provides an unprecedented opportunity to study the genetic basis of diseases and gene function, therefore it is paramount to determine reproductive parameters that guarantee proper colony maintenance. We studied the reproductive parameters of mice hemizygous for TDP-43 transgene, which are viable, fertile, and express a mutant human TAR DNA binding protein (hTDP-43) cDNA harboring an amino acid substitution associated with familial amyotrophic lateral sclerosis (fALS). TDP43 mice were backcrossed to a C57Bl6/J pure background for four consecutive generations. The Tg offspring genotype were then confirmed by PCR assays. Our statistical analysis indicated there were no differences in the sex and number of pups per offspring when hemizygous female and male TDP43 mice were backcrossed to C57Bl6/J mice. Interestingly, our results showed significant differences in the number of offspring expressing the transgene when hemizygous TDP43 male mice were used as breeders. Therefore, our findings suggest that male TDP43 mice transfer the transgene with a greater genetic strengths. Such is an important breeding consideration to ensure the principle of reduction in animal experimentation considering most basic research with models focuses on males and excludes female mice.
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http://dx.doi.org/10.3390/ani10122329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762410PMC
December 2020

Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.

N Engl J Med 2021 02 2;384(6):497-511. Epub 2020 Dec 2.

The affiliations of the members of the writing and steering committees are as follows: the Nuffield Department of Population Health and Medical Research Council Population Health Research Unit, University of Oxford, Oxford (H.P., R.P.), and the University of Bristol, Bristol (E.A., S.B., H.B.C.C.-P., D.H., J.K., C.A.R., J.A.C.S.) - both in the United Kingdom; the World Health Organization, Geneva (A.-M.H.-R., M.-P.P., V.S., P. Lydon, M.C.M.-M., K.S., S.S.), the University of Bern, Bern (S.A., M.B., S. McGinty, S.T.), and Lausanne University Hospital, Lausanne (O.M.) - all in Switzerland; the Centre for the AIDS Programme of Research in South Africa, Durban (Q.A.K.), and the University of the Witwatersrand (J.N.) and the Wits Reproductive Health and HIV Institute (H.R.), Johannesburg - all in South Africa; the Institute of National Epidemiology, National Institutes of Health, University of the Philippines, Manila (M.M.A.); the Agency of Medicine and Medical Devices (C.H.G.) and Hospital Clínico San Carlos, Universidad Complutense de Madrid, Spanish Clinical Research Network, Instituto de Investigación Sanitaria San Carlos (A.P.), Madrid; INSERM, Paris (M.-P.K.), and Hospices Civils de Lyon, Lyon (F.A.) - both in France; the Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran (R.M.); the University of British Columbia, Vancouver (S. Murthy), and the Public Health Agency of Canada, Ottawa (M.I.S.) - both in Canada; the Public Health Foundation of India, New Delhi (K.S.R.), and the Indian Council of Medical Research, National AIDS Research Institute, Pune (S.G.) - both in India; the National Academy of Sciences of Buenos Aires (M.R.P.) and Fundación del Centro de Estudios Infectológicos (G.L.), Buenos Aires; Rafic Hariri University Hospital (P.A.H.) and the Ministry of Public Health (R.H.), Beirut, Lebanon; the Ministry of Health (A.M.A.-B.) and Infectious Diseases Hospital (A. Alhasawi), Kuwait City, Kuwait; Universidad Nacional de Colombia and Clinica Colsanitas (C.A.A.-M.) and the Ministry of Health (M.L.M.R.), Bogota, Colombia; the Ministry for Preventive Health, Riyadh, Saudi Arabia (A. Asiri, A. Alotaibi); Oslo University Hospital (P.A., A.B.-D.) and Research Council of Norway (J.-A.R.), Oslo; Secretaria de Salud de Honduras (N. Cerrato) and the National Autonomous University of Honduras (M.T.M.), Tegucigalpa; Penang Hospital, Penang (T.S.C.), and Hospital Sungai Buloh and Jalan Hospital, Selangor (S.K.) - both in Malaysia; University Hospital Center Mother Theresa (N. Como) and the National Agency for Medicines and Medical Devices (N.S.), Tirana, Albania; the HRB Clinical Research Facility, University College Cork, Cork (J.E.), and the Department of Health and Children, Dublin (P. Lennon, T.M.) - both in Ireland; Universidad Peruana Cayetano Heredia, Lima, Peru (P.J.G., E.G.); Vilnius University Hospital Santaros Klinikos (L.G.) and Vilnius University, Institute of Clinical Medicine (L.J.), Vilnius, Lithuania; Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan (M. Hassan, A.R.); the National Hepatology and Tropical Medicine Research Institute (M. Hassany) and the Ministry of Health and Population (H.Z.), Cairo; the National Institute of Health Research and Development (I.I.) and Rumah Sakit Umum Pusat Persahabatan (M.R.R.), Jakarta, Indonesia; the Italian Medicines Agency, Rome (N.M.), and the University of Verona, Verona (E.T.) - both in Italy; the Ministry of Health (S. Manevska) and the University Clinic of Infectious Diseases and Febrile Conditions (M.S.), Skopje, North Macedonia; the Oswaldo Cruz Foundation, Rio de Janeiro (E.P.N., P.P.S.R.); and the Finnish Institute for Health and Welfare and the University of Finland (M.P.) and Helsinki University Hospital (K.A.O.T.), Helsinki, and South Karelian Central Hospital, Lappeenranta (K.A.O.T.) - all in Finland.

Background: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19).

Methods: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.

Results: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.

Conclusions: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).
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http://dx.doi.org/10.1056/NEJMoa2023184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727327PMC
February 2021

Added value of cerebrospinal fluid multimarker analysis in diagnosis and progression of dementia.

Eur J Neurol 2021 04 14;28(4):1142-1152. Epub 2020 Dec 14.

Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Spain.

Background And Purpose: Recently, some emerging cerebrospinal fluid (CSF) markers have been proposed as diagnostic tools for Alzheimer disease (AD) that can have an effect on disease progression. We analyze the accuracy of these CSF markers for diagnosis of AD in reference to brain amyloid positron emission tomography (PET). We also investigated whether they help in differentiating AD from other dementias and examined their influence in tracing the progression to dementia.

Methods: Amyloid-β (Aβ) 1-42, total tau (t-tau), phosphorylated tau, Aβ , Aβ , beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), neurogranin (ng), phosphorylated neurofilament heavy-chain, and α-synuclein (α-syn) CSF levels were analyzed in 319 subjects, among whom 57 also underwent an amyloid PET scan. We also analyzed longitudinal clinical data from 239 subjects.

Results: Emerging CSF markers, especially ng/BACE-1 ratio (area under the curve = 0.77) and their combinations with core AD CSF markers (all AUCs >0.85), showed high accuracy to discriminate amyloid PET positivity. Subjects with AD had higher CSF BACE-1, ng, and α-syn levels than those with non-AD dementia. CSF t-tau/α-syn ratio was higher in subjects with dementia with Lewy bodies than in those with frontotemporal dementia. Most emerging/core AD ratios predicted a faster conversion from mild cognitive impairment (MCI) stage to AD and appeared to be helpful when core AD CSF markers were discordant. In addition, the rate of cognitive decline was associated with all CSF core AD markers, several emerging/core AD two-marker ratios, and CSF ng levels.

Conclusions: These results suggest that emerging biomarkers in conjunction with core AD markers improve diagnosis of AD, are associated with the conversion from MCI into AD, and predict a faster progression of dementia.
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http://dx.doi.org/10.1111/ene.14658DOI Listing
April 2021
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