Publications by authors named "Diederick E Grobbee"

716 Publications

Associations between the fast-food environment and diabetes prevalence in the Netherlands: a cross-sectional study.

Lancet Planet Health 2022 Jan;6(1):e29-e39

Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands; Global Geo Health Data Center, Utrecht University, Utrecht, Netherlands.

Background: Diabetes is a major health concern and is influenced by lifestyle, which can be affected by the neighbourhood environment. Specifically, a fast-food environment can influence eating behaviours and thus diabetes prevalence. Therefore, our aim was to assess the relationship between fast-food environment and diabetes prevalence for urban and rural environments in the Netherlands, using multiple indicators and buffer sizes.

Methods: In this cross-sectional study, data on a nationwide sample of adults older than 19 years in the Netherlands were taken from the 2012 Dutch national health survey (from Public Health Monitor), in which participants were surveyed on topics related to health and lifestyle behaviour. Fast-food outlet exposures were determined within street-network buffers of 100 m, 400 m, 1000 m, and 1500 m around residential addresses. For each of these buffers, three indicators were calculated: presence (yes or no) of fast-food outlets, fast-food outlet density, and ratio. Logistic regression analyses were carried out to assess associations of these indicators with diabetes, adjusting for potential confounders and stratifying into urban and rural areas.

Findings: 387 195 adults were surveyed, 284 793 of whom were included in the study. 22 951 (8%) reported having diabetes. Fast-food outlet exposures were positively associated with diabetes prevalence. We did not observe large differences between urban and rural areas. The effect estimates were small for all indicators. For example, in the 400 m buffer in the urban environment, the odds ratio (OR) for having diabetes among people with a fast-food outlet present compared with those without, was 1·006 (95% CI 1·003-1·009) using the presence indicator. The presence indicator showed higher effect estimates and the most consistent results across buffer sizes (ranging from OR 1·005 [95% CI 1·000-1·010] with the 1000 m buffer to 1·016 [1·005-1·028] with the 1500 m buffer in urban areas and from 1·002 [0·998-1·005] with the 1500 m buffer to 1·009 [1·006-1·018] with the 100 m buffer in rural areas) compared with the density and ratio indicators.

Interpretation: The results confirm the evidence that the fast-food outlet environment is a diabetes risk factor. All data included were at the individual level and the variability was ensured by the spatial distribution and number of participants. In this study, we only accounted for residential exposure because we were unable to account for exposure outside the residential environment. The findings of this study encourage local governments to consider the potential adverse effects of fast-food exposures and aim at minimising unhealthy food access.

Funding: Global Geo Health Data Centre, Utrecht University, Netherlands.
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http://dx.doi.org/10.1016/S2542-5196(21)00298-9DOI Listing
January 2022

A population-based study of 92 clinically recognized risk factors for heart failure: co-occurrence, prognosis and preventive potential.

Eur J Heart Fail 2021 Dec 30. Epub 2021 Dec 30.

Institute of Health Informatics, University College London, London, UK.

Aims: Primary prevention strategies for heart failure (HF) have had limited success, possibly due to a wide range of underlying risk factors (RFs). Systematic evaluations of the prognostic burden and preventive potential across this wide range of risk factors are lacking. We aimed at estimating evidence, prevalence and co-occurrence for primary prevention and impact on prognosis of RFs for incident HF.

Methods And Results: We systematically reviewed trials and observational evidence of primary HF prevention across 92 putative aetiologic RFs for HF identified from US and European clinical practice guidelines. We identified 170 885 individuals aged ≥30 years with incident HF from 1997 to 2017, using linked primary and secondary care UK electronic health records (EHR) and rule-based phenotypes (ICD-10, Read Version 2, OPCS-4 procedure and medication codes) for each of 92 RFs. Only 10/92 factors had high quality observational evidence for association with incident HF; 7 had effective randomized controlled trial (RCT)-based interventions for HF prevention (RCT-HF), and 6 for cardiovascular disease prevention, but not HF (RCT-CVD), and the remainder had no RCT-based preventive interventions (RCT-0). We were able to map 91/92 risk factors to EHR using 5961 terms, and 88/91 factors were represented by at least one patient. In the 5 years prior to HF diagnosis, 44.3% had ≥4 RFs. By RCT evidence, the most common RCT-HF RFs were hypertension (48.5%), stable angina (34.9%), unstable angina (16.8%), myocardial infarction (15.8%), and diabetes (15.1%); RCT-CVD RFs were smoking (46.4%) and obesity (29.9%); and RCT-0 RFs were atrial arrhythmias (17.2%), cancer (16.5%), heavy alcohol intake (14.9%). Mortality at 1 year varied across all 91 factors (lowest: pregnancy-related hormonal disorder 4.2%; highest: phaeochromocytoma 73.7%). Among new HF cases, 28.5% had no RCT-HF RFs and 38.6% had no RCT-CVD RFs. 15.6% had either no RF or only RCT-0 RFs.

Conclusion: One in six individuals with HF have no recorded RFs or RFs without trials. We provide a systematic map of primary preventive opportunities across a wide range of RFs for HF, demonstrating a high burden of co-occurrence and the need for trials tackling multiple RFs.
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http://dx.doi.org/10.1002/ejhf.2417DOI Listing
December 2021

The GetReal Trial Tool: Design, Assess and Discuss Clinical Drug Trials in Light of RWE Generation.

J Clin Epidemiol 2021 Dec 17. Epub 2021 Dec 17.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Eli Lilly & Co Ltd, Bracknell, UK; Partnerships and IEG Office, Integrated Evidence Generation & Business Innovation, Medical Affairs & Pharmacovigilance, Bayer AG; Clinical Development, GSK Research & Development Ltd., Stevenage, Hertfordshire, SG1 2NY, UK; Department of Rheumatology & Clinical immunology, University Medical Center Utrecht, Utrecht, the Netherlands; Julius Clinical, Zeist, the Netherlands.

Methodologies incorporating Real World Elements into clinical trial design (also called pragmatic trials) offer an attractive opportunity to assess the effect of a treatment strategy in routine care and as such guide decision making in practice. Uptake of these methods is slow for several reasons, including uncertainty about acceptability of trial results, lack of experience with the methodology and operational challenges. We developed the 'Get Real Trial Tool', an easy-to-use interface, which allows users to assess the impact of design choices on generalisability to routine clinical practice, while taking into account risk of bias, precision, acceptability and operational feasibility. The tool is grounded in the scientific literature on pragmatic trials combined with knowledge of experts from academia, pharmaceutical companies, HTA bodies, patient organisations, and regulators. The aim is to help researchers optimise trial design and facilitate translation of evidence from pragmatic trials to clinical practice. In this paper we describe the development, structure and application of the GetReal Trial Tool.
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http://dx.doi.org/10.1016/j.jclinepi.2021.12.019DOI Listing
December 2021

The influence of HIV infection and antiretroviral treatment on pulmonary function in individuals in an urban setting in sub-Saharan Africa.

South Afr J HIV Med 2021 15;22(1):1312. Epub 2021 Nov 15.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.

Background: With the roll-out of antiretroviral treatment (ART), the life expectancy of people with HIV and, hence, morbidity from non-communicable diseases, including pulmonary diseases, have increased.

Objectives: This research study aims to investigate whether HIV infection and ART use are associated with pulmonary function, given the high frequency of pulmonary infections, including tuberculosis (TB), associated with HIV.

Method: Adults living with HIV (ART-naïve, on first- or second-line ART), and age and sex matched HIV-negative controls were included in a cross-sectional study in Johannesburg, South Africa. Spirometry was performed to determine lung function, measuring the forced expiratory volume in one second (FEV1), the forced vital capacity (FVC) and the FEV1/FVC ratio before (pre), and after (post), short-acting bronchodilator. The association of HIV infection and ART use with pulmonary function was analysed using linear regression models, adjusting for age, gender, body surface area (BSA), employment, education, smoking and TB.

Results: Overall, 548 participants (62% women) were included with a mean age of 38 (standard deviation [s.d.] 9.5) years. No effect of HIV or ART on post-FEV1 was observed in adjusted analysis. Additional adjustment for TB resulted in a higher post-FEV1 in participants on ART compared with HIV-negative participants, whereas TB was associated with a lower FEV1. No effect of HIV and ART on post-FEV1/FVC was observed.

Conclusion: HIV infection and ART use were not associated with reduced pulmonary function in this urban African population. Tuberculosis showed a mediating effect on the association between HIV, ART and pulmonary function.
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http://dx.doi.org/10.4102/sajhivmed.v22i1.1312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603101PMC
November 2021

Prognostic accuracy of antenatal Doppler ultrasound for adverse perinatal outcomes in low-income and middle-income countries: a systematic review.

BMJ Open 2021 Dec 2;11(12):e049799. Epub 2021 Dec 2.

Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Objectives: This systematic review examined available literature on the prognostic accuracy of Doppler ultrasound for adverse perinatal outcomes in low/middle-income countries (LMIC).

Design: We searched PubMed, Embase, Cochrane Library and Scopus from inception to April 2020.

Setting: Observational or interventional studies from LMICs.

Participants: Singleton pregnancies of any risk profile.

Interventions: Umbilical artery (UA), middle cerebral artery (MCA), cerebroplacental ratio (CPR), uterine artery (UtA), fetal descending aorta (FDA), ductus venosus, umbilical vein and inferior vena cava.

Primary And Secondary Outcome Measures: Perinatal death, stillbirth, neonatal death, expedited delivery for fetal distress, meconium-stained amniotic fluid, low birth weight, fetal growth restriction, admission to neonatal intensive care unit, neonatal acidosis, Apgar scores, preterm birth, fetal anaemia, respiratory distress syndrome, length of hospital stay, birth asphyxia and composite adverse perinatal outcomes (CAPO).

Results: We identified 2825 records, and 30 (including 4977 women) from Africa (40.0%, n=12), Asia (56.7%, n=17) and South America (3.3%, n=01) were included. Many individual studies reported associations and promising predictive values of UA Doppler for various adverse perinatal outcomes mostly in high-risk pregnancies, and moderate to high predictive values of MCA, CPR and UtA Dopplers for CAPO. A few studies suggested that the MCA and FDA may be potent predictors of fetal anaemia. No randomised clinical trial (RCT) was found. Most studies were of suboptimal quality, poorly powered and characterised by wide variations in outcome classifications, the timing for the Doppler tests and study populations.

Conclusion: Local evidence to guide how antenatal Doppler ultrasound should be used in LMIC is lacking. Well-designed studies, preferably RCTs, are required. Standardisation of practice and classification of perinatal outcomes across countries, following the international standards, is imperative.

Prospero Registration Number: CRD42019128546.
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http://dx.doi.org/10.1136/bmjopen-2021-049799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640672PMC
December 2021

Persistent Hypertension Up to One Year Postpartum among Women with Hypertensive Disorders in Pregnancy in a Low-Resource Setting: A Prospective Cohort Study.

Glob Heart 2021 9;16(1):62. Epub 2021 Sep 9.

Julius Global Health, Julius Center for Health Science and Primary Care, UMC Utrecht, Utrecht University, NL.

Background: Hypertensive disorders in pregnancy (HDPs) are associated with lifelong cardiovascular disease risk. Persistent postpartum hypertension in HDPs could suggest progression to chronic hypertension. This phenomenon has not been well examined in low- and middle-income countries (LIMCs), and most previous follow-ups typically last for maximally six weeks postpartum. We assessed the prevalence of persistent hypertension up to one year in women with HDPs in a low resource setting and determined associated risk factors.

Methodology: A prospective cohort study of women conducted at eight tertiary health care facilities in seven states of Nigeria. Four hundred and ten women with any HDP were enrolled within 24 hours of delivery and followed up at intervals until one year postpartum. Descriptive statistics were performed to express the participants' characteristics. Univariable and multivariable logistic regressions were conducted to identify associated risk factors.

Results: Of the 410 women enrolled, 278 were followed up to one year after delivery (follow-up rate 68%). Among women diagnosed with gestational hypertension and pre-eclampsia/eclampsia, 22.3% (95% CI; 8.3-36.3) and 62.1% (95% CI; 52.5-71.9), respectively, had persistent hypertension at six months and this remained similar at one year 22.3% (95% CI; 5.6-54.4) and 61.2% (95% CI; 40.6-77.8). Maternal age and body mass index were significant risk factors for persistent hypertension at one year [aORs = 1.07/year (95% CI; 1.02-1.13) and 1.06/kg/m (95% CI; 1.01-1.10)], respectively.

Conclusion: This study showed a substantial prevalence of persistent hypertension beyond puerperium. Health systems in LMICs need to be organized to anticipate and maintain postpartum monitoring until blood pressure is normalized, or women referred or discharged to family physicians as appropriate. In particular, attention should be given to women who are obese, and or of higher maternal age.
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http://dx.doi.org/10.5334/gh.854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428291PMC
November 2021

A prospective, randomized, single-blinded, crossover trial to investigate the effect of a wearable device in addition to a daily symptom diary for the Remote Early Detection of SARS-CoV-2 infections (COVID-RED): a structured summary of a study protocol for a randomized controlled trial.

Trials 2021 Oct 11;22(1):694. Epub 2021 Oct 11.

Julius Clinical, Zeist, the Netherlands.

Objectives: It is currently thought that most-but not all-individuals infected with SARS-CoV-2 develop symptoms, but the infectious period starts on average 2 days before the first overt symptoms appear. It is estimated that pre- and asymptomatic individuals are responsible for more than half of all transmissions. By detecting infected individuals before they have overt symptoms, wearable devices could potentially and significantly reduce the proportion of transmissions by pre-symptomatic individuals. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests [to determine if there are antibodies against the SARS-CoV-2 in the blood] or SARS-CoV-2 infection tests such as polymerase chain reaction [PCR] or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the following two algorithms to detect first time SARS-CoV-2 infection including early or asymptomatic infection: • The algorithm using Ava bracelet data when coupled with self-reported Daily Symptom Diary data (Wearable + Symptom Data Algo; experimental condition) • The algorithm using self-reported Daily Symptom Diary data alone (Symptom Only Algo; control condition) In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing.

Trial Design: The trial is a randomized, single-blinded, two-period, two-sequence crossover trial. The study will start with an initial learning phase (maximum of 3 months), followed by period 1 (3 months) and period 2 (3 months). Subjects entering the study at the end of the recruitment period may directly start with period 1 and will not be part of the learning phase. Each subject will undergo the experimental condition (the Wearable + Symptom Data Algo) in either period 1 or period 2 and the control condition (Symptom Only Algo) in the other period. The order will be randomly assigned, resulting in subjects being allocated 1:1 to either sequence 1 (experimental condition first) or sequence 2 (control condition first). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence.

Participants: The trial will be conducted in the Netherlands. A target of 20,000 subjects will be enrolled. Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence. This results in approximately 6500 normal-risk individuals and 3500 high-risk individuals per sequence. Subjects will be recruited from previously studied cohorts as well as via public campaigns and social media. All data for this study will be collected remotely through the Ava COVID-RED app, the Ava bracelet, surveys in the COVID-RED web portal and self-sampling serology and PCR kits. More information on the study can be found in www.covid-red.eu . During recruitment, subjects will be invited to visit the COVID-RED web portal. After successfully completing the enrolment questionnaire, meeting eligibility criteria and indicating interest in joining the study, subjects will receive the subject information sheet and informed consent form. Subjects can enrol in COVID-RED if they comply with the following inclusion and exclusion criteria: Inclusion criteria: • Resident of the Netherlands • At least 18 years old • Informed consent provided (electronic) • Willing to adhere to the study procedures described in the protocol • Must have a smartphone that runs at least Android 8.0 or iOS 13.0 operating systems and is active for the duration of the study (in the case of a change of mobile number, the study team should be notified) • Be able to read, understand and write Dutch Exclusion criteria: • Previous positive SARS-CoV-2 test result (confirmed either through PCR/antigen or antibody tests; self-reported) • Current suspected (e.g. waiting for test result) COVID-19 infection or symptoms of a COVID-19 infection (self-reported) • Participating in any other COVID-19 clinical drug, vaccine or medical device trial (self-reported) • Electronic implanted device (such as a pacemaker; self-reported) • Pregnant at the time of informed consent (self-reported) • Suffering from cholinergic urticaria (per the Ava bracelet's user manual; self-reported) • Staff involved in the management or conduct of this study INTERVENTION AND COMPARATOR: All subjects will be instructed to complete the Daily Symptom Diary in the Ava COVID-RED app daily, wear their Ava bracelet each night and synchronize it with the app each day for the entire period of study participation. Provided with wearable sensor and/or self-reported symptom data within the last 24 h, the Ava COVID-RED app's underlying algorithms will provide subjects with a real-time indicator of their overall health and well-being. Subjects will see one of three messages, notifying them that no seeming deviations in symptoms and/or physiological parameters have been detected; some changes in symptoms and/or physiological parameters have been detected and they should self-isolate; or alerting them that deviations in their symptoms and/or physiological parameters could be suggestive of a potential COVID-19 infection and to seek additional testing. We will assess the intraperson performance of the algorithms in the experimental condition (Wearable + Symptom Data Algo) and control conditions (Symptom Only Algo). Note that both algorithms will also instruct to seek testing when any SARS-CoV-2 symptoms are reported in line with those defined by the Dutch national institute for public health and the environment 'Rijksinstituut voor Volksgezondheid en Milieu' (RIVM) guidelines.

Main Outcomes: The trial will evaluate the use and performance of the Ava COVID-RED app and Ava bracelet, which uses sensors to measure breathing rate, pulse rate, skin temperature and heart rate variability for the purpose of early and asymptomatic detection and monitoring of SARS-CoV-2 in general and high-risk populations. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests, PCR tests and/or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each of the following two algorithms to detect first-time SARS-CoV-2 infection including early or asymptomatic infection: the algorithm using Ava bracelet data when coupled with the self-reported Daily Symptom Diary data and the algorithm using self-reported Daily Symptom Diary data alone. In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing. The protocol contains an additional twenty secondary and exploratory objectives which address, among others, infection incidence rates, health resource utilization, symptoms reported by SARS-CoV-2-infected participants and the rate of breakthrough and asymptomatic SARS-CoV-2 infections among individuals vaccinated against COVID-19. PCR or antigen testing will occur when the subject receives a notification from the algorithm to seek additional testing. Subjects will be advised to get tested via the national testing programme and report the testing result in the Ava COVID-RED app and a survey. If they cannot obtain a test via the national testing programme, they will receive a nasal swab self-sampling kit at home, and the sample will be tested by PCR in a trial-affiliated laboratory. In addition, all subjects will be asked to take a capillary blood sample at home at baseline (between month 0 and 3.5 months after the start of subject recruitment), at the end of the learning phase (month 3; note that this sampling moment is skipped if a subject entered the study at the end of the recruitment period), period 1 (month 6) and period 2 (month 9). These samples will be used for SARS-CoV-2-specific antibody testing in a trial-affiliated laboratory, differentiating between antibodies resulting from a natural infection and antibodies resulting from COVID-19 vaccination (as vaccination will gradually be rolled out during the trial period). Baseline samples will only be analysed if the sample collected at the end of the learning phase is positive, or if the subject entered the study at the end of the recruitment period, and samples collected at the end of period 1 will only be analysed if the sample collected at the end of period 2 is positive. When subjects obtain a positive PCR/antigen or serology test result during the study, they will continue to be in the study but will be moved into a so-called COVID-positive mode in the Ava COVID-RED app. This means that they will no longer receive recommendations from the algorithms but can still contribute and track symptom and bracelet data. The primary analysis of the main objective will be executed using the data collected in period 2 (months 6 through 9). Within this period, serology tests (before and after period 2) and PCR/antigen tests (taken based on recommendations by the algorithms) will be used to determine if a subject was infected with SARS-CoV-2 or not. Within this same time period, it will be determined if the algorithms gave any recommendations for testing. The agreement between these quantities will be used to evaluate the performance of the algorithms and how these compare between the study conditions.

Randomization: All eligible subjects will be randomized using a stratified block randomization approach with an allocation ratio of 1:1 to one of two sequences (experimental condition followed by control condition or control condition followed by experimental condition). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence, resulting in approximately equal numbers of high-risk and normal-risk individuals between the sequences.

Blinding (masking): In this study, subjects will be blinded to the study condition and randomization sequence. Relevant study staff and the device manufacturer will be aware of the assigned sequence. The subject will wear the Ava bracelet and complete the Daily Symptom Diary in the Ava COVID-RED app for the full duration of the study, and they will not know if the feedback they receive about their potential infection status will only be based on the data they entered in the Daily Symptom Diary within the Ava COVID-RED app or based on both the data from the Daily Symptom Diary and the Ava bracelet.

Numbers To Be Randomized (sample Size): A total of 20,000 subjects will be recruited and randomized 1:1 to either sequence 1 (experimental condition followed by control condition) or sequence 2 (control condition followed by experimental condition), taking into account their risk level. This results in approximately 6500 normal-risk and 3500 high-risk individuals per sequence.

Trial Status: Protocol version: 3.0, dated May 3, 2021. Start of recruitment: February 19, 2021. End of recruitment: June 3, 2021. End of follow-up (estimated): November 2021 TRIAL REGISTRATION: The Netherlands Trial Register on the 18 of February, 2021 with number NL9320 ( https://www.trialregister.nl/trial/9320 ) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-021-05643-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503725PMC
October 2021

Generalisability of Randomised Controlled Trials in Heart Failure with Reduced Ejection Fraction.

Eur Heart J Qual Care Clin Outcomes 2021 Oct 1. Epub 2021 Oct 1.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Heart failure (HF) trials have stringent in- and ex- clusion criteria, but limited data exists regarding generalisability of trials. We compared patient characteristics and outcomes between patients with HF and reduced ejection fraction (HFrEF) in trials and observational registries.

Methods And Results: Individual patient data for 16922 patients from five randomised clinical trials and 46914 patients from two HF registries were included. The registry patients were categorised into trial-eligible and non-eligible groups using the most commonly used in- and ex-clusion criteria. A total of 26104 (56%) registry patients fulfilled the eligibility criteria. Unadjusted all-cause mortality rates at one year were lowest in the trial population (7%), followed by trial-eligible patients (12%) and trial-non-eligible registry patients (26%). After adjustment for age and sex, all-cause mortality rates were similar between trial participants and trial-eligible registry patients (standardised mortality ratio (SMR) 0.97; 95% confidence interval (CI) 0.92 -1.03) but cardiovascular mortality was higher in trial participants (SMR 1.19; 1.12 -1.27). After full case-mix adjustment, the SMR for cardiovascular mortality remained higher in the trials at 1.28 (1.20- 1.37) compared to RCT-eligible registry patients.

Conclusion: In contemporary HF registries, over half of HFrEF patients would have been eligible for trial enrolment. Crude clinical event rates were lower in the trials, but, after adjustment for case-mix, trial participants had similar rates of survival as registries. Despite this, they had about 30% higher cardiovascular mortality rates. Age and sex were the main drivers of differences in clinical outcomes between HF trials and observational HF registries.
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http://dx.doi.org/10.1093/ehjqcco/qcab070DOI Listing
October 2021

Predictors of impaired pulmonary function in people living with HIV in an urban African setting.

South Afr J HIV Med 2021 17;22(1):1252. Epub 2021 Aug 17.

Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Studies have associated HIV with an increased risk of obstructive lung disease (OLD).

Objectives: We aimed to identify the predictive factors for impaired lung function in an urban, African, HIV-positive population.

Method: A cross-sectional study was performed in Johannesburg, South Africa, from July 2016 to November 2017. A questionnaire was administered and pre- and post-bronchodilator spirometry conducted. The predictors investigated included age, sex, antiretroviral treatment (ART) duration, body mass index, history of tuberculosis (TB) or pneumonia, occupational exposure, environmental exposure, smoking and symptoms of OLD (cough, wheeze, mucus and dyspnoea). Impaired lung function was defined as a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio of < 0.70, or below the 20th percentile of normal.

Results: The 98 ART-naïve participants (mean age = 34.0, standard deviation [s.d.] = 8.2), 85 participants on first-line ART (mean age = 36.9, s.d. = 6.6) and 189 participants on second-line ART (mean age = 43.5, s.d. = 7.9) were predominantly female (65.6%). Of the participants, 64 (17.2%) had impaired lung function and 308 had normal lung function. Linear regression identified age (β = -0.003, < 0.01), male sex (β = -0.016, = 0.03) and history of TB or pneumonia (β = -0.024, < 0.01) as independent predictors of a lower FEV1/FVC ratio. Following logistic regression, only a history of TB or pneumonia (odds ratio = 2.58, 95% confidence interval = 1.47-4.52) was significantly related to impaired lung function (area under the receiver operating characteristic curve = 0.64).

Conclusion: Our data show that a history of TB or pneumonia predicts impaired lung function. In order to improve timely access to spirometry, clinicians should be alert to the possibility of impaired lung function in people with a history of TB or pneumonia.
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http://dx.doi.org/10.4102/sajhivmed.v22i1.1252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424741PMC
August 2021

Alcohol consumption in relation to cardiovascular diseases and mortality: a systematic review of Mendelian randomization studies.

Eur J Epidemiol 2021 Aug 22. Epub 2021 Aug 22.

UMC Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht University, Utrecht, The Netherlands.

The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.
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http://dx.doi.org/10.1007/s10654-021-00799-5DOI Listing
August 2021

Patterns of Immune Activation in HIV and Non HIV Subjects and Its Relation to Cardiovascular Disease Risk.

Front Immunol 2021 5;12:647805. Epub 2021 Jul 5.

Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Introduction: Insight into inflammation patterns is needed to understand the pathophysiology of HIV and related cardiovascular disease (CVD). We assessed patterns of inflammation related to HIV infection and CVD risk assessed with carotid intima media thickness (CIMT).

Methods: A cross-sectional study was performed in Johannesburg, South Africa, including participants with HIV who were virally suppressed on anti-retroviral therapy (ART) as well as HIV-negative participants who were family members or friends to the HIV-positive participants. Information was collected on CVD risk factors and CIMT. Inflammation was measured with the Olink panel 'inflammation', allowing to simultaneously assess 92 inflammation markers. Differences in inflammation patterns between HIV-positive and HIV-negative participants were explored using a principal component analysis (PCA) and ANCOVA. The impact of differentiating immune markers, as identified by ANCOVA, on CIMT was assessed using linear regression while adjusting for classic CVD risk factors.

Results: In total, 185 HIV-positive and 104 HIV negative participants, 63% females, median age 40.7 years (IQR 35.4 - 47.7) were included. HIV-positive individuals were older (+6 years, p <0.01) and had a higher CIMT (p <0.01). No clear patterns of inflammation were identified by use of PCA. Following ANCOVA, nine immune markers differed significantly between HIV-positive and HIV-negative participants, including PDL1. PDL1 was independently associated with CIMT, but upon stratification this effect remained for HIV-negative individuals only.

Conclusion: HIV positive patients on stable ART and HIV negative controls had similar immune activation patterns. CVD risk in HIV-positive participants was mediated by inflammation markers included in this study.
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http://dx.doi.org/10.3389/fimmu.2021.647805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287326PMC
October 2021

A comparison of associations with childhood lung function between air pollution exposure assessment methods with and without accounting for time-activity patterns.

Environ Res 2021 11 16;202:111710. Epub 2021 Jul 16.

Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, the Netherlands.

Background: To investigate associations between annual average air pollution exposures and health, most epidemiological studies rely on estimated residential exposures because information on actual time-activity patterns can only be collected for small populations and short periods of time due to costs and logistic constraints. In the current study, we aim to compare exposure assessment methodologies that use data on time-activity patterns of children with residence-based exposure assessment. We compare estimated exposures and associations with lung function for residential exposures and exposures accounting for time activity patterns.

Methods: We compared four annual average air pollution exposure assessment methodologies; two rely on residential exposures only, the other two incorporate estimated time activity patterns. The time-activity patterns were based on assumptions about the activity space and make use of available external data sources for the duration of each activity. Mapping of multiple air pollutants (NO, NO, PM, PMabsorbance, PM) at a fine resolution as input to exposure assessment was based on land use regression modelling. First, we assessed the correlations between the exposures from the four exposure methods. Second, we compared estimates of the cross-sectional associations between air pollution exposures and lung function at age 8 within the PIAMA birth cohort study for the four exposure assessment methodologies.

Results: The exposures derived from the four exposure assessment methodologies were highly correlated (R > 0.95) for all air pollutants. Similar statistically significant decreases in lung function were found for all four methods. For example, for NO the decrease in FEV was -1.40% (CI; -2.54, -0.24%) per IQR (9.14 μg/m) for front door exposure, and -1.50% (CI; -2.68, -0.30%) for the methodology which incorporates time activity pattern and actual school addresses.

Conclusions: Exposure estimates from methods based on the residential location only and methods including time activity patterns were highly correlated and associated with similar decreases in lung function. Our study illustrates that the annual average exposure to air pollution for 8-year-old children in the Netherlands is sufficiently captured by residential exposures.
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http://dx.doi.org/10.1016/j.envres.2021.111710DOI Listing
November 2021

Polygenic risk scores predict diabetes complications and their response to intensive blood pressure and glucose control.

Diabetologia 2021 Sep 6;64(9):2012-2025. Epub 2021 Jul 6.

Ontario Institute for Cancer Research, Toronto, ON, Canada.

Aims/hypothesis: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk.

Methods: We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study.

Results: The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10 and p = 9.6 × 10, respectively) and a 4.4-fold (p = 6.8 × 10) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years.

Conclusions/interpretation: This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy.
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http://dx.doi.org/10.1007/s00125-021-05491-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382653PMC
September 2021

A prospective, randomized, single-blinded, crossover trial to investigate the effect of a wearable device in addition to a daily symptom diary for the remote early detection of SARS-CoV-2 infections (COVID-RED): a structured summary of a study protocol for a randomized controlled trial.

Trials 2021 Jun 22;22(1):412. Epub 2021 Jun 22.

Julius Clinical, Zeist, the Netherlands.

Objectives: It is currently thought that most-but not all-individuals infected with SARS-CoV-2 develop symptoms, but that the infectious period starts on average two days before the first overt symptoms appear. It is estimated that pre- and asymptomatic individuals are responsible for more than half of all transmissions. By detecting infected individuals before they have overt symptoms, wearable devices could potentially and significantly reduce the proportion of transmissions by pre-symptomatic individuals. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests [to determine if there are antibodies against the SARS-CoV-2 in the blood] or SARS-CoV-2 infection tests such as polymerase chain reaction [PCR] or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the following two algorithms to detect first time SARS-CoV-2 infection including early or asymptomatic infection: the algorithm using Ava bracelet data when coupled with self-reported Daily Symptom Diary data (Wearable + Symptom Data Algo; experimental condition) the algorithm using self-reported Daily Symptom Diary data alone (Symptom Only Algo; control condition) In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing.

Trial Design: The trial is a randomized, single-blinded, two-period, two-sequence crossover trial. All subjects will participate in an initial Learning Phase (varying from 2 weeks to 3 months depending on enrolment date), followed by two contiguous 3-month test phases, Period 1 and Period 2. Each subject will undergo the experimental condition (the Wearable + Symptom Data Algo) in one of these periods and the control condition (Symptom Only Algo) in the other period. The order will be randomly assigned, resulting in subjects being allocated 1:1 to either Sequence 1 (experimental condition first) or Sequence 2 (control condition first). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence.

Participants: The trial will be conducted in the Netherlands. A target of 20,000 subjects will be enrolled. Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence. This results in approximately 6,500 normal-risk individuals and 3,500 high-risk individuals per sequence. Subjects will be recruited from previously studied cohorts as well as via public campaigns and social media. All data for this study will be collected remotely through the Ava COVID-RED app, the Ava bracelet, surveys in the COVID-RED web portal, and self-sampling serology and PCR kits. During recruitment, subjects will be invited to visit the COVID-RED web portal ( www.covid-red.eu ). After successfully completing the enrolment questionnaire, meeting eligibility criteria and indicating interest in joining the study, subjects will receive the subject information sheet and informed consent form. Subjects can enrol in COVID-RED if they comply with the following inclusion and exclusion criteria.

Inclusion Criteria: Resident of the Netherlands At least 18 years old Informed consent provided (electronic) Willing to adhere to the study procedures described in the protocol Must have a smartphone that runs at least Android 8.0 or iOS 13.0 operating systems and is active for the duration of the study (in the case of a change of mobile number, study team should be notified) Be able to read, understand and write Dutch Exclusion criteria: Previous positive SARS-CoV-2 test result (confirmed either through PCR/antigen or antibody tests; self-reported) Previously received a vaccine developed specifically for COVID-19 or in possession of an appointment for vaccination in the near future (self-reported) Current suspected (e.g., waiting for test result) COVID-19 infection or symptoms of a COVID-19 infection (self-reported) Participating in any other COVID-19 clinical drug, vaccine, or medical device trial (self-reported) Electronic implanted device (such as a pacemaker; self-reported) Pregnant at time of informed consent (self-reported) Suffering from cholinergic urticaria (per the Ava bracelet's User Manual; self-reported) Staff involved in the management or conduct of this study INTERVENTION AND COMPARATOR: All subjects will be instructed to complete the Daily Symptom Diary in the Ava COVID-RED app daily, wear their Ava bracelet each night and synchronise it with the app each day for the entire period of study participation. Provided with wearable sensor and/or self-reported symptom data within the last 24 hours, the Ava COVID-RED app's underlying algorithms will provide subjects with a real-time indicator of their overall health and well-being. Subjects will see one of three messages, notifying them that: no seeming deviations in symptoms and/or physiological parameters have been detected; some changes in symptoms and/or physiological parameters have been detected and they should self-isolate; or alerting them that deviations in their symptoms and/or physiological parameters could be suggestive of a potential COVID-19 infection and to seek additional testing. We will assess intraperson performance of the algorithms in the experimental condition (Wearable + Symptom Data Algo) and control conditions (Symptom Only Algo).

Main Outcomes: The trial will evaluate the use and performance of the Ava COVID-RED app and Ava bracelet, which uses sensors to measure breathing rate, pulse rate, skin temperature, and heart rate variability for the purpose of early and asymptomatic detection and monitoring of SARS-CoV-2 in general and high-risk populations. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests, PCR tests and/or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each of the following two algorithms to detect first-time SARS-CoV-2 infection including early or asymptomatic infection: the algorithm using Ava Bracelet data when coupled with the self-reported Daily Symptom Diary data, and the algorithm using self-reported Daily Symptom Diary data alone. In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing. The protocol contains an additional seventeen secondary outcomes which address infection incidence rates, health resource utilization, symptoms reported by SARS-CoV-2 infected participants, and the rate of breakthrough and asymptomatic SARS-CoV-2 infections among individuals vaccinated against COVID-19. PCR or antigen testing will occur when the subject receives a notification from the algorithm to seek additional testing. Subjects will be advised to get tested via the national testing programme, and report the testing result in the Ava COVID-RED app and a survey. If they cannot obtain a test via the national testing programme, they will receive a nasal swab self-sampling kit at home, and the sample will be tested by PCR in a trial-affiliated laboratory. In addition, all subjects will be asked to take a capillary blood sample at home at baseline (Month 0), and at the end of the Learning Phase (Month 3), Period 1 (Month 6) and Period 2 (Month 9). These samples will be used for SARS-CoV-2-specific antibody testing in a trial-affiliated laboratory, differentiating between antibodies resulting from a natural infection and antibodies resulting from COVID-19 vaccination (as vaccination will gradually be rolled out during the trial period). Baseline samples will only be analysed if the sample collected at the end of the Learning Phase is positive, and samples collected at the end of Period 1 will only be analysed if the sample collected at the end of Period 2 is positive. When subjects obtain a positive PCR/antigen or serology test result during the study, they will continue to be in the study but will be moved into a so-called "COVID-positive" mode in the Ava COVID-RED app. This means that they will no longer receive recommendations from the algorithms but can still contribute and track symptom and bracelet data. The primary analysis of the main objective will be executed using data collected in Period 2 (Month 6 through 9). Within this period, serology tests (before and after Period 2) and PCR/antigen tests (taken based on recommendations by the algorithms) will be used to determine if a subject was infected with SARS-CoV-2 or not. Within this same time period, it will be determined if the algorithms gave any recommendations for testing. The agreement between these quantities will be used to evaluate the performance of the algorithms and how these compare between the study conditions.

Randomisation: All eligible subjects will be randomized using a stratified block randomization approach with an allocation ratio of 1:1 to one of two sequences (experimental condition followed by control condition or control condition followed by experimental condition). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence, resulting in equal numbers of high-risk and normal-risk individuals between the sequences.

Blinding (masking): In this study, subjects will be blinded as to study condition and randomization sequence. Relevant study staff and the device manufacturer will be aware of the assigned sequence. The subject will wear the Ava bracelet and complete the Daily Symptom Diary in the Ava COVID-RED app for the full duration of the study, and they will not know if the feedback they receive about their potential infection status will only be based on data they entered in the Daily Symptom Diary within the Ava COVID-RED app or based on both the data from the Daily Symptom Diary and the Ava bracelet.

Numbers To Be Randomised (sample Size): 20,000 subjects will be recruited and randomized 1:1 to either Sequence 1 (experimental condition followed by control condition) or Sequence 2 (control condition followed by experimental condition), taking into account their risk level. This results in approximately 6,500 normal-risk and 3,500 high-risk individuals per sequence.

Trial Status: Protocol version: 1.2, dated January 22, 2021 Start of recruitment: February 22, 2021 End of recruitment (estimated): April 2021 End of follow-up (estimated): December 2021 TRIAL REGISTRATION: The trial has been registered at the Netherlands Trial Register on the 18 of February, 2021 with number NL9320 ( https://www.trialregister.nl/trial/9320 ) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-021-05241-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218271PMC
June 2021

Prevalence and determinants of chronic kidney disease in women with hypertensive disorders in pregnancy in Nigeria: a cohort study.

BMC Nephrol 2021 06 18;22(1):229. Epub 2021 Jun 18.

Population Council, Washington DC, USA.

Background: Worldwide, hypertensive disorders in pregnancy (HDPs) complicate between 5 and 10% of pregnancies. Sub-Saharan Africa (SSA) is disproportionately affected by a high burden of HDPs and chronic kidney disease (CKD). Despite mounting evidence associating HDPs with the development of CKD, data from SSA are scarce.

Methods: Women with HDPs (n = 410) and normotensive women (n = 78) were recruited at delivery and prospectively followed-up at 9 weeks, 6 months and 1 year postpartum. Serum creatinine was measured at all time points and the estimated glomerular filtration rates (eGFR) using CKD-Epidemiology equation determined. CKD was defined as decreased eGFR< 60 mL/min/1.73m lasting for ≥ 3 months. Prevalence of CKD at 6 months and 1 year after delivery was estimated. Logistic regression analyses were conducted to evaluate risk factors for CKD at 6 months and 1 year postpartum.

Results: Within 24 h of delivery, 9 weeks, and 6 months postpartum, women with HDPs were more likely to have a decreased eGFR compared to normotensive women (12, 5.7, 4.3% versus 0, 2 and 2.4%, respectively). The prevalence of CKD in HDPs at 6 months and 1 year postpartum was 6.1 and 7.6%, respectively, as opposed to zero prevalence in the normotensive women for the corresponding periods. Proportions of decreased eGFR varied with HDP sub-types and intervening postpartum time since delivery, with pre-eclampsia/eclampsia showing higher prevalence than chronic and gestational hypertension. Only maternal age was independently shown to be a risk factor for decreased eGFR at 6 months postpartum (aOR = 1.18/year; 95%CI 1.04-1.34).

Conclusion: Prior HDP was associated with risk of future CKD, with prior HDPs being more likely to experience evidence of CKD over periods of postpartum follow-up. Routine screening of women following HDP-complicated pregnancies should be part of a postpartum monitoring program to identify women at higher risk. Future research should report on both the eGFR and total urinary albumin excretion to enable detection of women at risk of future deterioration of renal function.
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http://dx.doi.org/10.1186/s12882-021-02419-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212529PMC
June 2021

Metabolic syndrome following hypertensive disorders in pregnancy in a low-resource setting: A cohort study.

Pregnancy Hypertens 2021 Aug 4;25:129-135. Epub 2021 Jun 4.

Julius Global Health, Julius Center for Health Science and Primary Care, UMC Utrecht, Utrecht University, the Netherlands.

Objectives: Hypertensive disorders in pregnancy (HDPs) are associated with risk of future metabolic syndrome. Despite the huge burden of HDPs in sub-Saharan Africa, this association has not been adequately studied in this population.

Study Design: This was a prospective cohort study on pregnant women recruited between August 2017 - April 2018 and followed up to one year after their deliveries and evaluated for presence of metabolic syndrome at delivery, nine weeks, six months and one year.

Main Outcome Measures: Prevalence of metabolic syndrome RESULTS: A total of 488 pregnant women were included: 410 and 78 with HDPs and normotensive, respectively. None of the normotensive had metabolic syndrome until one year (1.7% = 1 out of 59 observations), while among those with HDPs were 17.4% (71 of 407), 8.7% (23 of 263), 4.7% (11 of 232) and 6.1% (17 of 278), at delivery, nine weeks, six months and one year postpartum, respectively. High BMI and blood pressure were the drivers of metabolic syndrome in this population. The incidence rate in HDPs versus normotensive at one year were, respectively, 57.5/1000 persons' year (95%CI; 35.8 - 92.6) and 16.9/1000 persons' years (95%CI; 2.4-118.3), with incidence rate ratio of 3.4/1000 person's years. Only parity significantly predicted the presence of metabolic syndrome at one year [(aOR= 3.26/delivery (95%CI; 1.21-8.79)].

Conclusion: HDPs were associated with a higher incidence of metabolic syndrome up to one year postpartum. Women with HDPs should be routinely screened for metabolic syndrome within the first year postpartum to reduce cardiometabolic risks.
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http://dx.doi.org/10.1016/j.preghy.2021.05.018DOI Listing
August 2021

Early health economic analysis of 1.5 T MRI-guided radiotherapy for localized prostate cancer: Decision analytic modelling.

Radiother Oncol 2021 08 3;161:74-82. Epub 2021 Jun 3.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands.

Background And Purpose: 1.5 Tesla magnetic resonance imaging radiotherapy linear accelerator (MR-Linac) is gaining interest for treatment of localized prostate cancer. Clinical evidence is lacking and it therefore remains uncertain whether MR-Linac is cost-effective. An early health economic analysis was performed to calculate the necessary relative reduction in complications and the maximum price of MR-Linac (5 fractions) to be cost-effective compared to 5, 20 and 39 fractionation schedules of external beam radiotherapy (EBRT) and low-dose-rate (LDR) brachytherapy.

Materials And Methods: A state transition model was developed for men with localized prostate cancer. Complication rates such as grade ≥2 urinary, grade ≥2 bowel and sexual complications, and utilities were based on systematic literature searches. Costs were estimated from a Dutch healthcare perspective. Threshold analyses were performed to identify the thresholds of complications and costs for MR-Linac to be cost-effective, while holding other outcomes such as biochemical progression and mortality constant. One-way sensitivity analyses were performed to outline uncertainty outcomes.

Results: At €6460 per patient, no reductions in complications were needed to consider MR-Linac cost-effective compared to EBRT 20 and 39 fractions. Compared to EBRT 5 fractions and LDR brachytherapy, MR-Linac was found to be cost-effective when complications are relatively reduced by 54% and 66% respectively. Results are highly sensitive to the utilities of urinary, bowel and sexual complications and the probability of biochemical progression.

Conclusions: MR-Linac is found to be cost-effective compared to 20 and 39 fractions EBRT at baseline. For MR-Linac to become cost-effective over 5 fractions EBRT and LDR brachytherapy, it has to reduce complications substantially or be offered at lower costs.
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http://dx.doi.org/10.1016/j.radonc.2021.05.022DOI Listing
August 2021

Erratum: Unexpected low frequency of respiratory symptoms in an HIV-positive urban sub-Saharan population compared to an HIV-negative control group.

South Afr J HIV Med 2021 19;22(1):1180. Epub 2021 Apr 19.

Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

[This corrects the article DOI: 10.4102/sajhivmed.v20i1.1010.].
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http://dx.doi.org/10.4102/sajhivmed.v22i1.1180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063566PMC
April 2021

Adiposity Phenotypes and Subclinical Atherosclerosis in Adults from Sub-Saharan Africa: An H3Africa AWI-Gen Study.

Glob Heart 2021 03 19;16(1):19. Epub 2021 Mar 19.

Department of Chemical Pathology, National Health Laboratory Service, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, ZA.

Background: Obesity and adipose tissue distribution contribute to an increased risk of cardiovascular disease (CVD) by promoting atherosclerosis. This association has been poorly studied in sub-Saharan Africa (SSA) despite the rising prevalence of cardiovascular disease.

Objectives: We determined the association between various adiposity phenotypes and carotid intima-media thickness (CIMT), a proxy of subclinical atherosclerosis, in a large SSA population.

Methods: A population-based cross-sectional study was performed from 2013-2016 in Burkina Faso, Ghana, Kenya and South Africa. Body mass index (BMI), waist (WC), hip circumferences (HC), visceral (VAT) and subcutaneous adipose tissue (SCAT) using B-mode ultrasound were measured. Ultrasonography of left and right far wall CIMT of the common carotid artery was used as an indicator of subclinical atherosclerosis. Individual participant data meta-analyses were used to determine the associations between adiposity phenotypes and CIMT in the pooled sample while adjusted multivariable linear regression analyses were used for site specific analyses.

Results: Data were obtained from 9,010 adults (50.3% women and a mean age of 50± 6years). Men had higher levels of visceral fat than women while women had higher BMI, waist and hip circumference and subcutaneous fat than men at all sites except Burkina Faso. In the pooled analyses, BMI (β-value [95% CIs]: 19.5 [16.8, 22.3] μm) showed the strongest relationship with CIMT followed by VAT (5.86 [4.65, 7.07] μm), SCAT (5.00 [2.85, 7.15] μm), WC (1.27 [1.09, 1.44] μm) and HC (1.23 [1.04, 1.42] μm). Stronger associations were observed in men than in women.

Conclusion: Obesity within SSA will likely result in higher levels of atherosclerosis and promote the occurrence of cardio- and cerebrovascular events, especially in males, unless addressed through primary prevention of obesity in both rural and urban communities across Africa. The inverse association of VAT with CIMT in Burkina Faso and Ghana requires further investigation.

Highlights: All adiposity phenotypes were positively associated with common carotid intima-media thickness (CIMT) in the entire cohort (pooled analyses).BMI had the strongest association with CIMT compared to other phenotypes.The magnitude of association between adiposity phenotypes and CIMT was higher in men than in women.Subcutaneous adipose tissue was inversely associated with CIMT only in women.An unexpected finding was the inverse association of visceral adipose tissue with CIMT in Burkina Faso and Ghana.
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http://dx.doi.org/10.5334/gh.863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977036PMC
March 2021

EAPC Core Curriculum for Preventive Cardiology.

Eur J Prev Cardiol 2021 04 1. Epub 2021 Apr 1.

Department of Prevention and Sports Medicine, University Hospital rechts der Isar, Technical University Munich, German Centre for Cardiovascular Research, Georg-Brauchle-Ring 56, 80992 Munich, Germany.

Preventive cardiology encompasses the whole spectrum of cardiovascular disease (CVD) prevention, at individual and population level, through all stages of life. This includes promotion of cardiovascular (CV) health, management of individuals at risk of developing CVD, and management of patients with established CVD, through interdisciplinary care in different settings. Preventive cardiology addresses all aspects of CV health in the context of the social determinants of health, including physical activity, exercise, sports, nutrition, weight management, smoking cessation, psychosocial factors and behavioural change, environmental, genetic and biological risk factors, and CV protective medications. This is the first European Core Curriculum for Preventive Cardiology, which will help to standardize, structure, deliver, and evaluate training in preventive cardiology across Europe. It will be the basis for dedicated fellowship programmes and a European Society of Preventive Cardiology (EAPC) subspecialty certification for cardiologists, with the intention to improve quality and outcome in CVD prevention.
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http://dx.doi.org/10.1093/eurjpc/zwab017DOI Listing
April 2021

Diagnostic performance and clinical implications for enhancing a hybrid quantitative flow ratio-FFR revascularization decision-making strategy.

Sci Rep 2021 03 19;11(1):6425. Epub 2021 Mar 19.

Department of Cardiology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.

Invasive fractional flow reserve (FFR) adoption remains low mainly due to procedural and operator related factors as well as costs. Alternatively, quantitative flow ratio (QFR) achieves a high accuracy mainly outside the intermediate zone without the need for hyperaemia and wire-use. We aimed to determine the diagnostic performance of QFR and to evaluate a QFR-FFR hybrid strategy in which FFR is measured only in the intermediate zone. This retrospective study included 289 consecutive patients who underwent invasive coronary angiography and FFR. QFR was calculated for all vessels in which FFR was measured. The QFR-FFR hybrid approach was modelled using the intermediate zone of 0.77-0.87 in which FFR-measurements are recommended. The sensitivity, specificity, and accuracy on a per vessel-based analysis were 84.6%, 86.3% and 85.6% for QFR and 88.0%, 92.9% and 90.3% for the QFR-FFR hybrid approach. The diagnostic accuracy of QFR-FFR hybrid strategy with invasive FFR measurement was 93.4% and resulted in a 56.7% reduction in the need for FFR. QFR has a good correlation and agreement with invasive FFR. A hybrid QFR-FFR approach could extend the use of QFR and reduces the proportion of invasive FFR-measurements needed while improving accuracy.
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http://dx.doi.org/10.1038/s41598-021-85933-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979768PMC
March 2021

Adherence to Drinking Guidelines and Reasons for Alcohol Consumption Cessation in the Southern Cone of Latin America - Findings from the CESCAS Study.

Glob Heart 2021 01 4;16(1). Epub 2021 Jan 4.

Instituto de Efectividad Clínica y Sanitaria, Buenos Aires, AR.

Introduction: Alcohol consumption is a risk factor for morbidity and mortality globally. Consumption levels in Southern Latin America are among the highest in the world.

Objectives: To describe consumption patterns and adherence to guidelines in the general adult population of Southern Latin America, as well as exploration of reasons for alcohol cessation and the advising role of the health worker in this decision.

Methods: In 7,520 participants from the Centro de Excelencia en Salud Cardiovascular para el America del Sur (CESCAS) cohort, consumption patterns were described and the proportion excessive drinkers (i.e. >7 units/week for women and >14 for men or binge drinking: >4 (women) or >5 (men) units at a single occasion) was calculated. Former drinkers were asked if they had quit alcohol consumption on the advice of a health worker and/or because of health reasons. Furthermore, among former drinkers, multivariable logistic regression analysis was performed to assess which participant characteristics were independently associated with the chance of quitting consumption on a health worker's advice.

Results: Mean age was 54.8 years (SD = 10.8), 42% was male. Current drinking was reported by 44.6%, excessive drinking by 8.5% of the population. In former drinkers, 23% had quit alcohol consumption because of health reasons, half of them had additionally quit on the advice of a health worker. The majority of former drinkers however had other, unknown, reasons. When alcohol cessation was based on a health worker's advice, sex, country of residence, educational status and frequency of visiting a physician were independent predictors.

Conclusion: In this Southern American population-based sample, most participants adhered to the alcohol consumption guidelines. The advising role of the health worker in quitting alcohol consumption was only modest and the motivation for the majority of former drinkers remains unknown. A more detailed assessment of actual advice rates and exploration of additional reasons for alcohol cessation might be valuable for alcohol policy making.
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http://dx.doi.org/10.5334/gh.840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792452PMC
January 2021

Poor cardiovascular health is associated with subclinical atherosclerosis in apparently healthy sub-Saharan African populations: an H3Africa AWI-Gen study.

BMC Med 2021 02 10;19(1):30. Epub 2021 Feb 10.

Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: The cardiovascular health index (CVHI) introduced by the American Heart Association is a valid, accessible, simple, and translatable metric for monitoring cardiovascular health in a population. Components of the CVHI include the following seven cardiovascular risk factors (often captured as life's simple 7): smoking, dietary intake, physical activity, body mass index, blood pressure, glucose, and total cholesterol. We sought to expand the evidence for its utility to under-studied populations in sub-Saharan Africa, by determining its association with common carotid intima-media thickness (CIMT).

Methods: We conducted a cross-sectional study involving 9011 participants drawn from Burkina Faso, Ghana, Kenya, and South Africa. We assessed established classical cardiovascular risk factors and measured carotid intima-media thickness of the left and right common carotid arteries using B-mode ultrasonography. Adjusted multilevel mixed-effect linear regression was used to determine the association of CVHI with common CIMT. In the combined population, an individual participant data meta-analyses random-effects was used to conduct pooled comparative sub-group analyses for differences between countries, sex, and socio-economic status.

Results: The mean age of the study population was 51 ± 7 years and 51% were women, with a mean common CIMT of 637 ± 117 μm and CVHI score of 10.3 ± 2.0. Inverse associations were found between CVHI and common CIMT (β-coefficients [95% confidence interval]: Burkina Faso, - 6.51 [- 9.83, - 3.20] μm; Ghana, - 5.42 [- 8.90, - 1.95]; Kenya, - 6.58 [- 9.05, - 4.10]; and South Africa, - 7.85 [- 9.65, - 6.05]). Inverse relations were observed for women (- 4.44 [- 6.23, - 2.65]) and men (- 6.27 [- 7.91, - 4.64]) in the pooled sample. Smoking (p < 0.001), physical activity (p < 0.001), and hyperglycemia (p < 0.001) were related to CIMT in women only, while blood pressure and obesity were related to CIMT in both women and men (p < 0.001).

Conclusion: This large pan-African population study demonstrates that CVHI is a strong marker of subclinical atherosclerosis, measured by common CIMT and importantly demonstrates that primary prevention of atherosclerotic cardiovascular disease in this understudied population should target physical activity, smoking, obesity, hypertension, and hyperglycemia.
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http://dx.doi.org/10.1186/s12916-021-01909-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874493PMC
February 2021

Electrocardiographic and echocardiographic abnormalities in urban African people living with HIV in South Africa.

PLoS One 2021 2;16(2):e0244742. Epub 2021 Feb 2.

Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Studies from high income countries report that HIV-positive people have an impaired systolic and diastolic cardiac function compared to HIV-negative people. It is unclear if results can be translated directly to the Sub-Saharan Africa context. This study assesses electro- and echocardiographic characteristics in an urban African population, comparing HIV-positive people (treated and not yet treated) with HIV-negative controls.

Methods: We conducted a cross-sectional study in Johannesburg, South Africa. We enrolled HIV-positive participants from three randomized controlled trials that had recruited participants from routine HIV testing programs. HIV-negative controls were recruited from the community. Data were collected on demographics, cardiovascular risk factors, medical history and electrocardiographic and echocardiographic characteristics.

Results: In total, 394 HIV-positive participants and 153 controls were enrolled. The mean age of HIV-positive participants was 40±9 years (controls: 35±10 years), and 34% were male (controls: 50%). Of HIV-positive participants 36% were overweight or obese (controls: 44%), 23% had hypertension (controls: 28%) and 12% were current smoker (controls: 37%). Median time since HIV diagnosis was 6.0 years (IQR 2.3-10.0) and median treatment duration was 4.0 years (IQR 0.0-8.0), 50% had undetectable viral load. The frequency of anatomical cardiac abnormalities was low and did not differ between people with and without HIV. We observed no relation between HIV or anti-retroviral therapy (ART) and systolic or diastolic heart function. There was an association between ART use and corrected QT interval: +11.8 ms compared to HIV-negative controls (p<0.01) and +18.9 ms compared to ART-naïve participants (p = 0.01). We also observed a higher left ventricular mass index in participants on ART (+7.8 g/m2, p<0.01), but this association disappeared after adjusting for CD4 cell count, viral load and HIV-duration.

Conclusion: The low number of major cardiac abnormalities in this relatively young, well managed urban African HIV-positive population is reassuring. The increase in corrected QT interval and left ventricular mass may contribute to higher cardiac mortality and morbidity in people living with HIV in the long term.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244742PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853516PMC
July 2021

Associations between the built environment and obesity: an umbrella review.

Int J Health Geogr 2021 02 1;20(1). Epub 2021 Feb 1.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht & Utrecht University, Utrecht, the Netherlands.

Background: In the past two decades, the built environment emerged as a conceptually important determinant of obesity. As a result, an abundance of studies aiming to link environmental characteristics to weight-related outcomes have been published, and multiple reviews have attempted to summarise these studies under different scopes and domains. We set out to summarise the accumulated evidence across domains by conducting a review of systematic reviews on associations between any aspect of the built environment and overweight or obesity.

Methods: Seven databases were searched for eligible publications from the year 2000 onwards. We included systematic literature reviews, meta-analyses and pooled analyses of observational studies in the form of cross-sectional, case-control, longitudinal cohort, ecological, descriptive, intervention studies and natural experiments. We assessed risk of bias and summarised results structured by built environmental themes such as food environment, physical activity environment, urban-rural disparity, socioeconomic status and air pollution.

Results: From 1850 initial hits, 32 systematic reviews were included, most of which reported equivocal evidence for associations. For food- and physical activity environments, associations were generally very small or absent, although some characteristics within these domains were consistently associated with weight status such as fast-food exposure, urbanisation, land use mix and urban sprawl. Risks of bias were predominantly high.

Conclusions: Thus far, while most studies have not been able to confirm the assumed influence of built environments on weight, there is evidence for some obesogenic environmental characteristics. Registration: This umbrella review was registered on PROSPERO under ID CRD42019135857.
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http://dx.doi.org/10.1186/s12942-021-00260-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852132PMC
February 2021

Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance.

Am Heart J 2021 05 24;235:104-112. Epub 2020 Oct 24.

Department of Cardiovascular Medicine, Cleveland Clinic and Cleveland Clinic Coordinating Center for Clinical Research.

Although statins play a pivotal role in the prevention of atherosclerotic cardiovascular disease, many patients fail to achieve recommended lipid levels due to statin-associated muscle symptoms. Bempedoic acid is an oral pro-drug that is activated in the liver and inhibits cholesterol synthesis in hepatocytes, but is not activated in skeletal muscle which has the potential to avoid muscle-related adverse events. Accordingly, this agent effectively lowers atherogenic lipoproteins in patients who experience statin-associated muscle symptoms. However, the effects of bempedoic acid on cardiovascular morbidity and mortality have not been studied. STUDY DESIGN: Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes is a randomized, double-blind, placebo-controlled clinical trial. Included patients must have all of the following: (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease, (ii) documented statin intolerance, and (iii) an LDL-C ≥100 mg/dL on maximally-tolerated lipid-lowering therapy. The study randomized 14,014 patients to treatment with bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy. The primary outcome is a composite of the time to first cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The trial will continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and minimum treatment duration of 36 months and a projected median treatment exposure of 42 months. CONCLUSIONS: CLEAR Outcomes will determine whether bempedoic acid 180 mg daily reduces the incidence of adverse cardiovascular events in high vascular risk patients with documented statin intolerance and elevated LDL-C levels.
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http://dx.doi.org/10.1016/j.ahj.2020.10.060DOI Listing
May 2021

Insights into therapeutic products, preclinical research models, and clinical trials in cardiac regenerative and reparative medicine: where are we now and the way ahead. Current opinion paper of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine.

Cardiovasc Res 2021 05;117(6):1428-1433

Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Doctor Esquerdo 46, 28007 Madrid, Spain.

Great expectations have been set around the clinical potential of regenerative and reparative medicine in the treatment of cardiovascular diseases [i.e. in particular, heart failure (HF)]. Initial excitement, spurred by encouraging preclinical data, resulted in a rapid translation into clinical research. The sobering outcome of the resulting clinical trials suggests that preclinical testing may have been insufficient to predict clinical outcome. A number of barriers for clinical translation include the inherent variability of the biological products and difficulties to develop potency and quality assays, insufficient rigour of the preclinical research and reproducibility of the results, manufacturing challenges, and scientific irregularities reported in the last years. The failure to achieve clinical success led to an increased scrutiny and scepticism as to the clinical readiness of stem cells and gene therapy products among clinicians, industry stakeholders, and funding bodies. The present impasse has attracted the attention of some of the most active research groups in the field, which were then summoned to analyse the position of the field and tasked to develop a strategy, to re-visit the undoubtedly promising future of cardiovascular regenerative and reparative medicine, based on lessons learned over the past two decades. During the scientific retreat of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine (CARE) in November 2018, the most relevant and timely research aspects in regenerative and/or reparative medicine were presented and critically discussed, with the aim to lay out a strategy for the future development of the field. We report herein the main ideas and conclusions of that meeting.
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http://dx.doi.org/10.1093/cvr/cvaa337DOI Listing
May 2021

Text-mining in electronic healthcare records can be used as efficient tool for screening and data collection in cardiovascular trials: a multicenter validation study.

J Clin Epidemiol 2021 04 25;132:97-105. Epub 2020 Nov 25.

Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Cardiology, Meander Medical Center, Amersfoort, the Netherlands; Dutch Network for Cardiovascular Research (WCN), Utrecht, the Netherlands.

Objective: This study aimed to validate trial patient eligibility screening and baseline data collection using text-mining in electronic healthcare records (EHRs), comparing the results to those of an international trial.

Study Design And Setting: In three medical centers with different EHR vendors, EHR-based text-mining was used to automatically screen patients for trial eligibility and extract baseline data on nineteen characteristics. First, the yield of screening with automated EHR text-mining search was compared with manual screening by research personnel. Second, the accuracy of extracted baseline data by EHR text mining was compared to manual data entry by research personnel.

Results: Of the 92,466 patients visiting the out-patient cardiology departments, 568 (0.6%) were enrolled in the trial during its recruitment period using manual screening methods. Automated EHR data screening of all patients showed that the number of patients needed to screen could be reduced by 73,863 (79.9%). The remaining 18,603 (20.1%) contained 458 of the actual participants (82.4% of participants). In trial participants, automated EHR text-mining missed a median of 2.8% (Interquartile range [IQR] across all variables 0.4-8.5%) of all data points compared to manually collected data. The overall accuracy of automatically extracted data was 88.0% (IQR 84.7-92.8%).

Conclusion: Automatically extracting data from EHRs using text-mining can be used to identify trial participants and to collect baseline information.
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http://dx.doi.org/10.1016/j.jclinepi.2020.11.014DOI Listing
April 2021

The ESC Global Affairs Committee (2018-20): tackling cardiovascular disease worldwide.

Cardiovasc Res 2020 12;116(14):e212-e214

Julius Global Health, Julius Center for Healh Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.

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http://dx.doi.org/10.1093/cvr/cvaa306DOI Listing
December 2020
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