Ronald Klein

Bio: Ronald Klein is an academic researcher from University of Wisconsin-Madison. The author has contributed to research in topics: Population & Diabetic retinopathy. The author has an hindex of 194, co-authored 1305 publications receiving 149140 citations. Previous affiliations of Ronald Klein include Los Angeles Biomedical Research Institute & Wake Forest University.

Prediction of proliferative diabetic retinopathy with hemoglobin level.

Abstract: Objective To investigate the role of hemoglobin (HGB) level in predicting proliferative diabetic retinopathy (PDR). Methods We assessed 426 individuals without PDR at baseline (213 men; 213 women) from the Pittsburgh Epidemiology of Diabetes Complications Study, an 18-year prospective cohort study of childhood-onset type 1 diabetes. Presence of PDR was determined by stereo fundus photography. Cox proportional hazards modeling with stepwise regression was used to determine the independent association of HGB level with PDR. Analyses were sex specific. Results There were 206 events. Although the incidence of PDR did not vary by sex (48% in both men and women), in men, HGB exhibited a positive linear relationship with 18-year incidence of PDR (hazard ratio, 1.33; 95% confidence interval, 1.10-1.60; P = .003), while in women, HGB level exhibited a quadratic relationship with PDR ( P P = .004) and women ( P = .04). Conclusion Higher HGB level predicts the incidence of PDR in type 1 diabetes mellitus, though the association varies by sex, being linear and positive in men and quadratic in women.

A population-based study of diabetic retinopathy in insulin-using patients diagnosed before 30 years of age.

Abstract: In a population-based study of the prevalence and severity of diabetic retinopathy in southern Wisconsin, 1210 insulin-taking persons who were diagnosed to have diabetes before 30 yr of age and who were receiving primary medical care in the area were identified in 1979-80. From 1980 to 1982, 996 patients were examined. Fundus photographs revealed that 72% of diabetic women and 69% of diabetic men had retinopathy. More men (12%) than women (7%) had severe proliferative retinopathy. Longer duration of diabetes, higher glycosylated hemoglobin, older age at examination, higher diastolic blood pressure, male gender, and presence of proteinuria all contributed significantly to describing increasing severity of retinopathy.

Association of blood glucose control and pancreatic reserve with diabetic retinopathy in the Veterans Affairs Diabetes Trial (VADT)

Abstract: The aim of this study was to test the hypothesis that intensive glycaemic control (INT) and higher plasma C-peptide levels in patients with poorly controlled diabetes would be associated with better eye outcomes. The incidence and progression of diabetic retinopathy (DR) was assessed by grading seven-field stereoscopic fundus photographs at baseline and 5 years later in 858 of 1,791 participants in the Veterans Affairs Diabetes Trial (VADT). After adjustment for all covariates, risk of progression (but not incidence) of DR increased by 30% for each 1% increase in baseline HbA1c (OR 1.3; 95% CI 1.123, 1.503; p = 0.0004). Neither assignment to INT nor age was independently associated with DR in the entire cohort. However, INT showed a biphasic interaction with age. The incidence of DR was decreased in INT participants ≤55 years of age (OR 0.49; 95% CI 0.24, 1.0) but increased in those ≥70 years old (OR 2.88; 95% CI 1.0, 8.24) (p = 0.0043). The incidence of DR was reduced by 67.2% with each 1 pmol/ml increment in baseline C-peptide (OR 0.328; 95% CI 0.155, 0.7; p = 0.0037). Baseline C-peptide was also an independent inverse risk factor for the progression of DR, with a reduction of 47% with each 1 pmol/ml increase in C-peptide (OR 0.53; 95% CI 0.305, 0.921; p = 0.0244). Poor glucose control at baseline was associated with an increased risk of progression of DR. INT was associated with a decreased incidence of DR in younger patients but with an increased risk of DR in older patients. Higher C-peptide at baseline was associated with reduced incidence and progression of DR.

Metformin in adults with type 1 diabetes: Design and methods of REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL): An international multicentre trial.

Abstract: Introduction: Cardiovascular (CV) disease is a major cause of reduced life expectancy in type 1 diabetes (T1D). Intensive insulin therapy prevents CV complications but is constrained by hypoglycaemia and weight gain. Adjunct metformin reduces insulin dose requirement and stabilises weight but there are no data on its cardiovascular effects. Aims: We have initiated an international double-blind, randomized, placebo-controlled trial (REMOVAL: REducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes) to examine whether metformin reduces progression of atherosclerosis in adults with T1D. Individuals ≥40 years of age with T1D for ≥5 years are eligible if they have ≥3 of 10 specified CV risk factors. The enrolment target is 500 participants in 17 international centres. Materials and Methods: After 12 weeks single-blind placebo-controlled run-in, participants with ≥70 % adherence are randomized to metformin or matching placebo for three years with insulin titrated towards HbA1c 7.0% (53 mmol/mol)]. The primary endpoint is progression of averaged mean far wall common carotid intima-media thickness (cIMT) measured by ultrasonography at baseline, 12, 24 and 36 months. This design provides 90% power to detect a mean difference of 0.0167 mm in cIMT progression between treatment arms (α = 0.05), assuming up to 20% withdraw or discontinue treatment. Other endpoints include HbA1c, weight, LDL cholesterol, insulin requirement, progression of retinopathy, endothelial function and frequency of hypoglycaemia. Results and Conclusions: REMOVAL is the largest clinical trial of adjunct metformin therapy in T1D to date and will provide clinically meaningful information on its potential to impact CV disease and other complications.

Carotid Intima Media Thickness, Atherosclerosis, and 5-Year Decline in Odor Identification: The Beaver Dam Offspring Study

Abstract: Although olfactory impairment is common in older adults, many are unaware of their dysfunction suggesting some decline in olfactory function occurs slowly over time (1,2). Gradual declines in olfactory function with age may have different etiologies than sudden impairments that are associated with specific events (trauma or infection). A slow progression of subclinical decline in olfactory function would be similar to the long trajectory recognized in the development of cardiovascular disease (CVD), which begins as vascular changes and atherosclerosis early in adulthood and manifests as clinical disease years later. In CVD, the risk factor profile in midlife is believed to an important predictor of healthy aging and longevity (3); this may be true for olfactory impairment as well. Olfactory impairment and CVD have some risk factors in common such as smoking, diabetes mellitus, and exercise. Smoking, an important risk factor for atherosclerosis (4,5), has been associated with olfactory dysfunction in some studies (1,2,6,7), but not all (8). People with diabetes mellitus have an increased risk of developing atherosclerosis (9) and CVD (10), and some studies have found people with diabetes have more olfactory dysfunction, though again, findings have not been consistent (1,2,8,11). Weinstock and coauthors (11) found within a diabetes cohort that those with macrovascular disease (coronary artery or peripheral vascular) had impaired olfaction compared with those without macrovascular disease. In population studies, older adults in the Epidemiology of Hearing Loss Study who were current smokers or had a history of stroke were more likely to have olfactory impairment in cross-sectional analyses (1). Longitudinal analyses found the use of lipid-lowering medication and regular exercise were associated with a reduced risk of developing olfactory impairment at 5 years (12) and exercise was also associated with a reduced risk at 10 years (13). In a younger cohort, the Beaver Dam Offspring Study (BOSS), thicker carotid artery intima media thickness (IMT), a subclinical marker of generalized atherosclerosis, was associated with prevalent olfactory impairment (2). Together, these findings suggest that atherosclerosis may be associated with olfactory dysfunction that occurs with aging. However, to establish temporal sequence, longitudinal data are needed from a younger cohort that has not yet entered the period of greatest risk for olfactory impairment. The purpose of this study was to determine if subclinical markers of atherosclerosis are associated with a decline in olfactory function at 5 years in a primarily midlife cohort of adults participating in the longitudinal BOSS.

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.

Abstract: Background Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. Methods A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. Results In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. Conclusions Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.

A New Equation to Estimate Glomerular Filtration Rate

Abstract: The Modification of Diet in Renal Disease (MDRD) Study equation underestimates glomerular filtration rate (GFR) in patients with mild kidney disease. Levey and associates therefore developed and va...

Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

Abstract: The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence-based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease (CVD) risk factor than diastolic BP; beginning at 115/75 mm Hg, CVD risk doubles for each increment of 20/10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high-risk conditions that are compelling indications for the use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician's judgment remains paramount.

2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

Abstract: ABCD : Appropriate Blood pressure Control in Diabetes ABI : ankle–brachial index ABPM : ambulatory blood pressure monitoring ACCESS : Acute Candesartan Cilexetil Therapy in Stroke Survival ACCOMPLISH : Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension ACCORD : Action to Control Cardiovascular Risk in Diabetes ACE : angiotensin-converting enzyme ACTIVE I : Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events ADVANCE : Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation AHEAD : Action for HEAlth in Diabetes ALLHAT : Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack ALTITUDE : ALiskiren Trial In Type 2 Diabetes Using Cardio-renal Endpoints ANTIPAF : ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation APOLLO : A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People ARB : angiotensin receptor blocker ARIC : Atherosclerosis Risk In Communities ARR : aldosterone renin ratio ASCOT : Anglo-Scandinavian Cardiac Outcomes Trial ASCOT-LLA : Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm ASTRAL : Angioplasty and STenting for Renal Artery Lesions A-V : atrioventricular BB : beta-blocker BMI : body mass index BP : blood pressure BSA : body surface area CA : calcium antagonist CABG : coronary artery bypass graft CAPPP : CAPtopril Prevention Project CAPRAF : CAndesartan in the Prevention of Relapsing Atrial Fibrillation CHD : coronary heart disease CHHIPS : Controlling Hypertension and Hypertension Immediately Post-Stroke CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease—EPIdemiology collaboration CONVINCE : Controlled ONset Verapamil INvestigation of CV Endpoints CT : computed tomography CV : cardiovascular CVD : cardiovascular disease D : diuretic DASH : Dietary Approaches to Stop Hypertension DBP : diastolic blood pressure DCCT : Diabetes Control and Complications Study DIRECT : DIabetic REtinopathy Candesartan Trials DM : diabetes mellitus DPP-4 : dipeptidyl peptidase 4 EAS : European Atherosclerosis Society EASD : European Association for the Study of Diabetes ECG : electrocardiogram EF : ejection fraction eGFR : estimated glomerular filtration rate ELSA : European Lacidipine Study on Atherosclerosis ESC : European Society of Cardiology ESH : European Society of Hypertension ESRD : end-stage renal disease EXPLOR : Amlodipine–Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine–Atenolol Combination FDA : U.S. Food and Drug Administration FEVER : Felodipine EVent Reduction study GISSI-AF : Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation HbA1c : glycated haemoglobin HBPM : home blood pressure monitoring HOPE : Heart Outcomes Prevention Evaluation HOT : Hypertension Optimal Treatment HRT : hormone replacement therapy HT : hypertension HYVET : HYpertension in the Very Elderly Trial IMT : intima-media thickness I-PRESERVE : Irbesartan in Heart Failure with Preserved Systolic Function INTERHEART : Effect of Potentially Modifiable Risk Factors associated with Myocardial Infarction in 52 Countries INVEST : INternational VErapamil SR/T Trandolapril ISH : Isolated systolic hypertension JNC : Joint National Committee JUPITER : Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin LAVi : left atrial volume index LIFE : Losartan Intervention For Endpoint Reduction in Hypertensives LV : left ventricle/left ventricular LVH : left ventricular hypertrophy LVM : left ventricular mass MDRD : Modification of Diet in Renal Disease MRFIT : Multiple Risk Factor Intervention Trial MRI : magnetic resonance imaging NORDIL : The Nordic Diltiazem Intervention study OC : oral contraceptive OD : organ damage ONTARGET : ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial PAD : peripheral artery disease PATHS : Prevention And Treatment of Hypertension Study PCI : percutaneous coronary intervention PPAR : peroxisome proliferator-activated receptor PREVEND : Prevention of REnal and Vascular ENdstage Disease PROFESS : Prevention Regimen for Effectively Avoiding Secondary Strokes PROGRESS : Perindopril Protection Against Recurrent Stroke Study PWV : pulse wave velocity QALY : Quality adjusted life years RAA : renin-angiotensin-aldosterone RAS : renin-angiotensin system RCT : randomized controlled trials RF : risk factor ROADMAP : Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention SBP : systolic blood pressure SCAST : Angiotensin-Receptor Blocker Candesartan for Treatment of Acute STroke SCOPE : Study on COgnition and Prognosis in the Elderly SCORE : Systematic COronary Risk Evaluation SHEP : Systolic Hypertension in the Elderly Program STOP : Swedish Trials in Old Patients with Hypertension STOP-2 : The second Swedish Trial in Old Patients with Hypertension SYSTCHINA : SYSTolic Hypertension in the Elderly: Chinese trial SYSTEUR : SYSTolic Hypertension in Europe TIA : transient ischaemic attack TOHP : Trials Of Hypertension Prevention TRANSCEND : Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease UKPDS : United Kingdom Prospective Diabetes Study VADT : Veterans' Affairs Diabetes Trial VALUE : Valsartan Antihypertensive Long-term Use Evaluation WHO : World Health Organization ### 1.1 Principles The 2013 guidelines on hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology …

A global reference for human genetic variation.

Abstract: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.