Holger Thiele - Academia.edu (original) (raw)

Papers by Holger Thiele

Research paper thumbnail of Comparison of Bare-Metal Stenting With Minimally Invasive Bypass Surgery for Stenosis of the Left Anterior Descending Coronary Artery A 5Year Follow-Up

Background—Randomized trials comparing stenting with minimally invasive direct coronary artery by... more Background—Randomized trials comparing stenting with minimally invasive direct coronary artery bypass surgery in patients with isolated proximal left anterior descending lesions have shown a significantly higher reintervention rate for stenting and similar results for mortality and reinfarction at short-term follow-up. Long-term follow-up data are sparse. Methods and Results—Patients with isolated proximal left anterior descending stenosis were randomized to either surgery

Research paper thumbnail of Restoration of Microvascular Function in the Infarct-Related Artery by Intracoronary Transplantation of Bone Marrow Progenitor Cells in Patients With Acute Myocardial Infarction The Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarcti...

Background—The Doppler Substudy of the randomized, double-blind, placebo-controlled Reinfusion of... more Background—The Doppler Substudy of the randomized, double-blind, placebo-controlled Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial aimed to investigate the effects of intracoronary infusion of bone marrow-derived progenitor cells (BMCs) on coronary blood flow regulation in patients with reperfused acute myocardial infarction. Methods and Results—In a total of 58 patients (BMC group, n! 30;

Research paper thumbnail of Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock

Research paper thumbnail of Myocardium at risk in ST-elevation myocardial infarction: comparison of T2-weighted edema imaging with the endocardial surface area assessed by magnetic resonance and validation against angiographic scoring

Journal of Cardiovascular Magnetic Resonance, 2011

Research paper thumbnail of Prognostic value and determinants of a hypointense core in T2-weighted cardiac magnetic resonance in acute reperfused ST-elevation myocardial infarction

Journal of The American College of Cardiology, 2011

Research paper thumbnail of Intracoronary abciximab in diabetic patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

Vascular Pharmacology, 2015

Research paper thumbnail of Comprehensive Prognosis Assessment by CMR Imaging After ST-Segment Elevation Myocardial Infarction

Journal of the American College of Cardiology, 2014

Research paper thumbnail of Magnetic resonance imaging assessment of myocardial inflammation in 132 unselected, consecutive patients with clinical suspicion of acute or chronic myocarditis - are we as good as we thought?

Journal of Cardiovascular Magnetic Resonance, 2011

Research paper thumbnail of Comparison of pre-hospital combination-fibrinolysis plus conventional care with pre-hospital combination-fibrinolysis plus facilitated percutaneous coronary intervention in acute myocardial infarction

Research paper thumbnail of Recommendations on pre-hospital and early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine - short version

European heart journal, Jan 21, 2015

Research paper thumbnail of Recommendations on pre-hospital & hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine

European journal of heart failure, Jan 21, 2015

Acute heart failure is a fatal syndrome. Emergency physicians, cardiologists, intensivists, nurse... more Acute heart failure is a fatal syndrome. Emergency physicians, cardiologists, intensivists, nurses and other health care providers have to cooperate to provide optimal benefit. However, many treatment decisions are opinion-based and few are evidenced-based. This consensus paper provides guidance to practicing physicians and nurses to manage acute heart failure in the pre-hospital and hospital setting. Criteria of hospitalization and of discharge are described. Gaps in knowledge and perspectives in the management of acute heart failure are also detailed. This consensus paper on acute heart failure might help enable contiguous practice.

Research paper thumbnail of Prognostic impact of established and novel renal function biomarkers in myocardial infarction with cardiogenic shock: A biomarker substudy of the IABP-SHOCK II-trial

International Journal of Cardiology, 2015

Research paper thumbnail of Mutations in XRCC4 causes primary microcephaly, short stature, and increased genomic instability

Human molecular genetics, Jan 3, 2015

DNA double strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can gi... more DNA double strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g., with short stature, facial dysmorphism, and immune dysfunction. By using whole-exome sequencing (WES) we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G>A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25.delC (p.His9Thrfs*8) and c.823C>T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism...

Research paper thumbnail of Randomized Sham-Controlled Trial of Renal Sympathetic Denervation in Mild Resistant Hypertension

Hypertension, Jan 30, 2015

Few data are available with regard to the effectiveness of renal sympathetic denervation in patie... more Few data are available with regard to the effectiveness of renal sympathetic denervation in patients with resistant hypertension yet only mildly elevated blood pressure (BP). Patients with resistant hypertension and slightly elevated BP (day-time systolic pressure, 135-149 and diastolic pressure, 90-94 mm Hg on 24-hour ambulatory measurement) were randomized in a 1:1 ratio to renal sympathetic denervation with the Symplicity Flex Catheter (Medtronic) or an invasive sham procedure. The primary efficacy end point was the change in 24-hour systolic BP at 6 months between groups in the intention to treat population. A total of 71 patients underwent randomization. Baseline day-time systolic BP was 144.4±4.8 mm Hg in patients assigned to denervation and 143.0±4.7 mm Hg in patients randomized to the sham procedure. The mean change in 24-hour systolic BP in the intention to treat cohort at 6 months was -7.0 mm Hg (95% confidence interval, -10.8 to -3.2) for patients undergoing denervation a...

Research paper thumbnail of CHD2 variants are a risk factor for photosensitivity in epilepsy

Brain : a journal of neurology, Jan 17, 2015

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as pa... more Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalize...

Research paper thumbnail of Use, efficacy and safety of prasugrel in patients with ST segment elevation myocardial infarction scheduled for primary percutaneous coronary intervention in clinical practice. Results of the prospective ATACS-registry

International journal of cardiology, Jan 26, 2015

Prasugrel compared to clopidogrel has been shown to improve outcome in patients with ST elevation... more Prasugrel compared to clopidogrel has been shown to improve outcome in patients with ST elevation myocardial infarction (STEMI) in the TRITON-TIMI 38 trial. Little is known about the use, efficacy and safety of prasugrel in patients with STEMI in clinical practice. We conducted a prospective registry including patients with STEMI scheduled for primary percutaneous coronary intervention (PCI). Between October 2009 and February 2013 a total of 3291 patients with STEMI receiving a loading dose of either clopidogrel or prasugrel were included in this analysis. Prasugrel was predominantly used in patients <75years, body weight >60kg and those without prior stroke. In-hospital mortality was numerically lower in the prasugrel group (1.7% vs. 4.4%), as well as non-fatal reinfarction (0.2% vs. 0.5%), non-fatal stroke (0.1% vs. 0.3%) and major cardiac and cerebrovascular events (MACCE) (2.1% vs. 5.2%), while there was no difference in major bleeding complications (0.8% vs. 0.9%). In the...

Research paper thumbnail of Frequency and significance of myocardial bridging and recurrent segment of the left anterior descending coronary artery in patients with takotsubo cardiomyopathy

The American journal of cardiology, Jan 15, 2014

Despite intensive research efforts, the causative mechanisms of takotsubo cardiomyopathy (TC) are... more Despite intensive research efforts, the causative mechanisms of takotsubo cardiomyopathy (TC) are still unknown. Recently, morphologic characteristics of the left anterior descending coronary artery (LAD) have been proposed as a potential pathophysiological substrate. Hence, the aim of the present study was to evaluate the prevalence of myocardial bridging and LAD recurrent segments in a large cohort of patients with TC. A total of 161 patients with TC were matched for age and gender with 161 controls without coronary artery or valvular heart disease. Myocardial bridging was diagnosed according to indirect signs in coronary angiography. Furthermore, the LAD was evaluated regarding parts of the vessel outreaching the left ventricular apex (LAD recurrent segment). The prevalence of myocardial bridging was similar in the TC and control groups (11.8% vs 6.8%, p = 0.18). Any part of the LAD outreaching the left ventricular apex was observed in 55.6% of patients with TC compared with 35.4...

Research paper thumbnail of Importance of visualization the myocardium at risk in myocardial infarction

European heart journal cardiovascular Imaging, 2014

Research paper thumbnail of Low vs. higher-dose dark chocolate and blood pressure in cardiovascular high-risk patients

American journal of hypertension, 2010

Dark chocolate may have blood pressure-lowering properties. We conducted a prospective randomized... more Dark chocolate may have blood pressure-lowering properties. We conducted a prospective randomized open-label blinded end-point design trial to study a potential dose dependency of the presumed antihypertensive effect of dark chocolate by directly comparing low vs. higher doses of dark chocolate over the course of 3 months. We enrolled a total of 102 patients with prehypertension/stage 1 hypertension and established cardiovascular end-organ damage or diabetes mellitus. Patients were randomly assigned to receive either 6 or 25 g/day of flavanol-rich dark chocolate for 3 months. The difference in 24-h mean blood pressure between groups was defined as the primary outcome measure. Significant reductions in mean ambulatory 24-h blood pressure were observed between baseline and follow-up in both groups (6 g/day: -2.3 mm Hg, 95% confidence interval -4.1 to -0.4; 25 g/day: -1.9 mm Hg, 95% confidence interval -3.6 to -0.2). There were no significant differences in blood pressure changes betwe...

Research paper thumbnail of Effect of cocoa products on blood pressure: systematic review and meta-analysis

American journal of hypertension, 2010

Cocoa products such as dark chocolate and cocoa beverages may have blood pressure (BP)-lowering p... more Cocoa products such as dark chocolate and cocoa beverages may have blood pressure (BP)-lowering properties due to their high content of plant-derived flavanols. We performed a meta-analysis of randomized controlled trials assessing the antihypertensive effects of flavanol-rich cocoa products. The primary outcome measure was the change in systolic and diastolic BP between intervention and control groups. In total, 10 randomized controlled trials comprising 297 individuals were included in the analysis. The populations studied were either healthy normotensive adults or patients with prehypertension/stage 1 hypertension. Treatment duration ranged from 2 to 18 weeks. The mean BP change in the active treatment arms across all trials was -4.5 mm Hg (95% confidence interval (CI), -5.9 to -3.2, P < 0.001) for systolic BP and -2.5 mm Hg (95% CI, -3.9 to -1.2, P < 0.001) for diastolic BP. The meta-analysis confirms the BP-lowering capacity of flavanol-rich cocoa products in a larger set...

Research paper thumbnail of Comparison of Bare-Metal Stenting With Minimally Invasive Bypass Surgery for Stenosis of the Left Anterior Descending Coronary Artery A 5Year Follow-Up

Background—Randomized trials comparing stenting with minimally invasive direct coronary artery by... more Background—Randomized trials comparing stenting with minimally invasive direct coronary artery bypass surgery in patients with isolated proximal left anterior descending lesions have shown a significantly higher reintervention rate for stenting and similar results for mortality and reinfarction at short-term follow-up. Long-term follow-up data are sparse. Methods and Results—Patients with isolated proximal left anterior descending stenosis were randomized to either surgery

Research paper thumbnail of Restoration of Microvascular Function in the Infarct-Related Artery by Intracoronary Transplantation of Bone Marrow Progenitor Cells in Patients With Acute Myocardial Infarction The Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarcti...

Background—The Doppler Substudy of the randomized, double-blind, placebo-controlled Reinfusion of... more Background—The Doppler Substudy of the randomized, double-blind, placebo-controlled Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial aimed to investigate the effects of intracoronary infusion of bone marrow-derived progenitor cells (BMCs) on coronary blood flow regulation in patients with reperfused acute myocardial infarction. Methods and Results—In a total of 58 patients (BMC group, n! 30;

Research paper thumbnail of Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock

Research paper thumbnail of Myocardium at risk in ST-elevation myocardial infarction: comparison of T2-weighted edema imaging with the endocardial surface area assessed by magnetic resonance and validation against angiographic scoring

Journal of Cardiovascular Magnetic Resonance, 2011

Research paper thumbnail of Prognostic value and determinants of a hypointense core in T2-weighted cardiac magnetic resonance in acute reperfused ST-elevation myocardial infarction

Journal of The American College of Cardiology, 2011

Research paper thumbnail of Intracoronary abciximab in diabetic patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

Vascular Pharmacology, 2015

Research paper thumbnail of Comprehensive Prognosis Assessment by CMR Imaging After ST-Segment Elevation Myocardial Infarction

Journal of the American College of Cardiology, 2014

Research paper thumbnail of Magnetic resonance imaging assessment of myocardial inflammation in 132 unselected, consecutive patients with clinical suspicion of acute or chronic myocarditis - are we as good as we thought?

Journal of Cardiovascular Magnetic Resonance, 2011

Research paper thumbnail of Comparison of pre-hospital combination-fibrinolysis plus conventional care with pre-hospital combination-fibrinolysis plus facilitated percutaneous coronary intervention in acute myocardial infarction

Research paper thumbnail of Recommendations on pre-hospital and early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine - short version

European heart journal, Jan 21, 2015

Research paper thumbnail of Recommendations on pre-hospital & hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine

European journal of heart failure, Jan 21, 2015

Acute heart failure is a fatal syndrome. Emergency physicians, cardiologists, intensivists, nurse... more Acute heart failure is a fatal syndrome. Emergency physicians, cardiologists, intensivists, nurses and other health care providers have to cooperate to provide optimal benefit. However, many treatment decisions are opinion-based and few are evidenced-based. This consensus paper provides guidance to practicing physicians and nurses to manage acute heart failure in the pre-hospital and hospital setting. Criteria of hospitalization and of discharge are described. Gaps in knowledge and perspectives in the management of acute heart failure are also detailed. This consensus paper on acute heart failure might help enable contiguous practice.

Research paper thumbnail of Prognostic impact of established and novel renal function biomarkers in myocardial infarction with cardiogenic shock: A biomarker substudy of the IABP-SHOCK II-trial

International Journal of Cardiology, 2015

Research paper thumbnail of Mutations in XRCC4 causes primary microcephaly, short stature, and increased genomic instability

Human molecular genetics, Jan 3, 2015

DNA double strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can gi... more DNA double strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g., with short stature, facial dysmorphism, and immune dysfunction. By using whole-exome sequencing (WES) we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G>A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25.delC (p.His9Thrfs*8) and c.823C>T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism...

Research paper thumbnail of Randomized Sham-Controlled Trial of Renal Sympathetic Denervation in Mild Resistant Hypertension

Hypertension, Jan 30, 2015

Few data are available with regard to the effectiveness of renal sympathetic denervation in patie... more Few data are available with regard to the effectiveness of renal sympathetic denervation in patients with resistant hypertension yet only mildly elevated blood pressure (BP). Patients with resistant hypertension and slightly elevated BP (day-time systolic pressure, 135-149 and diastolic pressure, 90-94 mm Hg on 24-hour ambulatory measurement) were randomized in a 1:1 ratio to renal sympathetic denervation with the Symplicity Flex Catheter (Medtronic) or an invasive sham procedure. The primary efficacy end point was the change in 24-hour systolic BP at 6 months between groups in the intention to treat population. A total of 71 patients underwent randomization. Baseline day-time systolic BP was 144.4±4.8 mm Hg in patients assigned to denervation and 143.0±4.7 mm Hg in patients randomized to the sham procedure. The mean change in 24-hour systolic BP in the intention to treat cohort at 6 months was -7.0 mm Hg (95% confidence interval, -10.8 to -3.2) for patients undergoing denervation a...

Research paper thumbnail of CHD2 variants are a risk factor for photosensitivity in epilepsy

Brain : a journal of neurology, Jan 17, 2015

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as pa... more Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalize...

Research paper thumbnail of Use, efficacy and safety of prasugrel in patients with ST segment elevation myocardial infarction scheduled for primary percutaneous coronary intervention in clinical practice. Results of the prospective ATACS-registry

International journal of cardiology, Jan 26, 2015

Prasugrel compared to clopidogrel has been shown to improve outcome in patients with ST elevation... more Prasugrel compared to clopidogrel has been shown to improve outcome in patients with ST elevation myocardial infarction (STEMI) in the TRITON-TIMI 38 trial. Little is known about the use, efficacy and safety of prasugrel in patients with STEMI in clinical practice. We conducted a prospective registry including patients with STEMI scheduled for primary percutaneous coronary intervention (PCI). Between October 2009 and February 2013 a total of 3291 patients with STEMI receiving a loading dose of either clopidogrel or prasugrel were included in this analysis. Prasugrel was predominantly used in patients <75years, body weight >60kg and those without prior stroke. In-hospital mortality was numerically lower in the prasugrel group (1.7% vs. 4.4%), as well as non-fatal reinfarction (0.2% vs. 0.5%), non-fatal stroke (0.1% vs. 0.3%) and major cardiac and cerebrovascular events (MACCE) (2.1% vs. 5.2%), while there was no difference in major bleeding complications (0.8% vs. 0.9%). In the...

Research paper thumbnail of Frequency and significance of myocardial bridging and recurrent segment of the left anterior descending coronary artery in patients with takotsubo cardiomyopathy

The American journal of cardiology, Jan 15, 2014

Despite intensive research efforts, the causative mechanisms of takotsubo cardiomyopathy (TC) are... more Despite intensive research efforts, the causative mechanisms of takotsubo cardiomyopathy (TC) are still unknown. Recently, morphologic characteristics of the left anterior descending coronary artery (LAD) have been proposed as a potential pathophysiological substrate. Hence, the aim of the present study was to evaluate the prevalence of myocardial bridging and LAD recurrent segments in a large cohort of patients with TC. A total of 161 patients with TC were matched for age and gender with 161 controls without coronary artery or valvular heart disease. Myocardial bridging was diagnosed according to indirect signs in coronary angiography. Furthermore, the LAD was evaluated regarding parts of the vessel outreaching the left ventricular apex (LAD recurrent segment). The prevalence of myocardial bridging was similar in the TC and control groups (11.8% vs 6.8%, p = 0.18). Any part of the LAD outreaching the left ventricular apex was observed in 55.6% of patients with TC compared with 35.4...

Research paper thumbnail of Importance of visualization the myocardium at risk in myocardial infarction

European heart journal cardiovascular Imaging, 2014

Research paper thumbnail of Low vs. higher-dose dark chocolate and blood pressure in cardiovascular high-risk patients

American journal of hypertension, 2010

Dark chocolate may have blood pressure-lowering properties. We conducted a prospective randomized... more Dark chocolate may have blood pressure-lowering properties. We conducted a prospective randomized open-label blinded end-point design trial to study a potential dose dependency of the presumed antihypertensive effect of dark chocolate by directly comparing low vs. higher doses of dark chocolate over the course of 3 months. We enrolled a total of 102 patients with prehypertension/stage 1 hypertension and established cardiovascular end-organ damage or diabetes mellitus. Patients were randomly assigned to receive either 6 or 25 g/day of flavanol-rich dark chocolate for 3 months. The difference in 24-h mean blood pressure between groups was defined as the primary outcome measure. Significant reductions in mean ambulatory 24-h blood pressure were observed between baseline and follow-up in both groups (6 g/day: -2.3 mm Hg, 95% confidence interval -4.1 to -0.4; 25 g/day: -1.9 mm Hg, 95% confidence interval -3.6 to -0.2). There were no significant differences in blood pressure changes betwe...

Research paper thumbnail of Effect of cocoa products on blood pressure: systematic review and meta-analysis

American journal of hypertension, 2010

Cocoa products such as dark chocolate and cocoa beverages may have blood pressure (BP)-lowering p... more Cocoa products such as dark chocolate and cocoa beverages may have blood pressure (BP)-lowering properties due to their high content of plant-derived flavanols. We performed a meta-analysis of randomized controlled trials assessing the antihypertensive effects of flavanol-rich cocoa products. The primary outcome measure was the change in systolic and diastolic BP between intervention and control groups. In total, 10 randomized controlled trials comprising 297 individuals were included in the analysis. The populations studied were either healthy normotensive adults or patients with prehypertension/stage 1 hypertension. Treatment duration ranged from 2 to 18 weeks. The mean BP change in the active treatment arms across all trials was -4.5 mm Hg (95% confidence interval (CI), -5.9 to -3.2, P < 0.001) for systolic BP and -2.5 mm Hg (95% CI, -3.9 to -1.2, P < 0.001) for diastolic BP. The meta-analysis confirms the BP-lowering capacity of flavanol-rich cocoa products in a larger set...