Pupillary Responses to High-Irradiance Blue Light Correlate with Glaucoma Severity

PurposeTo evaluate whether a chromatic pupillometry test can be used to detect impaired function of intrinsically photosensitive retinal ganglion cells (ipRGCs) in patients with primary open-angle glaucoma (POAG) and to determine if pupillary responses correlate with optic nerve damage and visual loss.DesignCross-sectional study.ParticipantsOne hundred sixty-one healthy controls recruited from a community polyclinic (55 men; 151 ethnic Chinese) and 40 POAG patients recruited from a glaucoma clinic (22 men; 35 ethnic Chinese) 50 years of age or older.MethodsSubjects underwent monocular exposure to narrowband blue light (469 nm) or red light (631 nm) using a modified Ganzfeld dome. Each light stimulus was increased gradually over 2 minutes to activate sequentially the rods, cones, and ipRGCs that mediate the pupillary light reflex. Pupil diameter was recorded using an infrared pupillography system.Main Outcome MeasuresPupillary responses to blue light and red light were compared between control subjects and those with POAG by constructing dose-response curves across a wide range of corneal irradiances (7–14 log photons/cm2 per second). In patients with POAG, pupillary responses were evaluated relative to standard automated perimetry testing (Humphrey Visual Field [HVF]; Carl Zeiss Meditec, Dublin, CA) and scanning laser ophthalmoscopy parameters (Heidelberg Retinal Tomography [HRT]; Heidelberg Engineering, Heidelberg, Germany).ResultsThe pupillary light reflex was reduced in patients with POAG only at higher irradiance levels, corresponding to the range of activation of ipRGCs. Pupillary responses to high-irradiance blue light associated more strongly with disease severity compared with responses to red light, with a significant linear correlation observed between pupil diameter and HVF mean deviation (r = −0.44; P = 0.005) as well as HRT linear cup-to-disc ratio (r = 0.61; P < 0.001) and several other optic nerve head parameters.ConclusionsIn glaucomatous eyes, reduced pupillary responses to high-irradiance blue light were associated with greater visual field loss and optic disc cupping. In POAG, a short chromatic pupillometry test that evaluates the function of ipRGCs can be used to estimate the degree of damage to retinal ganglion cells that mediate image-forming vision. This approach could prove useful in detecting glaucoma

Rate control efficacy in permanent atrial fibrillation:a comparison between lenient versus strict rate control in patients with and without heart failure. Background, aims, and design of RACE II

BACKGROUND: Recent studies demonstrated that rate control is an acceptable alternative for rhythm control in patients with persistent atrial fibrillation (AF). However, optimal heart rate during AF is still unknown. OBJECTIVE: To show that in patients with permanent AF, lenient rate control is not inferior to strict rate control in terms of cardiovascular mortality, morbidity, neurohormonal activation, New York Heart Association class for heart failure, left ventricular function, left atrial size, quality of life, and costs. METHODS: The RACE II study is a prospective multicenter trial in The Netherlands that will randomize 500 patients with permanent AF (< or = 12 months) to strict or lenient rate control. Strict rate control is defined as a mean resting heart rate < 80 beats per minute (bpm) and heart rate during minor exercise < 110 bpm. After reaching the target, a 24-hour Holter monitoring will be performed. If necessary, drug dose reduction and/or pacemaker implantation will be performed. Lenient rate control is defined as a resting heart rate < 110 bpm. Patients will be seen after 1, 2, and 3 months (for titration of rate control drugs) and yearly thereafter. We anticipate a 25% 2.5-year cardiovascular morbidity and mortality in both groups. RESULTS: Enrollment started in January 2005 in 29 centers in The Netherlands and is expected to be concluded in June 2006. Follow-up will be at least 2 years with a maximum of 3 years. CONCLUSION: This study should provide data how to treat patients with permanent AF

Effect of a nurse-coordinated prevention programme on cardiovascular risk after an acute coronary syndrome: main results of the RESPONSE randomised trial

Objective To quantify the impact of a practical, hospital-based nurse-coordinated prevention programme on cardiovascular risk, integrated into the routine clinical care of patients discharged after an acute coronary syndrome, as compared with usual care only. Design RESPONSE (Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists) was a randomised clinical trial. Setting Multicentre trial in secondary and tertiary healthcare settings. Participants 754 patients admitted for acute coronary syndrome. Intervention A nurse-coordinated prevention programme, consisting of four outpatient nurse clinic visits, focusing on healthy lifestyles, biometric risk factors and medication adherence, in addition to usual care. Main outcome measures The main outcome was 10-year cardiovascular mortality risk as estimated by Systematic Coronary Risk Evaluation at 12 months follow-up. Secondary outcomes included Framingham Coronary Risk Score at 12 months, in addition to changes in individual risk factors. Risk factor control was classified as ‘poor’ if 0 to 3 factors were on target, ‘fair’ if 4 to 6 factors were on target, and ‘good’ if 7 to 9 were on target. Results The mean Systematic Coronary Risk Evaluation at 12 months was 4.4 per cent (SD 4.5) in the intervention group and 5.4 per cent (SD 6.2) in the control group (p=0.021), representing a 17.4% relative risk reduction. At 12 months, risk factor control classified as ‘good’ was achieved in 35% of patients in the intervention group compared with 25% in the control group (p=0.003). Attendance to the nurse-coordinated prevention programme was 92%. In the intervention group, 86 rehospitalisations were observed against 132 in the control group (relative risk reduction 34.8%, p=0.023). Conclusions The nurse-coordinated hospital-based prevention programme in addition to usual care is a practical, yet effective method for reduction of cardiovascular risk in patients with coronary disease. Our data suggest that the counselling component of the programme may lead to a reduction in hospital readmissions

Dronedarone in high-risk permanent atrial fibrillation

BACKGROUND: Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation. METHODS: We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death. RESULTS: After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P = 0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P = 0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P = 0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P = 0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P = 0.02). CONCLUSIONS: Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137.) Copyright © 2011 Massachusetts Medical Society. All rights reserved.published_or_final_versio

Treatment and Management of Upper Extremity Dysfunction Following Transradial Percutaneous Coronary Intervention:A Prospective Cohort Study

Background:The transradial artery access is the benchmark approach in transradial percutaneous coronary intervention (TR-PCI). The purpose of this study was to evaluate the different complications, treatments, and outcome of upper extremity dysfunction following a TR-PCI.Methods:This was a prospective cohort substudy of patients with access-site complications. The study population consisted of 433 patients treated with TR-PCI. Referral to the hand center was mandated if the patient experienced new-onset or increase of preexistent symptoms in the upper extremity. Patients were followed up to the last control visit (5-7 months after the index procedure) at the hand center. Outcome results were categorized in "symptom-free," "improvement of symptoms," and "no improvement."Results:Forty-one (9% of total) patients underwent assessment at the hand center. Most frequent referral indication was pain in the intervention arm. Women, preexisting sensibility disorder, and osteoarthritis in the intervention arm were associated with increased odds of referral. The most common complications diagnosed were carpal tunnel syndrome (n = 18) and osteoarthritis (n = 15). Thirty patients required further medical treatment. Immobilization therapy was most applied. Seventeen (4% of total) patients had persisting symptoms despite medical treatment.Conclusions:The occurrence of complications in the upper extremity after a TR-PCI is small. Despite medical treatment, symptoms persisted in 4% of all patients treated with TR-PCI. Possible explanations for the persisting symptoms are exacerbation of latent osteoarthritis and carpal tunnel syndrome by trauma-induced edema. Awareness of TR-PCI-induced complications among all specialists is essential to optimize patient care

Ncs2* mediates in vivo virulence of pathogenic yeast through sulphur modification of cytoplasmic transfer RNA.

Fungal pathogens threaten ecosystems and human health. Understanding the molecular basis of their virulence is key to develop new treatment strategies. Here, we characterize NCS2*, a point mutation identified in a clinical baker's yeast isolate. Ncs2 is essential for 2-thiolation of tRNA and the NCS2* mutation leads to increased thiolation at body temperature. NCS2* yeast exhibits enhanced fitness when grown at elevated temperatures or when exposed to oxidative stress, inhibition of nutrient signalling, and cell-wall stress. Importantly, Ncs2* alters the interaction and stability of the thiolase complex likely mediated by nucleotide binding. The absence of 2-thiolation abrogates the in vivo virulence of pathogenic baker's yeast in infected mice. Finally, hypomodification triggers changes in colony morphology and hyphae formation in the common commensal pathogen Candida albicans resulting in decreased virulence in a human cell culture model. These findings demonstrate that 2-thiolation of tRNA acts as a key mediator of fungal virulence and reveal new mechanistic insights into the function of the highly conserved tRNA-thiolase complex

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

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 0.4e8.5%) of all data points compared to manually collected data. The overall accuracy of automatically extracted data was 88.0% (IQR 84.7e92.8%). Conclusion: Automatically extracting data from EHRs using text-mining can be used to identify trial participants and to collect baseline informatio

Comparing adolescent- and adult-onset unexplained cardiac arrest:Results from the Dutch Idiopathic VF Registry

Background: Current cohorts of patients with idiopathic ventricular fibrillation (IVF) primarily include adult-onset patients. Underlying causes of sudden cardiac arrest vary with age; therefore, underlying causes and disease course may differ for adolescent-onset vs adult-onset patients. Objective: The purpose of this study was to compare adolescent-onset with adult-onset patients having an initially unexplained cause of VF. Methods: The study included 39 patients with an index event aged ≤19 years (adolescent-onset) and 417 adult-onset patients from the Dutch Idiopathic VF Registry. Data on event circumstances, clinical characteristics, change in diagnosis, and arrhythmia recurrences were collected and compared between the 2 groups. Results: In total, 42 patients received an underlying diagnosis during follow-up (median 7 [2–12] years), with similar yields (15% adolescent-onset vs 9% adult-onset; P = .16). Among the remaining unexplained patients, adolescent-onset patients (n = 33) had their index event at a median age of 17 [16–18] years, and 72% were male. The youngest patient was aged 13 years. In comparison with adults (n = 381), adolescent-onset patients more often had their index event during exercise (P &lt;.01). Adolescent-onset patients experienced more appropriate implantable cardioverter-defibrillator (ICD) therapy during follow-up compared with adults (44% vs 26%; P = .03). Inappropriate ICD therapy (26% vs 17%; P = .19), ICD complications (19% vs 14%; P = .41), and deaths (3% vs 4%; P = 1) did not significantly differ between adolescent-onset and adult-onset patients. Conclusion: IVF may occur during adolescence. Adolescent-onset patients more often present during exercise compared with adults. Furthermore, they are more vulnerable to ventricular arrhythmias as reflected by a higher incidence of appropriate ICD therapy.</p

Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation

Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit.We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason).We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group.Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.)

The genetic basis of apparently idiopathic ventricular fibrillation:A retrospective overview

Aims: During the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias. However, consensus for gene panel testing is still lacking, and variants of uncertain significance (VUS) are often identified. The aim of this study was to evaluate genetic testing and its results in idiopathic VF patients. Methods and results: We investigated 419 patients with available medical records from the Dutch Idiopathic VF Registry. Genetic testing was performed in 379 (91%) patients [median age at event 39 years (27-51), 60% male]. Single-gene testing was performed in 87 patients (23%) and was initiated more often in patients with idiopathic VF before 2010. Panel testing was performed in 292 patients (77%). The majority of causal (likely) pathogenic variants (LP/P, n = 56, 15%) entailed the DPP6 risk haplotype (n = 39, 70%). Moreover, 10 LP/P variants were found in cardiomyopathy genes (FLNC, MYL2, MYH7, PLN (two), TTN (four), RBM20), and 7 LP/P variants were identified in genes associated with cardiac arrhythmias (KCNQ1, SCN5A (2), RYR2 (four)). For eight patients (2%), identification of an LP/P variant resulted in a change of diagnosis. In 113 patients (30%), a VUS was identified. Broad panel testing resulted in a higher incidence of VUS in comparison to single-gene testing (38% vs. 3%, P &lt; 0.001). Conclusion: Almost all patients from the registry underwent, albeit not broad, genetic testing. The genetic yield of causal LP/P variants in idiopathic VF patients is 5%, increasing to 15% when including DPP6. In specific cases, the LP/P variant is the underlying diagnosis. A gene panel specifically for idiopathic VF patients is proposed.</p