Effectiveness of cardiac resynchronization therapy in heart failure patients with valvular heart disease: comparison with patients affected by ischaemic heart disease or dilated cardiomyopathy. The InSync/InSync ICD Italian Registry

AimsTo analyse the effectiveness of cardiac resynchronization therapy (CRT) in patients with valvular heart disease (a subset not specifically investigated in randomized controlled trials) in comparison with ischaemic heart disease or dilated cardiomyopathy patients.Methods and resultsPatients enrolled in a national registry were evaluated during a median follow-up of 16 months after CRT implant. Patients with valvular heart disease treated with CRT (n = 108) in comparison with ischaemic heart disease (n = 737) and dilated cardiomyopathy (n = 635) patients presented: (i) a higher prevalence of chronic atrial fibrillation, with atrioventricular node ablation performed in around half of the cases; (ii) a similar clinical and echocardiographic profile at baseline; (iii) a similar improvement of LVEF and a similar reduction in ventricular volumes at 6-12 months; (iv) a favourable clinical response at 12 months with an improvement of the clinical composite score similar to that occurring in patients with dilated cardiomyopathy and more pronounced than that observed in patients with ischaemic heart disease; (v) a long-term outcome, in term of freedom from death or heart transplantation, similar to patients affected by ischaemic heart disease and basically more severe than that of patients affected by dilated cardiomyopathy.ConclusionIn 'real world' clinical practice, CRT appears to be effective also in patients with valvular heart disease. However, in this group of patients the outcome after CRT does not precisely overlap any of the two other groups of patients, for which much more data are currently available

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

Safety, Tolerability, and Pharmacokinetics of PA-824 in Healthy Subjects▿

PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compound's MIC is between 0.015 and 0.25 μg/ml for drug-sensitive strains and between 0.03 and 0.53 μg/ml for drug-resistant strains. In addition, it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clinical studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approximately 3 μg/ml (1,500-mg dose) in the single-dose study and 3.8 μg/ml (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approximately 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compound for the treatment of tuberculosis

Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients▿ †

PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. Eight subjects received once daily standard antituberculosis treatment as positive control. The primary efficacy endpoint was the mean rate of change in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/ml (± standard deviation [SD]). The drug demonstrated increases that were dose linear but less than dose proportional in serum concentrations in doses from 200 to 1,000 mg daily. Dosing of 1,200 mg gave no additional exposure compared to 1,000 mg daily. The mean daily CFU fall under standard treatment was 0.148 (±0.055), consistent with that found in previous studies. The mean daily fall under PA-824 was 0.098 (±0.072) and was equivalent for all four dosages. PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored

Impact of mitral regurgitation on the outcome of patients treated with CRT-D: data from the InSync ICD Italian Registry.

Background: We assessed the influence of clinically significant mitral regurgitation (MR) on clinical-echocardiographic response and outcome in heart failure (HF) patients treated with a biventricular defibrillator (cardiac resynchronization therapy defibrillator [CRT-D]). Methods and Results: A total of 659 HF patients underwent successful implantation of CRT-D and were enrolled in a multicenter prospective registry (median follow-up of 15 months). Following baseline echocardiographic evaluation, patients were stratified into two groups according to the severity of MR: 232 patients with more than mild MR (Group MR+: grade 2, 3, and 4 MR) versus 427 patients with mild (grade 1) or no functional MR (Group MR−). On 6- and 12-month echocardiographic evaluation, MR was seen to have improved in the vast majority of MR+ patients, while it remained unchanged in most MR− patients. On 12-month follow-up evaluation, a comparable response to CRT was observed in the two groups, in terms of the extent of left ventricular reverse remodeling and combined clinical and echocardiographic response. During long-term follow-up, event-free survival did not differ between MR+ and MR− patients, even when subpopulations of patients with ischemic heart disease and with dilated cardiomyopathy were analyzed separately. On multivariate analysis, the only independent predictor of death from any cause was the lack of β-blocker use. Conclusions: This observational analysis supports the use of CRT-D in HF patients with clinically significant MR; MR had no major influence on patient outcom

Executive Summary:Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

International audienceAbstract Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29–39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

: Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified