Heritability of fractional anisotropy in human white matter: a comparison of Human Connectome Project and ENIGMA-DTI data

The degree to which genetic factors influence brain connectivity is beginning to be understood. Large-scale efforts are underway to map the profile of genetic effects in various brain regions. The NIH-funded Human Connectome Project (HCP) is providing data valuable for analyzing the degree of genetic influence underlying brain connectivity revealed by state-of-the-art neuroimaging methods. We calculated the heritability of the fractional anisotropy (FA) measure derived from diffusion tensor imaging (DTI) reconstruction in 481 HCP subjects (194/287 M/F) consisting of 57/60 pairs of mono- and dizygotic twins, and 246 siblings. FA measurements were derived using (Enhancing NeuroImaging Genetics through Meta-Analysis) ENIGMA DTI protocols and heritability estimates were calculated using the SOLAR-Eclipse imaging genetic analysis package. We compared heritability estimates derived from HCP data to those publicly available through the ENIGMA-DTI consortium, which were pooled together from five-family based studies across the US, Europe, and Australia. FA measurements from the HCP cohort for eleven major white matter tracts were highly heritable (h2 = 0.53–0.90, p < 10− 5), and were significantly correlated with the joint-analytical estimates from the ENIGMA cohort on the tract and voxel-wise levels. The similarity in regional heritability suggests that the additive genetic contribution to white matter microstructure is consistent across populations and imaging acquisition parameters. It also suggests that the overarching genetic influence provides an opportunity to define a common genetic search space for future gene-discovery studies. Uniquely, the measurements of additive genetic contribution performed in this study can be repeated using online genetic analysis tools provided by the HCP ConnectomeDB web application

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

A fluorogenic monolayer to detect the co-immobilization of peptides that combine cartilage targeting and regeneration

Strategies to generate platforms combining tissue targeting and regeneration properties are in great demand in the regenerative medicine field. Here we employ an approach to directly visualize the immobilization of cysteine-terminated peptides on a novel fluorogenic surface. Peptides with relevant biological properties, CLPLGNSH and CLRGRYW, were synthesized to function as peptide binders to transforming growth factor (TGF)-β1 and collagen type II (CII). The selective immobilization of the peptides was directly detected using a fluorogenic surface. Adhered proteins were confined to patterns of these peptides matching with the fluorogenic areas. These results show that the fluorogenic signal can be used to detect the chemo-selective immobilization of non-fluorescent biomolecules and to correlate the cell response with the patterned peptides. After analyzing the sequence specificity and cross-reactivity of the binding of TGF-β1 and CII to the respective peptide regions employing immunofluorescence assays, both peptides were co-immobilized in a step-wise process as detected by the fluorogenic surface. TGF-β1 and CII could be self-sorted from a mixture in a regio-selective manner resulting in a bi-functional protein platform. Surfaces of CLPLGNSH pre-loaded with TGF-β1 showed excellent bioactivity in combination with human articular chondrocytes (HACs) and stimulated expression of chondrogenic marker

O-Phenanthroline as modulator of the hypoxic and catabolic response in cartilage tissue-engineering models

Hypoxia has been shown to be important for maintaining cartilage homeostasis as well as for inducing chondrogenic differentiation. Ensuring low oxygen levels during in vitro culture is difficult, therefore we assessed the chondro-inductive capabilities of the hypoxia-mimicking agent O-phenanthroline, which is also known as a non-specific matrix metalloproteinase (MMP) inhibitor. We found that O-phenanthroline reduced the expression of MMP3 and MMP13 mRNA levels during chondrogenic differentiation of human chondrocytes (hChs), as well as after TNFα/IL-1β exposure in an explant model. Interestingly, O-phenanthroline significantly inhibited matrix degradation in a TNFα/IL-1β-dependent model of cartilage degeneration when compared to control and natural hypoxia (2.5% O2). O-Phenanthroline had limited ability to improve the chondrogenic differentiation or matrix deposition in the chondrogenic pellet model. Additionally, O-phenanthroline alleviated MMP-induced cartilage degradation without affecting chondrogenesis in the explant culture. The data presented in this study indicate that the inhibitory effect of O-phenanthroline on MMP expression is dominant over the hypoxia-mimicking effect

Rationale, design and baseline results of the Treatment Optimisation in Primary care of Heart failure in the Utrecht region (TOPHU) study : a cluster randomised controlled trial

BACKGROUND: Heart failure (HF) is mainly detected and managed in primary care, but the care is considered suboptimal. We present the rationale, design and baseline results of the Treatment Optimisation in Primary care of Heart failure in the Utrecht region (TOPHU) study. In this study we assess the effect of a single training of GPs in the pharmacological management of patients with HF. METHODS/DESIGN: A cluster randomised controlled trial. Thirty primary care practices are randomly assigned to care as usual or intervention defined as a single training in the up-titration and management of HF drug therapy according to the heart failure guidelines of the European Society of Cardiology (ESC). Patients with a GP's diagnosis of HF will be re-evaluated by an expert panel of two cardiologists and a GP with expertise in HF to come to a definite diagnosis of HF according to the ESC heart failure guidelines. Those with definite HF will be analysed in this study. Drug use will be measured after six months, health status after twelve months, and heart-related hospital admissions and all-cause mortality after two years. DISCUSSION: Our cluster randomised trial will show whether a single training of GPs improves the pharmacological management of patients with HF and confers beneficial effects on health status after one year, and cardiac hospital admissions and all-cause mortality after two years of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01662323

Extended prediction rule to optimise early detection of heart failure in older persons with non-acute shortness of breath : A cross-sectional study

Objectives: There is a need for a practical tool to aid general practitioners in early detection of heart failure in the elderly with shortness of breath. In this study, such a screening rule was developed based on an existing rule for detecting heart failure in older persons with a diagnosis of chronic obstructive pulmonary disease. The original rule included a history of ischaemic heart disease, body mass index, laterally displaced apex beat, heart rate, elevated N-terminal pro B-type natriuretic peptide and an abnormal ECG. Design: Cross-sectional data were used to validate, update and extend the original prediction rule according to a standardised state-of-the-art stepwise approach. Setting: Primary care with 30 participating general practices. Participants: Community-dwelling people aged ≥65 years with shortness of breath on exertion. Methods and results: Validation of the existing screening rule in our population showed satisfying discrimination with a concordance statistic of 0.84 (range 0.80-0.85), but poor calibration. Performance measures were most improved by adding the predictors age >75 years, peripheral oedema and systolic murmur, resulting in a concordance statistic of 0.88 (range 0.85-0.90) and a net reclassification improvement of 31%. A risk score was computed, which showed high accuracy with a negative predictive value of 87% and a positive predictive value of 73%. Evaluating the improved rule in the derivation set and an independent set of patients with type 2 diabetes aged 60 years or older showed satisfying generalisability of the rule. Conclusions: Our rule resulted in excellent prediction of heart failure in the large domain of the elderly with shortness of breath, and would help general practitioners to select those needing echocardiography. Trial registration number: NCT01202006

Effect of training general practitioners in drug treatment of newly detected heart failure patients with reduced or preserved ejection fraction : A cluster randomized trial

Objective To assess the effect of training general practitioners (GPS) in the optimization of drug treatment for newly detected heart failure (HF). Design Cluster randomized trial comparing the training programme to care as usual. Participants Community-dwelling older persons with a new HF diagnosis after diagnostic work-up. Methods Thirty GPS were randomized to care as usual or the training. Sixteen GPS of the latter group received a half-day training on optimizing HF medication in HF patients with a reduced (HFrEF), or with a preserved ejection fraction (HFpEF). At baseline and after six months of follow-up, the 46 HF patients in the intervention group and the 46 cases in the care as usual group were assessed on medication use, functionality, health status, and health care visits. Results After 6 months, uptake of HF medication and health status were similar in the two groups. Interestingly, patients in the intervention group had a longer walking distance with the six-minute walk test than those in the care as usual group (mean difference in all-type HF 28.0 (95% CI 2.9 to 53.1) meters; HFpEF patients 28.2 (95% CI 8.8 to 47.5) meters and HFrEF patients 55.9 (95% CI - 16.3 to 128.1) meters). They also had more HF-related GP visits (RR 1.8, 95% CI 1.3 to 2.5) and fewer visits to the cardiologist (RR 0.6, 95% CI 0.3 to 1.1). Conclusions Training GPS in optimization of drug treatment of newly detected HFrEF and HFpEF did not clearly increase HF medication, but resulted in improvement in walking distance

Overdiagnosis of heart failure in primary care : A cross-sectional study

Background Access to echocardiography in primary care is limited, but is necessary to accurately diagnose heart failure (HF). Aim To determine the proportion of patients with a GP's diagnosis of HF who really have HF. Design and setting A cross-sectional study of patients in 30 general practices with a GP's diagnosis of heart failure, based on the International Classification of Primary Care (ICPC) code K77, between June and November 2011. Method Electronic medical records of the patients' GPs were scrutinised for information on the diagnosis. An expert panel consisting of two cardiologists and an experienced GP used all available diagnostic information, and established the presence or absence of HF according to the criteria of the European Society of Cardiology (ESC) HF guidelines. Results In total, 683 individuals had a GP's diagnosis of HF. The mean age was 77.9 (SD 11.4) years, and 42.2% were male. Of these 683, 79.6% received cooperative care from a cardiologist. In 73.5% of cases, echocardiography was available for panel re-evaluation. Based on consensus opinion of the panel, 434 patients (63.5%, 95% confidence interval [CI] = 59.9 to 67.1) had definite HF, of which 222 (32.5%, 95% CI = 30.9 to 34.1) had HF with a reduced ejection fraction (HFrEF), 207 (30.3%, 95% CI = 29.0 to 31.6) had HF with a preserved ejection fraction (HFpEF), and five (0.7%, 95% CI = 1.2 to 2.6) had isolated right-sided HF. In 17.3% of cases (95% CI = 14.4 to 20.0), the panel considered HF absent, and in 19.2% (95% CI = 16.3 to 22.2) the diagnosis remained uncertain. Conclusion More than one-third of primary care patients labelled with HF may not have HF, and such overdiagnosis may result in inadequate patient management