Directed evolution of a magnetic resonance imaging contrast agent for noninvasive imaging of dopamine

The development of molecular probes that allow in vivo imaging of neural signaling processes with high temporal and spatial resolution remains challenging. Here we applied directed evolution techniques to create magnetic resonance imaging (MRI) contrast agents sensitive to the neurotransmitter dopamine. The sensors were derived from the heme domain of the bacterial cytochrome P450-BM3 (BM3h). Ligand binding to a site near BM3h's paramagnetic heme iron led to a drop in MRI signal enhancement and a shift in optical absorbance. Using an absorbance-based screen, we evolved the specificity of BM3h away from its natural ligand and toward dopamine, producing sensors with dissociation constants for dopamine of 3.3–8.9 μM. These molecules were used to image depolarization-triggered neurotransmitter release from PC12 cells and in the brains of live animals. Our results demonstrate the feasibility of molecular-level functional MRI using neural activity–dependent sensors, and our protein engineering approach can be generalized to create probes for other targets.Charles A. Dana Foundation. Brain and Immuno-ImagingRaymond and Beverley Sackler FoundationNational Institutes of Health (U.S.) (grant R01-DA28299)National Institutes of Health (U.S.) (grant DP2-OD2441)National Institutes of Health (U.S.) (grant R01-GM068664)Jacobs Institute for Molecular Engineering for Medicine. Jacobs Institute for Molecular Engineering for MedicineNational Institutes of Health (U.S.) (grant R01-DE013023

Congenital and childhood atrioventricular blocks: pathophysiology and contemporary management

Atrioventricular block is classified as congeni- tal if diagnosed in utero, at birth, or within the first month of life. The pathophysiological process is believed to be due to immune-mediated injury of the conduction system, which occurs as a result of transplacental pas- sage of maternal anti-SSA/Ro-SSB/La antibodies. Childhood atrioventricular block is therefore diagnosed between the first month and the 18th year of life. Genetic variants in multiple genes have been described to date in the pathogenesis of inherited progressive car- diac conduction disorders. Indications and techniques of cardiac pacing have also evolved to allow safe perma- nent cardiac pacing in almost all patients, including those with structural heart abnormalities

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Is there an optimal minimally invasive technique for left anterior descending coronary artery bypass?

<p>Abstract</p> <p>Background</p> <p>The aim of this retrospective study was to evaluate the clinical outcome of three different minimally invasive surgical techniques for left anterior descending (LAD) coronary artery bypass grafting (CABG): Port-Access surgery (PA-CABG), minimally invasive direct CABG (MIDCAB) and off-pump totally endoscopic CABG (TECAB).</p> <p>Methods</p> <p>Over a decade, 160 eligible patients for elective LAD bypass were referred to one of the three techniques: 48 PA-CABG, 53 MIDCAB and 59 TECAB. In MIDCAB group, Euroscore was higher and target vessel quality was worse. In TECAB group, early patency was systematically evaluated using coronary CT scan. During follow-up (mean 2.7 ± 0.1 years, cumulated 438 years) symptom-based angiography was performed.</p> <p>Results</p> <p>There was no conversion from off-pump to on-pump procedure or to sternotomy approach. In TECAB group, there was one hospital cardiac death (1.7%), reoperation for bleeding was higher (8.5% vs 3.7% in MIDCAB and 2% in PA-CABG) and 3-month LAD reintervention was significantly higher (10% vs 1.8% in MIDCAB and 0% in PA-CABG). There was no difference between MIDCAB and PA-CABG groups. During follow-up, symptom-based angiography (n = 12) demonstrated a good patency of LAD bypass in all groups and 4 patients underwent a no LAD reintervention. At 3 years, there was no difference in survival; 3-year angina-free survival and reintervention-free survival were significantly lower in TECAB group (TECAB, 85 ± 12%, 88 ± 8%; MIDCAB, 100%, 98 ± 5%; PA-CABG, 94 ± 8%, 100%; respectively).</p> <p>Conclusions</p> <p>Our study confirmed that minimally invasive LAD grafting was safe and effective. TECAB is associated with a higher rate of early bypass failure and reintervention. MIDCAB is still the most reliable surgical technique for isolated LAD grafting and the least cost effective.</p

Telepsychotherapy with children and families: Lessons gleaned from two decades of translational research

This is the author accepted manuscript. The final version is available from the American Psychological Association via the DOI in this recordThe novel coronavirus, COVID-19, has led to sweeping changes in psychological practice and the concomitant rapid uptake of telepsychotherapy. Although telepsychotherapy is new to many clinical psychologists, there is considerable research on telepsychotherapy treatments. Nearly two decades of clinical research on telepsychotherapy treatments with children with neurological conditions has the potential to inform emerging clinical practice in the age of COVID-19. Toward that end, we synthesized findings from 14 clinical trials of telepsychotherapy problemsolving and parent training interventions involving more than 800 children and families with diverse diagnoses including traumatic brain injury, epilepsy, brain tumors, congenital heart disease, and perinatal stroke. We summarize efficacy across studies and clinical populations and report feasibility and acceptability data from the perspectives of parents, children, and therapists. We describe adaptation for international contexts and strategies for troubleshooting technological challenges and working with families of varying socioeconomic strata. The extensive research literature reviewed and synthesized provides considerable support for the utility of telepsychotherapy with children with neurological conditions and their families and underscores its high level of acceptability with both diverse clinical populations and providers. During this period of heightened vulnerability and stress and reduced access to usual supports and services, telepsychotherapy approaches such as online family problem-solving treatment and online parenting skills training may allow psychologists to deliver traditional evidence-based treatments virtually while preserving fidelity and efficacyNational Institute for Health Research (NIHR

What do we know about chronic kidney disease in India: first report of the Indian CKD registry

<p>Abstract</p> <p>Background</p> <p>There are no national data on the magnitude and pattern of chronic kidney disease (CKD) in India. The Indian CKD Registry documents the demographics, etiological spectrum, practice patterns, variations and special characteristics.</p> <p>Methods</p> <p>Data was collected for this cross-sectional study in a standardized format according to predetermined criteria. Of the 52,273 adult patients, 35.5%, 27.9%, 25.6% and 11% patients came from South, North, West and East zones respectively.</p> <p>Results</p> <p>The mean age was 50.1 ± 14.6 years, with M:F ratio of 70:30. Patients from North Zone were younger and those from the East Zone older. Diabetic nephropathy was the commonest cause (31%), followed by CKD of undetermined etiology (16%), chronic glomerulonephritis (14%) and hypertensive nephrosclerosis (13%). About 48% cases presented in Stage V; they were younger than those in Stages III-IV. Diabetic nephropathy patients were older, more likely to present in earlier stages of CKD and had a higher frequency of males; whereas those with CKD of unexplained etiology were younger, had more females and more frequently presented in Stage V. Patients in lower income groups had more advanced CKD at presentation. Patients presenting to public sector hospitals were poorer, younger, and more frequently had CKD of unknown etiology.</p> <p>Conclusions</p> <p>This report confirms the emergence of diabetic nephropathy as the pre-eminent cause in India. Patients with CKD of unknown etiology are younger, poorer and more likely to present with advanced CKD. There were some geographic variations.</p

Associations between adherence, depressive symptoms and health-related quality of life in young adults with cystic fibrosis

BACKGROUND: Cystic fibrosis (CF) is a life shortening disease, however prognosis has improved and the adult population is growing. Most adults with cystic fibrosis live independent lives and balance the demands of work and family life with a significant treatment burden. The aim of this study was to examine the relationships among treatment adherence, symptoms of depression and health-related quality of life (HRQoL) in a population of young adults with CF. METHODS: We administered three standardized questionnaires to 67 patients with CF aged 18–30 years; Morisky Medication Adherence Scale, Major Depression Inventory, and Cystic Fibrosis Questionnaire-Revised. RESULTS: There was a response rate of 77 % and a majority of the young adults (84 %) were employed or in an education program. Most participants (74 %) reported low adherence to medications. One third (32.8 %) of the participants reported symptoms of depression. HRQoL scores were especially low on Vitality and Treatment Burden, and symptoms of depression were associated with low HRQoL scores (p < 0.01) with medium to large deficits across on all HRQoL domains (Cohen’s d 0.60–1.72) except for the domain treatment burden. High depression symptom scores were associated with low adherence (r = −0.412, p < 0.001). CONCLUSIONS: Despite improved physical health, many patients with CF report poor adherence, as well as impaired mental wellbeing and HRQoL. Thus, more attention to mental health issues is needed