Prevalence and incidence of intraventricular conduction delays and outcomes in patients with heart failure and reduced ejection fraction: Insights from PARADIGM-HF and ATMOSPHERE

Aims: The importance of intraventricular conduction delay (IVCD), incidence of new IVCD and its relationship to outcomes in heart failure and reduced ejection fraction (HFrEF) is not well studied. We addressed these questions in the PARADIGM-HF and ATMOSPHERE trials. Methods and results: Risk of the primary composite outcome of cardiovascular death or HF hospitalization and all-cause mortality were estimated by use of Cox regression according to baseline QRS duration and morphology in 11,861 patients without an intracardiac device. At baseline, 1,789 (15.1%) patients had left bundle branch block (LBBB), 524 (4.4%) RBBB, 454 (3.8%) non-specific IVCD, 2588 (21.8%) "mildly abnormal" QRS (110-129 milliseconds [ms]) and 6506 (54.9%) QRS <110 ms. During a median follow-up of 2.5 years, the risk of the primary composite endpoint was higher among those with a wide QRS, irrespective of morphology: hazard ratios (95% CI) LBBB 1.36 (1.23, 1.50), RBBB 1.54 (1.31, 1.79), nonspecific IVCD 1.65 (1.40, 1.94) and QRS 110-129 ms 1.35 (95% CI 1.23, 1.47), compared with QRS duration <110 ms. A total of 1,234 (15.6%) patients developed new-onset QRS-widening ≥130 ms (6.1 per 100 py). Incident LBBB occurred in 495 (6.3%) patients (2.4 per 100 py) and was associated with a higher risk of the primary composite outcome; HR 1.42 (1.12, 1.82). Conclusion: In patients with HFrEF, a wide QRS was associated with worse clinical outcomes irrespective of morphology. The annual incidence of new-onset LBBB was around 2.5%, and associated with a higher risk of adverse outcomes, highlighting the importance of repeat ECG review

A mobile telehealth intervention for adults with insulin-requiring diabetes: early results of a mixed-methods randomized controlled trial

BACKGROUND: The role of technology in health care delivery has grown rapidly in the last decade. The potential of mobile telehealth (MTH) to support patient self-management is a key area of research. Providing patients with technological tools that allow for the recording and transmission of health parameters to health care professionals (HCPs) may promote behavior changes that result in improved health outcomes. Although for some conditions the evidence of the effectiveness of MTH is clear, to date the findings on the effects of MTH on diabetes management remain inconsistent. OBJECTIVE: This study aims to evaluate an MTH intervention among insulin-requiring adults with diabetes to establish whether supplementing standard care with MTH results in improved health outcomes-glycated hemoglobin (HbA1c), blood pressure (BP), health-related quality of life (HRQoL), diabetes self-management behaviors, diabetes health care utilization, and diabetes self-efficacy and illness beliefs. An additional objective was to explore the acceptability of MTH and patients' perceptions of, and experience, using it. METHODS: A mixed-method design consisting of a 9-month, two-arm, parallel randomized controlled trial (RCT) was used in combination with exit qualitative interviews. Quantitative data was collected at baseline, 3 months, and 9 months. Additional intervention fidelity data, such as participants' MTH transmissions and contacts with the MTH nurse during the study, were also recorded. RESULTS: Data collection for both the quantitative and qualitative components of this study has ended and data analysis is ongoing. A total of 86 participants were enrolled into the study. Out of 86 participants, 45 (52%) were randomized to the intervention group and 36 (42%) to the control group. Preliminary data on MTH training sessions and MTH usage by intervention participants are presented in this paper. We expect to publish complete study results in 2015. CONCLUSIONS: The range of data collected in this study will allow for a comprehensive evaluation of processes and outcomes. The early results presented suggest that MTH usage decreases over time and that MTH participants would benefit from attending more than one training session. TRIAL REGISTRATION: ClinicalTrials.gov NCT00922376; http://clinicaltrials.gov/ct2/show/NCT00922376 (Archived by WebCite at http://www.webcitation.org/6Vu4nhLI6)

Estimates of array and pool-construction variance for planning efficient DNA-pooling genome wide association studies

<p>Abstract</p> <p>Background</p> <p>Until recently, genome-wide association studies (GWAS) have been restricted to research groups with the budget necessary to genotype hundreds, if not thousands, of samples. Replacing individual genotyping with genotyping of DNA pools in Phase I of a GWAS has proven successful, and dramatically altered the financial feasibility of this approach. When conducting a pool-based GWAS, how well SNP allele frequency is estimated from a DNA pool will influence a study's power to detect associations. Here we address how to control the variance in allele frequency estimation when DNAs are pooled, and how to plan and conduct the most efficient well-powered pool-based GWAS.</p> <p>Methods</p> <p>By examining the variation in allele frequency estimation on SNP arrays between and within DNA pools we determine how array variance [var(e_array)] and pool-construction variance [var(e_construction)] contribute to the total variance of allele frequency estimation. This information is useful in deciding whether replicate arrays or replicate pools are most useful in reducing variance. Our analysis is based on 27 DNA pools ranging in size from 74 to 446 individual samples, genotyped on a collective total of 128 Illumina beadarrays: 24 1M-Single, 32 1M-Duo, and 72 660-Quad.</p> <p>Results</p> <p>For all three Illumina SNP array types our estimates of var(e_array) were similar, between 3-4 × 10^-4for normalized data. Var(e_construction) accounted for between 20-40% of pooling variance across 27 pools in normalized data.</p> <p>Conclusions</p> <p>We conclude that relative to var(e_array), var(e_construction) is of less importance in reducing the variance in allele frequency estimation from DNA pools; however, our data suggests that on average it may be more important than previously thought. We have prepared a simple online tool, PoolingPlanner (available at <url>http://www.kchew.ca/PoolingPlanner/</url>), which calculates the effective sample size (ESS) of a DNA pool given a range of replicate array values. ESS can be used in a power calculator to perform pool-adjusted calculations. This allows one to quickly calculate the loss of power associated with a pooling experiment to make an informed decision on whether a pool-based GWAS is worth pursuing.</p

Is annual surveillance of all treated hypothyroid patients necessary?

Peer reviewedPublisher PD

F- and G-Actin Concentrations in Lamellipodia of Moving Cells

Cells protrude by polymerizing monomeric (G) into polymeric (F) actin at the tip of the lamellipodium. Actin filaments are depolymerized towards the rear of the lamellipodium in a treadmilling process, thereby supplementing a G-actin pool for a new round of polymerization. In this scenario the concentrations of F- and G-actin are principal parameters, but have hitherto not been directly determined. By comparing fluorescence intensities of bleached and unbleached regions of lamellipodia in B16-F1 mouse melanoma cells expressing EGFP-actin, before and after extraction with Triton X-100, we show that the ratio of F- to G-actin is 3.2+/−0.9. Using electron microscopy to determine the F-actin content, this ratio translates into F- and G-actin concentrations in lamellipodia of approximately 500 µM and 150 µM, respectively. The excess of G-actin, at several orders of magnitude above the critical concentrations at filament ends indicates that the polymerization rate is not limited by diffusion and is tightly controlled by polymerization/depolymerization modulators

The elementary events underlying force generation in neuronal lamellipodia

We have used optical tweezers to identify the elementary events underlying force generation in neuronal lamellipodia. When an optically trapped bead seals on the lamellipodium membrane, Brownian fluctuations decrease revealing the underlying elementary events. The distribution of bead velocities has long tails with frequent large positive and negative values associated to forward and backward jumps occurring in 0.1–0.2 ms with varying amplitudes up to 20 nm. Jump frequency and amplitude are reduced when actin turnover is slowed down by the addition of 25 nM Jasplakinolide. When myosin II is inhibited by the addition of 20 μM Blebbistatin, jump frequency is reduced but to a lesser extent than by Jasplainolide. These jumps constitute the elementary events underlying force generation

Non-invasive management of peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is common and symptoms can be debilitating and lethal. Risk management, exercise, radiological and surgical intervention are all valuable therapies, but morbidity and mortality rates from this disease are increasing. Circulatory enhancement can be achieved using simple medical electronic devices, with claims of minimal adverse side effects. The evidence for these is variable, prompting a review of the available literature. METHODS: Embase and Medline were interrogated for full text articles in humans and written in English. Any external medical devices used in the management of peripheral arterial disease were included if they had objective outcome data. RESULTS: Thirty-one papers met inclusion criteria, but protocols were heterogenous. The medical devices reported were intermittent pneumatic compression (IPC), electronic nerve (NMES) or muscle stimulators (EMS), and galvanic electrical dressings. In patients with intermittent claudication, IPC devices increase popliteal artery velocity (49-70 %) and flow (49-84 %). Gastrocnemius EMS increased superficial femoral artery flow by 140 %. Over 4.5-6 months IPC increased intermittent claudication distance (ICD) (97-150 %) and absolute walking distance (AWD) (84-112 %), with an associated increase in quality of life. NMES of the calf increased ICD and AWD by 82 % and 61-150 % at 4 weeks, and 26 % and 34 % at 8 weeks. In patients with critical limb ischaemia IPC reduced rest pain in 40-100 % and was associated with ulcer healing rates of 26 %. IPC had an early limb salvage rate of 58-83 % at 1-3 months, and 58-94 % at 1.5-3.5 years. No studies have reported the use of EMS or NMES in the management of CLI. CONCLUSION: There is evidence to support the use of IPC in the management of claudication and CLI. There is a building body of literature to support the use of electrical stimulators in PAD, but this is low level to date. Devices may be of special benefit to those with limited exercise capacity, and in non-reconstructable critical limb ischaemia. Galvanic stimulation is not recommended

Differences in Immunoglobulin Light Chain Species Found in Urinary Exosomes in Light Chain Amyloidosis (AL)

Renal involvement is a frequent consequence of plasma cell dyscrasias. The most common entities are light chain amyloidosis, monoclonal immunoglobulin deposition disease and myeloma cast nephropathy. Despite a common origin, each condition has its own unique histologic and pathophysiologic characteristic which requires a renal biopsy to distinguish. Recent studies have shown urinary exosomes containing kidney-derived membrane and cytosolic proteins that can be used to probe the proteomics of the entire urinary system from the glomerulus to the bladder. In this study, we analyzed urine exosomes to determine the differences between exosomes from patients with light chain amyloidosis, multiple myeloma, monoclonal gammopathy of undetermined significance, and non-paraproteinemia related kidney disease controls. In patients with light chain amyloidosis, multiple myeloma and monoclonal gammopathy of undetermined significance, immunoreactive proteins corresponding to monomeric light chains were found in exosomes by western blot. In all of the amyloidosis samples with active disease, high molecular weight immunoreactive species corresponding to a decamer were found which were not found in exosomes from the other diseases or in amyloidosis exosomes from patients in remission. Few or no light chains monomeric bands were found in non-paraproteinemia related kidney disease controls. Our results showed that urinary exosomes may have tremendous potential in furthering our understanding of the pathophysiology and diagnosis of plasma cell dyscrasia related kidney diseases

A proposal for calculating the no-observed-adverse-effect level (NOAEL) for organic compounds responsible for liver toxicity based on their physicochemical properties

Objectives: Both environmental and occupational exposure limits are based on the no-observed-adverse-effect level (NOAEL), lowest-observed-adverse-effect level (LOAEL) or benchmark dose (BMD) deriving from epidemiological and experimental studies. The aim of this study is to investigate to what extent the NOAEL values for organic compounds responsible for liver toxicity calculated based on their physicochemical properties could be used for calculating occupational exposure limits. Material and Methods: The distribution coefficients from air to the liver (log Kliver) were calculated according to the Abraham solvation equation. NOAEL and LOAEL values for early effects in the liver were obtained from the literature data. The descriptors for Abraham's equation were found for 59 compounds, which were divided into 2 groups: "non-reactive" (alcohols, ketones, esters, ethers, aromatic and aliphatic hydrocarbons, amides) and "possibly reactive" (aldehydes, allyl compounds, amines, benzyl halides, halogenated hydrocarbons, acrylates). Results: The correlation coefficients between log-log K and log NOAEL for non-reactive and reactive compounds amounted to r = -0.8123 and r = -0.8045, respectively, and were statistically significant. It appears that the Abraham equation could be used to predict the NOAEL values for compounds lacking information concerning their liver toxicity. Conclusions: In view of the tendency to limit animal testing procedures, the method proposed in this paper can improve the practice of setting exposure guidelines for the unstudied compounds