Algorithm-based reduction of inappropriate defibrillator shock: Results of the Inappropriate Shock Reduction wIth PARAD+ Rhythm DiScrimination-Implantable Cardioverter Defibrillator Study.

BACKGROUND: Inappropriate shocks (IS) continue to have a major negative impact on patients implanted with defibrillators. OBJECTIVE: The purpose of this study was to assess IS reduction with the PARAD+ discrimination algorithm in a general population implanted for primary or secondary prevention. METHODS: ISIS-ICD (Inappropriate Shock Reduction wIth PARAD+ Rhythm DiScrimination-Implantable Cardioverter Defibrillator) was a 2-year international, interventional study in patients implanted with a dual implantable cardioverter-defibrillator (ICD) or triple-chamber defibrillator (cardiac resynchronization therapy-defibrillator [CRT-D]) featuring PARAD+. IS (shocks not delivered for ventricular tachycardia or fibrillation) were independently adjudicated. The primary endpoint was percentage of IS-free patients at 24 months. Primary and worst-case analyses of annual incidence rates of patients with ≥1 IS, overall and per defibrillator type, were conducted. RESULTS: In total, 1013 patients (80.7% male; age 67.1 ± 11.4 years; 68%/30%/2% primary/secondary/other indication) were enrolled and followed for a median of 552 days (interquartile range 354; 725). Of 993 analyzed patients programmed with PARAD+, 14 had ≥1 IS, corresponding to a percentage free from IS of 98.1% (95% confidence interval [CI] 96.8%- 98.9%). Annual incidence rates (per 100 person-years) of patients with IS were 1.0 (95% CI 0.59-1.69) and 2.1 (95% CI 1.46-3.02) in the primary and worst-case analyses, respectively. In ICD patients, rates were 1.2 (95% CI 0.68-2.23) and 2.3 (95% CI 1.47-3.53), and in CRT-D patients 0.59 (95% CI 0.19-1.83) and 1.8 (95% CI 0.93-3.44) per 100 person-years. CONCLUSION: The annual rate of defibrillator patients with IS using the enhanced PARAD+ discrimination algorithm alone ranged from 1.0 to 2.1 per 100 person-years in a general population implanted for primary or secondary prevention.

A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease.

BACKGROUND: Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease. METHODS: Ninety-six patients with early-stage Huntington's disease were randomized to 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed-effects model for repeated measures was used to assess treatment effect, expressed as the least-squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo. RESULTS: At 18 months, the treatment effect was not statistically significant - least-squares mean difference, -1.5 ± 1.71 (P = 0.385) - although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated. CONCLUSIONS: Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society.

The Kora Pacemaker is Safe and Effective for Magnetic Resonance Imaging.

BACKGROUND: The impact of magnetic resonance imaging (MRI) on pacemakers is potentially hazardous. We present clinical results from a novel MRI conditional pacing system with the capability to switch automatically to asynchronous mode in the presence of a strong magnetic field. AIMS: The IKONE (Assessment of the MRI solution: KORA 100™ and Beflex™ pacing leads system) study is an open-label, prospective, multicenter study aimed at confirming the safety and effectiveness of the system, when used in patients undergoing MRI of anatomical regions excluding the chest. METHODS: Primary eligibility criteria included patients implanted with the system, with or without a clinically indicated MRI. The primary endpoint was to confirm no significant change in pacing capture thresholds at 1 month after an MRI, with an absolute difference of ≤0.75 V between the pre- and 1-month post-MRI for both atrial and ventricular capture thresholds. RESULTS: Out of 33 patients enrolled (mean age: 72.8 ± 11.4 years, 70% male, implant indication or device), 29 patients implanted with the MRI conditional system underwent an MRI 6-8 week postimplant. The study reached its primary endpoint: the mean absolute difference in pacing capture threshold at 1-month post-MRI versus pre-MRI was less than 0.75 V in the atrium (Δ = 0.18 ± 0.16 V, P-value < 0.001) and in the ventricle (Δ = 0.18 ± 0.22 V, P-value < 0.001). There were no adverse events related to the MRI procedure nor were there reports of patient symptoms or discomfort associated. MR image quality was of diagnostic quality in all patients. CONCLUSION: Lead electrical performance as measured by difference in capture thresholds were not impacted by MRI. This first clinical evaluation of a novel MRI conditional system demonstrates it is safe and effective for use in out-of-chest, 1.5-T MR imaging.

The most appropriate primary outcomes to design clinical trials on Huntington's disease: meta-analyses of cohort studies and randomized placebo-controlled trials.

Huntington's disease (HD) is a rare multifactorial neurodegenerative disease. Both its natural course and any placebo effect are poorly known. All are obstacles to design randomized controlled trials (RCTs). We conducted meta-analyses of RCTs and cohorts on all parameters of the Unified Huntington's Disease Rating Scale to determine the most appropriate outcomes and to minimize the number of patients required to design RCTs in HD. Twenty-four RCTs were included, involving 838 patients with a mean age of 50.0 ± 2.3 years and a mean total functional capacity (TFC) score of 9.8 ± 0.6. Nineteen cohorts were included involving 1939 patients with a mean age of 48.9 ± 2.3 years and a mean TFC of 10.1 ± 0.7. Significant deterioration was observed in RCTs for all scores except behavioral score. Effect sizes were comparable between RCTs and cohorts for each test except that there was a significant difference for TFC. The weighted mean deterioration per year on the TFC scale was -0.5 (0.2) in RCTs and -0.8 (0.2) in cohorts. The lowest number of patients required per group in a RCT was for TFC (19 per group), whereas 30 patients would be required per group for the total motor score (TMS). For cognition, the verbal fluency test required the smallest number of patients: 104 per group. In conclusion, TMS and TFC are the most appropriate outcomes to design RCTs on HD likewise the verbal fluency test for cognition. Our results suggest an effect of placebo administration on the total functional capacity.

Role of the single-stranded DNA-binding protein SsbB in pneumococcal transformation: maintenance of a reservoir for genetic plasticity.

Bacteria encode a single-stranded DNA (ssDNA) binding protein (SSB) crucial for genome maintenance. In Bacillus subtilis and Streptococcus pneumoniae, an alternative SSB, SsbB, is expressed uniquely during competence for genetic transformation, but its precise role has been disappointingly obscure. Here, we report our investigations involving comparison of a null mutant (ssbB(-)) and a C-ter truncation (ssbBΔ7) of SsbB of S. pneumoniae, the latter constructed because SSBs' acidic tail has emerged as a key site for interactions with partner proteins. We provide evidence that SsbB directly protects internalized ssDNA. We show that SsbB is highly abundant, potentially allowing the binding of ~1.15 Mb ssDNA (half a genome equivalent); that it participates in the processing of ssDNA into recombinants; and that, at high DNA concentration, it is of crucial importance for chromosomal transformation whilst antagonizing plasmid transformation. While the latter observation explains a long-standing observation that plasmid transformation is very inefficient in S. pneumoniae (compared to chromosomal transformation), the former supports our previous suggestion that SsbB creates a reservoir of ssDNA, allowing successive recombination cycles. SsbBΔ7 fulfils the reservoir function, suggesting that SsbB C-ter is not necessary for processing protein(s) to access stored ssDNA. We propose that the evolutionary raison d'être of SsbB and its abundance is maintenance of this reservoir, which contributes to the genetic plasticity of S. pneumoniae by increasing the likelihood of multiple transformation events in the same cell.

Interactions between poloxamers in aqueous solutions: micellization and gelation studied by differential scanning calorimetry, small angle X-ray scattering, and rheology.

Poloxamers F88 (EO97PO39EO97) and P85 (EO27PO39EO27) are triblock copolymers of ethylene oxide (EO) and propylene oxide (PO), which have the same hydrophobic PO block. We studied aqueous solutions of these two copolymers by the conjoint use of differential scanning calorimetry (DSC), rheology, and small-angle X-ray scattering (SAXS). The results showed that the temperature-induced micellization of aqueous solutions of F88 and P85 was a progressive process followed by gelation for sufficiently concentrated samples. Gelation was due to the ordered packing of micelles under a hexagonal compact (HC) structure for P85 and a body-centered cubic (BCC) phase for F88. Importantly, the phase diagram of F88/P85 mixtures in water was elucidated and showed the destabilization of the HC phase upon addition of small amounts of F88.