Background: The Subcutaneous ICD (S-ICD) is safe and effective for sudden cardiac death prevention. However, patients in previous S-ICD studies had fewer comorbidities, less left ventricular dysfunction and received more inappropriate shocks (IAS) than in typical transvenous (TV)-ICD trials. The UNTOUCHED trial was designed to evaluate the IAS rate in a more typical, contemporary ICD patient population implanted with the S-ICD using standardized programming and enhanced discrimination algorithms. Methods: Primary prevention patients with left ventricular ejection fraction (LVEF) ≤ 35% and no pacing indications were included. Generation 2 or 3 S-ICD devices were implanted and programmed with rate-based therapy delivery for rates ≥ 250 beats per minute (bpm) and morphology discrimination for rates ≥200 and < 250 bpm. Patients were followed for 18 months. The primary endpoint was the IAS free rate compared to a 91.6% performance goal, derived from the results for the ICD-only patients in the MADIT-RIT study. Kaplan-Meier analyses were performed to evaluate event-free rates for IAS, all cause shock, and complications. Multivariable proportional hazard analysis was performed to determine predictors of endpoints. Results: S-ICD implant was attempted in 1116 patients and 1111 patients were included in post-implant follow-up analysis. The cohort had a mean age of 55.8±12.4 years, 25.6% women, 23.4% black race, 53.5% with ischemic heart disease, 87.7% with symptomatic heart failure and a mean LVEF of 26.4±5.8%. Eighteen-month freedom from IAS was 95.9% (Lower confidence limit LCL 94.8%). Predictors of reduced incidence of IAS were implanting the most recent generation of device, using the three-incision technique, no history of atrial fibrillation, and ischemic etiology. The 18-month all cause shock free rate was 90.6% (LCL 89.0%), meeting the prespecified performance goal of 85.8%. Conversion success rate for appropriate, discrete episodes was 98.4%. Complication free rate at 18 months was 92.7%. Conclusions: This study demonstrates high efficacy and safety with contemporary S-ICD devices and programming despite the relatively high incidence of co-morbidities in comparison to earlier S-ICD trials. The inappropriate shock rate (3.1% at one year) is the lowest reported for the S-ICD and lower than many TV ICD studies using contemporary programming to reduce IAS. Clinical Trial Registration: URL https://clinicaltrials.gov Unique Identifier NCT02433379

Nearly finished sequences for model organisms provide a foundation from which to explore genomic diversity among other taxonomic groups. We explore genome-wide microsynteny patterns between the rice sequence and two sorghum physical maps that integrate genetic markers, bacterial artificial chromosome (BAC) fingerprints, and BAC hybridization data. The sorghum maps largely tile a genomic component containing 41% of BACs but 80% of single-copy genes that shows conserved microsynteny with rice and partially tile a nonsyntenic component containing 46% of BACs but only 13% of single-copy genes. The remaining BACs are centromeric (4%) or unassigned (8%). The two genomic components correspond to cytologically discernible ''euchromatin'' and ''heterochromatin.'' Gene and repetitive DNA distributions support this classification. Greater microcolinearity in recombinogenic (euchromatic) than nonrecombinogenic (heterochromatic) regions is consistent with the hypothesis that genomic rearrangements are usually deleterious, thus more likely to persist in nonrecombinogenic regions by virtue of Muller's ratchet. Interchromosomal centromeric rearrangements may have fostered diploidization of a polyploid cereal progenitor. Model plant sequences better guide studies of related genomes in recombinogenic than nonrecombinogenic regions. Bridging of 35 physical gaps in the rice sequence by sorghum BAC contigs illustrates reciprocal benefits of comparative approaches that extend at least across the cereals and perhaps beyond.comparative genomics ͉ Oryza ͉ synteny T he grasses (Poaceae) provide most of mankind's caloric intake and a growing share of our fuel. The best-studied grasses, leading cereal crops, shared a common paleopolyploid ancestor Ϸ42-47 million years ago (mya) (1). Cereals show much colinearity of genetic maps and often have important traits controlled by quantitative trait loci at corresponding locations (2). Despite these similarities, the cereals have diverged remarkably in genome size from Ϸ430 million base pairs (MBP) in rice (3) to 15,966 MBP in wheat (3), largely due to differential repetitive DNA amplification and elimination.As a model for tropical grasses, sorghum [Sorghum bicolor (SB)] is a logical complement to rice (Oryza), in that it has biochemical and morphological specializations to improve carbon assimilation at high temperatures (C4 photosynthesis). By contrast, rice uses C3 photosynthesis more typical of temperate grasses. The Ϸ760-MBP (3) sorghum genome is a logical bridge to the Ϸ2,500-MBP (3) maize genome, and the Ϸ4,000-MBP (3) genome of sugarcane, the world's leading biomass͞biofuels crop. Sorghum shared common ancestry with maize (12 mya) and sugarcane (5 mya), much more recently than rice (42-47 mya). The most recent whole-genome duplication in sorghum appears to be Ϸ70 mya (1) vs. Ϸ12 mya in maize (4) and Ͻ5 mya in sugarcane (5), promising a higher success rate in relating sorghum genes to phenotypes by knockouts than either maize or sugarcane genes. Comparison of SB and closely related Sorghum...

The aim of the study was to determine the possible effect of melatonin treatment on disturbed sleep, fatigue and pain symptoms observed in fibromyalgia (FM) patients. Twenty-one consecutive patients with FM were included in an open 4-week-duration pilot study. Before and after treatment with melatonin 3 mg at bedtime, patients were evaluated using tender point count by palpation of 18 classic anatomical regions, pain score in four predesignated areas, pain severity on a 10 cm visual analogue scale (VAS), sleep disturbances, fatigue, depression, anxiety, and patient and physician global assessments, also by a VAS. Urine 6-sulphatoxymelatonin levels (aMT-6S) were measured in the patients and 20 age- and sex-matched controls. Nineteen patients completed the study. One patient withdrew because of migraine and another was lost to follow-up. At day 30, median values for the tender point count and severity of pain at selected points, patient and physician global assessments and VAS for sleep significantly improved with melatonin treatment. Other variables improved but did not reach statistical significance. Adverse events were mild and transient. Lower levels of aMT-6S were found in FM patients compared with normal median controls (+/-SD, 9.16 +/- 7.9 microg/24 h vs 16.8 +/- 12.8 microg/24 h) (p = 0.06). Although this is an open study, our preliminary results suggest that melatonin can be an alternative and safe treatment for patients with FM. Double-blind placebo controlled studies are needed.

NCT02373982 (http://clinicaltrials.gov/ct2/show/NCT02373982).