Transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): A phase 2, randomized, sham-controlled trial

Background -In non-randomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), less symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and mid-range or preserved ejection fraction (EF ≥ 40%). We conducted the first randomized, sham-controlled trial to evaluate the IASD in HF with EF ≥ 40%. Methods -REDUCE LAP-HF I was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association (NYHA) class III or ambulatory class IV HF, EF ≥ 40%, exercise PCWP ≥ 25 mmHg, and PCWP-right atrial pressure gradient ≥ 5 mmHg. Participants were randomized (1:1) to the IASD vs. a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness endpoint was exercise PCWP at 1 month. The primary safety endpoint was major adverse cardiac, cerebrovascular, and renal events (MACCRE) at 1 month. PCWP during exercise was compared between treatment groups using a mixed effects repeated measures model analysis of covariance that included data from all available stages of exercise. Results -A total of 94 patients were enrolled, of which n=44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared to sham-control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mmHg in the treatment group vs. 0.5±5.0 mmHg in the control group (P=0.14). There were no peri-procedural or 1-month MACCRE in the IASD group and 1 event (worsening renal function) in the control group (P=1.0). Conclusions -In patients with HF and EF ≥ 40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation. Clinical Trial Registration -URL: http://clinicaltrials.gov. Unique identifier: NCT02600234

Estimating the Burden of Acute Gastrointestinal Illness in Grenada

This is the first study conducted in Grenada, with a population of approximately 108,000, to quantify the magnitude, distribution, and burden of self-reported acute gastroenteritis (AGE). A retrospective population survey was conducted in October 2008 and April 2009 and a laboratory survey from October 2008 to September 2009. The estimated monthly prevalence of AGE was 10.7% (95% CI 9.0-12.6; 1.4 episodes/ person-year), with a median of 3 days of illness. Of those who reported AGE, 31% sought medical care (stool samples were requested from 12.5%); 10% took antibiotics; 45% took non-prescribed medication; and 81% reported restricted activity. Prevalence of AGE was significantly higher among children aged <5 years (23.5%, p<0.001). Of the AGE stool samples submitted to the laboratory for analysis, 12.1% were positive for a foodborne pathogen. Salmonella enteritidis was the most common foodborne pathogen associated with AGE-related illness. The estimated percentage of underreporting of syndromic AGE to the Ministry of Health was 69%. In addition, for every laboratory-confirmed foodborne/AGE pathogen, it was estimated that there were 316 additional cases occurring in the population. The minimum estimated cost associated with treatment for AGE was US$ 703,950 each year, showing that AGE has a potentially significant economic impact in Grenada

Next-to-leading order QCD predictions for W+W+jj production at the LHC

Because the LHC is a proton-proton collider, sizable production of two positively charged W-bosons in association with two jets is possible. This process leads to a distinct signature of same sign high-pt leptons, missing energy and jets. We compute the NLO QCD corrections to the QCD-mediated part of pp -> W+W+jj. These corrections reduce the dependence of the production cross-section on the renormalization and factorization scale to about +- 10 percent. We find that a large number of W+W+jj events contain a relatively hard third jet. The presence of this jet should help to either pick up the W+W+jj signal or to reject it as an unwanted background.Comment: 15 pages, 5 (lovely) figures, v3 accepted for publication in JHEP, corrects tables in appendi

Genetic, environmental and stochastic factors in monozygotic twin discordance with a focus on epigenetic differences

PMCID: PMC3566971This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Gluon-gluon contributions to W+ W- production and Higgs interference effects

In this paper we complete our re-assessment of the production of W boson pairs at the LHC, by calculating analytic results for the gg -> W+ W- -> (\nu l l\nu) process including the effect of massive quarks circulating in the loop. Together with the one-loop amplitudes containing the first two generations of massless quarks propagating in the loop, these diagrams can give a significant contribution with a large flux of gluons. One of the component parts of this calculation is the production of a standard model Higgs boson, gg -> H and its subsequent decay, H -> W+(-> \nu l) W-(-> l \nu). We will quantify the importance of the interference between the Higgs boson production process and the gluon-induced continuum production in the context of searches for the Higgs boson at the Tevatron and the LHC. For instance, for mH < 140 GeV the effect of the interference typically results in around a 10% reduction in the expected number of Higgs signal events. The majority of this interference is due to non-resonant contributions. Therefore cuts on the transverse mass such as those currently used by the ATLAS collaboration reduce the destructive interference to about a 1% effect. We advocate that a cut on the maximum transverse mass be used in future Higgs searches in this channel

Stabilization of mismatch repair gene PMS2 by glycogen synthase kinase 3β is implicated in the treatment of cervical carcinoma

<p>Abstract</p> <p>Background</p> <p>PMS2 expression loss was reported in a variety of human. However, its importance has not been fully understood in cervical carcinoma. The aim of this study was to determine the expression of PMS2 in cervical carcinoma and evaluate the significance of mismatch repair gene PMS2 regulated by glycogen synthase kinase 3β (GSK-3β) in chemosensitivity.</p> <p>Methods</p> <p>We examined PMS2 and phosphorylated GSK-3β(<it>s</it>9) expression in cervical carcinoma tissues using immunohistochemical staining. Furthermore, we detected PMS2 expression in HeLa cells and evaluate the interaction with GSK-3β after transfection with GSK-3β by small interference RNA (siRNA), co-immunoprecipitation and immunoblotting. We also evaluated the effect of PMS2 transfection on HeLa cells' chemosensitivity to cisplatin treatment.</p> <p>Results</p> <p>We found significant downregulation of PMS2 in cervical carcinoma, which was negatively associated with phosphorylated GSK-3β (<it>s</it>9). Furthermore, we demonstrated GSK-3β transfection was able to interact with PMS2 and enhance PMS2 production in HeLa cells, and increased PMS2 production was responsible for enhanced chemosensitivity.</p> <p>Conclusions</p> <p>Our results provide the evidence that stabilization of PMS2 production by GSK-3β was important to improve chemosensitization, indicating the significance of GSK-3β-related PMS2 downregulation in the development of cervical carcinoma and in developing a potential strategy for chemotherapy.</p

Use of stochastic simulation to evaluate the reduction in methane emissions and improvement in reproductive efficiency from routine hormonal interventions in dairy herds

This study predicts the magnitude and between herd variation in changes of methane emissions and production efficiency associated with interventions to improve reproductive efficiency in dairy cows. Data for 10,000 herds of 200 cows were simulated. Probability of conception was predicted daily from the start of the study (parturition) for each cow up to day 300 of lactation. Four scenarios of differing first insemination management were simulated for each herd using the same theoretical cows: A baseline scenario based on breeding from observed oestrus only, synchronisation of oestrus for pre-set first insemination using 2 methods, and a regime using prostaglandin treatments followed by first insemination to observed oestrus. Cows that did not conceive to first insemination were re-inseminated following detection of oestrus. For cows that conceived, gestation length was 280 days with cessation of milking 60 days before calving. Those cows not pregnant after 300 days of lactation were culled and replaced by a heifer. Daily milk yield was calculated for 730 days from the start of the study for each cow. Change in mean reproductive and economic outputs were summarised for each herd following the 3 interventions. For each scenario, methane emissions were determined by daily forage dry matter intake, forage quality, and cow replacement risk. Linear regression was used to summarise relationships. In some circumstances improvement in reproductive efficiency using the programmes investigated was associated with reduced cost and methane emissions compared to reliance on detection of oestrus. Efficiency of oestrus detection and the time to commencement of breeding after calving influenced variability in changes in cost and methane emissions. For an average UK herd this was a saving of at least £50 per cow and a 3.6% reduction in methane emissions per L of milk when timing of first insemination was pre-set

The OSU1/QUA2/TSD2-Encoded Putative Methyltransferase Is a Critical Modulator of Carbon and Nitrogen Nutrient Balance Response in Arabidopsis

The balance between carbon (C) and nitrogen (N) nutrients must be tightly coordinated so that cells can optimize their opportunity for metabolism, growth and development. However, the C and N nutrient balance perception and signaling mechanism remains poorly understood. Here, we report the isolation and characterization of two allelic oversensitive to sugar1 mutants (osu1-1, osu1-2) in Arabidopsis thaliana. Using the cotyledon anthocyanin accumulation and root growth inhibition assays, we show that the osu1 mutants are more sensitive than wild-type to both of the imbalanced C/N conditions, high C/low N and low C/high N. However, under the balanced C/N conditions (low C/low N or high C/high N), the osu1 mutants have similar anthocyanin levels and root lengths as wild-type. Consistently, the genes encoding two MYB transcription factors (MYB75 and MYB90) and an Asn synthetase isoform (ASN1) are strongly up-regulated by the OSU1 mutation in response to high C/low N and low C/high N, respectively. Furthermore, the enhanced sensitivity of osu1-1 to high C/low N with respect to anthocyanin accumulation but not root growth inhibition can be suppressed by co-suppression of MYB75, indicating that MYB75 acts downstream of OSU1 in the high C/low N imbalance response. Map-based cloning reveals that OSU1 encodes a member of a large family of putative methyltransferases and is allelic to the recently reported QUA2/TSD2 locus identified in genetic screens for cell-adhesion-defective mutants. Accumulation of OSU1/QUA2/TSD2 transcript was not regulated by C and N balance, but the OSU1 promoter was slightly more active in the vascular system. Taken together, our results show that the OSU1/QUA2/TSD2-encoded putative methyltransferase is required for normal C/N nutrient balance response in plants

Keeping Pace with Your Eating: Visual Feedback Affects Eating Rate in Humans

Deliberately eating at a slower pace promotes satiation and eating quickly has been associated with a higher body mass index. Therefore, understanding factors that affect eating rate should be given high priority. Eating rate is affected by the physical/textural properties of a food, by motivational state, and by portion size and palatability. This study explored the prospect that eating rate is also influenced by a hitherto unexplored cognitive process that uses ongoing perceptual estimates of the volume of food remaining in a container to adjust intake during a meal. A 2 (amount seen; 300ml or 500ml) x 2 (amount eaten; 300ml or 500ml) between-subjects design was employed (10 participants in each condition). In two ‘congruent’ conditions, the same amount was seen at the outset and then subsequently consumed (300ml or 500ml). To dissociate visual feedback of portion size and actual amount consumed, food was covertly added or removed from a bowl using a peristaltic pump. This created two additional ‘incongruent’ conditions, in which 300ml was seen but 500ml was eaten or vice versa. We repeated these conditions using a savoury soup and a sweet dessert. Eating rate (ml per second) was assessed during lunch. After lunch we assessed fullness over a 60-minute period. In the congruent conditions, eating rate was unaffected by the actual volume of food that was consumed (300ml or 500ml). By contrast, we observed a marked difference across the incongruent conditions. Specifically, participants who saw 300ml but actually consumed 500ml ate at a faster rate than participants who saw 500ml but actually consumed 300ml. Participants were unaware that their portion size had been manipulated. Nevertheless, when it disappeared faster or slower than anticipated they adjusted their rate of eating accordingly. This suggests that the control of eating rate involves visual feedback and is not a simple reflexive response to orosensory stimulatio