Antihypertensive treatment decreases arterial stiffness at night but not during the day. Results from the Hypertension in the Very Elderly Trial

The main Hypertension in the Very Elderly Trial (HYVET) demonstrated a very marked reduction in cardiovascular events by treating hypertensive participants 80 years or older with a low dose, sustained release prescription of indapamide (indapamide SR, 1.5 mg) to which was added a low dose of an angiotensin converting enzyme inhibitor in two-thirds of cases (perindopril 2–4 mg). This report from the ambulatory blood pressure sub-study investigates whether changes in arterial stiffness and ambulatory blood pressure (BP) could both explain the benefits observed in the main trial. A total of 139 participants were randomized to placebo [67] and to active treatment [72] and had both day and night observations of BP and arterial stiffness as determined from the Q wave Korotkoff diastolic (QKD) interval. The QKD interval was 5.6 ms longer (p = 0.017) in the actively treated group at night than in the placebo group. This was not true for the more numerous daytime readings so that 24-h results were similar in the two groups. The QKD interval remained longer at night in the actively treated group even when adjusted for systolic pressure, heart rate and height. The reduced arterial stiffness at night may partly explain the marked benefits observed in the main trial

An Extremely Luminous and Variable Ultraluminous X-Ray Source in the Outskirts of Circinus Observed with NuSTAR

Following a serendipitous detection with the Nuclear Spectroscopic Telescope Array (NuSTAR), we present a multi-epoch spectral and temporal analysis of an extreme ultraluminous X-ray source (ULX) located in the outskirts of the Circinus galaxy, hereafter Circinus ULX5, including coordinated XMM-Newton+NuSTAR follow-up observations. The NuSTAR data presented here represent one of the first instances of a ULX reliably detected at hard (E > 10 keV) X-rays. Circinus ULX5 is variable on long time scales by at least a factor of ~5 in flux, and was caught in a historically bright state during our 2013 observations (0.3-30.0 keV luminosity of 1.6 × 10^(40) erg s^(–1)). During this epoch, the source displayed a curved 3-10 keV spectrum, broadly similar to other bright ULXs. Although pure thermal models result in a high energy excess in the NuSTAR data, this excess is too weak to be modeled with the disk reflection interpretation previously proposed to explain the 3-10 keV curvature in other ULXs. In addition to flux variability, clear spectral variability is also observed. While in many cases the interpretation of spectral components in ULXs is uncertain, the spectral and temporal properties of all the high quality data sets currently available strongly support a simple disk-corona model reminiscent of that invoked for Galactic binaries, with the accretion disk becoming more prominent as the luminosity increases. However, although the disk temperature and luminosity are well correlated across all time scales currently probed, the observed luminosity follows L ∝ T^(1.70±0.17), flatter than expected for simple blackbody radiation. The spectral variability displayed here is highly reminiscent of that observed from known Galactic black hole binaries (BHBs) at high luminosities. This comparison implies a black hole mass of ~90 M_⊙ for Circinus ULX5. However, given the diverse behavior observed from Galactic BHB accretion disks, this mass estimate is still uncertain. Finally, the limits placed on any undetected iron absorption features with the 2013 data set imply that we are not viewing the central regions of Circinus ULX5 through any extreme super-Eddington outflow

Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.

BACKGROUND: Many patients with severe aortic stenosis and coexisting conditions are not candidates for surgical replacement of the aortic valve. Recently, transcatheter aortic-valve implantation (TAVI) has been suggested as a less invasive treatment for high-risk patients with aortic stenosis. METHODS: We randomly assigned patients with severe aortic stenosis, whom surgeons considered not to be suitable candidates for surgery, to standard therapy (including balloon aortic valvuloplasty) or transfemoral transcatheter implantation of a balloon-expandable bovine pericardial valve. The primary end point was the rate of death from any cause. RESULTS: A total of 358 patients with aortic stenosis who were not considered to be suitable candidates for surgery underwent randomization at 21 centers (17 in the United States). At 1 year, the rate of death from any cause (Kaplan–Meier analysis) was 30.7% with TAVI, as compared with 50.7% with standard therapy (hazard ratio with TAVI, 0.55; 95% confidence interval [CI], 0.40 to 0.74; P<0.001). The rate of the composite end point of death from any cause or repeat hospitalization was 42.5% with TAVI as compared with 71.6% with standard therapy (hazard ratio, 0.46; 95% CI, 0.35 to 0.59; P<0.001). Among survivors at 1 year, the rate of cardiac symptoms (New York Heart Association class III or IV) was lower among patients who had undergone TAVI than among those who had received standard therapy (25.2% vs. 58.0%, P<0.001). At 30 days, TAVI, as compared with standard therapy, was associated with a higher incidence of major strokes (5.0% vs. 1.1%, P=0.06) and major vascular complications (16.2% vs. 1.1%, P<0.001). In the year after TAVI, there was no deterioration in the functioning of the bioprosthetic valve, as assessed by evidence of stenosis or regurgitation on an echocardiogram. CONCLUSIONS: In patients with severe aortic stenosis who were not suitable candidates for surgery, TAVI, as compared with standard therapy, significantly reduced the rates of death from any cause, the composite end point of death from any cause or repeat hospitalization, and cardiac symptoms, despite the higher incidence of major strokes and major vascular events. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.)

Broadband X-ray spectra of the ultraluminous x-ray source Holmberg IX X-1 observed with NuSTAR, XMM-Newton, and Suzaku

We present results from the coordinated broadband X-ray observations of the extreme ultraluminous X-ray source Holmberg IX X-1 performed by NuSTAR, XMM-Newton and Suzaku in late 2012. These observations provide the first high-quality spectra of Holmberg IX X-1 above 10 keV to date, extending the X-ray coverage of this remarkable source up to ~30 keV. Broadband observations were undertaken at two epochs, between which Holmberg IX X-1 exhibited both flux and strong spectral variability, increasing in luminosity from Lx = (1.90+/-0.03)e40 erg/s to Lx = (3.35+/-0.03)e40 erg/s. Neither epoch exhibits a spectrum consistent with emission from the standard low/hard accretion state seen in Galactic black hole binaries, that would have been expected if Holmberg IX X-1 harbors a truly massive black hole accreting at substantially sub-Eddington accretion rates. The NuSTAR data confirm that the curvature observed previously in the 3-10 keV bandpass does represent a true spectral cutoff. During each epoch, the spectrum appears to be dominated by two optically thick thermal components, likely associated with an accretion disk. The spectrum also shows some evidence for a non-thermal tail at the highest energies, which may further support this scenario. The available data allow for either of the two thermal components to dominate the spectral evolution, although both scenarios require highly non-standard behavior for thermal accretion disk emission.Comment: 12 pages, 9 figures, accepted for publication in Ap

Anxiety and Depression in Adults with Autism Spectrum Disorder: A Systematic Review and Meta-analysis

Adults with autism spectrum disorder (ASD) are thought to be at disproportionate risk of developing mental health comorbidities, with anxiety and depression being considered most prominent amongst these. Yet, no systematic review has been carried out to date to examine rates of both anxiety and depression focusing specifically on adults with ASD. This systematic review and meta-analysis examined the rates of anxiety and depression in adults with ASD and the impact of factors such as assessment methods and presence of comorbid intellectual disability (ID) diagnosis on estimated prevalence rates. Electronic database searches for studies published between January 2000 and September 2017 identified a total of 35 studies, including 30 studies measuring anxiety (n = 26 070; mean age = 30.9, s.d. = 6.2 years) and 29 studies measuring depression (n = 26 117; mean age = 31.1, s.d. = 6.8 years). The pooled estimation of current and lifetime prevalence for adults with ASD were 27% and 42% for any anxiety disorder, and 23% and 37% for depressive disorder. Further analyses revealed that the use of questionnaire measures and the presence of ID may significantly influence estimates of prevalence. The current literature suffers from a high degree of heterogeneity in study method and an overreliance on clinical samples. These results highlight the importance of community-based studies and the identification and inclusion of well-characterized samples to reduce heterogeneity and bias in estimates of prevalence for comorbidity in adults with ASD and other populations with complex psychiatric presentations

Two-year outcomes after transcatheter or surgical aortic-valve replacement.

BACKGROUND: The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that among high-risk patients with aortic stenosis, the 1-year survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical replacement. However, longer-term follow-up is necessary to determine whether TAVR has prolonged benefits. METHODS: At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either surgical aortic-valve replacement or TAVR. All patients were followed for at least 2 years, with assessment of clinical outcomes and echocardiographic evaluation. RESULTS: The rates of death from any cause were similar in the TAVR and surgery groups (hazard ratio with TAVR, 0.90; 95% confidence interval [CI], 0.71 to 1.15; P=0.41) and at 2 years (Kaplan-Meier analysis) were 33.9% in the TAVR group and 35.0% in the surgery group (P=0.78). The frequency of all strokes during follow-up did not differ significantly between the two groups (hazard ratio, 1.22; 95% CI, 0.67 to 2.23; P=0.52). At 30 days, strokes were more frequent with TAVR than with surgical replacement (4.6% vs. 2.4%, P=0.12); subsequently, there were 8 additional strokes in the TAVR group and 12 in the surgery group. Improvement in valve areas was similar with TAVR and surgical replacement and was maintained for 2 years. Paravalvular regurgitation was more frequent after TAVR (P<0.001), and even mild paravalvular regurgitation was associated with increased late mortality (P<0.001). CONCLUSIONS: A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative to surgery in high-risk patients. The two treatments were similar with respect to mortality, reduction in symptoms, and improved valve hemodynamics, but paravalvular regurgitation was more frequent after TAVR and was associated with increased late mortality. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.)

Re A (A Child) and the United Kingdom Code of Practice for the Diagnosis and Confirmation of Death: Should a Secular Construct of Death Override Religious Values in a Pluralistic Society?

The determination of death by neurological criteria remains controversial scientifically, culturally, and legally, worldwide. In the United Kingdom, although the determination of death by neurological criteria is not legally codified, the Code of Practice of the Academy of Medical Royal Colleges is customarily used for neurological (brainstem) death determination and treatment withdrawal. Unlike some states in the US, however, there are no provisions under the law requiring accommodation of and respect for residents’ religious rights and commitments when secular conceptions of death based on medical codes and practices conflict with a traditional concept well-grounded in religious and cultural values and practices. In this article, we analyse the medical, ethical, and legal issues that were generated by the recent judgement of the High Court of England and Wales in Re: A (A Child) [2015] EWHC 443 (Fam). Mechanical ventilation was withdrawn in this case despite parental religious objection to a determination of death based on the code of practice. We outline contemporary evidence that has refuted the reliability of tests of brainstem function to ascertain the two conjunctive clinical criteria for the determination of death that are stipulated in the code of practice: irreversible loss of capacity for consciousness and somatic integration of bodily biological functions

Polymersome-Mediated Delivery of Combination Anticancer Therapy to Head and Neck Cancer Cells: 2D and 3D in Vitro Evaluation

Polymersomes have the potential to encapsulate and deliver chemotherapeutic drugs into tumor cells, reducing off-target toxicity that often compromises anticancer treatment. Here, we assess the ability of the pH-sensitive poly 2-(methacryloyloxy)ethyl phosphorylcholine (PMPC)- poly 2-(diisopropylamino)ethyl methacrylate (PDPA) polymersomes to encapsulate chemotherapeutic agents for effective combinational anticancer therapy. Polymersome uptake and ability to deliver encapsulated drugs into healthy normal oral cells and oral head and neck squamous cell carcinoma (HNSCC) cells was measured in two and three-dimensional culture systems. PMPC-PDPA polymersomes were more rapidly internalized by HNSCC cells compared to normal oral cells. Polymersome cellular uptake was found to be mediated by class B scavenger receptors. We also observed that these receptors are more highly expressed by cancer cells compared to normal oral cells, enabling polymersome-mediated targeting. Doxorubicin and paclitaxel were encapsulated into pH-sensitive PMPC-PDPA polymersomes with high efficiencies either in isolation or as a dual-load for both singular and combinational delivery. In monolayer culture, only a short exposure to drug-loaded polymersomes was required to elicit a strong cytotoxic effect. When delivered to three-dimensional tumor models, PMPC-PDPA polymersomes were able to penetrate deep into the center of the spheroid resulting in extensive cell damage when loaded with both singular and dual-loaded chemotherapeutics. PMPC-PDPA polymersomes offer a novel system for the effective delivery of chemotherapeutics for the treatment of HNSCC. Moreover, the preferential internalization of PMPC polymersomes by exploiting elevated scavenger receptor expression on cancer cells opens up the opportunity to target polymersomes to tumors

Search for supersymmetry in events with large missing transverse momentum, jets, and at least one tau lepton in 20 fb−1 of √s=8 TeV proton-proton collision data with the ATLAS detector

A search for supersymmetry (SUSY) in events with large missing transverse momentum, jets, at least one hadronically decaying tau lepton and zero or one additional light leptons (electron/muon), has been performed using 20.3fb−1 of proton-proton collision data at √s= 8 TeV recorded with the ATLAS detector at the Large Hadron Collider. No excess above the Standard Model background expectation is observed in the various signal regions and 95% confidence level upper limits on the visible cross section for new phenomena are set. The results of the analysis are interpreted in several SUSY scenarios, significantly extending previous limits obtained in the same final states. In the framework of minimal gauge-mediated SUSY breaking models, values of the SUSY breaking scale Λ below 63 TeV are excluded, independently of tan β. Exclusion limits are also derived for an mSUGRA/CMSSM model, in both the R-parity-conserving and R-parity-violating case. A further interpretation is presented in a framework of natural gauge mediation, in which the gluino is assumed to be the only light coloured sparticle and gluino masses below 1090 GeV are excluded