Levosimendan for the prevention of acute organ dysfunction in sepsis

BACKGROUND Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. METHODS We conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events. RESULTS The trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group (6.68±3.96 vs. 6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], −0.07 to 1.29; P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, −4.5 to 11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04). CONCLUSIONS The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS Current Controlled Trials number, ISRCTN12776039.

The Thermal Design, Characterization, and Performance of the SPIDER Long-Duration Balloon Cryostat

We describe the SPIDER flight cryostat, which is designed to cool six millimeter-wavelength telescopes during an Antarctic long-duration balloon flight. The cryostat, one of the largest to have flown on a stratospheric payload, uses liquid helium-4 to deliver cooling power to stages at 4.2 and 1.6 K. Stainless steel capillaries facilitate a high flow impedance connection between the main liquid helium tank and a smaller superfluid tank, allowing the latter to operate at 1.6 K as long as there is liquid in the 4.2 K main tank. Each telescope houses a closed cycle helium-3 adsorption refrigerator that further cools the focal planes down to 300 mK. Liquid helium vapor from the main tank is routed through heat exchangers that cool radiation shields, providing negative thermal feedback. The system performed successfully during a 17 day flight in the 2014-2015 Antarctic summer. The cryostat had a total hold time of 16.8 days, with 15.9 days occurring during flight.Comment: 15 pgs, 17 fig

Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

Understanding the experience of initiating community-based physical activity and social support by people with serious mental illness: a systematic review using a meta-ethnographic approach

Background People with long-term serious mental illness live with severe and debilitating symptoms that can negatively influence their health and quality of life, leading to outcomes such as premature mortality, morbidity and obesity. An interplay of social, behavioural, biological and psychological factors is likely to contribute to their poor physical health. Participating in regular physical activity could bring symptomatic improvements, weight loss benefits, enhanced wellbeing and when undertaken in a community-based group setting can yield additional, important social support benefits. Yet poor uptake of physical activity by people with serious mental illness is a problem. This review will systematically search, appraise and synthesise the existing evidence that has explored the experience of community-based physical activity initiation and key features of social support within these contexts by adults with schizophrenia, bipolar affective disorder, major depressive disorder or psychosis using the meta-ethnography approach. This new understanding may be key in designing more acceptable and effective community-based group PA programmes that meet patients’ need and expectations. Methods This will be a systematic review of qualitative studies using the meta-ethnography approach. The following databases will be searched: ASSIA, CINAHL, Cochrane Central Register of Controlled Trials, EMBASE, Health Technology Assessment Database, MEDLINE, PsycINFO, Sociological Abstracts, SPORTDiscus and Web of Science. Grey literature will also be sought. Eligible studies will use qualitative methodology; involve adults (≥18 years) with schizophrenia, bipolar affective disorder, major depressive disorder or psychosis; will report community-based group physical activity; and capture the experience of physical activity initiation and key features of social support from the perspective of the participant. Study selection and assessment of quality will be performed by two reviewers. Data will be extracted by one reviewer, tabled, and checked for accuracy by the second reviewer. The meta-ethnography approach by Noblit and Hare [1] will be used to synthesise the data. Discussion This systematic review is expected to provide new insights into the experience of community-based group physical activity initiation for adults who have a serious mental illness to inform person-centred improvements to the management of serious mental illness through physical activity. Registration The protocol has been registered on the International Prospective Register of Systematic Reviews (PROSPERO) on 22/03/2017; http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017059948 (registration number CRD42017059948). Keywords Serious mental illness - Physical activity - Community - Social support - Exercise - Sport - Adults - Patient experience - Qualitative research - Meta-ethnography - Systematic revie

Leave entitlements, time off work and the household financial impacts of quarantine compliance during an H1N1 outbreak

The Australian state of Victoria, with 5.2 million residents, enforced home quarantine during a H1N1 pandemic in 2009. The strategy was targeted at school children. The objective of this study was to investigate the extent to which parents’ access to paid sick leave or paid carer’s leave was associated with (a) time taken off work to care for quarantined children, (b) household finances, and (c) compliance with quarantine recommendations.This project was funded by two NHMRC Strategic Awards: “Call for research on H1N1 influenza 09 to inform public policy” (#628962) and “Changing patterns of work: Impacts on physical and mental health and the mediating role of resilience and social capital” (#375196). JM is supported by a NHMRC Career Development Award; DS is funded by an ARC Federation Fellowship

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

High genetic diversity at the extreme range edge: nucleotide variation at nuclear loci in Scots pine (Pinus sylvestris L.) in Scotland

Nucleotide polymorphism at 12 nuclear loci was studied in Scots pine populations across an environmental gradient in Scotland, to evaluate the impacts of demographic history and selection on genetic diversity. At eight loci, diversity patterns were compared between Scottish and continental European populations. At these loci, a similar level of diversity (θsil=~0.01) was found in Scottish vs mainland European populations, contrary to expectations for recent colonization, however, less rapid decay of linkage disequilibrium was observed in the former (ρ=0.0086±0.0009, ρ=0.0245±0.0022, respectively). Scottish populations also showed a deficit of rare nucleotide variants (multi-locus Tajima's D=0.316 vs D=−0.379) and differed significantly from mainland populations in allelic frequency and/or haplotype structure at several loci. Within Scotland, western populations showed slightly reduced nucleotide diversity (πtot=0.0068) compared with those from the south and east (0.0079 and 0.0083, respectively) and about three times higher recombination to diversity ratio (ρ/θ=0.71 vs 0.15 and 0.18, respectively). By comparison with results from coalescent simulations, the observed allelic frequency spectrum in the western populations was compatible with a relatively recent bottleneck (0.00175 × 4Ne generations) that reduced the population to about 2% of the present size. However, heterogeneity in the allelic frequency distribution among geographical regions in Scotland suggests that subsequent admixture of populations with different demographic histories may also have played a role

Health-related quality of life after treatment for bladder cancer in England

Background Little is known about quality of life after bladder cancer treatment. This common cancer is managed using treatments that can affect urinary, sexual and bowel function. Methods To understand quality of life and inform future care, the Department of Health (England) surveyed adults surviving bladder cancer 1–5 years after diagnosis. Questions related to disease status, co-existing conditions, generic health (EQ-5D), cancer-generic (Social Difficulties Inventory) and cancer-specific outcomes (Functional Assessment of Cancer Therapy—Bladder). Results In total, 673 (54%) patients responded; including 500 (74%) men and 539 (80%) with co-existing conditions. Most respondents received endoscopic treatment (60%), while 92 (14%) and 99 (15%) received radical cystectomy or radiotherapy, respectively. Questionnaire completion rates varied (51–97%). Treatment groups reported ≥1 problem using EQ-5D generic domains (59–74%). Usual activities was the most common concern. Urinary frequency was common after endoscopy (34–37%) and radiotherapy (44–50%). Certain populations were more likely to report generic, cancer-generic and cancer-specific problems; notably those with co-existing long-term conditions and those treated with radiotherapy. Conclusion The study demonstrates the importance of assessing patient-reported outcomes in this population. There is a need for larger, more in-depth studies to fully understand the challenges patients with bladder cancer face

Amplified surface temperature response of cold, deep lakes to inter-annual air temperature variability

Summer lake surface water temperatures (LSWTs) have previously been shown to respond more rapidly to climatic warming compared to local summer surface air temperatures (SATs). In a global- scale analysis, we explore the factors underpinning the observation of an amplified response of summer LSWT to SAT variability using 20 years of satellite-derived temperatures from 144 lakes. We demonstrate that the degree of amplification in inter-annual summer LSWT is variable, and is greater for cold lakes (e.g. high latitude and high altitude), which are characterised by a short warming season, and deep lakes, that exhibit long correlation timescales of temperature anomalies due to increased thermal inertia. Such lakes are more likely to display responses in excess of local inter-annual summer SAT variability. Climatic modification of LSWT has numerous consequences for water quality and lake ecosystems, so quantifying this amplified response at a global scale is important