The SKA and "High-Resolution" Science

"High-resolution", or "long-baseline", science with the SKA and its precursors covers a broad range of topics in astrophysics. In several research areas, the coupling between improved brightness sensitivity of the SKA and a sub-arcsecond resolution would uncover truly unique avenues and opportunities for studying extreme states of matter, vicinity of compact relativistic objects, and complex processes in astrophysical plasmas. At the same time, long baselines would secure excellent positional and astrometric measurements with the SKA and critically enhance SKA image fidelity at all scales. The latter aspect may also have a substantial impact on the survey speed of the SKA, thus affecting several key science projects of the instrument.Comment: JENAM-2010: Invited talk at JENAM session S7: The Square Kilometre Array: Paving the way for the new 21st century radio astronomy paradigm; 9 page

Restoration of beta-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer.

Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing cellular proteins that may improve cardiac performance. Our laboratory has been focusing on the feasibility of restoring beta-adrenergic signaling deficiencies that are a characteristic of chronic CHF. We have now studied isolated ventricular myocytes from rabbits that have been chronically paced to produce hemodynamic failure. We document molecular beta-adrenergic signaling defects including down-regulation of myocardial beta-adrenergic receptors (beta-ARs), functional beta-AR uncoupling, and an up-regulation of the beta-AR kinase (betaARK1). Adenoviral-mediated gene transfer of the human beta2-AR or an inhibitor of betaARK1 to these failing myocytes led to the restoration of beta-AR signaling. These results demonstrate that defects present in this critical myocardial signaling pathway can be corrected in vitro using genetic modification and raise the possibility of novel inotropic therapies for CHF including the inhibition of betaARK1 activity in the heart

Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation

The structure-specific endonuclease XPF-ERCC1 participates in multiple DNA damage repair pathways including nucleotide excision repair (NER) and inter-strand crosslink repair (ICLR). How XPF-ERCC1 is catalytically activated by DNA junction substrates is not currently understood. Here we report cryo-electron microscopy structures of both DNA-free and DNA-bound human XPF-ERCC1. DNA-free XPF-ERCC1 adopts an auto-inhibited conformation in which the XPF helical domain masks the ERCC1 (HhH)2 domain and restricts access to the XPF catalytic site. DNA junction engagement releases the ERCC1 (HhH)2 domain to couple with the XPF-ERCC1 nuclease/nuclease-like domains. Structure-function data indicate xeroderma pigmentosum patient mutations frequently compromise the structural integrity of XPF-ERCC1. Fanconi anaemia patient mutations in XPF often display substantial in-vitro activity but are resistant to activation by ICLR recruitment factor SLX4. Our data provide insights into XPF-ERCC1 architecture and catalytic activation

Study protocol: A phase III randomised, double-blind, parallel arm, stratified, block randomised, placebo-controlled trial investigating the clinical effect and cost-effectiveness of sertraline for the palliative relief of breathlessness in people with chronic breathlessness

© Published by the BMJ Publishing Group Limited. Introduction: Breathlessness remains a highly prevalent and distressing symptom for many patients with progressive life-limiting illnesses. Evidence-based interventions for chronic breathlessness are limited, and there is an ongoing need for high-quality research into developing management strategies for optimal palliation of this complex symptom. Previous studies have suggested that selective serotonin reuptake inhibitors such as sertraline may have a role in reducing breathlessness. This paper presents the protocol for a large, adequately powered randomised study evaluating the use of sertraline for chronic breathlessness in people with progressive life-limiting illnesses. Methods and analysis: A total of 240 participants with modified Medical Research Council Dyspnoea Scale breathlessness of level 2 or higher will be randomised to receive either sertraline or placebo for 28 days in this multisite, double-blind study. The dose will be titrated up every 3 days to a maximum of 100 mg daily. The primary outcome will be to compare the efficacy of sertraline with placebo in relieving the intensity of worst breathlessness as assessed by a 0-100 mm Visual Analogue Scale. A number of other outcome measures and descriptors of breathlessness as well as caregiver assessments will also be recorded to ensure adequate analysis of participant breathlessness and to allow an economic analysis to be performed. Participants will also be given the option of continuing blinded treatment until either study data collection is complete or net benefit ceases. Appropriate statistical analysis of primary and secondary outcomes will be used to describe the wealth of data obtained. Ethics and dissemination: Ethics approval was obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals and the key findings presented at national and international conferences. Trial registration number ACTRN12610000464066

A liftless intervention to prevent preterm birth and low birthweight among pregnant Ghanaian women : protocol of a stepped-wedge cluster randomized controlled trial

Background: Preterm birth (PTB) is a leading cause of infant morbidity and mortality worldwide. Every year, 20 million babies are born with low birthweight (LBW), about 96% of which occur in low-income countries. Despite the associated dangers, in about 40%-50% of PTB and LBW cases, the causes remain unexplained. Existing evidence is inconclusive as to whether occupational physical activities such as heavy lifting are implicated. African women bear the transport burden of accessing basic needs for their families. Ghana’s PTB rate is 14.5%, whereas the global average is 9.6%. The proposed liftless intervention aims to decrease lifting exposure during pregnancy among Ghanaian women. We hypothesize that a reduction in heavy lifting among pregnant women in Ghana will increase gestational age and birthweight. Objective: To investigate the effects of the liftless intervention on the incidence of PTB and LBW among pregnant Ghanaian women. Methods: A cohort stepped-wedge cluster randomized controlled trial in 10 antenatal clinics will be carried out in Ghana. A total of 1000 pregnant participants will be recruited for a 60-week period. To be eligible, the participant should have a singleton pregnancy between 12 and 16 weeks gestation, be attending any of the 10 antenatal clinics, and be exposed to heavy lifting. All participants will receive standard antenatal care within the control phase; by random allocation, two clusters will transit into the intervention phase. The midwife-led 3-component liftless intervention consists of health education, a take-home reminder card mimicking the colors of a traffic light, and a shopping voucher. The primary outcome are gestational ages of <28, 28-32, and 33-37 weeks. The secondary outcomes are LBW (preterm LBW, term but LBW, and postterm), compliance, prevalence of low back and pelvic pain, and premature uterine contractions. Study midwives and participants will not be blinded to the treatment allocation. Results: Permission to conduct the study at all 10 antenatal clinics has been granted by the Ghana Health Service. Application for funding to begin the trial is ongoing. Findings from the main trial are expected to be published by the end of 2019. Conclusions: To the best of our knowledge, there has been no randomized trial of this nature in Ghana. Minimizing heavy lifting among pregnant African women can reduce the soaring rates of PTB and LBW. The findings will increase the knowledge of the prevention of PTB and LBW worldwide. Trial Registration: Pan African Clinical Trial Register (PACTR201602001301205); http://apps.who.int/trialsearch/ Trial2.aspx?TrialID=PACTR201602001301205 (Archived by WebCite at http://www.webcitation.org/71TCYkHzu) Registered Report Identifier: RR1-10.2196/1009

Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial

Copyright ©ERS 2019. Does sertraline provide symptomatic relief for chronic breathlessness in people with advanced disease whose underlying cause(s) are optimally treated?223 participants with chronic breathlessness (modified Medical Research Council breathlessness scale ≥2) who had optimal treatment of underlying cause(s) were randomised 1:1 to sertraline 25-100 mg (titrated upwards over 9 days) or placebo for 4 weeks. The primary outcome was the proportion who had an improvement in intensity of current breathlessness >15% from baseline on a 100-mm visual analogue scale.The proportion of people responding to sertraline was similar to placebo for current breathlessness on days 26-28 (OR 1.00, 95% CI 0.71-1.40) and for other measures of breathlessness. Quality of life in the sertraline arm had a higher likelihood of improving than in the placebo arm over the 4 weeks (OR 0.21, 95% CI 0.01-0.41; p=0.044). No differences in performance status, anxiety and depression, or survival were observed. Adverse event rates were similar between arms.Sertraline does not appear to provide any benefit over placebo in the symptomatic relief of chronic breathlessness in this patient population

Assessing the state of health research in the Eastern Mediterranean Region.

Member states across the Eastern Mediterranean region face unprecedented health challenges, buffeted by demographic change, a dual disease burden, rising health costs, and the effects of ongoing conflict and population movements - exacerbated in the near-term by instability arising from recent political upheaval in the Middle East. However, health actors in the region are not well positioned to respond to these challenges because of a dearth of good quality health research. This review presents an assessment of the current state of health research systems across the Eastern Mediterranean based on publicly available literature and data sources. The review finds that - while there have been important improvements in productivity in the Region since the early 1990s - overall research performance is poor with critical deficits in system stewardship, research training and human resource development, and basic data surveillance. Translation of research into policy and practice is hampered by weak institutional and financial incentives, and concerns over the political sensitivity of findings. These problems are attributable primarily to chronic under-investment - both financial and political - in Research and Development systems. This review identifies key areas for a regional strategy and how to address challenges, including increased funding, research capacity-building, reform of governance arrangements and sustained political investment in research support. A central finding is that the poverty of publicly available data on research systems makes meaningful cross-comparisons of performance within the EMR difficult. We therefore conclude by calling for work to improve understanding of health research systems across the region as a matter of urgency

Cognition in stroke rehabilitation and recovery research: Consensus-based core recommendations from the second Stroke Recovery and Rehabilitation Roundtable

Cognitive impairment is an important target for rehabilitation as it is common following stroke, is associated with reduced quality of life and interferes with motor and other types of recovery interventions. Cognitive function following stroke was identified as an important, but relatively neglected area during the first Stroke Recovery and Rehabilitation Roundtable (SRRR I), leading to a Cognition Working Group being convened as part of SRRR II. There is currently insufficient evidence to build consensus on specific approaches to cognitive rehabilitation. However, we present recommendations on the integration of cognitive assessments into stroke recovery studies generally and define priorities for ongoing and future research for stroke recovery and rehabilitation. A number of promising interventions are ready to be taken forward to trials to tackle the gap in evidence for cognitive rehabilitation. However, to accelerate progress requires that we coordinate efforts to tackle multiple gaps along the whole translational pathway

Cognition in Stroke Rehabilitation and Recovery Research: Consensus-Based Core Recommendations From the Second Stroke Recovery and Rehabilitation Roundtable

Cognitive impairment is an important target for rehabilitation as it is common following stroke, is associated with reduced quality of life and interferes with motor and other types of recovery interventions. Cognitive function following stroke was identified as an important, but relatively neglected area during the first Stroke Recovery and Rehabilitation Roundtable (SRRR I), leading to a Cognition Working Group being convened as part of SRRR II. There is currently insufficient evidence to build consensus on specific approaches to cognitive rehabilitation. However, we present recommendations on the integration of cognitive assessments into stroke recovery studies generally and define priorities for ongoing and future research for stroke recovery and rehabilitation. A number of promising interventions are ready to be taken forward to trials to tackle the gap in evidence for cognitive rehabilitation. However, to accelerate progress requires that we coordinate efforts to tackle multiple gaps along the whole translational pathway