The relationship between springtime mid-latitude cyclones and background ozone (O
) is explored using a combination of observational and reanalysis data sets. First, the relationship between surface ...O
observations at two rural monitoring sites on the west coast of Europe - Mace Head, Ireland and Monte Velho, Portugal - and cyclone track frequency in the surrounding regions is examined. Second, detailed case study examination of four individual mid-latitude cyclones and the influence of the associated frontal passage on surface O
is performed. Cyclone tracks have a greater influence on the O
measurements at the more northern coastal European station, Mace Head, located within the main North Atlantic (NA) storm track. In particular, when cyclones track north of 53° N, there is a significant relationship with high levels of surface O
(> 75th percentile). The further away a cyclone is from the NA storm track, the more likely it will be associated with both high and low (< 25th percentile) levels of O
at the observation site during the cyclone's life cycle. The results of the four case studies demonstrate a) the importance of the passage of a cyclone's cold front in relation to surface O
measurements, b) the ability of mid-latitude cyclones to bring down high levels of O
from the stratosphere and c) that accompanying surface high pressure systems and their associated transport pathways play an important role in the temporal variability of surface O
. The main source of high O
to these two sites in springtime is from the stratosphere, either from direct injection into the cyclone or associated with aged airstreams from decaying downstream cyclones that can become entrained and descend toward the surface within new cyclones over the NA region.
Abstract
Background
Although many people with chronic low back pain (LBP) improve following conservative treatment, one in five will experience worsening symptoms after discharge from treatment and ...seek health care again. The current LBP clinical care pathway in many health services lacks a well-integrated, systematic approach to support patients to remain physically active and self-manage their symptoms following discharge from treatment. Health coaching can support people to improve physical activity levels and may potentially reduce health care utilisation for LBP. The primary aim of this study is to evaluate the effect of introducing a coordinated support system (linking hospital outpatient physiotherapy services to a public health coaching service) at discharge from LBP treatment, on the future use of hospital, medical, and health services for LBP, compared with usual care provided at discharge.
Methods
Three hundred and seventy-four adults with chronic non-specific LBP will be recruited from the outpatient physiotherapy departments of public hospitals in New South Wales, Australia. Participants will be individually randomised to a support system (
n
= 187) or usual care group (
n
= 187). All participants will receive usual care provided at discharge from treatment. Participants allocated to the support system will also receive up to 10 telephone-based health coaching sessions, delivered by the Get Healthy Service®, over a 6-month period. Health coaches will monitor and support participants to improve physical activity levels and achieve personal health-related goals. The primary outcome is the total number of encounters with hospital, medical, and health services for LBP, at 12 months from baseline. A within-trial economic evaluation will quantify the incremental costs and benefits of the support system from a health system perspective, to support reimbursement decision making.
Discussion
This study will establish the effect of a coordinated support system, introduced at discharge from treatment, on the future use of hospital, medical, and health services for LBP and various health outcomes.
Conclusion
Innovative community-driven solutions to support people with chronic LBP after discharge from treatment are urgently needed. Study findings will help inform health care policy and clinical practice in Australia.
Trial Registration
Prospectively registered on the Australian New Zealand Clinical Trials Registry (
ACTRN12620000889954
) on 10/09/2020.
The COVID-19 pandemic has caused wide-spread disruptions to the conduct of randomised controlled trials (RCTs), particularly those involving public health services. Using the Get Back to Healthy ...trial as an example, this study aimed to contextualise the challenges imposed by the COVID-19 pandemic on implementation of RCTs involving public health services in Australia, summarise the effect of common and novel contingency strategies employed to mitigate these challenges, and describe key lessons learned.
The main challenges, the effect of contingency strategies employed, and key lessons learned were summarised descriptively.
The main COVID-19-related challenge has been slow recruitment due to the suspension of clinical services for the trial target population. This challenge has been addressed through carefully considered adjustments to trial design (i.e., expanding the trial eligibility criteria), which has markedly improved trial recruitment rates. Other challenges have included the rapid transition to remote consent and data collection methods, increased complexity of monitoring participant safety, and future statistical challenges with disentangling the impact of the COVID-19 pandemic from treatment effects. The key lessons learned are: (i) adaptations to trial design may be necessary during a pandemic; (ii) offering remote methods may encourage trial participation from all age groups during a pandemic; (iii) enhanced monitoring of safety is critical during a pandemic; (iv) statistical challenges are likely to occur and should be considered when interpreting trial results.
Key lessons learned may be useful for informing the conduct of resilient RCTs, particularly those involving public health services, in the present and future.
ABSTRACT
The genomes of malaria parasites (Plasmodium spp.) contain a family of genes encoding proteins with a Plasmodium helical interspersed subtelomeric (PHIST) domain, most of which are predicted ...to be exported into the parasite‐infected human red blood cell (iRBC). Here, using transgenic parasites and a combination of cellular, biochemical, and biophysical assays, we have characterized and determined the function of a novel member of the PHIST protein family in Plasmodium falciparum, termed lysine‐rich membrane‐associated PHISTb (LyMP). LyMP was shown to associate directly with the cytoskeleton of iRBCs where it plays a role in their abnormal ability to adhere to a protein expressed on vascular endothelial cells, resulting in sequestration. Deletion of LyMP dramatically reduced adhesion of iRBCs to CD36 by 55%, which was completely restored to wild‐type levels on complementation. Intriguingly, in the absence of LyMP, formation of RBC membrane knobs and the level of surface exposure of the parasites' major cytoadhesive ligand, PfEMP1, were identical to those for the parental parasite line, demonstrating for the first time an additional mechanism that enhances cytoadherence of iRBCs beyond those already recognized. Our findings identify LyMP as a previously unknown RBC cytoskeletal‐binding protein that is likely to be of major significance in the complex pathophysiology of falciparum malaria.—Proellocks, N. I., Herrmann, S., Buckingham, D. W., Hanssen, E., Hodges, E. K., Elsworth, B., Morahan, B. J., Coppel, R. L., Cooke, B. M. A lysine‐rich membrane‐associated PHISTb protein involved in alteration of the cytoadhesive properties of Plasmodium falciparum infected red blood cells. FASEB J. 28, 3103–3113 (2014). www.fasebj.org
Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral ...CFTR gene therapy in patients with cystic fibrosis.
We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50–90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene–liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867.
Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1–7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups.
Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials.
Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme.
Background
Cystic fibrosis (CF) is a chronic, life-limiting disease caused by mutations in the CF transmembrane conductance regulator (
CFTR
) gene leading to abnormal airway surface ion transport, ...chronic lung infections, inflammation and eventual respiratory failure. With the exception of the small-molecule potentiator, ivacaftor (Kalydeco
®
, Vertex Pharmaceuticals, Boston, MA, USA), which is suitable for a small proportion of patients, there are no licensed therapies targeting the basic defect. The UK Cystic Fibrosis Gene Therapy Consortium has taken a cationic lipid-mediated
CFTR
gene therapy formulation through preclinical and clinical development.
Objective
To determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF.
Design
This was a randomised, double-blind, placebo-controlled Phase IIb trial of the
CFTR
gene–liposome complex pGM169/GL67A. Randomisation was performed via InForm™ version 4.6 (Phase Forward Incorporated, Oracle, CA, USA) and was 1 : 1, except for patients in the mechanistic subgroups (2 : 1). Allocation was blinded by masking nebuliser chambers.
Settings
Data were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database.
Participants
Patients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV
1
) between 50% and 90% predicted and any combination of
CFTR
mutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised).
Interventions
Subjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year.
Main outcome measures
The primary end point was the relative change in percentage predicted FEV
1
over the 12-month period. A number of secondary clinical outcomes were assessed alongside safety measures: other spirometric values; lung clearance index (LCI) assessed by multibreath washout; structural disease on computed tomography (CT) scan; the Cystic Fibrosis Questionnaire – Revised (CFQ-R), a validated quality-of-life questionnaire; exercise capacity and monitoring; systemic and sputum inflammatory markers; and adverse events (AEs). A mechanistic study was performed in a subgroup in whom transgene deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) was measured alongside nasal and lower airway potential difference.
Results
There was a significant (
p
= 0.046) treatment effect (TE) of 3.7% 95% confidence interval (CI) 0.1% to 7.3% in the primary end point at 12 months and in secondary end points, including forced vital capacity (FVC) (
p
= 0.031) and CT gas trapping (
p
= 0.048). Other outcomes, although not reaching statistical significance, favoured active treatment. Effects were noted by 1 month and were irrespective of sex, age or
CFTR
mutation class. Subjects with a more severe baseline FEV
1
had a FEV
1
TE of 6.4% (95% CI 0.8% to 12.1%) and greater changes in many other secondary outcomes. However, the more mildly affected group also demonstrated benefits, particularly in small airway disease markers such as LCI. The active group showed a significantly (
p
= 0.032) greater bronchial chloride secretory response. No difference in treatment-attributable AEs was seen between the placebo and active groups.
Conclusions
Monthly application of the pGM169/GL67A gene therapy formulation was associated with an improvement in lung function, other clinically relevant parameters and bronchial CFTR function, compared with placebo.
Limitations
Although encouraging, the improvement in FEV
1
was modest and was not accompanied by detectable improvement in patients’ quality of life.
Future work
Future work will focus on attempts to increase efficacy by increasing dose or frequency, the coadministration of a CFTR potentiator, or the use of modified viral vectors capable of repeated administration.
Trial registration
ClinicalTrials.gov NCT01621867.
Funding
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.
In conjunction with the second International Environmental Omics Symposium (iEOS) conference, held at the University of Liverpool (United Kingdom) in September 2014, a workshop was held to bring ...together experts in toxicology and regulatory science from academia, government and industry. The purpose of the workshop was to review the specific roles that high-content omics datasets (eg, transcriptomics, metabolomics, lipidomics, and proteomics) can hold within the adverse outcome pathway (AOP) framework for supporting ecological and human health risk assessments. In light of the growing number of examples of the application of omics data in the context of ecological risk assessment, we considered how omics datasets might continue to support the AOP framework. In particular, the role of omics in identifying potential AOP molecular initiating events and providing supportive evidence of key events at different levels of biological organization and across taxonomic groups was discussed. Areas with potential for short and medium-term breakthroughs were also discussed, such as providing mechanistic evidence to support chemical read-across, providing weight of evidence information for mode of action assignment, understanding biological networks, and developing robust extrapolations of species-sensitivity. Key challenges that need to be addressed were considered, including the need for a cohesive approach towards experimental design, the lack of a mutually agreed framework to quantitatively link genes and pathways to key events, and the need for better interpretation of chemically induced changes at the molecular level. This article was developed to provide an overview of ecological risk assessment process and a perspective on how high content molecular-level datasets can support the future of assessment procedures through the AOP framework.
Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing ...structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD.
Research aimed at investigating sexual behaviour and assessing interventions to improve sexual health has increased in recent decades. The resulting data, despite regional differences in quantity and ...quality, provide a historically unique opportunity to describe patterns of sexual behaviour and their implications for attempts to protect sexual health at the beginning of the 21st century. In this paper we present original analyses of sexual behaviour data from 59 countries for which they were available. The data show substantial diversity in sexual behaviour by region and sex. No universal trend towards earlier sexual intercourse has occurred, but the shift towards later marriage in most countries has led to an increase in premarital sex, the prevalence of which is generally higher in developed countries than in developing countries, and is higher in men than in women. Monogamy is the dominant pattern everywhere, but having had two or more sexual partners in the past year is more common in men than in women, and reported rates are higher in industrialised than in non-industrialised countries. Condom use has increased in prevalence almost everywhere, but rates remain low in many developing countries.
The huge regional variation indicates mainly social and economic determinants of sexual behaviour, which have implications for intervention. Although individual behaviour change is central to improving sexual health, efforts are also needed to address the broader determinants of sexual behaviour, particularly those that relate to the social context. The evidence from behavioural interventions is that no general approach to sexual-health promotion will work everywhere and no single-component intervention will work anywhere. Comprehensive behavioural interventions are needed that take account of the social context in mounting individual-level programmes, attempt to modify social norms to support uptake and maintenance of behaviour change, and tackle the structural factors that contribute to risky sexual behaviour.
There is a growing recognition that application of mechanistic approaches to understand cross-species shared molecular targets and pathway conservation in the context of hazard characterization, ...provide significant opportunities in risk assessment (RA) for both human health and environmental safety. Specifically, it has been recognized that a more comprehensive and reliable understanding of similarities and differences in biological pathways across a variety of species will better enable cross-species extrapolation of potential adverse toxicological effects. Ultimately, this would also advance the generation and use of mechanistic data for both human health and environmental RA.
A workshop brought together representatives from industry, academia and government to discuss how to improve the use of existing data, and to generate new NAMs data to derive better mechanistic understanding between humans and environmentally-relevant species, ultimately resulting in holistic chemical safety decisions. Thanks to a thorough dialogue among all participants, key challenges, current gaps and research needs were identified, and potential solutions proposed.
This discussion highlighted the common objective to progress toward more predictive, mechanistically based, data-driven and animal-free chemical safety assessments. Overall, the participants recognized that there is no single approach which would provide all the answers for bridging the gap between mechanism-based human health and environmental RA, but acknowledged we now have the incentive, tools and data availability to address this concept, maximizing the potential for improvements in both human health and environmental RA.
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•Thirty representatives from diverse fields and affiliations gathered to discuss holistic chemical safety decisions.•Key challenges, current gaps and research needs were identified, and potential solutions proposed.•It was agreed that while no single solution will answer all the problems, we now have the tools to start addressing them.
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