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Background The private sector plays a large role in malaria treatment provision in Nigeria. To improve access to, and affordability of, quality-assured artemisinin-based combination therapy (QA-ACT) within this sector, the Affordable Medicines Facility-Malaria began operations in 2010 and transitioned to a private sector co-payment mechanism (PSCM) until 2017. To assess the impact of the scheme on the ACT market, cross-sectional household and outlet surveys were conducted in 2018 to coincide with the final stockages of ACT medicines procured under the PSCM. Methods An outlet survey was conducted targeting private pharmacies and Proprietary and Patent Medicine Vendors (PPMVs) across different regions of Nigeria to assess supply-side market factors related to availability and cost of anti-malarials, including artemisinin-based combinations subsidised under the PSCM (called green leaf ACT on account of their green leaf logo) and those not subsidised (non-green leaf ACT). A concurrent household survey was conducted to determine demand-side factors related to treatment-seeking practices, ACT brand preference and purchase decision. Data were compared with previous ACTWatch surveys to consider change over time. Results Availability of artemisinin-based combinations increased significantly over the PSCM period and was almost universal by the time of the 2018 market survey. This increase was seen particularly among PPMVs. While the cost of green leaf ACT remained relatively stable over time, the cost of non-green leaf ACT reduced significantly so that by 2018 they had equivalent affordability. Unsubsidised brands were also available in different formulations and dosages, with double-strength artemisinin-based combination reported as the most frequently purchased dosage type, and child artemisinin-based combinations popular in suspension and dispersible forms (forms not subsidised by the PSCM). Conclusions The PSCM had a clear impact on increasing not only the reach of subsidized QA brands, but also of non-subsidised brands. Increased market competition led to innovation from unsubsidised brands and large reductions in costs to make them competitive with subsidised brands. Concerns are drawn from the large market share that non-QA brands have managed to gain as well as the continued market share of oral artemisinin monotherapies. Continued monitoring of the market is recommended, along with improved local capacity for QA-certification and monitoring.

Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks.

ObjectiveTo evaluate the effectiveness and cost-effectiveness of the National PReCePT Programme (NPP) in increasing use of magnesium sulfate (MgSO4) in preterm births.DesignBefore-and-after study.SettingMaternity units (N=137) within NHS England and the Academic Health Science Network (AHSN) in 2018.ParticipantsBabies born ≤30 weeks’ gestation admitted to neonatal units in England.InterventionsThe NPP was a quality improvement (QI) intervention including the PReCePT (Preventing Cerebral Palsy in Pre Term labour) QI toolkit and materials (preterm labour proforma, staff training presentations, parent leaflet, posters for the unit and learning log), regional AHSN-level support, and up to 90 hours funded backfill for a midwife ‘champion’ to lead implementation.Main outcome measuresMgSO4uptake post implementation was compared with pre-NPP implementation uptake. Implementation and lifetime costs were estimated.ResultsCompared with pre-implementation estimates, the average MgSO4uptake for babies born ≤30 weeks’ gestation, in 137 maternity units in England, increased by 6.3 percentage points (95% CI 2.6 to 10.0 percentage points) to 83.1% post implementation, accounting for unit size, maternal, baby and maternity unit factors, time trends, and AHSN. Further adjustment for early/late initiation of NPP activities increased the estimate to 9.5 percentage points (95% CI 4.3 to 14.7 percentage points). From a societal and lifetime perspective, the health gains and cost savings associated with the NPP effectiveness generated a net monetary benefit of £866 per preterm baby and the probability of the NPP being cost-effective was greater than 95%.ConclusionThis national QI programme was effective and cost-effective. National programmes delivered via coordinated regional clinical networks can accelerate uptake of evidence-based therapies in perinatal care.

Background To avoid misuse of anti-malarials, correct diagnosis of fever prior to drug prescription is essential. Presumptive treatment in the private healthcare sector is a concern in Nigeria, where availability of affordable artemisinin-based combination therapy (ACT) is high following the implementation of subsidy schemes from 2010 to 2017. Similar subsidies have not, however, been implemented for malaria rapid diagnostic tests (RDTs). A market survey in 2018 predominantly designed to assess the ACT market in the private sector also collected data related to RDTs, results of which are presented herein. Methods A 2018 market survey consisted of (i) an outlet survey targeting private pharmacies and Proprietary and Patent Medicine Vendors (PPMVs) across different regions of Nigeria to assess supply-side market factors related to availability of RDTs (defined as having stock available for purchase at the time of the survey) and (ii) a household survey to determine demand-side factors related to knowledge of RDTs, healthcare-seeking practices and affordability. Results Availability of RDTs at the time of the survey was low in both outlet types and significantly lower in PPMVs (22.1%, 95% CI) among pharmacies versus (13.6%, 95% CI) among PPMVs (p Conclusions Low availability of RDTs among PPMVs and pharmacies may be attributed to lack of demand, supply-side issues and cost. Increasing household knowledge of RDTs may aid increasing demand, while subsidized RDTs may address supply and price issues. Addressing the deficit in RDT provision is important for targeting of ACT medicines.

ObjectiveTo evaluate the effectiveness and cost-effectiveness of the National PreCePT Programme (NPP) in increasing magnesium sulphate (MgSO4) in pre-term births.DesignA quasi-experimental before-and-after designSettingMaternity units within NHS England and the AHSN network in 2018.ParticipantsMaternity units in England (n=137) who participated in the NPP.InterventionsNPP support which included the PReCePT QI toolkit and materials (pre-term labour proforma, staff training presentations, parent leaflet, posters for the unit, learning log), regional AHSN level support, and up to 90 hours funded backfill for a midwife ‘champion’ to lead implementation.Main outcome measuresMgSO4 post-implementation uptake compared to pre-implementation uptake. Implementation and lifetime costs were estimated.ResultsCompared to pre-implementation estimates, the average MgSO4 uptake in 137 maternity units in England increased by 6.3 percentage points (95% CI 2.6 to 10.0 percentage points) to 83.1% post-implementation, accounting for unit size, maternal, baby, and maternity unit factors, time trends, and AHSN. Further adjustment for early or late initiation of NPP activities increased the estimate to 9.5 percentage points (95% CI 4.3 to 14.7 percentage points). From a societal and lifetime perspective, the health gains and cost-savings associated with the NPP effectiveness generated a net monetary benefit of £866 per preterm baby and the probability of the NPP being cost-effective was greater than 95%.ConclusionThis national QI programme was effective and cost-effective. National programmes delivered via coordinated regional clinical networks can accelerate uptake of evidence-based therapies in perinatal care.WHAT IS ALREADY KNOWN ON THIS TOPICSince 2015 the UK National Institute for Health and Care Excellence (NICE) has recommended administration of Magnesium Sulphate (MgSO4) for fetal neuroprotection in very preterm deliveries as a core part of maternity care. By 2017, only two-thirds of all eligible women in England were being given MgSO4, with wide regional variation. The PReCePT pilot study showed an increase in uptake from 21% (2012-2013) to 88% after the introduction of the tool in2015 in 5 units. The National PReCePT Programme (NPP) was rolled out in 2018 by the national network of Academic Health Science Networks with a target to increase MgSO4 administration in England to 85% by 2020.WHAT THIS STUDY ADDSThe study has shown that the nationwide implementation of the NPP, which provided a Quality Improvement (QI) toolkit and materials, cross unit AHSN regional level support, and funded backfill for a unit midwife ‘champion’ through local regional support was effective and cost-effective. Scaling-up of network supported QI programmes at national level can accelerate uptake of new therapies and promote improvements in perinatal care delivery.

ObjectiveTo compare the impact of the National PReCePT Programme (NPP) versus an enhanced Quality Improvement (QI) support programme in improving magnesium sulfate (MgSO4) uptake in English maternity units.DesignUnblinded cluster randomised controlled trial.SettingEngland, Academic Health Sciences Network (AHSN), 2018.ParticipantsMaternity units with ≥10 preterm deliveries annually and MgSO4uptake ≤70%. 40 maternity units (27 NPP, 13 enhanced support) were included (randomisation stratified by MgSO4uptake).InterventionsNHS England commissioned the NPP to increase MgSO4uptake in very preterm deliveries to reduce risk of cerebral palsy. NPP maternity units received PReCePT QI materials, regional support, and midwife backfill funding. Enhanced support units received this plus extra backfill funding and unit-level QI coaching.Outcome measuresMgSO4uptake post-implementation was compared between groups using routine data and multivariable linear regression. Net monetary benefit was estimated, based on implementation costs, lifetime quality-adjusted life-years and societal costs. The implementation process was assessed through qualitative process evaluation.ResultsMgSO4uptake increased in all units, with no evidence of difference between groups (0.84 percentage points lower uptake in the enhanced group, 95% Confidence Interval -5.03 to 3.35 percentage points). The probability of enhanced support being cost-effective was ConclusionPReCePT improved MgSO4uptake in all maternity units. Enhanced support did not further improve uptake but may improve teamwork, and more accurately represented the time needed for implementation. Targeted enhanced support, sustainability of improvements and the possible indirect benefits of stronger teamwork associated with enhanced support should be explored further.Trial registrationISRCTN 40938673 (https://www.isrctn.com/ISRCTN40938673)WHAT IS ALREADY KNOWN ON THIS TOPICDespite long-standing evidence that Magnesium Sulfate (MgSO4) confers fetal neuroprotection and reduces risk of cerebral palsy in very preterm babies, by 2017 only two-thirds of eligible women in England were receiving it, with wide regional variation.The pilot PReCePT (Prevention of Cerebral Palsy in preterm labour) Quality Improvement (QI) study appeared to effectively accelerate uptake of MgSO4,and a version of this support model was rolled-out nationwide in 2018.WHAT THIS STUDY ADDSPReCePT improved MgSO4uptake in all maternity units, and the full (‘enhanced’) support model did not appear to improve uptake beyond the achievements of the standard support model used in the National PReCePT Programme. However, enhanced support may be associated with improved perinatal team working, and the funding more accurately represented the staff time needed for implementation.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYPReCePT may serve as a blueprint for other improvement programs to accelerate uptake of evidence-based interventions, and future studies should consider the potential for indirect but far-reaching benefits to staff and patients.

BackgroundTo avoid misuse of antimalarials, correct diagnosis of fever prior to drug prescription is essential. Presumptive treatment in the private healthcare sector is a concern in Nigeria where availability of affordable artemisinin combination therapy is high following the implementation of subsidy schemes from 2010 to 2017. Similar subsidies have not, however, been implemented for malaria rapid diagnostic tests (mRDTs). A market survey in 2018 predominantly designed to assess the ACT market in the private sector also collected data related to mRDTs, results of which are presented herein. MethodsA 2018 market survey consisted of i) an outlet survey targeting private pharmacies and Proprietary and Patent Medicine Vendors (PPMVs) across different regions of Nigeria to assess supply-side market factors related to availability of mRDTs and ii) a household survey to determine demand-side factors related to knowledge of mRDTs, healthcare-seeking practices and affordability. ResultsAvailability of mRDTs at the time of the survey was low in both outlet types and significantly lower in PPMVs (22.1%, 95% CI [17.7-27.1] among pharmacies versus 13.6%, 95% CI [10.3-17.5] among PPMVs, p

Climate change poses a serious threat to the development of the current and future generations. Therefore, Carbon Dioxide Capture, Transportation, Utilization and Storage (CCUS) has emerged as an essential tool to mitigate such impacts of global warming along with other initiatives and strategic decisions such as energy transition and conservation, sustainable practices amongst others. This article is focused on the CCUS practices and more specifically the peculiarities of CCUS vis-à-vis the standardization rules at the International Organization for Standardization (ISO). The main question this article aims to address is to determine if CCUS should have its own standing technical committee (TC) or if it should be somehow related to the existing Carbon Capture and Storage (CCS) technical committee.

Background Systematic reviews of prenatal alcohol exposure effects generally only include conventional observational studies. However, estimates from such studies are prone to confounding and other biases. Objectives To systematically review the evidence on the effects of prenatal alcohol exposure from randomized controlled trials (RCTs) and observational designs using alternative analytical approaches to improve causal inference. Search strategy Medline, Embase, Web of Science, PsychINFO from inception to 21 June 2018. Manual searches of reference lists of retrieved papers. Selection criteria RCTs of interventions to stop/reduce drinking in pregnancy and observational studies using alternative analytical methods (quasi-experimental studies e.g. Mendelian randomization and natural experiments, negative control comparisons) to determine the causal effects of prenatal alcohol exposure on pregnancy and longer-term offspring outcomes in human studies. Data collection and analysis One reviewer extracted data and another checked extracted data. Risk of bias was assessed using customized risk of bias tools. A narrative synthesis of findings was carried out and a meta-analysis for one outcome. Main results Twenty-three studies were included, representing five types of study design, including 1 RCT, 9 Mendelian randomization and 7 natural experiment studies, and reporting on over 30 outcomes. One study design–outcome combination included enough independent results to meta-analyse. Based on evidence from several studies, we found a likely causal detrimental role of prenatal alcohol exposure on cognitive outcomes, and weaker evidence for a role in low birthweight. Conclusion None of the included studies was judged to be at low risk of bias in all domains, results should therefore be interpreted with caution. Systematic review registration This study is registered with PROSPERO, registration number CRD42015015941

Background Despite great success in significantly reducing the malaria burden in Viet Nam over recent years, the ongoing presence of malaria vectors and Plasmodium infection in remote forest areas and among marginalised groups presents a challenge to reaching elimination and a threat to re-emergence of transmission. Often transmission persists in a population despite high reported coverage of long-lasting insecticidal nets (LLINs), the mainstay control method for malaria. To investigate what factors may contribute to this, a mixed-methods study was conducted in Son Thai commune, a community in south-central Viet Nam that has ongoing malaria cases despite universal LLIN coverage. A cross-sectional behavioural and net-coverage survey was conducted along with observations of net use and entomological collections in the village, farm huts and forest sites used by members of the community. Results Most community members owned a farm hut plot and 71.9% of adults aged 18+ years sometimes slept overnight in the farm hut, while one-third slept overnight in the forest. Ownership and use of nets in the village households was high but in the farm huts and forest was much lower; only 44.4% reported regularly using a bednet in the farm and 12.1% in the forest. No primary anopheline species were captured in the village, but Anopheles dirus (s.l.) (n = 271) and An. maculatus (s.l.) (n = 14) were captured as far as 4.5 km away in farm huts and forest. A high proportion of biting was conducted in the early evening before people were under nets. Entomological inoculation rates (EIR) of An. dirus (s.l.) were 17.8 and 25.3 infectious bites per person per year in the outdoor farm hut sites and forest, respectively, for Plasmodium falciparum and 25.3 in the forest sites for P. vivax. Conclusions Despite high net coverage in the village, gaps in coverage and access appear in the farm huts and forest where risk of anopheline biting and parasite transmission is much greater. Since subsistence farming and forest activities are integral to these communities, new personal protection methods need to be explored for use in these areas that can ideally engage with the community, be durable, portable and require minimal behavioural change.

Background: Mental health policies advocate service user participation in care planning. However, service users often feel they’re not fully involved and direct access to users’ own electronic care plans in the community can be an obstacle. To address this, an electronic care pathway tool (CPT) was co-designed by service users, staff and software developers, to facilitate co-production of care and crisis plans.Aims: To investigate the feasibility and acceptability of the pilot implementation of the CPT in professionals’ practice to co-produce care plans and enable efficient working. Method: Qualitative interviews with fifteen mental health practitioners, and five service development/ management staff. Normalisation process theory, which outlines the social processes involved in implementing technology, and co-production theory, informed interviews and data analysis. Results: Multiple factors influenced CPT usage, including people’s views of technology, practitioners’ relationships with service users, service users’ mental health needs, and their capacity for reflective thinking. The CPT’s visual and interactive features could enable co-production of care plans. The CPT supported practitioners’ efficiency, but its features did not easily streamline with electronic patient records.Conclusions: CPT interactive touchpoints supported service users’ therapeutic reflection and facilitated care planning involvement. Information technology system interoperability was an obstacle.

BackgroundThe private sector plays a large role in malaria treatment provision in Nigeria. To improve access to, and affordability of, quality-assured artemisinin combination therapies (QA-ACTs) within this sector, the Affordable Medicines Facility - Malaria began operations in 2010 and transitioned to a private sector co-payment mechanism (PSCM) until 2017. To assess the impact of the scheme on the ACT market, cross-sectional household and outlet surveys were conducted in 2018 to coincide with the final stockages of ACTs procured under the PSCM. MethodsAn outlet survey was conducted targeting private pharmacies and Proprietary and Patent Medicine Vendors (PPMVs) across different regions of Nigeria to assess supply-side market factors related to availability and cost of antimalarials, including ACTs subsidised under the PSCM (called green leaf ACTs on account of their green leaf logo) and those not subsidised (non-green leaf ACTs). A concurrent household survey was conducted to determine demand-side factors related to treatment seeking practices, ACT brand preference and purchase decision. Data were compared with previous ACTWatch surveys to consider change over time.ResultsAvailability of ACTs increased significantly over the PSCM period and was almost universal by the time of the 2018 market survey. This increase was seen particularly among PPMVs. While the cost of green leaf ACTs remained relatively stable over time, the cost of non-green leaf ACTs reduced significantly so that by 2018 they had equivalent affordability. Unsubsidised brands were also available in different formulations and dosages, with double-strength ACTs reported as the most frequently purchased dosage type, and child ACTs popular in suspension and dispersible forms (forms not subsidised by the PSCM).ConclusionsThe PSCM had a clear impact on increasing not only the reach of subsidised QA brands, but also of non-subsidised brands. Increased market competition led to innovation from unsubsidised brands and large reductions in costs to make them competitive with subsidised brands. Concerns are drawn from the large market share that non-QA brands have managed to gain as well as the continued market share of oral artemisinin monotherapies. Continued monitoring of the market is recommended, along with improved local capacity for QA-certification and monitoring.

Our understanding of the pathogenic yeasts Cryptococcus neoformans and Cryptococcus gattii has been greatly enhanced by use of genome sequencing technologies. Found ubiquitously as saprotrophs in the environment, inhalation of infectious spores from these pathogens can lead to the disease cryptococcosis. Individuals with compromised immune systems are at particular risk, most notably those living with HIV/AIDS. Genome sequencing in combination with laboratory and clinical studies has revealed diverse lineages with important differences in their observed frequency, virulence and clinical outcomes. However, to date, genomic analyses have focused primarily on clinical isolates that represent only a subset of the diversity in the environment. Enhanced genomic surveillance of these yeasts in their native environments is needed in order to understand their ecology, biology and evolution and how these influence the epidemiology and pathophysiology of clinical disease. This is particularly relevant on the African continent from where global cryptococcal diversity may have originated, yet where environmental sampling and sequencing has been sparse despite harbouring the largest population at risk from cryptococcosis. Here, we review what scientifically and clinically relevant insights have been provided by analysis of environmental Cryptococcus isolates to date and argue that with further sampling, particularly in Africa, many more important discoveries await., We summarise important insights unveiled by environmental sampling and genomics of the pathogenic fungi, Cryptococcus, but argue there is still much to learn with increased focus in this area.

The UK’s National Institute for Health and Care Excellence Preterm labour and birth guideline recommends use of magnesium sulfate (MgSO4) in deliveries below 30 weeks’ gestation to prevent cerebral palsy and other neurological problems associated with preterm delivery. Despite national guidance, the uptake of MgSO4 administration in eligible women has been slow. National Health Service England has rolled out the PReCePT (PRevention of Cerebral Palsy in Pre-Term labour) quality improvement (QI) toolkit to increase uptake of MgSO4 in preterm deliveries. The toolkit is designed to increase maternity staff knowledge about MgSO4 and provides training and practical tools to help staff consider use in eligible women. The PReCePT trial compares the effectiveness of two different methods of implementing the QI toolkit (standard versus enhanced support). The standard support arm (control) receives the QI toolkit and regional-level support for a midwife/obstetric ‘champion’. The enhanced support arm (intervention) receives this plus additional clinical backfill funding and unit-level QI microcoaching. It is funded by The Health Foundation. This is a cluster randomised controlled trial designed to include 48 maternity units randomised (2:1 ratio) to standard or enhanced support. Units are eligible for inclusion if they have 10 or more preterm (4 uptake of 70% or less. Randomisation is stratified by previous level of MgSO4 uptake. The QI intervention is implemented over 9 months. All units are followed up for a further 9 months. Blinding is not possible due to the nature of the intervention. The primary outcome is the proportion of MgSO4 uptake among eligible women at follow-up, adjusting for uptake before implementation of the toolkit. The effectiveness of the intervention will be assessed using weighted linear regression on data from the National Neonatal Research Database. Semistructured qualitative staff interviews will inform understanding of the process and outcomes. Economic evaluation will describe total costs and cost-effectiveness.Trial registration number SRCTN 40938673.

Introduction Viral outbreaks present a particular challenge in countries in Africa where there is already a high incidence of other infectious diseases, including malaria which can alter immune responses to secondary infection. Ebola virus disease (EVD) is one such problem; understanding how Plasmodium spp. and Ebolavirus (EBOV) interact is important for future outbreaks. Methods We conducted a systematic review in PubMed and Web of Science to find peer-reviewed papers with primary data literature to determine 1) prevalence of EBOV/Plasmodium spp. coinfection, 2) effect of EBOV/Plasmodium spp. coinfection on EVD pathology and the immune response, 3) impact of EBOV/Plasmodium spp. coinfection on the outcome of EVD-related mortality. Random effects meta-analyses were conducted with the R package meta to produce overall proportion and effect estimates as well as measure between-study heterogeneity. Results From 322 peer-reviewed papers, 17 were included in the qualitative review and nine were included in a meta-analysis. Prevalence of coinfection was between 19% and 72%. One study reported significantly lower coagulatory response biomarkers in coinfected cases but no difference in inflammatory markers. Case fatality rates were similar between EBOV(+)/Pl(+) and EBOV(+)/Pl(-) cases (62.8%, 95% CI 49.3–74.6 and 56.7%, 95% CI 53.2–60.1, respectively), and there was no significant difference in risk of mortality (RR 1.09, 95% CI 0.90–1.31) although heterogeneity between studies was high. One in vivo mouse model laboratory study found no difference in mortality by infection status, but another found prior acute Plasmodium yoeli infection was protective against morbidity and mortality via the IFN-γ signalling pathway. Conclusion The literature was inconclusive; studies varied widely and there was little attempt to adjust for confounding variables. Laboratory studies may present the best option to answer how pathogens interact within the body but improvement in data collection and analysis and in diagnostic methods would aid patient studies in the future.

Amyloid-β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ generation, we postulated that 5HT2A -Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real-time using in vivo microdialysis. Both compounds reduced ISF Aβ levels by almost 50% within hours, but had no effect on Aβ levels in 5HT2A -R knock-out mice. The Aβ-lowering effects of Pimavanserin were blocked by extracellular-regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aβ levels and Aβ pathology and improved cognitive function in these mice. Pimavanserin is FDA-approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease-modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease. Read the Editorial Highlight for this article on page 560.

Malaria incidence in Myanmar has significantly reduced over recent years, however, completeness and timeliness of incidence data remain a challenge. The first ever nationwide malaria infection and seroprevalence survey was conducted in Myanmar in 2015 to better understand malaria epidemiology and highlight gaps in Annual Parasite Index (API) data. The survey was a cross-sectional two-stage stratified cluster-randomised household survey conducted from July-October 2015. Blood samples were collected from household members for ultra-sensitive PCR and serology testing for P. falciparum and P. vivax. Data was gathered on demography and a priori risk factors of participants. Data was analysed nationally and within each of four domains defined by API data. Prevalence and seroprevalence of malaria were 0.74% and 16.01% nationwide, respectively. Prevalent infection was primarily asymptomatic P. vivax, while P. falciparum was predominant in serology. There was large heterogeneity between villages and by domain. At the township level, API showed moderate correlation with P. falciparum seroprevalence. Risk factors for infection included socioeconomic status, domain, and household ownership of nets. Three K13 P. falciparum mutants were found in highly prevalent villages. There results highlight high heterogeneity of both P. falciparum and P. vivax transmission between villages, accentuated by a large hidden reservoir of asymptomatic P. vivax infection not captured by incidence data, and representing challenges for malaria elimination. Village-level surveillance and stratification to guide interventions to suit local context and targeting of transmission foci with evidence of drug resistance would aid elimination efforts.

Emerging fungal pathogens pose a serious, global and growing threat to food supply systems, wild ecosystems, and human health. However, historic chronic underinvestment in their research has resulted in a limited understanding of their epidemiology relative to bacterial and viral pathogens. Therefore, the untargeted nature of genomics and, more widely, -omics approaches is particularly attractive in addressing the threats posed by and illuminating the biology of these pathogens. Typically, research into plant, human and wildlife mycoses have been largely separated, with limited dialogue between disciplines. However, many serious mycoses facing the world today have common traits irrespective of host species, such as plastic genomes; wide host ranges; large population sizes and an ability to persist outside the host. These commonalities mean that -omics approaches that have been productively applied in one sphere and may also provide important insights in others, where these approaches may have historically been underutilised. In this review, we consider the advances made with genomics approaches in the fields of plant pathology, human medicine and wildlife health and the progress made in linking genomes to other -omics datatypes and sets; we identify the current barriers to linking -omics approaches and how these are being underutilised in each field; and we consider how and which -omics methodologies it is most crucial to build capacity for in the near future.

The UK’s National Institute for Health and Care Excellence (NICE) Preterm labour and birth guideline recommends use of magnesium sulphate (MgSO4) in deliveries below 30 weeks’ gestation to prevent cerebral palsy and other neurological problems associated with preterm delivery. Despite national guidance, the uptake of MgSO4 administration in eligible women has been slow. NHS England has rolled out the PReCePT Quality Improvement (QI) toolkit to increase uptake of MgSO4 in preterm deliveries. The toolkit is designed to increase maternity staff knowledge about MgSO4 and provides training and practical tools to help staff consider use in eligible women. The PReCePT trial will evaluate the effectiveness of an enhanced support model of implementing the QI toolkit, compared with the standard support model. The standard support arm (control) receives the QI toolkit and regional-level support for a midwife/obstetric ‘champion’. The enhanced support arm (intervention) receives this plus additional clinical backfill funding and unit-level QI micro-coaching.This is a cluster randomised controlled trial designed to include 48 maternity units randomised (2:1 ratio) to standard or enhanced support. Units are eligible for inclusion if they have ten or more pre-term (< 30 weeks’ gestation) deliveries annually and MgSO4 uptake of 70% or less. Randomisation is stratified by previous level of MgSO4 uptake. The QI intervention is implemented over nine months. All units are followed up for a further nine months. Blinding is not possible due to the nature of the intervention.The primary outcome is the proportion of MgSO4 uptake amongst eligible women at follow-up, adjusting for uptake before implementation of the toolkit. The effectiveness of the intervention will be assessed using weighted linear regression on data from the National Neonatal Research Database. Semi-structured qualitative staff interviews will inform understanding of the process and outcomes. Economic evaluation will describe total costs and cost-effectiveness.STRENGTHS AND LIMITATIONSStrengthsThe first randomised controlled trial comparing two models of supporting the implementation of a Quality Improvement toolkit in perinatal medicine.A comprehensive evaluation, involving quantitative, qualitative and process measures including costs, to assess impact of the toolkit on the uptake of magnesium sulphate and team working.The National Neonatal Audit Programme (NNAP) and National Neonatal Registry Database (NNRD) provides robust routine data collection infrastructure for the primary outcome, also allowing future assessment of sustainability within participating units as well as uptake across the country.LimitationsThis pragmatic trial will reflect the conduct of scaling up a local initiative to a national level, where adherence to trial timelines may vary due to differences in local settings, procedures for permissions/approvals, and team capacity.Communication about the trial through formal and informal media channels may raise general awareness and thus improve background uptake nationally. Such contamination across trial groups may require assessment and adjustment in sensitivity analyses.

Objective To evaluate the effectiveness and predictive accuracy of early warning scores (EWS) to predict deteriorating patients in pre-hospital settings. Methods Systematic review. Seven databases searched to August 2017. Study quality was assessed using QUADAS-2. A narrative synthesis is presented. Eligibility Studies that evaluated EWS predictive accuracy or that compared outcomes in populations that did or did not use EWS, in any pre-hospital setting were eligible for inclusion. EWS were included if they aggregated three or more physiological parameters. Results Seventeen studies (157,878 participants) of predictive accuracy were included (16 in ambulance service and 1 in nursing home). AUCs ranged from 0.50 (CI not reported) to 0.89 (95%CI 0.82, 0.96). AUCs were generally higher (>0.80) for prediction of mortality within short time frames or for combination outcomes that included mortality and ICU admission. Few patients with low scores died at any time point. Patients with high scores were at risk of deterioration. Results were less clear for intermediate thresholds (≥4 or 5). Five studies were judged at low or unclear risk of bias, all others were judged at high risk of bias. Conclusions Very low and high EWS are able to discriminate between patients who are not likely and those who are likely to deteriorate in the pre-hospital setting. No study compared outcomes pre- and post-implementation of EWS so there is no evidence on whether patient outcomes differ between pre-hospital settings that do and do not use EWS. Further studies are required to address this question and to evaluate EWS in pre-hospital settings.

Cryptococcus gattii is an environmental pathogen that causes severe systemic infection in immunocompetent individuals more often than in immunocompromised humans. Over the past 2 decades, researchers have shown that C. gattii falls within four genetically distinct major lineages. By combining field work from an understudied ecological region (the Central Miombo Woodlands of Zambia, Africa), genome sequencing and assemblies, phylogenetic and population genetic analyses, and phenotypic characterization (morphology, histopathological, drug-sensitivity, survival experiments), we discovered a hitherto unknown lineage, which we name VGV (variety gattii five). The discovery of a new lineage from an understudied ecological region has far-reaching implications for the study and understanding of fungal pathogens and diseases they cause., We discovered a new lineage of the globally important fungal pathogen Cryptococcus gattii on the basis of analysis of six isolates collected from three locations spanning the Central Miombo Woodlands of Zambia, Africa. All isolates were from environments (middens and tree holes) that are associated with a small mammal, the African hyrax. Phylogenetic and population genetic analyses confirmed that these isolates form a distinct, deeply divergent lineage, which we name VGV. VGV comprises two subclades (A and B) that are capable of causing mild lung infection with negligible neurotropism in mice. Comparing the VGV genome to previously identified lineages of C. gattii revealed a unique suite of genes together with gene loss and inversion events. However, standard URA5 restriction fragment length polymorphism (RFLP) analysis could not distinguish between VGV and VGIV isolates. We therefore developed a new URA5 RFLP method that can reliably identify the newly described lineage. Our work highlights how sampling understudied ecological regions alongside genomic and functional characterization can broaden our understanding of the evolution and ecology of major global pathogens.

Background A mixed methods study was conducted to look at the magnitude of residual malaria transmission (RMT) and factors contributing to low (

BACKGROUND Mental health services aim to provide recovery-focused care and facilitate coproduced care planning. In practice, mental health providers can find supporting individualized coproduced care with service users difficult while balancing administrative and performance demands. To help meet this aim and using principles of coproduction, an innovative mobile digital care pathway tool (CPT) was developed to be used on a tablet computer and piloted in the West of England. OBJECTIVE The aim of this study was to examine mental health care providers’ views of and experiences with the CPT during the pilot implementation phase and identify factors influencing its implementation. METHODS A total of 20 in-depth telephone interviews were conducted with providers participating in the pilot and managers in the host organization. Interviews were audio recorded, transcribed, anonymized, and thematically analyzed guided by the Consolidated Framework for Implementation Research. RESULTS The tool was thought to facilitate coproduced recovery-focused care planning, a policy and organizational as well as professional priority. Internet connectivity issues, system interoperability, and access to service users’ health records affected use of the tool during mobile working. The organization’s resources, such as information technology (IT) infrastructure and staff time and IT culture, influenced implementation. Participants’ levels of use of the tool were dependent on knowledge of the tool and self-efficacy; perceived service-user needs and characteristics; and perceptions of impact on the therapeutic relationship. Training and preparation time influenced participants’ confidence in using the tool. CONCLUSIONS Findings highlight the importance of congruence between staff, organization, and external policy priorities and digital technologies in aiding intervention engagement, and the need for ongoing training and support of those intended to use the technology during and after the end of implementation interventions.

Background There is little evidence about either prevention or treatment of childhood arterial ischaemic stroke (AIS). However, drugs that regulate the immune and inflammatory response could theoretically prevent occurrence or recurrence of AIS. Additionally, as an acute treatment, they may limit the neurological damage caused by AIS. Here, we systematically review the evidence on the use of immunotherapy in childhood AIS.Design A systematic review of publications in databases Embase and Medline from inception. All types of evidence were included from trials, cohorts, case–control and cross-sectional studies and case reports.Results 34 reports were included: 32 observational studies and 2 trials. Immunotherapy was used in two key patient groups: arteriopathy and acute infection. The majority were cases of varicella and primary angiitis of the central nervous system. All three cohorts and 80% of the case studies were treated with steroids. Recurrence rates were low. Analytical studies weakly associated steroids with lower odds of new stroke and neurological deficits, and better cognitive outcomes in the context of Moyamoya disease and tuberculosis.Conclusions Immunotherapies are used in children with AIS, mainly as steroids for children with arteriopathy. However, there is currently little robust evidence to either encourage or discourage this practice. There is weak evidence consistent with the hypothesis that in certain children at risk, steroids may both reduce the risk of occurrent/recurrent stroke and enhance neurological outcomes. As the potential benefit is still uncertain, this indicates that a trial of steroids in childhood AIS may be justified.

OBJECTIVE Arterial ischemic stroke (AIS) is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood AIS have been completed. We aimed to investigate the outcome of childhood AIS 12 months after the event in a population-based cohort. METHODS Children aged 29 days to

BACKGROUND In Seychelles, the common myna has been shown to have a negative impact on endangered endemic birds on Denis Island, interfering with breeding attempts and attacking adult endemic birds at their nests. This stimulated an attempt to eradicate the island's mynas. RESULTS The eradication was undertaken in three phases, overall killing 1186 mynas and lasting 5 years. Decoy trapping was the most effective method for catching mynas, but the last birds were shot. Decoy trapping was compromised by catches of non-target species. Data collection from killed birds indicated that trapping did not favour either sex, and that most breeding occurred during the wetter season, November to March. CONCLUSIONS Eradication of mynas from small tropical islands is feasible. The Denis Island eradication was prolonged by difficulties in management and staffing. Using volunteers, the cost of the eradication was similar to that of eradicating rodents from the island. In future eradication attempts in Seychelles, possible food stress during the drier season (May to September) might facilitate trapping at this time. Habitat management, especially the removal of short mown grass, could enhance eradication progress. Continued monitoring is needed to confirm eradication and detect any immigration, and also to record responses in the endemic birds. © 2016 Society of Chemical Industry

BackgroundTuberous Sclerosis Complex (TSC) is a genetic disorder characterised by the development of benign tumours secondary to loss of inhibitory regulation of the mTOR (mechanistic Target of Rapamycin) intracellular growth pathway. Metformin inhibits the mTOR pathway. We investigated whether metformin would reduce growth of hamartomas associated with tuberous sclerosis complex.MethodsIn this multicentre randomized, double-blind, placebo-controlled trial, patients with a clinical diagnosis of tuberous sclerosis, aged over 10 years and with at least one renal angiomyolipoma of greater than 1 cm in diameter were enrolled. Participants were randomly allocated (1:1) by a secure website to receive metformin or placebo for 12 months. The primary outcome was percentage volume change of renal angiomyolipomas (AML) at 12 months compared to baseline. Secondary outcomes were percentage change at 12 months from baseline in volume of cerebral Subependymal Giant Cell Astrocytomas (SEGA); appearance of facial and ungual hamartomas; frequency of epileptic seizures; and adaptive behaviour. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 92545532, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2011-001319-30.• View related content for this articleFindingsBetween 1 November 2012 and 30 September 2015 72 patients were screened and 55 were randomly assigned to metformin (28) or placebo (27). Four participants withdrew between randomisation and starting treatment. All 51 patients who started therapy completed the trial and were assessed for outcome at 12 months. The median percentage change in angiomyolipoma (AML) volume was +7.6% (IQR -1.8% to +42.6%) for the placebo group and +8.9% (IQR 1.3% to 19.5%) for the metformin group (p = 0.28). Twenty-seven patients had SEGAs: 13 received placebo and 14 metformin. The median percentage change in SEGA volume was +3.0% (IQR -22.8% to +27.7%) for the placebo group and – 20.8% (IQR – 47.1% to - 5.0%) for the metformin group (p = 0.03). Twenty-one patients were assessed for seizure frequency: 9 received placebo and 12 received metformin. In the metformin group, a mean reduction of 43.7% from baseline in seizures was observed and in the placebo group a 3.1% mean reduction was observed, with a difference in response of 40.6% (95% CI -3.1% to +84.2%, p = 0.03). There were no significant differences between metformin and placebo groups for the other secondary outcomes. There were no deaths. Three serious adverse events (SAEs) occurred during the trial (all patients on metformin).InterpretationMetformin did not reduce AML volume. Metformin did reduce SEGA volume and seizure frequency compared with placebo. There may be a role for metformin in slowing or reversing growth of some life-threatening hamartomas in TSC and for reducing seizure frequency. Further study is justified.FundingThis study was funded by the National Institute for Health and Research (NIHR) through the The Research for Patient Benefit Programme (RfPB).

ObjectivesThe main and interactive effects of biological maturity status and relative age upon self-regulation in male academy soccer players are considered. Consistent with the ‘underdog’ hypothesis, whereby relatively younger players may benefit from competitive play with older peers, it was predicted later maturing and/or relatively younger players would report more adaptive self-regulation.DesignCross-sectional study.MethodPlayers (n = 171, aged 11–16 years) from four English professional soccer academies completed the modified Soccer Self-Regulation Scale. Date of birth, height, weight and parental height were obtained. Relative age was based on birth quarter for the selection year. Maturity status was based upon percentage of predicted adult height attained.ResultsLinear regression models showed later maturation was inversely associated with adaptive self-regulation, while relative age was unrelated to self-regulation.ConclusionsIn partial support of the underdog hypothesis, later maturing players appear to possess a psychological advantage.

Background: Total knee replacement (TKR) is a common procedure for the treatment of osteoarthritis that provides a substantial reduction of knee pain and improved function in most patients. We investigated whether sociodemographic factors could explain variations in the benefit resulting from TKR. Methods: Data were collected from 3 sources: the National Joint Registry for England, Wales, Northern Ireland, and the Isle of Man; National Health Service (NHS) England Patient Reported Outcome Measures; and Hospital Episode Statistics. These 3 sources were linked for analysis. Pain and function of the knee were measured with use of the Oxford Knee Score (OKS). The risk factors of interest were age group, sex, deprivation, and social support. The outcomes of interest were sociodemographic differences in preoperative scores, 6-month postoperative scores, and change in scores. Results: Ninety-one thousand nine hundred and thirty-six adults underwent primary TKR for the treatment of osteoarthritis in an NHS England unit from 2009 to 2012. Sixty-six thousand seven hundred and sixty-nine of those patients had complete knee score data and were included in the analyses for the present study. The preoperative knee scores were worst in female patients, younger patients, and patients from deprived areas. At 6 months postoperatively, the mean knee score had improved by 15.2 points. There were small sociodemographic differences in the benefit of surgery, with greater area deprivation (−0.71 per quintile of increase in deprivation; 95% confidence interval [CI], −0.76 to −0.66; p < 0.001) and younger age group (−3.51 for ≤50 years compared with 66 to 75 years; 95% CI, −4.00 to −3.02; p < 0.001) associated with less benefit. Cumulatively, sociodemographic factors explained Conclusions: Sociodemographic factors have a small influence on the benefit resulting from TKR. However, as they are associated with the clinical threshold at which the procedure is performed, they do affect the eventual outcomes of TKR. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of evidence.

The selective synthesis of 2,6-trans-tetrahydropyran derivatives employing the rhodium catalysed addition of organoboron reagents to dihydropyranone templates, derived from a zinc-catalysed hetero-Diels-Alder reaction, is reported. The addition of both arylboronic acids and potassium alkenyltrifluoroborates have been accomplished in high yields using commercially-available [Rh(cod)(OH)]2 catalyst. The selective formation of the 2,6-trans-tetrahydropyran stereoisomer is consistent with a mechanism involving alkene association and carbometalation on the less hindered face of the dihydropyranone.

ObjectivesTo examine patient and staff views, experiences and acceptability of a UK primary care online consultation system and ask how the system and its implementation may be improved.DesignMixed-method evaluation of a primary care e-consultation system.SettingPrimary care practices in South West England.MethodsQualitative interviews with 23 practice staff in six practices. Patient survey data for 756 e-consultations from 36 practices, with free-text survey comments from 512 patients, were analysed thematically. Anonymised patients’ records were abstracted for 485 e-consultations from eight practices, including consultation types and outcomes. Descriptive statistics were used to analyse quantitative data. Analysis of implementation and the usage of the e-consultation system were informed by: (1) normalisation process theory, (2) a framework that illustrates how e-consultations were co-produced and (3) patients’ and staff touchpoints.ResultsWe found different expectations between patients and staff on how to use e-consultations ‘appropriately’. While some patients used the system to try and save time for themselves and their general practitioners (GPs), some used e-consultations when they could not get a timely face-to-face appointment. Most e-consultations resulted in either follow-on phone (32%) or face-to-face appointments (38%) and GPs felt that this duplicated their workload. Patient satisfaction of the system was high, but a minority were dissatisfied with practice communication about their e-consultation.ConclusionsWhere both patients and staff interact with technology, it is in effect ‘co-implemented’. How patients used e-consultations impacted on practice staff’s experiences and appraisal of the system. Overall, the e-consultation system studied could improve access for some patients, but in its current form, it was not perceived by practices as creating sufficient efficiencies to warrant financial investment. We illustrate how this e-consultation system and its implementation can be improved, through mapping the co-production of e-consultations through touchpoints.

Introduction Tuberous Sclerosis Complex (TSC) is a genetic disorder characterised by the development of benign tumours, secondary to the loss of inhibitory regulation of the mTOR (mammalian Target Of Rapamycin) intracellular growth pathway. Metformin inhibits the mTOR pathway. We investigated the effect of Metformin in patients with TSC. Methods This was a multicentre randomised, double-blind, parallel group, placebo-controlled trial of metformin in children and adults with TSC. Patients were randomly allocated to placebo or metformin (1:1) for 12 months. The main outcomes were percentage volume change of renal angiomyolipomas (AML) and cerebral Subependymal Giant Cell Astrocytomas (SEGA). Blinded MRI assessments of AMLs and SEGAs were performed at baseline and at 12 months. Results Fifty-one patients participated, of whom 43 were adults (age range 10–50 years, median age 27, IQR 17). 24 received placebo and 27 received metformin. The mean AML volume increase from baseline was 25.5% for the placebo group and 9.6% for the metformin group. Difference in response, 15.9% (95% CI −9% to 41%) p=0.221. Twenty-seven patients had SEGAs: 13 received placebo and 14 metformin. The mean SEGA volume increased from baseline by 37% in the placebo group but reduced from baseline by 23.3% in the metformin group. Difference in response, 60.3% (95% CI −0.4% to 111, p=0.048). Three serious adverse events occurred that reflected the underlying disease. Two were AML haemorrhages and one was worsening seizures requiring hospitalisation. Conclusions Metformin is safe and well tolerated in children and adults with TSC. Patients on metformin had a significant reduction in SEGA volume compared with placebo. Metformin did not reduce AML size but growth appeared slower than in the placebo group, although this difference was not statistically significant. There may be a role for metformin in slowing or reversing the growth of life-threatening hamartomas in TSC. Further study is justified.

Why so much variation in extra-pair parentage occurs within and among populations remains unclear. Often the fitness costs and benefits of extra-pair parentage are hypothesised to explain its occurrence; therefore, linking extra-pair parentage with traits such as personality (behavioural traits that can be heritable and affect reproductive behaviour) may help our understanding. Here, we investigate whether reproductive outcomes and success are associated with exploratory behaviour in a natural population of cooperatively breeding Seychelles warblers (Acrocephalus sechellensis) on Cousin Island. Exploratory behaviour correlates positively with traits such as risk-taking behaviour and activity in other wild bird species and might promote extra-pair mating by increasing the rate at which potential extra-pair partners are encountered. We therefore predicted that fast-exploring individuals would have more extra-pair offspring. There is also a potential trade-off between pursuing extra-pair parentage and mate guarding in males. We therefore also predicted that fast-exploring males would be more likely to pursue extra-pair parentage and that this would increase the propensity of their mate to gain extra-pair parentage. We found that neither the total number of offspring nor the number of extra-pair offspring were associated with a male’s or female’s exploratory behaviour. However, there was a small but significant propensity for females to have extra-pair fertilisations in pairs that were behaviourally disassortative. Overall, we conclude that, due to the small effect size, the association between exploratory behaviour and extra-pair paternity is unlikely to be biologically relevant. Significance statement True genetic monogamy is rare, even in socially monogamous systems, and multiple factors, such as behaviour, social structure, morphology and physiology, determined by the biological system can cause variation in extra-pair parentage (EPP). Therefore, investigating the inherent differences in these factors among individuals could be informative. We investigated whether reproductive outcomes/success are associated with differences in the propensity to explore novel environments/objects in a promiscuous, island-dwelling cooperatively breeding bird, the Seychelles warbler. Our results showed that exploratory behaviour was not associated with the number of offspring produced by an individual, and thus the long-term fitness consequences of different exploratory tendencies did not differ. We also found that the propensity to engage in EPP in females was higher in dissimilar behavioural pairs, but due to the small effect size, we hesitate to conclude that there are personality-dependent mating outcomes in the population. Electronic supplementary material The online version of this article (10.1007/s00265-018-2448-z) contains supplementary material, which is available to authorized users.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objectives To evaluate the association between the quality of relationship between a person with dementia and their family carer and outcomes for the person with dementia. Design Systematic review. Eligibility criteria Cohort studies of people with clinically diagnosed dementia and their main carers. Exposures of interest were any elements of relationship quality, for example, attachment style, expressed emotion and coping style. Our primary outcome was institutionalisation, and secondary outcomes were hospitalisation, death, quality of life and behavioural and psychiatric symptoms of dementia ('challenging behaviour'). Data sources MEDLINE, Embase, Web of Science, PsycInfo, the Cochrane Library and Opengrey were searched from inception to May 2017. Study appraisal and synthesis methods The Newcastle-Ottawa Scale was used to assess risk of bias. A narrative synthesis of results was performed due to differences between studies. Results Twenty studies were included. None of the studies controlled for all prespecified confounding factors (age, gender, socioeconomic status and severity of dementia). Reporting of results was inadequate with many studies simply reporting whether associations were statistically significant' without providing effect size estimates or CIs. There was a suggestion of an association between relationship factors and global challenging behaviour. All studies evaluating global challenging behaviour provided statistical evidence of an association (most P values below 0.02). There was no consistent evidence for an association for any other outcome assessed. Conclusions There is currently no strong or consistent evidence on the effects of relationship factors on institutionalisation, hospitalisation, death or quality of life for people with dementia. There was a suggestion of an association between relationship factors and challenging behaviour, although the evidence for this was weak. To improve our ability to support those with dementia and their families, further robust studies are needed. PROSPERO registration number CRD42015020518.

BackgroundThe level of demand on primary care continues to increase. Electronic or e-consultations enable patients to consult their GP online and have been promoted as having potential to improve access and efficiency.AimTo evaluate whether an e-consultation system improves the ability of practice staff to manage workload and access.Design and settingA qualitative interview study in general practices in the West of England that piloted an e-consultation system for 15 months during 2015 and 2016.MethodPractices were purposefully sampled by location and level of e-consultation use. Clinical, administrative, and management staff were recruited at each practice. Interviews were transcribed and analysed thematically.ResultsTwenty-three interviews were carried out across six general practices. Routine e-consultations offered benefits for the practice because they could be completed without direct contact between GP and patient. However, most e-consultations resulted in GPs needing to follow up with a telephone or face-to-face appointment because the e-consultation did not contain sufficient information to inform clinical decision making. This was perceived as adding to the workload and providing some patients with an alternative route into the appointment system. Although this was seen as offering some patient benefit, there appeared to be fewer benefits for the practices.ConclusionThe experiences of the practices in this study demonstrate that the technology, in its current form, fell short of providing an effective platform for clinicians to consult with patients and did not justify their financial investment in the system. The study also highlights the challenges of remote consultations, which lack the facility for real time interactions.

Aim Currently there are few population-based data on the outcomes of stroke in childhood, and no data on what parents want from such research. We conducted a Delphi Consensus Process among parents of children (n = 26) who had suffered an arterial ischaemic stroke to investigate which research outcomes they think are most important to follow up, and what methods of assessment they would find most acceptable. Methods A postal Delphi Consensus Process was conducted. Results The Delphi panel reached consensus that motor, cognitive and communication outcomes are the most important outcome domains to assess. They strongly preferred home visits over hospital visits or telephone interview. The majority were happy with assessment visits lasting up to 1.5 h. Ongoing concerns for panel members related to the cause of the original stroke, the risk of recurrence and the long term outcome for their child. Interpretation Future outcome studies should preferably assess outcomes at home and focus on children's motor, cognitive and communication abilities. There is an ongoing need to clarify issues with regards to the likely cause of children's strokes and their risk of recurrence.

ObjectivesEvaluation of a pilot study of an online consultation system in primary care. We describe who used the system, when and why, and the National Health Service costs associated with its use.Design15-month observational study.SettingPrimary care practices in South West England.Results36 General practices covering 396 828 patients took part in the pilot. The online consultation website was viewed 35 981 times over the pilot period (mean 9.11 visits per 1000 patients per month). 7472 patients went on to complete an ‘e-consultation’ (mean 2.00 online consultations per 1000 patients per month). E-consultations were mainly performed on weekdays and during normal working hours. Patient records (n=485) were abstracted for eight practices and showed that women were more likely to use e-consultations than men (64.7% vs 35.3%) and users had a median age of 39 years (IQR 30–50). The most common reason for an e-consultation was an administrative request (eg, test results, letters and repeat prescriptions (22.5%)) followed by infections/immunological issues (14.4%). The majority of patients (65.2%) received a response within 2 days. The most common outcome was a face-to-face (38%) or telephone consultation (32%). The former were more often needed for patients consulting about new conditions (OR 1.56, 95% CI 1.05 to 2.27, p=0.049). The average cost of a practice’s response to an e-consultation was £36.28, primarily triage time and resulting face-to-face/telephone consultations needed.ConclusionsUse of e-consultations is very low, particularly at weekends. Unless this can be improved, any impact on staff workload and patient waiting times is likely to be negligible. It is possible that use of e-consultations increases primary care workload and costs. Online consultation systems could be developed to improve efficiency both for staff and patients. These findings have implications for software developers as well as primary care services and policy-makers who are considering investing in online consultation systems.

Objectives: To determine the effects of low-to-moderate levels of maternal alcohol consumption in pregnancy on pregnancy and longer-term offspring outcomes.Search Strategy: Medline, Embase, Web of Science, and Psychinfo from inception to 11-07-2016. Selection Criteria: Prospective observational studies, negative control and quasi-experimental studies of pregnant women estimating effects of light drinking in pregnancy (≤32g/week) versus abstaining. Pregnancy outcomes such as birth weight, and features of fetal alcohol syndrome were examined. Data Collection and Analysis: One reviewer extracted data and another checked extracted data. Random effects meta-analyses were performed where applicable, and a narrative summary of findings was carried out otherwise. Main Results: 24 cohort and two quasi-experimental studies were included. With the exception of birth size and gestational age, there was insufficient data to meta-analyse or make robust conclusions. Odds of small-for-gestational-age (SGA) and preterm birth were higher for babies whose mothers consumed up to 32g/week versus none, but estimates for preterm birth were also compatible with no association: summary odd ratios (OR) 1·08, 95% confidence intervals (CI) (1·02 to 1·14), I2 0%, (7 studies, all estimates were adjusted) OR 1·10, 95%CI (0·95 to1·28), I2 60%, (9 studies, includes one unadjusted estimates) respectively. The earliest time points of exposure were used in the analysis.Conclusion: Evidence of the effects of drinking