Establishing Ebola Virus Disease (EVD) diagnostics using GeneXpert technology at a mobile laboratory in Liberia: Impact on outbreak response, case management and laboratory systems strengthening.

The 2014-16 Ebola Virus Disease (EVD) outbreak in West Africa highlighted the necessity for readily available, accurate and rapid diagnostics. The magnitude of the outbreak and the re-emergence of clusters of EVD cases following the declaration of interrupted transmission in Liberia, reinforced the need for sustained diagnostics to support surveillance and emergency preparedness. We describe implementation of the Xpert Ebola Assay, a rapid molecular diagnostic test run on the GeneXpert platform, at a mobile laboratory in Liberia and the subsequent impact on EVD outbreak response, case management and laboratory system strengthening. During the period of operation, site coordination, management and operational capacity was supported through a successful collaboration between Ministry of Health (MoH), World Health Organization (WHO) and international partners. A team of Liberian laboratory technicians were trained to conduct EVD diagnostics and the laboratory had capacity to test 64-100 blood specimens per day. Establishment of the laboratory significantly increased the daily testing capacity for EVD in Liberia, from 180 to 250 specimens at a time when the effectiveness of the surveillance system was threatened by insufficient diagnostic capacity. During the 18 months of operation, the laboratory tested a total of 9,063 blood specimens, including 21 EVD positives from six confirmed cases during two outbreaks. Following clearance of the significant backlog of untested EVD specimens in November 2015, a new cluster of EVD cases was detected at the laboratory. Collaboration between surveillance and laboratory coordination teams during this and a later outbreak in March 2016, facilitated timely and targeted response interventions. Specimens taken from cases during both outbreaks were analysed at the laboratory with results informing clinical management of patients and discharge decisions. The GeneXpert platform is easy to use, has relatively low running costs and can be integrated into other national diagnostic algorithms. The technology has on average a 2-hour sample-to-result time and allows for single specimen testing to overcome potential delays of batching. This model of a mobile laboratory equipped with Xpert Ebola test, staffed by local laboratory technicians, could serve to strengthen outbreak preparedness and response for future outbreaks of EVD in Liberia and the region

Informing the development of Australia's national eating disorders research and translation strategy : a rapid review methodology

Background Eating disorders (EDs) are highly complex mental illnesses associated with significant medical complications. There are currently knowledge gaps in research relating to the epidemiology, aetiology, treatment, burden, and outcomes of eating disorders. To clearly identify and begin addressing the major deficits in the scientific, medical, and clinical understanding of these mental illnesses, the Australian Government Department of Health in 2019 funded the InsideOut Institute (IOI) to develop the Australian Eating Disorder Research and Translation Strategy, the primary aim of which was to identify priorities and targets for building research capacity and outputs. A series of rapid reviews (RR) were conducted to map the current state of knowledge, identify evidence gaps, and inform development of the national research strategy. Published peer-reviewed literature on DSM-5 listed EDs, across eight knowledge domains was reviewed: (1) population, prevalence, disease burden, Quality of Life in Western developed countries; (2) risk factors; (3) co-occurring conditions and medical complications; (4) screening and diagnosis; (5) prevention and early intervention; (6) psychotherapies and relapse prevention; (7) models of care; (8) pharmacotherapies, alternative and adjunctive therapies; and (9) outcomes (including mortality). While RRs are systematic in nature, they are distinct from systematic reviews in their aim to gather evidence in a timely manner to support decision-making on urgent or high-priority health concerns at the national level. Results Three medical science databases were searched as the primary source of literature for the RRs: Science Direct, PubMed and OVID (Medline). The search was completed on 31st May 2021 (spanning January 2009-May 2021). At writing, a total of 1,320 articles met eligibility criteria and were included in the final review. Conclusions For each RR, the evidence has been organised to review the knowledge area and identify gaps for further research and investment. The series of RRs (published separately within the current series) are designed to support the development of research and translation practice in the field of EDs. They highlight areas for investment and investigation, and provide researchers, service planners and providers, and research funders rapid access to quality current evidence, which has been synthesised and organised to assist decision-making

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Gothic Revival Architecture Before Horace Walpole's Strawberry Hill

The Gothic Revival is generally considered to have begun in eighteenth-century Britain with the construction of Horace Walpole’s villa, Strawberry Hill, Twickenham, in the late 1740s. As this chapter demonstrates, however, Strawberry Hill is in no way the first building, domestic or otherwise, to have recreated, even superficially, some aspect of the form and ornamental style of medieval architecture. Earlier architects who, albeit often combining it with Classicism, worked in the Gothic style include Sir Christopher Wren, Nicholas Hawksmoor, William Kent and Batty Langley, aspects of whose works are explored here. While not an exhaustive survey of pre-1750 Gothic Revival design, the examples considered in this chapter reveal how seventeenth- and eighteenth-century Gothic emerged and evolved over the course of different architects’ careers, and how, by the time that Walpole came to create his own Gothic ‘castle’, there was already in existence in Britain a sustained Gothic Revivalist tradition

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

National reporting of deaths after enhanced Ebola surveillance in Sierra Leone.

BACKGROUND:Sierra Leone experienced the largest documented epidemic of Ebola Virus Disease in 2014-2015. The government implemented a national tollfree telephone line (1-1-7) for public reporting of illness and deaths to improve the detection of Ebola cases. Reporting of deaths declined substantially after the epidemic ended. To inform routine mortality surveillance, we aimed to describe the trends in deaths reported to the 1-1-7 system and to quantify people's motivations to continue reporting deaths after the epidemic. METHODS:First, we described the monthly trends in the number of deaths reported to the 1-1-7 system between September 2014 and September 2019. Second, we conducted a telephone survey in April 2017 with a national sample of individuals who reported a death to the 1-1-7 system between December 2016 and April 2017. We described the reported deaths and used ordered logistic regression modeling to examine the potential drivers of reporting motivations. FINDINGS:Analysis of the number of deaths reported to the 1-1-7 system showed that 12% of the expected deaths were captured in 2017 compared to approximately 34% in 2016 and over 100% in 2015. We interviewed 1,291 death reporters in the survey. Family members reported 56% of the deaths. Nearly every respondent (94%) expressed that they wanted the 1-1-7 system to continue. The most common motivation to report was to obey the government's mandate (82%). Respondents felt more motivated to report if the decedent exhibited Ebola-like symptoms (adjusted odds ratio 2.3; 95% confidence interval 1.8-2.9). CONCLUSIONS:Motivation to report deaths that resembled Ebola in the post-outbreak setting may have been influenced by knowledge and experiences from the prolonged epidemic. Transitioning the system to a routine mortality surveillance tool may require a robust social mobilization component to match the high reporting levels during the epidemic, which exceeded more than 100% of expected deaths in 2015

Mobilizing a region to redesign a local system of care: lessons from a community-based learning collaborative.

Local efforts to redesign systems of care offer fertile ground for community-based participatory research approaches to take hold and flourish. Drawing on the experiences of a learning collaborative of maternal and child healthcare stakeholders in Allegheny County, Pennsylvania, this article describes 8 action steps for operationalizing key community-based participatory research principles in the context of local systems change. Highlights of the subsequent evolution of the collaborative and its work are provided, as well as comments regarding the generalizability and usefulness of this approach for other public health and community stakeholders who are interested in mobilizing collaborative action for systems change

RT-PCR Ct values for NP and GP gene targets from positive blood samples of EVD cases from the Duport Road cluster, November-December 2015 and the Central Monrovia cluster, March-April 2016.

<p>RT-PCR Ct values for NP and GP gene targets from positive blood samples of EVD cases from the Duport Road cluster, November-December 2015 and the Central Monrovia cluster, March-April 2016.</p

Timeline of key events in establishing and running the ELWA-III mobile EVD testing laboratory—September 2015 to March 2017.

<p>Timeline of key events in establishing and running the ELWA-III mobile EVD testing laboratory—September 2015 to March 2017.</p