An integrated primary care-based programme of PRE-Pregnancy cARE to improve pregnancy outcomes in women with type 2 Diabetes (The PREPARED study): protocol for a multi-method study of implementation, system adaptation and performance

Background: The number of women of childbearing age with Type 2 diabetes(T2DM) is increasing, and they now account for > 50% of pregnancies in women with pre-existing diabetes. Diabetes pregnancies without adequate pre-pregnancy care have higher risk for poor outcomes (miscarriages, birth-defects, stillbirths) and are associated with increased complications (caesarean deliveries, macrosomic babies, neonatal intensive-care admissions). The risks and costs of these pregnancies can be reduced with pregnancy preparation (HbA1c, ≤ 6.5%, 5 mg folic acid and stopping potentially harmful medicines). However, 90% of women with T2DM, most of whom are based in primary care, are not adequately prepared for pregnancy. This study will evaluate a programme of primary care-based interventions (decision-support systems; pre-pregnancy care-pathways; pregnancy-awareness resources; professional training; and performance monitoring) to improve pregnancy preparation in women with T2DM. Methods: The study aims to optimise the programme interventions and estimate their impact on pregnancy preparation, pre-pregnancy care uptake and pregnancy outcomes. To evaluate this multimodal intervention, we will use a multi-method research design following Complex Adaptive Systems (CAS) theory, refining the interventions iteratively during the study. Thirty GP practices with ≥ 25 women with T2DM of reproductive age (18–45 years) from two South London boroughs will be exposed to the intervention. This will provide > 750 women with an estimated pregnancy incidence of 80–100 to study. The research involves: a clinical audit of processes and outcomes; a process evaluation informing intervention feasibility, implementation, and behaviour change; and a cost-consequences analysis informing future economic evaluation. Performance data will be collected via audits of GP systems, hospital antenatal clinics and pregnancy outcomes. Following CAS theory, we will use repeated measurements to monitor intervention impact on pregnancy preparation markers at 4-monthly intervals over 18-months. We will use performance and feasibility data to optimise intervention effects iteratively. The target performance for the intervention is a 30% increase in the proportion of women meeting pre-pregnancy care criteria. Discussion: The primary output will be development of an integrated programme of interventions to improve pregnancy preparation, pre-pregnancy care uptake, and reduce adverse pregnancy outcomes in women with T2DM. We will also develop an implementation plan to support the introduction of the interventions across the NHS

Moving away from the "unit cost". Predicting country-specific average cost curves of VMMC services accounting for variations in service delivery platforms in sub-Saharan Africa.

BACKGROUND: One critical element to optimize funding decisions involves the cost and efficiency implications of implementing alternative program components and configurations. Program planners, policy makers and funders alike are in need of relevant, strategic data and analyses to help them plan and implement effective and efficient programs. Contrary to widely accepted conceptions in both policy and academic arenas, average costs per service (so-called "unit costs") vary considerably across implementation settings and facilities. The objective of this work is twofold: 1) to estimate the variation of VMMC unit costs across service delivery platforms (SDP) in Sub-Saharan countries, and 2) to develop and validate a strategy to extrapolate unit costs to settings for which no data exists. METHODS: We identified high-quality VMMC cost studies through a literature review. Authors were contacted to request the facility-level datasets (primary data) underlying their results. We standardized the disparate datasets into an aggregated database which included 228 facilities in eight countries. We estimated multivariate models to assess the correlation between VMMC unit costs and scale, while simultaneously accounting for the influence of the SDP (which we defined as all possible combinations of type of facility, ownership, urbanicity, and country), on the unit cost variation. We defined SDP as any combination of such four characteristics. Finally, we extrapolated VMMC unit costs for all SDPs in 13 countries, including those not contained in our dataset. RESULTS: The average unit cost was 73 USD (IQR: 28.3, 100.7). South Africa showed the highest within-country cost variation, as well as the highest mean unit cost (135 USD). Uganda and Namibia had minimal within-country cost variation, and Uganda had the lowest mean VMMC unit cost (22 USD). Our results showed evidence consistent with economies of scale. Private ownership and Hospitals were significant determinants of higher unit costs. By identifying key cost drivers, including country- and facility-level characteristics, as well as the effects of scale we developed econometric models to estimate unit cost curves for VMMC services in a variety of clinical and geographical settings. CONCLUSION: While our study did not produce new empirical data, our results did increase by a tenfold the availability of unit costs estimates for 128 SDPs in 14 priority countries for VMMC. It is to our knowledge, the most comprehensive analysis of VMMC unit costs to date. Furthermore, we provide a proof of concept of the ability to generate predictive cost estimates for settings where empirical data does not exist

Developing the Global Health Cost Consortium Unit Cost Study Repository for HIV and TB: methodology and lessons learned.

Consistently defined, accurate, and easily accessible cost data are a valuable resource to inform efficiency analyses, budget preparation, and sustainability planning in global health. The Global Health Cost Consortium (GHCC) designed the Unit Cost Study Repository (UCSR) to be a resource for standardised HIV and TB intervention cost data displayed by key characteristics such as intervention type, country, and target population. To develop the UCSR, the GHCC defined a typology of interventions for each disease; aligned interventions according to the standardised principles, methods, and cost and activity categories from the GHCC Reference Case for Estimating the Costs of Global Health Services and Interventions; completed a systematic literature review; conducted extensive data extraction; performed quality assurance; grappled with complex methodological issues such as the proper approach to the inflation and conversion of costs; developed and implemented a study quality rating system; and designed a web-based user interface that flexibly displays large amounts of data in a user-friendly way. Key lessons learned from the extraction process include the importance of assessing the multiple uses of extracted data; the critical role of standardising definitions (particularly units of measurement); using appropriate classifications of interventions and components of costs; the efficiency derived from programming data checks; and the necessity of extraction quality monitoring by senior analysts. For the web interface, lessons were: understanding the target audiences, including consulting them regarding critical characteristics; designing the display of data in "levels"; and incorporating alert and unique trait descriptions to further clarify differences in the data

Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

SummaryGlobal dispersal and increasing frequency of the SARS-CoV-2 Spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of Spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large data set, well represented by both Spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the Spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant.</jats:p

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science

Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA)

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min−1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems