Medical Research Council Grant Research Articles

Cost-effectiveness of diagnosis and treatment of early gestational diabetes mellitus: economic evaluation of the TOBOGM study, an international multicenter randomized controlled trial

A recently undertaken multicenter randomized controlled trial (RCT) "Treatment Of BOoking Gestational diabetes Mellitus" (TOBOGM: 2017-2022) found that the diagnosis and treatment of pregnant women with early gestational diabetes mellitus (GDM) improved pregnancy outcomes. Based on data from the trial, this study aimed to assess the cost-effectiveness of diagnosis and treatment of early GDM (from <20 weeks') among women with risk factors for hyperglycemia in pregnancy compared with usual care (no treatment until 24-28 weeks') from a healthcare perspective. Participants' healthcare resource utilization data were collected from their self-reported questionnaires and hospital records, and valued using the unit costs obtained from standard Australian national sources. Costs were reported in US dollars ($) using the purchasing power parity (PPP) estimates to facilitate comparison of costs across countries. Intention-to-treat (ITT) principle was followed. Missing cost data were replaced using multiple imputations. Bootstrapping method was used to estimate the uncertainty around mean cost difference and cost-effectiveness results. Bootstrapped cost-effect pairs were used to plot the cost-effectiveness (CE) plane and cost-effectiveness acceptability curve (CEAC). Diagnosis and treatment of early GDM was more effective and tended to be less costly, i.e., dominant (cost-saving) [-5.6% composite adverse pregnancy outcome (95% CI:-10.1%,-1.2%),-$1373 (95% CI:-$3,749, $642)] compared with usual care. Our findings were confirmed by both the CE plane (88% of the bootstrapped cost-effect pairs fall in the south-west quadrant), and CEAC (the probability of the intervention being cost-effective ranged from 84% at a willingness-to-pay (WTP) threshold value of $10,000-99% at a WTP threshold value of $100,000 per composite adverse pregnancy outcome prevented). Sub-group analyses demonstrated that diagnosis and treatment of early GDM among women in the higher glycemic range (fasting blood glucose 95-109mg/dl [5.3-6.0mmol/L], 1-h blood glucose ≥191mg/dl [10.6mmol/L] and/or 2-h blood glucose 162-199mg/dl [9.0-11.0mmol/L]) was more effective and less costly (dominant) [-7.8% composite adverse pregnancy outcome (95% CI:-14.6%,-0.9%),-$2795 (95% CI:-$6,638,-$533)]; the intervention was more effective and tended to be less costly [-8.9% composite adverse pregnancy outcome (95% CI:-15.1%,-2.6%),-$5548 (95% CI:-$16,740, $1547)] among women diagnosed before 14 weeks' gestation as well. Our findings highlight the potential health and economic benefits from the diagnosis and treatment of early GDM among women with risk factors for hyperglycemia in pregnancy and supports its implementation. Long-term follow-up studies are recommended as a key future area of research to assess the potential long-term health benefits and economic consequences of the intervention. National Health and Medical Research Council (grants 1104231 and 2009326), Region O¨rebro Research Committee (grants Dnr OLL-970566 and OLL-942177), Medical Scientific Fund of the Mayor of Vienna (project 15,205 and project 23,026), South Western Sydney Local Health District Academic Unit (grant 2016), and Western Sydney University Ainsworth Trust Grant (2019).

Determinants of lung function development from birth to age 5 years: an interrupted time series analysis of a South African birth cohort

Early life is a key period that determines long-term health. Lung development in childhood predicts lung function attained in adulthood and morbidity and mortality across the life course. We aimed to assess the effect of early-life lower respiratory tract infection (LRTI) and associated risk factors on lung development from birth to school age in a South African birth cohort. We prospectively followed children enrolled in a population-based cohort from birth (between March 5, 2012 and March 31, 2015) to age 5 years with annual lung function assessment. Data on multiple early-life exposures, including LRTI, were collected. The effect of early-life risk factors on lung function development from birth to age 5 years was assessed using the Generalised Additive Models for Location, Scale and Shape and Interrupted Time Series approach. 966 children (475 [49·2%] female, 491 [50·8%] male) had lung function measured with oscillometry, tidal flow volume loops, and multiple breath washout. LRTI occurred in 484 (50·1%) children, with a median of 2·0 LRTI episodes (IQR 1·0-3·0) per child. LRTI was independently associated with altered lung function, as evidenced by lower compliance (0·959 [95% CI 0·941-0·978]), higher resistance (1·028 [1·016-1·041]), and higher respiratory rate (1·018 [1·063-1·029]) over 5 years. Additional impact on lung function parameters occurred with each subsequent LRTI. Respiratory syncytial virus (RSV) LRTI was associated with lower expiratory flow ratio (0·97 [0·95-0·99]) compared with non-RSV LRTI. Maternal factors including allergy, smoking, and HIV infection were also associated with altered lung development, as was preterm birth, low birthweight, female sex, and coming from a less wealthy household. Public health interventions targeting LRTI prevention, with RSV a priority, are vital, particularly in low-income and middle-income settings. UK Medical Research Council Grant, The Wellcome Trust, The Bill & Melinda Gates Foundation, US National Institutes of Health Human Heredity and Health in Africa, South African Medical Research Council, Hungarian Scientific Research Fund, and European Respiratory Society.

Bone health in women with premature ovarian insufficiency/early menopause: a 23-year longitudinal analysis.

Bone health in women with premature ovarian insufficiency/early menopause: a 23-year longitudinal analysis.

Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions

SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability. We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor. A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n=85) compared with controls (1.1%, n=5) (p<0.0001) whereas GAA250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of+18 repeats per generation (r2=0.44; p<0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r2=0.63; p<0.0001)), resulting in the transmission bias observed in SCA27B pedigrees. SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling. This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.

Healthcare in England was affected by the COVID-19 pandemic across the pancreatic cancer pathway: A cohort study using OpenSAFELY-TPP.

Healthcare across all sectors, in the UK and globally, was negatively affected by the COVID-19 pandemic. We analysed healthcare services delivered to people with pancreatic cancer from January 2015 to March 2023 to investigate the effect of the COVID-19 pandemic. With the approval of NHS England, and drawing from a nationally representative OpenSAFELY-TPP dataset of 24 million patients (over 40% of the English population), we undertook a cohort study of people diagnosed with pancreatic cancer. We queried electronic healthcare records for information on the provision of healthcare services across the pancreatic cancer pathway. To estimate the effect of the COVID-19 pandemic, we predicted the rates of healthcare services if the pandemic had not happened. We used generalised linear models and the pre-pandemic data from January 2015 to February 2020 to predict rates in March 2020 to March 2023. The 95% confidence intervals of the predicted values were used to estimate the significance of the difference between the predicted and observed rates. The rate of pancreatic cancer and diabetes diagnoses in the cohort was not affected by the pandemic. There were 26,840 people diagnosed with pancreatic cancer from January 2015 to March 2023. The mean age at diagnosis was 72 (±11 SD), 48% of people were female, 95% were of White ethnicity, and 40% were diagnosed with diabetes. We found a reduction in surgical resections by 25-28% during the pandemic. In addition, 20%, 10%, and 4% fewer people received body mass index, glycated haemoglobin, and liver function tests, respectively, before they were diagnosed with pancreatic cancer. There was no impact of the pandemic on the number of people making contact with primary care, but the number of contacts increased on average by 1-2 per person amongst those who made contact. Reporting of jaundice decreased by 28%, but recovered within 12 months into the pandemic. Emergency department visits, hospital admissions, and deaths were not affected. The pandemic affected healthcare in England across the pancreatic cancer pathway. Positive lessons could be learnt from the services that were resilient and those that recovered quickly. The reductions in healthcare experienced by people with cancer have the potential to lead to worse outcomes. Current efforts should focus on addressing the unmet needs of people with cancer. This work was jointly funded by the Wellcome Trust (222097/Z/20/Z); MRC (MR/V015757/1, MC_PC-20059, MR/W016729/1); NIHR (NIHR135559, COV-LT2-0073), and Health Data Research UK (HDRUK2021.000, 2021.0157). This work was funded by Medical Research Council (MRC) grant reference MR/W021390/1 as part of the postdoctoral fellowship awarded to AL and undertaken at the Bennett Institute, University of Oxford. The views expressed are those of the authors and not necessarily those of the NIHR, NHS England, UK Health Security Agency (UKHSA), or the Department of Health and Social Care. Funders had no role in the study design, collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Forecasting seizure likelihood from cycles of self-reported events and heart rate: a prospective pilot study.

Seizure risk forecasting could reduce injuries and even deaths in people with epilepsy. There is great interest in using non-invasive wearable devices to generate forecasts of seizure risk. Forecasts based on cycles of epileptic activity, seizure times or heart rate have provided promising forecasting results. This study validates a forecasting method using multimodal cycles recorded from wearable devices. Seizure and heart rate cycles were extracted from 13 participants. The mean period of heart rate data from a smartwatch was 562 days, with a mean of 125 self-reported seizures from a smartphone app. The relationship between seizure onset time and phases of seizure and heart rate cycles was investigated. An additive regression model was used to project heart rate cycles. The results of forecasts using seizure cycles, heart rate cycles, and a combination of both were compared. Forecasting performance was evaluated in 6 of 13 participants in a prospective setting, using long-term data collected after algorithms were developed. The results showed that the best forecasts achieved a mean area under the receiver-operating characteristic curve (AUC) of 0.73 for 9/13 participants showing performance above chance during retrospective validation. Subject-specific forecasts evaluated with prospective data showed a mean AUC of 0.77 with 4/6 participants showing performance above chance. The results of this study demonstrate that cycles detected from multimodal data can be combined within a single, scalable seizure risk forecasting algorithm to provide robust performance. The presented forecasting method enabled seizure risk to be estimated for an arbitrary future period and could be generalised across a range of data types. In contrast to earlier work, the current study evaluated forecasts prospectively, in subjects blinded to their seizure risk outputs, representing a critical step towards clinical applications. This study was funded by an Australian Government National Health & Medical Research Council and BioMedTech Horizons grant. The study also received support from the Epilepsy Foundation of America's 'My Seizure Gauge' grant.

Spatio-temporal remodelling of the composition and architecture of the human ovarian cortical extracellular matrix during in vitro culture.

How does in vitro culture alter the human ovarian cortical extracellular matrix (ECM) network structure? The ECM composition and architecture vary in the different layers of the ovarian cortex and are remodelled during in vitro culture. The ovarian ECM is the scaffold within which follicles and stromal cells are organized. Its composition and structural properties constantly evolve to accommodate follicle development and expansion. Tissue preparation for culture of primordial follicles within the native ECM involves mechanical loosening; this induces undefined modifications in the ECM network and alters cell-cell contact, leading to spontaneous follicle activation. Fresh ovarian cortical biopsies were obtained from six women aged 28-38 years (mean ± SD: 32.7 ± 4.1 years) at elective caesarean section. Biopsies were cut into fragments of ∼4 × 1 × 1 mm and cultured for 0, 2, 4, or 6 days (D). Primordial follicle activation, stromal cell density, and ECM-related protein (collagen, elastin, fibronectin, laminin) positive area in the entire cortex were quantified at each time point using histological and immunohistological analysis. Collagen and elastin content, collagen fibre characteristics, and follicle distribution within the tissue were further quantified within each layer of the human ovarian cortex, namely the outer cortex, the mid-cortex, and the cortex-medulla junction regions. Primordial follicle activation occurred concomitantly with a loosening of the ovarian cortex during culture, characterized by an early decrease in stromal cell density from 3.6 ± 0.2 × 106 at day 0 (D0) to 2.8 ± 0.1 × 106 cells/mm3 at D2 (P = 0.033) and a dynamic remodelling of the ECM. Notably, collagen content gradually fell from 55.5 ± 1.7% positive area at D0 to 42.3 ± 1.1% at D6 (P = 0.001), while elastin increased from 1.1 ± 0.2% at D0 to 1.9 ± 0.1% at D6 (P = 0.001). Fibronectin and laminin content remained stable. Moreover, collagen and elastin distribution were uneven throughout the cortex and during culture. Analysis at the sub-region level showed that collagen deposition was maximal in the outer cortex and the lowest in the mid-cortex (69.4 ± 1.2% versus 53.8 ± 0.8% positive area, respectively, P < 0.0001), and cortical collagen staining overall decreased from D0 to D2 (65.2 ± 2.4% versus 60.6 ± 1.8%, P = 0.033) then stabilized. Elastin showed the converse distribution, being most concentrated at the cortex-medulla junction (3.7 ± 0.6% versus 0.9 ± 0.2% in the outer cortex, P < 0.0001), and cortical elastin peaked at D6 compared to D0 (3.1 ± 0.5% versus 1.3 ± 0.2%, P < 0.0001). This was corroborated by a specific signature of the collagen fibre type across the cortex, indicating a distinct phenotype of the ovarian cortical ECM depending on region and culture period that might be responsible for the spatio-temporal and developmental pattern of follicular distribution observed within the cortex. N/A. Ovarian cortical biopsies were obtained from women undergoing caesarean sections. As such, the data obtained may not accurately reflect the ECM distribution and structure of non-pregnant women. Clarifying the composition and architecture signature of the human ovarian cortical ECM provides a foundation for further exploration of ovarian microenvironments. It is also critical for understanding the ECM-follicle interactions regulating follicle quiescence and awakening, leading to improvements in both in vitro activation and in vitro growth techniques. Medical Research Council grant MR/R003246/1 and Wellcome Trust Collaborative Award in Science: 215625/Z/19/Z. The authors have no conflicts to declare. N/A.

Incident heart failure and the subsequent risk for progression to end stage kidney disease in South East Asian people with type 2 diabetes

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Singapore National Medical Research Council grants: CSA-INV/0020/2017 and CS-IRG (MOH-000066) Background Heart failure (HF) is a common but often unrecognized complication of type 2 diabetes (T2D). Both low eGFR and high albuminuria are strong risk factors for development of HF in diabetic population. However, data on the role of HF in long-term kidney disease outcome are sparse. Aim We sought to study the risk for progression to end stage kidney disease (ESKD) after incident HF in multi-ethnic South East Asian people with type 2 diabetes. Participants and Methods A total of 1,756 individuals with type 2 diabetes recruited from a regional hospital were followed for a median of 7.3 (interquartile range 6.8-7.8) years. Incident HF was identified according to European Society of Cardiology 2016 criteria. HF was subtyped into preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) with ventricular ejection fraction (LVEF) cut-off at ≥50% and &amp;lt;50% respectively. Progression to ESKD was defined as patients with sustained eGFR &amp;lt;15ml/min per 1.73m2 with confirmation measurement 3 months apart, or on sustained dialysis for at least 3 months or death attributable to renal cause, whichever occurred first. The risk of progression to ESKD after HF was assessed using Cox proportional hazard models. Results Average age of participants was 57±11 years with diabetes duration of 11 (IQR 4-15) years. There were 52% Chinese, 22% Malay and 26% Asian Indian in the study participants. We identified 113 incident HF events (65 HFpEF and 48 HFrEF) during 11,869 patient-years (crude incidence rate 9.5 per 1000 patient-years). Individuals with HF occurrence were older, had a longer diabetes duration, higher body mass index, HbA1c and systolic blood pressure, and prevalent diabetic kidney disease (DKD). We identified 75 ESKD events in the follow-up (incidence rate 6.0 per 1000 patient-years) and 22 occurred after incident HF. Cox regression model showed that incident HF was associated with 7.4-fold (95% CI 4.5-12.2) unadjusted risk for progression to ESKD. The association of HF with subsequent risk for ESKD remained statistically significant (adjusted hazard ratio, HR 2.3, 95% CI 1.3-4.2) after adjustment for multiple clinical risk factors including baseline eGFR and albuminuria. Similar outcome was obtained when death attributable to non-renal cause was taken as a competing risk for ESKD. In a fully adjusted model, both HFpEF and HFrEF patients had a higher risk for progression to ESKD (adjusted HR 2.8, 95%CI 1.4-5.9, and 2.2, 95%CI 1.0-4.7, respectively), as compared to those with no HF events. The incidence rate of ESKD in patients with incident HF was 5.6 per 100 patient-years whilst in propensity score-matched patients without HF event, the rate was 2.1 per 100 patient-years. Conclusion Incident HF is a strong independent risk factor for progression to ESKD in individuals with T2D. Our data highlight the importance for prevention, early diagnosis and treatment of HF to improve the renal outcomes in individuals with type 2 diabetes.

What have been the clinical outcomes of the Project Synergy/InnoWell digital health platform?

Project Synergy is a digital mental health tool for assessment, referral and follow-up of people with mental health problems. The Australian federal government Department of Health entered an AUD33 million formal funding arrangement with InnoWell, a proprietary company vehicle (primarily the consultancy firm PwC and University of Sydney) to continue development of Project Synergy. This followed an initial federal National Health and Medical Research Council grant of AUD5.5 million over the previous 3 years. However, based on the assessment of peer-reviewed research data, the Project Synergy/InnoWell platform does not seem to have demonstrated clinical outcomes of healthcare value to date.

Correspondence to " Emollients in infancy to prevent atopic dermatitis: A systematic review and meta‐analysis"

MK, SC, RP and HCW report no conflict of interest. AJL reports: My institution has received National Health and Medical Research Council grant and fellowship funding to undertake a skin barrier intervention study. I also declare that Primus Pharmaceuticals and PuraCap Pharmaceuticals have donated EpiCream (a skin barrier treatment) for use in these studies, free of charge. I have also received an investigator-initiated grant from GSK for unrelated research. RJB reports: I have received personal payment for participating in advisory boards for DBV Technologies and Prota Therapeutics, which develop allergy diagnostics or treatments; have received payment for designing a clinical trial for Dairy Goat Co-operative; and have received personal payment for providing expert testimony in a class action related to an infant formula health claim concerning the development of allergic conditions.

Underinvestment in nutrition research for at-risk populations: An analysis of research funding awarded in Australia from 2014 to 2021.

AimTo determine the proportion of research projects funded by the National Health and Medical Research Council and Australian Research Council research funding from 2014 to 2021 that aimed to understand or improve dietary behaviours for at‐risk populations in Australia and estimate the proportion of total funding allocated during this period.MethodsRetrospective analysis of the publicly available National Health and Medical Research Council and Australian Research Council funding grants over the 8 years from 2014 to 2021 (n = 18 098). At‐risk dietary populations included people living in rural and remote Australia, Aboriginal and Torres Strait Islander people, or people living in socioeconomically disadvantaged areas. Descriptive analysis was undertaken.ResultsIn total, 144 out of 18 098 (0.8%) individual grants totalling $96.8 million were identified relating to nutrition research from 2014 to 2021. Out of the 144, only 21 ($19.6 million; 0.1%) of all National Health and Medical Research Council grants were identified for nutritionally at‐risk populations, with the majority focused on Aboriginal and Torres Strait Islander people (15/21). The National Health and Medical Research Council and Australian Research Council grants that aimed to improve human dietary behaviours increased by 0.66% and 0.58%, respectively, from 2014 to 2021. However, the National Health and Medical Research Council grants aiming to improve nutritional behaviours in at‐risk populations decreased by 0.04% over the 8 years.ConclusionsDespite slight increases in the proportions of funding to improve dietary behaviours over the past decade, nutrition research specifically targeting at‐risk groups is scarce and appears to have decreased over time. Insufficient investment in research for these groups presents a risk for widening health disparities now and into the future. As such, they must be further supported and considered in the design of future funding schemes.

Population-wide contribution of medically assisted reproductive technologies to overall births in Australia: temporal trends and parental characteristics.

Population-wide contribution of medically assisted reproductive technologies to overall births in Australia: temporal trends and parental characteristics.

DunedinPACE, a DNA methylation biomarker of the pace of aging.

Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously, we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al., 2020). Here, we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome). We used data from the Dunedin Study 1972-1973 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets. DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge. DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience. This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.

Factors Explaining Inequalities in Colon Cancer Survival—Reply

We thank Dr. Vicendese for his interest in our article investigating the underlying reasons for socioeconomic inequalities in survival from colon cancer using causal mediation analysis (1). We acknowledge that surgical volume is not a perfect measure for quality of a hospital; therefore, we might have missed an (indirect) effect of quality on the observed socioeconomic differences in colon cancer survival due to measurement error. Dichotomizing surgical volume at the median (due to limitations of the current methods) might have also further limited our ability to detect this potential indirect effect. We did not have data on hospital characteristics such as whether they had multidisciplinary teams, specialized or high-volume surgeons, and specialist technology-based services, and the method of analysis Dr. Vicendese has proposed to overcome confounding by hospital characteristics cannot be incorporated into a causal mediation analysis; therefore, it would not address our research question.See the original Letter to the Editor, p. 296N. Afshar reports grants from the Australian National Health and Medical Research (NHMRC) Council during the conduct of the study. R.L. Milne reports grants from NHMRC during the conduct of the study. D.R. English reports grants from Australian National Health and Medical Research Council during the conduct of the study.This work was supported by the Australian National Health and Medical Research Council (grant number 1150012).

A 10-year impact assessment of the Efficacy and Mechanism Evaluation (EME) programme: an independent mixed-method evaluation study

Background The Efficacy and Mechanism Evaluation (EME) programme – a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership – funds trials that evaluate the efficacy of interventions with the potential to promote health and studies that improve our understanding of the mechanisms of underlying diseases and their treatments. Objective To conduct an independent review of the EME programme’s impact and identify opportunities for future improvement. Design A mixed-methods approach, including desk research, an analysis of secondary data, stakeholder consultation and the development of impact case studies. Participants Chief investigators of EME awards, unfunded applicants to the EME programme and key opinion leaders relevant to the programme and research ecosystem. Interventions No interventions were tested, as this was a retrospective programme evaluation. Main outcome measures The evaluation was guided by a set of 15 evaluation questions. Results The EME programme bridges the gap between proof-of-concept and effectiveness studies that are located among other MRC and NIHR schemes and grants from charities in the funding landscape. Mechanistic studies alongside EME trials add value by lending confidence to trial findings and providing insights into the underlying biology. Between 2009 and September 2018, £175.7M in funding was approved for 145 EME projects. EME programme-funded research has started to deliver value to the NHS and patients by improving treatments and providing more efficient use of resources. Of the 43 completed trials, 14% (n = 6) showed that the intervention had a positive effect, whereas 74% (n = 32) of trials did not. The remaining five (12%) trials were unable to recruit participants or did not proceed to the full-trial stage. Seven projects (i.e. 16% of completed trials) have informed clinical guidelines or regulatory approval decisions and another eight projects have the potential to do so in the future, given the nature of their findings. Projects in the EME programme portfolio address a range of UK health needs and government priority areas, but they do not fully align with the level of health needs present. Commissioned calls for applications steer applicants. However, many commissioned calls do not lead to funded awards, and a better understanding of the underlying reasons for this would enable targeted supported to address key health needs. The majority of EME projects investigate existing interventions of limited commercial interest, focusing on repurposing (67/136, 49%) and informing current practice (23/136, 17%). Although there is little evidence of wider economic impact from commercial benefits, the EME programme is important in funding research in which industry is unlikely to invest. Stronger co-ordination with other funders, such as charities, could lead to synergies, enhancing the potential for health impact and influence on other funders’ agendas. The main challenges identified for EME projects were ‘complex and slow contracting processes’ (35/46, 76%), ‘setting up of study sites’ (30/46, 65%) and patient recruitment (28/46, 61%). Enablers of research included a clinical research fellow position on the project and support from Clinical Research Networks and Biomedical Research Centres. Nearly all of the chief investigators consulted had engaged in patient and public involvement at some project stage, and a lack of patient and public involvement did not emerge as a barrier to research or impact. Research ideas stemming from patients were, however, over-represented among unfunded applications, but the reason for this is unclear. Limitations Only about one-third of all studies had been completed or had published their main findings, necessitating a purposive, rather than representative, sampling of the portfolio. The COVID-19 outbreak cut short the programme of interviews, limiting the depth to which some evaluation questions could be explored. Several data sources were based on self-reporting by chief investigators; whereas key self-reported aspects were verified through desk research, this was not possible for all findings. Conclusions The EME programme plays an important role in the UK research funding landscape and has started to deliver value to the NHS and patients. Based on the evidence gathered, seven recommendations were developed to enhance the EME programme’s health and economic impact and address challenges encountered by chief investigators in implementing research projects. Funding This project was funded by the EME programme, a MRC and NIHR partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 20. See the NIHR Journals Library website for further project information.

Out-of-hospital cardiac arrest in elderly individuals

Abstract Background Out-of-hospital cardiac arrest (OHCA) is associated with poor outcome, particularly in elderly people. Due to the shift in global demographics towards an ageing population, understanding risk factors for OHCA is essential for the development of primary prevention strategies. Thus, we aimed to identify predictors for OHCA in a large, community-dwelling cohort of elderly individuals. Methods We analyzed data from 11,156 participants enrolled in a randomized, placebo-controlled primary prevention trial, investigating the effect of low-dose aspirin in individuals aged 70 years or above. At baseline all participants had no prior cardiovascular disease events, dementia or major physical disability. OHCA events occurring within 5 years were identified by probabilistic data-linkage with a state-wide out-of-hospital cardiac arrest registry. Possible predictors included age, sex, anthropometric measures, conventional cardiovascular risk factors, renal function and frailty. To evaluate the association with OHCA, we performed univariable and multivariable Cox regression analyses. In exploratory analyses we also evaluated the effect of low-dose aspirin on OHCA events. Results In the cohort 54.7% were female and median age was 74.1 years (Interquartile Range [IQR] 71.8–77.7). During a median follow up time of 4.7 years (IQR 3.4–6.0) we recorded 67 OHCA events with presumed cardiac cause. The incidence rate was 1.07 per 1,000 person-years (95% Confidence-Interval [CI] 0.80–1.40). The mortality rate following OHCA was 91.2% (n=62). Univariable Cox regression analyses identified age, sex, weight, abdominal circumference, serum creatinine, diabetes, arterial hypertension, intake of antihypertensive medication and pre-frailty as predictors for the outcome. In multivariable Cox regression analyses we identified age (Hazard Ratio [HR] 1.06, CI 1.00–1.13), female sex (HR 0.49, CI 0.26–0.94) and pre-frailty (HR 1.92, CI 1.03–3.58) to be independent predictors (Table). In exploratory analyses there was no effect of low-dose aspirin on OHCA (HR 1.52, CI 0.87–2.70). Conclusion In a large, contemporary cohort of healthy, elderly individuals we describe a significant incidence of OHCA events associated with a very high mortality. We identified age, sex and pre-frailty, but interestingly not conventional cardiovascular risk factors as independent predictors of OHCA. We could not show a benefit of low-dose aspirin treatment, although the number of events was small. Our findings emphasize the importance of preventive strategies for pre-frailty in elderly individuals. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The ASPREE study was primarily funded by the National Institute of Aging and National Cancer Institute at the National Institutes of Health (grant number U01AG029824), the Australian National Health &amp; Medical Research Council (grants 334047 &amp; 1127060), Monash University (Australia) and the Victorian Cancer Agency (Australia). Multivariable Cox regression analyses

Examining health-related quality of life in pediatric cancer patients with febrile neutropenia: Factors predicting poor recovery in children and their parents.

BackgroundThe impact febrile neutropenia (FN) has on the health-related quality of life (HRQoL) of children with cancer and their families is poorly understood. We sought to characterize the course of child and parent HRQoL during and following FN episodes.MethodData on HRQoL were collected in the multisite Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study. Participants were enrolled between November 2016 to January 2018. The Child Health Utility (CHU9D) was used to assess HRQoL in children (N = 167 FN events) and the Assessment of Quality of Life (AQoL-8D) was used to assess HRQoL parents (N = 218 FN events) at three time points: 0–3 days, 7-days and 30-days following the onset of FN. Group-based trajectory modeling (GBTM) was used to characterize the course of HRQoL.FindingsFor children, three distinct groups were identified: persistently low HRQoL over the 30-day course of follow-up (chronic: N = 78/167; 47%), increasing HRQoL after the onset of FN to 30 days follow-up (recovering: N = 36/167; 22%), and persistently high HRQoL at all three timepoints (resilient: N = 53/167; 32%). Applying these definitions, parents were classified into two distinct groups: chronic (N = 107/218, 49%) and resilient (N = 111/218, 51%). The child being male, having solid cancer, the presence of financial stress, and relationship difficulties between the parent and child were significant predictors of chronic group membership for both parents and children. Children classified as high-risk FN were significantly more likely to belong to the recovery group. Being female, having blood cancers and the absence of financial or relationship difficulties were predictive of both parents and children being in the resilient group.InterpretationApproximately half the children and parents had chronically low HRQoL scores, which did not improve following resolution of the FN episode. The child's sex, cancer type, and presence of financial and relationship stress were predictive of chronic group membership for both parents and children. These families may benefit from increased financial and psychosocial support during anti-cancer treatment.FundingNational Health and Medical Research Council Grant (APP1104527).

Murine models of Duchenne muscular dystrophy: is there a best model?

Murine models of Duchenne muscular dystrophy: is there a best model?

Associations between physical multimorbidity patterns and common mental health disorders in middle-aged adults: A prospective analysis using data from the UK Biobank.

BackgroundWe aimed to identify specific patterns of physical multimorbidity, defined as the presence of two or more physical long-term conditions, and to examine the extent to which these specific patterns could predict future incident and persistent common mental health disorders (CMDs) in middle-aged adults enrolled in the UK Biobank.MethodsWe assessed prospective associations between physical multimorbidity status at the baseline assessment (2006–2010) and depression and anxiety ‘caseness’ according to the Patient Health Questionnaire (PHQ)-9 and the Generalised Anxiety Disorder Assessment (GAD)-7 at the follow-up assessment (2016) in 154,367 middle-aged adults enrolled in the UK Biobank (median age: 57 years, interquartile range = 50–62 years, 56.5% female, mean duration of follow-up: 7.6 years, standard deviation = 0.87). Patterns of physical multimorbidity were identified using exploratory factor analysis. Logistic regression was used to assess prospective associations between physical multimorbidity patterns at baseline and both incident and persistent depression and anxiety at follow-up.FindingsCompared to those with no physical multimorbidity, having two (adjusted odds ratio (aOR) =1.41, 95%CI 1.32 to 1.53), three (aOR = 1.94, 95%CI 1.76 to 2.14), four (aOR = 2.38, 95%CI 2.07 to 2.74), and five or more (aOR = 2.89, 95%CI 2.42 to 3.45) physical conditions was prospectively associated with incident depression at follow-up in a dose response manner. Similar trends emerged for incident anxiety, persistent depression, and persistent anxiety, but associations were strongest for incident CMDs. Regarding specific patterns of physical MM, the respiratory pattern (aOR = 3.23, 95%CI 2.44 to 4.27) and the pain/gastrointestinal pattern (aOR = 2.19, 95%CI 1.92 to 2.50) emerged as the strongest predictors of incident depression. Similar results emerged for incident anxiety.InterpretationThese findings highlight patterns of physical multimorbidity with the poorest prognosis for both emerging and persisting depression and anxiety. These findings might have significant implications for the implementation of integrated mental and physical healthcare and facilitate the development of targeted preventative interventions and treatment for those with physical multimorbidity.FundingAR is supported by Guy's Charity grant number EIC180702; JAT is funded by Medical Research Council (MRC) number MR/SO28188/1; AD is funded by Guy's Charity grant number EIC180702 and MRC grant number MR/SO28188/1. JD is part supported by the ESRC Centre for Society and Mental Health at King's College London (ES/S012567/1), grants from the ESRC (ES/S002715/1), by the Health Foundation working together with the Academy of Medical Sciences, for a Clinician Scientist Fellowship, and by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London and the National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King's College Hospital NHS Foundation Trust. The views expressed are those of the author[s] and not necessarily those of the ESRC, NIHR, the Department of Health and Social Care or King's College London.

Communicating with patients and the public about COVID-19 vaccine safety: recommendations from the Collaboration on Social Science and Immunisation.

Communicating with patients and the public about COVID-19 vaccine safety: recommendations from the Collaboration on Social Science and Immunisation.