UK Medical Research Council Research Articles

The public health impact and cost-effectiveness of the R21/Matrix-M malaria vaccine: a mathematical modelling study

The R21/Matrix-M vaccine has demonstrated high efficacy against Plasmodium falciparum clinical malaria in children in sub-Saharan Africa. Using trial data, we aimed to estimate the public health impact and cost-effectiveness of vaccine introduction across sub-Saharan Africa. We fitted a semi-mechanistic model of the relationship between anti-circumsporozoite protein antibody titres and vaccine efficacy to data from 3 years of follow-up in the phase 2b trial of R21/Matrix-M in Nanoro, Burkina Faso. We validated the model by comparing predicted vaccine efficacy to that observed over 12-18 months in the phase 3 trial. Integrating this framework within a mathematical transmission model, we estimated the cases, malaria deaths, and disability-adjusted life-years (DALYs) averted and cost-effectiveness over a 15-year time horizon across a range of transmission settings in sub-Saharan Africa. Cost-effectiveness was estimated incorporating the cost of vaccine introduction (dose, consumables, and delivery) relative to existing interventions at baseline. We report estimates at a median of 20% parasite prevalence in children aged 2-10 years (PfPR2-10) and ranges from 3% to 65% PfPR2-10. Anti-circumsporozoite protein antibody titres were found to satisfy the criteria for a surrogate of protection for vaccine efficacy against clinical malaria. Age-based implementation of a four-dose regimen of R21/Matrix-M vaccine was estimated to avert 181 825 (range 38 815-333 491) clinical cases per 100 000 fully vaccinated children in perennial settings and 202 017 (29 868-405 702) clinical cases per 100 000 fully vaccinated children in seasonal settings. Similar estimates were obtained for seasonal or hybrid implementation. Under an assumed vaccine dose price of US$3, the incremental cost per clinical case averted was $7 (range 4-48) in perennial settings and $6 (3-63) in seasonal settings and the incremental cost per DALY averted was $34 (29-139) in perennial settings and $30 (22-172) in seasonal settings, with lower cost-effectiveness ratios in settings with higher PfPR2-10. Introduction of the R21/Matrix-M malaria vaccine could have a substantial public health benefit across sub-Saharan Africa. The Wellcome Trust, the Bill & Melinda Gates Foundation, the UK Medical Research Council, the European and Developing Countries Clinical Trials Partnership 2 and 3, the NIHR Oxford Biomedical Research Centre, and the Serum Institute of India, Open Philanthropy.

Risk of death following chikungunya virus disease in the 100 Million Brazilian Cohort, 2015–18: a matched cohort study and self-controlled case series

Chikungunya virus outbreaks have been associated with excess deaths at the ecological level. Previous studies have assessed the risk factors for severe versus mild chikungunya virus disease. However, the risk of death following chikungunya virus disease compared with the risk of death in individuals without the disease remains unexplored. We aimed to investigate the risk of death in the 2 years following chikungunya virus disease. We used a population-based cohort study and a self-controlled case series to estimate mortality risks associated with chikungunya virus disease between Jan 1, 2015, and Dec 31, 2018, in Brazil. The dataset was created by linking national databases for social programmes, notifiable diseases, and mortality. For the matched cohort design, individuals with chikungunya virus disease recorded between Jan 1, 2015, and Dec 31, 2018, were considered as exposed and those who were arbovirus disease-free and alive during the study period were considered as unexposed. For the self-controlled case series, we included all deaths from individuals with a chikungunya virus disease record, and each individual acted as their own control according to different study periods relative to the date of disease. The primary outcome was all-cause natural mortality up to 728 days after onset of chikungunya virus disease symptoms, and secondary outcomes were cause-specific deaths, including ischaemic heart diseases, diabetes, and cerebrovascular diseases. In the matched cohort study, we included 143 787 individuals with chikungunya virus disease who were matched, at the day of symptom onset, to unexposed individuals using sociodemographic factors. The incidence rate ratio (IRR) of death within 7 days of chikungunya symptom onset was 8·40 (95% CI 4·83-20·09) as compared with the unexposed group and decreased to 2·26 (1·50-3·77) at 57-84 days and 1·05 (0·82-1·35) at 85-168 days, with IRR close to 1 and wide CI in the subsequent periods. For the secondary outcomes, the IRR of deaths within 28 days after disease onset were: 1·80 (0·58-7·00) for cerebrovascular diseases, 3·75 (1·33-17·00) for diabetes, and 3·67 (1·25-14·00) for ischaemic heart disease, and there was no evidence of increased risk in the subsequent periods. For the self-controlled case series study, 1933 individuals died after having had chikungunya virus disease and were included in the analysis. The IRR of all-cause natural death within 7 days of symptom onset of chikungunya virus disease was 8·75 (7·18-10·66) and decreased to 1·59 (1·26-2·00) at 57-84 days and 1·09 (0·92-1·29) at 85-168 days. For the secondary outcomes, the IRRs of deaths within 28 days after disease onset were: 2·73 (1·50-4·96) for cerebrovascular diseases, 8·43 (5·00-14·21) for diabetes, and 2·38 (1·33-4·26) for ischaemic heart disease, and there was no evidence of increased risk at 85-168 days. Chikungunya virus disease is associated with an increased risk of death for up to 84 days after symptom onset, including deaths from cerebrovascular diseases, ischaemic heart diseases, and diabetes. This study highlights the need for equitable access to approved vaccines and effective anti-chikungunya virus therapeutics and reinforces the importance of robust vector-control efforts to reduce viral transmission. Brazilian National Research Council (CNPq), Fundação de Amparo à Pesquisa do Estado da Bahia, Wellcome Trust, and UK Medical Research Council. For the Portuguese translation of the abstract see Supplementary Materials section.

Monthly engagement with EIP keyworkers was associated with a five-fold increase in the odds of engagement with psychosocial interventions.

Early intervention in psychosis (EIP) supports people who are experiencing their first episode of psychosis (FEP). A new Model of Care (MoC) for EIP services was launched in Ireland in 2019. Three EIP demonstration sites were chosen to test this MoC through a 'hub and spoke' approach. These services were a new way of organising care for people experiencing FEP, based upon a recovery model of care, and which sought to standardise care, improve access by clinically led multidisciplinary teams. This included newly created EIP keyworker roles whereby keyworkers assumed responsibilities regarding assessment, comprehensive individual care planning and coordination of care. A mixed methods design utilising the UK Medical Research Council's process evaluation framework. Purposive sampling techniques were utilised. Descriptive analyses and logistic regression were performed to examine how increased keyworker engagement influenced the use of other psychosocial interventions within the EIP demonstration sites. Thematic analyses was used for qualitative data. There was a strong positive relationship between keyworker contacts and psychosocial interventions offered. Specifically, the odds of achieving at least monthly engagement with cognitive behavioural therapy for psychosis (CBTp; (5.76 (2.43-13.64), p < 0.001), and behavioural family therapy (BFT; (5.52(1.63-18.69, p < 0.006)) increased by fivefold with each additional monthly keyworker contact. For individual placement support (IPS) each additional monthly keyworker contact was associated with a three-fold increase in the odds of achieving monthly attendance with IPS (3.73 (1.64-8.48), p < 0.002). Qualitative results found that the EIP keyworker role as viewed by both service users and staff as a valuable nodal point, with a particular emphasis on care coordination and effective communication. This study advances the understanding of keyworker effects through qualitative evidence of keyworkers functioning as a "linchpin" to the service, while the positive response association between keyworker contacts and engagement with other services provides quantitative support for keyworkers reducing the organisational or structural barriers to service access. Given the importance of these positions, health systems should ensure that EIP programmes identify qualified and experienced staff to fill these roles, as well as allocate the appropriate funding and protected time to support keyworker engagement and impact.

Process evaluation of school-based high-intensity interval training interventions for children and adolescents: a systematic review and meta-analysis of randomized controlled trials

BackgroundSeveral systematic reviews have been published to investigate the effectiveness of high-intensity interval training (HIIT) in schools. However, there has been limited attention given to understanding the functioning of the intervention processes, which is of paramount importance for interpreting and translating the intervention effectiveness. The aim of this systematic review is to determine the extent to which process evaluation is measured in school-based HIIT interventions and to explore the effects of process evaluation and intervention characteristics on cardiorespiratory fitness (CRF), body composition, muscular strength, and blood pressure.MethodsA comprehensive search was conducted in SPORT Discus (EBSCOhost), Web of Science, Scopus, Medline (Ovid) and Cochrane Central Register of Controlled Trials. The extent to which process evaluation is measured was narratively reported, alongside with the guidance of process evaluation of complex interventions by UK Medical Research Council. Meta-analyses and meta-regressions were conducted to determine the effects of process evaluation and intervention characteristics to the intervention outcomes.ResultsThe literature search identified 77 studies reporting on 45 school-based HIIT interventions. In total, five interventions reported process evaluation in a section or in a separate study, and only one intervention adopted a process evaluation framework. On average, 6 out of 12 process evaluation measures were reported in all interventions. Subgroup analyses did not indicate any beneficial treatment effects for studies with process evaluation group, whereas all pooled data and studies without process evaluation group showed significant improvement for CRF and body composition.ConclusionProcess evaluation is frequently omitted in the literature of school-based HIIT in children and adolescents. Although reporting of process evaluation measures may not directly associate with better intervention outcomes, it allows accurate interpretation of intervention outcomes, thereby enhancing the generalisability and dissemination of the interventions.

Promoting healthy populations as a pandemic preparedness strategy: a simulation study from Mexico

The underlying health status of populations was a major determinant of the impact of the COVID-19 pandemic, particularly obesity prevalence. Mexico was one of the most severely affected countries during the COVID-19 pandemic and its obesity prevalence is among the highest in the world. It is unknown by how much the COVID-19 burden could have been reduced if systemic actions had been implemented to reduce excess weight in Mexico before the onset of the pandemic. Using a dynamic epidemic model based on nationwide data, we compare actual deaths with those under hypothetical scenarios assuming a lower body mass index in the Mexican population, as observed historically. We also model the number of deaths that would have been averted due to earlier implementation of front-of-pack warning labels or due to increases in taxes on sugar-sweetened beverages and non-essential high-energy foods in Mexico. We estimate that 52.5% (95% prediction interval (PI) 43.2, 61.6%) of COVID-19 deaths were attributable to obesity for adults aged 20-64 and 23.8% (95% PI 18.7, 29.1%) for those aged 65 and over. Had the population BMI distribution remained as it was in 2000, 2006, or 2012, COVID-19 deaths would have been reduced by an expected 20.6% (95% PI 16.9, 24.6%), 9.9% (95% PI 7.3, 12.9%), or 6.9% (95% PI 4.5, 9.5%), respectively. If the food-labelling intervention introduced in 2020 had been introduced in 2018, an expected 6.2% (95% PI 5.2, 7.3%) of COVID-19 deaths would have been averted. If taxes on sugar-sweetened beverages and high-energy foods had been doubled, trebled, or quadrupled in 2018, COVID-19 deaths would have been reduced by an expected 4.1% (95% PI 2.5, 5.7%), 7.9% (95% PI 4.9, 11.0%), or 11.6% (95% PI 7.3, 15.8%), respectively. Public health interventions targeting underlying population health, including non-communicable chronic diseases, is a promising line of action for pandemic preparedness that should be included in all pandemic plans. This study received funding from Bloomberg Philanthropies, awarded to Juan A. Rivera from the National Institute of Public Health; Community Jameel, the UK Medical Research Council (MRC), Kenneth C Griffin, and the World Health Organization.

Examining the implementation of a community paediatric clinic in a socially disadvantaged Irish community: A retrospective process evaluation.

Understanding interventions and their implementation is essential for improving community initiatives. Kidscope is a community paediatric development clinic providing free health and developmental assessment and onward referral for children aged zero to six years in an urban area of southern Ireland where many children experience complex needs. Established in 2010, Kidscope developed an inter-disciplinary, multi-agency community team by drawing on the strengths of local services and practitioners to deliver holistic approaches to child health and development. Recent studies examining stakeholder engagement and Kidscope outcomes highlighted the need to examine implementation to better understand the processes and mechanisms of the clinic and how events have affected outcomes. Guided by the UK Medical Research Council Framework for Developing and Evaluating Complex Interventions, this study used a post-hoc qualitative process evaluation study design with multiple data sources; stakeholder perspectives (interviews, focus group, questionnaires) and document analysis (annual reports, meeting minutes, work plans). A diverse set of research questions were developed in conjunction with a Patient and Public Involvement Group. Guiding frameworks supported thematic analysis of primary data, document analysis of secondary data, and triangulation of findings across datasets. Data analysis yielded 17 themes and 18 sub-themes. Successful implementation hinged on developing a coalition of linked practitioners and services whose skills were utilised and enhanced within Kidscope to deliver a high-quality healthcare model to vulnerable children and families. Relational and multi-disciplinary working, innovative approaches to implementation and sustainability, training and education provision, and the accessible community location were among the mechanisms of change resulting in improved child, family, practitioner, and system-level outcomes. External factors such as COVID-19 and deficits in Ireland's disability services posed significant barriers to fidelity. This study provides evidence of the processes, mechanisms, and model of care employed by a community-based paediatric clinic to successfully engage society's most vulnerable families and promote health equity. This study makes an important contribution to the field of implementation research by offering an example of a robust approach to conceptualising and measuring implementation outcomes of community healthcare initiative in a changing, real-world context.

Disparities in COVID-19 mortality amongst the immunosuppressed: A systematic review and meta-analysis for enhanced disease surveillance

Effective disease surveillance, including that for COVID-19, is compromised without a standardised method for categorising the immunosuppressed as a clinical risk group. We conducted a systematic review and meta-analysis to evaluate whether excess COVID-associated mortality compared to the immunocompetent could meaningfully subdivide the immunosuppressed. Our study adhered to UK Immunisation against infectious disease (Green Book) criteria for defining and categorising immunosuppression. Using OVID (EMBASE, MEDLINE, Transplant Library, and Global Health), PubMed, and Google Scholar, we examined relevant literature between the entirety of 2020 and 2022. We selected for cohort studies that provided mortality data for immunosuppressed subgroups and immunocompetent comparators. Meta-analyses, grey literature and any original works that failed to provide comparator data or reported all-cause or paediatric outcomes were excluded. Odds Ratios (OR) and 95% confidence intervals (CI) of COVID-19 mortality were meta-analysed by immunosuppressed category and subcategory. Subgroup analyses differentiated estimates by effect measure, country income, study setting, level of adjustment, use of matching and publication year. Study screening, extraction and bias assessment were performed blinded and independently by two researchers; conflicts were resolved with the oversight of a third researcher. PROSPERO registration number is CRD42022360755. We identified 99 unique studies, incorporating data from 1,542,097 and 56,248,181 unique immunosuppressed and immunocompetent patients with COVID-19 infection, respectively. Compared to immunocompetent people (pooled OR, 95%CI), solid organ transplants (2.12, 1.50-2.99) and malignancy (2.02, 1.69-2.42) patients had a very high risk of COVID-19 mortality. Patients with rheumatological conditions (1.28, 1.13-1.45) and HIV (1.20, 1.05-1.36) had just slightly higher risks than the immunocompetent baseline. Case type, setting income and mortality data matching and adjustment were significant modifiers of excess immunosuppressed mortality for some immunosuppressed subgroups. Excess COVID-associated mortality among the immunosuppressed compared to the immunocompetent was seen to vary significantly across subgroups. This novel means of subdivision has prospective benefit for targeting patient triage, shielding and vaccination policies during periods of high disease transmission.

N-ECCO Grant Supporting psychosocial and emotional well-being and resilience in family members of people with IBD: an intervention co-design and feasibility study

Abstract Background and Aims This ongoing PhD project seeks to develop a person-centred, evidence-based, theoretically informed prototype intervention to support psychosocial and emotional well-being and resilience in people with IBD’s family members (FMs). PhD project focuses on the intervention development and feasibility testing. The development phase has already been undertaken using a co-design approach informed by Design Thinking. A systematic review and qualitative research have been conducted and published, and co-design workshops have been held with people with IBD (n=4), FMs (n=9), and IBD nurses (n=2), revealing a preference for online-based intervention. Therefore, the aim of this study is to translate the paper-based intervention prototype into electronic format. The online prototype will be a) tested for acceptability and b) effect signal. The feasibility of the study design will be evaluated. Methods A sequential mixed methods approach, based on the UK Medical Research Council (MRC) Evaluation Framework. The intervention feasibility study will test the acceptability of content and delivery of the intervention and ascertain active feedback. The feasibility of the study design will be evaluated the recruitment, data collection, retention, and analysis strategies. A two-arm feasibility RCT with nested qualitative evaluation will be used to evaluate the newly developed intervention among 60 FMs. Participants will be recruited via Crohn’s &amp; Colitis UK and Bowel Research UK charities. The 60 participants will be randomly allocated into intervention and control groups using 2:1 randomisation. The qualitative component will use purposive sampling from the intervention arm to elicit feedback on the content and format with up to 20 participants. Anticipated Impact Results from this intervention development and feasibility study will help revise the intervention, incorporate changes to the study protocol (if necessary), and develop a large-scale RCT for efficacy trailing of a complex intervention to benefit service users.

Effectiveness of poliovirus vaccines against circulating vaccine-derived type 2 poliomyelitis in Nigeria between 2017 and 2022: a case-control study

Between 2018 and 2022, Nigeria experienced continuous transmission of circulating vaccine-derived type 2 poliovirus (cVDPV2), with 526 cases of cVDPV2 poliomyelitis detected in total and approximately 180 million doses of monovalent type 2 oral poliovirus vaccine (mOPV2) and 450 million doses of novel type 2 oral poliovirus vaccine (nOPV2) delivered in outbreak response campaigns. Inactivated poliovirus vaccine (IPV) was introduced into routine immunisation in 2015, with a second dose added in 2021. We aimed to estimate the effectiveness of nOPV2 against cVDPV2 paralysis and compare nOPV2 effectiveness with that of mOPV2 and IPV. In this retrospective case-control study, we used acute flaccid paralysis (AFP) surveillance data in Nigeria from Jan 1, 2017, to Dec 31, 2022, using age-matched, onset-matched, and location-matched cVDPV2-negative AFP cases as test-negative controls. We also did a parallel prospective study from March, 2021, using age-matched community controls from the same settlement as the cases. We included children born after May, 2016, younger than 60 months, for whom polio immunisation history (doses of OPV from campaigns and IPV) was reported. We estimated the per-dose effectiveness of nOPV2 against cVDPV2 paralysis using conditional logistic regression and compared nOPV2 effectiveness with that of mOPV2 and IPV. In the retrospective case-control study, we identified 509 cVDPV2 poliomyelitis cases in Nigeria with case verification and paralysis onset between Jan 1, 2017, and Dec 31, 2022. Of these, 82 children were excluded for not meeting inclusion criteria, and 363 (85%) of 427 eligible cases were matched to 1303 test-negative controls. Cases reported fewer OPV and IPV doses than test-negative controls (mean number of OPV doses 5·9 [SD 4·2] in cases vs 6·7 [4·3] in controls; one or more IPV doses reported in 95 [26%] of 363 cases vs 513 [39%] of 1303 controls). We found low per-dose effectiveness of nOPV2 (12%, 95% CI -2 to 25) and mOPV2 (17%, 3 to 29), but no significant difference between the two vaccines (p=0·67). The estimated effectiveness of one IPV dose was 43% (23 to 58). In the prospective study, 181 (46%) of 392 eligible cases were matched to 1557 community controls. Using community controls, we found a high effectiveness of IPV (89%, 95% CI 83 to 93, for one dose), a low per-dose effectiveness of nOPV2 (-23%, -45 to -5) and mOPV2 (1%, -23 to 20), and no significant difference between the per-dose effectiveness of nOPV2 and mOPV2 (p=0·12). We found no significant difference in estimated effectiveness of the two oral vaccines, supporting the recommendation that the more genetically stable nOPV2 should be preferred in cVDPV2 outbreak response. Our findings highlight the role of IPV and the necessity of strengthening routine immunisation, the primary route through which IPV is delivered. Bill & Melinda Gates Foundation and UK Medical Research Council.

Comprehensive evaluation of smoking exposures and their interactions on DNA methylation

BackgroundSmoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (<1 year), persistence of differential methylation from in utero smoking exposure, and effects of environmental tobacco smoke (ETS). MethodsWe meta-analysed data from up to 15,014 adults across 5 cohorts with DNA methylation measured in blood using Illumina’s EPIC array for current smoking (2,560 exposed), quit <1 year (500 exposed), in utero (286 exposed), and ETS exposure (676 exposed). We also evaluated the interaction of current smoking with sex or diet (fibre, folate, and vitamin C). FindingsUsing false discovery rate (FDR<0.05), 65,857 CpGs were differentially methylated in relation to current smoking, 4,025 with recent quitting, 594 with in utero exposure, and 6 with ETS. Most current smoking CpGs attenuated within a year of quitting. CpGs related to in utero exposure in adults were enriched for those previously observed in newborns. Differential methylation by current smoking at 4-71 CpGs may be modified by sex or dietary intake. Nearly half (35-50%) of differentially methylated CpGs on the 450K array were associated with blood gene expression. Current smoking and in utero smoking CpGs implicated 3,049 and 1,067 druggable targets, including chemotherapy drugs. InterpretationMany smoking-related methylation sites were identified with Illumina’s EPIC array. Most signals revert to levels observed in never smokers within a year of cessation. Many in utero smoking CpGs persist into adulthood. Smoking-related druggable targets may provide insights into cancer treatment response and shared mechanisms across smoking-related diseases. FundingIntramural Research Program of the National Institutes of Health, Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, Chief Scientist Office of the Scottish Government Health Directorates and the Scottish Funding Council, Medical Research Council UK and the Wellcome Trust

Phylogenomic early warning signals for SARS-CoV-2 epidemic waves

Epidemic waves of coronavirus disease 2019 (COVID-19) infections have often been associated with the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Rapid detection of growing genomic variants can therefore serve as a predictor of future waves, enabling timely implementation of countermeasures such as non-pharmaceutical interventions (social distancing), additional vaccination (booster campaigns), or healthcare capacity adjustments. The large amount of SARS-CoV-2 genomic sequence data produced during the pandemic has provided a unique opportunity to explore the utility of these data for generating early warning signals (EWS). We developed an analytical pipeline (Transmission Fitness Polymorphism Scanner - designated in an R package mrc-ide/tfpscanner) for systematically exploring all clades within a SARS-CoV-2 virus phylogeny to detect variants showing unusually high growth rates. We investigated the use of these cluster growth rates as the basis for a variety of statistical time series to use as leading indicators for the epidemic waves in the UK during the pandemic between August 2020 and March 2022. We also compared the performance of these phylogeny-derived leading indicators with a range of non-phylogeny-derived leading indicators. Our experiments simulated data generation and real-time analysis. Using phylogenomic analysis, we identified leading indicators that would have generated EWS ahead of significant increases in COVID-19 hospitalisations in the UK between August 2020 and March 2022. Our results also show that EWS lead time is sensitive to the threshold set for the number of false positive (FP) EWS. It is often possible to generate longer EWS lead times if more FP EWS are tolerated. On the basis of maximising lead time and minimising the number of FP EWS, the best performing leading indicators that we identified, amongst a set of 1.4 million, were the maximum logistic growth rate (LGR) amongst clusters of the dominant Pango lineage and the mean simple LGR across a broader set of clusters. In the case of the former, the time between the EWS and wave inflection points (a conservative measure of wave start dates) for the seven waves ranged between a 20-day lead time and a 7-day lag, with a mean lead time of 5.4 days. The maximum number of FP EWS generated prior to a true positive (TP) EWS was two and this only occurred for two of the seven waves in the period. The mean simple LGR amongst a broader set of clusters also performed well in terms of lead time but with slightly more FP EWS. As a result of the significant surveillance effort during the pandemic, early detection of SARS-CoV-2 variants of concern Alpha, Delta, and Omicron provided some of the first examples where timely detection and characterisation of pathogen variants has been used to tailor public health response. The success of our method in generating early warning signals based on phylogenomic analysis for SARS-CoV-2 in the UK may make it a worthwhile addition to existing surveillance strategies. In addition, the method may be translatable to other countries and/or regions, and to other pathogens with large-scale and rapid genomic surveillance. This research was funded in whole, or in part, by the Wellcome Trust (220885_Z_20_Z). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. KOD, OB, VBF and EMV acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/X020258/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. RMC acknowledges funding from the Wellcome Trust Collaborators Award (206298/Z/17/Z).

Application of behavioural theories, models, and frameworks in pharmacy practice research based on published evidence: a scoping review.

Pharmacy practice research often focuses on the design, implementation and evaluation of pharmacy services and interventions. The use of behavioural theory in intervention research allows understanding of interventions' mechanisms of action and are more likely to result in effective and sustained interventions. To collate, summarise and categorise the reported behavioural frameworks, models and theories used in pharmacy practice research. PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and EBSCO (CINAHL PLUS, British Education index, ERIC) were systematically searched to capture all pharmacy practice articles that had reported the use of behavioural frameworks, theories, or models since inception of the database. Results were filtered to include articles published in English in pharmacy practice journals. Full-text screening and data extraction were independently performed by two reviewers. A narrative synthesis of the data was adopted. Studies were reviewed for alignment to the UK Medical Research Council (MRC) framework to identify in which phase(s) of the research that the theory/model/framework had been employed. Fifty articles met the inclusion criteria; a trend indicating an increasing frequency of behavioural theory/frameworks/models within pharmacy practice research was identified; the most frequently reported were Theory of Planned Behaviour and Theoretical Domains Framework. Few studies provided explicit and comprehensive justification for adopting a specific theory/model/framework and description of how it underpinned the research was lacking. The majority were investigations exploring determinants of behaviours, or facilitators and barriers to implementing or delivering a wide range of pharmacy services and initiatives within a variety of clinical settings (aligned to Phase 1 UK MRC framework). This review serves as a useful resource for future researchers to inform their investigations. Greater emphasis to adopt a systematic approach in the reporting of the use of behavioural theories/models/frameworks will benefit pharmacy practice research and will support researchers in utilizing behavioural theories/models/framework in aspects of pharmacy practice research beyond intervention development.

Pattern of pareses in 5q-spinal muscular atrophy.

This prospective study investigates the pattern of pareses in 5q-associated spinal muscular atrophy (SMA) to identify disease-specific characteristics and potential differences from amyotrophic lateral sclerosis (ALS) and spinobulbar muscular atrophy (SBMA). Detailed knowledge about pareses patterns in SMA facilitates differential diagnosis and supports therapeutic monitoring. Between January 2021, and June 2021, 66 SMA patients (59.1% male, aged 33.6 ± 15.2 years) were included in the study. Most patients had SMA type II (n = 28) or SMA type III (n = 28), seven patients had SMA type I, and three patients had SMA type IV. We analyzed the pattern of pareses using the UK Medical Research Council (MRC) scoring system. In both, upper and lower limbs muscle weakness was less pronounced in distal (upper limbs: MRC median 3.0 (interquartile range 1.5-3.5); lower limbs: 1.5 (0.5-3.0)) compared to proximal muscle groups (upper limbs: 2.0 (1.5-2.6); p < 0.001; lower limbs: 0.5 (0.5-1.5); p < 0.001). Thenar muscles were stronger than other small hand muscles (3.0 (2.0-3.5) vs 3.0 (1.5-3.5); p = 0.004). Muscles had more strength in upper (2.3 (1.5-3.1)) compared to lower limbs (1.1 (0.5-2.3); p < 0.001) and in flexors compared to extensors. We identified a specific pattern of muscle paresis in SMA which is different from the pattern of paresis in ALS and SBMA. As a rule of thumb, the pattern of pareses is similar, but not identical to ALS in distal, but different in proximal muscle groups.

In utero exposures to perfluoroalkyl substances and the human fetal liver metabolome in Scotland: a cross-sectional study

Perfluoroalkyl and polyfluoroalkyl substances are classed as endocrine disrupting compounds but continue to be used in many products such as firefighting foams, flame retardants, utensil coatings, and waterproofing of food packaging. Perfluoroalkyl exposure aberrantly modulates lipid, metabolite, and bile acid levels, increasing susceptibility to onset and severity of metabolic diseases, such as diabetes and metabolic dysfunction-associated steatotic liver disease. To date, most studies in humans have focused on perfluoroalkyl-exposure effects in adults. In this study we aimed to show if perfluoroalkyls are present in the human fetal liver and if they have metabolic consequences for the human fetus. In this cross-sectional study, human fetal livers from elective termination of pregnancies at the Aberdeen Pregnancy Counselling Service, Aberdeen, UK, were analysed by both targeted (bile acids and perfluoroalkyl substances) and combined targeted and untargeted (lipids and polar metabolites) mass spectrometry based metabolomic analyses, as well as with RNA-Seq. Only fetuses from normally progressing pregnancies (determined at ultrasound scan before termination), terminated for non-medical reasons, from women older than 16 years, fluent in English, and between 11 and 21 weeks of gestation were collected. Women exhibiting considerable emotional distress or whose fetuses had anomalies identified at ultrasound scan were excluded. Stringent bioinformatic and statistical methods such as partial correlation network analysis, linear regression, and pathway analysis were applied to this data to investigate the association of perfluoroalkyl exposure with hepatic metabolic pathways. Fetuses included in this study were collected between Dec 2, 2004, and Oct 27, 2014. 78 fetuses were included in the study: all 78 fetuses were included in the metabolomics analysis (40 female and 38 male) and 57 fetuses were included in the RNA-Seq analysis (28 female and 29 male). Metabolites associated with perfluoroalkyl were identified in the fetal liver and these varied with gestational age. Conjugated bile acids were markedly positively associated with fetal age. 23 amino acids, fatty acids, and sugar derivatives in fetal livers were inversely associated with perfluoroalkyl exposure, and the bile acid glycolithocholic acid was markedly positively associated with all quantified perfluoroalkyl. Furthermore, 7α-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis rate, was strongly positively associated with perfluoroalkyl levels and was detectable as early as gestational week 12. Our study shows direct evidence for the in utero effects of perfluoroalkyl exposure on specific key hepatic products. Our results provide evidence that perfluoroalkyl exposure, with potential future consequences, manifests in the human fetus as early as the first trimester of gestation. Furthermore, the profiles of metabolic changes resemble those observed in perinatal perfluoroalkyl exposures. Such exposures are already linked with susceptibility, initiation, progression, and exacerbation of a wide range of metabolic diseases. UK Medical Research Council, Horizon Europe Program of the European Union, Seventh Framework Programme of the European Union, NHS Grampian Endowments grants, European Partnership for the Assessment of Risks from Chemicals, Swedish Research Council, Formas, Novo Nordisk Foundation, and the Academy of Finland.

A sports‐related injury prevention program for Dutch youth volleyball players: Process evaluation alongside a quasi‐randomized controlled trial

AbstractObjectiveThis process evaluation aimed to gain insight into the implementation of the VolleyVeilig Youth program by Dutch volleyball clubs within the context of an effectiveness trial.MethodsWe applied the UK Medical Research Council framework for process evaluations and assessed the context, implementation and mechanisms of impact. Trainers participating in the effectiveness trial were asked to complete a questionnaire at the end of the study. A subsample of the trainers based on the self‐reported adherence score was invited to participate in an interview accordingly. We used a thematic analysis to present the data.ResultsThirty‐one trainers (100%) completed the questionnaire, and seven agreed to participate in an interview. Although adherence gradually decreased over the volleyball season, most trainers reported partially adhere with the program until the end of the study. The main themes included factors associated with the (1) VolleyVeilig Youth program, (2) trainer, (3) players, and (4) volleyball club.ConclusionAlthough (partial) adherence to the VolleyVeilig Youth program was high in this study, implementation strategies must be developed to target the barriers reported by the trainers before the program can be successfully implemented nationwide in the Netherlands.

Co-production of a rehabilitation programme for young adult cancer survivors

Introduction: Globally, the focus on user involvement in health research has increased substantially. In Denmark, it is still at an early stage, with individual researchers being met with increasing demands without having much experience, guidance, or good practices to act upon. We are a group of researchers affiliated with User Perspectives and Community-based Interventions at the University of Southern Denmark and the Center for Research with Patients and Relatives (ForSa-P) at the Odense University Hospital. We work with patients and relatives in several aspects of our work – research and teaching; we share our experiences and learning in a joint session.&#x0D; This presentation describes a co-creation process of developing a rehabilitation programme for young adult cancer survivors (YACS)&#x0D; Background: Because of the cancer and late effects of treatment, YACS face numerous age-specific physical, psychological, existential, and social issues impacting participation in everyday life and decreasing their health-related quality of life (HRQoL). Rehabilitation may improve participation in life roles, leisure activities and work and thus, heighten HRQoL. However, YACS rehabilitation needs are not being adequately met and multicomponent age-specific rehabilitation for YACS is limited.&#x0D; Objective: To develop an evidence-based, age-specific, multicomponent, and peer-based rehabilitation programme involving YACS and relevant stakeholders aiming to improve YACS participation in everyday life and their HRQoL.&#x0D; Methods: The development process of the programme drawn on the Medical Research Council UK framework for developing and evaluating complex interventions and is inspired by Hawkins et al.’s three-staged framework for co-production. From September 2019 to March 2023, YACS, professionals and researchers co-developed a rehabilitation programme through three stages: 1) Evidence review and stakeholder consultations; 2) Co-production of the intervention by involving users in four workshops, and 3) Articulating the programme theory, developing an intervention manual, recruitment strategy and referral pathways and selecting outcome measures. Key findings from each stage were incorporated into the subsequently stage.&#x0D; Results: We developed a comprehensive goal-oriented and peer-based rehabilitation programme called the Young Adults Taking ACtion (YATAC). The programme draws on a person-centered approach, the Social Cognitive Theory, and John Dewey’s learning theory. It consists of nine components delivered by an interdisciplinary team: 1) Need assessment, 2) Goal setting, 3) Everyday life, 4) Physical activity, 5) Psychological issues, 6) Work and education, 7) Sexuality and relationship, 8) Rights and finance, 9) Friends and Family and 10) Peer-to-peer support. Further, outcome measures for the programme were chosen, recruitment strategies were described, and referral pathways were identified. The evaluation showed advantages and disadvantages and future points to pay attention to when participating in a co-production process. &#x0D; Conclusions: A multicomponent rehabilitation programme for YACS was developed involving the preferences and needs of YACS and stakeholders. Using co-production in the whole process of developing the programme will most likely lead to better evaluation and implementation in clinical practice. In addition, the comprehensive description of the development process and the knowledge derived from the process can inform future research of how to involve users in the development of rehabilitation interventions. Next step will be to feasibility test the programme.

Mortality from leading cancers in districts of England from 2002 to 2019: a population-based, spatiotemporal study

Cancers are the leading cause of death in England. We aimed to estimate trends in mortality from leading cancers from 2002 to 2019 for the 314 districts in England. We did a high-resolution spatiotemporal analysis of vital registration data from the UK Office for National Statistics using data on all deaths from the ten leading cancers in England from 2002 to 2019. We used a Bayesian hierarchical model to obtain robust estimates of age-specific and cause-specific death rates. We used life table methods to calculate the primary outcome, the unconditional probability of dying between birth and age 80 years by sex, cancer cause of death, local district, and year. We reported Spearman rank correlations between the probability of dying from a cancer and district-level poverty in 2019. In 2019, the probability of dying from a cancer before age 80 years ranged from 0·10 (95% credible interval [CrI] 0·10-0·11) to 0·17 (0·16-0·18) for women and from 0·12 (0·12-0·13) to 0·22 (0·21-0·23) for men. Variation in the probability of dying was largest for lung cancer among women, being 3·7 times (95% CrI 3·2-4·4) higher in the district with the highest probability than in the district with the lowest probability; and for stomach cancer for men, being 3·2 times (2·6-4·1) higher in the district with the highest probability than in the one with the lowest probability. The variation in the probability of dying was smallest across districts for lymphoma and multiple myeloma (95% CrI 1·2 times [1·1-1·4] higher in the district with the highest probability than the lowest probability for women and 1·2 times [1·0-1·4] for men), and leukaemia (1·1 times [1·0-1·4] for women and 1·2 times [1·0-1·5] for men). The Spearman rank correlation between probability of dying from a cancer and district poverty was 0·74 (95% CrI 0·72-0·76) for women and 0·79 (0·78-0·81) for men. From 2002 to 2019, the overall probability of dying from a cancer declined in all districts: the reductions ranged from 6·6% (95% CrI 0·3-13·1) to 30·1% (25·6-34·5) for women and from 12·8% (7·1-18·8) to 36·7% (32·2-41·2) for men. However, there were increases in mortality for liver cancer among men, lung cancer and corpus uteri cancer among women, and pancreatic cancer in both sexes in some or all districts with posterior probability greater than 0·80. Cancers with modifiable risk factors and potential for screening for precancerous lesions had heterogeneous trends and the greatest geographical inequality. To reduce these inequalities, factors affecting both incidence and survival need to be addressed at the local level. Wellcome Trust, Imperial College London, UK Medical Research Council, and the National Institute of Health Research.

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

The EMPA-KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62-0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16-1·59), representing a 50% (42-58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council.

Non-linear associations of maternal pre-pregnancy body mass index with risk of stillbirth, infant, and neonatal mortality in over 28 million births in the USA: a retrospective cohort study

Higher maternal pre-pregnancy body mass index (BMI) has been associated with higher risk of stillbirth, infant and neonatal mortality. Studies exploring underweight have varied in their conclusions. Our aim was to examine the risk of stillbirth, infant and neonatal mortality across the BMI distribution and establish a likely healthy BMI range. In this retrospective cohort study, we used publicly available datasets (covering 1st January 2014 to 31st December 2021) from the US National Center for Health Statistics National Vital Statistics System. All births were eligible; analyses included those with non-missing data. Fractional polynomial multivariable logistic regression was used to examine the associations of maternal pre-pregnant BMI with stillbirth (birth with no signs of life at ≥24 weeks), infant mortality (death of a live born baby aged <365 days) and neonatal mortality (death of a live born baby aged <28 days). There were 77,896/28,310,154 (2.8 per 1000 births) stillbirths, 143,620/28,231,807 (5.1 per 1000 live births) infant deaths and 94,246/28,231,807 (3.3 per 1000 live births) neonatal deaths among complete cases. Mean (SD) BMI was 27.1kg/m2 (6.7kg/m2). We found non-linear associations between BMI and all three outcomes; risk was elevated at both low and high BMIs although, for stillbirth, the increased risk at low BMI was less marked than for infant/neonatal mortality. The lowest risk was at a BMI of 21kg/m2 for infant and neonatal mortality and 19kg/m2 for stillbirth. Public health messaging for preconception and postnatal care should focus on healthy weight to maximise maternal and child health, and not focus solely on maternal overweight or obesity. European Research Council, US National Institute of Health, UK Medical Research Council and National Institute for Health and Care Research.

Durability and cross-reactive immune memory to SARS-CoV-2 in individuals 2 years after recovery from COVID-19: a longitudinal cohort study

SARS-CoV-2-specific adaptive immunity more than 1 year after initial infection has not been well characterised. The aim of this study was to investigate the durability and cross-reactivity of immunological memory acquired from natural infection against SARS-CoV-2 in individuals recovered from COVID-19 2 years after infection. In this longitudinal cohort study, we recruited patients who had recovered from laboratory-confirmed COVID-19 and were discharged from Jinyintan Hospital (Wuhan, China) between Jan 7 and May 29, 2020. We carried out three successive follow-ups between June 16 and Sept 3, 2020 (6 months), Dec 16, 2020, and Feb 7, 2021 (1 year), and Nov 16, 2021, and Jan 10, 2022 (2 years), in which blood samples were taken. We included participants who did not have re-infection or receive a SARS-CoV-2 vaccination (infected-unvaccinated), and participants who received one to three doses of inactivated vaccine 1-2 years after infection (infected-vaccinated). We evaluated the presence of IgG antibodies, neutralising antibodies, and memory B-cell and memory T-cell responses against the prototype strain and delta and omicron variants. In infected-unvaccinated participants, neutralising antibody titres continually declined from 6-month to 2-year follow-up visits, with a half-life of about 141·2 days. Neutralising antibody responses to omicron sublineages (BA.1, BA.1.1, BA.2, BA.4/5, BF.7, BQ.1, and XBB) were poor. Memory B-cell responses to the prototype strain were retained at 2 years and presented cross-reactivity to the delta and omicron BA.1 variants. The magnitude of interferon γ and T-cell responses to SARS-CoV-2 were not significantly different between 1 year and 2 years after infection. Multifunctional T-cell responses against SARS-CoV-2 spike protein and nucleoprotein were detected in most participants. Recognition of the BA.1 variant by memory T cells was not affected in most individuals. The antibody titres and the frequencies of memory B cells, but not memory T cells, increased in infected-vaccinated participants after they received the inactivated vaccine. This study improves the understanding of the duration of SARS-CoV-2-specific immunity without boosting, which has implications for the design of vaccination regimens and programmes. Our data suggest that memory T-cell responses primed by initial viral infection remain highly cross-reactive after 2 years. With the increasing emergence of variants, effective vaccines should be introduced to boost neutralising antibody and overall T-cell responses to newly emerged SARS-CoV-2 variants. Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Fundamental Research Funds for the Central Universities for Peking Union Medical College, Beijing Natural Science Foundation, UK Medical Research Council.