National Institute For Health Research Research Articles

Abstract B009: Advancing health equity in cancer survivorship research: A review of the National Institutes of Health (NIH) 2017-2021 portfolio

Abstract Background: Over the past decade there has been a call for a research paradigm shift from describing health disparities to a health equity research agenda that links and addresses the social, environmental, economic, health system, and policy contextual factors that drive health disparities. However, it is unknown if cancer survivorship research has made this transition. Methods: Research project grants funded during Fiscal Year (FY) 2017 to 2021 focused on cancer survivorship were identified using a text mining algorithm of words from the NIH Research, Condition, and Disease Categorization thesaurus with survivorship-relevant terms. A total of 586 grants were identified, of which the title and abstract were reviewed to identify grants focused on health disparities. Characteristics for each grant focused on health disparities were abstracted. We then coded the determinants of heath disparities by levels of influence (individual, interpersonal, organizational/community, societal) and domains of influence (biological, behavioral, physical/built environment, sociocultural environment, healthcare system).Results: A total of 134 grants were identified that focused on health disparities. These grants were funded by 5 NIH institutes with NCI funding 85%. The majority of grants (63%) used the R01 mechanism. The populations of focus included racial and ethnic minority survivors (75%), survivors living in rural areas (25%), socioeconomically disadvantaged cancer survivors (22%), and SGM survivors (2%). Half of the studies were of observational design, and half were interventional. Study topics included: late effects (44%), patient activation (28%), adherence to care guidelines (25%), health communication (18%), physical activity (13%), nutrition (8%), and policy research (4%). Nearly all grants included at least one individual-level of influence (95%), as compared to higher levels of influence (26% interpersonal, 33% organizational/community, 15% societal). Behavioral and healthcare system domains of influence were commonly represented, especially at the individual-level (76% and 43%). Determinants from the physical/built environment and sociocultural environment were less frequent. Conclusions: Our findings highlight that NIH-funded survivorship research on health disparities is still focused on the individual-level and behavioral domains of influence. However, the portfolio analysis also suggests that survivorship research is transitioning to a health equity research agenda by incorporating structural/institutional level factors. Gaps in funded research on understudied populations were identified, including SGM, American Indian and Alaska Native, and Native Hawaiian and other Pacific Islander. Future research is needed to identify mechanisms to address the upstream social drivers/determinants or contextual factors of where cancer survivors live, work, learn, play, age, and access care. Such work would inform the development or implementation of evidence-based interventions to prevent inequitable care and achieve the goal of health equity. Citation Format: Michelle Doose, Michelle A. Mollica, Amanda Acevedo, Crystal Reed, Gina Tesauro, Lisa Gallicchio, Jennifer Guida, Molly E. Maher, Shobha Srinivasan, Emily Tonorezos. Advancing health equity in cancer survivorship research: A review of the National Institutes of Health (NIH) 2017-2021 portfolio [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B009.

Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses

Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks. Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality. Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% CI 0·95-1·01), stroke (1·01, [0·97-1·05]), or all-cause mortality (0·99, 0·95-1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations. Stratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status. British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.

Identification of tax options for high fat, sugar, salt foods for the HEALTHEI Project: a mixed-methods study

BackgroundThe health economic analysis incorporating effects on labour outcomes, households, environment, and inequalities (HEALTHEI) explores which food taxes would have greatest benefits to health, labour, and work outcomes; household expenditure; environmental sustainability; and inequalities within the UK food system. Work package 1 includes a rapid review and workshops, aiming to explore the effects of price increases in food and non-alcoholic beverages to facilitate the specification of food taxes and research design. MethodsIn this mixed-methods study, we first did a rapid review to examine relevant published evidence. A preplanned framework ensured a systematic approach, in which we searched PubMed, HMIC, Scopus, Google, Mintel/Mintel Food and Drink, and Business Source Ultimate for papers published in English from Jan 1, 2010, to Nov 2, 2022. This review was followed by three online workshops (in March, 2023), which used interactive padlets to explore food systems, food taxation policy, tax rationales, and a rapid review infographic. 14 stakeholders from non-governmental organisations (n=10), academia (n=2), the Civil Service (n=1), and a local authority (n=1) took part (gender or ethnicity were not recorded). A stakeholder recruitment grid was developed to ensure representation across public sectors and disciplines of public health, nutrition, environment, and economics. FindingsThe rapid review identified six tax options with a broadly positive impact on consumption and health (high fat, high sugar, high salt, “junk food”, sugar-sweetened-beverages, and meats plus sugar-sweetened beverages). It generated five core rationales for a food tax: change consumption, reduce or prevent harm, change product affordability, raise revenue, and industry impact. Using the workshop feedback, health inequalities, economics, ease of implementation and animal welfare were additional key areas for a so-called real-world application of tax. Stakeholders questioned the taxes in the current economic and political climate. InterpretationThe work highlights the need to develop an impactful food tax option that encompasses the five core rationales identified in the findings. The workshops identified key areas to explore further to understand the feasibility, impact, and logistics of implementing future food taxes. Being unable to deliver workshops in person due to difficulties of participants travelling to London was a limitation. However, switching online allowed for varied and well attended workshops. FundingNational Institute of Health Research (Ref: NIHR133927).

Clinical and health inequality risk factors for non-COVID-related sepsis during the global COVID-19 pandemic: a national case-control and cohort study

Sepsis, characterised by significant morbidity and mortality, is intricately linked to socioeconomic disparities and pre-admission clinical histories. This study aspires to elucidate the association between non-COVID-19 related sepsis and health inequality risk factors amidst the pandemic in England, with a secondary focus on their association with 30-day sepsis mortality. With the approval of NHS England, we harnessed the OpenSAFELY platform to execute a cohort study and a 1:6 matched case-control study. A sepsis diagnosis was identified from the incident hospital admissions record using ICD-10 codes. This encompassed 248,767 cases with non-COVID-19 sepsis from a cohort of 22.0 million individuals spanning January 1, 2019, to June 31, 2022. Socioeconomic deprivation was gauged using the Index of Multiple Deprivation score, reflecting indicators like income, employment, and education. Hospitalisation-related sepsis diagnoses were categorised as community-acquired or hospital-acquired. Cases were matched to controls who had no recorded diagnosis of sepsis, based on age (stepwise), sex, and calendar month. The eligibility criteria for controls were established primarily on the absence of a recorded sepsis diagnosis. Associations between potential predictors and odds of developing non-COVID-19 sepsis underwent assessment through conditional logistic regression models, with multivariable regression determining odds ratios (ORs) for 30-day mortality. The study included 224,361 (10.2%) cases with non-COVID-19 sepsis and 1,346,166 matched controls. The most socioeconomic deprived quintile was associated with higher odds of developing non-COVID-19 sepsis than the least deprived quintile (crude OR 1.80 [95% CI 1.77-1.83]). Other risk factors (after adjusting comorbidities) such as learning disability (adjusted OR 3.53 [3.35-3.73]), chronic liver disease (adjusted OR 3.08 [2.97-3.19]), chronic kidney disease (stage 4: adjusted OR 2.62 [2.55-2.70], stage 5: adjusted OR 6.23 [5.81-6.69]), cancer, neurological disease, immunosuppressive conditions were also associated with developing non-COVID-19 sepsis. The incidence rate of non-COVID-19 sepsis decreased during the COVID-19 pandemic and rebounded to pre-pandemic levels (April 2021) after national lockdowns had been lifted. The 30-day mortality risk in cases with non-COVID-19 sepsis was higher for the most deprived quintile across all periods. Socioeconomic deprivation, comorbidity and learning disabilities were associated with an increased odds of developing non-COVID-19 related sepsis and 30-day mortality in England. This study highlights the need to improve the prevention of sepsis, including more precise targeting of antimicrobials to higher-risk patients. The UK Health Security Agency, Health Data Research UK, and National Institute for Health Research.

Impact of the COVID-19 pandemic on routine surveillance for adults with chronic hepatitis B virus (HBV) infection in the UK.

To determine the impact of the COVID-19 pandemic on the population with chronic Hepatitis B virus (HBV) infection under hospital follow-up in the UK, we quantified the coverage and frequency of measurements of biomarkers used for routine surveillance (alanine transferase [ALT] and HBV viral load). We used anonymized electronic health record data from the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) pipeline representing five UK National Health Service (NHS) Trusts. We report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID-19 years, both in terms of the proportion of patients who had ≥1 measurement annually, and the mean number of measurements per patient. These results demonstrate the real-time utility of HIC data in monitoring health-care provision, and support interventions to provide catch-up services to minimise the impact of the pandemic. Further investigation is required to determine whether these disruptions will be associated with increased rates of adverse chronic HBV outcomes.

The effect of combination prevention strategies on HIV incidence among gay and bisexual men who have sex with men in the UK: a model-based analysis

In the UK, the number of new HIV diagnoses among gay and bisexual men who have sex with men (GBMSM) has decreased substantially. We aimed to understand the contribution of different interventions in reducing HIV incidence so far; to estimate future HIV incidence with continuation of current policies and with further scaling up of current interventions; and to estimate the maximum additional annual cost that should be spent towards these interventions for them to offer value for money. We calibrated a dynamic, individual-based, stochastic simulation model, the HIV Synthesis Model, to multiple sources of data on HIV among GBMSM aged 15 years or older in the UK. Primarily these were routine HIV surveillance data collected by the UK Health Security Agency. We compared HIV incidence in 2022 with the counterfactual incidence: if HIV testing rates stopped increasing in 2012 and the policy of antiretroviral therapy (ART) at diagnosis was not introduced in mid-2015; if pre-exposure prophylaxis (PrEP) was not introduced; if condom use was low from 2012 in all GBMSM, at levels similar to those observed in 1980; and in the first and second scenario combined. We also projected future outcomes under the assumption of continuation of current policies and considering increases in PrEP and HIV testing uptake and a decrease in condomless sex. Our model estimated a 77% (90% uncertainty interval [UI] 61-88) decline in HIV incidence since around 2014, with an estimated 597 infections ([90% UI 312-956]; 1·1 per 1000 person-years [90% UI 0·6-1·8]) in men aged 15-64 years in 2022. Both PrEP introduction and increased HIV testing with ART initiation at diagnosis each had a substantial effect on HIV incidence. Without PrEP introduction, we estimate there would have been 2·16 times the number of infections that actually occurred (90% UI 1·06-3·75) between 2012 and 2022; without increased HIV testing and ART initiation at diagnosis there would have been 2·18 times the number of infections that actually occurred (1·18-3·60), and if condomless sex was at the levels before the HIV epidemic, there would have been 2·27 times the number of infections that actually occurred (0·9-5·4). If rates of testing, ART use, and PrEP use remain as they are currently, there is a predicted decline in incidence to 388 HIV infections in 2025 (90% UI 226-650) and to 263 (137-433) in 2030. Increases in HIV testing and PrEP use were predicted to accelerate the decline in HIV incidence. Given the quality-adjusted life-year (QALY) benefit and a cost-effectiveness threshold of £30 000 per QALY gained, in order to be cost-effective an additional £1·62 million could be spent per year to increase testing levels by 34% (90% UI 25-46) and PrEP use by 55% (10-107). To achieve that, a 16% reduction in the cost of delivery of testing and PrEP would be required. Combination prevention, including a PrEP strategy, played a major role in the reduction in HIV incidence observed so far in the UK among GBMSM. Continuation of current activities should lead to a continued decline; however, it is unlikely to lead to reaching the target of fewer than 50 HIV infections per year among GBMSM by 2030. It will be important to reduce costs for testing and PrEP for their continued expansion to be cost-effective. National Institute for Health Research under its Programme Grants for Applied Research Programme and Medical Research Council-UK Research and Innovation.

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study

Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%. This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics. European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation.

How to… support others in developing a career in clinical education research.

The Incubator for Clinical Education Research (ClinEdR) is a UK-wide network, established with support from the National Institute for Health Research, to lead initiatives to build capacity in the field. A key barrier identified by this group is that many experienced educators, clinicians, and researchers, who may be committed to supporting others, have little guidance on how best to do this. In this "How to …" paper, we draw on relevant literature and our individual and collective experiences as members of the National Institute for Health Research ClinEdR incubator to offer suggestions on how educators can support others to develop successful careers involving ClinEdR. This article offers guidance and inspiration for all professionals whose role involves research and scholarship and who encounter aspiring or developing clinical education researchers in the course of their work. It will also be of interest to researchers who are starting out and progressing in the field.

Collaboration between the National Institute of Health Somalia and the Public Health Agency of Sweden

Abstract Public Health Agency Sweden (PHAS) has been funded by Sida to provide support and assist in capacity building of the National Institute of Health (NIH) Somalia for six years (2019-2025). The PHAS work closely with the Federal Ministry of Health Somalia, Member States and partners like WHO Somalia, Africa CDC and academic institutions to establish NIHS as an institution that can be sustained and grow over time, and that can contribute to the public health and health system infrastructure of Somalia. Main areas of collaboration 2019-2023 have been technical support to the joint taskforce on Integrated Disease Surveillance and Response (IDSR); supporting basic level field epidemiology training to front line health care workers; organizing workshops in data analyses, visualisation and reporting together with SPIDER/Stockholm University and Statistics Sweden. Building research capacity has included organizing a digital workshop: Reconstructing public health institutions in Somalia at the16th World Congress on Public Health 2020, Rome, Italy and support to the 1st NIH Research Conference 30 January - 1 February 2022 in Garowe, Puntland: “Laying the Foundation for Health Research in Somalia”. The hybrid conference attracted more than 180 participants from different universities. The tentative plan for the remaining project period include recruiting two Somali-speaking public health experts to develop the human resources and institutional capacities in order for NIH to become a centre of excellence for public health in Somalia. The main focus area for the remaining project period is supporting the development of the disease surveillance system including methods for analysis and reporting data. Research capacity workshops will be organized and supported, as well as a 2nd NIH Research Conference in 2024. Another important task is resource mobilization for long-term sustainability and coordination with other stakeholders. Key messages • Supporting the development of the disease surveillance system including analytical skills and reporting of data is key. • Coordination with other stakeholders and resource mobilization for long-term sustainability is essential.

Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Empagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic, and haemodynamic effects. The RECOVERY trial aimed to assess its safety and efficacy in patients admitted to hospital with COVID-19. In the randomised, controlled, open-label RECOVERY trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. In this analysis, we assess eligible and consenting adults who were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus oral empagliflozin 10 mg once daily for 28 days or until discharge (whichever came first) using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality; secondary outcomes were duration of hospitalisation and (among participants not on invasive mechanical ventilation at baseline) the composite of invasive mechanical ventilation or death. On March 3, 2023 the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on March 7, 2023. The ongoing RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Between July 28, 2021 and March 6, 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Primary and secondary outcome data were known for greater than 99% of randomly assigned patients. Overall, 289 (14%) of 2113 patients allocated to empagliflozin and 307 (14%) of 2158 patients allocated to usual care died within 28 days (rate ratio 0·96 [95% CI 0·82-1·13]; p=0·64). There was no evidence of significant differences in duration of hospitalisation (median 8 days for both groups) or the proportion of patients discharged from hospital alive within 28 days (1678 [79%] in the empagliflozin group vs 1677 [78%] in the usual care group; rate ratio 1·03 [95% CI 0·96-1·10]; p=0·44). Among those not on invasive mechanical ventilation at baseline, there was no evidence of a significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (338 [16%] of 2084 vs 371 [17%] of 2143; risk ratio 0·95 [95% CI 0·84-1·08]; p=0·44). Two serious adverse events believed to be related to empagliflozin were reported: both were ketosis without acidosis. In adults hospitalised with COVID-19, empagliflozin was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death so is not indicated for the treatment of such patients unless there is an established indication due to a different condition such as diabetes. UK Research and Innovation (Medical Research Council) and National Institute of Health Research (MC_PC_19056), and Wellcome Trust (222406/Z/20/Z). For the Nepali, Hindi, Indonesian (Bahasa) and Vietnamese translations of the abstract see Supplementary Materials section.

Development of neonatal-specific sequences for portable ultralow field magnetic resonance brain imaging: a prospective, single-centre, cohort study

Magnetic Resonance (MR) imaging is key for investigation of suspected newborn brain abnormalities. Access is limited in low-resource settings and challenging in infants needing intensive care. Portable ultralow field (ULF) MRI is showing promise in bedside adult brain imaging. Use in infants and children has been limited as brain-tissue composition differences necessitate sequence modification. The aim of this study was to develop neonatal-specific ULF structural sequences and test these across a range of gestational maturities and pathologies to inform future validation studies. Prospective cohort study within a UK neonatal specialist referral centre. Infants undergoing 3T MRI were recruited for paired ULF (64mT) portable MRI by convenience sampling from the neonatal unit and post-natal ward. Key inclusion criteria: 1) Infants with risk or suspicion of brain abnormality, or 2) preterm and term infants without suspicion of major genetic, chromosomal or neurological abnormality. Exclusions: presence of contra-indication for MR scanning. ULF sequence parameters were optimised for neonatal brain-tissues by iterative and explorative design. Neuroanatomic and pathologic features were compared by unblinded review, informing optimisation of subsequent sequence generations in a step-wise manner. Main outcome: visual identification of healthy and abnormal brain tissues/structures. ULF MR spectroscopy, diffusion, susceptibility weighted imaging, arteriography, and venography require pre-clinical technical development and have not been tested. Between September 23, 2021 and October 25, 2022, 102 paired scans were acquired in 87 infants; 1.17 paired scans per infant. Median age 9 days, median postmenstrual age 40+2 weeks (range: 31+3-53+4). Infants had a range of intensive care requirements. No adverse events observed. Optimised ULF sequences can visualise key neuroanatomy and brain abnormalities. In finalised neonatal sequences: T2w imaging distinguished grey and white matter (7/7 infants), ventricles (7/7), pituitary tissue (5/7), corpus callosum (7/7) and optic nerves (7/7). Signal congruence was seen within the posterior limb of the internal capsule in 10/11 infants on finalised T1w scans. In addition, brain abnormalities visualised on ULF optimised sequences have similar MR signal patterns to 3T imaging, including injury secondary to infarction (6/6 infants on T2w scans), hypoxia-ischaemia (abnormal signal in basal ganglia, thalami and white matter 2/2 infants on T2w scans, cortical highlighting 1/1 infant on T1w scan), and congenital malformations: polymicrogyria 3/3, absent corpus callosum 2/2, and vermian hypoplasia 3/3 infants on T2w scans. Sequences are susceptible to motion corruption, noise, and ULF artefact. Non-identified pathologies were small or subtle. On unblinded review, optimised portable MR can provide sufficient contrast, signal, and resolution for neuroanatomical identification and detection of a range of clinically important abnormalities. Blinded validation studies are now warranted. The Bill and Melinda Gates Foundation, the MRC, the Wellcome/EPSRC Centre for Medical Engineering, the MRC Centre for Neurodevelopmental Disorders, and the National Institute for Health Research (NIHR) Biomedical Research Centres based at Guy's and St Thomas' and South London & Maudsley NHS Foundation Trusts and King's College London.

Duration of birth depression and neurodevelopmental outcomes after whole-body hypothermia for hypoxic ischemic encephalopathy in India, Sri Lanka and Bangladesh – an exploratory analysis of the HELIX trial

Effect of duration of birth depression on neurodevelopmental outcomes in low- and middle-income countries (LMICs) is not known. We examined the association of birth depression with brain injury, neurodevelopmental outcomes, and hypothermia after hypoxic ischemic encephalopathy (HIE) in south Asia. We compared cerebral magnetic resonance (MR) at 2 weeks, and adverse outcomes (death or moderate or severe disability) at 18 months in 408 babies with moderate or severe HIE who had long birth depression (positive pressure ventilation (PPV)>10min or Apgar score<6at 10min or cord pH<7.0) and short birth depression (PPV for 5-10min or Apgar score<6at 5min, but ≥6at 10min). Long depression group (n=201) had more severe HIE (32.8% versus 6.8%), mortality (47.5% versus 26.4%), death or disability at 18 months (62.2% versus 35.4%) (all p<0.001), MR injury (Odds ratio; 95% CI) to basal ganglia (2.4 (1.3, 4.1); p=0.003), posterior limb of internal capsule (2.3 (1.3, 4.3); p<0.001) and white matter (1.7 (1.1, 2.7); p=0.021), and lower thalamic N-acetylaspartate levels (7.69±1.84 versus 8.29±1.60); p=0.031) than short depression group (n=207). Three babies had no heartbeat at 5min, of which 1 died and 2 survived with severe disability. No significant interaction between the duration of birth depression and whole-body hypothermia was seen for any of the MR biomarker or clinical outcomes. Long birth depression was associated with more brain injury and adverse outcomes than short depression. Effect of hypothermia was not modified by duration of birth depression. National Institute for Health Research.

EMBIO trial study protocol: left gastric artery embolisation for weight loss in patients living with obesity with a BMI 35–50 kg/m2

IntroductionLeft gastric artery embolisation (LGAE) is a well-established treatment for major upper gastrointestinal (GI) bleeding when control is not established via upper GI endoscopy and recently has shown promising results...

Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial

Maintenance antipsychotic medication is recommended for people with schizophrenia or recurrent psychosis, but the adverse effects are burdensome, and evidence on long-term outcomes is sparse. We aimed to assess the benefits and harms of a gradual process of antipsychotic reduction compared with maintenance treatment. Our hypothesis was that antipsychotic reduction would improve social functioning with a short-term increase in relapse. RADAR was an open, parallel-group, randomised trial done in 19 National Health Service Trusts in England. Participants were aged 18 years and older, had a diagnosis of recurrent, non-affective psychotic disorder, and were prescribed an antipsychotic. Exclusion criteria included people who had a mental health crisis or hospital admission in the past month, were considered to pose a serious risk to themselves or others by a treating clinician, or were mandated to take antipsychotic medication under the Mental Health Act. Through an independent, internet-based system, participants were randomly assigned (1:1) to gradual, flexible antipsychotic reduction, overseen by treating clinicians, or to maintenance. Participants and clinicians were aware of treatment allocations, but assessors were masked to them. Follow-up was for 2 years. Social functioning, assessed by the Social Functioning Scale, was the primary outcome. The principal secondary outcome was severe relapse, defined as requiring admission to hospital. Analysis was done blind to group identity using intention-to-treat data. The trial is completed and has been registered with ISRCTN registry (ISRCTN90298520) and with ClinicalTrials.gov (NCT03559426). 4157 people were screened, of whom 253 were randomly allocated, including 168 (66%) men, 82 (32%) women, and 3 (1%) transgender people, with a mean age of 46 years (SD 12, range 22-79). 171 (67%) participants were White, 52 (21%) were Black, 16 (6%) were Asian, and 12 (5%) were of other ethnicity. The median dose reduction at any point during the trial was 67% in the reduction group and zero in the maintenance group; at 24 months it was 33% versus zero. At the 24-month follow-up, we assessed 90 of 126 people assigned to the antipsychotic dose reduction group and 94 of 127 assigned to the maintenance group, finding no difference in the Social Functioning Scale (β 0·19, 95% CI -1·94 to 2·33; p=0·86). There were 93 serious adverse events in the reduction group affecting 49 individuals, mainly comprising admission for a mental health relapse, and 64 in the maintenance group, relating to 29 individuals. At 2-year follow-up, a gradual, supported process of antipsychotic dose reduction had no effect on social functioning. Our data can help to inform decisions about the use of long-term antipsychotic medication. National Institute for Health Research.

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2-6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5-5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4-10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32-4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23-11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification. UK Research and Innovation and National Institute for Health Research.

Statistical methods and data visualisation of patient-reported outcomes in early phase dose-finding oncology trials: a methodological review

Traditionally, within dose-finding clinical trials, treatment toxicity and tolerability are assessed by clinicians. Research has shown that clinician reporting may have inadequate inter-rater reliability, poor correlation with patient reported outcomes, and under capture the true toxicity burden. The introduction of patient-reported outcomes (PROs), where the patient can assess their own symptomatic adverse events or quality of life, has potential to complement current practice to aid dose optimisation. There are no international recommendations offering guidance for the inclusion of PROs in dose-finding trial design and analysis. Our review aimed to identify and describe current statistical methods and data visualisation techniques employed to analyse and visualise PRO data in published early phase dose-finding oncology trials (DFOTs). DFOTs published from June 2016-December 2022, which presented PRO analysis methods, were included in this methodological review. We extracted 35 eligible papers indexed in PubMed. Study characteristics extracted included: PRO objectives, PRO measures, statistical analysis and visualisation techniques, and whether the PRO was involved in interim and final dose selection decisions. Most papers (30, 85.7%) did not include clear PRO objectives. 20 (57.1%) papers used inferential statistical techniques to analyse PROs, including survival analysis and mixed-effect models. One trial used PROs to classify a clinicians' assessed dose-limiting toxicities (DLTs). Three (8.6%) trials used PROs to confirm the tolerability of the recommended dose. 25 trial reports visually presented PRO data within a figure or table within their publication, of which 12 papers presented PRO score longitudinally. This review highlighted that the statistical methods and reporting of PRO analysis in DFOTs are often poorly described and inconsistent. Many trials had PRO objectives which were not clearly described, making it challenging to evaluate the appropriateness of the statistical techniques used. Drawing conclusions based on DFOTs which are not powered for PROs may be misleading. With no guidance and standardisation of analysis methods for PROs in early phase DFOTs, it is challenging to compare study findings across trials. Therefore, there is a crucial need to establish international guidance to enhance statistical methods and graphical presentation for PRO analysis in the dose-finding setting. EA has been supported to undertake this work as part of a PhD studentship from the Institute of Cancer Research within the MRC/NIHR Trials Methodology Research Partnership. AM is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust, the Institute of Cancer Research and Imperial College.

‘Filling the void with melody’: Therapists’ reflections on group songwriting using GarageBand in music therapy for adults with depression

Songwriting is widely used in individual music therapy but less often in groups. This article draws on the authors’ experience of facilitating music therapy groups for adults with severe depression using songwriting. This work was part of the SYNCHRONY study, funded by the National Institute for Health Research, to assess the feasibility of conducting a randomised controlled trial of group music therapy with a songwriting component for patients with long-term depression (1 year or longer) within the community. The authors (all music therapists in the study) describe their experiences and reflections on the group processes and use of songwriting, drawing on semi-structured interviews conducted as part of the study. Themes of the work included pre-composed songs as a more accessible way to talk about difficult experiences, musical improvisation enabling an environment for songwriting, the impact of difficulties in attendance on group cohesion and the songwriting process, building confidence through song development and recording, and considerations around the end process and creating the song album. These are illustrated with clinical vignettes. Some recommendations for practice are also offered. The authors hope to identify the potentials and challenges of a songwriting approach in a community mental health context.

Transmission dynamics and effect of control measures on the 2022 outbreak of mpox among gay, bisexual, and other men who have sex with men in England: a mathematical modelling study

The 2022 global outbreak of mpox (formerly known as monkeypox) spread primarily among gay, bisexual, and other men who have sex with men (GBMSM), with the initial cluster being identified in England in May, 2022. Understanding its epidemiological characteristics and the reasons for its downturn in July, 2022, will help to control future outbreaks. We collated data for all diagnosed mpox cases (3621) from England from May 1, 2022, to Nov 16, 2022. Data from 75 individuals with mpox allowed estimation of the incubation period, while data from 121 case-contact pairs were used to estimate the serial interval. Six methods, including a structured dynamic compartmental transmission model, were used to estimate the basic reproduction number (R0). The structured model assumed all male individuals with mpox were GBMSM, who were then stratified into subgroups for those at low risk and high risk for mpox. This best fitting model was used to estimate the reduction in transmissibility, and the effective infectious period (before isolating), that resulted in the outbreak downturn, and the effect of vaccination initiated from June 27, 2022. Bayesian methods were used for parameter estimation and model calibration. Most cases occurred in men (3544 of 3621, 97·9%). The median incubation period for mpox was 6·90 days (95% credible interval [CrI] 4·08-20·21), and the serial interval was 8·82 days (5·22-25·81). R0 estimates ranged from 1·41 to 2·17. The structured transmission model estimated that 83·8% of infections (95% CrI 83·5-85·3) resulted from sexual partnerships with GBMSM individuals at high risk of mpox. The outbreak downturn probably resulted from a 44·5% reduction in the sexual partner rate among all GBMSM (24·9-55·8) and 20·0% reduction in the effective infectious period (4·1-33·9), preventing 165 896 infections (115 584-217 730). Vaccination marginally increased the number of infections prevented (166 081, 115 745-217 947), but minimised a resurgence in cases from January, 2023, and could have averted four times more infections if initiated earlier. Our findings were sensitive to assumptions regarding the vaccine's effectiveness and the GBMSM subgroup at high risk of mpox. The mpox outbreak in England probably resulted from high sexual partner rates among some GBMSM, with reductions in partner rates reversing the outbreak, and with vaccination minimising future outbreaks. National Institute for Health Research (UK).

Academic productivity and NIH funding for anesthesiology departmental chairs: A 15-year comparison

Study objectiveThis study evaluated whether there were improvements in the number of departmental National Institutes of Health (NIH) training grants and the academic productivity of departmental chairs in terms of NIH research funding and PubMed-cited publications when compared to chairs of the same departments in 2006. DesignEach chair was identified from the Society of Academic Associations of Academic Anesthesiology & Perioperative Medicine's Association of Academic Anesthesiology Chairs and entered into the NIH Research Portfolio Online Reporting Tools (RePORTER), PubMed, SCOPUS, and the National Provider Identifier Registry. MeasurementsThe number and funding amounts of training grants awarded to the department in 2010, 2015, and 2020 were obtained as well as the department's national ranking and total dollar amount for NIH funding in 2020. For the current chair cohort, total publications and m-quotient (h-index corrected for active research years) were recorded along with each chair's history of NIH grant funding. These data were compared to a previous study of anesthesiology chairs that reviewed funding and publications through 2006. Main resultsWe analyzed data from 100 academic departments of anesthesiology and compared their scholarly activity relative to data gathered in 2006. In 2020, 52 of 100 departments of anesthesiology had evidence of NIH funding. There were not statistically significant (P > 0.05) differences in grants funding obtained by chairs between 2006 and 2020 with the exception that more chairs in 2006 had program or center grants. Median publications for chairs significantly increased from 35 in 2006 to 55 in 2021 (IRR = 1.5, 95% CI = 1.2–2.0, P = 0.003). Nineteen percent of chairs were female, which did not significantly differ from the proportion of women in the 2006 paper (15%, χ2 = 0.57, df = 1, P = 0.452). Of the male chairs, 90% were professors whereas 63% of female chairs were professors (χ2 = 8.8, df = 1, P = 0.003). Female chairs had fewer publications than male chairs (IRR = 1.8, 95% CI = 1.2–1.8, P = 0.002); however, m-quotients were not significantly different between men and women (P = 0.602). ConclusionsWhen compared to 2006, department of anesthesiology chairs had more publications in 2021; however, NIH funding rates remained unchanged. The specialty had 19% female chairs, and those chairs had fewer publications than their male counterparts, though sex differences were attenuated using metrics that account for disparities in career length.

Codesigning a systemic discharge intervention for inpatient mental health settings (MINDS): a protocol for integrating realist evaluation and an engineering-based systems approach

IntroductionTransition following discharge from mental health hospital is high risk in terms of relapse, readmission and suicide. Discharge planning supports transition and reduces risk. It is a complex activity involving...