National Institute For Health Research Research Articles

PP18 Horizon Scanning For Clinical Biosimilar Medicines: Informing The Lifecycle Of Health Technology Assessment And Market Access

IntroductionThe National Institute for Health and Care Research (NIHR) Innovation Observatory (IO) national horizon scanning research centre, has a remit to notify its stakeholders, including the National Institute for Health and Care Excellence (NICE), about innovative interventions; including biosimilar medicines in the pipeline. Biosimilar medicines bypass many developmental steps, making them substantially cheaper to manufacture for providers, which increases market availability and improves treatment access for patients.MethodsSince 2017, the NIHR IO has monitored biosimilars in clinical development that align to the NICE health technology assessment remit. The data set explored was exported from our internal medicines innovation database - MInD.Data sets were created that included information on the characteristics of biosimilars and their associated clinical trials. Analyses and visualization creation were carried out using Microsoft Excel and Microsoft Power BI.ResultsA total of 100 unique biosimilar medicines in 136 clinical trials were included in the MInD since April 2017. Of these, 44 percent of biosimilars are currently EMA-approved (Nov 2021). Adalimumab was the reference medicine with the most unique biosimilars identified (12%). Seventy-two percent of the biosimilars in MInD were indicated for non-oncology conditions, twenty percent for oncology condition and eight percent for both.There were 46 biosimilars unapproved, which were in active development. Of these biosimilars 17.4 percent are indicated for an oncology condition, 78.3 percent for non-oncology conditions, and 4.3 percent for biosimilars for both. Aflibercept was the reference product with the most (eight) biosimilars in active development.There were 56 individual clinical trials in the MInD that list a biosimilar in development. For 26 trials, the primary completion date (PCD) was prior to 2021, whilst 28 trials listed a PCD post-2021, and 2 PCD’s were unavailableConclusionsOur analysis identified high levels of active clinical development for biosimilars. The majority of biosimilars being developed are indicated for non-oncology conditions, with many in trials due to readout in the near future. Early identification, monitoring and reporting of biosimilars allows for expedited patient access and benefits, including cost-savings for health services.This study is funded by the National Institute for Health Research (NIHR) [(HSRIC-2016-10009)/Innovation Observatory].

A radiomics-based decision support tool improves lung cancer diagnosis in combination with the Herder score in large lung nodules.

Large lung nodules (≥15mm) have the highest risk of malignancy, and may exhibit important differences in phenotypic or clinical characteristics to their smaller counterparts. Existing risk models do not stratify large nodules well. We aimed to develop and validate an integrated segmentation and classification pipeline, incorporating deep-learning and traditional radiomics, to classify large lung nodules according to cancer risk. 502 patients from five U.K. centres were recruited to the large-nodule arm of the retrospective LIBRA study between July 2020 and April 2022. 838 CT scans were used for model development, split into training and test sets (70% and 30% respectively). An nnUNet model was trained to automate lung nodule segmentation. A radiomics signature was developed to classify nodules according to malignancy risk. Performance of the radiomics model, termed the large-nodule radiomics predictive vector (LN-RPV), was compared to three radiologists and the Brock and Herder scores. 499 patients had technically evaluable scans (mean age 69±11, 257 men, 242 women). In the test set of 252 scans, the nnUNet achieved a DICE score of 0.86, and the LN-RPV achieved an AUC of 0.83 (95% CI 0.77-0.88) for malignancy classification. Performance was higher than the median radiologist (AUC 0.75 [95% CI 0.70-0.81], DeLong p=0.03). LN-RPV was robust to auto-segmentation (ICC 0.94). For baseline solid nodules in the test set (117 patients), LN-RPV had an AUC of 0.87 (95% CI 0.80-0.93) compared to 0.67 (95% CI 0.55-0.76, DeLong p=0.002) for the Brock score and 0.83 (95% CI 0.75-0.90, DeLong p=0.4) for the Herder score. In the international external test set (n=151), LN-RPV maintained an AUC of 0.75 (95% CI 0.63-0.85). 18 out of 22 (82%) malignant nodules in the Herder 10-70% category in the test set were identified as high risk by the decision-support tool, and may have been referred for earlier intervention. The model accurately segments and classifies large lung nodules, and may improve upon existing clinical models. This project represents independent research funded by: 1) Royal Marsden Partners Cancer Alliance, 2) the Royal Marsden Cancer Charity, 3) the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, 4) the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College London, 5) Cancer Research UK (C309/A31316).

Epigenetic drug screen identified IOX1 as an inhibitor of Th17-mediated inflammation through targeting TET2.

Targeting helper T cells, especially Th17cells, has become a plausible therapy for many autoimmune diseases. Using an invitro culture system, we screened an epigenetics compound library for inhibitors of IFN-γ and IL-17 expression in murine Th1 and Th17 cultures. This identified IOX1 as an effective suppressor of IL-17 expression in both murine and human CD4+ T cells. Furthermore, we found that IOX1 suppresses Il17a expression directly by targeting TET2 activity on its promoter in Th17cells. Using established pre-clinical models of intraocular inflammation, treatment with IOX1 invivo reduced the migration/infiltration of Th17cells into the site of inflammation and tissue damage. These results provide evidence of the strong potential for IOX1 as a viable therapy for inflammatory diseases, in particular of the eye. This study was supported by the National Key Research and Development Program of China 2021YFA1101200 (2021YFA1101204) to LW and XW; the National Natural Science Foundation of China 81900844 to XH and 82171041 to LW; the China Postdoctoral Science Foundation 2021M700776 and the Scientific Research Project of Guangdong Provincial Bureau of Traditional Chinese Medicine 20221373 to YZ; and the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS (National Health Service) Foundation Trust and University College London Institute of Ophthalmology, UK (DAC, LPS, PJPL, MS, ADD and RWJL). The views expressed are those of the authors and not necessarily those of the NIHR or the UK's Department of Health and Social Care.

OP86 Chatbot-Based Symptom-Checkers: A Systematic Review

IntroductionSymptom-checkers are digital health applications (DHA) with diagnostic algorithms. These symptom-checkers claim to improve the diagnostic process and patient guidance. After asking the user to describe the symptoms using a chatbot interface, the symptom-checkers offer a list of potential diagnoses, and/or give recommendations for appropriate action (self-care, doctor’s visit, or emergency care). Because of the growing number and increasing use of these diagnostic DHA, there is a need to evaluate the evidence.MethodsWe updated a British evidence synthesis on symptom-checkers from the National Institute for Health Research (NIHR, 2019). For the systematic update search, we selected four databases. The following endpoints were selected: effectiveness, safety, diagnostic accuracy, triage accuracy, organizational and patient-relevant endpoints. For accuracy studies included from the update search, we assessed the risk of bias (RoB) using the quality assessment tool of diagnostic accuracy studies (QUADAS-2).ResultsThe NIHR-report included 27 studies. We added 14 additional studies via update search. One randomized-controlled-trial (RCT) reported a prolonged illness duration when using symptom-checkers (statistically non-significant). No harms when using symptom-checkers were identified (six observational studies). The diagnostic accuracy ranged from 14-84.3 percent (ten observational studies), the triage accuracy ranged from 33-100 percent (eleven observational studies). For organizational endpoints, the results were inconsistent (one RCT, six observational studies). The patient perspective indicates a high usability for symptom-checkers, but the limited description of symptoms and the missing verbal interaction with health personnel were mentioned as hindering factors (nine survey-studies). The QUADAS-2 assessment for RoB was low in one, and high in seven studies.ConclusionsThe studies were often conducted using fictitious case-vignettes, limiting the validity of the evidence. Therefore, the results for the diagnostic and triage accuracy are insufficient to demonstrate a benefit in real-world settings. Additionally, there is a concern for misdiagnosis and overdiagnosis. We recommend a continuous monitoring of these diagnostic DHA, using high-quality studies.

Renin–Angiotensin System Inhibition in Advanced Chronic Kidney Disease

BackgroundRenin–angiotensin system (RAS) inhibitors — including angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) — slow the progression of mild or moderate chronic kidney disease. However, the results of some studies have suggested that the discontinuation of RAS inhibitors in patients with advanced chronic kidney disease may increase the estimated glomerular filtration rate (eGFR) or slow its decline.MethodsIn this multicenter, open-label trial, we randomly assigned patients with advanced and progressive chronic kidney disease (eGFR, <30 ml per minute per 1.73 m2 of body-surface area) either to discontinue or to continue therapy with RAS inhibitors. The primary outcome was the eGFR at 3 years; eGFR values that were obtained after the initiation of renal-replacement therapy were excluded. Secondary outcomes included the development of end-stage kidney disease (ESKD); a composite of a decrease of more than 50% in the eGFR or the initiation of renal-replacement therapy, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria.ResultsAt 3 years, among the 411 patients who were enrolled, the least-squares mean (±SE) eGFR was 12.6±0.7 ml per minute per 1.73 m2 in the discontinuation group and 13.3±0.6 ml per minute per 1.73 m2 in the continuation group (difference, −0.7; 95% confidence interval [CI], −2.5 to 1.0; P=0.42), with a negative value favoring the outcome in the continuation group. No heterogeneity in outcome according to the prespecified subgroups was observed. ESKD or the initiation of renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99 to 1.65). Adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events (108 vs. 88) and deaths (20 vs. 22).ConclusionsAmong patients with advanced and progressive chronic kidney disease, the discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISRCTN number, 62869767.)

Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans.

Ageing is a heterogenous process characterised by cellular and molecular hallmarks, including changes to haematopoietic stem cells and is a primary risk factor for chronic diseases. X chromosome inactivation (XCI) randomly transcriptionally silences either the maternal or paternal X in each cell of 46, XX females to balance the gene expression with 46, XY males. Age acquired XCI-skew describes the preferential selection of cells across a tissue resulting in an imbalance of XCI, which is particularly prevalent in blood tissues of ageing females, and yet its clinical consequences are unknown. We assayed XCI in 1575 females from the TwinsUK population cohort using DNA extracted from whole blood. We employed prospective, cross-sectional, and intra-twin study designs to characterise the relationship of XCI-skew with molecular and cellular measures of ageing, cardiovascular disease risk, and cancer diagnosis. We demonstrate that XCI-skew is independent of traditional markers of biological ageing and is associated with a haematopoietic bias towards the myeloid lineage. Using an atherosclerotic cardiovascular disease risk score, which captures traditional risk factors, XCI-skew is associated with an increased cardiovascular disease risk both cross-sectionally and within XCI-skew discordant twin pairs. In a prospective 10 year follow-up study, XCI-skew is predictive of future cancer incidence. Our study demonstrates that age acquired XCI-skew captures changes to the haematopoietic stem cell population and has clinical potential as a unique biomarker of chronic disease risk. KSS acknowledges funding from the Medical Research Council [MR/M004422/1 and MR/R023131/1]. JTB acknowledges funding from the ESRC [ES/N000404/1]. MM acknowledges funding from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London.

Implementing public involvement standards in cerebral palsy register research.

In 2018, the National Institute for Health Research launched Draft Standards for Public Involvement in Research. The Northern Ireland Cerebral Palsy Register (NICPR) was competitively selected as a "test-bed" project to pilot the Draft Standards over a one-year period. This perspective paper aims to describe the NICPR's experience of piloting the Draft Standards for Public Involvement in Research, highlighting successes and challenges. Three of the six Draft Standards were piloted from April 2018 to April 2019: Standard 2 "working together", Standard 4 "communications" and Standard 5, "impact". Implementation of Standard 2 resulted in formation of a dedicated Public Involvement Group. Standard 4 was implemented by revision of the NICPR's Privacy Notice and development of the NICPR website. Standard 5 was not implemented during the test-bed pilot period. Benefits of use of the Draft Standards in cerebral palsy register research included development of relationships, improving quality, accessibility and relevance of NICPR materials, increasing skills and confidence, networking opportunities, advocating for others and feeling empowered to shape cerebral palsy research. Challenges included administrative issues, absence of dedicated and sustained funding, limitations in the availability and applicability of public involvement training and the time required for meaningful public involvement. Standards for Public Involvement provide a useful framework for structuring and embedding meaningful public involvement. Sustained, authentic public involvement in cerebral palsy register research ensures that people affected by the condition are empowered to engage, inform, develop and lead research that meets their needs.

Effects of Tai Chi and Qigong on the mobility of stroke survivors: A systematic review and meta-analysis of randomized trials.

Stroke survivors often experience impaired mobility and physical functions. Tai Chi and Qigong have been shown to have physical and psychological benefits for stroke patients. To summarize the evidence on Tai Chi and Qigong for improving mobility in stroke survivors, specifically the ability to walk, dynamic balance, and activities of daily living (ADL). Independent searches of 16 electronic databases in English, Korean, and Chinese from their inception until December 2021 were conducted by two research teams. Methodological quality was assessed using Cochrane's risk of bias tool 2.0. Comprehensive Meta-Analysis 3.0 software was used to calculate effect sizes with subgroup analysis and to assess heterogeneity and publication bias. The meta-analysis included 27 randomized trials (18 with Tai Chi and 9 with Qigong) on stroke survivors (N = 1,919). None of the studies were considered at high risk of bias, about 70% had some concerns, and 30% were considered low risk. Meta-analysis of 27 randomized controlled trials with random-effects models indicated that Tai Chi and Qigong effectively improved mobility, specifically on the ability to walk (Hedges'g = 0.81), dynamic balance (Hedges'g = 1.04), and ADL (Hedges'g = 0.43). The effects of Tai Chi and Qigong were significant for short-term and long-term programs (Hedges'g 0.91 vs. 0.75), and when compared with active controls and no treatment group (Hedges'g 0.81 vs. 0.73). Tai Chi and Qigong performed for 12 weeks or less were effective in improving the mobility of stroke survivors. Further studies are warranted to assess whether Tai Chi and Qigong work best as an adjunct to rehabilitation, an effective alternative to rehabilitation or as a maintenance strategy, and whether the results could be further optimized by assessing different schools of Tai Chi and Qigong, different types of stroke patients, and different points in the post-stroke recovery process. This study has been registered on the UK National Institute for Health Research (http://www.crd.york.ac.uk/PROSPERO) PROSPERO registration number: CRD42020220277.

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial

HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda. The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.

Clinical utility of C-reactive protein-based triage for presumptive pulmonary tuberculosis in South African adults

BackgroundIdentification of an accurate, low-cost triage test for pulmonary TB among people presenting to healthcare facilities is an urgent global research priority. We assessed the diagnostic accuracy and clinical utility of C-reactive protein (CRP) for TB triage among symptomatic adult outpatients, irrespective of HIV status. MethodsWe prospectively enrolled adults reporting at least one (for people with HIV) or two (for people without HIV) symptoms of cough, fever, night sweats, or weight loss at two TB clinics in Cape Town, South Africa. Participants provided sputum for culture and Xpert MTB/RIF Ultra. We evaluated the diagnostic accuracy of CRP (measured using a laboratory-based assay) against a TB-culture reference standard as the area under the receiver operating characteristic curve (AUROC), and sensitivity and specificity at pre-specified thresholds. We assessed clinical utility using decision curve analysis and benchmarked against WHO recommendations. ResultsOf 932 included individuals, 255 (27%) had culture-confirmed pulmonary TB and 389 (42%) were living with HIV. CRP demonstrated an AUROC of 0·80 (95% confidence interval 0·77–0·83), with sensitivity 93% (89–95%) and specificity 54% (50–58%) using a primary cut-off of ≥10 mg/L. Performance was similar among people with HIV to those without. In decision curve analysis, CRP-based triage offered greater clinical utility than confirmatory testing for all up to a number willing to test threshold of 20 confirmatory tests per true positive pulmonary TB case diagnosed (threshold probability 5%). If it is possible to perform more confirmatory tests than this, a ‘confirmatory test for all’ strategy performed better. ConclusionsCRP achieved the WHO-defined sensitivity, but not specificity, targets for a triage test for pulmonary TB and showed evidence of clinical utility among symptomatic outpatients, irrespective of HIV status. FundingSouth African Medical Research Council, EDCTP2, Royal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, Royal College of Physicians.

Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial

Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and the rituximab group (97 mL [234]); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was -40 mL (95% CI -153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 [95% CI 0·11 to 1·68]). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group. Rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy. Efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK).

Impact of the COVID-19 Pandemic on National Institutes of Health-Funded Researchers and Their Projects: The Role of Age, Sex, Experience, and Team Size.

The COVID-19 pandemic has disrupted the social life, work environment, and well-being of millions of people. We examined COVID-19's impact on National Institutes of Health (NIH)-funded extramural principal investigators (PIs) affiliated with public health and preventive medicine departments across the country and their projects; assessed PIs' confidence in achieving project goals; and investigated the role of age, sex, experience, and team size on PIs' confidence in achieving project goals during the pandemic. We sent an anonymous online survey in January 2021 to 1076 extramural PIs affiliated with public health and preventive medicine departments at US institutions; 133 (12.4%) responded. We examined the impact of COVID-19 on the PIs, their project team operations, and their confidence that project objectives would be met, using Likert scales based on age, sex, team size, and PI experience. Of 126 PIs, 94 (74.6%) felt that their day-to-day professional life was impacted a lot or a great deal by COVID-19. More female PIs than male PIs reported that their level of stress changed because of the COVID-19 pandemic. Of 125 PIs, 67 (53.6%) made major adjustments to research operations, 46 (36.8%) made minor adjustments, 5 (4.0%) halted research, and 7 (5.6%) reported not being affected. Of 123 PIs, 89 (72.4%) reported not using NIH COVID-19 accommodations. PIs who led projects 4 or 5 times felt more confident about meeting their research objectives than PIs who led projects 2 or 3 times. Future studies should investigate how to develop more engaging support and communication strategies to assist NIH researchers in mitigating the effects of pandemics or large-scale emergencies.

Effectiveness and cost effectiveness of digital hearing aids in patients with tinnitus and hearing loss: a randomised feasibility trial (THE HUSH Trial)

BackgroundEducation and advice is provided for tinnitus management in all UK audiology clinics. Sound therapy, including provision of hearing aids may be offered, but this is often dependent on a clinician’s decision rather than UK policy. This inconsistent management reflects a lack of evidence around the effectiveness of hearing aids for tinnitus. This open-label, two-arm multicentre randomised controlled feasibility trial gathered data around recruitment, acceptability and outcome assessments to determine the feasibility of conducting a large randomised controlled trial investigating the effectiveness of hearing aids for tinnitus management.MethodsAdults referred to audiology for tinnitus, with an aidable hearing loss were recruited at five UK audiology clinics. They were randomised 1:1 to either education and advice (treatment as usual (TAU), n = 41) or TAU plus hearing aids (n = 42). Outcomes were collected by questionnaires 12 weeks after randomisation. After participation, interviews were conducted with a subset of both participants and clinicians from each trial centre.ResultsEighty three participants from five sites were randomised. Non-aidable hearing loss was the main reason for ineligibility to participate in the trial reported by the sites. Seventy three percent of participants returned the 12-week questionnaires, with return rates by site ranging from 61 to 100%. Fifteen out of 33 participants (45%) reported using hearing aids for the clinician-recommended time, or longer, during the day. The Tinnitus Functional Index (TFI) was the outcome measure most responsive to change. The majority of participants also agreed it was relevant to their tinnitus and hearing loss. Qualitative data demonstrated that the trial was acceptable to participants. Feedback from clinicians revealed a potential lack of equipoise. It also highlighted the differences in referral and treatment pathways between departments and differences in audiometric criteria for fitting hearing aids. Health economic measures were well completed for those returned. No change in health-related quality of life was observed. Costs were higher in the intervention arm, but self-reports of healthcare service use indicated participant confusion in treatment pathways.ConclusionsThis feasibility trial is the first step towards obtaining high quality evidence to determine potential clinical effectiveness and cost effectiveness of hearing aids for tinnitus versus usual care. A definitive trial was deemed to be feasible, with some modifications based on feasibility findings and using the TFI as the primary outcome.This trial was funded by the National Institute for Health Research, Research for Patient Benefit Programme (PB-PG-0816–20,014) and registered with ISRCTN (ISRCTN14218416).

Molecular subtypes of leiomyosarcoma: Moving toward a consensus

Molecular subtypes of leiomyosarcoma: Moving toward a consensus

The longitudinal effect of social media use on adolescent mental health in the UK: findings from the UK Longitudinal Household Study

BackgroundCross-sectional studies have suggested an association between the use of social media and depression and anxiety in young people. We examined the longitudinal relationship between social media use and young people's mental health, and the role of self-esteem and social connectedness as potential mediators. MethodsAdolescents (aged 10–15 years) from the UK Longitudinal Household Study (2009–19) were included. Mental health was measured by the Strengths and Difficulties Questionnaire Total Difficulties score. The number of hours spent on social media was measured on a 5-point scale, from zero to ≥7 h. Self-esteem and social connectedness were measured at ages 13–14 years. Covariates included demographic and household variables. Unadjusted and adjusted multilevel linear regression models explored whether social media use at ages 12–13 years predicted mental health at ages 14–15 years (expressed as beta values and 95% CIs). Path analysis with structural equation modelling was used to investigate the mediation pathways. FindingsWe included 3228 adolescents (1659 [51·4%] girls and 1569 [48·6%] boys) for whom social media and mental health data at ages 12–13 years and 14–15 years were available. In adjusted analysis, no association between time spent on social media and poorer mental health was identified (n=2603; b=0·21 [95% CI –0·43 to 0·84]; p=0·52). In adjusted path analysis, there was no mediation of self-esteem (indirect effect; n=2316; b=0·24 [95% CI –0·12 to 0·66]; p=0·22) or social connectedness (indirect effect; –0·03 [–0·20 to 0·12]; p=0·74), but in unadjusted analysis, 68% of the effect of social media use on mental health was mediated by self-esteem (indirect effect; n=2569; 0·70 [0·15 to 1·30]; p=0.016) but not by social connectedness. Similar results were found when the analysis was re-run on a multiply imputed dataset that filled in missing values using multiple imputation. InterpretationOur data show the importance of longitudinal evidence. We found there was little evidence to suggest a causal relationship between the use of social media and mental health issues 2 years later. Interventions that address social media use alone might not improve young people's mental health, and considering factors such as self-esteem might be more effective. FundingUK National Institute for Health Research School for Public Health Research (grant reference PD-SPH-2015). The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the UK Department of Health and Social Care.

Catastrophic expenditure and treatment attrition in patients seeking comprehensive colorectal cancer treatment in India: A prospective multicentre study.

Although colorectal cancer is increasing in India, the cost of comprehensive treatment and its consequences for patients and households are unknown. This study aimed to describe catastrophic expenditure and treatment attrition in patients with a treatment plan for colorectal cancer. A prospective, multicentre, cohort study was conducted in five tertiary hospitals in India from December 2020 to March 2022. Consecutive patients with a new treatment plan for colorectal cancer were followed-up for six months. The total cost of treatment was reported, including out-of-pocket payments (OOPP, paid by patients at the time-of-service use) and covered by third parties (insurance, public funds). The primary outcome was catastrophic expenditure, defined as OOPPs greater than 25% of patient's annual household income and the secondary outcome was treatment attrition, defined as unplanned interruption of the treatment course not recommended by the clinical team. Of 226 patients included, 20 died within six months of being offered a treatment plan and four were lost to follow-up. The median total cost of colorectal cancer treatment was 407,508 Indian Rupees (INR/5340 USD), to which the biggest contributor was the patient's OOPP (median 330,277 INR/4328 USD). Surgery and anaesthesia costs (median 85,944 INR/1126 USD) were higher than radiotherapy (median 55,525 INR/728 USD) and chemotherapy (median 14,780 INR/194 USD). The overall catastrophic expenditure rate was 90.1% (182/202) and the treatment attrition rate was 9.4% (19/202). Patients with treatment attrition made lower OOPPs than those who completed treatment (median 205,926 vs 349,398 INR, p<0.01) but had a similar risk of catastrophic expenditure (OR 0.23, 95%CI 0.03-2.28, p = 0.186). Most treatment costs for colorectal cancer were paid out-of-pocket by patients and catastrophic expenditure was common. Treatment attrition rates at tertiary centres were low, suggesting greater attrition at previous stages of care. Better financial protection may allow more patients to receive comprehensive cancer treatment while avoiding household financial catastrophe. This research was funded by the National Institute for Health Research (NIHR) (NIHR 16.136.79) using UK aid from the UK Government to support global health research, by the India Institute of the University of Birmingham and by the Global Challenges program of the University of Birmingham. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK government.

Quantifying the contribution of poverty and family adversity to adverse child outcomes in the UK: evidence from the UK Millennium Cohort Study

BackgroundAdolescent health is poor in the UK, with higher prevalence of adverse outcomes in adolescents exposed to family adversities that cluster with poverty from early life. However, little evidence exists to quantify the contribution of these exposures to poor child health in the UK to inform policy. The aim of this study was to estimate the proportion of child physical, mental, cognitive, and behavioural outcomes that could be prevented if exposure to poverty and family adversity during childhood were eliminated. MethodsWe used nationally representative birth cohort data from the UK Millennium Cohort Study to calculate population attributable fractions. Exposure trajectories were characterised using previously developed group-based multi-trajectory models of childhood adversities up to age 14 years, including low poverty and family adversity, persistent poverty, persistent parental alcohol use, persistent domestic violence and abuse, and persistent poverty and poor parental mental health trajectory; and we assessed the effect of these trajectories on adolescent outcomes using regression models. These models were used to calculate population attributable fractions by contrasting a hypothetical scenario in which all children were in a low poverty and family adversity trajectory with the real-world scenario. FindingsThe identified exposure trajectories contributed substantially to the burden of childhood developmental problems. Compared with the low poverty and family adversity trajectory, the overall percentage of socioemotional behavioural problems at age 14 years attributable to persistent poverty and family adversity trajectories was 54% (95% CI 45–60). A percentage of 36·1% (95% CI 21·8–46·2) was reported for drug experimentation, 32·6% (18·8–40·7) for cognitive disability, and 27·4% (12·9–34·9) for obesity (appendix). InterpretationPoverty and family adversity contribute to a substantial burden of adverse child health and developmental outcomes in the UK population. FundingThe National Institute for Health Research (NIHR) Policy Research Programme, NIHR Applied Research Collaboration South London at King's College Hospital NHS Foundation Trust, and the UK Medical Research Council.

The relationship between academic influence, NIH funding, and industry payments among academic shoulder and elbow surgeons.

The effect of academic influence, or the volume and quality of a surgeon's publications, on industry payments and National Institutes of Health (NIH) funding has recently been studied in some academic orthopedic subspecialities. The purpose of this study is to evaluate the relationship between academic influence, industry payments, and NIH funding among American Shoulder and Elbow Surgeons accredited shoulder and elbow fellowship faculty. Shoulder and elbow fellowships and affiliated faculty members were identified from the American Shoulder and Elbow Surgeons website. Academic influence, measured by the Hirsch (h)-index, and the number of articles published were determined for faculty members using the Scopus Database Author Identifier tool. Industry payments were derived from the Centers for Medicare and Medicaid Services Open Payments database. NIH funding was determined using the NIH's Research Portfolio Online Reporting tool. Statistical analysis used Spearman correlations and the Mann-Whitney U-test with an alpha value of 0.05 (P<.05). A total of 146 faculty members were included. Twenty-two percent (42 of 146) received nonresearch payments, whereas 78% (114 of 146) received industry research funding averaging $6364 (standard deviation=$21,213). NIH funding averaged $272,589 (standard deviation=$224,635), and 5% received NIH funding (7 of 146). Faculty members who received NIH funding had a higher average h-index than those who did not (38±22 vs. 22.64±22.7, P=.02), whereas those receiving industry research payments had a greater number of publications than those who did not (127.97±127.2 vs. 100.3±122.3, P=.03). Industry nonresearch payments did not impact the number of publications or the h-index. This study demonstrated that academic influence among academic shoulder and elbow surgeons is not greater in those who receive nonresearch industry funding. However, surgeons with industry research funding did produce more publications, whereas NIH funding is associated with greater academic influence.

Elective surgery system strengthening: development, measurement, and validation of the surgical preparedness index across 1632 hospitals in 119 countries

The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index to support local elective surgical system strengthening and address growing backlogs. First, we performed an international consultation through a four-stage consensus process to develop a multidomain index for hospital-level assessment (surgical preparedness index; SPI). Second, we measured surgical preparedness across a global network of hospitals in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) to explore the distribution of the SPI at national, subnational, and hospital levels. Finally, using COVID-19 as an example of an external system shock, we compared hospitals' SPI to their planned surgical volume ratio (SVR; ie, operations for which the decision for surgery was made before hospital admission), calculated as the ratio of the observed surgical volume over a 1-month assessment period between June 6 and Aug 5, 2021, against the expected surgical volume based on hospital administrative data from the same period in 2019 (ie, a pre-pandemic baseline). A linear mixed-effects regression model was used to determine the effect of increasing SPI score. In the first phase, from a longlist of 103 candidate indicators, 23 were prioritised as core indicators of elective surgical system preparedness by 69 clinicians (23 [33%] women; 46 [67%] men; 41 from HICs, 22 from MICs, and six from LICs) from 32 countries. The multidomain SPI included 11 indicators on facilities and consumables, two on staffing, two on prioritisation, and eight on systems. Hospitals were scored from 23 (least prepared) to 115 points (most prepared). In the second phase, surgical preparedness was measured in 1632 hospitals by 4714 clinicians from 119 countries. 745 (45·6%) of 1632 hospitals were in MICs or LICs. The mean SPI score was 84·5 (95% CI 84·1-84·9), which varied between HIC (88·5 [89·0-88·0]), MIC (81·8 [82·5-81·1]), and LIC (66·8 [64·9-68·7]) settings. In the third phase, 1217 (74·6%) hospitals did not maintain their expected SVR during the COVID-19 pandemic, of which 625 (51·4%) were from HIC, 538 (44·2%) from MIC, and 54 (4·4%) from LIC settings. In the mixed-effects model, a 10-point increase in SPI corresponded to a 3·6% (95% CI 3·0-4·1; p<0·0001) increase in SVR. This was consistent in HIC (4·8% [4·1-5·5]; p<0·0001), MIC (2·8 [2·0-3·7]; p<0·0001), and LIC (3·8 [1·3-6·7%]; p<0·0001) settings. The SPI contains 23 indicators that are globally applicable, relevant across different system stressors, vary at a subnational level, and are collectable by front-line teams. In the case study of COVID-19, a higher SPI was associated with an increased planned surgical volume ratio independent of country income status, COVID-19 burden, and hospital type. Hospitals should perform annual self-assessment of their surgical preparedness to identify areas that can be improved, create resilience in local surgical systems, and upscale capacity to address elective surgery backlogs. National Institute for Health Research (NIHR) Global Health Research Unit on Global Surgery, NIHR Academy, Association of Coloproctology of Great Britain and Ireland, Bowel Research UK, British Association of Surgical Oncology, British Gynaecological Cancer Society, and Medtronic.

Identification of the ideal recruitment situation in pandemic research: learning from the RECOVERY trial in Northern England: a qualitative study

BackgroundIn early 2020, little was known about treatments for COVID-19. The UK responded by initiating a call for research, leading to the formation of the National Institute for Health Research...