National Institute For Health Research Research Articles

Comparative physiological effects of antipsychotic drugs in children and young people: a network meta-analysis

The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the effects of various antipsychotic medications on physiological variables in children and adolescents with neuropsychiatric and neurodevelopmental conditions. For this network meta-analysis, we searched Medline, EMBASE, PsycINFO, Web of Science, and Scopus from database inception until Dec 22, 2023, and included randomised controlled trials comparing antipsychotics with placebo in children or adolescents younger than 18 years with any neuropsychiatric and neurodevelopmental condition. Primary outcomes were mean change from baseline to end of acute treatment in bodyweight, BMI, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, prolactin, heart rate, systolic blood pressure (SBP), and QT interval corrected for heart rate (QTc) for patients receiving either active treatment or placebo. For multigroup trials reporting several doses, we calculated a summary value for each physiological variable for all doses. After transitivity assessment, we fitted frequentist random-effects network meta-analyses for all comparisons in the network. A Kilim plot was used to summarise the results for all treatments and outcomes, providing information regarding the strength of the statistical evidence of treatment effects, using p values. Network heterogeneity was assessed with τ, risk of bias of individual trials was assessed with the Cochrane Collaboration's Tool for Assessing Risk of Bias, and the credibility of findings from each network meta-analysis was assessed with the Confidence in Network Meta-Analysis (CINEMA) app. This study is registered on PROSPERO (CRD42021274393). Of 6676 studies screened, 47 randomised controlled trials were included, which included 6500 children (mean age 13·29 years, SD 2·14) who received treatment for a median of 7 weeks (IQR 6-8) with either placebo (n=2134) or one of aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, pimozide, quetiapine, risperidone, or ziprasidone (n=4366). Mean differences for bodyweight change gain compared with placebo ranged from -2·00 kg (95% CI -3·61 to -0·39) with molindone to 5·60 kg (0·27 to 10·94) with haloperidol; BMI -0·70 kg/m2 (-1·21 to -0·19) with molindone to 2·03 kg/m2 (0·51 to 3·55) with quetiapine; total cholesterol -0·04 mmol/L (-0·39 to 0·31) with blonanserin to 0·35 mmol/L (0·17 to 0·53) with quetiapine; LDL cholesterol -0·12 mmol/L (-0·31 to 0·07) with risperidone or paliperidone to 0·17 mmol/L (-0·06 to 0·40) with olanzapine; HDL cholesterol 0·05 mmol/L (-0·19 to 0·30) with quetiapine to 0·48 mmol/L (0·18 to 0·78) with risperidone or paliperidone; triglycerides -0·03 mmol/L (-0·12 to 0·06) with lurasidone to 0·29 mmol/L (0·14 to 0·44) with olanzapine; fasting glucose from -0·09 mmol/L (-1·45 to 1·28) with blonanserin to 0·74 mmol/L (0·04 to 1·43) with quetiapine; prolactin from -2·83 ng/mL (-8·42 to 2·75) with aripiprazole to 26·40 ng/mL (21·13 to 31·67) with risperidone or paliperidone; heart rate from -0·20 bpm (-8·11 to 7·71) with ziprasidone to 12·42 bpm (3·83 to 21·01) with quetiapine; SBP from -3·40 mm Hg (-6·25 to -0·55) with ziprasidone to 10·04 mm Hg (5·56 to 14·51) with quetiapine; QTc from -0·61 ms (-1·47 to 0·26) with pimozide to 0·30 ms (-0·05 to 0·65) with ziprasidone. Children and adolescents show varied but clinically significant physiological responses to individual antipsychotic drugs. Treatment guidelines for children and adolescents with a range of neuropsychiatric and neurodevelopmental conditions should be updated to reflect each antipsychotic drug's distinct profile for associated metabolic changes, alterations in prolactin, and haemodynamic alterations. UK Academy of Medical Sciences, Brain and Behaviour Research Foundation, UK National Institute of Health Research, Maudsley Charity, the Wellcome Trust, Medical Research Council, National Institute of Health and Care Research Biomedical Centre at King's College London and South London and Maudsley NHS Foundation Trust, the Italian Ministry of University and Research, the Italian National Recovery and Resilience Plan, and Swiss National Science Foundation.

SMIM1 absence is associated with reduced energy expenditure and excess weight

Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments. We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan. We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure. This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them. This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.

The National Center for Complementary and Integrative Health: Priorities for Cannabis and Cannabinoid Research.

The National Center for Complementary and Integrative Health (NCCIH), which is part of the US National Institutes of Health (NIH), has a broad interest in studying the biologic activities of natural products, especially those for which compelling evidence from preclinical research suggests biologic activities that may be beneficial to health or have a potential role in disease treatment, as well as products used extensively by the American public. As of 2023, use of cannabis for medical purposes is legal in 38 states and Washington, D.C. Such use continues to climb generally without sufficient knowledge regarding risks and benefits. In keeping with NCCIH's natural product research priorities and recognizing this gap in knowledge, NCCIH formally launched a research program in 2019 to expand research on the possible benefits for pain management of certain substances found in cannabis: minor cannabinoids and terpenes. This Viewpoint provides additional details and the rationale for this research priority at NCCIH. In addition, NCCIH's efforts and initiatives to facilitate and coordinate an NIH research agenda focused on cannabis and cannabinoid research are described. SIGNIFICANCE STATEMENT: Use of cannabis for purported medical purposes continues to increase despite insufficient knowledge regarding risks and benefits. Research is needed to help health professionals and patients make knowledgeable decisions about using cannabis and cannabinoids for medical purposes. The National Center for Complementary and Integrative Health, along with other NIH Institutes, Centers, and Offices, is expanding study on the safety, efficacy, and harms of cannabis-a complex mixture of phytochemicals that needs to be studied alone and in combination.

Associations between BMI and hospital resource use in patients hospitalised for COVID-19 in England: a community-based cohort study

Excess weight is a major risk factor for severe disease after infection with SARS-CoV-2. However, the effect of BMI on COVID-19 hospital resource use has not been fully quantified. This study aimed to identify the association between BMI and hospital resource use for COVID-19 admissions with the intention of informing future national hospital resource allocation. In this community-based cohort study, we analysed patient-level data from 57 415 patients admitted to hospital in England with COVID-19 between April 1, 2020, and Dec 31, 2021. Patients who were aged 20-99 years, had been registered with a general practitioner (GP) surgery that contributed to the QResearch database for the whole preceding year (2019) with at least one BMI value measured before April 1, 2020, available in their GP record, and were admitted to hospital for COVID-19 were included. Outcomes of interest were duration of hospital stay, transfer to an intensive care unit (ICU), and duration of ICU stay. Costs of hospitalisation were estimated from these outcomes. Generalised linear and logit models were used to estimate associations between BMI and hospital resource use outcomes. Patients living with obesity (BMI >30·0 kg/m2) had longer hospital stays relative to patients in the reference BMI group (18·5-25·0 kg/m2; IRR 1·07, 95% CI 1·03-1·10); the reference group had a mean length of stay of 8·82 days (95% CI 8·62-9·01). Patients living with obesity were more likely to be admitted to ICU than the reference group (OR 2·02, 95% CI 1·86-2·19); the reference group had a mean probability of ICU admission of 5·9% (95% CI 5·5-6·3). No association was found between BMI and duration of ICU stay. The mean cost of COVID-19 hospitalisation was £19 877 (SD 17 918) in the reference BMI group. Hospital costs were estimated to be £2736 (95% CI 2224-3248) higher for patients living with obesity. Patients admitted to hospital with COVID-19 with a BMI above the healthy range had longer stays, were more likely to be admitted to ICU, and had higher health-care costs associated with hospital treatment of COVID-19 infection as a result. This information can inform national resource allocation to match hospital capacity to areas where BMI profiles indicate higher demand. National Institute for Health Research.

Designing studies and reviews to produce informative, trustworthy evidence about complex interventions in rehabilitation: a narrative review and commentary.

According to Cochrane Rehabilitation's recently published definition for research purposes, rehabilitation is inherently complex. Rehabilitation teams frequently implement multiple strategies concurrently, draw on input from a range of different health professionals, target multiple outcomes, and personalize therapeutic plans. The success of rehabilitation lies not only in the specific therapies employed, but also in how they are delivered, when they are delivered, and the capability and willingness of patients to engage in them. In 2021, the UK Medical Research Council (MRC) and the National Institute of Health Research (NIHR) released the second major update of its framework for developing and evaluating complex interventions. This framework has direct relevance to the development and implementation of evidence-based practice in the field of rehabilitation. While previous iterations of this framework positioned complex interventions as anything that involved multiple components, multiple people, multiple settings, multiple targets of effect, and behavior change, this latest framework expanded on this concept of complexity to also include the characteristics and influence of the context in which interventions occur. The revised MRC-NIHR framework presents complex intervention research as comprising the following four inter-related and overlapping phases: 1) development or identification of the intervention; 2) feasibility; 3) evaluation; and 4) implementation, with different methods and tools required to address each of these phases. This paper provides an overview of the MRC-NIHR framework and its application to rehabilitation, with examples from past research. Rehabilitation researchers are encouraged to learn about the MRC-NIHR framework and its application. Funders of rehabilitation research are also encouraged to place greater emphasis on supporting studies that involve the right design to address key uncertainties in rehabilitation clinical practice. This will require investment into a broader range of types of research than simply individual-level randomized controlled trials. Rehabilitation research can both learn from and contribute to future iterations of the MRC-NIHR framework as it is an excellent environment for exploring complexity in clinical practice.

Are we bridging the gap? A ten-year probe into NIH grants for early-career and independent investigators in oncology.

9010 Background: Ongoing gender disparities persist within National Institutes of Health (NIH) funding, specifically evident in NIH R01 grants within Oncology. A crucial aspect of addressing this issue involves a comprehensive investigation of discrepancies between early-career and independent principal investigators (PI). Here we present a ten-year analysis of gender distribution of early career vs. independent grants in the NIH under the field of Oncology. Methods: We implemented an R script utilizing NIH rePORTER, tidyverse, and janitor libraries for data retrieval. This script defined fields for retrieval which looped over fiscal years 2012 to 2022. The script executed API requests with criteria that included fiscal years, activity codes, and search terms that are relevant to oncology to extract grants from NIH rePORTER. We defined the early-career grant category to encompass the top 3 most active NIH K and F grants (K01,K08,K23, F31,F32,F33). In contrast, the independent research grant category included the top 3 most active NIH R grants (R01,R21,R35). The gender library was used to predict the gender of each principal investigator (PI) based on their first name. Ggplot and gtsummary packages were employed for data visualization and statistical analysis, automatically selecting appropriate tests based on data type. Results: Over the fiscal years 2012 to 2022, a total of 44,545 active early-career grants were funded by the NIH. Females (n = 24,243: 54.4% [95% CI:53.7%,55.0%]) surpassed their male counterparts (n = 20,302: 45.6% [95% CI:44.9%, 46.3%]) by holding more active early-career research grants. From 2012 to 2022, there was a significant upward trend that was noted in active early-career grants funded to females (1,818 to 2,969, p < 0.01). Similarly, males exhibited a noteworthy increase in these grants when comparing 2012 to 2022 (1,780 to 1,986, p < 0.001). Despite both genders experiencing an uptrend in active early-career NIH grants, females demonstrated a 48.3% increase, while males experienced a more modest 11.5% increase. In comparison, a total of 236,804 active independent research NIH grants were disbursed in the NIH R category from 2012 to 2022. Females (78,439: 33.1% [95% CI:32.7%,33.4%]) had fewer active independent NIH research grants compared to males (158,365: 66.9% [95% CI:66.6%,67.1%]). Males observed a 6.4% increase in independent NIH grants, rising from 14,419 to 15,343, while females exhibited a notable 48% increase, expanding from 6,193 to 9,195, from 2012 to 2022. Conclusions: In the realm of oncology, gender disparities are not evident among early career investigators as there were 53.7% of early career grants funded to females over the decade. Conversely, females accounted for only 33.3% of independent research grants. These observations emphasize the importance for targeted interventions to foster equal opportunities within the field of Oncology.

Trajectories of biomedical research leading to Nobel Prize-winning discoveries.

Significant advancements in public health come from scientific discoveries, but more are needed to meet the ever-growing societal needs. Examining the best practices of outstanding scientists may help develop future researchers and lead to more discoveries. This study compared the comprehensive work of 49 Nobel laureates in Physiology or Medicine from 2000 to 2019 to a matched control of National Institutes of Health (NIH)-funded biomedical investigators. Our unique data set, comprising 11,737 publications, 571 US patents, and 1693 NIH research awards produced by pre-Nobel laureates, was compared to a similar data set of control researchers. Compared to control researchers, pre-Nobel laureates produce significantly more publications annually (median = 5.66; interquartile range [IQR] = 5.16); significantly fewer coauthors per publication (median = 3.32; IQR = 1.95); consistently higher Journal Impact Factor publications (median = 12.04; IQR = 6.83); and substantially more patents per researcher (median = 5; IQR = 14). Such differences arose from nearly identical cumulative NIH award budgets of pre-Nobel laureates (median $25.3M) and control researchers. Nobel laureates are neither hyper-prolific (>72 papers per year) nor hyper-funded (>$100M cumulative). An academic age-specific trajectory graph allows aspiring researchers to compare their productivity and collaboration patterns to those of pre-Nobel laureates.

Primary care for cancer survivors: a review of national institutes of health-funded grants 2017-2022.

To describe the characteristics of National Institutes of Health (NIH) grants on primary care cancer research in cancer survivorship funded over the past 5years. Research project grants (RPG) funded during Fiscal Year (FY) 2017 to 2022 focused on cancer survivorship were identified using a text mining algorithm of words from the NIH Research, Condition, and Disease Categorization (RCDC) thesaurus with survivorship-relevant terms. Grants were then reviewed and double-coded to identify those that were carried out in a primary care setting, targeted primary care providers, or had primary care providers in the study team. A total of 24 grants were identified; 23 were funded by the National Cancer Institute and one was funded by the National Institute on Minority Health and Health Disparities. The majority were funded under the R01 mechanism (70.8%) and led by established investigators. Most were interventional design (91.7%), including both survivors and providers (79.2%), and focused care coordination or healthcare utilization (91.7%). Grants focused on primary care cancer survivorship are uncommon in the NIH portfolio. For the over 18 million cancer survivors in the USA, being cared for in a primary care setting is common. Yet, NIH-funded research on primary care cancer survivorship is sparse.

Efficacy and cost-effectiveness of a digital guided self-management intervention to support transition from intensive care to community care in anorexia nervosa (TRIANGLE): pragmatic multicentre randomised controlled trial and economic evaluation

There is uncertainty regarding how best to support patients with anorexia nervosa following inpatient or day care treatment. This study evaluated the impact of augmenting intensive treatment with a digital, guided, self-management intervention (ECHOMANTRA) for patients with anorexia nervosa and their carers. In this pragmatic multicentre randomised controlled trial and economic evaluation, patients with a diagnosis of anorexia nervosa or atypical anorexia nervosa, aged 16+ and attending one of the 31 inpatient or day-patient services in the UK were randomised with one of their carers to receive ECHOMANTRA plus treatment as usual (TAU), or TAU alone. ECHOMANTRA was hosted on a digital platform and included a workbook, recovery-oriented video-clips and online facilitated groups (patients only, carers only, joint patient-carer). Participants were randomised on a 1:1 ratio using a minimisation algorithm to stratify by site (N=31) and severity (defined by BMI <15 and≥15kg/m2 at baseline). The primary outcome was patient depression, anxiety, and stress at 12months. Primary and secondary outcomes were compared between trial arms on an intention-to-treat basis (ITT). This trial is registered with the ISRSTN registry, ISRCTN14644379. Between July 01, 2017 and July 20, 2020, 371 patient-carer dyads were enrolled and randomly assigned to ECHOMANTRA+TAU (N=185) or TAU alone (N=186). There were no significant differences between trial arms with regards to the primary outcome (completed by N=143 patients in the TAU group, Mean=61.7, SD=29.4 and N=109 patients in the ECHOMANTRA+TAU group, Mean=58.3, SD=26.9; estimated mean difference 0.48 points; 95% CI-5.36 to 6.33; p=0.87). Differences on secondary outcomes were small and non-significant (standardised effect size estimates ≤0.25). Five patients died (2 from suicide and 3 from physical complications) over the course of the trial, and this was unrelated to their participation in the study. ECHOMANTRA added to TAU was not superior to TAU alone in reducing patient depression, anxiety, and stress symptoms. This may be explained by limited engagement with the intervention materials and changes in usual care practices since the beginning of the trial. National Institute for Health Research (NIHR), under its Health Technology Assessment Programme (HTA) Programme (Grant Reference Number 14/68/09). NIHR Maudsley Biomedical Research Centre (BRC), South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, and King's College London. NIHR Applied Research Collaboration South London (NIHR ARC South London) at King's College Hospital NHS Foundation Trust.

Investigating the Genetic Diversity of Hepatitis Delta Virus in Hepatocellular Carcinoma (HCC): Impact on Viral Evolution and Oncogenesis in HCC.

Hepatitis delta virus (HDV), an RNA virus with two forms of the delta antigen (HDAg), relies on hepatitis B virus (HBV) for envelope proteins essential for hepatocyte entry. Hepatocellular carcinoma (HCC) ranks third in global cancer deaths, yet HDV's involvement remains uncertain. Among 300 HBV-associated HCC serum samples from Taiwan's National Health Research Institutes, 2.7% (8/300) tested anti-HDV positive, with 62.7% (5/8) of these also HDV RNA positive. Genotyping revealed HDV-2 in one sample, HDV-4 in two, and two samples showed mixed HDV-2/HDV-4 infection with RNA recombination. A mixed-genotype infection revealed novel mutations at the polyadenylation signal, coinciding with the ochre termination codon for the L-HDAg. To delve deeper into the possible oncogenic properties of HDV-2, the predominant genotype in Taiwan, which was previously thought to be less associated with severe disease outcomes, an HDV-2 cDNA clone was isolated from HCC for study. It demonstrated a replication level reaching up to 74% of that observed for a widely used HDV-1 strain in transfected cultured cells. Surprisingly, both forms of HDV-2 HDAg promoted cell migration and invasion, affecting the rearrangement of actin cytoskeleton and the expression of epithelial-mesenchymal transition markers. In summary, this study underscores the prevalence of HDV-2, HDV-4, and their mixed infections in HCC, highlighting the genetic diversity in HCC as well as the potential role of both forms of the HDAg in HCC oncogenesis.

Bed-rest and exercise remobilisation: concurrent adaptations in muscle glucose and protein metabolism

Bed rest (BR) of only a few days duration reduces muscle protein synthesis and induces skeletal muscle atrophy and insulin resistance, but the scale and juxtaposition of these events has not been investigated concurrently in the same individuals. Moreover, the impact of short-term exercise-supplemented remobilisation (ESR) on muscle volume, protein turnover and leg glucose uptake (LGU) in humans is unknown. Ten healthy males (24±1 years, body mass index (BMI) 22.7±0.6) underwent 3 days of BR, followed immediately by 3 days of ESR consisting of 5x30 maximal voluntary single leg isokinetic knee-extensions at 90o/sec each day. An isoenergetic diet was maintained throughout the study (30% fat,15% protein, 55% carbohydrate). Resting LGU was calculated from arteriovenous-venous difference across the leg and leg blood flow during the steady-state of a 3 hr hyperinsulinaemic euglycaemic clamp (60 mU/m2/min) measured pre BR, post BR and after remobilisation. Glycogen content was measured in Vastus Lateralis muscle biopsy samples obtained before and after each clamp. Leg muscle volume (LMV) was measured using magnetic resonance imaging pre BR, post BR and after remobilisation. Cumulative myofibrillar protein fractional synthesis rate (FSR), and whole-body muscle protein breakdown (MPB) were measured over the course of BR and remobilisation using deuterium oxide and 3-methylhistidine stable isotope tracers that were administered orally. Compared with pre BR, there was a 45% decline in insulin-stimulated LGU (p&lt;0.05) after BR, which was paralleled by a reduction in insulin stimulated leg blood flow (p&lt;0.01) and removal of insulin stimulated muscle glycogen storage. These events were accompanied by a 43% reduction in myofibrillar protein FSR (p&lt;0.05) and a 2.5% decrease in LMV (p&lt;0.01) during BR, along with a 30% decline in whole-body muscle myofibrillar protein breakdown after 2 days BR (p&lt;0.05). Myofibrillar protein FSR and LMV were restored by 3 days of ERS (p&lt;0.01, p&lt;0.01; respectively), but not by ambulation alone. However, insulin stimulated LGU and muscle glycogen storage were not restored by ESR. Three days of BR caused concurrent reductions in LMV, myofibrillar protein FSR, myofibrillar protein breakdown and insulin stimulated LGU, leg blood flow and muscle glycogen storage in healthy, young volunteers. Resistance ESR restored LMV and myofibrillar protein FSR, but LGU and muscle glycogen storage remained depressed, highlighting divergences in muscle fuel and protein metabolism. Furthermore, ambulation alone did not restore LMV and myofibrillar protein FSR in the non-exercised contralateral limb, emphasising the importance of exercise rehabilitation following even short-term BR. This study was supported by the Biotechnology and Biological Sciences Research Council (BB/P005004/1), the Centre for Sport, Exercise and Osteoarthritis Research Versus Arthritis (grant no. 21595), and the National Institute of Health Research (NIHR) Nottingham Biomedical Research Centre. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Dialysis and Cardiovascular Disease in Patients With Stage 5 Chronic Kidney Disease.

No studies have reported the long-term outcomes of initiating sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with estimated glomerular filtration rates less than 20 mL/min/1.73 m2 to predialysis. To compare the risk for dialysis, cardiovascular events, and death between SGLT2i users and nonusers in patients with type 2 diabetes (T2D) and stage 5 chronic kidney disease (CKD). Target trial emulation study. Taiwan's National Health Insurance Research Database (NHIRD). By applying sequential target trial emulation principle, 23 854 SGLT2i users and 23 892 SGLT2i nonusers were selected from the NHIRD for patients with T2D and stage 5 CKD from 1 May 2016 to 31 October 2021. Conditional Cox proportional hazards models were used to compare the risks for dialysis, hospitalization for heart failure, acute myocardial infarction (AMI), diabetic ketoacidosis (DKA), acute kidney injury (AKI), and all-cause mortality between SGLT2i users and nonusers. In the intention-to-treat model, compared with no SGLT2i use, SGLT2i use was associated with lower risks for dialysis (hazard ratio [HR], 0.34 [95% CI, 0.27 to 0.43]), hospitalization for heart failure (HR, 0.80 [CI, 0.73 to 0.86]), AMI (HR, 0.61 [CI, 0.52 to 0.73]), DKA (HR, 0.78 [CI, 0.71 to 0.85]), and AKI (HR, 0.80 [CI, 0.70 to 0.90]), but there was no difference in the risk for all-cause mortality (HR, 1.11 [CI, 0.99 to 1.24]). The Kaplan-Meier curves and subgroup analyses also showed that initiation of an SGLT2i in stage 5 CKD was associated with a lower risk for long-term dialysis than no SGLT2i use. This result may not apply to patients without T2D. This emulated target trial showed that SGLT2i use was associated with a lower risk for dialysis, cardiovascular events, DKA, and AKI than no SGLT2i use in patients with T2D and stage 5 CKD. National Health Research Institutes, Taiwan.

Trends in financial payments from industry to US cancer centers, 2014-2021.

Industry payments to US cancer centers are poorly understood. US National Cancer Institute (NCI)-designated comprehensive cancer centers were identified (n = 51). Industry payments to NCI-designated comprehensive cancer centers from 2014 to 2021 were obtained from Open Payments and National Institutes of Health (NIH) grant funding from NIH Research Portfolio Online Reporting Tools (RePORT). Given our focus on cancer centers, we measured the subset of industry payments related to cancer drugs specifically and the subset of NIH funding from the NCI. Despite a pandemic-related decline in 2020-2021, cancer-related industry payments to NCI-designated comprehensive cancer centers increased from $482 million in 2014 to $972 million in 2021. Over the same period, NCI research grant funding increased from $2 481 million to $2 724 million. The large majority of nonresearch payments were royalties and licensing payments. Industry payments to NCI-designated comprehensive cancer centers increased substantially more than NCI funding in recent years but were also more variable. These trends raise concerns regarding the influence and instability of industry payments.

Understanding factors influencing the adoption of open science practices among Malaysia's NIH researchers

Background Open science practices, including research data sharing and reuse, are crucial for advancing scientific knowledge. However, the extent to which Malaysia's National Institutes of Health (NIH) researchers participate in open science remains a subject of inquiry. Methods This study employs an exploratory sequential mixed-method approach to investigate the factors influencing Malaysia NIH researchers’ participation in open science practices. The research combines in-depth interviews with key managers and administrators from NIH and a quantitative survey distributed to the researchers. Through in-depth interviews, administrators provide insights into the institute's perspective on open science. At the same time, the survey explores researchers’ views on factors influencing their participation in open science and how these factors influence the data-sharing practices at the institute. Results The findings reveal key factors that influence the participation of Malaysia NIH researchers in open science, shedding light on both motivating factors and barriers. The study identifies strategies to promote researchers’ involvement in open science practices through data sharing and highlights the practical implications for the Malaysia NIH and the broader scientific community. Conclusion Understanding these factors is essential for enhancing open science participation and fostering a culture of data sharing in Malaysia's scientific research landscape. The study suggests strategies for promoting open science practices and calls for collaborative efforts to maximise the benefits of data sharing and reuse.

P080 Supporting shared decision-making about osteoporosis medicines: Combining multiple methods to develop the prototype iFraP intervention

Abstract Background/Aims Shared decision-making (SDM) is a joint process in which a person and healthcare professional work together to reach decisions about care. The iFraP (Improving uptake of Fracture Prevention drug treatments) intervention comprises computerised decision aid (DA), Fracture Liaison Service (FLS) clinician training package, and information resources to support SDM about osteoporosis medicines. This abstract details our multi-method approach to develop this intervention. Methods Intervention development was underpinned by the Medical Research Council guidelines for development of complex interventions. Four studies guided intervention prototype development, including (1) an evidence synthesis of existing osteoporosis DAs to examine quality and effectiveness; (2) a review of patient information about osteoporosis to evaluate quality and optimal language for talking about osteoporosis; (3) a Delphi consensus survey with patients, carers, and health professionals to gain consensus on intervention content, informed by an evidence review of relevant clinical guidelines and behavioural theories; (4) and focus groups and interviews with patients recently attending FLS, FLS clinicians and general practitioners (GPs) to explore current FLS practice, and barriers and facilitators to change. Expert stakeholders and public contributors informed each sub-study. Results Studies one and two informed design of the iFraP computerised DA. Evidence reviews of existing osteoporosis DAs and patient information found that they did not meet patient needs and identified poor readability, variable quality, and unbalanced and confusing content. Public contributors preferred DAs which were individualised, and together with expert stakeholders, supported the development of understandable explanations of osteoporosis and osteoporosis medicines to include in iFraP resources. Study three identified essential components of the FLS consultation which directly informed DA content. Study four identified the need for complementary iFraP information resources, training, and potential barriers to iFraP DA use. Patients expressed that they did not feel adequately prepared for their FLS consultation, leading to the development of an enhanced leaflet to accompany their FLS appointment letter. Patients, FLS clinicians, and GPs all expressed the need for a patient-friendly individualised summary of the FLS consultation, to facilitate consistent information across services and reinforce FLS messaging. This finding informed development of the iFraP Bone Health Record, an individualised, easy-read PDF print-out of the iFraP DA. FLS clinicians identified training needs relating to communicating risk, involving patients in decisions and clinical decision-making. Barriers to use included concerns that the DA would increase consultation duration, and that SDM may undermine their goal to facilitate medicine adherence. Identified barriers to use and training needs informed the content and delivery of the interactive eLearning and role play session, with consideration of theoretically-informed behaviour change techniques. Conclusion The iFraP complex intervention development work demonstrates the use of multiple methods to develop an evidence-based and theoretically-driven intervention in-preparation for testing. Disclosure L. Bullock: None. J. Fleming: None. E.M. Clark: None. S. Leyland: None. S. Thomas: Grants/research support; ST owns Prescribing Decision Support Ltd that developed the iFraP decision aid. C. Gidlow: None. T.W. O'Neill: Grants/research support; TON is supported by the NIHR Manchester Biomedical Research Centre. C.P. Iglesias-Urrutia: None. A. Hawarden: Grants/research support; AH is funded by a Versus Arthritis Clinical Research Fellowship (reference 22726). F. Manning: None. J. Protheroe: None. J. Lefroy: None. S. Ryan: None. R. Horne: None. C.D. Mallen: Grants/research support; CM is funded by the NIHR Applied Research Collaboration West Midlands and the NIHR School for Primary Care Research. C. Jinks: Grants/research support; CJ is part funded by NIHR Applied Research Collaboration (ARC) West Midlands. Z. Paskins: Consultancies; ZP has received consultancy fees from UCB Pharma. Grants/research support; ZP is funded by the National Institute for Health Research (NIHR) [Clinician Scientist Award (CS-2018-18-ST2-010)/NIHR Academy].

P155 Gene expression in hypermobility and the role of inflammation

Abstract Background/Aims Hypermobile conditions, including Ehlers-Danlos syndrome and joint hypermobility syndrome, encompass a broad spectrum of heterogenous clinical entities characterised by excessive range of joint movements and variable extra-articular features. The etiological basis of these conditions is thought to relate to abnormal collagen assembly, which impairs the structural integrity of connective tissue, although precise mechanisms remain both debated and incompletely understood. Despite the established strong heritability of hypermobility, a definitive genetic cause remains unidentifiable in most hypermobile patients, highlighting the need to further characterize the genetic landscape of hypermobile conditions. In this study, we therefore employ transcriptomic analysis as an alternate means of elucidating the genetic basis of hypermobility. Methods We tested for the effects of hypermobility on gene expression, at baseline and following an inflammatory challenge, by re-analysing existing transcriptomic data gathered from healthy subjects and patients with fibromyalgia and chronic fatigue using total RNA sequencing of blood samples (Illumina NextSeq 500). From each participant, two blood samples were taken on separate occasions: one after a saline injection and the other after an inflammatory challenge, the typhoid vaccination, in a cross-over design. Participants were assigned to hypermobile or non-hypermobile conditions in accordance with criterion 1: generalized joint hypermobility of the Diagnostic Criteria for Hypermobile Ehlers-Danlos Syndrome (hEDS) produced by the International Consortium on Ehlers-Danlos Syndromes &amp; Related disorders. Differential gene expression analysis comparing hypermobile and non-hypermobile participants was performed using EdgeR software in R studio. Baseline differences were determined by comparing post-saline samples between groups. Differential responses to the inflammatory challenge were detected by comparison of post-typhoid samples between groups. Gene ontology on differentially expressed genes was performed using DAVID’s Functional Annotation Clustering tool. Results We found 288 differentially expressed genes post-saline (i.e at baseline) and 1113 post-typhoid at p &amp;lt; 0.05 although none passed false discovery rate. At baseline, differentially expressed genes were significantly enriched for nuclear, endoplasmic reticulum, and microtubular genes (enrichment score = 2.96, 2.02, 1.3 respectively); and post-typhoid, for 24 clusters, the three most significant being synaptic, ion transport, and plasma membrane genes (enrichment score = 11.34, 8.71, and 7.3 respectively). Conclusion These data demonstrate distinct patterns of gene expression, both at baseline and during inflammation, which implicate potential biological pathways in the pathophysiology of hypermobility. These results also contribute to a growing understanding of the genetic basis of hypermobility and may inform future higher-powered studies to validate our findings. Disclosure J. Porter: None. M. Amato: None. K. Themelis: None. H. Critchley: None. S. Newbury: None. K. Davies: None. N. Harrison: None. B. Towler: None. J. Eccles: Grants/research support; J.E. has received funding from Versus Arthritis, National Institute for Health Research and the Fibroduck Foundation.

“I am in favour of organ donation, but I feel you should opt-in”—qualitative analysis of the #options 2020 survey free-text responses from NHS staff toward opt-out organ donation legislation in England

BackgroundIn May 2020, England moved to an opt-out organ donation system, meaning adults are presumed to be an organ donor unless within an excluded group or have opted-out. This change aims to improve organ donation rates following brain or circulatory death. Healthcare staff in the UK are supportive of organ donation, however, both healthcare staff and the public have raised concerns and ethical issues regarding the change. The #options survey was completed by NHS organisations with the aim of understanding awareness and support of the change. This paper analyses the free-text responses from the survey.MethodsThe #options survey was registered as a National Institute of Health Research (NIHR) portfolio trial [IRAS 275992] 14 February 2020, and was completed between July and December 2020 across NHS organisations in the North-East and North Cumbria, and North Thames. The survey contained 16 questions of which three were free-text, covering reasons against, additional information required and family discussions. The responses to these questions were thematically analysed.ResultsThe #options survey received 5789 responses from NHS staff with 1404 individuals leaving 1657 free-text responses for analysis. The family discussion question elicited the largest number of responses (66%), followed by those against the legislation (19%), and those requiring more information (15%). Analysis revealed six main themes with 22 sub-themes.ConclusionsThe overall #options survey indicated NHS staff are supportive of the legislative change. Analysis of the free-text responses indicates that the views of the NHS staff who are against the change reflect the reasons, misconceptions, and misunderstandings of the public. Additional concerns included the rationale for the change, informed decision making, easy access to information and information regarding organ donation processes. Educational materials and interventions need to be developed for NHS staff to address the concepts of autonomy and consent, organ donation processes, and promote family conversations. Wider public awareness campaigns should continue to promote the positives and refute the negatives thus reducing misconceptions and misunderstandings.Trial registrationNational Institute of Health Research (NIHR) [IRAS 275992].

Changes in hospital mortality in patients with cancer during the COVID-19 pandemic (ISARIC-CCP-UK): a prospective, multicentre cohort study

Patients with cancer are at greater risk of dying from COVID-19 than many other patient groups. However, how this risk evolved during the pandemic remains unclear. We aimed to determine, on the basis of the UK national pandemic protocol, how factors influencing hospital mortality from COVID-19 could differentially affect patients undergoing cancer treatment. We also examined changes in hospital mortality and escalation of care in patients on cancer treatment during the first 2 years of the COVID-19 pandemic in the UK. We conducted a prospective cohort study of patients aged older than 19 years and admitted to 306 health-care facilities in the UK with confirmed SARS-CoV-2 infection, who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol (CCP) across the UK from April 23, 2020, to Feb 28, 2022; this analysis included all patients in the complete dataset when the study closed. The primary outcome was 30-day in-hospital mortality, comparing patients on cancer treatment and those without cancer. The study was approved by the South Central-Oxford C Research Ethics Committee in England (Ref: 13/SC/0149) and the Scotland A Research Ethics Committee (Ref 20/SS/0028), and is registered on the ISRCTN Registry (ISRCTN66726260). 177 871 eligible adult patients either with no history of cancer (n=171 303) or on cancer treatment (n=6568) were enrolled; 93 205 (52·4%) were male, 84 418 (47·5%) were female, and in 248 (13·9%) sex or gender details were not specified or data were missing. Patients were followed up for a median of 13 (IQR 6-21) days. Of the 6568 patients receiving cancer treatment, 2080 (31·7%) died at 30 days, compared with 30 901 (18·0%) of 171 303 patients without cancer. Patients aged younger than 50 years on cancer treatment had the highest age-adjusted relative risk (hazard ratio [HR] 5·2 [95% CI 4·0-6·6], p<0·0001; vs 50-69 years 2·4 [2·2-2·6], p<0·0001; 70-79 years 1·8 [1·6-2·0], p<0·0001; and >80 years 1·5 [1·3-1·6], p<0·0001) but a lower absolute risk (51 [6·7%] of 763 patients <50 years died compared with 459 [30·2%] of 1522 patients aged >80 years). In-hospital mortality decreased for all patients during the pandemic but was higher for patients on cancer treatment than for those without cancer throughout the study period. People with cancer have a higher risk of mortality from COVID-19 than those without cancer. Patients younger than 50 years with cancer treatment have the highest relative risk of death. Continued action is needed to mitigate the poor outcomes in patients with cancer, such as through optimising vaccination, long-acting passive immunisation, and early access to therapeutics. These findings underscore the importance of the ISARIC-WHO pandemic preparedness initiative. National Institute for Health Research and the Medical Research Council.

Incidence of urinary infections and pharmacological sensitivity in elective urine samples in a prospective cohort from Luanda, Angola

This prospective cohort study evaluated 107 urine samples from patients suspected of urinary tract infection (UTI) treated at Cajueiros General Hospital in Angola from January to March 2023. Inclusion criteria involved obtaining urine samples for clinical examinations from adult patients with suspected UTI, regardless of gender, age, or previous clinical condition. The samples were transported to the reference laboratory of the National Institute of Health Research for microbiological evaluation and antibiotic sensitivity testing using the VITEK 2 system. Of the 107 patients evaluated, 39.3% (n= 42) showed bacterial growth in their urine. Escherichia coli was the predominant pathogen (23.8%), followed by Sphingomonas paucimobilis, Pseudomonas luteola, and Klebsiella pneumoniae. Antimicrobial resistance was observed, with ampicillin (90.5%) being the most resistant, while imipenem (95.2%) and ertapenem (90.5%) exhibited high sensitivity. Statistical analysis revealed common clinical characteristics, such as fever (61.7%) and dysuria (73.8%). This study provides a comprehensive understanding of microbial ecology in urinary infections, highlighting the prevalence of pathogens and antibiotic resistance patterns in a specific patient population in Angola. Importantly, this research represents the first prospective study of its kind in Angola.

Machine Learning-based Analysis of Publications Funded by the National Institutes of Health's Initial COVID-19 Pandemic Response.

The National Institutes of Health (NIH) mobilized more than $4 billion in extramural funding for the COVID-19 pandemic. Assessing the research output from this effort is crucial to understanding how the scientific community leveraged federal funding and responded to this public health crisis. NIH-funded COVID-19 grants awarded between January 2020 and December 2021 were identified from NIH Research Portfolio Online Reporting Tools Expenditures and Results using the "COVID-19 Response" filter. PubMed identifications of publications under these grants were collected and the NIH iCite tool was used to determine citation counts and focus (eg, clinical, animal). iCite and the NIH's LitCOVID database were used to identify publications directly related to COVID-19. Publication titles and Medical Subject Heading terms were used as inputs to a machine learning-based model built to identify common topics/themes within the publications. We evaluated 2401 grants that resulted in 14 654 publications. The majority of these papers were published in peer-reviewed journals, though 483 were published to preprint servers. In total, 2764 (19%) papers were directly related to COVID-19 and generated 252 029 citations. These papers were mostly clinically focused (62%), followed by cell/molecular (32%), and animal focused (6%). Roughly 60% of preprint publications were cell/molecular-focused, compared with 26% of nonpreprint publications. The machine learning-based model identified the top 3 research topics to be clinical trials and outcomes research (8.5% of papers), coronavirus-related heart and lung damage (7.3%), and COVID-19 transmission/epidemiology (7.2%). This study provides key insights regarding how researchers leveraged federal funding to study the COVID-19 pandemic during its initial phase.