Innovative Medicines Initiative Research Articles

Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study.

Type 2 diabetes is a chronic condition that is caused by hyperglycaemia. Our aim was to characterise the metabolomics to find their association with the glycaemic spectrum and find a causal relationship between metabolites and type 2 diabetes. As part of the Innovative Medicines Initiative - Diabetes Research on Patient Stratification (IMI-DIRECT) consortium, 3000 plasma samples were measured with the Biocrates AbsoluteIDQ p150 Kit and Metabolon analytics. A total of 911 metabolites (132 targeted metabolomics, 779 untargeted metabolomics) passed the quality control. Multivariable linear and logistic regression analysis estimates were calculated from the concentration/peak areas of each metabolite as an explanatory variable and the glycaemic status as a dependent variable. This analysis was adjusted for age, sex, BMI, study centre in the basic model, and additionally for alcohol, smoking, BP, fasting HDL-cholesterol and fasting triacylglycerol in the full model. Statistical significance was Bonferroni corrected throughout. Beyond associations, we investigated the mediation effect and causal effects for which causal mediation test and two-sample Mendelian randomisation (2SMR) methods were used, respectively. In the targeted metabolomics, we observed four (15), 34 (99) and 50 (108) metabolites (number of metabolites observed in untargeted metabolomics appear in parentheses) that were significantly different when comparing normal glucose regulation vs impaired glucose regulation/prediabetes, normal glucose regulation vs type 2 diabetes, and impaired glucose regulation vs type 2 diabetes, respectively. Significant metabolites were mainly branched-chain amino acids (BCAAs), with some derivatised BCAAs, lipids, xenobiotics and a few unknowns. Metabolites such as lysophosphatidylcholine a C17:0, sum of hexoses, amino acids from BCAA metabolism (including leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine and formiminoglutamate) and lactate, as well as an unknown metabolite (X-24295), were associated with HbA1c progression rate and were significant mediators of type 2 diabetes from baseline to 18 and 48 months of follow-up. 2SMR was used to estimate the causal effect of an exposure on an outcome using summary statistics from UK Biobank genome-wide association studies. We found that type 2 diabetes had a causal effect on the levels of three metabolites (hexose, glutamate and caproate [fatty acid (FA) 6:0]), whereas lipids such as specific phosphatidylcholines (PCs) (namely PC aa C36:2, PC aa C36:5, PC ae C36:3 and PC ae C34:3) as well as the two n-3 fatty acids stearidonate (18:4n3) and docosapentaenoate (22:5n3) potentially had a causal role in the development of type 2 diabetes. Our findings identify known BCAAs and lipids, along with novel N-lactoyl-amino acid metabolites, significantly associated with prediabetes and diabetes, that mediate the effect of diabetes from baseline to follow-up (18 and 48 months). Causal inference using genetic variants shows the role of lipid metabolism and n-3 fatty acids as being causal for metabolite-to-type 2 diabetes whereas the sum of hexoses is causal for type 2 diabetes-to-metabolite. Identified metabolite markers are useful for stratifying individuals based on their risk progression and should enable targeted interventions.

168 Real-world walking of people with the chronic lung disease COPD

Abstract Purpose Walking is crucial for active and healthy ageing, but it changes with age and in the presence of diverse health conditions, such as non-communicable diseases. In the field of the chronic lung disease COPD (chronic obstructive pulmonary disease), extensive research has been done on physical activity limitation, but little is known about the patterns of walking during daily life (i.e., real-world). We aimed to assess the levels and distribution of real-world walking (walking activity and gait parameters) in people with COPD compared with healthy adults, and across disease severity; and to identify domains of walking in COPD, using a single wearable device. Methods In a cross-sectional study, 550 people with COPD (37% women, with a mean (SD) age of 68 (8) years, postbronchodilator FEV1 54 (21) %) and 19 age-matched healthy adults were recruited in ten cities across eight countries. Subjects were given a single wearable device to wear at their lower back for one week. Twenty-five walking activity and gait parameters (e.g., number of steps, number of walking bouts (WB)>30s, walking speed in WB > 30s, cadence in WB > 30s, walking speed and cadence variability) were derived from the device outputs. Results Most walking activity and gait parameters were reduced in people with COPD compared to healthy adults, and according to COPD severity. Differences remained statistically significant after adjusting for age, sex, height and comorbidities in multivariable analyses. Factor analysis identified six distinct walking domains: Amount of walking, Patterns of walking, Pace, Rhythm, Pace variability and Rhythm variability. Conclusion Real-world walking in people with COPD is a multi-dimensional behaviour that is impaired as the disease progresses. These results may be used to set priorities and improve patient centricity in clinical practice, research and public health initiatives. Support/Funding Source This work was supported by the Mobilise-D project that has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 820820. This JU receives support from the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA).

Exploratory multi-omics analysis reveals host-microbe interactions associated with disease severity in psoriatic skin

Psoriasis (Pso) is a chronic inflammatory skin disease that poses both physical and psychological challenges. Dysbiosis of the skin microbiome has been implicated in Pso, yet a comprehensive multi-omics analysis of host-microbe interactions is still lacking. To bridge this gap, we conducted an exploratory study by adopting the integrated approach that combines whole metagenomic shotgun sequencing with skin transcriptomics. This was a cross-sectional study, adult patients with plaque-type Psoriasis (Pso) and healthy volunteers were included. Skin microbiota samples and biopsies were collected from both lesional and non-lesional skin areas on the lower back. Weighted Gene Correlation Network Analysis (WGCNA) was employed for co-expression network analysis, and cell deconvolution was conducted to estimate cell fractions. Taxonomic and functional features of the microbiome were identified using whole metagenomic shotgun sequencing. Association between host genes and microbes was analyzed using Spearman correlation. Host anti-viral responses and interferon-related networks were identified and correlated with the severity of psoriasis. The skin microbiome showed a greater prevalence of Corynebacterium simulans in the PASI severe-moderate groups, which correlated with interferon-induced host genes. Two distinct psoriatic clusters with varying disease severities were identified. Variations in the expression of cell apoptosis-associated antimicrobial peptides (AMPs) and microbial aerobic respiration I pathway may partly account for these differences in disease severity. Our multi-omics analysis revealed for the first time anti-viral responses and the presence of C.simulans associated with psoriasis severity. It also identified two psoriatic subtypes with distinct AMP and metabolic pathway expression. Our study provides new insights into understanding the host-microbe interaction in psoriasis and lays the groundwork for developing subtype-specific strategies for managing this chronic skin disease. The research has received funding from the FP7 (MAARS-Grant 261366) and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 821511 (BIOMAP). The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author's view and the JU is not responsible for any use that may be made of the information it contains. GAM was supported by a scholarship provided by CAPES-PRINT, financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES (Brazilian Government Agency). The authors thank all patients who participated in our study.

Research protocol for an observational health data analysis to assess the applicability of randomized controlled trials focusing on newly diagnosed metastatic prostate cancer using real-world data: PIONEER IMI’s “big data for better outcomes” program

Background: Metastatic prostate cancer (PCa) constitutes ~5% of all new PCa diagnoses in Western countries. For most cases, primary consideration should be given to systemic therapies as the first-line approach based on evidence from randomized controlled trials (RCTs). Despite the importance of RCTs as the pinnacle of evidence in modern medicine, concerns have been raised about their applicability to real-life scenarios. These trials often feature participants who are younger with better performance statuses and prognoses compared to their real-world counterparts. The PIONEER project falls under the Innovative Medicine Initiative’s (IMI) “Big Data for Better Outcomes” initiative, aimed at revolutionizing PCa care in Europe. The central focus lies in improving cancer-related outcomes, enhancing health system efficiency, and elevating the quality of health and social care. This study endeavours to evaluate the generalizability of RCT findings concerning newly diagnosed metastatic PCa. Methods: A systematic review of the literature will be conducted to compile patient characteristics from RCTs addressing this subject within the past decade. To create a real-world benchmark, patients with recently diagnosed metastatic PCa from a network of population-based databases will serve as a comparison group. The objective is to assess the applicability of RCT results in two ways. First, a comparison will be made between the characteristics of patients with newly diagnosed metastatic PCa enroled in RCTs and those with the same condition included in our databases which might represent the real-world setting. Second, an evaluation will be undertaken to determine the proportion of real-world patients with newly diagnosed metastatic PCa who meet the criteria for RCT enrolment. This study will rely on extensive observational data, primarily sourced from population-based registries, electronic health records, and insurance claims data. The study cohort is established upon routinely gathered healthcare data, meticulously mapped to the Observational Medical Outcomes Partnership Common Data Model.

The Association of Cardiometabolic, Diet and Lifestyle Parameters With Plasma Glucagon-like Peptide-1: An IMI DIRECT Study.

The role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood. We investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. We analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D. Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin-resistant phenotype and observe a strong independent relationship with male sex, increased adiposity, and liver fat, particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycemia, higher adiposity, liver fat, male sex, and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit, and vegetables in people with prediabetes, and with a high intake of red meat and alcohol in people with diabetes. These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake, and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D.

Past and future of an IMI-PharmaTrain (IMI-PhT)-initiated multinational pharmaceutical medicine course at the Semmelweis University in Hungary.

The pharmaceutical medicine course at the Semmelweis University of Budapest, Hungary, was initiated as part of the Innovative Medicines Initiative (IMI is the main program, IMI-PharmaTrain is one of the IMI projects) Pharmaceutical Medicine Training Programs (16 IMI Call 2008/1/16). The aim was to extend training in the development of pharmaceutical medicine to those EU member states where no such education was present. The final program envisaged the development of a cooperative education supported by universities located in Central and Eastern Europe. It was considered to be the economically and scientifically most viable approach to combine the expertise from these countries to form a united teaching staff and provide education jointly for young professionals of the region. Semmelweis University was selected to manage this coordinated program. In this report, we describe the organization and functioning of this international university-based pharmaceutical medicine education project called the Cooperative European Medicines Development Course (CEMDC) and evaluate its successes and shortcomings. During the pandemic, the educational course was interrupted. The follow-on program is reorganized as a postgraduate MSc course named "Semmelweis Pharma MBA" and will be started in 2025. It will continue the established PharmaTrain educational tradition. However, it will deal in more detail with the transition from basic pharmacological to industrial research, as well as biopharmaceutical formulation and manufacturing and marketing aspects of medicines development.

OA42 Effect of intra-articular corticosteroid injections for osteoarthritis on subsequent use of pain medications: an instrumental variable and propensity score analysis

Abstract Background/Aims Intra-articular corticosteroid injections (IACI) are recommended in the UK by NICE as an adjunctive treatment for uncontrolled pain from osteoarthritis (OA). NICE guidance states there is no evidence for therapeutic benefit lasting beyond three months, and that more evidence is needed on effectiveness at non-knee joints. We therefore aimed to assess the longer-term effect of IACI use on pain medication prescriptions among people with hand, hip, knee or shoulder OA. Methods We conducted a cohort study using UK primary care (CPRD GOLD) data for patients aged ≥20 years with a first diagnosis of OA during 2005-2019, excluding those with prior orthopaedic surgery referral or OA diagnosed at multiple joints. Exposure to IACI was defined using Read codes. The primary outcome was incident prescribing of pain medication: oral non-steroidal anti-inflammatory drugs (NSAIDs), opioids, oral corticosteroids, paracetamol, partial opioids, and topical NSAIDs. In main analyses, an instrumental variable (IV) approach was used. Index date was six months after OA diagnosis date and IV was defined as practice preference for IACI use in the year prior to index date (single and recurrent use considered separately). Outcomes were measured over five years from index date. Covariate balance was assessed, and two-step Poisson regression used where assumptions met. In secondary analyses, propensity score (PS) matching was carried out and time-varying exposure Cox models used to estimate treatment effect. Results Of 181,818 eligible patients, 92,157 (50.7%) were retained in IV analyses of single IACI and 89,103 (49.0%) of repeat IACI. Covariates were well balanced (SMD ≤0.1) across IV groups for hand (single IACI only) and knee OA, but not hip or shoulder OA. In IV analyses of hand OA, single IACI was associated with lower 5-year cumulative incidence of several pain medications including oral corticosteroids (relative risk [RR] 0.27 [95% CI 0.10, 0.76], paracetamol (RR 0.27 [0.09, 0.78] and partial opioids (RR 0.24 [0.10, 0.60]). IACI for knee OA was associated with lower 5-year cumulative incidence of most pain medications, e.g., for partial opioids a RR 0.46 [95% CI 0.34, 0.61] and RR 0.33 [0.21, 0.51] for single and recurrent IACI, respectively. Most PS matched analyses had >20,000 included patients (all joints combined), with covariates well balanced across IACI exposure status. PS matching confirmed a reduction in incidence of several pain medications associated with single IACI, e.g., lower incidence of partial opioids following IACI for any of hand, hip, knee or shoulder OA. Conclusion Our main findings suggest IACI use for hand or knee OA may reduce subsequent need for analgesics. Among knee OA patients, generally larger reductions were observed following recurrent than single IACI. In secondary analyses, single IACI for hand, hip, knee or shoulder OA was associated with lower subsequent use of partial opioids. Disclosure S. Hawley: None. A. Prats-Uribe: Grants/research support; European Medicines Agency. G. Matharu: Grants/research support; National Institute of Health and Care Research, Academy of Medical Sciences. A. Delmestri: None. D. Prieto-Alhambra: Consultancies; AstraZeneca, UCB Biopharma. Grants/research support; European Medicines Agency, Innovative Medicines Initiative, Amgen, Chiesi-Taylor, Lilly, Janssen, Novartis, UCB Biopharma. Other; Amgen, Astrellas, Janssen, Synapse Management Partners, UCB Biopharma. A. Judge: Grants/research support; National Institute of Health and Care Research, Health Data Research UK, Versus Arthritis, Healthcare Quality Improvement Partnership (HQIP), Royal College of Physicians (RCP), Tommy's, The Health Foundation. M. Whitehouse: Royalties; Taylor Francis. Member of speakers’ bureau; Heraeus. Grants/research support; National Institute of Health and Care Research, Healthcare Quality Improvement Partnership (HQIP), Ceramtec.

P014 Treatment response in psoriatic arthritis: a comparison between the disease activity scores psoriatic arthritis response criteria and disease activity score-28

Abstract Background/Aims Despite NICE guidelines recommending the use of the PsA response criteria (PsARC), to assess response to biologic therapies in patients with psoriatic arthritis (PsA), some clinicians use the Disease Activity Score (DAS-28) criteria, developed for rheumatoid arthritis. However, whether the two scores are interchangeable and/or capture similar information has not yet been explored. Here, we investigate the differences and overlap between these two disease activity scores, in identifying good/poor responders, in PsA. Methods Utilising treatment response data from the OUTPASS cohort; a UK based multi-centre observational study, PsA patients assessed with PsARC and DAS-28 scores were calculated at baseline (pre-treatment), 3-months and 6-months (3M),(6M), following treatment, where available. EULAR good/moderate response was combined and compared with PsARC responder status. Subgroup analysis of patients with both PsARC and DAS-28 scores at either 3M or 6M, were tested for agreement using the Cohen’s Kappa test. Statistical tests were also used, as appropriate, to investigate differences between the baseline subcomponents, in the observed concordant and discordant data. Results Response data from 418 patients was available. An average of 76% were classified as responders according to PsARC, and 80% according to the EULAR response criteria, for both 3M and 6M, with 12% discordance. A subgroup analysis of 218 patients assessed with both scores, (up to 6M), revealed 17.9% responder discordance between PSARC and DAS-28, and 82.1% concordance. The Cohen’s Kappa test defined the assessment of responder/non-responder outcome, as an ‘almost perfect agreement’ (0.82) between the two criteria. Further statistical analyses, of baseline subcomponents, of both response criteria, between these discordant/concordant subsets, showed no significant difference, except for PsARC Physician’s and Patient’s Global Assessments (PhGA), (PGA), (P = 0.01, P = 0.02, Table 1). Conclusion PsARC and EULAR response criteria show ‘almost perfect agreement’, strongly supporting clinical use for either score. PhGA, (not a subcomponent of DAS-28) and PsARC PGA were the only significantly different (P < 0.05) components between the discordant and concordant groups, highlighting the importance of considering psychosocial factors which may affect pain tolerance and treatment response. Comparative analyses with other widely used scores, such as DAPSA, would also be informative for future work. Disclosure K. Patel: Grants/research support; This project has received support from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101007757 (HIPPOCRATES), the JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA, the results reflect only the author's view and the JU are not responsible for any use that may be made of the information it contains.. N. Nair: None. M. Jani: None. H. Chinoy: Consultancies; H.C. has received Consulting for PTC Therapeutics. Member of speakers’ bureau; H.C. has received fees as a speaker for GSK, UCB. Other; H.C. for Advisory Board member for Astra Zeneca, Pfizer, Argenx, Galapagos; Data and Science Monitoring Board chair for Horizon Therapeutics. J. Bluett: Grants/research support; J.B. has received a research grant award from Pfizer and travel/conference fees from UCB, Fresenius Kabi, Pfizer and Eli Lilly. (Pfizer: WI239449). A. Barton: Grants/research support; A.B. has received research grants from Bristol Myers Squibb and Pfizer and speaker fees from Galapagos.. P. Curry: None.

P177 The prevalence and incidence of psoriasis and psoriatic arthritis in England from 2009-2019: an observational study using primary care data

Abstract Background/Aims Psoriasis (PsO) and psoriatic arthritis (PsA) greatly impact quality of life and result in substantial personal and societal costs. Complete and up-to-date data on the prevalence and incidence of these conditions and whether these change over time and vary by age is important for healthcare service planning so that specialist care and funding can be appropriately allocated. Objective to determine the prevalence and incidence of PsO and PsA in males and females from 2009-2019 across all age groups in England. Methods We used Clinical Practice Research Datalink AURUM, a primary care electronic health record database, including 20% of the English population. The codes used to identify patients with PsO and PsA were selected by rheumatologists and dermatologists and cross-checked with published code lists from other studies. All included patients must have data for at least 1 year before their diagnosis. The annual incidence and point prevalence were calculated from 2009-2019 and stratified by age/sex. The study period ended in 2019 to avoid COVID-19 pandemic affecting results. Results The prevalence of PsO and PsA in males and females has increased annually, peaking in 2019 (PsO males 2.41% [95% confidence interval (CI) 2.40, 2.42]; PsO females 2.60% [95% CI 2.59-2.61]; PsA males 0.20% [95% CI 0.20-0.20]; PsA females 0.21% [95% CI 0.21- 0.22]), as illustrated in Table 1. In 2019, the prevalence of PsO and PsA was highest in the over 65 years age group; PsO 4.25% [95% CI 4.22-4.28] and PsA 0.38% [95% CI 0.37-0.38]. The annual incidence (per 100,000 person years) of PsO has gradually decreased in males (from 168 [164-171] in 2009 to 148 [145-151] in 2019) but in females it has been stable with a slight annual decrease (from 180 [177-184] in 2009 to 173 [170-176]) in 2019. The annual incidence for PsA has increased in both males and females; 13 (12-14) in 2009 and 15 (14-16) in 2019 for males and 12 (11-13) in 2009 and 18 (17-19) in 2019 for females. Conclusion The increasing prevalence of PsO and PsA highlights the importance of organising healthcare services to meet this need, particularly in the elderly population. Disclosure A. Vivekanantham: None. E. Burn: None. M. Pineda Moncusi: None. S. Khalid: None. D. Prieto Alhambra: Consultancies; DP-A’s research group has received consultancy or speaker fees from Astellas, Amgen, AstraZeneca, and UCB Biopharma. Grants/research support; DP-A’s research group has received research grants from the European Medicines Agency; the Innovative Medicines Initiative; and Amgen, Chiesi, and UCB Biopharma. L.C. Coates: Grants/research support; LCC has received grants/research support from AbbVie, Amgen, Celgene, Eli Lilly, Novartis and Pfizer; worked as a paid consultant for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene.

Patient preferences in genetic newborn screening for rare diseases: study protocol

IntroductionRare diseases (RDs) collectively impact over 30 million people in Europe. Most individual conditions have a low prevalence which has resulted in a lack of research and expertise in this...

Ad26.ZEBOV, MVA-BN-Filo Ebola virus disease vaccine regimen plus Ad26.ZEBOV booster at 1 year versus 2 years in health-care and front-line workers in the Democratic Republic of the Congo: secondary and exploratory outcomes of an open-label, randomised, phase 2 trial

Health-care providers and front-line workers are at risk of contracting Ebola virus disease during an Ebola virus outbreak and consequently of becoming drivers of the disease. We aimed to assess the long-term immunogenicity of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen and the safety of and immune memory response to an Ad26.ZEBOV booster vaccination at 1 year or 2 years after the first dose in this at-risk population. This open-label, single-centre, randomised, phase 2 trial was conducted at one study site within a hospital in Boende, Democratic Republic of the Congo. Adult health-care providers and front-line workers, excluding those with a known history of Ebola virus disease, were vaccinated with a two-dose heterologous regimen administered at a 56-day interval via a 0·5 mL intramuscular injection in the deltoid muscle, comprising Ad26.ZEBOV as the first dose and MVA-BN-Filo as the second dose. After the initial vaccination on day 1, participants were randomly assigned (1:1) via randomisation envelopes, opened in a sequential order, to receive an Ad26.ZEBOV booster vaccination at 1 year (group 1) or 2 years (group 2) after the first dose. We present the secondary and exploratory objectives of the trial-results of the primary objective have been published elsewhere. We measured immunogenicity at six timepoints per group as geometric mean concentrations (GMCs) of Ebola virus glycoprotein-specific IgG binding antibodies, using the Filovirus Animal Non-Clinical Group ELISA. We assessed serious adverse events occurring up to 6 months after the last dose and local and systemic solicited and unsolicited adverse events reported for 7 days after the booster vaccination. Antibody responses were analysed per protocol, serious adverse events per full analysis set (FAS), and adverse events for all boosted FAS participants. This trial is registered as completed on ClinicalTrials.gov (NCT04186000). Between Dec 18, 2019, and Feb 8, 2020, 699 health-care providers and front-line workers were enrolled and 698 were randomly assigned (350 to group 1 and 348 to group 2 [FAS]); 534 (77%) participants were male and 164 (23%) were female. 319 in group 1 and 317 in group 2 received the booster. 29 (8%) in group 1 and 26 (7%) in group 2 did not complete the study, mostly due to loss to follow-up or moving out of the study area. In both groups, injection-site pain or tenderness (87 [27%] of 319 group 1 participants vs 90 [28%] of 317 group 2 participants) and headache (91 [29%] vs 93 [29%]) were the most common solicited adverse events related to the investigational product. One participant (in group 2) had a related serious adverse event after booster vaccination (fever of ≥40·0°C). Before booster vaccination, Ebola virus glycoprotein-specific IgG binding antibody GMCs were 279·9 ELISA units (EU) per mL (95% CI 250·6-312·7) in 314 group 1 participants (1 year after first dose) and 274·6 EU/mL (242·1-311·5) in 310 group 2 participants (2 years after first dose). These values were 5·2 times higher in group 1 and 4·9 times higher in group 2 than before vaccination on day 1. 7 days after booster vaccination, these values increased to 10 781·6 EU/mL (9354·4-12 426·4) for group 1 and 10 746·9 EU/mL (9208·7-12 542·0) for group 2, which were approximately 39 times higher than before booster vaccination in both groups. 1 year after booster vaccination in 299 group 1 participants, a GMC that was 7·6-times higher than before booster vaccination was still observed (2133·1 EU/mL [1827·7-2489·7]). Overall, the vaccine regimen and booster dose were well tolerated. A similar and robust humoral immune response was observed for participants boosted 1 year and 2 years after the first dose, supporting the use of the regimen and flexibility of booster dose administration for prophylactic vaccination in at-risk populations. Innovative Medicines Initiative 2 Joint Undertaking and Coalition for Epidemic Preparedness Innovations.

An ethics framework for the transition to an operational learning healthcare system.

While Learning Healthcare Systems (LHSs) have received increasing attention in health care and research, the amount of operational LHSs remains limited. Given the investment of resources in these projects, a moral responsibility to pursue the transition toward an LHS falls on projects and their participating stakeholders. This paper provides an ethics framework for projects that have taken steps toward building an LHS and are in the position to transition to an operational LHS. To articulate relevant ethical requirements, we analyze established ethics frameworks in the fields of LHSs, data-intensive health research, and transitioning or innovating health systems. The overlapping content and shared values are used to articulate overarching ethical requirements. To provide necessary context, we apply the insights from the analysis to the Innovative Medicines Initiative ConcePTION project. This project is specifically designed to generate knowledge on the safety of medications used during pregnancy and lactation through the establishment of an LHS. Upon analyzing the consulted frameworks, we identified four overlapping ethical requirements that are also of significant relevance within the scope of our ethics framework. These requirements are: (1) public benefit and favorable harm-benefit ratio; (2) equity and justice; (3) stakeholder engagement; and (4) sustainability. Additionally, we apply these ethical requirements to the context of an LHS for pregnant and lactating people. Although tailored to the context of pregnancy and lactation, our ethics framework can provide guidance for the transition to an operational LHS across diverse healthcare domains.

Tryptophan degradation as a systems phenomenon in inflammation – an analysis across 13 chronic inflammatory diseases

Chronic inflammatory diseases (CIDs) are systems disorders that affect diverse organs including the intestine, joints and skin. The essential amino acid tryptophan (Trp) can be broken down to various bioactive derivatives important for immune regulation. Increased Trp catabolism has been observed in some CIDs, so we aimed to characterise the specificity and extent of Trp degradation as a systems phenomenon across CIDs. We used high performance liquid chromatography and targeted mass spectrometry to assess the serum and stool levels of Trp and Trp derivatives. Our retrospective study incorporates both cross-sectional and longitudinal components, as we have included a healthy population as a reference and there are also multiple observations per patient over time. We found reduced serum Trp levels across the majority of CIDs, and a prevailing negative relationship between Trp and systemic inflammatory marker C-reactive protein (CRP). Notably, serum Trp was low in several CIDs even in the absence of measurable systemic inflammation. Increases in the kynurenine-to-Trp ratio (Kyn:Trp) suggest that these changes result from increased degradation along the kynurenine pathway. Increases in Kyn:Trp indicate the kynurenine pathway as a major route for CID-related Trp metabolism disruption and the specificity of the network changes indicates excessive Trp degradation relative to other proteogenic amino acids. Our results suggest that increased Trp catabolism is a common metabolic occurrence in CIDs that may directly affect systemic immunity. This work was supported by the DFG Cluster of Excellence 2167 "Precision medicine in chronic inflammation" (KA, SSchr, PR, BH, SWa), the BMBF (e:Med Juniorverbund "Try-IBD" 01ZX1915A and 01ZX2215, the e:Med Network iTREAT 01ZX2202A, and GUIDE-IBD 031L0188A), EKFS (2020_EKCS.11, KA), DFG RU5042 (PR, KA), and Innovative Medicines Initiative 2 Joint Undertakings ("Taxonomy, Treatments, Targets and Remission", 831434, "ImmUniverse", 853995, "BIOMAP", 821511).

Identification of distinct subgroups of Sjögren's disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts

Sjögren's disease is a heterogenous autoimmune disease with a wide range of symptoms-including dryness, fatigue, and pain-in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups. This study included patients with Sjögren's disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues. 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43-64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43-63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0·0001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42-104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13-83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only. On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sjögren's disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials. Fondation pour la Recherche Médicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology.

A Federated Database for Obesity Research: An IMI-SOPHIA Study.

Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.

Building a Sustainable Learning Health Care System for Pregnant and Lactating People: Interview Study Among Data Access Providers.

In many areas of health care, learning health care systems (LHSs) are seen as promising ways to accelerate research and outcomes for patients by reusing health and research data. For example, considering pregnant and lactating people, for whom there is still a poor evidence base for medication safety and efficacy, an LHS presents an interesting way forward. Combining unique data sources across Europe in an LHS could help clarify how medications affect pregnancy outcomes and lactation exposures. In general, a remaining challenge of data-intensive health research, which is at the core of an LHS, has been obtaining meaningful access to data. These unique data sources, also called data access providers (DAPs), are both public and private organizations and are important stakeholders in the development of a sustainable and ethically responsible LHS. Sustainability is often discussed as a challenge in LHS development. Moreover, DAPs are increasingly expected to move beyond regulatory compliance and are seen as moral agents tasked with upholding ethical principles, such as transparency, trustworthiness, responsibility, and community engagement. This study aims to explore the views of people working for DAPs who participate in a public-private partnership to build a sustainable and ethically responsible LHS. Using a qualitative interview design, we interviewed 14 people involved in the Innovative Medicines Initiative (IMI) ConcePTION (Continuum of Evidence from Pregnancy Exposures, Reproductive Toxicology and Breastfeeding to Improve Outcomes Now) project, a public-private collaboration with the goal of building an LHS for pregnant and lactating people. The pseudonymized transcripts were analyzed thematically. A total of 3 themes were identified: opportunities and responsibilities, conditions for participation and commitment, and challenges for a knowledge-generating ecosystem. The respondents generally regarded the collaboration as an opportunity for various reasons beyond the primary goal of generating knowledge about medication safety during pregnancy and lactation. Respondents had different interpretations of responsibility in the context of data-intensive research in a public-private network. Respondents explained that resources (financial and other), scientific output, motivation, agreements collaboration with the pharmaceutical industry, trust, and transparency are important conditions for participating in and committing to the ConcePTION LHS. Respondents also discussed the challenges of an LHS, including the limitations to (real-world) data analyses and governance procedures. Our respondents were motivated by diverse opportunities to contribute to an LHS for pregnant and lactating people, primarily centered on advancing knowledge on medication safety. Although a shared responsibility for enabling real-world data analyses is acknowledged, their focus remains on their work and contribution to the project rather than on safeguarding ethical data handling. The results of our interviews underline the importance of a transparent governance structure, emphasizing the trust between DAPs and the public for the success and sustainability of an LHS.

Performance of biomarkers NF-L, NSE, Tau and GFAP in blood and cerebrospinal fluid in rat for the detection of nervous system injury.

Target organ toxicity is often a reason for attritions in nonclinical and clinical drug development. Leveraging emerging safety biomarkers in nonclinical studies provides an opportunity to monitor such toxicities early and efficiently, potentially translating to early clinical trials. As a part of the European Union's Innovative Medicines Initiative (IMI), two projects have focused on evaluating safety biomarkers of nervous system (NS) toxicity: Translational Safety Biomarker Pipeline (TransBioLine) and Neurotoxicity De-Risking in Preclinical Drug Discovery (NeuroDeRisk). Performance of fluid-based NS injury biomarker candidates neurofilament light chain (NF-L), glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE) and total Tau in plasma and cerebrospinal fluid (CSF) was evaluated in 15 rat in vivo studies. Model nervous system toxicants as well as other compounds were used to evaluate sensitivity and specificity. Histopathologic assessments of nervous tissues and behavioral observations were conducted to detect and characterize NS injuries. Receiver operator characteristic (ROC) curves were generated to compare the relative performance of the biomarkers in their ability to detect NS injury. NF-L was the best performer in detecting both peripheral nervous system (PNS) and CNS injury in plasma, (AUC of 0.97-0.99; respectively). In CSF, Tau correlated the best with CNS (AUC 0.97), but not PNS injury. NSE and GFAP were suitable for monitoring CNS injury, but with lesser sensitivity. In summary, NF-L is a sensitive and specific biomarker in rats for detecting compound-induced central and peripheral NS injuries. While NF-L measurement alone cannot inform the site of the injury, addition of biomarkers like Tau and NSE and analysis in both blood and CSF can provide additional information about the origin of the NS injury. These results demonstrate the utility of emerging safety biomarkers of drug-induced NS injury in rats and provide additional supporting evidence for biomarker translation across species and potential use in clinical settings to monitor drug-induced NS injury in patients.

Development and performance of the c4c national clinical trial networks for optimizing pediatric trial facilitation.

The high failure rate of industry-driven pediatric clinical trials leads to insufficient timely labeling of drugs in children and a lack of scientific evidence, resulting in the persistently high off-label drug use. National clinical trial networks can facilitate collaboration between sites, investigators, and experts, increasing the likelihood of successful trials. Within the conect4children (c4c) network, an Innovative Medicines Initiative 2-funded project, National Hubs hosted by National Clinical Trials Networks were set up across 21 European countries to facilitate the setup and execution of pediatric clinical trials. In this paper, we aim to present the performance metrics of the trial feasibility process as well as learnings and challenges encountered by the Belgian and Dutch Networks in working within the European c4c project. The c4c National Hubs streamline pediatric clinical trials by initiating early country outreach, identifying overlapping studies, recommending quality trial sites, and supporting trial budgeting for both industry and academic settings. To show the impact of Pedmed-NL and Belgian Pediatric Clinical Research Network (BPCRN), internal metrics were collected from 2019 to 2022 on four industry-sponsored and three academic trials performed within the c4c network. Timelines and outcomes of the site identification were collected and analyzed for industry trials. A qualitative analysis was conducted through c4c platforms, sponsor interactions, and stakeholder engagement to evaluate the added value of a research network. In industry-sponsored trials, full feasibility questionnaires were completed within 2 weeks (n = 48), and inclusion rates were up to 80% of clinical sites. Before committing to c4c, 14% of sites were contacted by industry, leading to communication burdens. Utilizing national infrastructure knowledge and therapeutic environment insights helped optimize trial timelines and address feasibility challenges. In addition, national adaptations, such as bilingual staff and site development, played a role in streamlining trial operations in both academic and industry settings. Performance and experiences were similar for both networks. The early-facilitation examples from the c4c trials demonstrated promising metrics for two National Hubs, including optimized start-up timelines and aiding site selection quality. The learnings and challenges of the Belgian and Dutch Networks provided insights for the development of clinical research networks.

Proteomic signatures of eosinophilic and neutrophilic asthma from serum and sputum

Eosinophilic and neutrophilic asthma defined by high levels of blood and sputum eosinophils and neutrophils exemplifies the inflammatory heterogeneity of asthma, particularly severe asthma. We analysed the serum and sputum proteome to identify biomarkers jointly associated with these different phenotypes. Proteomic profiles (N=1129 proteins) were assayed in sputum (n=182) and serum (n=574) from two cohorts (U-BIOPRED and ADEPT) of mild-moderate and severe asthma by SOMAscan. Using least absolute shrinkage and selection operator (LASSO)-penalised logistic regression in a stability selection framework, we sought sparse sets of proteins associated with either eosinophilic or neutrophilic asthma with and without adjustment for established clinical factors including oral corticosteroid use and forced expiratory volume. We identified 13 serum proteins associated with eosinophilic asthma, including 7 (PAPP-A, TARC/CCL17, ALT/GPT, IgE, CCL28, CO8A1, and IL5-Rα) that were stably selected while adjusting for clinical factors yielding an AUC of 0.84 (95% CI: 0.83-0.84) compared to 0.62 (95% CI: 0.61-0.63) for clinical factors only. Sputum protein analysis selected only PAPP-A (AUC=0.81 [95% CI: 0.80-0.81]). 12 serum proteins were associated with neutrophilic asthma, of which 5 (MMP-9, EDAR, GIIE/PLA2G2E, IL-1-R4/IL1RL1, and Elafin) complemented clinical factors increasing the AUC from 0.63 (95% CI: 0.58-0.67) for the model with clinical factors only to 0.89 (95% CI: 0.89-0.90). Our model did not select any sputum proteins associated with neutrophilic status. Targeted serum proteomic profiles are a non-invasive and scalable approach for subtyping of neutrophilic and eosinophilic asthma and for future functional understanding of these phenotypes. U-BIOPRED has received funding from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115010, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013), and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in-kind contributions (www.imi.europa.eu). ADEPT was funded by Johnson & Johnson/Janssen pharmaceutical Company.

Changes in the global hospitalisation burden of respiratory syncytial virus in young children during the COVID-19 pandemic: a systematic analysis

The COVID-19 pandemic is reported to have affected the epidemiology of respiratory syncytial virus (RSV), which could have important implications for RSV prevention and control strategies. We aimed to assess the hospitalisation burden of RSV-associated acute lower respiratory infection (ALRI) in children younger than 5 years during the pandemic period and the possible changes in RSV epidemiology from a global perspective. We conducted a systematic literature search for studies published between Jan 1, 2020, and June 30, 2022, in MEDLINE, Embase, Global Health, Web of Science, the WHO COVID-19 Research Database, CINAHL, LILACS, OpenGrey, CNKI, WanFang, and CqVip. We included unpublished data on RSV epidemiology shared by international collaborators. Eligible studies reported data on at least one of the following measures for children (aged <5 years) hospitalised with RSV-associated ALRI: hospital admission rates, in-hospital case fatality ratio, and the proportion of hospitalised children requiring supplemental oxygen or requiring mechanical ventilation or admission to intensive care. We used a generalised linear mixed-effects model for data synthesis to measure the changes in the incidence, age distribution, and disease severity of children hospitalised with RSV-associated ALRI during the pandemic, compared with the year 2019. We included 61 studies from 19 countries, of which 14 (23%) studies were from the published literature (4052 identified records) and 47 (77%) were from unpublished datasets. Most (51 [84%]) studies were from high-income countries; nine (15%) were from upper-middle-income countries, one (2%) was from a lower-middle-income country (Kenya), and none were from a low-income country. 15 studies contributed to the estimates of hospitalisation rate and 57 studies contributed to the severity analyses. Compared with 2019, the rates of RSV-associated ALRI hospitalisation in all children (aged 0-60 months) in 2020 decreased by 79·7% (325 000 cases vs 66 000 cases) in high-income countries, 13·8% (581 000 cases vs 501 000 cases) in upper-middle-income countries, and 42·3% (1 378 000 cases vs 795 000 cases) in Kenya. In high-income countries, annualised rates started to rise in 2021, and by March, 2022, had returned to a level similar to 2019 (6·0 cases per 1000 children [95% uncertainty interval 5·4-6·8] in April, 2021, to March, 2022, vs 5·0 cases per 1000 children [3·6-6·8] in 2019). By contrast, in middle-income countries, rates remained lower in the latest period with data available than in 2019 (for upper-middle-income countries, 2·1 cases [0·7-6·1] in April, 2021, to March, 2022, vs 3·4 [1·2-9·7] in 2019; for Kenya, 2·2 cases [1·8-2·7] in 2021 vs 4·1 [3·5-4·7] in 2019). Across all time periods and income regions, hospitalisation rates peaked in younger infants (aged 0 to <3 months) and decreased with increasing age. A significantly higher proportion of children aged 12-24 months were hospitalised with RSV-associated ALRI in high-income and upper-middle-income countries during the pandemic years than in 2019, with odds ratios ranging from 1·30 (95% uncertainty interval 1·07-1·59) to 2·05 (1·66-2·54). No consistent changes in disease severity were observed. The hospitalisation burden of RSV-associated ALRI in children younger than 5 years was significantly reduced during the first year of the COVID-19 pandemic. The rebound in hospitalisation rates to pre-pandemic rates observed in the high-income region but not in the middle-income region by March, 2022, suggests a persistent negative impact of the pandemic on health-care systems and health-care access in the middle-income region. RSV surveillance needs to be established (or re-established) to monitor changes in RSV epidemiology, particularly in low-income and lower-middle-income countries. EU Innovative Medicines Initiative Preparing for RSV Immunisation and Surveillance in Europe (PROMISE), Bill & Melinda Gates Foundation, and WHO.