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Objective To examine the characteristics of comparative non-randomised studies that assess the effectiveness or safety, or both, of drug treatments.Design Cross sectional study.Data sources Medline (Ovid), for reports published from 1 June 2022 to 31 August 2022.Eligibility criteria for selecting studies Reports of comparative non-randomised studies that assessed the effectiveness or safety, or both, of drug treatments were included. A randomly ordered sample was screened until 200 eligible reports were found. Data on general characteristics, reporting characteristics, and time point alignment were extracted, and possible related biases, with a piloted form inspired by reporting guidelines and the target trial emulation framework.Results Of 462 reports of non-randomised studies identified, 262 studies were excluded (32% had no comparator and 25% did not account for confounding factors). To assess time point alignment and possible related biases, three study time points were considered: eligibility, treatment assignment, and start of follow-up. Of the 200 included reports, 70% had one possible bias, related to: inclusion of prevalent users in 24%, post-treatment eligibility criteria in 32%, immortal time periods in 42%, and classification of treatment in 23%. Reporting was incomplete, and only 2% reported all six of the key elements considered: eligibility criteria (87%), description of treatment (46%), deviations in treatment (27%), causal contrast (11%), primary outcomes (90%), and confounding factors (88%). Most studies used routinely collected data (67%), but only 7% reported using validation studies of the codes or algorithms applied to select the population. Only 7% of reports mentioned registration on a trial registry and 3% had an available protocol.Conclusions The findings of the study suggest that although access to real world evidence could be valuable, the robustness and transparency of non-randomised studies need to be improved.

Background Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets.Methods We performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort.Results Unsupervised clustering identified two “TME subtypes”, in each of the cohorts: the “immune-enriched” and the “immune-low”. Within AXIPAP trial cohort, the “immune-enriched” cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the “immune-enriched” group (adjusted p

Objective To evaluate the efficacy of covid-19 convalescent plasma to treat patients admitted to hospital for moderate covid-19 disease with or without underlying immunodeficiency (CORIPLASM trial).Design Open label, randomised clinical trial.Setting CORIMUNO-19 cohort (publicly supported platform of open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease) based on 19 university and general hospitals across France, from 16 April 2020 to 21 April 2021.Participants 120 adults (n=60 in the covid-19 convalescent plasma group, n=60 in the usual care group) admitted to hospital with a positive SARS-CoV2 test result, duration of symptoms 40.Main outcome measures Primary outcomes were proportion of patients with a WHO Clinical Progression Scale score of ≥6 on the 10 point scale on day 4 (higher values indicate a worse outcome), and survival without assisted ventilation or additional immunomodulatory treatment by day 14. Secondary outcomes were changes in WHO Clinical Progression Scale scores, overall survival, time to discharge, and time to end of dependence on oxygen supply. Predefined subgroups analyses included immunosuppression status, duration of symptoms before randomisation, and use of steroids.Results 120 patients were recruited and assigned to covid-19 convalescent plasma (n=60) or usual care (n=60), including 22 (covid-19 convalescent plasma) and 27 (usual care) patients who were immunocompromised. 13 (22%) patients who received convalescent plasma had a WHO Clinical Progression Scale score of ≥6 at day 4 versus eight (13%) patients who received usual care (adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24). By day 14, 19 (31.6%) patients in the convalescent plasma group and 20 (33.3%) patients in the usual care group needed ventilation, additional immunomodulatory treatment, or had died. For cumulative incidence of death, three (5%) patients in the convalescent plasma group and eight (13%) in the usual care group died by day 14 (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53), and seven (12%) patients in the convalescent plasma group and 12 (20%) in the usual care group by day 28 (adjusted hazard ratio 0.51, 0.20 to 1.32). In a subgroup analysis performed in patients who were immunocompromised, transfusion of covid-19 convalescent plasma was associated with mortality (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10).Conclusions In this study, covid-19 convalescent plasma did not improve early outcomes in patients with moderate covid-19 disease. The efficacy of convalescent plasma in patients who are immunocompromised should be investigated further.Trial registration ClinicalTrials.gov NCT04345991.

Objective To evaluate the effect of covid-19 vaccination on the severity of symptoms in patients with long covid.Design Target trial emulation based on ComPaRe e-cohort.Data source ComPaRe long covid cohort, a nationwide e-cohort (ie, a cohort where recruitment and follow-up are performed online) of patients with long covid, in France.Methods Adult patients (aged ≥18 years) enrolled in the ComPaRe cohort before 1 May 2021 were included in the study if they reported a confirmed or suspected SARS-CoV-2 infection, symptoms persistent for >3 weeks after onset, and at least one symptom attributable to long covid at baseline. Patients who received a first covid-19 vaccine injection were matched with an unvaccinated control group in a 1:1 ratio according to their propensity scores. Number of long covid symptoms, rate of complete remission of long covid, and proportion of patients reporting an unacceptable symptom state at 120 days were recorded.Results 910 patients were included in the analyses (455 in the vaccinated group and 455 in the control group). By 120 days, vaccination had reduced the number of long covid symptoms (mean 13.0 (standard deviation 9.4) in the vaccinated group v 14.8 (9.8) in the control group; mean difference −1.8, 95% confidence interval −3.0 to −0.5) and doubled the rate of patients in remission (16.6% v 7.5%, hazard ratio 1.93, 95% confidence interval 1.18 to 3.14). Vaccination reduced the effect of long covid on patients' lives (mean score on the impact tool 24.3 (standard deviation 16.7) v 27.6 (16.7); mean difference −3.3, 95% confidence interval −5.7 to −1.0) and the proportion of patients with an unacceptable symptom state (38.9% v 46.4%, risk difference −7.4%, 95% confidence interval −14.5% to −0.3%). In the vaccinated group, two (0.4%) patients reported serious adverse events requiring admission to hospital.Conclusion In this study, covid-19 vaccination reduced the severity of symptoms and the effect of long covid on patients' social, professional, and family lives at 120 days in those with persistent symptoms of infection.

Background In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab.Methods In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1–4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated.Results At data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug–drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges.Conclusions M9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.

Objectives Randomised controlled trials conducted using cohorts and routinely collected data, including registries, electronic health records and administrative databases, are increasingly used in healthcare intervention research. A Consolidated Standards of Reporting Trials (CONSORT) statement extension for trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE) has been developed with the goal of improving reporting quality. This article describes the processes and methods used to develop the extension and decisions made to arrive at the final checklist.Methods The development process involved five stages: (1) identification of the need for a reporting guideline and project launch; (2) conduct of a scoping review to identify possible modifications to CONSORT 2010 checklist items and possible new extension items; (3) a three-round modified Delphi study involving key stakeholders to gather feedback on the checklist; (4) a consensus meeting to finalise items to be included in the extension, followed by stakeholder piloting of the checklist; and (5) publication, dissemination and implementation of the final checklist.Results 27 items were initially developed and rated in Delphi round 1, 13 items were rated in round 2 and 11 items were rated in round 3. Response rates for the Delphi study were 92 of 125 (74%) invited participants in round 1, 77 of 92 (84%) round 1 completers in round 2 and 62 of 77 (81%) round 2 completers in round 3. Twenty-seven members of the project team representing a variety of stakeholder groups attended the in-person consensus meeting. The final checklist includes five new items and eight modified items. The extension Explanation & Elaboration document further clarifies aspects that are important to report.Conclusion Uptake of CONSORT-ROUTINE and accompanying Explanation & Elaboration document will improve conduct of trials, as well as the transparency and completeness of reporting of trials conducted using cohorts and routinely collected data.

Background The Nutri-Score, a front-of-pack nutrition label, has been adopted in 2017 in France but its impact on low-income populations is unknown, and they are more at risk of having unhealthy diets. The present study assessed the effects of the Nutri-Score on the nutritional quality of purchasing intentions among low-income individuals, compared with the current French labelling situation: references intakes (RIs) and no label, using a three-arm parallel-group randomised controlled trial.Methods Low-income active adults from the NutriNet-Santé cohort (household income below €1200/month) were asked to perform a shopping task in an experimental online supermarket after being randomised in one of the three conditions (Nutri-Score, RIs or no labelling). The main outcome was the overall nutritional quality of the virtual shopping cart, assessed with the French-modified Food Standards Agency Nutrient Profiling System (FSAm-NPS), and secondary outcomes were the nutrient content of the shopping carts. 524 subjects were randomised, and 336 included in the analyses.Results The Nutri-Score resulted in the highest overall nutritional quality of the shopping cart, as reflected by a FSAm-NPS score (1.86 (SD 3.59) points) significantly lower (reflecting higher nutritional quality) than the RIs (3.21 (SD 4.14) points, p≤0.05) but not significantly lower than no label (2.60 (SD 3.09) points, p=0.3). The Nutri-Score also resulted into significantly lower contents in calories and saturated fatty acids in the shopping cart, compared with the RIs only (p≤0.05).Conclusion The implementation of the front of pack nutrition label Nutri-Score, adopted in France and in different European countries, appears to have the potential to encourage purchasing intentions of foods from higher nutritional quality among low-income individuals, compared with the RIs label promoted by food manufacturers.Trial registration number: NCT02769455

Background The extent to which response and survival benefits with immunotherapy-based regimens persist informs optimal first-line treatment options. We provide long-term follow-up in patients with advanced renal cell carcinoma (aRCC) receiving first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the phase 3 CheckMate 214 trial. Survival, response, and safety outcomes with NIVO+IPI versus SUN were assessed after a minimum of 42 months of follow-up.Methods Patients with aRCC were enrolled from October 16, 2014, through February 23, 2016. Patients stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk and region were randomized to nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or SUN (50 mg) once per day for 4 weeks (6-week cycle). Primary endpoints: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) per independent radiology review committee in IMDC intermediate-risk/poor-risk patients. Secondary endpoints: OS, PFS, and ORR in the intention-to-treat (ITT) population and safety. Favorable-risk patient outcomes were exploratory.Results Among ITT patients, 550 were randomized to NIVO+IPI (425 intermediate/poor risk; 125 favorable risk) and 546 to SUN (422 intermediate/poor risk; 124 favorable risk). Among intermediate-risk/poor-risk patients, OS (HR, 0.66; 95% CI, 0.55–0.80) and PFS (HR, 0.75; 95% CI, 0.62–0.90) benefits were observed, and ORR was higher (42.1% vs 26.3%) with NIVO+IPI versus SUN. In ITT patients, both OS benefits (HR, 0.72; 95% CI, 0.61–0.86) and higher ORR (39.1% vs 32.6%) were observed with NIVO+IPI versus SUN. In favorable-risk patients, HR for death was 1.19 (95% CI, 0.77–1.85) and ORR was 28.8% with NIVO+IPI versus 54.0% with SUN. Duration of response was longer (HR, 0.46–0.54), and more patients achieved complete response (10.1%–12.8% vs 1.4%–5.6%) with NIVO+IPI versus SUN regardless of risk group. The incidence of treatment-related adverse events was consistent with previous reports.Conclusions NIVO+IPI led to improved efficacy outcomes versus SUN in both intermediate-risk/poor-risk and ITT patients that were maintained through 42 months’ minimum follow-up. A complete response rate >10% was achieved with NIVO+IPI regardless of risk category, with no new safety signals detected in either arm. These results support NIVO+IPI as a first-line treatment option with the potential for durable response.Trial registration number NCT02231749.

Background We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β)RII receptor (a TGF-β ‘trap’) fused to a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated squamous cell carcinoma of the head and neck (SCCHN).Methods In this phase I dose-expansion cohort, patients with advanced SCCHN not amenable to curative therapy that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or

Background Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma.Methods Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome.Results 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24–43), and median treatment duration was 2.8 months (range 0.5–42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses.Conclusions After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.

Objectives: Little data are available regarding the rate and predicting factors of serious infections in patients with rheumatoid arthritis (RA) treated with abatacept (ABA) in daily practice. We therefore addressed this issue using real-life data from the Orencia and Rheumatoid Arthritis (ORA) registry.Methods: ORA is an independent 5-year prospective registry promoted by the French Society of Rheumatology that includes patients with RA treated with ABA. At baseline, 3 months, 6 months and every 6 months or at disease relapse, during 5 years, standardised information is prospectively collected by trained clinical nurses. A serious infection was defined as an infection occurring during treatment with ABA or during the 3 months following withdrawal of ABA without any initiation of a new biologic and requiring hospitalisation and/or intravenous antibiotics and/or resulting in death.Results: Baseline characteristics and comorbidities: among the 976 patients included with a follow-up of at least 3 months (total follow-up of 1903 patient-years), 78 serious infections occurred in 69 patients (4.1/100 patient-years). Predicting factors of serious infections: on univariate analysis, an older age, history of previous serious or recurrent infections, diabetes and a lower number of previous anti-tumour necrosis factor were associated with a higher risk of serious infections. On multivariate analysis, only age (HR per 10-year increase 1.44, 95% CI 1.17 to 1.76, p=0.001) and history of previous serious or recurrent infections (HR 1.94, 95% CI 1.18 to 3.20, p=0.009) were significantly associated with a higher risk of serious infections.Conclusions: In common practice, patients treated with ABA had more comorbidities than in clinical trials and serious infections were slightly more frequently observed. In the ORA registry, predictive risk factors of serious infections include age and history of serious infections. [ABSTRACT FROM AUTHOR]

Objectives Very limited data are available regarding the efficacy of abatacept (ABA) in real life. The aims of this study were to determine the efficacy of ABA in rheumatoid arthritis and predicting factors of efficacy in common practice. Methods The Orencia and Rheumatoid Arthritis" (ORA) prospective registry, promoted by the French Society of Rheumatology, has included 1003 patients with RA. Results 773 patients had already fulfilled the 6-month follow-up visit. Only 21.3% of patients would have fulfilled inclusion criteria used in pivotal controlled trials. The European League Against Rheumatism (EULAR) response, was observed in 330 (59.1%) of the 558 assessed patients (good response: 20.4%, moderate response: 38.7%) and was similar in patients who did and in patients who did not fulfilled inclusion criteria of controlled trials. Among EULAR responders, initial 28-joint disease activity score (5.4 (4.7-6.5) in responders vs 4.9 (4.0-6.0) in non responders, p< 0.0001), the proportion of rheumatoid factor (75.6% vs 66.7%, p= 0.03) and the proportion of anti-cyclic citrullinated peptide antibody (anti-CCP)-positivity (75.9% vs 62.2%, p= 0.001) were significantly higher. In multivariate analysis adjusted on initial 28-joint disease activity score and CRP, anti-CCP positivity was associated with EULAR response (OR=1.9;95% CI=1.2 to 2.9, p=0.007), but not rheumatoid factor (OR=1.0;95% CI=0.6 to 1.6, p=0.9). Anti-CCP positivity was also significantly associated with a higher ABA retention rate at 6 months. Conclusions Real life efficacy of ABA in the ORA registry was similar as that reported in clinical trials. Anti-CCP positivity was associated with a better response to ABA, independently from disease activity. [ABSTRACT FROM AUTHOR]

Objectives: To develop a score for assessment of patients' symptoms in primary Sjögren's syndrome (SS): the EULAR SS Patient Reported Index (ESSPRI).Methods: Dryness, pain, somatic and mental fatigue were identified as the main symptoms of patients with primary SS, in studies developing the Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptoms Inventory (SSI). It was suspected that a single 0-10 numerical scale for each domain was sufficient to assess these symptoms. These four scales were gathered to form the ESSPRI. 230 patients, from 12 countries completed the ESSPRI, SSI and PROFAD questionnaires and a 0-10 patient global assessment (PGA). Correlations between each symptom and PGA were obtained. Multiple regression modelling, using PGA as 'gold standard' was used to select domains and estimate their weights.Results: PGA had good correlation with dryness, limb pain, fatigue and mental fatigue (r=0.49-0.59, all p<0.0001), but correlated less well with individual dryness features. In multivariate analysis, dryness, limb pain and fatigue, but not mental fatigue, were significantly associated with PGA; weights derived from the regression were identical for these three domains. Thus, ESSPRI was redefined as the mean of the three scales: dryness, limb pain and fatigue. Lastly, ESSPRI significantly correlated with PGA (r=0.70), PROFAD (r=0.73) and SSI (r=0.66).Conclusion: ESSPRI is a very simple index designed to measure patients' symptoms in primary SS. It has good construct validity and is well correlated with SSI and PROFAD. ESSPRI should now be validated for use as an outcome measure in clinical trials. [ABSTRACT FROM AUTHOR]

Background Anti-tumour necrosis factor (TNF) therapy may be associated with opportunistic infections (OIs). Objective To describe the spectrum of non-tuberculosis OIs associated with anti-TNF therapy and identify their risk factors. Methods A 3-year national French registry (RATIO) collected all cases of OI in patients receiving anti-TNF treatment for any indication in France. A case–control study was performed with three controls treated with anti-TNF agents per case, matched for gender and underlying inflammatory disease. Results 45 cases were collected of non-TB OIs in 43 patients receiving infliximab (n=29), adalimumab (n=10) or etanercept (n=4) for rheumatoid arthritis (n=26), spondyloarthritides (n=3), inflammatory colitis (n=8), psoriasis (n=1) or other conditions (n=5). One-third (33%) of OIs were bacterial (4 listeriosis, 4 nocardiosis, 4 atypical mycobacteriosis, 3 non-typhoid salmonellosis), 40% were viral (8 severe herpes zoster, 3 varicella, 3 extensive herpes simplex, 4 disseminated cytomegalovirus infections), 22% were fungal (5 pneumocystosis, 3 invasive aspergillosis, 2 cryptococcosis) and 4% were parasitic (2 leishmaniasis). Ten patients (23%) required admission to the intensive care unit, and four patients (9%) died. Risk factors for OIs were treatment with infliximab (OR=17.6 (95% CI 4.3 - 72.9); p<0.0001)or adalimumab (OR=10.0 (2.3 to 44.4); p=0.002) versus etanercept, and oral steroid use >10 mg/day or intravenous boluses during the previous year (OR=6.3 (2.0 to 20.0); p=0.002). Conclusion Various and severe OIs, especially those with intracellular micro-organisms, may develop in patients receiving anti-TNF treatment. Monoclonal anti-TNF antibody rather than soluble TNF receptor therapy and steroid use >10 mg/day are independently associated with OI. [ABSTRACT FROM PUBLISHER]

Objective: To develop a disease activity index for patients with primary Sjögren's syndrome (SS): the European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI).Methods: Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific 'domains' contributing to disease activity. For each domain, features of disease activity were classified in three or four levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0-10 physician global assessment (PhGA) scale, each expert scored the disease activity of five patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain.Results: All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p<0.001). Compared with 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true.Conclusions: The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardised evaluation of primary SS should facilitate clinical research and be helpful as an outcome measure in clinical trials. [ABSTRACT FROM AUTHOR]

Objectives To determine clinical and ultrasonographic predictors of joint replacement surgery across Europe in primary osteoarthritis (OA) of the knee. Methods This was a 3-year prospective study of a painful OA knee cohort (from a EULAR-sponsored, multicentre study). All subjects had clinical evaluation, radiographs and ultrasonography (US) at study entry. The rate of knee replacement surgery over the 3-year follow-up period was determined using Kaplan–Meier survival data analyses. Predictive factors for joint replacement were identified by univariate log-rank test then multivariate analysis using a Cox proportional-hazards regression model. Potential baseline predictors included demographic, clinical, radiographic and US features. Results Of the 600 original patients, 531 (88.5%), mean age 67±10 years, mean disease duration 6.1±6.9 years, had follow-up data and were analysed. During follow-up (median 3 years; range 0–4 years), knee replacement was done or required for 94 patients (estimated event rate of 17.7%). In the multivariate analysis, predictors of joint replacement were as follows: Kellgren and Lawrence radiographic grade (grade ≥III vs

Objective: To determine the incremental cost-effectiveness ratios (ICERs) of two therapeutic regimens of infliximab for ankylosing spondylitis (AS). Methods: 230 patients with active AS who were participating in a randomised controlled trial comparing two infliximab infusion modalities—every 6 weeks (Q6) and on demand (DEM)—were included in an economic evaluation within the trial. Data were collected by phone every 3 months for 1 year. Direct and indirect costs were calculated from a payer perspective. Health-related quality of life was assessed with a general health rating scale. ICERs were calculated for one 20% improvement (ASAS20), for one partial remission and for one quality-adjusted life year (QALY) gained. Results: The Q6 regimen was significantly more efficacious than the DEM regimen but also more costly (€22 388 vs €17 596; p<0.001), because it required significantly more infliximab infusions per patient (8.4 vs 6.2). The ICERs of the Q6 to DEM regimen were €15 841 for one ASAS20 response, €23 296 for one partial remission and €50 760 for one QALY gained. Conclusion: The administration of infliximab every 6 weeks is cost effective as compared with a DEM regimen; however, the ICER is close to the acceptability threshold of €50 000 for one QALY gained. Trial registration number: NCT 00439283. [ABSTRACT FROM PUBLISHER]

Objective: To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare the risks for different anti-TNF agents. Methods: A national prospective registry was designed (Research Axed on Tolerance of bIOtherapies; RATIO) to collect all cases of lymphoma in French patients receiving anti-TNF therapy from 2004 to 2006, whatever the indication. A case–control analysis was conducted including two controls treated with anti-TNF per case and an incidence study of lymphoma with the French population was used as the reference. Results: 38 cases of lymphoma, 31 non-Hodgkin’s lymphoma (NHL) (26 B cell and five T cell), five Hodgkin’s lymphoma (HL) and two Hodgkin’s-like lymphoma were collected. Epstein–Barr virus was detected in both of two Hodgkin’s-like lymphoma, three of five HL and one NHL. Patients receiving adalimumab or infliximab had a higher risk than those treated with etanercept: standardised incidence ratio (SIR) 4.1 (2.3–7.1) and 3.6 (2.3–5.6) versus 0.9 (0.4–1.8). The exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma in the case–control study: odds ratio 4.7 (1.3–17.7) and 4.1 (1.4–12.5), respectively. The sex and age-adjusted incidence rate of lymphoma was 42.1 per 100 000 patient-years. The SIR was 2.4 (95% CI 1.7 to 3.2). Conclusion: The two to threefold increased risk of lymphoma in patients receiving anti-TNF therapy is similar to that expected for such patients with severe inflammatory diseases. Some lymphomas associated with immunosuppression may occur, and the risk of lymphoma is higher with monoclonal-antibody therapy than with soluble-receptor therapy. [ABSTRACT FROM PUBLISHER]

Background: The Health Assessment Questionnaire Disability Index (HAQ-DI) is the most widely used measure of function in rheumatoid arthritis (RA). Objective: To evaluate individualised forms of the HAQ-DI and thus enhance the incorporation of patients’ views in outcome assessment. Patients and methods: HAQ-DI data were prospectively obtained from 370 outpatients with RA treated with leflunomide over a 6-month period. At baseline and final visits, patients had to rate the importance they attached to each activity addressed by the 20 HAQ-DI items, and to select the five activities they considered the most important. Different individualised scales were evaluated: scales preserving all domains, in which the score for each item is multiplied by or added to its importance; and scales involving, for each patient, only the five most important items. The psychometric properties of these scales were compared with those of the HAQ-DI. Results: For each HAQ-DI item, severity and importance scores were weakly correlated. Scores for all individualised scales were highly correlated with the HAQ-DI score (r>0.75). All scales had a good internal consistency (Cronbach’s α 0.87–0.88). Compared with the HAQ-DI, individualised scales did not have better sensitivity to change (standardised response mean 0.64–0.69 vs 0.74). Conclusion: Individualised scales have similar properties to the HAQ-DI. However, individualised questionnaires measuring importance gave complementary information to the measure of disability. Individualisation is probably not needed for group assessment in all randomised controlled trials but, the use of individualised questionnaires may be clinically relevant for individual patients with RA. [ABSTRACT FROM PUBLISHER]

Objectives: To describe the characteristics, treatment, and outcomes of active infective endocarditis (IE) in Europe. Design: Prospective survey of medical practices in Europe. Setting: 92 centres from 25 countries. Patients: The EHS (Euro heart survey) on valvar heart disease (VHD) enrolled 5001 adult patients between April and July 2001. 01 those, 159 had active IE. Results: 118 patients (74%) had native IE and 41(26%) had prosthetic IE. Mean (SD) age was 57 (16) years. Blood cultures were obtained for 113 patients (71 %) before antibiotic treatment was started. Surgery was performed in 52% of patients. Reasons for surgery were heart failure in 60%, persistent sepsis in 40%, vegetation size in 48%, or embolism in 18%. Surgery was for implantation of mechanical prosthesis in 63%, bioprosthesis in 21%, aortic homograft in 5%, and valve repair in 11%. In-hospital mortality was 12.6%, being 10.4% in the medical group and 15.6% in the surgical group. Among the total population of 5001 patients, only 50% of those with native VHD had been educated on endocarditis prophylaxis and only 33% regularly attended dental follow up. Of patients with IE who had had a procedure at risk during the preceding year only 50% had received adequate prophylaxis. Conclusions: The ENS on YHD shows that patients with active IE have a high risk profile and often undergo surgery. However, there are deficiencies in obtaining blood cultures and applying prophylaxis. Mortality remains high, which is a Justification for the improvement of patient management through education and the implementation of guidelines. [ABSTRACT FROM AUTHOR]

Objective: To compare radiographic reading procedures and evaluate their impact on sample size in hip osteoarthritis (OA) longitudinal studies.Methods: Pelvic radiographs performed twice, three years apart, in 104 patients with hip OA were read by a single reader using the Kellgren and Lawrence system, joint space narrowing scale, and joint space width (JSW). Reading procedures were (a) films read as single radiographs, (b) films grouped by patient but read in random order, (c) films grouped by patient and chronologically ordered, all with landmarks for JSW measurements, (d) films read as single radiographs, without landmarks for JSW measurements. JSW was measured at the narrowest point with a 0.1 mm graduated magnifying glass.Results: More Kellgren and Lawrence or joint space narrowing grades were modified respectively with the single (42% and 37%) than with the paired (32% and 23%) or chronologically ordered (34% and 29%) reading procedures. Variability of JSW progression was principally related to mean progression (88.3%) and landmarks (almost 10%). Standardised response means were -0.71 with the paired reading procedure with landmarks, -0.68 with the single reading procedure with landmarks, -0.65 with the single reading procedure without landmarks. With landmarks, 10% more patients would be needed using single than paired reading. Using single reading, 10% more patients would be needed without landmarks than with landmarks.Conclusion: Kellgren and Lawrence grading seems to be influenced by the reading procedure, as is joint space narrowing grading, for assessing hip OA. Paired reading procedure with landmarks for JSW should be recommended in longitudinal studies. [ABSTRACT FROM AUTHOR]

Background: To be certain that the joint space width is abnormal in the case of hip joint pain when compared with the contralateral hip requires knowledge of physiological dissymmetry.Aim Of the Study: To assess interindividual variability and dissymmetry in pelvic radiological joint space width.Methods: Pelvic radiographs of subjects without hip joint disease. Measurement with a 0.1 mm graduated magnifying glass and 0.5 mm graduated flat ruler at the hip superointermediate site (vertical going through the femoral head centre). After randomisation of the side to measure, analysis of nine groups of 19 plain films by one investigator blind for the result of the contralateral side.Results: The difference between the left and right hip was plotted against the corresponding mean for all 171 normal subjects. This shows the frequency and the limits of the asymmetry at each measurement site. The asymmetry is independent of interindividual variability of the joint space width and greater than the measurement error in most subjects.Conclusion: This study confirms the interindividual variability of hip joint space width, shows the frequency of hip joint space asymmetry and defines its limit. [ABSTRACT FROM AUTHOR]

Objectives: (1) To assess reproducibility of medial knee joint space width (JSW) measurement in healthy subjects and osteoarthritic (OA) patients. (2) To define minimal relevant radiological change in knee JSW based on the reproducibility of its measurement.Patients and Methods: (1) Healthy volunteers: in the first part of the study, 20 knees of healthy adult volunteers were radiographed in the weightbearing, anteroposterior extended view, twice, two weeks apart, using three different radiographic procedures: (a) without guidelines, (b) with guidelines and without fluoroscopy, (c) with guidelines and fluoroscopy. (2) Knee OA patients: in the second part of the study, 36 knees of OA patients were radiographed twice with guidelines and without fluoroscopy. JSW was measured blindly using a graduated magnifying glass. Based on the Bland and Altman graphic approach, cut off points defining minimal relevant radiological change are proposed.Results: Standard deviation (SD) of differences in JSW measurement between two sets of knee radiographs in healthy subjects were 0.66 mm for radiography performed without guidelines, 0.37 mm for radiography performed with guidelines and without fluoroscopy, and 0.31 mm for radiography with guidelines and fluoroscopy. SD of differences in JSW measurement in OA patients were 0.32 mm for radiography performed with guidelines and without fluoroscopy. A minimal relevant change in JSW between two radiographs performed in healthy subjects can be defined by a change of at least 1.29 or 0.59 mm when radiographs are taken without guidelines, and with guidelines and fluoroscopy, respectively. When radiographs are taken with guidelines and without fluoroscopy, the change must be at least 0.73 mm. A similar figure, 0.64 mm was observed in knee OA patients.Conclusion: Definition of radiological progression varies greatly according to the radiographic procedure chosen. Use of guidelines reduces the threshold of progression required to consider that change between two measures is relevant. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of standing position on joint space width (JSW) measurements of the hips with and without osteoarthritis (OA) on pelvic radiographs.Methods: Adult patients aged 18 or more had pelvic anteroposterior conventional radiographs standing and supine performed by a single radiologist in the same radiology unit according to standardised guidelines. JSW measurements in mm were made by a single reader blind to patients' identity and type of view, using a 0.1 mm graduated magnifying glass directly laid over the radiograph, at the narrowest point for OA hips or at the vertical joint space for non-OA hips. Agreement of JSW between both views was assessed using the Bland and Altman graphical analysis.Results: JSW was greater on standing than supine radiographs, for example, 7.1% for OA hips. Mean (SD) differences and limits of agreement (mm) between both views were 0.08 (0.27) and -0.46 to 0.62 for the 70 non-OA hips, 0.02 (0.31) and -0.60 to 0.64 for the 46 OA hips. Corresponding 95% confidence intervals of mean difference were 0.02, -0.14 mm and -0.07, -0.11 mm.Conclusions: Measurements of JSW of the hip on pelvic standing and supine radiographs are concordant. Changes less than or equal to 0.64 mm between the two views are similar or inferior to radiological progression of OA. [ABSTRACT FROM AUTHOR]

BACKGROUND: Informed consent in clinical research is mandated throughout the world. Both patient subjects and investigators are required to understand and accept the distinction between research and treatment. AIM: To document the extent and to identify factors associated with therapeutic misconception in a population of patient subjects or parent proxies recruited from a variety of multicentre trials (parent studies). Patients and METHODS: The study comprised two phases: the development of a questionnaire to assess the quality of informed consent and a survey of patient subjects based on this questionnaire. RESULTS: A total of 303 patient subjects or parent proxies were contacted and 279 questionnaires were analysed. The median age was 49.5 years, sex ratio was 1 and 61% of respondents were professionally active. Overall memorisation of the oral or written communication of informed consent was good (69-97%), and satisfaction with the process was around 70%. Therapeutic misconception was present in 70% of respondents, who expected to receive better care and ignored the consequence of randomisation and treatment comparisons. This was positively associated with the acuteness and severity of the disease. CONCLUSION: The authors suggest that the risk of therapeutic misconception be specifically addressed in consent forms as an educational tool for both patients and investigators. [ABSTRACT FROM AUTHOR]

Objective To our knowledge, the effect of front-of-pack nutrition labels such as the Nutri-Score on food purchases has never been assessed among individuals suffering from nutrition-related chronic diseases specifically, while dietary modifications are generally part of their care. This study aimed to investigate the effect of the Nutri-Score on the nutritional quality of purchasing intentions among adults suffering from a cardiometabolic disease, compared with no label and the Reference Intakes (RIs), a label already implemented by some food manufacturers in France.Setting Secondary prevention—mainland France.Participants 2431 eligible participants were randomly assigned and 1180 participants (65.5% women, mean age 65.0±7.1 years) completed the shopping task and were included in the analyses.Intervention A three-arm randomised controlled trial using an experimental online supermarket was conducted in 2017. Participants with cardiometabolic diseases were invited to simulate food purchases with the Nutri-Score, the RIs or no label.Primary and secondary outcome measures The primary outcome was the nutritional quality of the shopping cart, estimated using the French-modified Food Standard Agency Nutrient Profiling System (FSAm-NPS), and secondary outcomes included the nutrient content of purchases.Results The mean (SD) FSAm-NPS score was significantly lower in the Nutri-Score arm (1.29 (3.61) points), reflecting a higher overall nutritional quality of purchasing intentions, compared with the RIs (1.86 (3.23) points) and no label (1.92 (2.90) points) arms (p=0.01). Moreover, the Nutri-Score led to significantly lower content in calories and saturated fatty acids compared with the two other arms. These differences resulted from participants avoiding some packaged products (sweets, dairy and starches) and purchasing larger amounts of fresh fruit and meat.Conclusions The Nutri-Score exhibited a significant higher nutritional quality of purchasing intentions, encouraging healthier food choices among individuals suffering from cardiometabolic chronic diseases.Trial registration number NCT02769455.

Abstract Background Antibodies targeting programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) have shown clinical activity in the treatment of metastatic renal cell carcinoma (mRCC). This phase Ib cohort of the JAVELIN Solid Tumor trial assessed the efficacy and safety of avelumab (anti–PD-L1) monotherapy in patients with mRCC as either first-line (1 L) or second-line (2 L) treatment. Methods Patients with mRCC with a clear-cell component who were treatment naive (1 L subgroup) or had disease progression after one prior line of therapy (2 L subgroup) received avelumab 10 mg/kg intravenous infusion every 2 weeks. Endpoints included confirmed best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), PD-L1 expression, and safety. Results A total of 62 patients were enrolled in the 1 L subgroup, and 20 patients were enrolled in the 2 L subgroup. In the 1 L and 2 L subgroups, confirmed objective response rates were 16.1 and 10.0%, median DOR was 9.9 months (95% confidence interval [CI], 2.8–not evaluable) and not evaluable (95% CI, 6.9–not evaluable), median PFS was 8.3 months (95% CI, 5.5–9.5) and 5.6 months (95% CI, 2.3–9.6), and median OS was not evaluable (95% CI, not evaluable) and 16.9 months (95% CI, 8.3–not evaluable), respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 51 patients in the 1 L subgroup (82.3%) and 14 patients in the 2 L subgroup (70.0%). Grade ≥ 3 TRAEs occurred in eight patients in the 1 L subgroup (12.9%) and one patient in the 2 L subgroup (5.0%). No treatment-related deaths occurred. Conclusion Avelumab showed clinical activity and a manageable safety profile in both the 1 L and 2 L treatment setting in patients with mRCC. These data support the use of avelumab in combination with other agents in mRCC. Trial registration ClinicalTrials.gov: NCT01772004; registered 21 January, 2013.

Recent advances in medical and information technologies, the availability of new types of medical data, the requirement of increasing numbers of study participants, as well as difficulties in recruitment and retention, all present serious problems for traditional models of specific and informed consent to medical research. However, these advances also enable novel ways to securely share and analyse data. This paper introduces one of these advances-blockchain technologies-and argues that they can be used to share medical data in a secure and auditable fashion. In addition, some aspects of consent and data collection, as well as data access management and analysis, can be automated using blockchain-based smart contracts. This paper demonstrates how blockchain technologies can be used to further all three of the bioethical principles underlying consent requirements: the autonomy of patients, by giving them much greater control over their data; beneficence, by greatly facilitating medical research efficiency and by reducing biases and opportunities for errors; and justice, by enabling patients with rare or under-researched conditions to pseudonymously aggregate their data for analysis. Finally, we coin and describe the novel concept of prosent, by which we mean the blockchain-enabled ability of all stakeholders in the research process to pseudonymously and proactively consent to data release or exchange under specific conditions, such as trial completion., Competing Interests: Competing interests: SPM reports grants from Carlsberg Foundation, during the conduct of the study; and is a co-founder of A&BC Consulting, which offers editing and academic consulting services. JS reports grants from Wellcome Trust, grants from Uehiro Foundation on Ethics and Education, grants from Murdoch Children's Research Institute, grants from Melbourne Law School, during the conduct of the study; grants from Wellcome Trust, grants from Oxford Martin School, personal fees and other from Various, outside the submitted work. PR has nothing to disclose. MB reports non-financial support from SunnyLake, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)