Rationale and design of the FRENch CoHort of myocardial Infarction Evaluation (FRENCHIE) study.

BACKGROUND: Despite major advances in prevention and treatment, cardiovascular diseases - particularly acute myocardial infarction - remain a leading cause of death worldwide and in France. Collecting contemporary data about the characteristics, management and outcomes of patients with acute myocardial infarction in France is important. AIMS: The main objectives are to describe baseline characteristics, contemporary management, in-hospital and long-term outcomes of patients with acute myocardial infarction hospitalized in tertiary care centres in France; secondary objectives are to investigate determinants of prognosis (including periodontal disease and sleep-disordered breathing), to identify gaps between evidence-based recommendations and management and to assess medical care costs for the index hospitalization and during the follow-up period. METHODS: FRENCHIE (FRENch CoHort of myocardial Infarction Evaluation) is an ongoing prospective multicentre observational study (ClinicalTrials.gov Identifier: NCT04050956) enrolling more than 19,000 patients hospitalized for acute myocardial infarction with onset of symptoms within 48hours in 35 participating centres in France since March 2019. Main exclusion criteria are age<18 years, lack of health coverage and procedure-related myocardial infarction (types 4a and 5). Detailed information was collected prospectively, starting at admission, including demographic data, risk factors, medical history and treatments, initial management, with prehospital care pathways and medication doses, and outcomes until hospital discharge. The follow-up period (up to 20 years for each patient) is ensured by linking with the French national health database (Système national des données de santé), and includes information on death, hospital admissions, major clinical events, healthcare consumption (including drug reimbursement) and total healthcare costs. FRENCHIE is also used as a platform for cohort-nested studies - currently three randomized trials and two observational studies. CONCLUSIONS: This nationwide large contemporary cohort with very long-term follow-up will improve knowledge about acute myocardial infarction management and outcomes in France, and provide a useful platform for nested studies and trials.

Assessment of US Food and Drug Administration-Approved Digital Medical Devices for Just-in-Time Interventions: A Systematic Review.

Importance: Just-in-time interventions (JITIs) are a type of digital therapeutic intervention that combines remote monitoring tools and algorithms to personalize the delivery of specific interventions at the right time. The US Food and Drug Administration (FDA) regulatory approval documents are often the only available source of information on the effectiveness of therapeutic interventions based on these devices. Objective: To systematically review the publicly available information from the FDA on all recently approved medical devices used in JITIs to (1) assess how they operate to deliver JITIs and (2) appraise the evidence supporting their performance and clinical effectiveness. Evidence Review: Two reviewers systematically searched the Premarket Notifications (510(k)), Premarket Approvals, De Novo, and Humanitarian Device Exemption databases from January 2019 to December 2021 for all entries associated with devices that monitored patients' data over time to personalize the delivery of interventions to treat, prevent, or mitigate health conditions or events. They assessed whether the product summaries (1) enabled an understanding of how the device operated to deliver a JITI (eg, the nature, type, and frequency of the monitoring, the nature of the decision algorithm, and the nature and intended receiver of the intervention); (2) informed about the performance and effectiveness of the JITI; and (3) included information on data security and ownership. Findings: In total, 38 devices were included in this review. These were mainly intended for cardiac conditions (12 [31.6%]), diabetes (10 [26.3%]), and neurological diseases (4 [10.5%]). Monitoring devices ranged from wearable (18 of 28 [64.4%]; eg, smartwatches) to implanted sensors (6 of 28 [21.4%]; eg, inserted electrocardiographic sensors). Only 10 of 38 product summaries (26.3%) allowed a full understanding of how the device operated to deliver a JITI. Similarly, only 12 of 28 (42.9%), 12 of 36 (33.3%), and 5 of 38 (13.2%) reported the assessment of the performance of the monitoring device, assessment of the decision algorithm, and results of clinical studies assessing the effectiveness of the JITI, respectively. Finally, 14 of 36 product summaries (38.9%) included some information on data security, but none included information on data ownership. Conclusion and Relevance: The results of this systematic review suggest that the information publicly available in the FDA databases on the performance and effectiveness of digital medical devices used in JITIs is heterogeneous.

Assessment of transparency and selective reporting of interventional trials studying colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is currently one of the most frequently diagnosed cancers. Our aim was to evaluate transparency and selective reporting in interventional trials studying CRC. METHODS: First, we assessed indicators of transparency with completeness of reporting, according to the CONSORT statement, and data sharing. We evaluated a selection of reporting items for a sample of randomized controlled trials (RCTs) studying CRC with published full-text articles between 2021-03-22 and 2018-03-22. Selected items were issued from the previously published CONSORT based peer-review tool (COBPeer tool). Then, we evaluated selective reporting through retrospective registration and primary outcome(s) switching between registration and publication. Finally, we determined if primary outcome(s) switching favored significant outcomes. RESULTS: We evaluated 101 RCTs with published full-text articles between 2021-03-22 and 2018-03-22. Five trials (5%) reported all selected CONSORT items completely. Seventy-four (73%), 53 (52%) and 13 (13%) trials reported the primary outcome(s), the allocation concealment process and harms completely. Twenty-five (25%) trials were willing to share data. In our sample, 49 (49%) trials were retrospectively registered and 23 (23%) trials had primary outcome(s) switching. The influence of primary outcome(s) switching could be evaluated in 16 (16/23 = 70%) trials, with 6 (6/16 = 38%) trials showing a discrepancy that favored statistically significant results. CONCLUSIONS: Our results highlight a lack of transparency as well as frequent selective reporting in interventional trials studying CRC.

Acceptability of and Willingness to Take Digital Pills by Patients, the Public, and Health Care Professionals: Qualitative Content Analysis of a Large Online Survey.

BACKGROUND: Digital pills are pills combined with a sensor, which sends a signal to a patch connected to a smartphone when the pills are ingested. Health care professionals can access patient data from digital pills online via their own interface, thus allowing them to check whether a patient took the drug. Digital pills were developed for the stated goal of improving treatment adherence. The US Food and Drug Administration approved the first digital pills in November 2017, but the manufacturer withdrew its application to the European Medicines Agency in July 2020 because of insufficient evaluation. OBJECTIVE: As recommended for the evaluation of health technologies, this study assesses the prospective acceptability of and willingness to take digital pills among patients, the public, and health care professionals. METHODS: Participants were patients who were receiving long-term treatment for a chronic condition, public participants (both groups recruited from a representative sample), and health care professionals. Participants answered 5 open-ended questions regarding the acceptability of digital pills and 1 close-ended question regarding the willingness to take digital pills, which were developed in a preliminary qualitative study. We explored the 5 theoretical dimensions of acceptability by performing an abductive qualitative content analysis of all free-text responses. We assessed data saturation with mathematical models. We fitted a multivariate logistic regression model to identify the sociodemographic and health characteristics associated with the willingness to take digital pills. RESULTS: Between January 29, 2020, and April 18, 2020, 767 patients, 1238 public participants, and 246 health care professionals provided 11,451 free-text responses. We identified 98 codes related to the acceptability of digital pills: 29 codes on perceived clinical effectiveness (eg, sensor safety cited by 66/2251 participants, 29.5%), 6 on perceived burden (eg, increased doctors' workload, 164/2251 participants, 7.3%), 25 on perceived ethicality (eg, policing, 345/2251 participants, 15.3%), 30 codes on perceived opportunity (eg, exclusively negative perception, 690/2251 participants, 30.7%), and 8 on affective attitude (eg, anger, 541/2251, 24%). Overall, 271/767 (35.3%) patients, 376/1238 (30.4%) public participants, and 39/246 (15.8%) health care professionals reported willingness to take digital pills. This willingness was associated with male sex (odds ratio 1.98, 95% CI 1.62-2.43) and current use of a connected device to record health settings (with a dose-response relationship). CONCLUSIONS: The prospective acceptability of and willingness to take digital pills were limited by clinical and ethical concerns both at the individual and societal level. Our results suggest that digital pills should not be considered a mere change in the form of drug administration but a complex intervention requiring specific evaluation before extended use in clinical routine practice as well as an ethical and legal framework to ensure safe and ethical collection and use of health data through a patient-centered approach.

Important Issues to Severe Trauma Survivors: A Qualitative Study.

OBJECTIVE: Identify issues that are important to severe trauma survivors up to 3 years after the trauma. BACKGROUND: Severe trauma is the first cause of disability-adjusted life years worldwide, yet most attention has focused on acute care and the impact on long-term health is poorly evaluated. METHOD: We conducted a large-scale qualitative study based on semi-structured phone interviews. Qualitative research methods involve the systematic collection, organization, and interpretation of conversations or textual data with patients to explore the meaning of a phenomenon experienced by individuals themselves. We randomly selected severe trauma survivors (abbreviated injury score ≥3 in at least 1 body region) who were receiving care in 6 urban academic level-I trauma centers in France between March 2015 and March 2018. We conducted double independent thematic analysis. Issues reported by patients were grouped into overarching domains by a panel of 5 experts in trauma care. Point of data saturation was estimated with a mathematical model. RESULTS: We included 340 participants from 3 months to 3 years after the trauma [median age: 41 years (Q1-Q3 24-54), median injury severity score: 17 (Q1-Q3 11-22)]. We identified 97 common issues that we grouped into 5 overarching domains: body and neurological issues (29 issues elicited by 277 participants), biographical disruption (23 issues, 210 participants), psychological and personality issues (21 issues, 147 participants), burden of treatment (14 issues, 145 participants), and altered relationships (10 issues, 87 participants). Time elapsed because the trauma, injury location, or in-hospital trauma severity did not affect the distribution of these domains across participants' answers. CONCLUSIONS: This qualitative study explored trauma survivors' experiences of the long-term effect of their injury and allowed for identifying a set of issues that they consider important, including dimensions that seem overlooked in trauma research. Our findings confirm that trauma is a chronic medical condition that demands new approaches to post-discharge and long-term care.

Future of evidence ecosystem series: 3. From an evidence synthesis ecosystem to an evidence ecosystem.

The "one-off" approach of systematic reviews is no longer sustainable; we need to move toward producing "living" evidence syntheses (i.e., comprehensive, based on rigorous methods, and up-to-date). This implies rethinking the evidence synthesis ecosystem, its infrastructure, and management. The three distinct production systems-primary research, evidence synthesis, and guideline development-should work together to allow for continuous refreshing of synthesized evidence and guidelines. A new evidence ecosystem, not just focusing on synthesis, should allow for bridging the gaps between evidence synthesis communities, primary researchers, guideline developers, health technology assessment agencies, and health policy authorities. This network of evidence synthesis stakeholders should select relevant clinical questions considered a priority topic. For each question, a multidisciplinary community including researchers, health professionals, guideline developers, policymakers, patients, and methodologists needs to be established and commit to performing the initial evidence synthesis and keeping it up-to-date. Encouraging communities to work together continuously with bidirectional interactions requires greater incentives, rewards, and the involvement of health care policy authorities to optimize resources. A better evidence ecosystem with collaborations and interactions between each partner of the network of evidence synthesis stakeholders should permit living evidence syntheses to justify their status in evidence-informed decision-making.

The research burden of randomized controlled trial participation: a systematic thematic synthesis of qualitative evidence.

BACKGROUND: Participation in randomized controlled trials (RCTs) may be quite demanding and could represent an important burden for patients. We aimed to explore this research burden (i.e., the psychological, physical, and financial burdens) experienced by patients through their participation in a RCT. METHODS: We conducted a systematic review of qualitative studies exploring adult patients' experiences with RCT participation. We searched MEDLINE (PubMed), CINAHL, PSYCHINFO, and Embase (search date March 2018) for eligible reports. Qualitative data coding and indexing were assisted by NVivo. The quality of reports was assessed by using the Critical Appraisal Skills Program (CASP) tool. RESULTS: We included 45 qualitative studies that involved 1732 RCT participants. Important psychological burdens were identified at every stage of the trial process. Participants reported feeling anxiety and being afraid of "being a 'guinea pig'" and described undergoing randomization and allocation to a placebo as particularly difficult resulting in disappointment, anger, and depression. Patients' follow-up and trial closure were also responsible for a wide range of psychological, physical, and financial burdens. Furthermore, factors related to burdensome impacts and consequences were discerned. These factors involved trial information, poorly organized and too-demanding follow-up, and lack of appropriate management when the patient's participation ended. Trial participation was also associated with beneficial effects such as the satisfaction of feeling "useful," gaining "a sense of control," and receiving special attention. CONCLUSIONS: Our finding provides a detailed description of research burden across the whole RCT process. Many of the burdens described could be anticipated, and some avoided in a movement toward minimally disruptive clinical research. Such an approach could improve trial recruitment and retention. REVIEW REGISTRATION: PROSPERO CRD42018098994.

Impact of blinding on estimated treatment effects in randomised clinical trials: meta-epidemiological study.

OBJECTIVES: To study the impact of blinding on estimated treatment effects, and their variation between trials; differentiating between blinding of patients, healthcare providers, and observers; detection bias and performance bias; and types of outcome (the MetaBLIND study). DESIGN: Meta-epidemiological study. DATA SOURCE: Cochrane Database of Systematic Reviews (2013-14). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Meta-analyses with both blinded and non-blinded trials on any topic. REVIEW METHODS: Blinding status was retrieved from trial publications and authors, and results retrieved automatically from the Cochrane Database of Systematic Reviews. Bayesian hierarchical models estimated the average ratio of odds ratios (ROR), and estimated the increases in heterogeneity between trials, for non-blinded trials (or of unclear status) versus blinded trials. Secondary analyses adjusted for adequacy of concealment of allocation, attrition, and trial size, and explored the association between outcome subjectivity (high, moderate, low) and average bias. An ROR lower than 1 indicated exaggerated effect estimates in trials without blinding. RESULTS: The study included 142 meta-analyses (1153 trials). The ROR for lack of blinding of patients was 0.91 (95% credible interval 0.61 to 1.34) in 18 meta-analyses with patient reported outcomes, and 0.98 (0.69 to 1.39) in 14 meta-analyses with outcomes reported by blinded observers. The ROR for lack of blinding of healthcare providers was 1.01 (0.84 to 1.19) in 29 meta-analyses with healthcare provider decision outcomes (eg, readmissions), and 0.97 (0.64 to 1.45) in 13 meta-analyses with outcomes reported by blinded patients or observers. The ROR for lack of blinding of observers was 1.01 (0.86 to 1.18) in 46 meta-analyses with subjective observer reported outcomes, with no clear impact of degree of subjectivity. Information was insufficient to determine whether lack of blinding was associated with increased heterogeneity between trials. The ROR for trials not reported as double blind versus those that were double blind was 1.02 (0.90 to 1.13) in 74 meta-analyses. CONCLUSION: No evidence was found for an average difference in estimated treatment effect between trials with and without blinded patients, healthcare providers, or outcome assessors. These results could reflect that blinding is less important than often believed or meta-epidemiological study limitations, such as residual confounding or imprecision. At this stage, replication of this study is suggested and blinding should remain a methodological safeguard in trials.

Is My Patient Overwhelmed?: Determining Thresholds for Acceptable Burden of Treatment Using Data From the ComPaRe e-Cohort.

OBJECTIVE: To estimate the highest burden of treatment beyond which patients with chronic conditions consider their current investments of time and effort in health care unsustainable. PATIENTS AND METHODS: We used data collected between January 1, 2017 and October 1, 2018 in the Community of Patients for Research (ComPaRe), an ongoing e-cohort of adult patients with chronic conditions in France. We matched participants' answers to the Treatment Burden Questionnaire (TBQ) and to a Yes/No anchor question: "Think about all the things you do to care for yourself. Do you think you could continue investing the same amount of time, energy, and money in your health care lifelong?" We defined the Patient Acceptable Symptom State (PASS) for the burden of treatment as the TBQ score below which 75% of patients reported an acceptable burden state. RESULTS: We analyzed data for 2413 patients (1781 [73.8%] women, 1248 [51.7%] multimorbid, median age: 48 (interquartile range, 36-59] years) enrolled in ComPaRe. Of these, 38% (917 of 2413) reported that they would be unable to continue the same investment of energy, time, and money in health care lifelong. The PASS for the burden of treatment was at 39% of the maximal score (ie, TBQ score = 59/150; 95% CI, 52-64) Using these results, clinicians can detect patients at risk for becoming overwhelmed by their medical care by identifying patients with TBQ scores of 59 or higher. CONCLUSION: About 40% of patients with chronic conditions report being unable to sustain current investments of energy, time, and money in health care lifelong. The PASS for treatment burden provides a practical yardstick to help clinicians and researchers interpret scores for burden of treatment.

Overcoming Barriers to Mobilizing Collective Intelligence in Research: Qualitative Study of Researchers With Experience of Collective Intelligence.

BACKGROUND: Innovative ways of planning and conducting research have emerged recently, based on the concept of collective intelligence. Collective intelligence is defined as shared intelligence emerging when people are mobilized within or outside an organization to work on a specific task that could result in more innovative outcomes than those when individuals work alone. Crowdsourcing is defined as "the act of taking a job traditionally performed by a designated agent and outsourcing it to an undefined, generally large group of people in the form of an open call." OBJECTIVE: This qualitative study aimed to identify the barriers to mobilizing collective intelligence and ways to overcome these barriers and provide good practice advice for planning and conducting collective intelligence projects across different research disciplines. METHODS: We conducted a multinational online open-ended question survey and semistructured audio-recorded interviews with a purposive sample of researchers who had experience in running collective intelligence projects. The questionnaires had an interactive component, enabling respondents to rate and comment on the advice of their fellow respondents. Data were analyzed thematically, drawing on the framework method. RESULTS: A total of 82 respondents from various research fields participated in the survey (n=65) or interview (n=17). The main barriers identified were the lack of evidence-based guidelines for implementing collective intelligence, complexity in recruiting and engaging the community, and difficulties in disseminating the results of collective intelligence projects. We drew on respondents' experience to provide tips and good practice advice for governance, planning, and conducting collective intelligence projects. Respondents particularly suggested establishing a diverse coordination team to plan and manage collective intelligence projects and setting up common rules of governance for participants in projects. In project planning, respondents provided advice on identifying research problems that could be answered by collective intelligence and identifying communities of participants. They shared tips on preparing the task and interface and organizing communication activities to recruit and engage participants. CONCLUSIONS: Mobilizing collective intelligence through crowdsourcing is an innovative method to increase research efficiency, although there are several barriers to its implementation. We present good practice advice from researchers with experience of collective intelligence across different disciplines to overcome barriers to mobilizing collective intelligence.

Cost-effectiveness of rituximab versus azathioprine for maintenance treatment in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: Rituximab was proven superior to azathioprine for maintenance treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The high cost of rituximab might, however, limit its routine use. This study determined the cost-effectiveness of intravenous rituximab (5 x 500 mg until month 18), versus oral azathioprine (2 mg/kg per day, gradually decreased between month 12 and 22), for maintenance treatment of patients with granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited vasculitis, aged 18-75. METHODS: We performed a single-trial based economic evaluation. MAINRITSAN was a 28-month multicentre, prospective, randomised, controlled open-label trial. We estimated the cost of healthcare resources and quality of life using prospectively collected data. Healthcare costs were estimated from the perspective of the French Social Health Insurance's perspective, using 2016 tariffs for reimbursement. Utilities were derived from Short Form 36 scores. We estimated total average cost, incremental cost per incremental relapse averted and per quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed to assess uncertainty over relapses, severe adverse events, discount rate, utility weights, time horizon and the cost of rituximab. Costs drivers were tested using a generalised linear model. RESULTS: Total average costs were €13,387 (€11,605-€15,646) and €10,217 (€7,567-12,949) in the rituximab and azathioprine groups respectively. The incremental cost-effectiveness ratio (ICER) was €12,824 per relapse averted and the incremental cost-utility ratio (ICUR) €37,782 per QALY gained. Besides the unit cost of rituximab, the major cost drivers were relapses and severe adverse events. CONCLUSIONS: Maintenance treatment by rituximab could be cost-effective for preventing relapses in patients with AAV.

Disagreements in risk of bias assessment for randomised controlled trials included in more than one Cochrane systematic reviews: a research on research study using cross-sectional design.

OBJECTIVES: Assess the frequency and reasons for disagreements in risk of bias assessments for randomised controlled trials (RCTs) included in more than one Cochrane review. DESIGN: Research on research study, using cross-sectional design. DATA SOURCES: 2796 Cochrane reviews published between March 2011 and September 2014. DATA SELECTION: RCTs included in more than one review. DATA EXTRACTION: Risk of bias assessment and support for judgement for five key risk of bias items. DATA SYNTHESIS: For each item, we compared risk of bias assessment made in each review and calculated proportion of agreement. Two reviewers independently analysed 50% of all disagreements by comparing support for each judgement with information from study report to evaluate whether disagreements were related to a difference in information (eg, contact the study author) or a difference in interpretation (same support for judgement but different interpretation). They also identified main reasons for different interpretation. RESULTS: 1604 RCTs were included in more than one review. Proportion of agreement ranged from 57% (770/1348 trials) for incomplete outcome data to 81% for random sequence generation (1193/1466). Most common source of disagreement was difference in interpretation of the same information, ranging from 65% (88/136) for random sequence generation to 90% (56/62) for blinding of participants and personnel. Access to different information explained 32/136 (24%) disagreements for random sequence generation and 38/205 (19%) for allocation concealment. Disagreements related to difference in interpretation were frequently related to incomplete or unclear reporting in the study report (83% of disagreements related to different interpretation for random sequence generation). CONCLUSIONS: Risk of bias judgements of RCTs included in more than one Cochrane review differed substantially. Most disagreements were related to a difference in interpretation of an incomplete or unclear description in the study report. A clearer guidance on common causes of incomplete information may improve agreement.

Patients' perspectives on how to decrease the burden of treatment: a qualitative study of HIV care in sub-Saharan Africa.

OBJECTIVE: Patients living with HIV infection (PLWH) in sub-Saharan Africa face an important burden of treatment related to everything they do to take care of their health: doctor visits, tests, regular refills, travels, and so on. In this study, we involved PLWH in proposing ideas on how to decrease their burden of treatment and assessed to what extent these propositions could be implemented in care. METHODS: Adult PLWH recruited in three HIV care centres in Côte d'Ivoire participated in qualitative interviews starting with 'What do you believe are the most important things to change in your care to improve your burden of treatment?' Two independent investigators conducted a thematic analysis to identify and classify patients' propositions to decrease their burden of treatment. A group of experts involving patients, health professionals, hospital leaders and policymakers evaluated each patient proposition to assess its feasibility. RESULTS: Between February and April 2017, 326 participants shared 748 ideas to decrease their burden of treatment. These ideas were grouped into 59 unique patient propositions to improve their personal care and the organisation of their hospital or clinic and/or the health system. Experts considered that 27 (46%), 19 (32%) and 13 (22%) of patients' propositions were easy, moderate and difficult, respectively, to implement. A total of 118 (36%) participants offered at least one proposition considered easily implementable by our experts. CONCLUSION: Asking PLWH in sub-Saharan Africa about how their care could be improved led to identifying meaningful propositions. According to experts, half of the ideas identified could be implemented easily at low cost for minimally disruptive HIV care.

Acceptable medication non-adherence: A crowdsourcing study among French physicians for commonly prescribed medications.

BACKGROUND: Achieving good medication adherence is a major challenge for patients with chronic conditions. Our study aimed to assess the Threshold for Unacceptable Risk of Non-adherence (TURN), defined as the threshold at which physicians consider the health risks incurred by patients due to medication non-adherence unacceptable, for the most commonly prescribed drugs in France. METHODS: We conducted an online study using a crowdsourcing approach among French general practitioners and specialists from September 2016 to August 2017. Physicians assessed the TURN for various levels of missed doses by evaluating a series of randomly presented clinical vignettes, each presenting a given medication with a given therapeutic indication. For each "drug-indication group" (i.e., all drugs from the same pharmacological class with a similar therapeutic indication): 1) we described the distribution of physicians' assessments, 2) we provided a summary estimate of the TURN, defined as the frequency of missed doses above which 75% of the physicians' assessments were located; 3) we computed the number of pill boxes reimbursed in France in 2016 to put our results into context. RESULTS: We collected a total of 5365 assessments from 544 physicians, each of whom evaluated a random sample among 528 distinct clinical vignettes. Estimates of the TURN varied widely across drug-indication groups, ranging from risk considered unacceptable with 1 daily dose missed per month (e.g., insulin for diabetes) to risk always considered acceptable (e.g., anti-dementia drugs). Drugs with an estimated TURN of over one missing daily dose per week represented 44.9% of the prescription volume of the medications assessed in our study. CONCLUSIONS: According to physicians, the impact of non-adherence may vary greatly. Patient-physician discussions on the variable consequences of non-adherence could lead to a paradigm shift by seeking to reach "optimal adherence" depending on drugs rather than unrealistic "perfect adherence" to all drugs.

Cost-effectiveness analysis of strategies using new immunological diagnostic tests of latent tuberculosis infection before TNF-blockers therapy.

Several tests have been proposed to detect latent tuberculosis (LTB). OBJECTIVE: To evaluate the cost-effectiveness of different interferon-gamma release assays based strategies used to screen LTB before tumour necrosis factor (TNF) blockers initiation. METHODS: Consecutive patients with rheumatoid arthritis, spondyloarthritis or Crohn's disease for whom TNF-blockers were considered, were recruited in 15 tertiary care centres. All were screened for LTB with tuberculin skin test (TST), QuantiFERON TB Gold® in tube (QFT) and T-SPOT.TB® (TSpot) on the same day. Cost-minimization and cost-effectiveness analysis, testing 8 screening test combinations, were conducted. Effectiveness was defined as the percentage of LTB treatment avoided and compared with TST alone. Cost were elicited in the payer perspective, included all the costs related to the screening procedure. RESULTS: No tuberculosis reactivation was observed after TNF-blocker initiation. TST followed by QFT if TST was positive was found as the best screening strategy, i.e. the less costly (-54€ compared to reference) and most effective (effectiveness 0.93), resulting in an incremental cost-effectiveness ratio of -192€ per treatment avoided. A probabilistic sensitivity analysis confirmed this result in 72.3% of simulations. CONCLUSION: TST followed by QFT if TST was positive is the most cost-effective strategy in screening for LTB in patients before starting anti-TNF therapy. TRIALREGNO: NCT00811343.

A mapping of 115,000 randomized trials revealed a mismatch between research effort and health needs in non-high-income regions.

BACKGROUND: Concerns exist as to whether the allocation of resources in clinical research is aligned with public health needs. We evaluated the alignment between the effort of clinical research through the conduct of randomized controlled trials (RCTs) and health needs measured as the burden of diseases for all regions and a broad range of diseases. METHODS: We grouped countries into seven regions and diseases into 27 groups. We mapped all RCTs initiated between 2006 and 2015 that were registered at the WHO International Clinical Trials Registry Platform to regions and diseases. The burden of diseases in 2005 was mapped as disability-adjusted life years (DALYs), based on the 2010 Global Burden of Diseases study. Within regions, we defined a research gap when the proportion of RCTs concerning a disease in the region was less than half the relative burden of the disease. RESULTS: We mapped 117,180 RCTs planning to enroll 42.6 million patients and 2,220 million DALYs. In high- versus non-high-income countries, 130.9 versus 6.9 RCTs per million DALYs were conducted. We did not identify any research gap in high-income countries. We identified research gaps for all other regions. In particular, for Sub-Saharan Africa, we identified research gaps for common infectious diseases (CID) and neonatal disorders (ND): 5.8% (95% uncertainty interval 4.7-6.9) and 2.0% (0.9-4.5) of RCTs in Sub-Saharan Africa concerned CID and ND, although these diseases represented 22.9% and 11.6% of the burden in the region, respectively. For South Asia, we identified research gaps for the same two groups of diseases. CONCLUSIONS: In non-high-income regions, the conduct of RCTs was misaligned with the distribution of major causes of burden, in particular infectious diseases and neonatal disorders in Sub-Saharan Africa and South Asia.

The Association Between Fibroblast Growth Factor 23 and Renal Transplantation Outcome Is Modified by Follow-up Duration and Glomerular Filtration Rate Assessment Method.

INTRODUCTION: Fibroblast growth factor 23 (FGF23) could contribute to cardiovascular morbidity in chronic kidney disease. In studies of kidney transplant recipients, a high circulating level of FGF23 has been associated with death and graft loss independently of estimated glomerular filtration rate (GFR). Whether FGF23 is associated with adverse outcomes in the early posttransplantation period is unknown. METHODS: We analyzed a cohort of 845 kidney transplant recipients in stable condition who had GFR measured in the first years after transplantation with a median follow-up of 71 months. RESULTS: A high FGF23 concentration was associated with death or graft loss in univariate analysis, but this association was lost after adjustment for measured GFR. In contrast, FGF23 remained significantly associated with the composite outcome when estimated GFR was substituted for measured GFR. We also observed that follow-up duration modified the association between FGF23 and outcome. Although FGF23 was not associated with any endpoint in the full duration of the study, we found an independent association between FGF23 and the incidence of graft loss within the 4 years after FGF23 measurement. We did not find an association between FGF23 levels and left ventricular mass in a subgroup of 227 patients who had echocardiography performed within 3 months of FGF23 measurement. DISCUSSION: This study demonstrates that FGF23 measured during the first year after transplantation is not an independent predictor of death and graft loss and is not associated with left ventricular hypertrophy in the posttransplantation period. It further unveils important factors modifying the association between FGF23 and outcome in this population.

Postmarketing studies for novel drugs approved by both the FDA and EMA between 2005 and 2010: a cross-sectional study.

OBJECTIVES: To characterise postmarketing studies for drugs that were newly approved by the US Food and Drug Administration and the European Medicines Agency. DESIGN AND SETTING: Cross-sectional analysis of postmarketing studies registered in ClinicalTrials.gov until September 2014 for all novel drugs approved by both regulators between 2005 and 2010. Regulatory documents from both agencies were used. PRIMARY AND SECONDARY OUTCOME MEASURES: All identified postmarketing studies were classified according to planned enrolment, funding, status and geographical location, and we determined whether studies studied the originally approved indication. RESULTS: Overall, 69 novel drugs approved between 2005 and 2010 were eligible for inclusion. A total of 6679 relevant postmarketing studies were identified; 5972 were interventional (89.4%). The median number of studies per drug was 55 (IQR 33-119) and median number of patients to be enrolled per study was 60 (IQR 28-183). Industry was the primary sponsor of 2713 studies (40.6%) and was a primary or secondary sponsor in 4176 studies (62.5%). In all, 2901 studies (43.4%) were completed, 487 (7.3%) terminated, 1013 (15.2%) active yet not recruiting, 1895 (28.4%) recruiting and 319 (4.8%) not yet recruiting. A total of 80% of studies were conducted in only one country and 84.4% took place in Europe and/or North America; 2441 (36.5%) studied another indication than the originally approved indication. Studies designed in the originally approved indication were found to be more industry-sponsored than others 68.7%vs53.7%; P<0.0001. CONCLUSIONS: Postmarketing pharmaceutical research was highly variable and predominantly located in North America and Europe. Postmarketing studies were frequently designed to study indications other than the originally approved one. Although some findings were reassuring, others question the lack of coordination of postmarketing research.

Socioeconomic Deprivation and Utilization of Anesthetic Care During Pregnancy and Delivery: A Secondary Analysis of a French Prospective, Multicenter, Cohort Study.

BACKGROUND: Socioeconomic deprivation is associated with reduced use of antenatal resources and poor maternal outcomes with pregnancy. Research examining the association between socioeconomic deprivation and use of obstetric anesthesia care in a country providing universal health coverage is scarce. We hypothesized that in a country providing universal health coverage, France, socioeconomic deprivation is not associated with reduced use of anesthetic care during pregnancy and delivery. This study aimed to examine the association between socioeconomic deprivation and (1) completion of a mandatory preanesthetic evaluation during pregnancy and (2) use of neuraxial analgesia during labor. METHODS: Data were from a cohort of 10,419 women who delivered between 2010 and 2011 in 4 public teaching hospitals in Paris. We used a deprivation index that included 4 criteria: social isolation, poor housing condition, no work-related household income, and state-funded health care insurance. Socioeconomic deprivation was defined as a deprivation index greater than 1. Preanesthetic evaluation was considered completed if performed more than 48 hours before delivery. The association between socioeconomic deprivation and completion of the preanesthetic evaluation and use of neuraxial labor analgesia was assessed by multivariable logistic regression adjusting for education level, country of birth, and maternal and pregnancy characteristics. RESULTS: Preanesthetic evaluation was completed for 8142 of the 8624 women (94.4%) analyzed and neuraxial labor analgesia was used by 6258 of the 6834 women analyzed (91.6%). After adjustment, socioeconomic deprivation was associated with reduced probability of completed preanesthetic evaluation (adjusted odds ratio 0.88 [95% confidence interval, 0.79-0.98]; P = .027) but not use of neuraxial labor analgesia (adjusted odds ratio 0.97 [95% confidence interval, 0.87-1.07]; P = .540). CONCLUSIONS: In a country providing universal health care coverage, women who were socioeconomically deprived showed reduced completion of preanesthetic evaluation during pregnancy but not reduced use of neuraxial labor analgesia. Interventions should be targeted to socioeconomically deprived women to increase the completion of the preanesthetic evaluation.