Optimizing Communication on HPV Vaccination to Parents of 11- to 14-Year-Old Adolescents in France: A Discrete Choice Experiment.

BACKGROUND: With the aim to optimize communication during HPV vaccination campaigns in France, we elicited parental preferences around HPV vaccination. METHODS: We conducted a single-profile discrete choice experiment (DCE) among parents of 11- to 14-year-old middle-school pupils, who completed an anonymous, self-administered, internet-based questionnaire during 2020-2021. The DCE comprised five attributes (vaccine-preventable disease, justification of optimal age, information on safety, indirect protection and coverage) of vaccination against an unnamed disease that were presented to respondents in ten choice tasks, or scenarios. We use fixed effect logit models to estimate attribute weights on theoretical vaccine acceptance, and random effect linear regression to estimate attribute coefficients on vaccine eagerness (decision and decision certainty). We estimated marginal effects of attributes on expected vaccine acceptance. RESULTS: Vaccination scenarios were accepted by 55.6-89.2% of the 1291 participants. The largest marginal effects on expected vaccine acceptance in the full sample arose from prevention of cancer versus genital warts (+ 11.3 percentage points); from a "severe side effect suspicion that was not scientifically confirmed" versus a statement about "more benefits than risks" (+ 8.9 percentage points), and information on 80% vaccine coverage in neighbouring countries versus on "insufficient coverage" (+ 4.2 percentage points). Explaining the early age of vaccination by sexual debut had a strong negative impact among French monolingual parents with lower education level (vs age-independent, OR 0.48, 95% CI 0.27-0.86), but not other socio-economic groups. After removing low-quality responses (unvaried certainty and short questionnaire completion), among serial non-demanders with children not vaccinated against HPV, only disease elimination impacted vaccine eagerness positively (coefficient 0.54, 0.06-1.02). DISCUSSION: Using DCEs to elicit parents' preferences around communication messages, notably on cancer prevention, vaccine coverage and information about vaccine safety, could help to optimize HPV vaccination promotion efforts.

Do patients with type 2 diabetes mellitus included in randomised clinical trials differ from general-practice patients? A cross-sectional comparative study.

OBJECTIVES: To compare the characteristics of patients with type 2 diabetes mellitus in general practice and those included in randomised controlled trials on which clinical practice guidelines are based. DESIGN: Cross-sectional comparative study. SETTING: We asked 45 general practitioners from three French Departments to identify the 15 patients with type 2 diabetes mellitus they most recently saw in consultation. In parallel, we selected randomised controlled trials included in the Cochrane systematic review on which the clinical practice guidelines for type 2 diabetes mellitus were based. PARTICIPANTS: We included 675 patients with type 2 diabetes mellitus, and data were collected from 23 randomised controlled trials, corresponding to 36 059 patients. OUTCOME MEASURES: Characteristics of general-practice patients were extracted from medical records by a unique observer. The same baseline characteristics of patients included in randomised controlled trials from the Cochrane systematic review were extracted and meta-analysed. We assessed standardised differences between these two series of baseline characteristics. A difference greater than 0.10 in absolute value was considered meaningful. RESULTS: General-practice patients were older than randomised controlled trial patients (mean (SD) 68.8 (1.1) vs 59.9 years (standardised difference 0.8)) and had a higher body mass index (mean (SD) 31.5 (6.9) vs 28.2 kg/m2 (standardised difference 0.5)) but smoked less (11.0% vs 29.3% (standardised difference -0.6)). They more frequently used antihypertensive drugs (82.1% vs 37.5% (standardised difference 1.2)) but less frequently had a myocardial infarction (7.6% vs 23.1% (standardised difference -1.1)). CONCLUSIONS: Patients with type 2 diabetes mellitus cared for in general practice differ in a number of important aspects from patients included in randomised controlled trials on which clinical practice guidelines are based. This situation hampers the applicability of these guidelines. Future randomised trials should include patients who better fit the 'average' general-practice patient with type 2 diabetes mellitus to help improve the translation of study findings in daily practice.

Why and when should we cluster randomize?

A cluster randomized trial is defined as a randomized trial in which intact social units of individuals are randomized rather than individuals themselves. Outcomes are observed on individual participants within clusters (such as patients). Such a design allows assessing interventions targeting cluster-level participants (such as physicians), individual participants or both. Indeed, many interventions assessed in cluster randomized trials are actually complex ones, with distinct components targeting different levels. For a cluster-level intervention, cluster randomization is an obvious choice: the intervention is not divisible at the individual-level. For individual-level interventions, cluster randomization may nevertheless be suitable to prevent group contamination, for logistical reasons, to enhance participants' adherence, or when objectives pertain to the cluster level. An unacceptable reason for cluster randomization would be to avoid obtaining individual consent. Indeed, participants in cluster randomized trials have to be protected as in any type of trial design. Participants may be people from whom data are collected, but they may also be people who are intervened upon, and this includes both patients and physicians (for example, physicians receiving training interventions). Consent should be sought as soon as possible, although there may exist situations where participants may consent only for data collection, not for being exposed to the intervention (because, for instance, they cannot opt-out). There may even be situations where participants are not able to consent at all. In this latter situation a waiver of consent must be granted by a research ethics committee.

The intentions of French health university students to recommend and to receive the HPV vaccine are mainly influenced by vaccine knowledge, confidence in vaccines and personal HPV vaccination.

INTRODUCTION: Despite documented effectiveness in preventing several cancers, genital warts and safety of Human Papillomavirus (HPV) vaccine, immunization coverage among French adolescents remains far from the 80 % target. University health students (HS) in France may promote HPV vaccine through a national service (Service Sanitaire des Etudiants en Santé). We aimed to evaluate intentions to recommend the HPV vaccine to friends and relatives, to receive HPV vaccine, and to identify factors associated with these attitudes. METHODS: We conducted a cross-sectional survey in five French Universities from October 2019 to February 2020, using a self-administered online questionnaire. We used bivariable and multivariable logistic regression models to identify determinants of behavior around HPV vaccine: (i) individual intention for vaccination, and (ii) vaccine recommendation to friends and relatives. RESULTS: Among the 732 respondents (180 men, 552 women), 305 (41.7%) reported previous HPV vaccination (54.5 % among women), 504 (68.9%) would recommend the HPV vaccine to friends and relatives, 532 (72.7%) respondents would be vaccinated today if it was recommended for them. Intentions to recommend or to receive the HPV vaccine were less frequent in nursing students compared to medical and pharmacy students. After adjustment for demographical factors, HPV vaccine knowledge was associated with intention [aOR 1.30 (95%-confidence interval, 1.15-1.47)] and recommendation [1.26 (1.10-1.45)], respectively. Additionally, adjusting for knowledge about HPV infections, and confidence in vaccines in general was associated with vaccine intention [1.55, (1.30-1.84)] and recommendation [1.52 (1.24-1.86)]. HPV-vaccinated HS were more prone to recommend the HPV vaccine to friends and relatives [10.9 (6.6-17.9)]. CONCLUSION: A majority of HS would accept and/or recommend HPV vaccines. HS with greater knowledge about the HPV vaccine were more prone to recommend it. Strengthening knowledge about HPV and its vaccination is probably necessary before their Involvement in a HPV immunization program.

Drug clustering to anticipate new aspects of drug safety profile: Application to gabapentinoids and other voltage-gated calcium channel ligand drugs.

AIMS: Gabapentin and pregabalin bind to α2-δ subunit of voltage-gated calcium channels (Cav ). Other drugs targeting Cav include cardiovascular calcium channel blockers (CCBs) and anticonvulsants (levetiracetam, ethosuximide and zonisamide). In addition to pharmacodynamics, the safety profile of gabapentinoids seems to overlap with the one of cardiovascular CCBs (oedema) and Cav -blocking anticonvulsants (suicide and ataxia). The objective of this study was to cluster the safety profile of different Cav -ligand drugs by focusing on whether gabapentinoids present a distinct adverse drug reaction (ADR) signature from cardiovascular CCBs and anticonvulsants. METHODS: We extracted all ADRs with at least one significant disproportionate reporting (reporting odds ratio) related to gabapentinoids, CCBs or anticonvulsants in VigiBase. After principal component analysis preprocessing, a hierarchical ascendent classification was performed to cluster gabapentinoids and other Cav -ligand drugs that share a similar ADR signature. The robustness of the results was determined through four sensitivity analyses, varying on the dataset or the clustering method. RESULTS: A total of 16 drugs and 65 ADRs were included. Gabapentinoids were in Cluster #1, which included eight other drugs (isradipine, nicardipine, lacidipine, lercanidipine, ethosuximide, levetiracetam, zonisamide and nimodipine). Cluster #2 contained two drugs (diltiazem and verapamil) and Cluster #3 contained four drugs (amlodipine, felodipine, nifedipine and nitrendipine). The clustering results were consistent in all sensitivity analyses. CONCLUSIONS: The safety profile of gabapentinoids overlaps with those of some dihydropyridine CCBs and Cav -blocking anticonvulsants. These results could be used to anticipate some unidentified ADRs of gabapentinoids from information accumulated with older drugs and sharing a common molecular target and ADR signature.

Indication for a Pneumocystis Prophylaxis Therapy in Patients with Vascular Anomalies Treated with PIK3/AKT/mTOR Pathway Inhibitors: Experts' Opinion and Systematic Review from the Literature.

BACKGROUND: Vascular anomalies (VAs) are increasingly being treated with PI3K/AKT/mTOR pathway inhibitors. These drugs have immunosuppressive properties and thus theoretically overexpose patients to opportunistic infections, especially Pneumocystis jirovecii pneumonia (PJP). PJP prophylaxis use lacks consensus. We aimed to investigate the prevalence of PJP in patients receiving mTOR/PI3K/AKT inhibitors for VAs and determine any indication for pneumocystis prophylaxis in this population. METHODS: The study was conducted in 2 parts: (1) we sent a survey to a panel of international experts of VAs asking about their use of pneumocystis prophylaxis drugs and (2) we performed a systematic review of the literature of all published cases of patients receiving these drugs for VA to estimate the prevalence of PJP in this population. RESULTS: Answers from 68 experts were analyzed: 21 (30.9%) answered they always add PJP prophylaxis when prescribing mTOR inhibitors, 20 (29.4%) case-by-case, and 27 (39.7%) never. For the systematic review, among 3,053 reports screened, 217 were included involving 1,189 patients (1,143 received sirolimus, 38 everolimus, 4 alpelisib, 4 miransertib). Among the 1,189 cases, 2 (0.2%) PJP were reported: one under sirolimus and one under everolimus. Thus, the prevalence of PJP was estimated at 0.88 cases/1,000 patients under sirolimus (95% CI: -0.84 to 2.59) and 26.31 cases/1,000 under everolimus (95% CI: -24.58 to 77.18). Patients with PJP never received prophylaxis drugs. We found no PJP cases under alpelisib and miransertib. PJP prophylaxis was given in 218 (18.3%) cases, more frequently for children (91.3 vs. 77.2% in the non-prophylaxis group, p = 0.012), mostly trimethoprim-sulfamethoxazole (186 patients, 85.3%). CONCLUSION: Our study shows that even if PJP is a rare event, it may occur in patients with VAs treated with an mTOR inhibitor. Although our results cannot allow for revising guidelines, prophylaxis with TMP-SMX might be appropriate for a subgroup of patients with risk factors for PJP.

Designs used in published therapeutic studies of rare superficial vascular anomalies: a systematic literature search.

BACKGROUND: Rare superficial vascular anomalies represent a wide range of diseases. Their management is difficult given the broad spectrum and the lack of clinical trials assessing treatment efficacy. A randomized clinical trial of vascular anomalies is difficult because of the rarity of the diseases and is enhanced by the population of interest often being children. Therefore, suitable designs are needed. We conducted a methodological systematic literature search to identify designs implemented for investigating the treatment of rare superficial vascular anomalies. METHODS: We conducted a literature search on January 25, 2021, of the PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, ClinicalTrials.gov and European Union Clinical Trials Register databases. This systematic methodological literature search was registered at the Prospective Register of Systematic Reviews (PROSPERO: CRD42021232449). Randomized and non-randomized studies were included if they met the following criteria: were prospective studies of rare superficial vascular anomaly therapies, dealt with humans (adults and children) and were published in English from 2000. We excluded case reports/case series reporting fewer than 10 patients, reviews, retrospective studies, animal studies, studies of systemic or common vascular anomalies and non-therapeutic studies. We did not assess risk of bias in the included studies because our review was a methodological one focused on the design used. The review provided a descriptive analysis of relevant features of eligible research studies. RESULTS: From 2046 articles identified, we included 97 studies (62 reports and 35 ongoing studies): 25 randomized controlled studies, 7 non-randomized comparative studies, 64 prospective cohorts and 1 case series. Among the 32 comparative studies included, 21 used a parallel-group design. The 11 other studies used different designs such as cross-over, randomized placebo phase, delayed-start, within-person, or challenge-dechallenge-rechallenge or used a historical control group or an observational run-in period. CONCLUSIONS: Our systematic literature search highlights the lack of randomized control trials in superficial vascular anomalies due to the rarity of patients and their heterogeneity. New designs are emerging and can overcome the limitations of testing treatments in parallel groups.

Cluster randomized trials in nursing homes should better be planned as open-cohort than as closed-cohort.

OBJECTIVES: Two designs are frequently used in cluster randomized trials in nursing homes: closed cohort and open cohort. The former design includes residents at the beginning of the trial and then follows them. In the latter design, participants are enrolled at the beginning of the trial or although it is ongoing; at dates of assessment, all residents present in the nursing home are assessed. The open-cohort design is much less used than the closed-cohort design, but it offers several advantages such as less exposure to individual attrition. Objective was to assess whether an open-cohort design could have been feasible in trials with a closed-cohort design. STUDY DESIGN AND SETTING: Twenty-two closed-cohort trials in nursing homes. RESULTS: An open-cohort design was considered a relevant alternative for 20 trials. For 16 trials, a resident newly admitted could not opt out of the intervention, and for all trials, the resident could benefit from an intervention effect if it existed. For two trials, newly admitted residents could not benefit from the intervention effect, if it existed. CONCLUSION: The open-cohort design is well-adapted for most of the interventions assessed in nursing homes by means of a cluster randomized trial and should be considered more often.

Co-development of a school-based and primary care-based multicomponent intervention to improve HPV vaccine coverage amongst French adolescents (the PrevHPV Study).

INTRODUCTION: Despite various efforts to improve human papillomavirus (HPV) vaccine coverage in France, it has always been lower than in most other high-income countries. The health authorities launched in 2018 the national PrevHPV research programme to (1) co-develop with stakeholders and (2) evaluate the impact of a multicomponent complex intervention aimed at improving HPV vaccine coverage amongst French adolescents. OBJECTIVE: To describe the development process of the PrevHPV intervention using the GUIDance for rEporting of intervention Development framework as a guide. METHODS: To develop the intervention, we used findings from (1) published evidence on effective strategies to improve vaccination uptake and on theoretical frameworks of health behaviour change; (2) primary data on target populations' knowledge, beliefs, attitudes, preferences, behaviours and practices as well as the facilitators and barriers to HPV vaccination collected as part of the PrevHPV Programme and (3) the advice of working groups involving stakeholders in a participatory approach. We paid attention to developing an intervention that would maximise reach, adoption, implementation and maintenance in real-world contexts. RESULTS: We co-developed three components: (1) adolescents' and parents' education and motivation using eHealth tools (web conferences, videos, and a serious video game) and participatory learning at school; (2) general practitioners' e-learning training on HPV using motivational interviewing techniques and provision of a decision aid tool and (3) easier access to vaccination through vaccination days organised on participating middle schools' premises to propose free of charge initiation of the HPV vaccination. CONCLUSION: We co-developed a multicomponent intervention that addresses a range of barriers and enablers of HPV vaccination. The next step is to build on the results of its evaluation to refine it before scaling it up if proven efficient. If so, it will add to the small number of multicomponent interventions aimed at improving HPV vaccination worldwide. PATIENT OR PUBLIC CONTRIBUTION: The public (adolescents, their parents, school staff and health professionals) participated in the needs assessment using a mixed methods approach. The public was also involved in the components' development process to generate ideas about potential activities/tools, critically revise the successive versions of the tools and provide advice about the intervention practicalities, feasibility and maintenance.

Design and Methodological Issues of Within-Person (Split-Body) Randomized Controlled Trials Evaluating a Topical Treatment: A Systematic Review.

BACKGROUND: Topical drugs are often used as first-line treatment for dermatological conditions. A within-person design may then be well adapted: it consists of randomizing lesions/body sites rather than patients, which are then concomitantly treated by the different drugs compared, reducing inter-group variability and therefore requiring fewer patients than the classical parallel-group trial. OBJECTIVES: The aim of this review was to provide a methodological overview of within-person randomized trials (WP-RCTs) in dermatology. METHODS: We searched for eligible trials published between 2017 and 2021 in MEDLINE, Embase, and Central in dermatology journals and the 6 highest-impact-factor general medical journals. Two authors selected publications and extracted data independently. RESULTS: From 1,034 articles identified, we included 54 WP-RCTs, mainly for acne vulgaris, psoriasis, actinic keratosis, and atopic dermatitis. In most of the trials, patients had only 2 lesions/body sites. In none of the trials, did we detect a potential carry-across effect (known to be the major methodological problem in WP-RCTs). Twelve studies reported a care provider applying the treatment, and in 26 studies, the patients themselves applied the treatment. Finally, we also highlight statistical issues for the statistical analysis: overall, 14 (26.9%) studies used a test for independent observations, thus ignoring the between-lesion correlation. CONCLUSION: Our systematic review highlights that despite the publication of the CONSORT checklist extension for WP-RCTs in 2017, this design is rarely used, and when it is, there are methodological and reporting concerns.

Hydrocortisone in Severe Community-Acquired Pneumonia.

BACKGROUND: Whether the antiinflammatory and immunomodulatory effects of glucocorticoids may decrease mortality among patients with severe community-acquired pneumonia is unclear. METHODS: In this phase 3, multicenter, double-blind, randomized, controlled trial, we assigned adults who had been admitted to the intensive care unit (ICU) for severe community-acquired pneumonia to receive intravenous hydrocortisone (200 mg daily for either 4 or 7 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) or to receive placebo. All the patients received standard therapy, including antibiotics and supportive care. The primary outcome was death at 28 days. RESULTS: A total of 800 patients had undergone randomization when the trial was stopped after the second planned interim analysis. Data from 795 patients were analyzed. By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006). Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 40 of 222 (18.0%) in the hydrocortisone group and in 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among the patients who were not receiving vasopressors at baseline, such therapy was initiated by day 28 in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25.0%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82). The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups; patients in the hydrocortisone group received higher daily doses of insulin during the first week of treatment. CONCLUSIONS: Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).

Continued enteral nutrition until extubation compared with fasting before extubation in patients in the intensive care unit: an open-label, cluster-randomised, parallel-group, non-inferiority trial.

BACKGROUND: Fasting is frequently imposed before extubation in patients in intensive care units, with the aim to reduce risk of aspiration. This unevaluated practice might delay extubation, increase workload, and reduce caloric intake. We aimed to compare continued enteral nutrition until extubation with fasting before extubation in patients in the intensive care unit. METHODS: We conducted an open-label, cluster-randomised, parallel-group, non-inferiority trial in 22 intensive care units in France. Patients aged 18 years or older were eligible for enrolment if they had received invasive mechanical ventilation for at least 48 h in the intensive care unit and received prepyloric enteral nutrition for at least 24 h at the time of extubation decision. Centres were randomly assigned (1:1) to continued enteral nutrition until extubation or 6-h fasting with concomitant gastric suctioning before extubation, to be applied for all patients within the unit. Masking was not possible because of the nature of the trial. The primary outcome was extubation failure (composite criteria of reintubation or death) within 7 days after extubation, assessed in both the intention-to-treat and per-protocol populations. The non-inferiority margin was set at 10%. Pneumonia within 14 days of extubation was a key secondary endpoint. This trial is now complete and is registered with ClinicalTrials.gov, NCT03335345. FINDINGS: Between April 1, 2018, and Oct 31, 2019, 7056 patients receiving enteral nutrition and mechanical ventilation were admitted to the intensive care units and 4198 were assessed for eligibility. 1130 patients were enrolled and included in the intention-to-treat population and 1008 were included in the per-protocol population. In the intention-to-treat population, extubation failure occurred in 106 (17·2%) of 617 patients assigned to receive continued enteral nutrition until extubation versus 90 (17·5%) of 513 assigned to fasting, meeting the a priori defined non-inferiority criterion (absolute difference -0·4%, 95% CI -5·2 to 4·5). In the per-protocol population, extubation failure occurred in 101 (17·0%) of 595 patients assigned to receive continued enteral nutrition versus 74 (17·9%) of 413 assigned to fasting (absolute difference -0·9%, 95% CI -5·6 to 3·7). Pneumonia within 14 days of extubation occurred in ten (1·6%) patients assigned to receive continued enteral nutrition and 13 (2·5%) assigned to fasting (rate ratio 0·77, 95% CI 0·22 to 2·69). INTERPRETATION: Continued enteral nutrition until extubation in critically ill patients in the intensive care unit was non-inferior to a 6-h fasting maximum gastric vacuity strategy comprising continuous gastric tube suctioning, in terms of extubation failure within 7 days (a patient-centred outcome), and thus represents a potential alternative in this population. FUNDING: French Ministry of Health. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A Smoking Prevention Intervention Among Young People in an Online Community Game: Results from a Pilot Randomized Controlled Trial.

Background: Innovative methods for smoking prevention interventions need to be investigated to increase attractiveness, access hard-to-reach populations, and increase effectiveness. We studied the feasibility and immediate effects of an intervention to reinforce norms and behaviors of young people related to antismoking, integrated into a popular online community game. Methods: A pilot randomized controlled trial was conducted through the HABBO online community. The intervention group was exposed to repeated discussion sessions with small groups of peer players and two facilitators once a week for 1 month (four sessions), inside the game. The control group had access to antismoking information websites. Process indicators (attractiveness, participation) and immediate outcomes (norms and intentions with regard to smoking) were assessed by questionnaire. Results: One hundred sixteen players were invited to participate in the intervention; 10 did not meet eligibility criteria, 30 were allocated to the intervention group, and 76 to the control group. Median age was 23. Twenty-four percent were not in education, employment, or training. A median of eight players attended each session and the median number of exchange chats by session was 399; 70% of chat time was occupied by the players. Twenty players attended all four sessions. Immediate norms, representations, and intentions were evaluated in 39 players and showed small differences between groups. Conclusion: Delivering and evaluating a smoking prevention intervention in an online game is feasible. In the targeted online community game, the intervention was attractive and allowed the delivery of innovative interventions to audiences with diverse social profiles. Long-term effects, sustainability, and evaluation methodology are discussed.

Intervention effect estimates in randomised controlled trials conducted in primary care versus secondary or tertiary care settings: a meta-epidemiological study.

BACKGROUND: Many clinical practice guidelines are based on randomised controlled trials conducted in secondary or tertiary care setting and general practitioners frequently question their relevance for primary care patients. Our aim was to compare the intervention effect estimates between primary care setting randomised controlled trials (PC-RCTs) and secondary or tertiary care setting randomised controlled trials (ST-RCTs). METHODS: Meta-epidemiological study of meta-analyses (MAs) of a binary outcome including at least one PC-RCT and one ST-RCT. PC-RCTs were defined as trials recruiting patients in general practices, primary care practices, family practices, community centers or community pharmacies. ST-RCTs were defined as trials recruiting in hospitals, including hospitalized patients, hospital outpatients and patients from emergency departments. For each MA, we estimated a ratio of odds ratio (ROR) by using random-effects meta-regression, with an ROR less than 1 indicating lower estimates of the intervention effect in PC-RCTs than ST-RCTs. Finally, we estimated a combined ROR across MAs by using a random-effects meta-analysis. We performed subgroup analyses considering the type of outcomes (objective vs subjective), type of experimental intervention (pharmacological vs non-pharmacological), and control group (active vs inactive) as well as analyses adjusted on items of the Cochrane Risk of Bias tool. RESULTS: Among 1765 screened reviews, 76 MAs with 230 PC-RCTs and 384 ST-RCTs were selected. The main medical fields were pneumology (13.2%) and psychiatry or addictology (38.2%). Intervention effect estimates did not significantly differ between PC-RCTs and ST-RCTs (ROR = 0.97, 95% confidence interval 0.88 to 1.08), with moderate heterogeneity across MAs (I2 = 45%). Subgroup and adjusted analyses led to consistent results. CONCLUSION: We did not observe any significant difference in intervention effect estimates between PC-RCTs and ST-RCTs. Nevertheless, most of the medical fields in this meta-epidemiological study were not representative of the pathologies encountered in primary care. Further studies with pathologies more frequently encountered in primary care are needed.

Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: A double blinded randomized placebo-controlled trial.

INTRODUCTION: This trial evaluates whether daily low-dose aspirin initiated before 16 weeks of gestation can reduce preeclampsia and fetal growth restriction in nulliparous women identified by first-trimester uterine artery Dopplers as at high risk of preeclampsia. METHODS: This randomized, blinded, placebo-controlled, parallel-group trial took place in 17 French obstetric departments providing antenatal care. Pregnant nulliparous women aged ≥ 18 years with a singleton pregnancy at a gestational age < 16 weeks of gestation with a lowest pulsatility index ≥ 1.7 or a bilateral protodiastolic notching for both uterine arteries on an ultrasound performed between 11+0 and 13+6 weeks by a certified sonographer were randomized at a 1:1 ratio to 160 mg of low-dose aspirin or to placebo to be taken daily from inclusion to their 34th week of gestation. The main outcome was preeclampsia or a birthweight ≤ 5th percentile. Other outcomes included preeclampsia, severe preeclampsia, preterm preeclampsia, preterm delivery before 34 weeks, mode of delivery, type of anesthesia, birthweight ≤ 5th percentile and perinatal death. RESULTS: The trial was interrupted due to recruiting difficulties. Between June 2012 and June 2016, 1104 women were randomized, two withdrew consent, and two had terminations of pregnancies. Preeclampsia or a birthweight ≤ 5th percentile occurred in 88 (16.0%) women in the low-dose aspirin group and in 79 (14.4%) in the placebo group (proportion difference 1.6 [-2.6; 5.9] p = 0.45). The two groups did not differ significantly for the secondary outcomes. CONCLUSION: Low-dose aspirin was not associated with a lower rate of either preeclampsia or birthweight ≤ 5th percentile in women identified by their first-trimester uterine artery Doppler as at high risk of preeclampsia. TRIAL REGISTRATION: (NCT0172946).

Heterogeneity in pragmatic randomised trials: sources and management.

BACKGROUND: Pragmatic trials aim to generate evidence to directly inform patient, caregiver and health-system manager policies and decisions. Heterogeneity in patient characteristics contributes to heterogeneity in their response to the intervention. However, there are many other sources of heterogeneity in outcomes. Based on the expertise and judgements of the authors, we identify different sources of clinical and methodological heterogeneity, which translate into heterogeneity in patient responses-some we consider as desirable and some as undesirable. For each of them, we discuss and, using real-world trial examples, illustrate how heterogeneity should be managed over the whole course of the trial. MAIN TEXT: Heterogeneity in centres and patients should be welcomed rather than limited. Interventions can be flexible or tailored and control interventions are expected to reflect usual care, avoiding use of a placebo. Co-interventions should be allowed; adherence should not be enforced. All these elements introduce heterogeneity in interventions (experimental or control), which has to be welcomed because it mimics reality. Outcomes should be objective and possibly routinely collected; standardised assessment, blinding and adjudication should be avoided as much as possible because this is not how assessment would be done outside a trial setting. The statistical analysis strategy must be guided by the objective to inform decision-making, thus favouring the intention-to-treat principle. Pragmatic trials should consider including process analyses to inform an understanding of the trial results. Needed data to conduct these analyses should be collected unobtrusively. Finally, ethical principles must be respected, even though this may seem to conflict with goals of pragmatism; consent procedures could be incorporated in the flow of care.

An analysis of published trials found that current use of pragmatic trial labels is uninformative.

OBJECTIVES: Randomized trials labelled as "pragmatic" are attractive to funders, patients, and clinicians as the label implies that the results are directly applicable to clinical care. We examined how authors justify use of the label (e.g., by referring to one or more PRECIS [PRagmatic Explanatory Continuum Indicator Summary]-2 domains). STUDY DESIGN AND SETTING: We reviewed primary trial reports published 2014-2019, registered in ClinicalTrials.gov and using the pragmatic label anywhere in the report. RESULTS: Among 415 trials, the label was justified by reference to at least one design element in 282 (68.0%); of these, 240 (85.1%) referenced trial characteristics that can be mapped to one or more of the PRECIS-2 domains, most commonly eligibility (91, 32.3%), setting (90, 31.9%), flexibility delivery (89, 31.6%), and organization (75, 26.6%); 42 (14.9%) referenced characteristics that are not PRECIS-2 domains, most commonly type of intervention/comparator (48, 17%), recruitment without consent (22, 7.8%), routinely collected data (22, 7.8%), and cluster randomization (20, 7.1%). Most reports referenced only one or two design elements. Overall, 9/415 (2.2%) provided PRECIS wheels. CONCLUSION: Current use of pragmatic labels is uninformative. Authors should clarify the decision the trial is intended to support and include a PRECIS-2 table to make the design transparent.