[French version of The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, in a French law context]. / Version française des recommandations de la déclaration d'Ottawa sur la conception et la conduite éthique d'essais randomisés en clusters, dans le contexte législatif français.

INTRODUCTION: There is growing evidence on the ethical challenges raised by cluster randomized trials. This specificity is not reflected in the legal texts regulating research, which creates difficulties for researchers implementing these experimental designs. The Ottawa Statement (Weijer et al. 2012) aims to provide detailed guidance on the ethical design, conduct and assessment of cluster trials. More broadly aims to help research stakeholders and decision-makers to make informed ethical decisions regarding the particularity of these experimental designs. It seems that this international statement, written in English, is not sufficiently accessible to all of the French professionals involved in health research. The aim of this article is to provide these professionals with a contextualized and illustrated French translation of the "Ottawa statement". METHOD: . The "complex design" working group of the RECaP network (Research in Clinical Epidemiology and Public Health), carried out this work. A first version was discussed by the authors in several meetings. It was completed by contextual explanations and examples of French studies currently conducted by the authors. The final version was obtained by consensus and validated by the group. RESULTS: . This work reports 15 recommendations grouped into 7 key questions: How to justify cluster design? How to submit an article to an ethics committee? How to identify research participants? How and when to obtain informed consent? Who are the gatekeepers? How to assess benefits and harm? How to protect vulnerable participants? Each of these recommendations is specific to cluster trials. The recommendations are explained and detailed through concrete examples. CONCLUSION: Without interfering with current French laws, this work provides a framework for the organization, conduct and ethical assessment of cluster randomized trials in France. In the present-day context, it is essential that all concerned groups can base their decisions on recommendations in line with the elementary principles of health research ethics.

Acute acral eruptions in children during the COVID-19 pandemic: Characteristics of 103 children and their family clusters.

BACKGROUND: A marked increase in frequency of acute acral eruptions (AAE) was observed in children during the COVID-19 pandemic in the spring period. OBJECTIVES: In this observational multicenter study, based on children with AAE, we aimed to assess the proportion of household members possibly infected by SARS-CoV-2. METHODS: We collected data from all children observed with AAE, prospectively from April 7, 2020 to June 22, 2020, and retrospectively since February 28, 2020. The primary outcome was the household infection rate, defined as the proportion of family clusters having at least one member with COVID-19 infection other than the child with AAE ("index child"). The definition of a case was based on characteristic clinical signs and a positive PCR or serology. RESULTS: The study included 103 children in 10 French departments and in Quebec. The median age was 13 years and the interquartile range [8-15], with a female-to-male ratio of 1/1.15. In children with AAE, all PCR tests were negative (n=18), and serology was positive in 2/14 (14.3%) cases. We found no significant anomalies in the lab results. A total of 66 of the 103 families (64.1%) of included children had at least one other infected member apart from the index child. The total number of household members was 292, of whom 119 (40.8%) were considered possibly infected by SARS-CoV-2. No index children or households exhibited severe COVID-19. DISCUSSION: Among the 103 households included, 64.1% had at least one infected member. Neither children with AAE nor their households showed severe COVID-19.

Vaginal self-sampling is a cost-effective way to increase participation in a cervical cancer screening programme: a randomised trial.

BACKGROUND: Cervical cancer screening coverage remains insufficient in most countries. Our objective was to assess whether in-home vaginal self-sampling with a dry swab for high-risk human papillomavirus (HR-HPV) testing is effective and cost-effective in increasing participation in cervical cancer screening. METHODS: In March 2012, 6000 unscreened women aged 30-65 years, living in a French region covered by a screening programme, who had not responded to an initial invitation to have a Pap smear were equally randomised to three groups: 'no intervention'; 'recall', women received a letter to have a Pap smear; and 'self-sampling', women received a self-sampling kit to return to a centralised virology laboratory for PCR-based HPV testing. RESULTS: Participation was higher in the 'self-sampling' than in the 'no intervention' group (22.5% vs 9.9%, P<0.0001; OR 2.64) and 'recall' group (11.7%, P<0.0001; OR 2.20). In the 'self-sampling' group, 320 used the self-sampling kit; for 44 of these women with positive HR-HPV test results, 40 had the recommended triage Pap smear. The ICER per extra screened woman was 77.8[euro ] and 63.2[euro ] for the 'recall' and 'self-sampling' groups, respectively, relative to the 'no intervention' group. CONCLUSIONS: Offering an in-home, return-mail kit for vaginal self-sampling with a dry swab is more effective and cost-effective than a recall letter in increasing participation in cervical cancer screening.

Accuracy of dry vaginal self-sampling for detecting high-risk human papillomavirus infection in cervical cancer screening: a cross-sectional study.

OBJECTIVE: Cervical cancer screening coverage remains insufficient in most countries. Testing self-collected samples for high-risk human papillomavirus (HR-HPV) could be an alternative to the Pap smear, but costs, sampling methods and transport issues hamper its wide use. Our objective was to compare diagnostic accuracy of 2 vaginal self-collection methods, a dry swab (vsc-DRY) or swab in liquid medium (vsc-LIQ), for detecting HR-HPV cervical infection assessed by a cervical clinician-collected sample in liquid medium (ccc-LIQ). METHODS: Women 20 to 65 years attending a Pap smear were recruited between September, 2009 and March, 2011. Each sample (3 per woman) underwent HPV DNA testing. Samples were classified as HR-HPV+ with detection of at least one HR-HPV or probable HR-HPV type. RESULTS: Of 734 women included, 722 had complete HPV data. HR-HPV was detected in 20.9% of ccc-LIQ samples. Estimated sensitivity and specificity to detect HR-HPV in vsc-DRY samples were 88.7% and 92.5%, respectively, and in vsc-LIQ samples, 87.4% and 90.9%. Cytology findings were abnormal for 79 women (10.9%): among 27 samples of low-grade squamous intraepithelial lesions, 25 were HR-HPV+ in vsc-DRY, vsc-LIQ and ccc-LIQ samples. Among 6 samples of high-grade squamous intraepithelial lesions, all were HR-HPV+ in vsc-DRY samples, 1 was HR-HPV- in vsc-LIQ samples and 1 was HR-HPV- in ccc-LIQ samples. CONCLUSIONS: Vaginal self-sampling with a dry swab is accurate to detect HR-HPV infection as compared with cervical clinician-collection and accurate as compared with cytology results. This cheap and easy-to-ship sampling method could be widely used in a cervical cancer screening program.

FIRE Stones: impact of forced diuresis on the residual fragment rate after flexible ureteroscopy for destruction of kidney stones with laser-protocol for a randomized controlled two-parallel group multicenter trial with blinding evaluation.

BACKGROUND: Lithiasis is a common and recurrent disease. Flexible ureteroscopy (fURS) is the cornerstone of laser treatment of kidney stones. Kidney stones destruction requires its laser pulverization into small fragments in order to remove them through the ureter or improve their spontaneous expulsion along the urinary tract. However, most of the time, all the micro-fragments and dust created cannot be extracted using our surgical tools and may stay intra-renally at the end of the procedure. Adjuvant treatments (such as forced diuresis, inversion or mechanical pressure) were previously described to improve the expulsion of stone fragments after extra-corporeal shock wave lithotripsy. Nevertheless, the impact of adjuvant treatment after fURS remains unclear and mainly theoretical. OBJECTIVE: The primary objective is to show that the injection of 40 mg of furosemide in slow intravenous during 10 min, after the procedure, increases the stone-free rate 3 months after a fURS for destruction of kidney stones with laser. METHODS/DESIGN: The study will be a two-parallel group randomized, controlled, multicentric trial with a blinding evaluation. Nine French departments of urology will participate. Patients will be randomized in 2 groups: the experimental group (injection of 40 mg of furosemide at the end of the surgery) and a control one (usual care). Patients will be followed up for 3 months (± 2 weeks) after the surgery. Then, we will perform a low dose abdomino-pelvic CT scan. The primary outcome is the stone-free rate at 3 months. A centralized review of the images will be performed by two specialized radiologists, in a blind and crossed way to allow a homogenization of the results. The secondary outcomes will include the rate of early post-operative urinary tract infection (UTI), the evaluation of post-operative pain, and the safety of the use of furosemide in patients treated by fURS for renal stone laser destruction. As secondary objectives, it is also planned to look at the effect of the prescription of an alpha-blocker as usual treatment on stone-free rate and to assess the agreement between the imaging analysis of the urologist and the specialized radiologist. DISCUSSION: Lithiasis is a public health problem. It affects about 10% of the general population. This prevalence is increasing (multiplied by 3 in 40 years), partly due to changes in the population's eating habits over the years. The lithiasis patient is a patient with a chronic disease requiring annual follow-up and who may suffer from multiple recurrences, with a recurrence rate at 5 years of 50%. Recurrences are partly due to residual fragments left in the kidneys at the end of the operation. Other risk factors for recurrence include dietary hygiene and the presence of an associated metabolic disease. The metabolic blood and urine tests recommended by the Association Française d'Urologie (AFU) can be used to manage these last two problems. As far as residual fragments are concerned, their presence leads to an early recurrence of stones because they form the bed for a new aggregation of crystals in the kidneys. Being able to reduce the rate of residual fragments in patients with the use of furosemide at the end of the intervention therefore seems essential in the management of recurrences in our patients. This will also improve our patients' quality of life. Indeed, lithiasis disease leads to chronic pain associated with acute pain that motivates consultations to the emergency for specialized management. This study is the first to evaluate the impact of forced diuresis with the use of furosemide on the stone-free rate after a fURS for destruction of kidney stone with laser. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05916963 , first received: 22 June 2023. EU Clinical Trials Register EudraCT Number: 2022-502890-40-00.

Propensity scores used for analysis of cluster randomized trials with selection bias: a simulation study.

Cluster randomized trials (CRTs) are often prone to selection bias despite randomization. Using a simulation study, we investigated the use of propensity score (PS) based methods in estimating treatment effects in CRTs with selection bias when the outcome is quantitative. Of four PS-based methods (adjustment on PS, inverse weighting, stratification, and optimal full matching method), three successfully corrected the bias, as did an approach using classical multivariable regression. However, they showed poorer statistical efficiency than classical methods, with higher standard error for the treatment effect, and type I error much smaller than the 5% nominal level.

Heterogeneity in meta-analyses of treatment of acute postoperative pain: a review.

BACKGROUND: Heterogeneity and its causes must be assessed using meta-analyses (meta-analysis). Especially in meta-analysis dealing with treatment of acute postoperative pain, the type of surgery is a source of heterogeneity. We aimed to assess whether the type of surgery is considered a source of heterogeneity in meta-analysis and how it is taken into account in meta-analysis evaluating the efficacy of treatment of acute postoperative pain. We further compared meta-analysis that pooled trials of surgeries with highly heterogeneous postoperative pain levels, the heterogeneous group, with meta-analysis that pooled trials involving surgeries with homogeneous pain levels, the homogenous group. METHODS: The meta-analysis reports available in Issue 3, 2011 of the electronic database of the Cochrane library and pooling results of randomized or quasi-randomized controlled trials that assessed the efficacy of treatment of acute postoperative pain alone were considered. A survey of experts established a rating of the postoperative pain levels for the type of surgery. For each meta-analysis, the different pain level ratings associated with the trials included in the meta-analysis were considered and the standard deviation (sd) of these ratings calculated. From the distribution of sd values, we defined the heterogeneous and homogeneous groups. RESULTS: Sixty-one meta-analyses were included; all assessed heterogeneity. Twenty-six meta-analyses considered the type of surgery as a subgroup (50% vs 38% in the homogeneous group vs heterogeneous group). Forty-four reports discussed the type of surgery as a source of clinical heterogeneity (85% vs 62% for the homogeneous vs heterogeneous group). Twenty-nine meta-analyses compared 'postoperative pain from dental surgery' to 'other type of surgery'. CONCLUSIONS: Meta-analyses evaluating treatment of postoperative pain should explore clinical heterogeneity associated with the type of surgery for better implications for practice.

Effect of physician dress style on patient confidence.

BACKGROUND: We lack data on how physicians can instill confidence in patients. OBJECTIVES: We aimed to determine whether dress style (professional white coat or formal, semiformal or casual attire) affects confidence in the physician by patients (children, teenagers, adults) with dermatology complaints consulting in the hospital or private practice. METHODS: Design. Descriptive prospective cross sectional study carried out from July 1, 2008 to July 1, 2009. Setting. Outpatients in the department of dermatology of a French tertiary care hospital, and two dermatological private consulting rooms. Participants and design. Consulting patients were ≥ 7 years and classified as children 7-11 years old, accompanying parents, teenagers (12-17 years), and adults ≥ 18 years consulting alone. Subjects viewed two iconographic boards containing 4 photographs in a random order of a male physician on 1 board and a female physician on the other board in 4 different dress styles: professional (white coat and stethoscope), formal (shirt and tie for men), semiformal, and casual (T-shirt, jeans). Subjects then completed a questionnaire asking them to rate, on a scale of 0-10, their confidence in the physicians portrayed and answered whether they considered physician dress important. Main outcomes and measures. The main outcome was subjects' ranking of photos of physicians by dress style, according to the confidence they felt. For children 7-11 years old, we considered the frequency of the chosen dress style. The secondary outcome was whether physician dress was important to patients. RESULTS: We included 329 patients. Children at the hospital most frequently chose the photo of the physician, both male (62%) and female (64%), with the white coat. Teenagers' choices were professional dress, then semiformal, formal, and casual attire. Accompanying adults and adults consulting alone had the same ranking. CONCLUSIONS: In France, patients of all ages who consult for dermatology complaints in hospital and in private practice have the most confidence in a physician who wears a professional white coat.

Topical sirolimus solution for lingual microcystic lymphatic malformations in children and adults (TOPGUN): study protocol for a multicenter, randomized, assessor-blinded, controlled, stepped-wedge clinical trial.

BACKGROUND: Lingual microcystic lymphatic malformations (LMLMs) are rare congenital vascular malformations presenting as clusters of cysts filled with lymph fluid or blood. Even small well-limited lesions can be responsible for a heavy burden, inducing pain, aesthetic prejudice, or oozing, bleeding, infections. The natural history of LMLMs is progressive worsening punctuated by acute flares. Therapeutic options include surgery, laser excision, and radiofrequency ablation but all are potentially detrimental and expose to local relapse. Therefore, the management frequently relies on a "watchful waiting" approach. In complicated LMLMs, treatment with oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is often used. Topical applications of sirolimus on the buccal mucosae have been reported in other oral diseases with good tolerance and none to slight detectable blood sirolimus concentrations. We aim to evaluate the efficacy and safety of a 1 mg/mL sirolimus solution applied once daily on LMLM of any stage in children and adults after 4, 8, 12, 16, 20, and 24 weeks of treatment compared to usual care (no treatment). METHODS: This is a randomized, multicentric study using an individually randomized stepped-wedge design over 24 weeks to evaluate topical application of a 1 mg/mL sirolimus solution once daily, on LMLM, versus usual care (no treatment), the control condition. Participants begin with an observational period and later switch to the intervention at a randomized time (week 0, 4, 8, or 12). Visits occur every 4 weeks, either in the study center or by teleconsulting. The primary outcome will be the evaluation of global severity of the LMLM on monthly standardized photographs by 3 independent blinded experts using the physical global assessment (PGA) 0 to 5 scale. Secondary outcomes will include lesion size measurement and quality of life assessment, investigator, and patient-assessed global disease and specific symptoms (oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain, and global discomfort) assessment. A biological monitoring will be performed including residual blood sirolimus concentration and usual laboratory parameters. DISCUSSION: Given the disappointing state of current treatment options in LMLMs, topical sirolimus could become firstline therapy in treating LMLMs if its efficacy and safety were to be demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04128722 . Registered on 24 September 2019. EudraCT: EUCTR2019-001530-33-FR Sponsor (University Hospital Center of Tours - CHRU Tours): DR190041-TOPGUN French regulatory authorities: ID RCB: 2019-001530-33.

Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial.

BACKGROUND: Breast cancer becomes lethal when visceral metastases develop. At this stage, anti-cancer treatments aim at relieving symptoms and delaying death without resulting in additional toxicity. On the basis of their differential anti-oxidant defence level, tumour cells can be made more sensitive to chemotherapy than non-tumour cells when membrane lipids are enriched with docosahexaenoic acid (DHA), a peroxidisable and oxidative-stress-inducing lipid of marine origin. METHODS: This open-label single-arm phase II study evaluated the safety and efficacy (response rate), as primary end points, of the addition of 1.8 g DHA daily to an anthracycline-based chemotherapy (FEC) regimen in breast cancer patients (n = 25) with rapidly progressing visceral metastases. The secondary end points were time to progression (TTP) and overall survival (OS). RESULTS: The objective response rate was 44%. With a mean follow-up time of 31 months (range 2-96 months), the median TTP was 6 months. Median OS was 22 months and reached 34 months in the sub-population of patients (n = 12) with the highest plasma DHA incorporation. The most common grade 3 or 4 toxicity was neutropaenia (80%). CONCLUSION: DHA during chemotherapy was devoid of adverse side effects and can improve the outcome of chemotherapy when highly incorporated. DHA has a potential to specifically chemosensitise tumours.

[Real-time contrast-enhanced ultrasound in the evaluation of focal liver lesions: diagnostic efficacy and economical issues from a French multicentric study]. / Echographie de contraste temps réel dans la prise en charge diagnostique des lésions nodulaires hépatiques: évaluation des performances diagnostiques et de l'impact économique sur une étude multicentrique française.

The recent introduction of high-end ultrasound equipment combined with recent contrast agents provides marked improvements in the characterization of focal liver lesions as previously reported by monocentric studies. The aim of the present study was to evaluate the diagnostic performance of Contrast-Enhanced Ultrasonography (CEUS) using SonoVue as well as its medico-economic value for characterization of focal liver lesions. These nodules were not characterized on previous CT or conventional sonography. This prospective multicentric study conducted in 15 French centres found diagnostic performances similar to those reported for CT and MRI, with a concordance rate of 84.5%, sensitivity greater than 80% and specificity greater than 90% for all types of lesions. Higher acceptance was found for CEUS compared to other imaging modalities. Economical assessment based on examination reimbursment and contrast agent cost showed a lower cost for contrast ultrasound versus CT and MRI. This French multicentric study confirmed the high diagnostic value of CEUS for focal liver lesion characterization and demonstrated a lower economical impact compared to other imaging modalities such as CT and MRI.

[Creation of a regional stroke network in Tours hospital (France): consequences for stroke care and thrombolysis]. / Création d'une filière neuro-vasculaire régionale: évaluation de la prise en charge à 18 mois.

INTRODUCTION: Our university hospital serves a population of 300 000 inhabitants. Stroke is the leading cause of admission in our department of neurology. In June 2003, when the Emergency Department (ED) was closed in our institution, was created an acute stroke network (ASN), comprising 2 beds of direct admission and thrombolysis in the intensive care unit, and 4 beds dedicated to stroke care in the department of neurology, in which standardized stroke care protocols were implemented. OBJECTIVE: The aim of this study was to evaluate changes in stroke care related to the creation of the ASN in terms of delays of arrival, imaging, use of intravenous (IV) thrombolysis, and outcome of patients. We conducted a prospective study during 18 months to evaluate characteristics of patients admitted with suspected stroke or transient ischemic attack (TIA) in the newly created ASN and to assess conditions of treatment with IV thrombolysis in terms of safety and efficacy. We also compared the outcome data before and after the creation of the ASN. METHODS: For each patient admitted in our hospital for suspected stroke or TIA, were prospectively collected clinical and outcome data (age, mode of transport, delay of arrival after the onset of symptoms (OS), treatment with IV thrombolysis, outcome and discharge). This study was conducted in the ED during six months in 2002, and in the ASN during 18 months, for all patients admitted for stroke. RESULTS: Three hundred and sixty four patients were admitted in the ASN. Emergency medical services (EMS) were used in half of cases for transport, and median delay of admission after the OS was 2h and 52 min. Median delay of imaging was 1 h and 45 min. Seventeen patients (8.5 p. 100 of ischemic stroke patients) were treated with IV thrombolysis, with an initial good outcome in 9 patients, 7 with a dramatic recovery). The main reason for therapeutic abstention for untreated patients admitted in the first 3 hours was a mild deficit with a NIHSS<6. Compared with the previous management in the ED, patients in the ASN were younger, had more severe neurological symptoms, the EMS transport was the main mode of transport (versus used in 17 p. 100 of cases in 2002), and the delay of admission was significantly lower: 2 h 52 versus 5 h 10 (p<0.02). After adjustment on the main predictive factors, only patients with hemorrhagic strokes had a better outcome after the creation of the ASN. CONCLUSIONS: Creation of an ASN was associated with a significant decrease of admission and imaging delays, due to a strong collaboration with EMS, and with a better outcome for hemorrhagic stroke patients. Treatment with intravenous thrombolysis in the first 3 hours could be used widely and was efficient and safe. However, the creation of dedicated stroke units for all stroke patients remains necessary to improve quality of care and outcome.

[Power Doppler Index for preoperative ovarian tumors discrimination]. / Valeur de l'index de vascularisation (Power Doppler Index) pour la discrimination des masses ovariennes en préopératoire.

OBJECTIVE: To assess the performance of a power doppler vascularity index in the preoperative diagnosis of ovarian malignancy. PATIENTS AND METHODS: Two successive series of adnexal masses (N=101 and N=82) were examined prospectively with power Doppler before surgical treatment. A vascularity index, called Power Doppler Index (PDI), based on the number of colored pixels, was estimated on selected frames (defined region of interest covering the entire tumor) of the tumors using an in house color-quantifying program. The first study was monocentric to test the inter- and intraobserver reproducibilities and the availability of the parameter. The second was multicentric to validate the first results. The sensitivity and specificity of PDI, resistance index (RI) and subjective visual scoring were compared using receiver operating characteristic (ROC) curves. RESULTS: Histology identified 23 malignant and 78 benign lesions in the first study and 34 malignant and 48 benign tumors in the second. PDI was considerably higher in malignant than in benign lesions (0.34+/-0.04 vs 0.12+/-0.06 (P<0.001)). Intra-observer and interobserver variability of PDI was low (intraclass correlation coefficients estimated at 0.99 and 0.98, respectively). The PDI cut-off value for differential diagnosis was set at 0.265 (26.5% of the tumor is colored) in the first study and 0.107 in the second. Sensitivity and specificity were 100% (95% CI [87.8; 100.0]) and 97.4% (95% CI [91.0; 99.7]), respectively, for PDI in the first study compared to 75% (95% CI [72.9; 90.7]) and 60% (95% CI [56.3; 92.5]) in the second study. Using logistic regression, visual Doppler scoring performed best. DISCUSSION AND CONCLUSION: The Power Doppler Index obtained using our color quantifying software has discriminating power for adnexal masses but visual Doppler scoring performs best.