Methodological expectations for demonstration of health product effectiveness by observational studies

International audienceThe issue of assessing the effectiveness of health technologies (drugs, devices, etc.) through observational studies is becoming increasingly important as registration and market access agencies consider them in their evaluation process. In this context, observational studies must be able to provide real demonstrations of a level of reliability comparable to those produced by the conventional randomized controlled trial (RCT) approach. The objective of the roundtable was to establish the acceptability criteria for an observational study (non-randomized, non-interventional study) to be able to provide these demonstrations, and possibly serve as a confirmatory study for registration and market access authorities, the construction of therapeutic strategies or the development of recommendations. In order to do this, the study must be a real confirmatory study respecting the hypothetical-deductive approach and guaranteeing the absence of HARKing and p-hacking by attesting to the establishment of a protocol and a statistical analysis plan, recorded before any inferential analysis. It must also be part of a formalized approach to causal inference and demonstrate that it correctly identifies the causal estimand sought. The study should ensure that there is no residual confusion bias by taking into account all confounding factors affecting the comparison, which should be determined by a formal approach (such as a graphical causality approach, DAGs). Residual confusion bias diagnoses by forgery and nullification analysis should be non-existent. The study shall be at low risk of bias, in particular selection bias, among others by using a target test emulation design. Overall type I error risk should be strictly controlled. The absence of selective publication of results and selection bias should be ensured

Deep learning can accurately predict the prognosis of gynecologic smooth muscle tumors of uncertain malignant potential: a multicenter pilot study

International audienceSmooth muscle tumors of uncertain malignant potential (STUMP) of the gynecologic tract are a heterogeneous group of tumors, with ambiguous or worrisome features, whose biological behavior is difficult to predict. Several ancillary techniques have been used to try to predict their prognosis, with limited success. This study aimed to explore whether deep learning (DL)-based features can be used to predict progression-free survival (PFS) in STUMP and identify high-risk patients, directly from histological slides. A cohort of 95 STUMP was collected from 7 academic centers (79 for training and 16 for external validation). Nonoverlapping tiles were extracted from the tumor area and used to train a DL model to predict PFS. Python's scikit-learn library and the R software environment were used for data analysis. After 4-fold cross-validation, mean C-indexes of 0.7052 (95% CI, 0.4951-0.9152) and 1.0 (95% CI, 1.0-1.0) were achieved, in the training and external validation cohorts, respectively. The predicted PFS probabilities were used to classify the patients into low-risk and high-risk groups, based on the thresholds of the median and the first quartile of predicted PFS probabilities. Significant differences between both groups were observed, at 10 years, with both thresholds. Cox regression analysis showed that the output of the DL model was associated with a worse prognosis (P = .0356). Both STUMP groups were compared with a cohort of leiomyomas (n = 160) and leiomyosarcomas (n = 58). The lowest hazard ratio was observed in leiomyomas, followed, consecutively, by low-risk STUMP, high-risk STUMP, and leiomyosarcomas. The Cox model showed good discriminatory potential between the 4 groups (all pairwise comparisons were statistically significant). These findings suggest that DL-based features can be used for outcome prediction of STUMP. Additional work is needed to establish whether this "high-risk" group can be identified via molecular markers and used to tailor patient surveillance

Steatotic liver disease after pediatric liver transplantation

International audienceMetabolic dysfunction–associated steatotic liver disease is becoming an increasingly frequent cause of chronic liver disease in children. It has been reported as a complication of liver transplantation in adults but remains poorly evaluated in liver-transplanted children. The aim of this study was to assess the prevalence and characteristics of steatotic liver disease in a large cohort of liver-transplanted children and to identify factors associated with it. In this single-center study of patients with pediatric liver transplants (n=122) with a median follow-up time of 14.0 years, steatosis was found in 41 protocol biopsies (33.6%). The median time to the discovery of steatosis was 5.0 years posttransplantation, with a median age of 9.0 years at the time of diagnosis. Steatosis was predominantly mild to moderate and tended to resolve spontaneously on subsequent biopsies (48.8% of cases showed resolution). Steatosis mostly corresponded to metabolic dysfunction–associated steatotic liver disease (56.1%), but other patients had cryptogenic steatosis. The study found no association between the presence of steatosis and the immunosuppressive regimen, but a significant association between the onset of steatosis and an older donor age ( p <0.001). Therefore, steatotic liver disease is a noteworthy histological feature during the follow-up of pediatric liver transplant recipients, yet it had a low burden on the health of the patients in this cohort. However, it needs to be monitored in the context of the increasing prevalence of metabolic syndrome

Characterization of biomechanical risk factors during endoscopic submucosal dissection: an ergonomic pilot study

International audienceIntroduction: The prevalence of musculoskeletal disorders (MSDs) among endoscopists is frequent. The aim of this study was to evaluate biomechanical risk factors for MSDs in gastroenterologists performing ESD. Methods: An observational study was performed among interventional endoscopists performing ESD in 3 French centers. The physical constraints were assessed using an analog scale of perceived physical effort intensity and physiological sensors to measure joint angulation kinematics and muscle activity levels (flexor and extensor carpi radialis muscles) during diagnostic colonoscopy and ESD. High muscle strain was defined as any muscle activation exceeding 10% of the maximum voluntary contraction (MVC). Two distinct sub-tasks of ESD were identified: lesion marking and circumferential incision phase (ESD-1) and dissection phase (ESD-2). Results: Six interventional gastroenterologists participated in the study. Perceived physical effort was significantly greater for ESD compared to colonoscopy (p = 0.03). Time spent at more than 10% MVC for the right extensor carpi radialis was significantly higher during ESD-1 than during colonoscopy (+15%, p=0.04). The greatest strain was observed in the left extensor carpi radialis. This muscle was particularly exposed since more than 50% of the time was spent at more than 10% of MVC during colonoscopy and up to more than 80% during ESD-1 and -2. Time spent in the neck flexion risk zone was significantly higher during ESD-2 than during colonoscopy (+42%, p = 0.046). Conclusion: ESD increased the risk of musculoskeletal strain. It is crucial to develop prevention programs to reduce the risk of MSD in the gastroenterologist population

Reimagining Urban River Bathing in Europe: A Multisectoral and Interdisciplinary Dive Into Lyon's Rivers (France)

International audienceUrban river bathing is re‐emerging across Europe, driven by social demand and climate change impacts. The Urban Bathing Consortium, an interdisciplinary and intersectoral consortium initiated at the University of Lyon (France), is at the forefront of studying the challenges and opportunities of creating and managing healthy, safe, and accessible river bathing spaces. Through interdisciplinary collaboration among researchers and stakeholders, the consortium proposed an analytical framework, identifying seven critical dimensions for urban river bathing: the history and revival of city‐river relationships, legal and regulatory frameworks, bathing water quality, river drowning risks, river ecosystems, social perspectives, and urban planning. By examining these dimensions with state‐of‐the‐art approaches and drawing on Lyon's experiences, the study provides scientific insights and practical recommendations for future sustainable urban river bathing development. These include revitalizing historical city‐river connections, aligning local regulations with EU guidance, advancing holistic microbial water quality control, enhancing safety measures, incorporating ecological considerations, balancing competing river uses in urban planning, and addressing social needs for inclusive river governance

Is 2 h of Hypothermic Machine Perfusion for Pancreas Preservation Effective in Improving Graft Reperfusion?

International audienceBackground: Static cold storage (SCS) remains the standard method for organ preservation. The development of parenchymal edema during prolonged hypothermic machine perfusion (HMP) was a major barrier to the introduction of this technique for the preservation of pancreases. A short period of HMP could optimize the pancreas for reperfusion while minimizing the side effects related to perfusion. Our objective is to evaluate the impact of short-term HMP on the pancreatic reperfusion. Methods: A preclinical study using a controlled donation after circulatory death porcine model was conducted. After procurement, the pancreases were preserved under hypothermic conditions for 2 h either by SCS (n = 4) or HMP (n = 4). After these 2 h of preservation, the pancreases were reperfused using a normothermic machine perfusion (NMP) for 2 h. During NMP, oxygenation, perfusion parameters, biochemical analyses, a glucose stimulation insulin secretion test, and an evaluation of ischemia/reperfusion injury by photoacoustic tomography were assessed. Results: During NMP, resistance indices were significantly lower in the HMP group compared with the SCS group, even after 2 h of reperfusion. The tissue oxygen partial pressure was higher throughout NMP after HMP preservation. Lactate and amylase levels were equal between the 2 groups. Lipase levels were higher in the HMP group. The glucose stimulation test showed no difference between the 2 groups. Photoacoustic tomography assessment showed no endothelial damage in either group. Conclusions: Our study suggests that a short-term HMP applied to pancreases for 2 h is effective in reducing resistance indexes and improving oxygenation

Extracellular vesicle microRNAs are biomarkers of focal epilepsy but not epilepsy‐related respiratory dysfunction

International audienceAbstract Objective This study was undertaken to evaluate the diagnostic value of a set of preselected candidate microRNAs (miRNAs) extracted from plasma‐based extracellular vesicles (EVs) to identify patients with seizure‐related respiratory dysfunction. Methods A two‐step design was applied. Step 1 entailed selection of the relevant miRNAs based on the combination of a literature review and an exploratory study in epileptic rats with or without interictal respiratory dysfunction. Step 2 involved evaluation of the diagnostic value of this preselected panel of circulating exosomal miRNAs in a case–control study conducted in 25 healthy subjects and 50 patients with drug‐resistant focal epilepsy undergoing video‐electroencephalographic (EEG) monitoring. Based on video‐EEG data, patients were separated into two groups: those with ictal/postictal hypoxemia (PIH; n = 24) and those without (noPIH; n = 26). Blood samples were collected in the interictal period (>24 h after the last seizure). Expression level of each miRNAs in EVs was compared (1) between all patients with epilepsy and controls and (2) between PIH and noPIH. Receiver operating characteristic (ROC) curves were generated, and the area under the curve (AUC) was calculated. Results Following Step 1, the final set of miRNAs selected for evaluation in the case–control study included 24 miRNAs, with nine selected from published data in patients because of their potential regulatory role in the serotoninergic pathway, brain response to hypoxia, or epilepsy and 15 selected from the preclinical study in epileptic rats. Three miRNAs significantly differed between patients with epilepsy and controls (ROC curve AUC: hsa‐miR‐22‐3p, .74 [95% confidence interval (CI) = .63–.85]; hsa‐miR‐106b‐5p, .69 [95% CI = .57–.82]; and hsa‐miR‐26a‐5p, .72 [95% CI = .58–.85]). Only a trend toward higher expression levels was observed for hsa‐miR‐140‐3p in PIH compared to noPIH (+5%, p = .064). Significance Whereas three miRNAs were robustly associated with epilepsy, none was significantly associated with seizure‐related respiratory dysfunction. Additional studies are required, including analysis of the expression of plasmatic cell‐free miRNAs, especially the miRNAs associated with interictal respiratory dysfunction in epileptic rats

Management of Major Orthopaedic Surgery in a Patient With the Rare Thrombomodulin c.1611C>a Mutation: A Case of an Uncommon Bleeding Disorder

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Aarskog-Scott syndrome: a clinical study based on a large series of 111 male patients with a pathogenic variant in FGD1 and management recommendations

International audienceBackground: Aarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in the FGD1 gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients.Methods: Phenotypic characterisation of the largest reported AAS cohort, comprising 111 male patients with proven causative variants in FGD1, through comprehensive analyses of clinical data including congenital anomalies, growth and neurodevelopment. Review of photographs and radiographs by experts in dysmorphology and skeletal disorders.Results: This study refines the phenotypic spectrum of AAS, with the description of new morphological and radiological features, and refines the prevalence of the features. Short stature is less frequent than previously reported and has a prenatal onset in more than half of the patients. The growth has a specific course with a catch-up during the first decade often leading to low-normal stature in adulthood. Whereas intellectual disability is rare, patients with AAS have a high prevalence of specific learning difficulties and attention hyperactivity disorder. In light of this better knowledge of AAS, we provide management recommendations.Conclusion: A better knowledge of the natural history and phenotypic spectrum of AAS will be helpful for the clinical diagnosis and for the interpretation of FGD1 variants using a retrophenotyping strategy, which is becoming the most common way of diagnosis nowadays. Recommendations for care will improve the management of the patients

A three‐dimensional scoring system for assessment of individual bony and laxity phenotype restoration (knee SIPR) in personalised TKA as a base for treatment guidance

International audienceAbstract Purpose Although personalised alignment has become popular in total knee arthroplasty (TKA), it is unclear which workflow and alignment strategy best restores the bony and laxity phenotype and whether this varies between knee phenotypes. The aim of this study was, therefore, to develop a three‐dimensional (3D) scoring system which assesses bony anatomy, laxity and alignment parameters for TKA. This novel 3D scoring system was tested using a validated TKA simulator on three different knee phenotypes with various alignment workflows. 3D scores were compared between phenotypes and workflows. Methods In this 3D scoring system, analyses of bony resections of all six joint planes were included (maximum score for anatomical resections ± 1 mm) as well as joint laxity/gap analysis (maximum score for balanced extension/flexion gap, medial and lateral side ± 2 mm). Additional alignment parameters (hip–knee–ankle angle, medial proximal tibial angle, lateral distal femoral angle, Tibia slope and coronal plane alignment of the knee) were integrated. All data points were obtained from preoperative long leg x‐rays, intraoperative gap analysis with CAS and intraoperative cartilage measurements. The maximum score for all categories was 27 points (12/10/5). The 3D scores were analysed for nine knees with three knee phenotypes (neutral, varus and valgus) with six different alignment workflows (mechanical alignment—femur first, adjusted mechanical alignment—femur first, unrestricted kinematic alignment, restricted kinematic alignment, inverse kinematic alignment and functional alignment‐tibia first) using the Knee‐computational alignment trainer simulator. Comparison between workflows in all phenotypes was performed for each category. Results In neutral phenotypes, all alignment workflows, including mechanical alignment, showed similar high mean scores. In varus and valgus phenotypes, personalised alignment workflows scored higher than systematic workflows. While in varus phenotypes, scoring of personalised alignment workflows was similarly high to that in straight knees phenotypes, it showed lower means in valgus phenotypes. Measured‐resection workflows restored bony phenotypes in a higher percentage while gap‐balanced workflows performed better in the category of laxity/gap balance. None of the personalised workflows performed best in all knees. Conclusions The new 3D scoring system for individual knee phenotype restoration in TKA allowed a quantitative analysis of the individual reconstruction of the bony and laxity anatomy in different knee phenotypes. First preliminary results show that personalised alignment workflows perform better than systematic mechanical alignment in varus and valgus phenotypes, while in neutral phenotypes, the difference was minimal. None of the personalised workflows scored best in all knees, showing the potential for a 3D phenotype workflow including more bony alignment and laxity parameters. Testing of this 3D scoring system in a larger series of cases is crucial to prove the concept and test correlations between 3D scores and clinical outcomes. Level of Evidence Level IIa