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

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

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

Answer to the letter to the editor of S. Pan, et al. concerning “Influence of socioeconomic deprivation and geographic disparities in the management of surgical adolescent idiopathic scoliosis: a multicentric retrospective cohort in Northern France” by B. Kipper, et al. (Eur Spine J [2024]: doi: 10.1007/s00586-024-08556-4)

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Association between pertactin-producing Bordetella pertussis and fulminant pertussis in infants: a multicentre study in France, 2008–2019

International audienceObjectivesVirulence factors of the causative agent, Bordetella pertussis, may be involved in fulminant pertussis, the most severe form of whooping cough (pertussis) in infants. We aimed to assess the association between fulminant pertussis and the status of pertactin (PRN) production of B. pertussis clinical isolates.MethodsSymptomatic infants aged <6 months with a positive B. pertussis culture from 2008–2019 were included. B. pertussis isolates and clinical data were collected from French hospital laboratories through the national pertussis surveillance network. Fulminant pertussis was defined as a case with a leukocyte count >40 × 109/L and at least one of the following criteria: respiratory failure, pulmonary hypertension, shock, or multiple organ failure. PRN production was assessed by western blotting. Baseline characteristics of infants and microbiological findings were compared between patients with and without fulminant pertussis. To identify patient and microbiological features associated with fulminant pertussis, a multivariable modified Poisson regression model was developed with confounders selected using a directed acyclic graph.ResultsWe included 361 infants with pertussis (median age 63 days [interquartile range, 39–86]), of whom 32 (9%) progressed to fulminant pertussis. None of the mothers was vaccinated during pregnancy. Of the 361 implicated B. pertussis isolates, 294 (81%) produced PRN. Patients with fulminant pertussis were more often neonates (adjusted relative risk [aRR]: 3.62, 95% confidence interval [CI]: 1.76–7.44), infants with a history of prematurity (aRR: 7.08, 95% CI: 3.06–16.36), unvaccinated infants (aRR: 4.42, 95% CI: 1.02–19.24), and infants infected by PRN-producing isolates (aRR: 3.76, 95% CI: 1.02–13.83).DiscussionPRN-producing B. pertussis was independently associated with an increased risk of fulminant pertussis. In a context where PRN-containing acellular pertussis vaccines favour the emergence of PRN-deficient isolates, our study suggests a positive role for such vaccines in driving the evolution of B. pertussis populations towards reduced virulence

Centralized investigator review of radiological and functional imaging reports in real‐world oncology studies: The SACHA‐France experience

International audienceSACHA‐France (NCT04477681) is a prospective real‐world study that collects clinical safety and efficacy data of novel anticancer therapies prescribed off‐label or on compassionate use to patients <25 years. From March 2020 until February 2024, 640 patients with solid tumors or lymphomas were included, with 176 (28%) reported objective tumor responses. Centralized medical monitoring of local radiological/functional imaging reports by the SACHA coordinating investigator led to response modification in 45 out of 176 cases (26%), highlighting the relevance of the medical review of study data. We suggest this pragmatic approach for improving clinical trial data when centralized radiological review is not performed

Topical review. Dental pain and odontoblasts: facts and hypotheses.

International audienceDental pain arises from exposed dentin following bacterial, chemical, or mechanical erosion of enamel and/or recession of gingiva. Thus, dentin tissue and more specifically patent dentinal tubules represent the first structure involved in dentin sensitivity. Interestingly, the architecture of dentin could allow for the transfer of information to the underlying dental pulp via odontoblasts (dentin-forming cells), via their apical extension bathed in the dentinal fluid running in the tubules, or via a dense network of trigeminal sensory axons intimately related to odontoblasts. Therefore, external stimuli causing dentinal fluid movements and odontoblasts and/or nerve complex responses may represent a unique mechanosensory system bringing a new role for odontoblasts as sensor cells. How cells sense signals and how the latter are transmitted to axons represent the main questions to be resolved. However, several lines of evidence have demonstrated that odontoblasts express mechano- and/or thermosensitive transient receptor potential ion channels (TRPV1, TRPV2, TRPV3, TRPV4, TRPM3, KCa, TREK-1) that are likely to sense heat and/or cold or movements of dentinal fluid within tubules. Added to this, voltage-gated sodium channels confer excitable properties of odontoblasts in vitro in response to injection of depolarizing currents. In vivo, sodium channels co-localize with nerve terminals at the apical pole of odontoblasts and correlate with the spatial distribution of stretch-activated KCa channels. This highlights the terminal web as the pivotal zone of the pulp/dentin complex for sensing external stimuli. Crosstalk between odontoblasts and axons may take place by the release of mediators in the gap space between odontoblasts and axons in view of evidence for nociception-transducing receptors on trigeminal afferent fibers and expression of putative effectors by odontoblasts. Finally, how axons are guided to the target cells and which kind of signaling molecules are involved is extensively discussed in this review

Association Between Surgeon Stress and Major Surgical Complications

International audienceImportance Surgeon stress can influence technical and nontechnical skills, but the consequences for patient outcomes remain unknown. Objective To investigate whether surgeon physiological stress, as assessed by sympathovagal balance, is associated with postoperative complications. Design, Setting, and Participants This multicenter prospective cohort study included 14 surgical departments involving 7 specialties within 4 university hospitals in Lyon, France. Exclusion criteria consisted of patient age younger than 18 years, palliative surgery, incomplete operative time-stamping data, procedures with a duration of less than 20 minutes, and invalid surgeon heart rate variability (HRV) data. Data were accrued between November 1, 2020, and December 31, 2021, with 30-day follow-up completed on May 8, 2022. Analyses were performed from January 1 to May 31, 2024. Exposure Sympathovagal balance of the attending surgeon in the first 5 minutes of surgery. Main Outcomes and Measures Major surgical complications, extended intensive care unit stay, and mortality within 30 days, after adjustment via mixed-effects multivariable logistic regression for surgeon age, professional status, the time of incision, the random effect of the surgeon, and a composite risk score incorporating patient comorbidities and surgery characteristics. Sympathovagal balance was quantified by the low frequency to high frequency (LF:HF) ratio derived from HRV data measured by chest monitors worn intraoperatively. The LF:HF ratio was normalized at the surgeon level to the median value observed for each surgeon during the study period to control for baseline differences. Results A total of 793 surgical procedures performed by 38 attending surgeons were included in the analysis. Median patient age was 62 (IQR, 47-72) years, and 412 (52.0%) were female, with a median of 2 (IQR, 1-4) comorbidities. Median surgeon age was 46 (IQR, 39-52) years, 39 (78.9%) were male, and 22 (57.9%) were professors. Median surgeon heart rate was 88 (IQR, 77-99) beats per minute. Median surgeon LF:HF ratio was 7.16 (IQR, 4.52-10.72) before and 1.00 (IQR, 0.71-1.32) after normalization. Increased surgeon sympathovagal balance during the first 5 minutes of surgery was associated with significantly reduced major surgical complications (adjusted odds ratio [AOR], 0.63; 95% CI, 0.41-0.98; P = .04), though not with reduced intensive care unit stay (AOR, 0.34; 95% CI, 0.11-1.01; P = .05) or mortality (AOR, 0.18; 95% CI, 0.03-1.03; P = .05). Conclusions and Relevance Increased surgeon stress at the beginning of a procedure was associated with improved clinical patient outcomes. The results are illustrative of the complex relationship between physiological stress and performance, identify a novel association between measurable surgeon human factors and patient outcomes, and may highlight opportunities to improve patient care

Actualisation des recommandations de prise en charge des pneumonies aiguës communautaires chez l’adulte par la Société de pathologie infectieuse de langue française (SPILF) et la Société de pneumologie de langue française (SPLF). Avec le soutien de la Société de réanimation de langue française, (SRLF), de la Société française de microbiologie (SFM), de la Société française de radiologie (SFR) et de la Société française de médecine d’urgence (SFMU)

International audienceLa durée de traitement antibiotique est réduite à trois jours si le patient est cliniquement stable à J3.L’hémisuccinate d’hydrocortisone est indiqué en cas de pneumonie aiguë communautaire (PAC) grave et doit être instauré rapidement.L’indication des PCR multiplex respiratoire doit être réservée à certaines situations précises.L’échographie pleuropulmonaire peut être utilisée en première intention pour le diagnostic radiologique de PAC.Le scanner thoracique est indiqué en cas de radiographie thoracique douteuse ou non interprétable

Association between treatment center volume and survival of endometrial cancer patients: A multicenter study: A Francogyn group study

International audienceIntroduction: Endometrial cancer (EC) is the fourth most common cancer in women worldwide. The quality of care for EC patients may vary depending on the treatment center volume. The present study aimed to investigate the impact of center volume on the survival of EC patients.Methods: This multicenter retrospective study analyzed a large cohort of EC patients with type 1 and type 2 tumors treated between 2001 and 2020 in France. The study analyzed the impact of center volume on overall survival, as well as the impact of other factors such as age, FIGO stage, lymph node involvement, laparoscopic surgery, and overall recurrence.Results: The study found that treatment center volume had a significant impact on the overall survival of type 1 EC patients but not on type 2 EC patients. Other factors such as age, FIGO stage, lymph node involvement, laparoscopic surgery, and overall recurrence also impacted survival.Conclusion: Our study provides important insights into the quality of care for EC patients in France. The study's results highlight the impact of treatment center volume and other factors on survival and underscore the importance of high-quality care for all EC patients