University of Tours

Excessive brain tissue pulsations (BTP), measured by ultrasound, have been associated with depression and are hypothesized to contribute to brain damage in this population at risk for cerebrovascular lesions. However, previous research has been limited by small sample sizes. To address this issue, our study pooled data from three separate investigations, resulting in the largest cohort of depressed participants with BTP measurements to date. We analysed 123 participants (74 individuals with depression and 49 healthy controls) using ultrasound tissue pulsatility imaging (TPI) to assess resting BTP. Results showed that both MeanBTP and MaxBTP were significantly associated with depression, as determined by multiple linear regression models that included age, sex and blood pressure as covariates. Additionally, we found that age, sex and diastolic blood pressure were significant predictors of BTP. Specifically, BTP decreased with age, was higher in men, and was more strongly predicted by diastolic blood pressure than by systolic blood pressure. In this large cohort, we replicated the association between depression and increased BTP, supporting the notion that elevated BTP may be a potential mechanism underlying brain damage over time. Our findings suggest that TPI could serve as a valuable surrogate marker for brain health in clinical practice.

Purpose To systematically evaluate and synthesize the existing literature on environmental aspects related to urological endoscopy procedures. Methods A literature search was conducted through January 2024 using PubMed/Medline, and Web of Science databases. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed to identify eligible studies. Results The review reveals varying environmental footprints across procedures. In cystoscopy, studies suggest that disposable scopes result in decreased waste and water usage compared to reusable ones. However, life-cycle assessments did not conclusively highlight environmental superiority in favor of disposable devices. This discrepancy might dwell in the reprocessing methods used for the reusable cystoscopes that vary greatly among centers. For ureteroscopy, studies tend to show comparable carbon footprints for disposable and reusable scopes. Regarding transurethral resection of bladder tumors, a shift towards day-case surgery is associated with a substantial reduction in carbon emissions. Transurethral prostatic surgery assessments reveal significant discrepancies in the carbon footprints of disposable minimally invasive surgical devices, highlighting the need for recycling programs and manufacturing modifications. Conclusions This review shed light on the necessity to develop strategies to reduce environmental impact such as individual assessments of single-use devices, optimizing reusable scope reprocessing, reconsidering the use of draping during cystoscopies, and minimizing hospital stays. This study serves as a call to industries to conduct similar audits and standardized studies for healthcare products and services, fostering evidence-based decisions to mitigate the environmental impact of urological endoscopy procedures.

Objectives To assess the real‐world efficacy and safety of recombinant factor IX albumin fusion protein (rIX‐FP) in patients with hemophilia B (HB) in France. Methods Data on dosing frequency, weekly consumption, and bleeds before‐and‐after switching to rIX‐FP, were collected from December 2021 to February 2024. Annualized (spontaneous) bleeding rates [A(s)BRs] were calculated only in patients on prophylaxis with a follow‐up ≥ 6 months. Results This interim analysis focused on 77 patients ≥ 12 years; 62 (81%) had severe HB. After switching to rIX‐FP, the infusion interval was 14 (7–14) days. Weekly consumption was 43 (35.5–53) IU/kg. ABRs and AsBRs were 0.5 (0–1.9) and 0 (0–0.7) (n = 63) at 18.2 (12.3–21.9) months of follow‐up. Prophylactic efficacy of rIX‐FP was considered ‘Excellent’/‘Good’ in 65/68 (95%) patients. Among the 43 patients previously treated with rFIXFc, 21 increased the infusion interval from 7 (7–11) days with rFIXFc to 14 (7–14) days with rIX‐FP; 33/43 (77%) reduced weekly factor IX (FIX) consumption from 59.95 (46.35–77.93) to 42.5 (35.88–50.25) IU/kg. Patients maintained good protection against bleeds. Conclusion This analysis confirmed that switching to rIX‐FP allows for reducing injection frequency and FIX consumption while maintaining good bleed protection.

Entry of viral capsids into the nucleus induces the formation of biomolecular condensates called HIV-1 membraneless organelles (HIV-1-MLOs). Several questions remain about their persistence, in vivo formation, composition, and function. Our study reveals that HIV-1-MLOs persisted for several weeks in infected cells, and their abundance correlated with viral infectivity. Using an appropriate animal model, we show that HIV-1-MLOs were formed in vivo during acute infection. To explore the viral structures present within these biomolecular condensates, we used a combination of double immunogold labeling, electron microscopy and tomography, and unveiled a diverse array of viral core structures. Our functional analyses showed that HIV-1-MLOs remained stable during treatment with a reverse transcriptase inhibitor, maintaining the virus in a dormant state. Drug withdrawal restored reverse transcription, promoting efficient virus replication akin to that observed in latently infected patients on antiretroviral therapy. However, when HIV-1 MLOs were deliberately disassembled by pharmacological treatment, we observed a complete loss of viral infectivity. Our findings show that HIV-1 MLOs shield the final reverse transcription product from host immune detection.

Exploratory Data Analysis (EDA) is the interactive process of gaining insights from a dataset. Comparisons are popular insights that can be specified with comparison queries, i.e., specifications of the comparison of subsets of data. In this work, we consider the problem of automatically computing sequences of comparison queries that are coherent, significant and whose overall cost is bounded. Such an automation is usually done by either generating all insights and solving a multi-criteria optimization problem, or using reinforcement learning. In the first case, a large search space has to be explored using exponential algorithms or dedicated heuristics. In the second case, a dataset-specific, time and energy-consuming training, is necessary. We contribute with a novel approach, consisting of decomposing the optimization problem in two: the original problem, that is solved over a smaller search space, and a new problem of generating comparison queries, aiming at generating only queries improving existing solutions of the first problem. This allows to explore only a portion of the search space, without resorting to reinforcement learning. We show that this approach is effective, in that it finds good solutions to the original multi-criteria optimization problem, and efficient, allowing to generate sequences of comparisons in reasonable time.

Background Although hemophilia A mainly affects males, carriers (defined as females with hemophilia A, as well as symptomatic or asymptomatic hemophilia A carriers) are at risk of excessive bleeding, particularly during trauma or during surgical procedures. Clinical trials have focused on male patients with severe disease, and data for females are limited. Improved, evidence-based treatment guidelines for management of hemophilia A carriers are required. Objectives and design The NuDIMENSION study is a phase IV, prospective, open-label, single-arm study that will evaluate the perioperative efficacy and safety of simoctocog alfa (Nuwiq®), a recombinant factor VIII (FVIII), in women/girls with hemophilia A undergoing major surgery. The study will be conducted at approximately 15 centers worldwide. Women/girls aged ⩾12 years, with mild or moderate hemophilia A (residual FVIII activity (FVIII:C) ⩾1% to <40%) and with no current/past FVIII inhibitors are eligible. All patients must be scheduled to undergo a major surgical procedure during which simoctocog alfa will be administered. Methods and analysis The primary endpoint is overall perioperative hemostatic efficacy (“success” or “failure”) of simoctocog alfa. Hemostatic efficacy will be assessed at the end of surgery and at the end of the postoperative period (i.e., completion of wound healing), with overall adjudication by an Independent Data Monitoring Committee. Safety endpoints will include the incidences of thrombotic events and FVIII inhibitor development. The aim is to recruit 28 patients to achieve 26 evaluable surgeries. Ethics Ethical approval will be received from institutional review boards/independent ethics committees, and the study will be conducted in compliance with the Declaration of Helsinki. Discussion Data from NuDIMENSION will generate much-needed evidence on surgical management of women/girls with hemophilia A, which will help to enable the development of treatment guidelines specific for such patients. Trial Registration CT EU 2022-502061-17-00; NCT05936580

Objective To assess the opinion, practices, and challenges of international key opinion leaders about two minimal invasive surgical techniques in supraglottic laryngeal tumours: transoral laser microsurgery (TLM) and the transoral robotic surgery (TORS). Methods Design of a questionnaire composed of seven sections and fifty questions covering descriptive data of participants, practitioners experience procedural sequences, considerations related to airways, feeding, and voice, intraoperative haemorrhage, postoperative management, and a comparative analysis of TLM and TORS in treating supraglottic laryngeal cancer. Results A total of 27 head and neck surgeons replied to the survey. The experts had an average experience in laryngeal surgery of 20.0 ± 9.4 years, ranging from 5 to 36 years. We noted a significantly shorter installation time in TLM compared to TORS (19% of experts estimated the installation time of over 20 min with TLM vs 44% with TORS; p = 0.02). According to complications, the experts considered that bleeding was the major concern with supraglottic laryngeal surgery, especially intraoperative bleeding in TLM (52% in TLM vs 26% in TORS) (p = 0.09) and postoperative bleeding in TORS (56% in TORS vs 44% in TLM). Conclusion The experts did not identify a clear superiority of one technology (TLM) over the other (TORS). The two techniques seemed equivalent to the experts, except for the control of intraoperative haemostasis and visualisation of the surgical field, where TORS was perceived as superior to TLM.

This study aimed at leveraging data from phase I/II clinical trials to build a nonlinear joint model of serum M‐protein kinetics and progression‐free survival (PFS) accounting for the effects of isatuximab (Isa), pomalidomide (Pom), and dexamethasone (Dex) in patients with relapsed and/or refractory multiple myeloma. Serum M‐protein levels and PFS data from 203 evaluable patients, included either in a phase I/II study (n = 173) or in a phase I study (n = 30), were used to build the model. First, we independently developed a longitudinal model and a PFS model. Then, we linked them in a nonlinear joint model by selecting the link function that best captured the association between serum M‐protein kinetics and PFS. A Claret tumor growth‐inhibition model accounting for the additive effects of Isa, with an Emax function, Pom, and Dex on serum M‐protein elimination was selected to describe serum M‐protein kinetics. PFS was best described with a log‐logistic model and associations with baseline beta‐2 microglobulin level, age, and coadministration of Dex were identified. The instantaneous change in serum M‐protein level was found to be associated with PFS in the final joint model. Using model simulations, we retrospectively supported the Isa 10 mg/kg weekly for 4 weeks, then biweekly (QW/Q2W) dosing regimen of the ICARIA‐MM phase III pivotal study, and validated it using the same phase III pivotal study data.

The formulation of safe electrolytes for supercapacitors based on phosphazene used as a flame‐retardant (FR) is carried out. 3 molecules are used: hexafluorocyclotriphosphazene (FR1), (ethoxy)pentafluorocyclotriphosphazene (FR2) and pentafluoro(phenoxy)cyclotriphosphazene (FR3). A comparative study on the efficacy from a safety point of view is performed to determine the minimum percentages of each to be used in a conventional acetonitrile (ACN)/1.0 M tetraethylammonium tetrafluoroborate (Et4NBF4) electrolyte to make it non‐flammable. Flammability tests have shown that 5%FR1, 15%FR2 or 20%FR3 are required to do that. The FTIR coupled to the TGA as well as the measurements of surface tensions and contact angles showed that the FRs tend to protect the surface of the electrolyte. The transport properties always remain good, superior to PC/1.0 M Et4NBF4 for example, and the electrochemical stability windows determined in 3‐electrode cells with platinum or activated carbon are at least 2.5 V. The cycling performances are also interesting because the AC|AC EDLCs made in this study are compatible with these FRs, which makes it possible to operate devices providing energies and powers of 23.0 Wh.kg‐1 and 3.7 kW.kg‐1 with the electrolytes based on FR1 or FR2 between 0 and 2.5 V.

Over the last two decades, the EU's foreign trade strategy shifted diametrically from the multilateral World Trade Organization to the bilateral free trade agreements (FTA) route. Accompanying this shift, the EU's regulatory ambitions became more apparent, as can be gleaned from its strategy documents. The main question is whether the EU is succeeding in effectively exporting or promoting its regulations. In this paper, we combine the two disciplines of law and international relations to gauge the EU's success in achieving its external regulatory goals through FTAs. The EU is described in the political science literature as a regulatory power which is trying to promote or export its regulations outside its own jurisdiction. Using two case studies of the recent EU FTAs with Canada and Japan, we conduct a rigorous legal analysis of these FTA texts as well as their implementation in the local jurisdiction by focusing on the area of Geographical Indications (GI). These regulations are compared with the EU's goals mentioned in its strategy documents and from interviews with EU representatives involved in the FTA negotiations. Our results show that the EU has been moderately successful in both FTAs in achieving its general goals such as equal protection for foodstuffs and alcoholic drinks, ex officio protection, and the clawback of some generic names. Overall, the EU was most successful in getting Japan to embrace an EU‐inspired sui generis GI system, whereas Canada showed less leniency and favoured its trademark system.

Despite the numerous published syntheses and applications of sulfoximines, very few studies describe their physico‐chemical properties and in particular their acidic, basic and lipophilic or hydrophilic characters. We report for the first time the acidity values (pKa) of fluorinated sulfoximines in water and in acetonitrile, as well as the basicity (pKaH) measurements of fluorinated and non‐fluorinated sulfoximines in acetonitrile. The same sulfoximine library was also studied in terms of lipophilicity with measurement of the Hansch parameters of the sulfoximine moieties. Finally, these new data allowed us to optimize the N‐alkylation reaction of fluorinated sulfoximines.

Individual sorting and identification of thousands of insects collected in mass trapping biosurveillance programmes is a labour-intensive and time-consuming process. Metabarcoding allows the simultaneous identification of multiple individuals in a single mixed sample and has the potential to expedite this process. However, detecting all the species present in a bulk sample can be challenging, especially when under-represented non-native specimens are intercepted. In this study, we quantified the effectiveness of DNA metabarcoding at detecting exotic species within six different mock communities of native and non-native species of European xylophagous cerambycid beetles. The main objective is to compare three different sequencing technologies (MinION, Illumina and IonTorrent) to evaluate which one is the most suitable in this context. Additionally, dry and wet (monopropylene glycol and water) collection methods were compared. Although not observing significant differences in the total number of species detected amongst the three sequencing technologies, the MinION detected a greater number of species in field-like samples. All three sequencing technologies achieved success in detecting and identifying closely-related species and species in low abundance. The capture method of insects in the field greatly influenced sample preservation and detection. Individuals captured in traps containing monopropylene and water had lower DNA concentration, leading to lower species detection rates compared to individuals killed using just an insecticide without any collection medium.

PURPOSE Alkylating agents (ALKY) are the main chemotherapies used for advanced neuroendocrine tumors (NETs). O ⁶ -Methylguanine-DNA methyltransferase (MGMT) status, as proficient (p) or deficient (d), may predict the response to ALKY. PATIENTS AND METHODS MGMT-NET (ClinicalTrials.gov identifier: NCT03217097 ) was a phase II trial randomly assigning 1:1 for pMGMT or 2:1 for dMGMT-NETs to either ALKY or oxaliplatin (Ox). Inclusion criteria were a confirmed advanced pancreatic, thoracic, or unknown primary NETs with an indication for chemotherapy and tissue available. The primary aim was to detect a difference of 35% between the 3-month objective response rate (ORR) in pMGMT-NETs versus in dMGMT-NETs when treated with ALKY. A biomarker-stratified design was performed to compare ALKY and Ox in the dMGMT and pMGMT strata for the secondary end points. dMGMT was defined using pyrosequencing (PSQ; methylated MGMT ≥9%) and using immunochemistry ( H -score of MGMT <50) when PSQ was not interpretable. RESULTS From October 2018 to October 2021, 105 patients (55 pancreas, 38 thorax, 12 unknown) started either ALKY (n = 62) or Ox (n = 43). The median age was 63 years (range, 30-84), and 59% were males. NETs were G1 (19%), G2 (69%), or G3 (10%). Among patients with interpretable MGMT status, 56.9% (58 of 102) had a dMGMT-NET. The primary end point was not reached; the 3-month ORR was 10 (29.4%) versus 2 (8%), and the odds ratio was 3.5 (0.58-21.16), P = .172. However, best ORR (18 [52.9%] v 3 [11.5%]) and median progression-free survival (14.6 [95% CI, 7.2 to 22.1] v 11.3 [9.4 to 13.2] months) were higher for dMGMT-NETs versus pMGMT-NETs. MGMT status does not seem to affect the Ox efficacy. CONCLUSION Despite the fact that the primary end point was not reached, ALKY has clinical activity in patients with dMGMT-NETs.

Rationale Sirolimus is a treatment for slow‐flow vascular malformations (SFVMs). However, the long‐term management remains challenging. Objectives The SIROLO study assessed the long‐term effects and real‐life management of oral sirolimus for SFVMs by investigating data from 15 French tertiary centres for vascular anomalies. Methods Participants were retrospectively included if they had a SFVM that was being/had been treated with sirolimus for at least 3 years in total. Data were collected on treatment goals when initiating sirolimus, investigator‐reported efficacy, safety, dosages and treatment withdrawal. Results The cohort involved 67 patients with various SFVM entities (mean [±SD] age 19.6 ± 12.5 years, 35 children, 52.2%). We found a heterogeneity of predefined treatment goals, the most frequent being cessation of pain. The investigators considered that sirolimus had persistent efficacy for bleeding, ulceration and pain but only slight efficacy for reducing volume. It was reported to be well‐tolerated, although serious adverse events (mainly infections and also two ovarian cysts) were reported in 6 patients (9.0%) and required definitive sirolimus discontinuation for one. Overall, 11 patients (16.4%) had at least one temporary withdrawal period, leading to symptom recurrence and sirolimus resumption at a mean of 6.4 ± 9.6 months. The mean sirolimus concentration was 6.4 ± 3.7 ng/mL during the first 6 months and decreased over time (mean concentration during the last 6 months: 4.2 ± 3.2 ng/mL), probably to target the minimal efficient dosage. Eight patients (11.9%) switched to alpelisib because of insufficient efficacy of sirolimus. Conclusion This real‐life study gives answers to frequent questions patients and parents ask before sirolimus initiation for SFVMs, such as persistence of efficacy over time, long‐term side effects and time to recurrence in case of withdrawal.

Objectives The first COVID-19 lockdown raised concerns about reduced access to primary care, especially for people with chronic diseases particularly at risk in the absence of follow-up. However, the COVIQuest trial, evaluating the impact of a general practitioner (GP) phone call (intervention) to chronic patients with cardiovascular disease (CVD) or mental health disorder (MHD) concluded that the intervention had no effect at 1 month on the rate of self-reported hospitalisations in the CVD subtrial, whereas the intervention group in MHD subtrial might have a higher rate. This second part of the study aimed to describe the 6 month hospitalisation and specialised consultation rates, using the French health data system ( Système National des Données de Santé ). The secondary objective was to describe these rates during the same period in 2019. Design A cluster randomised controlled trial, with clusters being GPs. Setting Primary care, 149 GPs from eight French regions. Participants Patients ≥70 years old with chronic CVD or ≥18 years old with MHD. Interventions A standardised GP-initiated phone call aiming to evaluate patient’s need for urgent care (vs usual care for control groups). Primary and secondary outcome measures The occurrence of at least one hospitalisation at end point 31 October 2020 (randomisation 30 April 2020), excluding those starting on 30 April 2020, was measured as planned. Another main outcome was the occurrence of at least one specialised consultation during the same period. These 6 month effects were studied, using a logistic regression model within a generalised estimating equation framework, for each subtrial. Results 4640 patients were included: 3274 cardiovascular (mean age 79.9±7.0 years; 57.8% male) and 1366 psychiatric (53.2±7.0; 36.5%). For both subtrials, the intervention patients were significantly more hospitalised than the control patients, respectively, 17.3% versus 14.9% of CVD patients (OR=1.26 (1.05 to 1.52)); 14.4% versus 10.7% of MHD patients (OR=1.40 (1.00 to 1.96)). During the same period in 2019, the hospitalisation rates were, respectively, 16.3%, 18.2%, 15.8% and 14.8%. The proportions of patients with at least one specialised consultation were not different between the intervention and control groups, respectively, 24.6% versus 24.3% for CVD patients (OR=1.06 (0.85 to 1.32)); 26.5% versus 24.4% for MHD patients (OR=1.15 (0.84 to 1.57)). During the same period in 2019, these rates were, respectively, 22.7%, 24.6%, 28.0% and 25.5%. Conclusions The intervention was associated with higher rates of hospitalisation at 6 months in patients with MHD or CVD. No intervention impact was found in outpatient care. These results are difficult to interpret because of a potential artefact induced by national campaigns promoting medical use during lockdown, overlapping the study inclusion period. This study showed that medico-administrative databases could represent a complementary cost-effective tool to clinical research for long-term and healthcare consumption outcomes. Trial registration number NCT04359875 .