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Abstract Objectives Pulmonary arterial hypertension (PAH) is characterized by the remodeling of the pulmonary vascular bed leading to elevation of the pulmonary arterial pressure. Oxidized fatty acids, such as hydroxyeicosatetraenoic acids (HETEs), play a critical role in PAH. We have previously established that dietary supplementation of 15-HETE is sufficient to cause PH in mice, suggesting a role for the gut-lung axis. However, the mechanisms are not known. Approach Analysis of RNA-seq data obtained from the lungs and intestines of mice on 15-HETE diet together with transcriptomic data from PAH patient lungs identified IFN inducible protein 44 (IFI44) as the only gene significantly upregulated in mice and humans. We demonstrate that IFI44 is also significantly increased in PBMCs from PAH patients. In mice, 15-HETE diet enhances IFI44 and its inducer IFN⍺4 expression sequentially in the intestine first and then in the lungs. IFI44 expression in PAH is highly correlated with expression of Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), which is upregulated in CD8 cells in PH lungs of both mice and humans. We show that IFNα4 produced by intestinal epithelial cells facilitates IFI44 expression in CD8 cells. Finally, we demonstrate that IFN receptor 1-KO in mice do not develop PH on 15-HETE diet. In addition, silencing IFI44 expression in the lungs of mice on 15-HETE diet prevents the development of PH and is associated with significantly lower expression of IFI44 and TRAIL in CD8 cells in the lungs. Conclusion Our data reveal a novel gut-lung axis driven by 15-HETE in PH.

Abstract Background In the present work, we aimed at modeling a relaxation experiment which consists in selecting a subfraction of a cell population and observing the speed at which the entire initial distribution for a given marker is reconstituted. Methods For this we first proposed a modification of a previously published mechanistic two-state model of gene expression to which we added a state-dependent proliferation term. This results in a system of two partial differential equations. Under the assumption of a linear dependence of the proliferation rate with respect to the marker level, we could derive the asymptotic profile of the solutions of this model. Results In order to confront our model with experimental data, we generated a relaxation experiment of the CD34 antigen on the surface of TF1-BA cells, starting either from the highest or the lowest CD34 expression levels. We observed in both cases that after approximately 25 days the distribution of CD34 returns to its initial stationary state. Numerical simulations, based on parameter values estimated from the dataset, have shown that the model solutions closely align with the experimental data from the relaxation experiments. Conclusion Altogether our results strongly support the notion that cells should be seen and modeled as probabilistic dynamical systems.

Background Despite improvement in devices, in‐stent restenosis remains a frequent and challenging complication of percutaneous coronary interventions. Methods and Results The RESTO (Morphological Parameters of In‐Stent Restenosis Assessed and Identified by OCT [Optical Coherence Tomography]; study NCT04268875) was a prospective multicenter registry including patients presenting with coronary syndromes related to in‐stent restenosis. All patients underwent preintervention OCT analysis, which led to analysis of in‐stent restenosis phenotype, number of strut layers, and presence of stent underexpansion. The primary end point was the in‐stent restenosis type according to the OCT morphological classification. The 1‐year incidence of target vessel failure (a composite of death from cardiac causes, target‐vessel myocardial infarction, or ischemia‐driven target‐vessel revascularization) was assessed. The study included 297 patients. The culprit stent was a drug‐eluting stent in 74.2% of cases. OCT analysis revealed the presence of neoatherosclerosis in 57% (52% calcified), neointimal hyperplasia in 43% (58% homogeneous), stent underexpansion (minimal stent area

Bladder cancer remains a prevalent and challenging malignancy. Myeloid-derived suppressor cells (MDSCs) have emerged as key contributors to the immunosuppressive tumor microenvironment, facilitating tumor progression, immune evasion, and resistance to therapies. This review explores the role of MDSC in bladder cancer, highlighting their involvement in immune regulation; tumor progression; and resistance to therapies such as bacillus Calmette–Guérin (BCG) therapy, chemotherapy, and immune checkpoint inhibitors (ICIs). We also discuss their potential as biomarkers and therapeutic targets, with current evidence suggesting that targeting MDSCs, either alone or in combination with existing treatments such as BCG and ICIs, may enhance anti-tumor immunity and improve clinical outcomes. However,, challenges remain, particularly regarding the identification and therapeutic modulation of MDSC subpopulations. Further research is warranted to fully elucidate their role in bladder cancer and to optimize MDSC-targeted therapies.

Abstract Background Mortality data obtained from death certificates have been studied to explore causal associations between diseases. However, these analyses are subject to collider and reporting biases (selection and information biases, respectively). We aimed to assess to what extent associations of causes of death estimated from individual mortality data can be extrapolated as associations of disease states in the general population. Methods We used a multistate model to generate populations of individuals and simulate their health states up to death from national health statistics and artificially replicate collider bias. Associations between health states can then be estimated from such simulated deaths by logistic regression and the magnitude of collider bias assessed. Reporting bias can be approximated by comparing the estimates obtained from the observed death certificates (subject to collider and reporting biases) with those obtained from the simulated deaths (subject to collider bias only). As an illustrative example, we estimated the association between cancer and suicide in French death certificates and found that cancer was negatively associated with suicide. Collider bias, due to conditioning inclusion in the study population on death, increasingly downwarded the associations with cancer site lethality. Reporting bias was much stronger than collider bias and depended on the cancer site, but not prognosis. Results The magnitude of the biases ranged from 1.7 to 9.3 for collider bias, and from 4.7 to 64 for reporting bias. Conclusions These results argue for an assessment of the magnitude of both collider and reporting biases before performing analyses of cause of death associations exclusively from mortality data. If these biases cannot be corrected, results from these analyses should not be extrapolated to the general population.

Abstract Background Work circumstances can substantially negatively impact health. To explore this, large occupational cohorts of free-text job descriptions are manually coded and linked to exposure. Although several automatic coding tools have been developed, accurate exposure assessment is only feasible with human intervention. Methods We developed OPERAS, a customizable decision support system for epidemiological job coding. Using 812,522 entries, we developed and tested classification models for the Professions et Catégories Socioprofessionnelles (PCS)2003, Nomenclature d’Activités Française (NAF)2008, International Standard Classifications of Occupation (ISCO)-88, and ISCO-68. Each code comes with an estimated correctness measure to identify instances potentially requiring expert review. Here, OPERAS’ decision support enables an increase in efficiency and accuracy of the coding process through code suggestions. Using the Formaldehyde, Silica, ALOHA, and DOM job-exposure matrices, we assessed the classification models’ exposure assessment accuracy. Results We show that, using expert-coded job descriptions as gold standard, OPERAS realized a 0.66–0.84, 0.62–0.81, 0.60–0.79, and 0.57–0.78 inter-coder reliability (in Cohen’s Kappa) on the first, second, third, and fourth coding levels, respectively. These exceed the respective inter-coder reliability of expert coders ranging 0.59–0.76, 0.56–0.71, 0.46–0.63, 0.40–0.56 on the same levels, enabling a 75.0–98.4% exposure assessment accuracy and an estimated 19.7–55.7% minimum workload reduction. Conclusions OPERAS secures a high degree of accuracy in occupational classification and exposure assessment of free-text job descriptions, substantially reducing workload. As such, OPERAS significantly outperforms both expert coders and other current coding tools. This enables large-scale, efficient, and effective exposure assessment securing healthy work conditions.

Ion beam processes related to focused ion beam milling, surface patterning, and secondary ion mass spectrometry require precision and control. Quality and cleanliness of the sample are also crucial factors. Furthermore, several domains of nanotechnology and industry use nanoscaled samples that need to be controlled to an extreme level of precision. To reduce the irradiation-induced damage and to limit the interactions of the ions with the sample, low-energy ion beams are used because of their low implantation depths. Yet, low-energy ion beams come with a variety of challenges. When such low energies are used, the residual gas molecules in the instrument chamber can adsorb on the sample surface and impact the ion beam processes. In this paper we pursue an investigation on the effects of the most common contaminant, water, sputtered by ultralow-energy ion beams, ranging from 50 to 500 eV and covering the full range of incidence angles, using molecular dynamics simulations with the ReaxFF potential. We show that the expected sputtering yield trends are maintained down to the lowest sputtering yields. A region of interest with low damage is obtained for incidence angles around 60° to 75°. We also demonstrate that higher energies induce a larger removal of the water contaminant and, at the same time, induce an increased amorphization, which leads to a trade-off between sample cleanliness and damage.

Abstract The white‐clawed crayfish (Austropotamobius pallipes) is an emblematic taxon of European rivers, found mainly in oxygenated streams, known to be an excellent indicator of river quality. Since several decades, the population of A. pallipes declined in relation to anthropogenic pressure, habitat loss, and competition with pests (invasive crayfish, crayfish plague). This endangered species is now submitted to conservation strategies by freshwater managers in order to survey and protect the remaining populations. In France, traditional surveys in freshwater environments were performed by electric fishing, kick‐net fishing, or trapping, particularly disruptive for the environment and very time‐consuming. However, with the rise of molecular genetic technology, new methods based on the detection of environmental DNA (eDNA) have emerged. We present here the results of an optimized study for the detection of the endangered crayfish Austropotamobius pallipes in France, considering certain environmental co‐factors and comparing two PCR methods (qPCR and ddPCR). After improving laboratory procedures, we were able to detect the presence of the crayfish up to 2 km downstream from a known point of presence and unfortunately highlight the disappearance of a historical population, after sampling two consecutive years. Such a level of precision is interesting because it makes it possible to precise the presence of specimens in a relatively restricted area and to orient traditional prospecting, necessary for certain additional studies. During our study, we observed better probabilities of detection during the summer period, but in a growing context of climate change, we advise to adapt the sampling year by year. That said, this methodology is a very useful tool for the detection of rare and/or endemic species and we did not observe any difference between the two PCR methods used.

IntroductionDual antithrombotic therapy (DAT) combining oral anticoagulation (OAC), preferentially Non-vitamin K antagonist OAC (NOAC) and single antiplatelet therapy (SAPT) for a period of 6–12 months is recommended after percutaneous coronary intervention (PCI) in patients with an indication for OAC.ObjectiveTo compare outcomes between vitamin K antagonist (VKA) and NOAC-treated patients in the nation-wide France PCI registry.MethodsAll consecutive patients from the France PCI registry treated by PCI and discharged with OAC between 2014 and 2020 were included and followed one-year. Major bleeding was defined as Bleeding Academic Research Consortium (BARC) classification ≥3 and major adverse cardiac events (MACE) as the composite of all-cause mortality, myocardial infarction (MI), and ischemic stroke. A propensity-score analysis was used.ResultsOf the 7,277 eligible participants, 2,432 (33.4%) were discharged on VKA and 4,845 (66.6%) on NOAC. After propensity-score adjustment, one-year major bleeding was less frequent in NOAC vs. VKA-treated participants [3.1% vs. 5.2%, −2.1% (−3.6% to −0.6%), p = 0.005 as well as the rate of MACE [9.2% vs. 11.9%, −2.7% (−5.0% to −0.4%), p = 0.02]. One-year mortality was also significantly decreased in NOAC vs. VKA-treated participants [7.4% vs. 9.9%, −2.6% (−4.7% to −0.5%), p = 0.02]. The area under ROC curves of the anticoagulant treatment propensity score was estimated at 0.93, suggesting potential indication biasConclusionsNOAC seems to have a better efficacy and safety profile than VKA. However, potential indication bias were found.

Protein supplementation in early life had beneficial effects on the growth and carcass characteristics of all the sheep breeds studied. The lambs had the highest feed utilization efficiency with fish meal and corn gluten-blood meal. Meat from control lambs was found to be juicier than from the test animals, but no other significant differences were found. Breed differences in growth and carcass characteristics and meat quality were accounted for by ancestry, whether prolific or meat-type sheep.

Background: A number of studies have reported reductions in mortality risk due to heat and cold over time. However, questions remain about the drivers of these adaptation processes to ambient temperatures. We aimed to analyse the demographic and socioeconomic drivers of the downward trends in vulnerability to heat- and cold-related mortality observed in Spain during recent decades (1980–2018). Methods: We collected data on all-cause mortality, temperature and relevant contextual indicators for 48 provinces in mainland Spain and the Balearic Islands between Jan 1, 1980, and Dec 31, 2018. Fourteen contextual indicators were analysed representing ageing, isolation, urbanicity, heating, air conditioning (AC), house antiquity and ownership, education, life expectancy, macroeconomics, socioeconomics, and health investment. The statistical analysis was separately performed for the range of months mostly causing heat- (June-September) and cold- (October-May) related mortality. We first applied a quasi-Poisson generalised linear regression in combination with distributed lag non-linear models (DLNM) to estimate province-specific temperature-mortality associations for different periods, and then we fitted univariable and multivariable multilevel spatiotemporal meta-regression models to evaluate the effect modification of the contextual characteristics on heat- and cold-related mortality risks over time. Findings: The average annual mean temperature has risen at an average rate of 0·36 °C per decade in Spain over 1980–2012, although the increase in temperature has been more pronounced in summer (0·40 °C per decade in June-September) than during the rest of the year (0·33 °C per decade). This warming has been observed, however, in parallel with a progressive reduction in the mortality risk associated to both hot and cold temperatures. We found independent associations for AC with heat-related mortality, and heating with cold-related mortality. AC was responsible for about 28·6% (31·5%) of the decrease in deaths due to heat (extreme heat) between 1989 and 1993 and 2009–2013, and heating for about 38·3% (50·8%) of the reductions in deaths due to cold (extreme cold) temperatures. Ageing (ie, proportion of population over 64 years) attenuated the decrease in cold-related mortality. Interpretation: AC and heating are effective societal adaptive measures to heat and cold temperatures. This evidence holds important implications for climate change health adaptation policies, and for the projections of climate change impacts on human health.

ObjectiveHolmium laser enucleation of the prostate (HoLEP) has been recommended for the surgical management of benign prostatic hyperplasia (BPH) in most of the international guidelines, regardless of prostatic volume. The main advantages reported by randomized clinical studies are reduced perioperative bleeding, catheterization time, and length of hospital stay, but this technique is also described as difficult to master with a steep learning curve. The objective of this study was to describe the clinical outcomes of HoLEP in the real-life setting of an academic department with multiple operators with no previous experience.MethodsA retrospective observational study was conducted including all consecutive cases performed in our department from April 2012 to October 2020. Over the study period, 31 different operators were involved. In April 2012, 2 surgeons were trained by an experienced urologist. The 29 others learned the technique progressively with the help of the first 2 surgeons (surgical mentoring).ResultsA total of 1259 patients were included. Preoperatively, the mean prostate volume and Qmax were 82.3 g and 9.4 mL/s, respectively. The mean operative time was 79.7 min. The intraoperative complication rate was 5.6% (n = 71), with the need for conversion being 0.6%. Postoperatively, the complication rate was 18.6% (n = 234). Surgeon’s experience reduced the perioperative complication rates (P = 0.01), operative time (P < 0.001), and length of hospital stay (P < 0.001), but the difference in blood transfusion rate was statistically non-significant (P = 0.3).ConclusionsMost of the 31 urologists in training were able to master HoLEP progressively, with good functional outcomes and acceptable complication rates. Supervision by trained urologists was critical for the safe dissemination of the technique in our department.

Abstract Daylight saving time (DST) consists in a one-hour advancement of legal time in spring offset by a backward transition of the same magnitude in fall. It creates a minimal circadian misalignment that could disrupt sleep and homoeostasis in susceptible individuals and lead to an increased incidence of pathologies and accidents during the weeks immediately following both transitions. How this shift affects mortality dynamics on a large population scale remains, however, unknown. This study examines the impact of DST on all-cause mortality in 16 European countries for the period 1998-2012. It shows that mortality decreases in spring and increases in fall during the first two weeks following each DST transition. Moreover, the alignment of time data around DST transition dates revealed a septadian mortality pattern (lowest on Sundays, highest on Mondays) that persists all-year round, irrespective of seasonal variations, in men and women aged above 40.

Summary: Background: Prostatic artery embolisation (PAE) is a minimally invasive treatment of symptomatic benign prostatic hyperplasia (BPH). Our aim was to compare patient's symptoms improvement after PAE and medical treatment. Methods: A randomised, open-label, superiority trial was set in 10 French hospitals. Patients with bothersome lower urinary tract symptoms (LUTS) defined by International Prostatic Symptom Score (IPSS) > 11 and quality of life (QoL) > 3, and BPH ≥50 ml resistant to alpha-blocker monotherapy were randomly assigned (1:1) to PAE or Combined Therapy ([CT], oral dutasteride 0.5 mg/tamsulosin hydrochloride 0.4 mg per day). Randomisation was stratified by centre, IPSS and prostate volume with a minimisation procedure. The primary outcome was the 9-month IPSS change. Primary and safety analysis were done according to the intention-to-treat (ITT) principle among patients with an evaluable primary outcome. ClinicalTrials.gov Identifier: NCT02869971. Findings: Ninety patients were randomised from September 2016 to February 2020, and 44 and 43 patients assessed for primary endpoint in PAE and CT groups, respectively. The 9-month change of IPSS was −10.0 (95% confidence interval [CI]: −11.8 to −8.3) and −5.7 (95% CI: −7.5 to −3.8) in the PAE and CT groups, respectively. This reduction was significantly greater in the PAE group than in the CT group (−4.4 [95% CI: −6.9 to −1.9], p = 0.0008). The IIEF-15 score change was 8.2 (95% CI: 2.9–13.5) and −2.8 (95% CI: −8.4 to 2.8) in the PAE and CT groups, respectively. No treatment-related AE or hospitalisation was noticed. After 9 months, 5 and 18 patients had invasive prostate re-treatment in the PAE and CT group, respectively. Interpretation: In patients with BPH ≥50 ml and bothersome LUTS resistant to alpha-blocker monotherapy, PAE provides more urinary and sexual symptoms benefit than CT up to 24 months. Funding: French Ministry of Health and a complementary grant from Merit Medical.

Focused ion beams (FIB) are a common tool in nanotechnology for surface analysis, sample preparation for electron microscopy and atom probe tomography, surface patterning, nanolithography, nanomachining, and nanoprinting. For many of these applications, a precise control of ion-beam-induced processes is essential. The effect of contaminations on these processes has not been thoroughly explored but can often be substantial, especially for ultralow impact energies in the sub-keV range. In this paper we investigate by molecular dynamics (MD) simulations how one of the most commonly found residual contaminations in vacuum chambers (i.e., water adsorbed on a silicon surface) influences sputtering by 100 eV argon ions. The incidence angle was changed from normal incidence to close to grazing incidence. For the simulation conditions used in this work, the adsorption of water favours the formation of defects in silicon by mixing hydrogen and oxygen atoms into the substrate. The sputtering yield of silicon is not significantly changed by the contamination, but the fraction of hydrogen and oxygen atoms that is sputtered largely depends on the incidence angle. This fraction is the largest for incidence angles between 70 and 80° defined with respect to the sample surface. Overall, it changes from 25% to 65%.

Background: Active surveillance (AS) is a management option for men diagnosed with low-risk prostate cancer. Opinions differ on whether it is safe to include young men (≤60 yr) or men with intermediate-risk disease. Objective: To assess whether reasons for discontinuation, treatment choice after AS, and adverse pathology at radical prostatectomy (RP; N1, or ≥GG3, or ≥pT3) differ for men ≤60 yr or those with European Association of Urology (EAU) intermediate-risk disease from those for men >60 yr or those with EAU low-risk disease. Design, setting, and participants: We analyzed data from 5411 men ≤60 yr and 14 959 men >60 yr, 14 064 men with low-risk cancer, and 2441 men with intermediate-risk cancer, originating from the GAP3 database (21 169 patients/27 cohorts worldwide). Outcome measurements and statistical analysis: Cumulative incidence curves were used to estimate the rates of AS discontinuation and treatment choice. Results and limitations: The probability of discontinuation of AS due to disease progression at 5 yr was similar for men aged ≤60 yr (22%) and those >60 yr (25%), as well as those of any age with low-risk disease (24%) versus those with intermediate-risk disease (24%). Men with intermediate-risk disease are more prone to discontinue AS without evidence of progression than men with low-risk disease (at 1/5 yr: 5.9%/14.2% vs 2.0%/8.8%). Adverse pathology at RP was observed in 32% of men ≤60 yr compared with 36% of men >60 yr (p = 0.029), and in 34% with low-risk disease compared with 40% with intermediate-risk disease (p = 0.048). Conclusions: Our descriptive analysis of AS practices worldwide showed that the risk of progression during AS is similar across the age and risk groups studied. The proportion of adverse pathology was higher among men >60 yr than among men ≤60 yr. These results suggest that men ≤60 yr and those with EAU intermediate-risk disease should not be excluded from opting for AS as initial management. Patient summary: Data from 27 international centers reflecting daily clinical practice suggest that younger men or men with intermediate-risk prostate cancer do not hold greater risk for disease progression during active surveillance.

Myocardial fibrosis and calcification associate with adverse outcomes in nonischemic heart failure. Cardiac fibroblasts (CF) transition into myofibroblasts (MF) and osteogenic fibroblasts (OF) to promote myocardial fibrosis and calcification. However, common upstream mechanisms regulating both CF-to-MF transition and CF-to-OF transition remain unknown. microRNAs are promising targets to modulate CF plasticity. Our bioinformatics revealed downregulation of miR–129-5p and upregulation of its targets small leucine–rich proteoglycan Asporin (ASPN) and transcription factor SOX9 as common in mouse and human heart failure (HF). We experimentally confirmed decreased miR–129-5p and enhanced SOX9 and ASPN expression in CF in human hearts with myocardial fibrosis and calcification. miR–129-5p repressed both CF-to-MF and CF-to-OF transition in primary CF, as did knockdown of SOX9 and ASPN. Sox9 and Aspn are direct targets of miR–129-5p that inhibit downstream β-catenin expression. Chronic Angiotensin II infusion downregulated miR–129-5p in CF in WT and TCF21-lineage CF reporter mice, and it was restored by miR–129-5p mimic. Importantly, miR–129-5p mimic not only attenuated progression of myocardial fibrosis, calcification marker expression, and SOX9 and ASPN expression in CF but also restored diastolic and systolic function. Together, we demonstrate miR–129-5p/ASPN and miR–129-5p/SOX9 as potentially novel dysregulated axes in CF-to-MF and CF-to-OF transition in myocardial fibrosis and calcification and the therapeutic relevance of miR–129-5p.

Gene expression is under tight regulation from the chromatin structure that regulates gene accessibility by the transcription machinery to protein degradation. At the transcript level, this regulation falls on RNA-binding proteins (RBPs). RBPs are a large and diverse class of proteins involved in all aspects of a transcript’s lifecycle: splicing and maturation, localization, stability, and translation. In the past few years, our understanding of the role of RBPs in cardiovascular diseases has expanded. Here, we discuss the general structure and function of RBPs and the latest discoveries of their role in pulmonary and systemic cardiovascular diseases.

Abstract Purpose The anatomy of the spring ligament complex, as well as its pathology, is not well known in daily clinical practice. The purpose of this study was to evaluate the shear‐wave elastography properties of the spring ligament and the posterior tibial tendon in healthy adults, and to assess the reliability and reproducibility of these measurements. Methods Shear‐wave elastography was used to evaluate both ankles in 20 healthy patients (10 females/10 males) resting on a hinge support with their ankles in neutral, valgus 20° and varus 30° positions. The stiffness of the spring ligament and posterior tibial tendon was assessed by measuring the speed of shear wave propagation through each structure. Results Posterior tibial tendon and spring ligament reach a maximum estimated stiffness in valgus 20° position (7.43 m/s vs 5.73 m/s, respectively). Flat feet were associated with greater spring ligament stiffness in the 20° valgus position (p = 0.01), but not for the posterior tibial tendon (p = 0.71). The physiologic weightbearing hindfoot attitude had no impact on the stiffness of the posterior tibial tendon or the spring ligament, regardless of the analysis position. Intra‐ and inter‐observer agreements were all excellent for spring ligament stiffness, regardless of ankle position, and were good or excellent for posterior tibial tendon. Conclusions This study describes a protocol to assess the stiffness of tibialis posterior and the spring ligament by shear‐wave elastography, which is reliable, reproducible, and defines a corridor of normality. Further studies should be conducted to define the role of elastography for diagnosis/ evaluation of pathology, follow‐up, or surgical strategies.

Abstract Aims Mitigation actions during the COVID-19 pandemic may impact mental health and suicide in general populations. We aimed to analyse the evolution in suicide deaths from 2020 to March 2022 in France. Methods Using free-text medical causes in death certificates, we built an algorithm, which aimed to identify suicide deaths. We measured its retrospective performances by comparing suicide deaths identified using the algorithm with deaths which had either a Tenth revision of the International Classification of Diseases (ICD-10) code for ‘intentional self-harm’ or for ‘external cause of undetermined intent’ as the underlying cause. The number of suicide deaths from January 2020 to March 2022 was then compared with the expected number estimated using a generalized additive model. The difference and the ratio between the observed and expected number of suicide deaths were calculated on the three lockdown periods and for periods between lockdowns and after the third one. The analysis was stratified by age group and gender. Results The free-text algorithm demonstrated high performances. From January 2020 to mid-2021, suicide mortality declined during France’s three lockdowns, particularly in men. During the periods between and after the two first lockdowns, suicide mortality remained comparable to the expected values, except for men over 85 years old and in 65–84 year-old age group, where a small number of excess deaths was observed in the weeks following the end of first lockdown, and for men aged 45–64 years old, where the decline continued after the second lockdown ended. After the third lockdown until March 2022, an increase in suicide mortality was observed in 18–24 year-old age group for both genders and in men aged 65–84 years old, while a decrease was observed in the 25–44 year-old age group. Conclusions This study highlighted the absence of an increase in suicide mortality during France’s COVID-19 pandemic and a substantial decline during lockdown periods, something already observed in other countries. The increase in suicide mortality observed in 18–24 year-old age group and in men aged 65–84 years old from mid-2021 to March 2022 suggests a prolonged impact of COVID-19 on mental health, also described on self-harm hospitalizations and emergency department’s attendances in France. Further studies are required to explain the factors for this change. Reactive monitoring of suicide mortality needs to be continued since mental health consequences and the increase in suicide mortality may be continued in the future with the international context.

Objective To determine the impact of SARS-CoV-2 pandemic on urological surgery in France during the year 2020.Design, setting and participants An observational descriptive study was conducted on anonymised data collected from the national healthcare database established each year as part of the Program for the Medicalization of Information Systems in Medicine, Surgery, Obstetrics and Odontology.Intervention None.Primary and secondary outcome measures We gathered the number of urology surgical procedures carried out between 2010 and 2019, and we observed the difference between the forecast and actual number of urological surgeries performed in 2020.Results Urological surgeries decreased by 11.4%, non-oncological surgeries being more affected (−13.1%) than oncological ones (−4.1%). Among the most relevant surgeries, female urinary incontinence (−44.7%) and benign prostatic hyperplasia (−20.8%) were the most impacted ones, followed by kidney cancer (−9%), urolithiasis (−8.7%), radical cystectomy for bladder cancer (−6.1%), prostate cancer (−3.6%) and transurethral resection of bladder tumour (−2%). Public hospitals had a more reduced activity (−17.7%) than private ones (−9.1%). Finally, the distribution of the reduction in urological activities by region did not correspond to the regional burden of SARS-CoV-2.Conclusions Urological care was severely affected during SARS-CoV-2 pandemic. Even if oncological surgeries were prioritised, the longer it takes to receive appropriate care, the greater the risk on survival impact.Trial registration The data collection and analysis was authorised by the French Data Protection Authority (CNIL) under the number1 861 282v2.

Summary: Background: The infant mortality rate (IMR) serves as a key indicator of population health. Methods: We used data from the French National Institute of Statistics and Economic Studies on births and deaths during the first year of life from 2001 to 2019 to calculate IMR aggregated by month. We ran joinpoint regressions to identify inflection points and assess the linear trend of each segment. Exploratory analyses were performed for overall IMR, as well as by age at death subgroups (early neonatal [D0-D6], late neonatal [D7-27], and post-neonatal [D28-364]), and by sex. We performed sensitivity analyses by excluding deaths at D0 and using other time-series modeling strategies. Results: Over the 19-year study period, 53,077 infant deaths occurred, for an average IMR of 3·63/1000 (4·00 in male, 3·25 in female); 24·4% of these deaths occurred during the first day of life and 47·8% during the early neonatal period. Joinpoint analysis identified two inflection points in 2005 and 2012. The IMR decreased sharply from 2001 to 2005 (slope: -0·0167 deaths/1000 live births/month; 95%CI: -0·0219 to -0·0116) and then decreased slowly between 2005 and 2012 (slope: -0·0041; 95%CI: -0·0065 to -0·0016). From 2012 onwards, a significant increase in IMR was observed (slope: 0·0033; 95%CI: 0·0011 to 0·0056). Subgroup analyses indicated that these trends were driven notably by an increase in the early neonatal period. Sensitivity analyses provided consistent results. Interpretation: The recent historic increase in IMR since 2012 in France should prompt urgent in-depth investigation to understand the causes and prepare corrective actions. Funding: No financial relationships with any organizations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

BackgroundThe recognition of medical entities from natural language is a ubiquitous problem in the medical field, with applications ranging from medical coding to the analysis of electronic health data for public health. It is, however, a complex task usually requiring human expert intervention, thus making it expansive and time-consuming. Recent advances in artificial intelligence, specifically the rise of deep learning methods, have enabled computers to make efficient decisions on a number of complex problems, with the notable example of neural sequence models and their powerful applications in natural language processing. However, they require a considerable amount of data to learn from, which is typically their main limiting factor. The Centre for Epidemiology on Medical Causes of Death (CépiDc) stores an exhaustive database of death certificates at the French national scale, amounting to several millions of natural language examples provided with their associated human-coded medical entities available to the machine learning practitioner. ObjectiveThe aim of this paper was to investigate the application of deep neural sequence models to the problem of medical entity recognition from natural language. MethodsThe investigated data set included every French death certificate from 2011 to 2016. These certificates contain information such as the subject’s age, the subject’s gender, and the chain of events leading to his or her death, both in French and encoded as International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) medical entities, for a total of around 3 million observations in the data set. The task of automatically recognizing ICD-10 medical entities from the French natural language–based chain of events leading to death was then formulated as a type of predictive modeling problem known as a sequence-to-sequence modeling problem. A deep neural network–based model, known as the Transformer, was then slightly adapted and fit to the data set. Its performance was then assessed on an external data set and compared to the current state-of-the-art approach. CIs for derived measurements were estimated via bootstrapping. ResultsThe proposed approach resulted in an F-measure value of 0.952 (95% CI 0.946-0.957), which constitutes a significant improvement over the current state-of-the-art approach and its previously reported F-measure value of 0.825 as assessed on a comparable data set. Such an improvement makes possible a whole field of new applications, from nosologist-level automated coding to temporal harmonization of death statistics. ConclusionsThis paper shows that a deep artificial neural network can directly learn from voluminous data sets in order to identify complex relationships between natural language and medical entities, without any explicit prior knowledge. Although not entirely free from mistakes, the derived model constitutes a powerful tool for automated coding of medical entities from medical language with promising potential applications.

Abstract Pulmonary hypertension (PH) developing secondarily in pulmonary fibrosis (PF) patients (PF-PH) is a frequent co-morbidity. The high prevalence of PH in PF patients is very concerning since the presence of PH is a strong predictor of mortality in PF patients. Until recently, PH was thought to arise solely from fibrotic destruction of the lung parenchyma, leading to hypoxic vasoconstriction and loss of vascular bed density. Thus, potential cellular and molecular dysregulation of vascular remodeling as a driver of PF-PH has been under-investigated. The recent demonstrations that there is no correlation between the severity of the fibrosis and development of PH, along with the finding that significant vascular histological and molecular differences exist between patients with and without PH have shifted the etiological paradigm of PF-PH. This review aims to provide a comprehensive translational overview of PH in PF patients from clinical diagnosis and outcome to the latest understanding of the histology and molecular pathophysiology of PF-PH.

Abstract The objective of the study was to identify the mechanism of action for a radiation mitigator of the gastrointestinal (GI) acute radiation syndrome (ARS), identified in an unbiased high‐throughput screen. We used mice irradiated with a lethal dose of radiation and treated with daily injections of the radiation mitigator 1‐[(4‐nitrophenyl)sulfonyl]‐4‐phenylpiperazine to study its effects on key pathways involved in intestinal stem cell (ISC) maintenance. RNASeq, quantitative reverse transcriptase‐polymerase chain reaction, and immunohistochemistry were performed to identify pathways engaged after drug treatment. Target validation was performed with competition assays, reporter cells, and in silico docking. 1‐[(4‐Nitrophenyl)sulfonyl]‐4‐phenylpiperazine activates Hedgehog signaling by binding to the transmembrane domain of Smoothened, thereby expanding the ISC pool, increasing the number of regenerating crypts and preventing the GI‐ARS. We conclude that Smoothened is a target for radiation mitigation in the small intestine that could be explored for use in radiation accidents as well as to mitigate normal tissue toxicity during and after radiotherapy of the abdomen.

Background and Aims: Surgery for pheochromocytoma (PCC) can cause excessive catecholamine release with severe hypertension. Alpha blockade is the mainstay of preoperative management. The aim of this study was to evaluate the efficacy and tolerance of intra-venous (IV) urapidil, a competitive short acting α1 receptor antagonist, in the prevention of peri-operative hemodynamic instability of patients with PCC. Material and Methods: This retrospective observational study included 75 patients (79 PCC) for PCC removal surgery from 2001 to 2017 at the Bordeaux University Hospital. They received, 3 days before surgery, continuous intravenous infusion of urapidil with stepwise increase to the maximum tolerated dose. Urapidil was maintained during the procedure and stopped after clamping the adrenal vein. Plasma catecholamine concentrations were measured during surgery. Hypertensive peaks (SAP >160 mmHg) and tachycardia >100 beats/min were treated with boluses of nicardipine 2 mg and esmolol 0.5 mg/kg. Results: We recorded 20/79 (25%) cases with systolic arterial pressure (SAP) >180 mmHg. Only 11/79 (14%) had hypotension with SAP