Imiquimod Reverses Chronic Toxoplasmosis-Associated Behavioral and Neurocognitive Anomalies in a Rat Model.

Toxoplasma gondii is the etiologic agent of toxoplasmosis, a highly prevalent parasitosis. Toxoplasma gondii (T. gondii) transits in the brain from acute (AT) to chronic toxoplasmosis (CT), under host immune control. In immunocompromised patients, reactivation of CT is potentially life-threatening. Behavioral and neurological complications have been associated with CT. Furthermore, an effective treatment targeting CT is still lacking. We previously reported the efficacy of imiquimod against CT. Here, we demonstrate the molecular effects of imiquimod or imiquimod followed by the clinically used combination of sulfadiazine and pyrimethamine (SDZ + PYR) on CT-associated behavior in a rat model. Imiquimod decreased the number of cysts in the brains of chronically infected rats due to an induced reactivation of bradyzoites into tachyzoites. Importantly, this decrease was more pronounced in rats treated with imiquimod followed by SDZ + PYR. Rats chronically infected with T. gondii exhibited an anxiety-like behavior. Notably, treatment with imiquimod reversed this behavior aberrancy, with even a more pronounced effect with imiquimod followed by SDZ/PYR. Similarly, rats chronically infected with T. gondii exhibited learning deficits, and imiquimod alone or followed by SDZ/PYR reversed this behavior. Our results enhance our knowledge of the implications of CT on behavioral aberrancies and highlight the potency of imiquimod followed by SDZ + PYR on these CT-associated complications.

Molecular engineering of 3-arylated tetrazo[1,2-b]indazoles: divergent synthesis and structure-property relationships.

The synthetic scope of 3-arylated tetrazo[1,2-b]indazoles is reported based on a Pd-catalyzed Liebeskind-Srogl cross-coupling reaction followed by an N-cyclisation process. The reactivity of the nitrogen atoms was used to further diversify these N-rich polyaromatic tetrazo[1,2-b]indazoles in a panel of reactions (protonation, selective oxidation, metallations). Selective ortho-C-H activation/functionalization on the heterocycle was also demonstrated with three transition metals (TM = Pd, Ir and Rh). The effects of all these molecular engineering strategies, particularly the N-modifications, on the optical and redox properties of the 3-arylated tetrazoindazoles were studied experimentally and theoretically. This study highlights the diversity of molecular structures and electronic properties offered by the tetrazo[1,2-b]indazole platform.

Automatic gross tumor volume segmentation with failure detection for safe implementation in locally advanced cervical cancer.

Background and Purpose: Automatic segmentation methods have greatly changed the RadioTherapy (RT) workflow, but still need to be extended to target volumes. In this paper, Deep Learning (DL) models were compared for Gross Tumor Volume (GTV) segmentation in locally advanced cervical cancer, and a novel investigation into failure detection was introduced by utilizing radiomic features. Methods and materials: We trained eight DL models (UNet, VNet, SegResNet, SegResNetVAE) for 2D and 3D segmentation. Ensembling individually trained models during cross-validation generated the final segmentation. To detect failures, binary classifiers were trained using radiomic features extracted from segmented GTVs as inputs, aiming to classify contours based on whether their Dice Similarity Coefficient ( DSC ) < T and DSC ⩾ T . Two distinct cohorts of T2-Weighted (T2W) pre-RT MR images captured in 2D sequences were used: one retrospective cohort consisting of 115 LACC patients from 30 scanners, and the other prospective cohort, comprising 51 patients from 7 scanners, used for testing. Results: Segmentation by 2D-SegResNet achieved the best DSC, Surface DSC ( SDSC 3 mm ), and 95th Hausdorff Distance (95HD): DSC = 0.72 ± 0.16, SDSC 3 mm =0.66 ± 0.17, and 95HD = 14.6 ± 9.0 mm without missing segmentation ( M =0) on the test cohort. Failure detection could generate precision ( P = 0.88 ), recall ( R = 0.75 ), F1-score ( F = 0.81 ), and accuracy ( A = 0.86 ) using Logistic Regression (LR) classifier on the test cohort with a threshold T = 0.67 on DSC values. Conclusions: Our study revealed that segmentation accuracy varies slightly among different DL methods, with 2D networks outperforming 3D networks in 2D MRI sequences. Doctors found the time-saving aspect advantageous. The proposed failure detection could guide doctors in sensitive cases.

Implementing a Biomedical Data Warehouse From Blueprint to Bedside in a Regional French University Hospital Setting: Unveiling Processes, Overcoming Challenges, and Extracting Clinical Insight.

Background: Biomedical data warehouses (BDWs) have become an essential tool to facilitate the reuse of health data for both research and decisional applications. Beyond technical issues, the implementation of BDWs requires strong institutional data governance and operational knowledge of the European and national legal framework for the management of research data access and use. Objective: In this paper, we describe the compound process of implementation and the contents of a regional university hospital BDW. Methods: We present the actions and challenges regarding organizational changes, technical architecture, and shared governance that took place to develop the Nantes BDW. We describe the process to access clinical contents, give details about patient data protection, and use examples to illustrate merging clinical insights. Unlabelled: More than 68 million textual documents and 543 million pieces of coded information concerning approximately 1.5 million patients admitted to CHUN between 2002 and 2022 can be queried and transformed to be made available to investigators. Since its creation in 2018, 269 projects have benefited from the Nantes BDW. Access to data is organized according to data use and regulatory requirements. Conclusions: Data use is entirely determined by the scientific question posed. It is the vector of legitimacy of data access for secondary use. Enabling access to a BDW is a game changer for research and all operational situations in need of data. Finally, data governance must prevail over technical issues in institution data strategy vis-à-vis care professionals and patients alike.

Disentangling Multiple Sclerosis heterogeneity in the French territory among genetic and environmental factors via Bayesian heritability analysis.

BACKGROUND: This study aimed to investigate the factors contributing to the variability of Multiple Sclerosis (MS) among individuals born and residing in France. Geographical variation in MS prevalence was observed in France, but the role of genetic and environmental factors in explaining this heterogeneity has not been yet elucidated. METHODS: We employed a heritability analysis on a cohort of 403 trios with an MS-affected proband in the French population. This sample was retrieved from REFGENSEP register of MS cases collected in 23 French hospital centers from 1992 to 2017. Our objective was to quantify the proportion of MS liability variability explained by genetic variability, sex, shared environment effects, region of birth and year of birth. We further considered gene x environment (GxE) interaction effects between genetic variability and region of birth. We have implemented a Bayesian liability threshold model to obtain posterior distributions for the parameters of interest adjusting for ascertainment bias. RESULTS: Our analysis revealed that GxE interaction effects between genetic variability and region of birth represent the primary significant explanatory factor for MS liability variability in French individuals (29 % [95 %CI: 5 %; 53 %]), suggesting that additive genetic effects are modified by environmental factors associated to the region of birth. The individual contributions of genetic variability and region of birth explained, respectively, ≈15 % and ≈16 % of MS variability, highlighting a significantly higher MS liability in individuals born in the Northern regions compared to the Southern region. Overall, the joint contribution of genetic variability, region of birth, and their interaction was then estimated to explain 65 % [95 %CI: 35 %; 92 %] of MS liability variability. The remaining proportion of MS variability is attributed to environmental exposures associated with the year of birth, shared within the same household, and specific to individuals. CONCLUSION: Overall, our analysis highlighted the interaction between genetic variability and environmental exposures linked to the region of birth as the main factor explaining MS variability within individuals born and residing in France. Among the environmental exposures prevalent in the Northern regions, and potentially interacting with genetic variability, lower vitamin D levels due to reduced sun exposure, higher obesity prevalence and higher pollution levels represent the main risk factors in influencing MS risk. These findings emphasize the importance of accounting for environmental factors linked to geographical location in the investigation of MS risk factors, as well as to further explore the influence of GxE interactions in modifying genetic risk.

Rheumatoid arthritis and changes on spirometry by smoking status in two prospective longitudinal cohorts.

OBJECTIVE: To compare longitudinal changes in spirometric measures between patients with rheumatoid arthritis (RA) and non-RA comparators. METHODS: We analysed longitudinal data from two prospective cohorts: the UK Biobank and COPDGene. Spirometry was conducted at baseline and a second visit after 5-7 years. RA was identified based on self-report and disease-modifying antirheumatic drug use; non-RA comparators reported neither. The primary outcomes were annual changes in the per cent-predicted forced expiratory volume in 1 s (FEV1%) and per cent predicted forced vital capacity (FVC%). Statistical comparisons were performed using multivariable linear regression. The analysis was stratified based on baseline smoking status and the presence of obstructive pattern (FEV1/FVC <0.7). RESULTS: Among participants who underwent baseline and follow-up spirometry, we identified 233 patients with RA and 37 735 non-RA comparators. Among never-smoking participants without an obstructive pattern, RA was significantly associated with more FEV1% decline (ß=-0.49, p=0.04). However, in ever smokers with ≥10 pack-years, those with RA exhibited significantly less FEV1% decline than non-RA comparators (ß=0.50, p=0.02). This difference was more pronounced among those with an obstructive pattern at baseline (ß=1.12, p=0.01). Results were similar for FEV1/FVC decline. No difference was observed in the annual FVC% change in RA versus non-RA. CONCLUSIONS: Smokers with RA, especially those with baseline obstructive spirometric patterns, experienced lower FEV1% and FEV1/FVC decline than non-RA comparators. Conversely, never smokers with RA had more FEV1% decline than non-RA comparators. Future studies should investigate potential treatments and the pathogenesis of obstructive lung diseases in smokers with RA.

A multi-ethnic reference panel to impute HLA classical and non-classical class I alleles in admixed samples: Testing imputation accuracy in an admixed sample from Brazil.

The MHC class I region contains crucial genes for the innate and adaptive immune response, playing a key role in susceptibility to many autoimmune and infectious diseases. Genome-wide association studies have identified numerous disease-associated SNPs within this region. However, these associations do not fully capture the immune-biological relevance of specific HLA alleles. HLA imputation techniques may leverage available SNP arrays by predicting allele genotypes based on the linkage disequilibrium between SNPs and specific HLA alleles. Successful imputation requires diverse and large reference panels, especially for admixed populations. This study employed a bioinformatics approach to call SNPs and HLA alleles in multi-ethnic samples from the 1000 genomes (1KG) dataset and admixed individuals from Brazil (SABE), utilising 30X whole-genome sequencing data. Using HIBAG, we created three reference panels: 1KG (n = 2504), SABE (n = 1171), and the full model (n = 3675) encompassing all samples. In extensive cross-validation of these reference panels, the multi-ethnic 1KG reference exhibited overall superior performance than the reference with only Brazilian samples. However, the best results were achieved with the full model. Additionally, we expanded the scope of imputation by developing reference panels for non-classical, MICA, MICB and HLA-H genes, previously unavailable for multi-ethnic populations. Validation in an independent Brazilian dataset showcased the superiority of our reference panels over the Michigan Imputation Server, particularly in predicting HLA-B alleles among Brazilians. Our investigations underscored the need to enhance or adapt reference panels to encompass the target population's genetic diversity, emphasising the significance of multiethnic references for accurate imputation across different populations.

RPA3-UMAD1 rs12702634 and rheumatoid arthritis-associated interstitial lung disease in European ancestry.

Objective: Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950. Methods: In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin. Results: Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 × 10-11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70). Conclusion: Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.

A microscopic model of the dose distribution in hepatocellular carcinoma after selective internal radiation therapy.

The dosimetry evaluation for the selective internal radiation therapy is currently performed assuming a uniform activity distribution, which is in contrast with literature findings. A 2D microscopic model of the perfused liver was developed to evaluate the effect of two different 90Y microspheres distributions: i) homogeneous partitioning with the microspheres equally distributed in the perfused liver, and ii) tumor-clustered partitioning where the microspheres distribution is inferred from the patient specific images. METHODS: Two subjects diagnosed with liver cancer were included in this study. For each subject, abdominal CT scans acquired prior to the SIRT and post-treatment 90Y positron emission tomography were considered. Two microspheres partitionings were simulated namely homogeneous and tumor-clustered partitioning. The homogeneous and tumor-clustered partitionings were derived starting from CT images. The microspheres radiation is simulated by means of Russell's law. RESULTS: In homogenous simulations, the dose delivery is uniform in the whole liver while in the tumor-clustered simulations a heterogeneous distribution of the delivered dose is visible with higher values in the tumor regions. In addition, in the tumor-clustered simulation, the delivered dose is higher in the viable tumor than in the necrotic tumor, for all patients. In the tumor-clustered case, the dose delivered in the non-tumoral tissue (NTT) was considerably lower than in the perfused liver. CONCLUSIONS: The model proposed here represents a proof-of-concept for personalized dosimetry assessment based on preoperative CT images.

Evaluating the participation of junior members and patient and healthcare professionals representatives in EULAR task forces: results from an international survey.

OBJECTIVE: European Alliance of Associations for Rheumatology (EULAR) task forces (TF) requires participation of ≥2 junior members, a health professional in rheumatology (HPR) and two patient research partners for the development of recommendations or points to consider. In this study, participation of these junior and representative members was compared with the one of traditional TF members (convenor, methodologist, fellow and expert TF members). METHODS: An online survey was developed and emailed to previous EULAR TF members. The survey comprised multiple-choice, open-ended and 0-100 rating scale (fully disagree to fully agree) questions. RESULTS: In total, 77 responded, 48 (62%) women. In total, 46 (60%) had participated as a junior or representative TF member. Most junior/representative members reported they felt unprepared for their first TF (10/14, 71%). Compared with traditional members, junior/representative members expressed a significantly higher level of uncertainty about their roles within the TF (median score 23 (IQR 7.0-52.0) vs 7 (IQR 0.0-21.0)), and junior/representative members felt less engaged by the convenor (54% vs 71%). Primary factors that facilitated interaction within a TF were experience, expertise and preparation (54%), a supportive atmosphere (42%) and a clear role (12%). CONCLUSION: Juniors, patients and HPR experience various challenges when participating in a EULAR TF. These challenges differ from and are generally less pronounced than those experienced by traditional TF members. The convenor should introduce the participants to the tasks, emphasise the value of their contributions and how to prepare accordingly for the TF meeting.

Scoping review of clinical decision support systems for multiple sclerosis management: Leveraging information technology and massive health data.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system, with numerous therapeutic options, but a lack of biomarkers to support a mechanistic approach to precision medicine. A computational approach to precision medicine could proceed from clinical decision support systems (CDSSs). They are digital tools aiming to empower physicians through the clinical applications of information technology and massive data. However, the process of their clinical development is still maturing; we aimed to review it in the field of MS. METHODS: For this scoping review, we screened systematically the PubMed database. We identified 24 articles reporting 14 CDSS projects and compared their technical and software development aspects. RESULTS: The projects position themselves in various contexts of usage with various algorithmic approaches: expert systems, CDSSs based on similar patients' data visualization, and model-based CDSSs implementing mathematical predictive models. So far, no project has completed its clinical development up to certification for clinical use with global release. Some CDSSs have been replaced at subsequent project iterations. The most advanced projects did not necessarily report every step of clinical development in a dedicated article (proof of concept, offline validation, refined prototype, live clinical evaluation, comparative prospective evaluation). They seek different software distribution options to integrate into health care: internal usage, "peer-to-peer," and marketing distribution. CONCLUSIONS: This review illustrates the potential of clinical applications of information technology and massive data to support MS management and helps clarify the roadmap for future projects as a multidisciplinary and multistep process.

Forced vital capacity trajectories and risk of lung transplant and ILD-related mortality among patients with rheumatoid arthritis-associated interstitial lung disease.

We aimed to determine the prevalence and outcomes for forced vital capacity percent predicted (FVCpp) decline among patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We identified patients with RA-ILD in the Mass General Brigham Healthcare system. RA-ILD diagnosis was determined by review of high-resolution computed tomography (HRCT) imaging by up to three thoracic radiologists. We abstracted FVCpp measurements, covariates, lung transplant, and ILD-related death from the medical record. We employed a relative FVCpp decline cutoff of > 10% within 24 months. We also used a group-based trajectory model to obtain patterns of change from RA-ILD diagnosis. We then assessed for associations of each FVC decline definition with risk of lung transplant or ILD-related death using multivariable logistic regression. We analyzed 172 patients with RA-ILD with a median of 6 FVCpp measurements per patient over 6.5 years of follow-up (mean age 62.2 years, 36% male). There were seven (4%) lung transplants and 44 (26%) ILD-related deaths. Ninety-eight (57%) patients had relative decline of FVCpp by > 10% in 24 months. We identified three trajectory groups of FVCpp change: rapidly declining (n = 24/168 [14%]), slowly declining (n = 90/168 [54%]), and stable/improving (n = 54/168 [32%]). The rapidly declining group and FVCpp > 10% had adjusted odds ratios (aOR) for lung transplant/ILD-related death of 19.2 (95%CI 4.9 to 75.5) and 2.8 (95%CI 1.3 to 6.1) respectively. Over half of patients with RA-ILD had declining FVCpp. The different trajectory patterns demonstrate the importance of FVC monitoring for identifying patients at the highest risk of poor outcomes. Key Points • Over half of patients with RA-ILD had declining FVCpp over a median of 6.5 years of follow-up. • The rapidly declining FVCpp trajectory group had stronger associations with lung transplant and ILD-related death compared to those with FVCpp decline by > 10%. • Clinicians can employ FVC monitoring to proactively treat patients who are at risk of poor outcomes.

Phosphetene-based polyaromatics: structure-property relationships and chiroptical tuning.

We describe the synthesis of π-extended phosphetene rings (4-member P-rings) flanked with PAH systems of various topologies. These compounds are fully characterized including X-ray diffraction. The impact of both the polyaromatic platform and the P-ring on the structure, and the optical and redox properties are investigated both experimentally and theoretically. Although neither the P centre nor the 4-membered ring significantly takes part in the HOMO or LUMO orbitals, both structural features have an important modulating role in distorting the symmetry of the orbitals, leading to chiroptical properties. The stereogenic P-atom is used as a remote chiral perturbator to induce circularly polarized luminescence of the polyaromatic system. The dissymmetry factor is highly dependent on the polyaromatic topology, as supported by theoretical calculations.

Dithieno[2,3-b;3,2-f]phosphepinium-Based Near-Infrared Fluorophores: px-π* Conjugation Inherent to Seven-Membered Phosphacycles.

Positively charged phosphorus-containing heterocycles are characteristic core skeletons for functional molecules. While various phosphonium-containing five- or six-membered ring compounds have been reported, seven-membered ring phosphepinium has not yet been fully studied. In this study, dithieno[2,3-b;3,2-f]phosphepinium ions containing electron-donating aminophenyl groups were synthesized. An X-ray crystallographic analysis of the resulting donor-acceptor-donor dyes revealed a bent conformation of the central seven-membered ring. This compound exhibited fluorescence in the near-infrared region with a bathochromic shift of 70 nm compared to phosphepine oxide congener and a large Stokes shift. High fluorescence quantum yields were obtained even in polar solvents due to the suppression of the nonradiative decay process. The theoretical study revealed that the phosphepinium skeleton is highly electron-accepting owing to the orbital interaction between a px orbital of the phosphonium moiety and a π* orbital of the 1,3,5-hexatriene moiety. Owing to the lower-lying px orbital in the phosphonium moiety compared with that of the phosphine oxide and the bent conformation of the seven-membered ring, the phosphepinium ring effectively furnishes a px-π* conjugation. A large structural relaxation with the contribution of a quinoidal resonance structure is suggested in the excited state, which is responsible for the intense emission with a large Stokes shift.

Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections among sexual assault victims referred to three French clinical forensic units.

BACKGROUND: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections are the most common bacterial sexually transmitted infections (STIs) worldwide. These STIs are frequently asymptomatic, which often delays diagnosis and treatment with the risk of serious long-term complications. Current French recommendations call for targeted screening of populations considered to be at risk, including victims of sexual assault. However, no recent data on the prevalence of these STIs in this population are available in France. The aim of this study was therefore to determine the prevalence of CT/NG infections among victims of sexual assault attending three Clinical Forensic Units (CFUs). METHODS: We retrospectively reviewed the forensic records of patients aged over 12 years reporting a sexual assault and referred between January 1, 2020 and December 31, 2021 to the CFU of Montpellier, Angers or Saint-Denis de La Réunion. Patients who had been screened for CT and NG infections were included. RESULTS: 341 alleged victims of sexual assault (324 women, 17 men, median age = 23 years) were screened for CT/NG STIs during the inclusion period (Montpellier, n=196; Angers, n=63; Saint-Denis, n=82). The median time between the sexual assault and the examination was 1 day. CT and NG were detected in 28 patients (8.2 %) and 8 patients (2.3 %) respectively, with no men tested positive. Positive results concerned genital samples, except for two CT-positive anorectal samples and one NG-positive oropharyngeal sample. Two patients (0.6 %) were co-infected with CT/NG. The overall prevalence of CT/NG STIs was 10.0 % and was higher in the 18-24 age group, reaching 13.2 % for CT. CONCLUSIONS: This multicenter study confirms the high prevalence of CT/NG STIs in victims of sexual assault, and the vulnerability of the youngest age groups to these infections. Systematic screening for CT/NG STIs at the time of the forensic examination is the key to early diagnosis and effective treatment to prevent transmission and subsequent complications in these patients.

Does long-term drought or repeated defoliation affect seasonal leaf N cycling in young beech trees?

Forest trees adopt effective strategies to optimize nitrogen (N) use through internal N recycling. In the context of more recurrent environmental stresses due to climate change, the question remains of whether increased frequency of drought or defoliation threatens this internal N recycling strategy. We submitted 8-year-old beech trees to 2 years of either severe drought (Dro) or manual defoliation (Def) to create a state of N starvation. At the end of the second year before leaf senescence, we labeled the foliage of the Dro and Def trees, as well as that of control (Co) trees, with 15N-urea. Leaf N resorption, winter tree N storage (total N, 15N, amino acids, soluble proteins) and N remobilization in spring were evaluated for the three treatments. Defoliation and drought did not significantly impact foliar N resorption or N concentrations in organs in winter. Total N amounts in Def tree remained close to those in Co tree, but winter N was stored more in the branches than in the trunk and roots. Total N amount in Dro trees was drastically reduced (-55%), especially at the trunk level, but soluble protein concentrations increased in the trunk and fine roots compared with Co trees. During spring, 15N was mobilized from the trunk, branches and twigs of both Co and Def trees to support leaf growth. It was only provided through twig 15N remobilization in the Dro trees, thus resulting in extremely reduced Dro leaf N amounts. Our results suggest that stress-induced changes occur in N metabolism but with varying severity depending on the constraints: within-tree 15N transport and storage strategy changed in response to defoliation, whereas a soil water deficit induced a drastic reduction of the N amounts in all the tree organs. Consequently, N dysfunction could be involved in drought-induced beech tree mortality under the future climate.

Preemptive treatment in the acute and early subacute phase of uncomplicated type B aortic dissections with poor prognosis factors.

Objective: Due to its favorable outcome regarding late morbidity and mortality, thoracic endovascular repair (TEVAR) is becoming more popular for uncomplicated type B aortic dissection (TBAD). This study aimed to compare preemptive endovascular treatment and optimal medical treatment (OMT) and OMT alone in patients presenting uncomplicated TBAD with predictors of aortic progression. Design: Retrospective multicenter study. Methods: We analyzed patients with uncomplicated TBAD and risk factors of progression in two French academic centers. Aortic events [defined as aortic-related (re)intervention or aortic-related death after initial hospitalization], postoperative complications, non-aortic events, and radiologic aortic progression and remodeling were recorded and analyzed. Analysis was performed on an intention-to-treat basis. Results: Between 2011 and 2021, preemptive endovascular procedures at the acute and early subacute phase (<30 days) were performed on 24 patients (group 1) and OMT alone on 26 patients (group 2). With a mean follow-up of 38.08 ± 24.53 months, aortic events occurred in 20.83% of patients from group 1 and 61.54% of patients from group 2 (p < .001). No patient presented aortic-related death during follow-up. There were no differences in postoperative events (p = 1.00) and non-aortic events (p = 1.00). OMT patients had significantly more aneurysmal progression of the thoracic aorta (p < .001) and maximal aortic diameter (p < .001). Aortic remodeling was found in 91.67% of patients in group 1 and 42.31% of patients in group 2 (p < .001). A subgroup analysis of patients in group 1 showed that patients treated with preemptive TEVAR and STABILISE had reduced maximum aortic diameters at the 1-year (p = .010) and last follow-up (p = .030) compared to those in patients treated with preemptive TEVAR alone. Conclusion: Preemptive treatment of uncomplicated TBAD with risk factors of progression reduces the risk of long-term aortic events. Over 60% of medically treated patients will require intervention during follow-up, with no benefit in terms of postoperative events. Even after surgical treatment, patients in the OMT group had significantly more aneurysmal progression, along with poorer aortic remodeling.

Predictive role of hepatic venous pressure gradient in bleeding events among patients with cirrhosis undergoing orthotopic liver transplantation.

Background & Aims: Major bleeding events during orthotopic liver transplantation (OLT) are associated with poor outcomes. The proportion of this risk related to portal hypertension is unclear. Hepatic venous pressure gradient (HVPG) is the gold standard for estimating portal hypertension. The aim of this study was to analyze the ability of HVPG to predict intraoperative major bleeding events during OLT in patients with cirrhosis. Methods: We retrospectively analyzed a prospective database including all patients with cirrhosis who underwent OLT between 2010 and 2020 and had liver and right heart catheterizations as part of their pre-transplant assessment. The primary endpoint was the occurrence of an intraoperative major bleeding event. Results: The 468 included patients had a median HVPG of 17 mmHg [interquartile range, 13-22] and a median MELD on the day of OLT of 16 [11-24]. Intraoperative red blood cell transfusion was required in 72% of the patients (median 2 units transfused), with a median blood loss of 1,000 ml [575-1,500]. Major intraoperative bleeding occurred in 156 patients (33%) and was associated with HVPG, preoperative hemoglobin level, severity of cirrhosis at the time of OLT (MELD score, ascites, encephalopathy), hemostasis impairment (thrombocytopenia, lower fibrinogen levels), and complications of cirrhosis (sepsis, acute-on-chronic liver failure). By multivariable regression analysis with backward elimination, HVPG, preoperative hemoglobin level, MELD score, and tranexamic acid infusion were associated with the primary endpoint. Three categories of patients were identified according to HVPG: low-risk (HVPG <16 mmHg), high-risk (HVGP ≥16 mmHg), and very high-risk (HVPG ≥20 mmHg). Conclusions: HVPG predicted major bleeding events in patients with cirrhosis undergoing OLT. Including HVPG as part of pre-transplant assessment might enable better anticipation of the intraoperative course. Impact and implications: Major bleeding events during orthotopic liver transplantation (OLT) are associated with poor outcomes but the proportion of this risk related to portal hypertension is unclear. Our work shows that hepatic venous pressure gradient (HVPG), the gold standard for estimating portal hypertension, is a strong predictor of major bleeding events and blood loss volume in patients with cirrhosis undergoing OLT. Three groups of patients can be identified according to their risk of major bleeding events: low-risk patients with HVPG <16 mmHg, high-risk patients with HVPG ≥16 mmHg, and very high-risk patients with HVPG ≥20 mmHg. HVPG could be systematically included in the pre-transplant assessment to anticipate intraoperative course and tailor patient management.

Self-rated health, epigenetic ageing, and long-term mortality in older Australians.

Self-rated health (SRH) is a subjective indicator of overall health based on a single questionnaire item. Previous evidence found that it is a strong predictor of mortality, although the underlying mechanism is poorly understood. Epigenetic age is an objective, emerging biomarker of health, estimated using DNA methylation data at hundreds of sites across the genome. This study aimed to assess the overlap and interaction between SRH and epigenetic ageing in predicting mortality risk. We used DNA methylation data from 1059 participants in the Melbourne Collaborative Cohort Study (mean age: 69 years) to calculate three age-adjusted measures of epigenetic ageing: GrimAge, PhenoAge, and DunedinPACE. SRH was assessed using a five-category questionnaire item ("excellent, very good, good, fair, poor"). Cox models were used to assess the associations of SRH, epigenetic ageing, and their interaction, with all-cause mortality over up to 17 years of follow-up (Ndeaths = 345). The association of SRH with mortality per category increase was HR = 1.29; 95%CI: 1.14-1.46. The association was slightly attenuated after adjusting for all three epigenetic ageing measures (HR = 1.25, 95%CI: 1.10-1.41). A strong gradient was observed in the association of GrimAge (Pinteraction = 0.006) and DunedinPACE (Pinteraction = 0.002) with mortality across worsening SRH strata. For example, the association between DunedinPACE and mortality in participants with "excellent" SRH was HR = 1.02, 95%CI: 0.73-1.43 and for "fair/poor" HR = 1.72, 95%CI: 1.35-2.20. SRH and epigenetic ageing were synergistic risk factors of mortality in our study. These findings suggest that consideration of subjective and objective factors may improve general health assessment, which has implications for the ongoing development of molecular markers of ageing.

The clinical manifestations and molecular pathogenesis of radiation fibrosis.

Advances in radiation techniques have enabled the precise delivery of higher doses of radiotherapy to tumours, while sparing surrounding healthy tissues. Consequently, the incidence of radiation toxicities has declined, and will likely continue to improve as radiotherapy further evolves. Nonetheless, ionizing radiation elicits tissue-specific toxicities that gradually develop into radiation-induced fibrosis, a common long-term side-effect of radiotherapy. Radiation fibrosis is characterized by an aberrant wound repair process, which promotes the deposition of extensive scar tissue, clinically manifesting as a loss of elasticity, tissue thickening, and organ-specific functional consequences. In addition to improving the existing technologies and guidelines directing the administration of radiotherapy, understanding the pathogenesis underlying radiation fibrosis is essential for the success of cancer treatments. This review integrates the principles for radiotherapy dosimetry to minimize off-target effects, the tissue-specific clinical manifestations, the key cellular and molecular drivers of radiation fibrosis, and emerging therapeutic opportunities for both prevention and treatment.