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Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear., Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis., Results: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing., Conclusion: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Diamond-Blackfan Anemia Syndrome (DBS) is a rare congenital disorder originally characterized by bone marrow failure with or without various congenital anomalies. At least 24 genes are implicated, the vast majority encoding for ribosomal proteins. RPL26 (ribosomal protein L26) is an emerging candidate (DBA11, MIM#614900). We aim to further delineate this rare condition., Methods: Patients carrying heterozygous RPL26 variants were recruited. In one of them, erythroid proliferation and differentiation from peripheral blood CD34 + cells were studied by flow cytometry, and RPL26 expression by qRT-PCR and immunoblotting., Results: We report on eight affected patients from four families. Detailed phenotyping reveals that RPL26 is mainly associated with multiple congenital anomalies (particularly radial ray anomalies), albeit with variable expression. Mandibulofacial dysostosis and neural tube defects are potential features in DBA11, expanding the growing list of DBS abnormalities. In one individual, we showed that RPL26 haploinsufficiency was responsible for subclinical impairment in erythroid proliferation and enucleation. The absence of hematological involvement in four adults from this series contributes to the mounting evidence that bone marrow failure is not universally central to all DBS genes., Conclusion: We confirm RPL26 as a DBS gene and expand the phenotypic spectrum of the gene and the disease., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Predicting effects of genomic variants has become a real challenge in the diagnosis of rare human diseases. Holt-Oram syndrome (HOS) is an autosomal condition characterized by the association of radial and heart defects, due to variants in TBX5. Most variants are predicted to be truncating and result in haploinsufficiency. The pathogenicity of missense or splice variants is harder to demonstrate., Methods: Fourteen TBX5 variants of uncertain significance (VUS) (5 missense, 9 splice) and 6 likely pathogenic missense variants were selected for functional testing, depending on the variant-type (immunolocalization, western blot, reporter assays, minigene splice assays and RT-PCR). Results were compared with in silico predictions., Results: Functional tests allowed to reclassify 9/14 VUS in TBX5 as likely pathogenic, confirming their role in HOS. We demonstrated loss-of-function (n=8) or gain-of-function (n=1) for 9 of the 11 missense variants, whereas no functional impact was shown for the 2 variants: p.(Gly195Ala) and p.(Ser261Cys), as suggested by contradictory predictions of in silico approaches. Of 9 splice variants predicted to affect splicing by SpliceAI, we observed partial or complete exon skipping (n=6), intron retention (n=2) or exon shortening (n=1), inducing frame-shifting with premature stop codons., Conclusion: Bioinformatic and biological approaches are complementary, together with a good knowledge of clinical conditions, for accurate ACMG classification in human rare diseases., (Copyright © 2024. Published by Elsevier Inc.)

Background: The combination of encorafenib with cetuximab has become the standard of care in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) after a prior systemic therapy. This study aims to describe the efficacy and safety of encorafenib/cetuximab +/- binimetinib in patients with BRAF V600E-mutated mCRC in a real-world setting., Patients and Methods: This retrospective study included patients with BRAF V600E-mutated mCRC who received this combination from January 2020 to June 2022 in 30 centers., Results: A total of 201 patients were included, with 55% of women, a median age of 62 years, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) >1 in 20% of cases. The main tumor characteristics were 60% of right-sided primary tumor, 11% of microsatellite instability/mismatch repair deficient phenotype, and liver and peritoneum being the two main metastatic sites (57% and 51%). Encorafenib/cetuximab +/- binimetinib was prescribed in the first, second, third, and beyond third line in 4%, 56%, 29%, and 11%, respectively, of cases, with the encorafenib/cetuximab/binimetinib combination for 21 patients (10%). With encorafenib/cetuximab treatment, 21% of patients experienced grade ≥3 adverse events (AEs), with each type of grade ≥3 AE observed in <5% of patients. The objective response rate was 32.2% and the disease control rate (DCR) was 71.2%. The median progression-free survival (PFS) was 4.5 months [95% confidence interval (CI) 3.9-5.4 months] and the median overall survival (OS) was 9.2 months (95% CI 7.8-10.8 months). In multivariable analysis, factors associated with a shorter PFS were synchronous metastases [hazard ratio (HR) 1.66, P = 0.04] and ECOG-PS >1 (HR 1.88, P = 0.007), and those associated with a shorter OS were the same factors (HR 1.71, P = 0.03 and HR 2.36, P < 0.001, respectively) in addition to treatment beyond the second line (HR 1.74, P = 0.003) and high carcinoembryonic antigen level (HR 1.72, P = 0.003)., Conclusion: This real-world study showed that in patients with BRAF V600E-mutated mCRC treated with encorafenib/cetuximab +/- binimetinib, efficacy and safety data confirm those reported in the BEACON registration trial. The main poor prognostic factors for this treatment are synchronous metastases and ECOG-PS >1., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The way that pain is assessed in the PACU could impact on postoperative pain and analgesic consumption. However, there is currently no evidence to support this speculation. The authors hypothesised that using a comfort scale reduces postoperative opioid consumption when compared with a standard numerical rating scale (NRS) to evaluate pain in the PACU., Methods: In this cluster-randomised trial, patients were assessed using either a comfort scale (comfort group) or a pain NRS (NRS group). The primary outcome was the opioid consumption in the PACU. The main secondary outcomes were postoperative pain, nausea and vomiting, length of stay in the PACU, and satisfaction., Results: Of 885 randomised patients, 860 were included in the analysis. Opioid consumption in the PACU was comparable in the comfort and NRS groups (median [interquartile range [IQR] 0 (0-5) vs 0 (0-6); P=0.2436), irrespective of the type of surgical procedure. The majority of patients did not need any postoperative opioid (59% in the comfort group and 56% in the NRS group, P=0.2260). There was no difference in postoperative pain, nausea and vomiting, time to reach an Aldrete score ≥9 after extubation, and global satisfaction., Conclusions: Using a comfort scale to assess pain in the PACU did not spare any opioid compared with use of a standard NRS. Further studies focusing on patients at risk of increased postoperative opioid consumption are necessary., Clinical Trial Registration: NCT05234216., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Introduction: There is little evidence to suggest that one educational intervention is superior to another when associated with a rehabilitation program in the management of persistent low back pain. The objective of the present study was to compare pain neuroscience education with spine physiology and ergonomics education as part of a one-week multidisciplinary rehabilitation program., Method: We conducted a randomized, controlled trial among patients having experienced persistent low back pain for at least 1 year. The patients participated in a one-week multidisciplinary rehabilitation program with an educational component. The members of the experimental and control groups received pain neuroscience education and spine physiology and ergonomics education, respectively. Outcomes were assessed before the program (day 0), immediately afterwards (day 5), and on day 90 after the start of the program. The primary outcome measure was functional disability on day 90., Results: A total of 88 patients were randomized. On day 90, a statistically significant mean [95% confidence interval] decrease in the level of disability was observed in the experimental (PNE) group (-3.4 [-5.0 to -1.8]). The mean [95%CI] difference versus the control group (-1.7 [-4.0 to 0.5]) was not statistically significant (p = 0.12). There were no statistically significant intergroup differences in the secondary outcome measures., Conclusion: There appears to be no advantage in replacing a conventional, non-neuroscientific educational program (based on spinal physiology and ergonomics) with a pain neuroscience education program as part of a one-week multidisciplinary rehabilitation program. Further research is needed to identify patients who will respond better to a pain neuroscience education module as part of a personalized care program., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study aimed to compare the diagnostic performance of visual assessment of electroencephalography (EEG) using the Grand Total EEG (GTE) score and quantitative EEG (QEEG) using spectral analysis in the context of cognitive impairment. This was a retrospective study of patients with mild cognitive impairment, with (MCI+V) or without (MCI) vascular dysfunction, and patients with dementia including Alzheimer's disease, Lewy Body Dementia and vascular dementia. The results showed that the GTE is a simple scoring system with some potential applications, but limited ability to distinguish between dementia subtypes, while spectral analysis appeared to be a powerful tool, but its clinical development requires the use of artificial intelligence tools., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) is characterized by low-grade chronic inflammation. Circulating neutrophils regroup 2 subtypes termed high- and low-density neutrophils (HDNs and LDNs). LDNs represent less than 2% of total neutrophil under physiological conditions, but their counts increase in multiple pathologies, releasing more inflammatory cytokines and neutrophil extracellular traps (NETs). The aims of this study were to assess the differential count and role of HDNs, LDNs, and NETs-related activities in patients with heart failure (HF)., Methods: HDNs and LDNs were isolated from human blood by density gradient and purified by fluorescence-activated cell sorting (FACS) and their counts obtained by flow cytometry. Formation of NETs (NETosis) was quantified by confocal microscopy. Circulating inflammatory and NETosis biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Neutrophil adhesion onto human extracellular matrix (hECM) was assessed by optical microscopy., Results: A total of 140 individuals were enrolled, including 33 healthy volunteers (HVs), 41 HFrEF (19 stable patients and 22 presenting acute decompensated HF [ADHF]), and 66 patients with HFpEF (36 stable patients and 30 presenting HF decompensation). HDNs and LDNs counts were significantly increased up to 39% and 2740%, respectively, in patients with HF compared with HVs. In patients with HF, the correlations among LDNs counts and circulating inflammatory (CRP, IL-6 and -8), troponin T, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and NETosis components were significant. In vitro, LDNs expressed more citrullinated histone H3 (H3Cit) and NETs and were more proadhesive, with ADHFpEF patients presenting the highest proinflammatory profile., Conclusions: Patients with HFpEF present higher levels of circulating LDNs- and NETs-related activities, which are the highest in the context of acute HF decompensation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In an extensive screening endeavor for anti-coronaviral compounds, we examined 824 tropical plant extracts from the Annonaceae and Rutaceae families. The screening identified an ethyl acetate extract from the aerial parts of Miliusa balansae for its potent inhibitory activity against Human coronavirus HCoV-229E. Subsequent bioassay-guided fractionation of this extract revealed two unreported miliusanes including a complex dimeric structure and seven known compounds, comprising miliusane XXXVI, (+)-miliusol, bistyryls, styryl-pyranones, and the flavonoid rhamnetin. The absolute configuration of the new dimeric miliusane was determined by X-ray crystallography and a putative biogenetic origin was proposed. Investigation of the antiviral effect of these nine phytochemicals within HCoV-229E-infected Huh-7 cells showed that (+)-miliusol and miliusane XXXVI exert antiviral activity at non-cytotoxic concentrations, with IC 50 values of 1.15 μM and 19.20 μM, respectively. Furthermore, these compounds significantly inhibited SARS-CoV-2 infection in Vero cells, presenting IC 50 values of 11.31 μM for (+)-miliusol and 17.92 μM for miliusane XXXVI. Additionally, both compounds exhibited a potent antiviral effect against the emergent mosquito-borne Zika virus, with IC 50 values of 1.34 μM and 23.45 μM, respectively. Time-of-addition assays suggest that their mechanism of action might target later stages of the viral cycle, indicating potential modulation of specific cellular pathways. These findings reinforce the invaluable contribution of medicinal flora as reservoirs of natural antiviral agents and emphasize their prospective role in combatting viruses of medical interest., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Osage orange trees (Maclura pomifera (Raf.) C.K.Schneid.) are distributed worldwide, particularly in south-east states of the USA. They produce large quantities of strong yellow fruits, bigger than oranges, but these fruits are inedible, with an acid milky juice which is little consumed by birds and insects. Extracts prepared from Osage orange fruits (hedge apple) have revealed a range of pharmacological properties of interest in human and veterinary medicine. In addition, Osage orange extracts can be used in agriculture and aquaculture, and as dyeing agent for the textile industry. Extracts contain potent antioxidant compounds, notably the isoflavonoids pomiferin and auriculasin, together with other terpenoids and flavonoids. The structural characteristics and pharmacological properties of the major prenylated isoflavones isolated from M. pomifera are discussed here, with a focus on the two phenolic compounds osajin and warangalone, and the two catechol analogues pomiferin and auriculasin. The mechanisms at the origin of their potent antioxidant and anti-inflammatory effects are presented, notably inhibition of xanthine oxidase, phosphodiesterase 5A and kinases such as RKS2 and kRAS. Osajin and auriculasin display marked anticancer properties, owing to their ability to inhibit tumor cell proliferation, migration and tumor angiogenesis. Different molecular mechanisms are discussed, including osajin‑copper complexation and binding to quadruplex DNA. An overview of the mechanism of action of the prenylated isoflavones from Osage orange is presented, with the objective to promote their knowledge and to raise opportunities to better exploit the fruits of Osage orange, abundant but largely neglected at present., Competing Interests: Declaration of competing interest The author declares no conflict of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)

Introduction: Recently, four randomized controlled trials (RCTs) have demonstrated the benefits of mechanical thrombectomy (MT) in patients with acute ischemic stroke (AIS) caused by anterior large vessel occlusion (LVO) and a large ischemic core at baseline (LIC). The purpose of this study was to investigate the features influencing the clinical outcome and the benefits of mechanical thrombectomy in this subgroup., Methods: We conducted a multicenter retrospective aggregate cohort study of patients with AIS-LVO and a LIC, assessed with quantitative core volume measures, treated with MT between 2012 and 2019. The data were queried through four registries, including patients with core volumes ≥50cc. Multivariable logistic regression models were employed to determine factors independently associated with clinical outcomes in patients with successful recanalization (modified-Thrombolysis-in-Cerebral-Infarction-score, mTICI=2b-3) and unsuccessful recanalization group (mTICI=0-2a). The primary endpoint was a favorable functional outcome at day-90, defined as a modified Rankin scale (mRS) of 0-3, accounting for the inherent severity of AIS with baseline LIC. Secondary outcomes included functional independence (mRS 0-2) at day-90, mortality, and symptomatic Intracranial Hemorrhage (sICH)., Results: A total of 460 patients were included (mean age 66±14.2 years; 39.6 % females). The mean baseline NIHSS was 20±5.2, and the core volume was 103.2±54.6 ml. Overall, 39.8 % (183/460) of patients achieved a favorable outcome at day-90 (mRS 0-3). Successful recanalization was significantly associated with a more frequent favorable outcome (aOR, 4.79; 95 %CI, 2.73-8.38; P<0.01) and functional independence (P<0.01). This benefit remained significant in older patients and in patients with cores above 100cc. At 90 days, 147/460 patients (32 %) were deceased, with successful recanalization significantly associated with less frequent mortality (OR, 0.34; 95 %CI, 0.22-0.53; P<0.01). The rate of sICH was 17.4 % and did not differ significantly between groups., Conclusions: In this large, pooled-cohort study of AIS-LVO patients with infarct cores over 50cc at baseline, we demonstrated that successful recanalization was associated with a better functional outcome, lower mortality, and similar rates of symptomatic intracranial hemorrhage for a wide spectrum of patients., Competing Interests: Declaration of Competing Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In the search for new small molecules for the therapy of neuropathic pain, we found that 2-{3-[N-(1-benzylpiperidin-4-yl)propyl]amino}-6-[N-methyl-N-(prop-2-yn-1-yl)amino]-4-phenylpyridine-3,5-dicarbonitrile (12) induced a robust antiallodynic effect in capsaicin-induced mechanical allodynia, a behavioural model of central sensitization, through σ 1 R antagonism. Furthermore, administration of compound 12 to neuropathic animals, fully reversed mechanical allodynia, increasing its mechanical threshold to levels that were not significantly different from those found in paclitaxel-vehicle treated mice or from basal levels before neuropathy was induced. Ligand 12 is thus a promising hit-compound for the therapy of neuropathic pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Given the poor outcome of refractory and relapsing T-cell acute lymphoblastic leukemia (T-ALL), identifying prognostic markers is still challenging. Using single nucleotide polymorphism (SNP) array analysis, we provide a comprehensive analysis of genomic imbalances in a cohort of 317 newly diagnosed patients with T-ALL including 135 children and 182 adults with respect to clinical and biological features and outcomes. SNP array results identified at least 1 somatic genomic imbalance in virtually all patients with T-ALL (∼96%). Del(9)(p21) (∼70%) and UPD(9)p21)/CDKN2A/B (∼28%) were the most frequent genomic imbalances. Unexpectedly del(13)(q14)/RB1/DLEU1 (∼14%) was the second most frequent copy number variant followed by del(6)(q15)/CASP8AP2 (∼11%), del(1)(p33)/SIL-TAL1 (∼11%), del(12)(p13)ETV6/CDKN1B (∼9%), del(18)(p11)/PTPN2 (∼9%), del(1)(p36)/RPL22 (∼9%), and del(17)(q11)/NF1/SUZ12 (∼8%). SNP array also revealed distinct profiles of genomic imbalances according to age, immunophenotype, and oncogenetic subgroups. In particular, adult patients with T-ALL demonstrated a significantly higher incidence of del(1)(p36)/RPL22, and del(13)(q14)/RB1/DLEU1, and lower incidence of del(9)(p21) and UPD(9p21)/CDKN2A/B. We determined a threshold of 15 genomic imbalances to stratify patients into high- and low-risk groups of relapse. Survival analysis also revealed the poor outcome, despite the low number of affected cases, conferred by the presence of chromothripsis (n = 6, ∼2%), del(16)(p13)/CREBBP (n = 15, ∼5%) as well as the newly-identified recurrent gain at 6q27 involving MLLT4 (n = 10, ∼3%). Genomic complexity, del(16)(p13)/CREBBP and gain at 6q27 involving MLLT4, maintained their significance in multivariate analysis for survival outcome. Our study thus demonstrated that whole genome analysis of imbalances provides new insights to refine risk stratification in T-ALL. This trial was registered at www.ClinicalTrials.gov as #NCT00222027 and #NCT00327678, and as #FRALLE 2000T trial., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Outcomes are poor in triple-class-exposed (TCE) relapsed/refractory multiple myeloma (RRMM). In the phase 3 KarMMa-3 (clinicaltrials.gov; NCT03651128) trial, patients with TCE RRMM and 2-4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary endpoint; 13.3 vs 4.4 months; P<.0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median (95% CI) was 41.4 (30.9-not reached [NR]) vs 37.9 (23.4-NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE RRMM. NCT03651128., (Copyright © 2024 American Society of Hematology.)

Background: Patients with mitral regurgitation (MR) and morphologic presence of relevant mitral annular calcification (MAC) represent a challenging phenotypic subset with limited treatment options., Objectives: The aim of this study was to assess the feasibility of transcatheter mitral valve replacement (TMVR) using dedicated devices for the treatment of MAC patients., Methods: Consecutive patients with symptomatic MR receiving TMVR and with available computed tomography data from the CHOICE-MI (Choice of Optimal Transcatheter Treatment for Mitral Insufficiency) multicenter registry were stratified by the presence of none or mild mitral annular calcification (MAC none/mild ) vs moderate or severe mitral annular calcification (MAC mod/sev )., Results: Among 279 eligible patients (median age = 76.0 years [Q1-Q3: 71.0-81.0 years], EuroSCORE II = 6.2% [Q1-Q3: 3.9%-12.1%]), 222 (79.6%) presented with MAC none/mild and 57 (20.4%) with MAC mod/sev . Patients with MAC mod/sev  had a higher prevalence of extracardiac arteriopathy (P = 0.011) and primary MR (P < 0.001). Although the technical success rate and the extent of MR elimination did not differ, TMVR treatment in MAC mod/sev patients was associated with higher rates of postprocedural bleeding complications (P = 0.02) and renal failure (P < 0.001). Functional improvement at the 1- and 2-year follow-up did not differ between groups. At the 2-year follow-up, there were no differences between patients with MAC mod/sev and MAC none/mild regarding all-cause mortality (38.5% vs 37.7%; P = 0.76), cardiovascular mortality (21.3% vs 24.9%; P = 0.97), and all-cause mortality or heart failure hospitalization (52.4% vs 46.7%; P = 0.28) CONCLUSIONS: TMVR in patients with MAC mod/sev is associated with higher rates of postprocedural complications but similar rates of survival, MR resolution, and functional improvement compared to MAC none/mild . Further studies are necessary to define the role of dedicated TMVR devices in this population. (Choice of Optimal Transcatheter Treatment for Mitral Insufficiency Registry [CHOICE-MI]; NCT04688190)., Competing Interests: Funding Support and Author Disclosures This study was supported by a grant from the German Heart Foundation. Dr Coisne is a proctor for Abbott Vascular; and has received speaker fees for Abbot Vascular, Edwards Lifesciences, GE Healthcare, Merck Sharp & Dohme, and Pfizer. Dr Ludwig has received travel compensation from Edwards Lifesciences; has received honoraria from Bayer and Abbott; is a consultant for NVT; and was supported by a research grant from the German Heart Foundation. Dr Ali has received research grants from Medtronic and Edwards Lifesciences. Dr Duncan is a consultant for and has received honoraria from Abbott Laboratories, Edward Lifesciences, and Medtronic. Dr Kalbacher has received personal fees from Abbott, Edwards Lifesciences, Pi-Cardia Ltd, and Medtronic. Dr Rudolph has received speaker honoraria from Abbott Vascular. Dr Hausleiter has received consulting fees, speaker honoraria, and support of research projects paid to the institution from Abbott Vascular and Edwards Lifesciences. Dr Ruge serves as a physician proctor for Abbott and Edwards Lifesciences; is a consultant for Medtronic, Abbott, and Edwards Lifesciences; and is a member of the Abbott Advisory Board. Dr Schmidt has received consultant fees and travel support from Cardiovalve. Dr Taramasso is consultant or has received consultancy fees from Abbott, Edwards Lifesciences, Medtronic, Boston Scientific, Shenqi Medical, MEDIRA, PiCardia, CoreMedic, Cardiovalve, Simulands, CoreQuest, HiD Imaging, and OneCrea Medical. Dr Denti has received speaker honoraria from Abbott and Edwards Lifesciences; and has received consultant fees from Approxima, HVR, InnovHeart, and Pi-Cardia Ltd. Dr Andreas is a proctor, consultant, and speaker for Edwards Lifesciences, Abbott, Medtronic, Boston, and Zoll; and has received institutional research grants from Edwards Lifesciences, Abbott, Medtronic, and LSI. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Despite numerous molecular targeted therapies tested in glioblastoma (GBM), no significant progress in patient survival has been achieved in the last 20 years in the overall population of GBM patients except with TTfield setup associated with the standard of care chemoradiotherapy. Therapy resistance is associated with target expression heterogeneity and plasticity between tumors and in tumor niches. We focused on α5 integrin implicated in aggressive GBM in preclinical and clinical samples. To address the characteristics of α5 integrin heterogeneity we started with patient data indicating that elevated levels of its mRNA are related to hypoxia pathways. We turned on glioma stem cells which are considered at the apex of tumor formation and recurrence but also as they localize in hypoxic niches. We demonstrated that α5 integrin expression is stem cell line dependent and is modulated positively by hypoxia in vitro. Importantly, heterogeneity of expression is conserved in in vivo stem cell-derived mice xenografts. In hypoxic niches, HIF-2α is preferentially implicated in α5 integrin expression which confers migratory capacity to GBM stem cells. Hence combining HIF-2α and α5 integrin inhibitors resulted in proliferation and migration impairment of α5 integrin expressing cells. Stabilization of HIF-2α is however not sufficient to control integrin α5 expression. Our results show that AHR (aryl hydrocarbon receptor) expression is inversely related to HIF-2α and α5 integrin expressions suggesting a functional competition between the two transcription factors. Collectively, data confirm the high heterogeneity of a GBM therapeutic target, its induction in hypoxic niches by HIF-2α and suggest a new way to attack molecularly defined GBM stem cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Teclistamab is a B‑cell maturation antigen (BCMA)-directed bispecific antibody approved for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma. In the phase 1/2 MajesTEC-1 study, a cohort of patients who had prior BCMA-targeted therapy (antibody-drug conjugate [ADC] or CAR-T cell therapy) were enrolled to explore teclistamab in patients previously exposed to anti-BCMA treatment. At median follow-up of 28.0 months (range, 0.7-31.1), 40 patients with prior BCMA-targeted therapy had received subcutaneous 1.5 mg/kg weekly teclistamab. Median prior lines of treatment were 6 (range, 3-14). Prior anti-BCMA therapy included ADC (n = 29), CAR-T (n = 15), or both (n = 4). Overall response rate was 52.5%; 47.5% of patients achieved very good partial response or better and 30.0% achieved complete response or better. Median duration of response was 14.8 months, median progression-free survival was 4.5 months, and median overall survival was 15.5 months. The most common treatment-emergent adverse events (TEAEs) were neutropenia, infections, cytokine release syndrome, and anemia; cytopenias and infections were the most common grade ≥3 TEAEs. Infections occurred in 28 (70.0%) patients (n = 13 [32.5%] maximum grade 3/4; n = 4 [10%] grade 5). Prior to starting teclistamab, baseline BCMA expression and immune characteristics were unaffected by prior anti-BCMA treatment. The MajesTEC-1 trial cohort C results demonstrate favorable efficacy and safety of teclistamab in patients with heavily pretreated RRMM and prior anti-BCMA treatment. NCT03145181; NCT04557098., (Copyright © 2024 American Society of Hematology.)

Background: Elexacaftor-tezacaftor-ivacaftor has been approved in Europe for people with cystic fibrosis with at least one F508del CFTR variant. Additionally, it is approved by the US Food and Drug Administration (FDA) for people with cystic fibrosis with at least one of 177 rare variants. The aims of this study were to describe the clinical response to elexacaftor-tezacaftor-ivacaftor for people with cystic fibrosis without a F508del CFTR variant in France and to determine CFTR variant responsiveness to elexacaftor-tezacaftor-ivacaftor based on the observed clinical response., Methods: The French compassionate programme expanded access to elexacaftor-tezacaftor-ivacaftor to people with cystic fibrosis, aged 6 years and older, without a F508del variant, excluding those with two variants previously characterised as non-responsive. Participants at France's 47 cystic fibrosis centres were given a 4-6 week trial of elexacaftor-tezacaftor-ivacaftor and response was determined by a centralised committee based on evolution of clinical data, lung function, and sweat chloride concentration. Responsiveness of individual CFTR variants was derived from observed clinical responses., Findings: The first compassionnate programme was launched on May 19, 2022; by March 8, 2024, 516 people with cystic fibrosis had been identified for inclusion in this real-word study: 37 were not included due to the presence of two variants previously characterised as non-responsive to elexacaftor-tezacaftor-ivacaftor, and 479 (229 females [48%] and 250 males [52%]) received elexacaftor-tezacaftor-ivacaftor for 4-6 weeks. Among 443 participants who received no CFTR modulator before elexacaftor-tezacaftor-ivacaftor, 83 had at least one FDA-approved variant, of whom 81 (98%) were responders and continued elexacaftor-tezacaftor-ivacaftor; in responders, mean absolute change in sweat chloride was -44·5 mmol/L (95% CI -39·1 to -49·8) and percentage of predicted FEV 1 (ppFEV 1 ) was 11·1 percentage points (95% CI 8·4 to 13·7; both comparisons p<0·0001). Among 360 participants with no FDA-approved variant and no previous CFTR modulator, 177 (49%) were responders; in responders, mean absolute change in sweat chloride was -20·5 mmol/L (-17·2 to -23·8) and ppFEV 1 was 13·2 percentage points (11·4 to 15·0; both comparisons p<0·0001). Among 36 participants who were receiving ivacaftor before elexacaftor-tezacaftor-ivacaftor, 32 (89%) continued elexacaftor-tezacaftor-ivacaftor. Of 251 individual CFTR variants, 64 (28 FDA-approved) were classified as responsive or possibly responsive to elexacaftor-tezacaftor-ivacaftor, and 123 (two FDA-approved) as non-responsive or possibly non-responsive to elexacaftor-tezacaftor-ivacaftor., Interpretation: In France, over half of the population with cystic fibrosis without a F508del variant responded to elexacaftor-tezacaftor-ivacaftor, with most responders having no FDA-approved variant. The treatment period was relatively short and further research is warranted to describe the long-term safety and effectiveness of elexacaftor-tezacaftor-ivacaftor in this population., Funding: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR., Competing Interests: Declaration of interests P-RB declares consulting fees from AstraZeneca, Chiesi, GSK, Insmed, MSD, Sanofi, Vertex, Viatris, and Zambon, outside of the submitted work. IS-G declares grants and consulting fees from Vertex, outside of the submitted work. ID declares support for attending meetings from Mylan and Zambon. CA declares consulting fees from Vertex and Viatris and support for attending meetings from SOS Oxygène, Viatris, and Zambon. DG declares support for attending meetings from Zambon. MM-E declares fees for report testimony from Vertex. MM declares consulting fees from Vertex. BD declares fees for participation on a data safety and monitoring board from Vertex. CR reports grants from Vaincre la Mucoviscidose and unpaid participation on the leadership of the French newborn screening programme and the French Rare Diseases Network. CM declares consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, and GSK, and support for attending meetings from Boehringer Ingelheim and Chiesi. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Bacterial-viral co-infections are frequent, but their reciprocal effects are not well understood. Here, we examined the effect Bordetella pertussis infection and the role of pertussis toxin (PT) on influenza A virus (IAV) infection and disease. In C57BL/6J mice, prior nasal administration of virulent B. pertussis BPSM and PT-deficient BPRA provided effective and sustained protection from IAV-induced mortality. However, BPSM or BPRA administered together with purified PT (BPRA + PT) had a stronger protective effect on weight loss compared to BPRA alone, reduced the viral load, and induced IL-17A in the lungs. In IL-17 -/- mice, BPSM- and BPRA + PT-mediated protection against viral replication was abolished, while BPSM, BPRA and BPRA + PT provided similar levels of protection against IAV-induced mortality and weight loss. In conclusion, B. pertussis infection protects against influenza by two mechanisms: one reducing viral replication depending on PT and IL-17, and the other, independently of PT and IL-17, resulting in protection against influenza disease without reducing the viral load., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Background: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes or pleiotropy, which have not been systematically described. In addition, the involvement of SCN5A in dilated cardiomyopathies (DCMs) remains controversial., Objective: We aimed to evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and to determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers., Methods: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced with a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped., Results: The study included 170 P/LP variants found in 495 patients. Of them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, 6 with progressive cardiac conduction disease, 4 with multifocal ectopic Purkinje-related premature contractions, and 3 with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Of those, 8 were carried by 8 patients presenting with DCM with a debatable causative genotype/phenotype link., Conclusion: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960) if not questionable., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Inflammation is an established contributor to the pathophysiology of depression and the prevalence of depression in those with chronic inflammatory disease is two- to four-fold higher than the general population. Yet little is known about the neurobiological changes that confer depression or resilience to depression, that occur when episodes of heightened inflammation are frequent or span many years., Methods: We used an innovative combination of longitudinal resting state functional magnetic resonance imaging coupled to segmental bronchial provocation with allergen (SBP-Ag) to assess changes in resting state functional connectivity (rsFC) of the salience network (SN) caused by an acute inflammatory exacerbation in twenty-six adults (15 female) with asthma and varying levels of depressive symptoms. Eosinophils measured in bronchoalveolar lavage fluid and blood provided an index of allergic inflammation and the Beck Depression Inventory provided an index of depressive symptoms., Results: We found that in those with the highest symptoms of depression at baseline, SN rsFC declined most from pre- to post-SBP-Ag in the context of a robust eosinophilic response to challenge, but in those with low depressive symptoms SN rsFC was maintained or increased, even in those with the most pronounced SBP-Ag response., Conclusions: Thus, the maintenance of SN rsFC during inflammation may be a biomarker of resilience to depression, perhaps via more effective orchestration of large-scale brain network dynamics by the SN. These findings advance our understanding of the functional role of the SN during inflammation and inform treatment recommendations for those with comorbid inflammatory disease and depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Children's bone loss of limbs represents a significant challenge for surgeons, especially given that children are growing individuals. In the pediatric population, we compared bone reconstruction using vascularized fibula flaps with the induced membrane technique. The primary purpose of this study was to evaluate the delay and quality of consolidation., Methods: Data from patients who underwent limb reconstruction using either the fibula flap or the induced membrane were retrospectively collected from files across two centers. Perioperative and long-term complications were documented, along with functional and aesthetic outcome., Results: Between 2004 and 2020, 31 children underwent limb reconstruction using a fibula flap, and 13 patients were treated using the induced membrane technique. The etiologies included 76% tumors, 20% congenital pseudarthroses, and 3.7% infections. The median size of the bone resection was 12.5 cm (range: 1.8 to 31 cm). The median time to consolidation after free fibula flap transfer was 10 months (range: 2 to 55 months) versus 7.5 months (range: 1 to 64 months) for the Masquelet technique (p = 0.54). Limb length inequality occurred in 52% of fibula cases and 39% of the induced membrane cases (p = 0.55)., Conclusions: Both of free fibula flap and the induced membrane technique are effective options for bone reconstructing long bones in children. These techniques yield good functional outcomes and have comparable consolidation times., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Mesothelioma is a rare and aggressive malignant neoplasm arising from mesothelial cells, which occasionally manifests recurrent fusions. EWSR1/FUS-CREB, YY1, MAP3K8, NR4A3, and ALK-rearranged proliferations have been reported in limited series with no clear histological or clinical correlations, limiting clinicians' ability to assess prognosis and integrate these new entities into therapeutic decisions. The aim of this study was to better characterize these rearranged proliferations histologically, molecularly, and clinically., Methods: Clinical, pathological, and comprehensive transcriptome and mutation data were collected for each case., Results: A total of 41 tumors were included, encompassing 7 ALK, 10 MAP3K8, 4 NR4A3, 8 ESWR1/FUS::ATF1, 8 EWSR1::YY1, and 4 SUFU-fused cases. We found a female predominance, except for cases harboring NR4A3 and SUFU; and most patients were around 60 years of age, but those harboring ALK or EWSR1/FUS::ATF1 gene fusions were younger. Each group exhibited distinct histological, immunohistochemical, molecular features, and oncological courses. Specifically, MAP3K8 and ALK presented PAX8+ papillary proliferations, ESWR1/FUS::ATF1 and EWSR1::YY1 displayed angiomatoid fibrous histiocytoma-like patterns, while SUFU showcased 'tissue culture'-like spindle cell proliferation. Poor prognosis factors were the pleural site, male sex, Ki67 ≥10%, and ESWR1/FUS::ATF1 or SUFU gene fusions., Conclusions: This study significantly broadens the spectrum of mesothelial tumors associated with fusions, offering insight into novel epithelioid (mesothelial) proliferations with distinctive histological appearances, molecular profiles, and prognoses to guide adapted treatments for patients., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Cardiovascular diseases are the leading cause of mortality worldwide, originating in the first decades of life. A better understanding of their early determinants would allow for better prevention. This study aimed to evaluate the impact of nutritional and activity-related characteristics during adolescence on young adult cardiovascular risk factors., Methods: The Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study included adolescents (aged 12.5-17.5 years) in 10 European centres. Four centres designed a nested cohort including 236 participants who were reassessed as young adults (21-32 years). Food consumption was evaluated by dietary recalls, physical activity by accelerometers, physical fitness using physical tests and nutritional knowledge by questionnaires. Cardiovascular health was assessed by Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study risk scores and its components. Factors associated with cardiovascular risk were identified using a multivariable regression model., Results: Higher Diet Quality Index (DQI, P = 0.012) and nutritional knowledge (P = 0.015) were significantly associated with lower modified PDAY risk scores. Ultra-processed foods were associated with a lower non-high-density lipoprotein (non-HDL) cholesterol (P = 0.003), whereas DQI (P = 0.014) and Planetary Health Diet Index (P = 0.016) were associated with a higher HDL cholesterol. Higher DQI was also related to a lower body mass index (BMI, P = 0.006). In addition, cardiorespiratory fitness was related to a lower BMI (P = 0.004)., Conclusions: Nutritional knowledge, diet quality and adherence to a sustainable diet in adolescence decrease cardiovascular risk in adulthood, whereas ultra-processed food consumption increases risk. These factors appear as targeted prevention tools for promoting a healthier adolescent lifestyle to decrease long-term cardiovascular risk., Clinical Trial Registry Number: Clinicaltrials.gov NCT02899416., Competing Interests: Conflicts of interest Pr. Frédéric Gottrand has received consulting fees from Nestlé. The remaining authors do not have any conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The precise mechanisms underlying the cellular response to static electric cues remain unclear, limiting the design and development of biomaterials that utilize this parameter to enhance specific biological behaviours. To gather information on this matter we have explored the interaction of collagen type-I, the most abundant mammalian extracellular protein, with poly(vinylidene fluoride) (PVDF), an electroactive polymer with great potential for tissue engineering applications. Our results reveal significant differences in collagen affinity, conformation, and interaction strength depending on the electric charge of the PVDF surface, which subsequently affects the behaviour of mesenchymal stem cells seeded on them. These findings highlight the importance of surface charge in the establishment of the material-protein interface and ultimately in the biological response to the material. STATEMENT OF SIGNIFICANCE: The development of new tissue engineering strategies relies heavily on the understanding of how biomaterials interact with biological tissues. Although several factors drive this process and their driving principles have been identified, the relevance and mechanism by which the surface potential influences cell behaviour is still unknown. In our study, we investigate the interaction between collagen, the most abundant component of the extracellular matrix, and poly(vinylidene fluoride) with varying surface charges. Our findings reveal substantial variations in the binding forces, structure and adhesion of collagen on the different surfaces, which collectively explain the differential cellular responses. By exposing these differences, our research fills a critical knowledge gap and paves the way for innovations in material design for advanced tissue regeneration strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: The relationship between ventilator-associated events (VAE) and microaspiration in intubated patients has not be studied. The objective of this study was to evaluate the relationship between abundant microaspiration of oropharyngeal secretions or gastric contents and the incidence of VAE., Patients and Methods: This was a post hoc analysis of the BESTCUFF study, which was a multicenter, cluster randomized, cross-over, controlled, open-label trial in adult patients ventilated for over 48 h. All tracheal aspirates were sampled for 48 h following enrollment, with quantitative measurement of pepsin and alpha-amylase. VAE were identified using National Healthcare Safety Network criteria, based on PEEP or FiO 2 variations compared to stable parameters in previous days. The primary objective was to assess the relationship between abundant global microaspiration and the incidence of VAE, adjusted for pre-specified confounding factors (sex, SAPS II score and Glasgow coma scale)., Results: 261 patients were included, of which 31 (11.9%) developed VAE, with an overall median age of 65 (interquartile range 52-74), a majority of male patients (164, 62.8%), a median SAPS II score of 50 [40-61], a median SOFA score of 8 [5-11], and acute respiratory failure as main reason for ICU admission (117, 44.8%).The incidence of VAE was not significantly associated with abundant global microaspiration (adjusted cause-specific hazard ratio (cHR): 1.55 [0.46-5.17), abundant gastric microaspiration (adjusted cHR: 1.24 [0.61-2.53), or with abundant oropharyngeal microaspiration (adjusted HR: 1.07 [0.47-2.42])., Conclusions: Our results suggest no significant association between abundant global, gastric or oropharyngeal microaspiration and the incidence of VAE., Implications for Clinical Practice: This study underscores that measuring microaspiration in intubated critically ill patients might not be useful to predict the diagnosis of VAE or to evaluate interventions aiming at preventing these complications., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SN has received lecture fees from MSD, Pfizer, Biomérieux, Medtronic, and Fisher and Paykel; he is a member of the advisory boards of Mundipharma. Other authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

In REACH4 (NCT03491215), a phase 1/2, open-label, single-arm, multicenter study, the pharmacokinetics (PK), efficacy, and safety of ruxolitinib were evaluated in treatment-naïve and steroid-refractory pediatric patients with grade II-IV acute graft-versus-host disease (aGVHD; n=45). Ruxolitinib dosing was based on age and targeted the exposure in adults receiving 10 mg twice daily; group 1 (≥12 to <18 years) received 10 mg twice daily and preliminary starting doses for groups 2 (≥6 to <12 years) and 3 (≥2 to <6 years) were 5 mg twice daily and 4 mg/m2 twice daily, respectively. Phase 1 primary objective was to assess ruxolitinib PK parameters and define an age-appropriate recommended phase 2 dose (RP2D) for patients <12 years of age. Phase 2 primary objective was to measure the activity of ruxolitinib as assessed by overall response rate (ORR) at day 28; the key secondary objective was to assess the durable ORR at day 56. Ruxolitinib exposure was comparable across age groups; starting doses were confirmed as the RP2D. The median duration of ruxolitinib exposure was 3.8 months (range 0.3-11.2). ORR in all patients was 84.4% (90% confidence interval [CI], 72.8-92.5) at day 28, with a durable ORR at day 56 of 66.7% (90% CI, 53.4-78.2); high response rates were observed across age groups and in both treatment-naïve and steroid-refractory subgroups. Adverse events were consistent with those expected in ruxolitinib-treated patients with aGvHD (anemia, decreased neutrophil and leukocyte count). In pediatric patients with aGvHD, ruxolitinib showed clinically meaningful efficacy with no new safety signals., (Copyright © 2024 American Society of Hematology.)

Background: Recent literature suggests that taking into consideration and evaluating preoperative expectations of Parkinson's disease (PD) patients candidates to deep brain stimulation (DBS), can contribute to treatment effectiveness. However, few validated instruments investigating preoperative expectations are available. We present the development and validation of the DBS-PS (Deep Brain Stimulation - Perception Scale)., Methods: The DBS-PS is an 11 questions self-administered scale, with answers rated on a 10-point Likert scale (1 completely false, 10 completely true). Items were generated on the basis of patient's interviews analyzed by an expert group and reached consensus. The scale is divided into three domains: expectations for PD, expectations for social-life and leisure, expectations for intimate life. Exploratory factor analysis (EFA) completed by item response theory (IRT) analysis was conducted to validate the theoretical structure of the DBS-PS., Results: 64 PD patients aged 59.18 (SD = 5.74) years with PD diagnosed since 9.36 (SD = 4.09) years completed the DBS-PS preoperatively. EFA confirmed a 3 factors scale structure (eigenvalue >1) explaining 69% of variance (factor 1: 43%; factor 2: 17%; factor 3: 9%). Reliability (Cronbach's α: 0.714 for factor 1, 0.781 for factor 2, 0.889 for factor 3) and discriminant validity (Pearson coefficient r < 0.50) were satisfactory. IRT showed good model fit, preserved unidimensionality, but some local dependences were observed., Conclusion: The DBS-PS shows satisfactory psychometric properties. It is easy to administer in routine practice with preoperative PD patients. It constitutes an interesting basis for cognitive restructuring before neurosurgery, by highlighting dysfunctional cognitions and measuring the benefits of cognitive restructuring therapy., Competing Interests: Declaration of competing interest J.C·C. has served in advisory boards for Alzprotect, Bayer, Biogen, Denali, Ferrer, Idorsia, Prevail Therapeutic, Servier, Theranexus, UCB; and received grants from Sanofi and the Michael J Fox Foundation outside of this work. D.D. Consultancies: Scientific Advisory Board for Abbvie, Alterity, Orkyn, Air Liquide, Apopharma, Lundbeck, Everpharma and Boston Scientific, Cure Parkinson Trust. Grants: French Ministry of Health: PHRC grants. French Ministry of Research: ANR. European Preclinical Research: Coen. European Clinical Research: Horizon 2020. Charities: France Parkinson, ARSLA Foundation. Foundations: University of Lille, CA. Equity stake: InBrain Pharma, InVenis Biotherapie. I.B. has served in advisory boards for Abbvie and Orkyn. S.C.C, A.S.R, M.M, H·D, R.S, E.S have no conflict of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aims: To gather real-life data on biliary tract cancer (BTC) in France, an ambispective ACABi GERCOR Pronobil cohort was initiated. This nested study, Amber, utilized data from this cohort to document clinical practices in this setting., Methods: Inclusion criteria encompassed patients with locally advanced/metastatic BTC managed between 2019 and 2021 in nine French referral hospitals. Objectives included describing demographic and clinical data, treatments outcomes (safety and efficacy), and overall survival., Results: Of the 138 patients (median age 65 years, a balanced sex ratio) included, most displayed ECOG 0-1 (83 %), at least one comorbidity (79 %), and had intrahepatic (56 %) and metastatic (82 %) BTC. Among surgically-resected patients, 60 % received adjuvant chemotherapy, mainly capecitabine (67 %). CisGem, the primary first-line palliative chemotherapy (69 %), showed a 23 % objective response rate, a median progression-free survival of 5.3 months, and a median overall survival of 13.4 months. Second-, third-, and fourth-line were given to 75 % (FOLFOX: 35 %, targeted therapy: 14 %), 32 %, and 13 % of patients. In total, 67 % of patients had a molecular profile (IDH1 mutations and FGFR2 fusions: accounting for 21 % each in intrahepatic cholangiocarcinoma)., Conclusion: BTC patients were predominantly treated according to international recommendations. The obtained demographic, tumor, and molecular data were consistent with existing literature., Competing Interests: Conflict of interest MD: reports receiving research funding from AstraZeneca. EA reports receiving consulting or advisory board fees from Astra Zeneca, MSD, BMS, Roche, Servier, Incyte, AAA and receiving research funding from ROCHE, BAYER. TL reported an advisory role with Amgen, Chugai, Bristol Myers Squibb, Merck Serono, Deciphera, Pierre Fabre, Servier, Astra Zeneca, BMS, Advanced Accelerator Applications, IPSEN, Lilly and Bayer outside of the submitted work; receiving grants from LEO Pharma and Pierre Fabre outside of the submitted work. VH has participated in consulting and/or advisory boards for Amgen, Merck, Servier, MSD, Pierre Fabre, AAA, Ipsen, Deciphera. DT reports receiving consulting or advisory board fees from Astra Zeneca, Sanofi, Amgen, MSD, BMS, Roche, Servier, Pierre Fabre; receiving research funding from Pierre Fabre and Sandoz. JE: Consulting: MSD, Eisai, BMS, AstraZeneca, Bayer, Roche, Ipsen, Basilea, Merck Serono, Incyte, Servier, Beigene, Taiho, Boston Scientific; Travel expense: Amgen; Research funding (institutional): BMS, Beigene, Boston Scientific, Exeliom biosciences AD and CB: Employee at AstraZeneca AT has received personal fees from Servier, Viatris, Incyte Bioscience, BMS, Merck and grants and personal fees from AstraZeneca and MSD outside the submitted work. CN received consulting fees from Amgen, AstraZeneca, Baxter, Bristol-Myers Squibb, Fresenius Kabi, Incyte Biosciences, Merck, MSD, Mundipharma, Mylan, Novartis, Nutricia, OSE Immunotherapeutics, Pierre Fabre, Roche, Sanofi, Servier, and Viatris; grants from OSE Immunotherapeutics, AstraZeneca, Bristol-Myers Squibb, Fresenius Kabi, and Nutricia; and support for attending meetings or travel from Merck, MSD, Mylan, Viatris, OSE Immunotherapeutics, and Pierre Fabre. AB, JH, JRP, NF, AH and DV: none declared., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Anti-TNF are usually maintained during pregnancy in patients with inflammatory bowel disease (IBD) but safety is still a concern for them., Aims: To provide data on management of anti-TNF agents during pregnancy, safety of live vaccines (BCG-MMR-rotavirus) and breastfeeding in newborns and dedicated information delivered to IBD women., Methods: We performed an observational study in 25 centers from 2016 to 2018. We administered questionnaires to women with IBD receiving anti-TNF during pregnancy with newborn follow-up ≥ one year., Results: Of 153 patients, 52 % maintained anti-TNF during the third trimester. Anti-TNF was shortly resumed in 79 % (58/73) after delivery. The rate of breastfeeding was 44 % (68/153) without any complication; 38 % of the mothers denied to breastfeed based on physician's advice. 26 % (34/129) of the newborns received live vaccines before 6 months-old (BCG:30 %; MMR:63 %; Rotavirus:8 %) and only 3 complications occurred (local BCGitis=1, fever=2). Information concerning anti-TNF during pregnancy/post-partum was delivered to 92 % of the patients, mainly by a gastroenterologist (97 %) who discussed with the obstetrician or the paediatrician in only 48 % and 25 %., Conclusion: In IBD patients, maintaining anti-TNF during pregnancy and breastfeeding is safe. Accidental live vaccines before 6 months did not lead to significant adverse events. The communication about these questions remains to improve., Competing Interests: Declaration of competing interest Romain Altwegg received board or lectures fees from Abbvie, Janssen, Pfizer, Takeda. Vered Abitbol received lecture fees from Biogen Amgen Sandoz Mylan Pfizer Takeda Janssen, Gilead, Tillots. Laurent Peyrin-Biroulet received consulting fees from Merck, Abbvie, Janssen, Genentech. Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB-Pharma. Hospira, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, Pfizer, and HAC-Pharma. This author also received lecture fees from Merck, Abbvie, Takeda, Janssen Cilag, Ferring. Norgine, Tillots, Vifor, Therakos, HAC-Pharma, and Mitsubishi. No conflicts of interest are claimed by the remaining authors., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The impact of intraprocedural results following transcatheter edge-to-edge repair (TEER) in primary mitral regurgitation (MR) is controversial., Objectives: This study sought to investigate the prognostic impact of intraprocedural residual mitral regurgitation (rMR) and mean mitral valve gradient (MPG) in patients with primary MR undergoing TEER., Methods: The PRIME-MR (Outcomes of Patients Treated With Mitral Transcatheter Edge-to-Edge Repair for Primary Mitral Regurgitation) registry included consecutive patients with primary MR undergoing TEER from 2008 to 2022 at 27 international sites. Clinical outcomes were assessed according to intraprocedural rMR and mean MPG. Patients were categorized according to rMR (optimal result: ≤1+, suboptimal result: ≥2+) and MPG (low gradient: ≤5 mm Hg, high gradient: > 5 mm Hg). The prognostic impact of rMR and MPG was evaluated in a Cox regression analysis. The primary endpoint was 2-year all-cause mortality or heart failure hospitalization., Results: Intraprocedural rMR and mean MPG were available in 1,509 patients (median age = 82 years [Q1-Q3: 76.0-86.0 years], 55.1% male). Kaplan-Meier analysis according to rMR severity showed significant differences for the primary endpoint between rMR ≤1+ (29.1%), 2+ (41.7%), and ≥3+ (58.0%; P < 0.001), whereas there was no difference between patients with a low (32.4%) and high gradient (42.1%; P = 0.12). An optimal result/low gradient was achieved in most patients (n = 1,039). The worst outcomes were observed in patients with a suboptimal result/high gradient. After adjustment, rMR ≥2+ was independently linked to the primary endpoint (HR: 1.87; 95% CI: 1.32-2.65; P < 0.001), whereas MPG >5 mm Hg was not (HR: 0.78; 95% CI: 0.47-1.31; P = 0.35)., Conclusions: Intraprocedural rMR but not MPG independently predicted clinical outcomes following TEER for primary MR. When performing TEER in primary MR, optimal MR reduction seems to outweigh the impact of high transvalvular gradients., Competing Interests: Funding Support and Author Disclosures Dr Ludwig has received travel compensation from Edwards Lifesciences; has received speaker honoraria from Abbott; has received advisory fees from Bayer; and is a consultant for New Valve Technology. Dr Koell has received personal fees from Edwards Lifesciences. Dr Donal has received research facilities from GE Healthcare and Abbott. Dr Stolz has received speaker honoraria from Edwards Lifesciences. Dr Scotti has served as a consultant for Edwards Lifesciences and NeoChord Inc. Dr Melica has served as a proctor for Abbott. Dr Samim has received funding for an online course from Edwards Lifesciences. Dr Dreyfus has received consulting or speaker fees from Abbott. Dr Karam has received consultant fees from Abbott, Edwards Lifesciences, and Medtronic. Dr Kessler has received speaker honoraria for Edwards Lifesciences and Abbott. Dr Lavie Badie has served as a consultant and proctor for Abbott; and has served as a proctor for Abbott. Dr Metra has received consulting honoraria of minimal amounts from Abbott Structural, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences Roche diagnostics Novo Nordisk, in the last 3 years. Dr Iliadis has received personal fees from Abbott and Edwards Lifesciences. Dr Gerçek has received funding from the Ruhr University Bochum (Advanced Clinician Scientist); and has served as a consultant for Edwards Lifesciences. Dr Latib has served on the Advisory Board for Medtronic, Abbott Vascular, Boston Scientific, Edwards Lifesciences, Shifamed, NeoChord Inc, V-dyne, and Philips. Dr Kalbacher has received personal fees from Abbott Medical, Edwards Lifesciences, Medtronic, and Pi-Cardia Ltd. Dr Coisne has served as a consultant for Abbott, Edwards Lifesciences, and GE Healthcare; and has received speaker fees from Abbott, AstraZeneca, GE Healthcare, Merck Sharp & Dohme, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)