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Introduction: Improvements in combat casualty care have increased survival rates, but these patients are at particular risk of developing multiple organ failure (MOF). We investigated the incidence and severity of MOF in a cohort of severe combat casualties., Materials and Methods: This retrospective study included all on-duty French land army war casualties with a severe combat injury requiring intensive care unit admission during 2009-2023. Demographic data, advanced life support interventions, and outcomes were collected. Each organ failure was then analyzed during a 7-day trauma course according to the Sequential Organ Failure Assessment (SOFA) score., Results: Of the 100 patients who met the inclusion criteria, those with persistent MOF at day 4 (MOF group) represented 22% of the total population (median SOFA score 6.0 [5.3-8.0]). Compared to those without persistent MOF, these patients were more severely injured (median Military Injury Severity Score 38.0 [interquartile range 33.0-56.8] vs 26.5 [20.0-34.0], p < 0.001) by an explosive mechanism (68.2%) and sustained more traumatic brain injury (TBI; 40.9% vs 14.1%, p = 0.013). The MOF group also received significantly more blood units (median 14.0 [8.3-24.8] vs 6.0 [0.0-12.0], p < 0.001) and massive transfusions (68.2% vs 32.1%, p = 0.002). Pulmonary and cardiovascular dysfunction were the most frequently observed trauma outcomes. A multivariable logistic regression model showed that MOF persistence at day 4 was significantly associated (odds ratios [95% confidence intervals]) with severe injuries (1.5 [1-2.3], p = 0.042)., Conclusion: A high number of severe lesions significantly and independently increased risk of MOF persistence at day 4 after combat-related trauma. These findings are particularly relevant to current and anticipated large-scale combat operations that will challenge battlefield casualty care and evacuation., Competing Interests: Conflict of interest statement and source of funding: None., (Copyright © 2024 by the Shock Society.)

C-terminally encoded peptides (CEPs) are small secreted signaling peptides that promote nitrogen-fixing root nodulation symbiosis in legumes, depending on soil mineral nitrogen availability. 1 In Medicago truncatula, their action is mediated by the leucine-rich repeat receptor-like protein kinase COMPACT ROOT ARCHITECTURE 2 (CRA2). 2 , 3 , 4 Like most land plants, under inorganic phosphate limitation, M. truncatula establishes another root endosymbiotic interaction with arbuscular fungi, the arbuscular mycorrhizal symbiosis (AMS). Because this interaction is beneficial for the plant but has a high energetic cost, it is tightly controlled by host plants to limit fungal infections mainly depending on phosphate availability. 5 We show in this study that the expression of a subset of CEP-encoding genes is enhanced in the low-phosphate conditions and that overexpression of the low-phosphate-induced MtCEP1 gene, previously shown to promote the nitrogen-fixing root nodulation symbiosis, enhances AMS from the initial entry point of the fungi. Conversely, a loss-of-function mutation of the CRA2 receptor required for mediating CEP peptide action 2 decreases the endomycorrhizal interaction from the same initial fungal entry stage. Transcriptomic analyses revealed that the cra2 mutant is negatively affected in the regulation of key phosphate transport and response genes as well as in the biosynthesis of strigolactone hormones that are required for establishing AMS. Accordingly, strigolactone contents were drastically decreased in cra2 mutant roots. Overall, we showed that the CEP/CRA2 pathway promotes both root nodulation and AMS in legume plants, depending on soil mineral nutrient availability., Competing Interests: Declaration of interests The authors declare no competing interests, (Copyright © 2024. Published by Elsevier Inc.)

Background: BK-polyomavirus (BKpyV) nephropathy (BKVN) is associated with end-stage kidney disease in kidney and non-kidney solid organ transplantation, with no curative treatment., Case Presentation: A 45-year-old woman with a past medical history of double lung transplantation subsequently developed end-stage kidney disease, of undetermined origin. One month after receiving a kidney transplant, a diagnosis of early BKVN was suspected, and in retrospect was a reasonable cause for the loss of her native kidneys. Minimisation of immunosuppression, achieved through extracorporeal photopheresis, allowed clearance of BKpyV and so prevented nephropathy. Both lung and kidney grafts had a satisfactory and stable function after one year of follow-up, with no rejection., Conclusions: Extracorporeal photopheresis may have facilitated minimisation of immunosuppression and BKpyV clearance without lung allograft rejection., (© 2024. The Author(s).)

Purpose: To compare functional and anatomical outcomes between posterior drainage of residual fluid using a 41G cannula, fluid tolerance (R-SRF), and conventional complete drainage methods, including removal through peripheral retinal breaks (PRB), perfluorocarbon liquid (PFCL), and posterior retinotomy (PR)., Methods: In this retrospective, multicenter study, we evaluated cases for visual acuity (VA) at 3 months of follow-up. Secondary outcomes included surgical success, postoperative metamorphopsia, shifts, full-thickness folds (FTF), optical coherence tomography (OCT) parameters, and safety. Subgroup analyses were also conducted., Results: VA did not differ significantly between the three main groups. Subgroup analyses revealed worse VA for PR with 1.131 LogMAR (20/270 in Snellen conversion, p=0,002), with significantly more grade C proliferative vitreoretinopathy (PVR, 40.0%, p=0,003). R-SRF tended to offer better secondary outcomes, without statistical significance except for postoperative epiretinal membrane (ERM, 30.8%, p=0,041). Subgroup analyses found significantly more shifts with PFCL (91,7%, p=0,036). No cases of postoperative FTF or macular holes were observed with the 41G., Conclusion: Our study introduced the 41G technique, indicating favourable outcomes for fovea-off retinal detachments. Nevertheless, fluid tolerance appeared to be the best option, offering a cost-effective and faster method, with an optimal microstructural profile and VA comparable to that of complete drainage techniques., Competing Interests: INTEREST STATEMENT: The authors declare that there is no conflict of interest.

Alkaptonuria is characterized by the accumulation of homogentisic acid which causes dark coloration of urine upon standing, ochronosis, and arthritis. A 4-year old child was referred to our pediatric nephrologist with hyperoxaluria and a history of unexplained pink-to-brown discolouration of his diapers associated with a brown-staining of clothes and skin since he was six months old. He had no other symptoms and his past medical history only included minor child illnesses. His 11-month-old brother had the same dark discoloration of his diapers. Laboratory testing on a spot urine sample showed hyperoxaluria and nephrotic range proteinuria with low creatinine and normal albumin concentrations. Considered causes were hyperoxaluria, alkaptonuria, interfering substance, adulteration. The further diagnostic work-up revealed increased homogentisic acid in urine, compatible with alkaptonuria. Urinary creatinine and total protein measurements on Roche Cobas were, respectively, falsely decreased and increased in the presence of homogentisic acid. The false-low creatinine resulted in an elevated oxalate/creatinine ratio. Alkaptonuria can cause a false increase of results expressed per creatinine and should be excluded in case of an unexplained marked increase of urine total protein without a concomitant increase of albumin., Competing Interests: Potential conflict of interest None declared., (Croatian Society of Medical Biochemistry and Laboratory Medicine.)

Purpose: Evaluate the safety and efficacy of an eco-friendly permanent agar-agar-based embolization agent (ABEA) (EmboBio®) for intra-arterial use., Materials and Methods: Six pigs embolized with one ABEA torpedo (6 lower polar renal and 6 lumbar arteries) and one coil (6 lower polar renal and 6 lumbar arteries). Technical success was defined as a complete occlusion with no residual flow in DSA. Short-term endpoints included safety (non-targeted embolization), ease of use (embolization preparation time, occlusion time), and DSA controls at day 7, month 1, and month 3. Tissue reaction was assessed via [18F]-FDG PET/CT at month 2 and histological study at month 3., Results: ABEA torpedoes achieved immediate and persistent occlusion at month 3 for all kidney and lumbar embolizations (n = 12/12). Control coils had technical success for 12/12, with a persistent occlusion at month 3 for 2/12. No off-target embolization occurred. ABEA torpedoes demonstrate faster occlusion (ABEA: 6 ± 4 s; coils: 427 ± 469 s; p = 0.0022, n = 12) and preparation times (ABEA: 96.9 1 ± 23 s; coils: 150.33 ± 58 s; p = 0.0432, n = 12) after device placement than coil. No significant difference in inflammation between ABEA and coil groups at month 2 (ABEA: 3.35e -6  ± 1.7e -6 %ID/mm 3 ; coils: 2.24e -6  ± 8.5e -7 %ID/mm3; p = 0.5) on PET imaging. These results were confirmed by histological analysis at month 3., Conclusion: Permanent dry foam torpedo comprising agar-agar is effective for arterial embolization. In animal model, one ABEA torpedo demonstrates a faster and more persistent occlusion than one fiber coil., Levels of Evidence: Not applicable., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Rationale: Allogeneic hematopoietic stem-cell transplantation (Allo-HSCT) recipients are still believed to be poor candidates for ICU management. Methods: We investigated outcomes and determinants of mortality in a large multicenter retrospective cohort of Allo-HSCT patients admitted between January 1, 2015, and December 31, 2020, to 14 French ICUs. The primary endpoint was 90-day mortality. Measurements and Main Results: In total, 1,164 patients were admitted throughout the study period. At the time of ICU admission, 765 (66%) patients presented with multiple organ dysfunction, including acute respiratory failure in 40% ( n  = 461). The median sepsis-related organ failure assessment score was 6 (interquartile range, 4-8). Invasive mechanical ventilation, renal replacement therapy, and vasopressors were required in 438 (38%), 221 (19%), and 468 (41%) patients, respectively. ICU mortality was 26% (302 deaths). Ninety-day, 1-year, and 3-year mortality rates were 48%, 63%, and 70%, respectively. By multivariable analysis, age > 56 years (odds ratio [OR], 2.0 [95% confidence interval (CI), 1.53-2.60]; P  < 0.001), time from Allo-HSCT to ICU admission between 30 and 90 days (OR, 1.68 [95% CI, 1.17-2.40]; P  = 0.005), corticosteroid-refractory acute graft-versus-host disease (OR, 1.63 [95% CI, 1.38-1.93]; P  < 0.001), need for vasopressors (OR, 1.9 [95% CI, 1.42-2.55]; P  < 0.001), and mechanical ventilation (OR, 3.1 [95% CI, 2.29-4.18]; P  < 0.001) were independently associated with 90-day mortality. In patients requiring mechanical ventilation, mortality rates ranged from 39% (no other risk factors for mortality) to 100% (four associated risk factors for mortality). Conclusions: Most critically ill Allo-HSCT recipients survive their ICU stays, including those requiring mechanical ventilation, with an overall 90-day survival rate reaching 51.8%. A careful assessment of goals of care is required in patients with two or more risk factors for mortality.

Background: Compulsive- and anxiety-like behaviour can be efficiently modelled in SAPAP3 knockout (KO) mice, a preclinical model of relevance to obsessive-compulsive disorder (OCD). Although there is emerging evidence in the clinical literature of gastrointestinal dysfunction in OCD, no previous studies have investigated gut function in preclinical models of relevance to OCD. Similarly, the effects of voluntary exercise (EX) or environmental enrichment (EE) have not yet been explored in this context., Method: We comprehensively phenotyped the SAPAP3 KO mouse model, including the assessment of grooming microstructure, anxiety- and depressive-like behaviour, and gastrointestinal function. Mice were exposed to either standard housing (SH), exercise (EX, provided by giving mice access to running wheels), or environmental enrichment (EE) for 4 weeks to investigate the effects of enriched housing conditions in this animal model relevant to OCD., Findings: Our study is the first to assess grooming microstructure, perseverative locomotor activity, and gastrointestinal function in SAPAP3 KO mice. We are also the first to report a sexually dimorphic effect of grooming in young-adult SAPAP3 KO mice; along with changes to grooming patterning and indicators of gut dysfunction, which occurred in the absence of gut dysbiosis in this model. Overall, we found no beneficial effects of voluntary exercise or environmental enrichment interventions in this mouse model; and unexpectedly, we revealed a deleterious effect of wheel-running exercise on grooming behaviour. We suspect that the detrimental effects of experimental housing in our study may be indicative of off-target effects of stress-a conclusion that warrants further investigation into the effects of chronic stress in this preclinical model of compulsive behaviour., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

PET/CT is an imaging modality that is increasingly being used to diagnose large-vessel vasculitis. In the case of giant cell arteritis, it was first used to demonstrate inflammation of the walls of large arterial trunks such as the aorta and its main branches, showing that aortic involvement is common in this vasculitis and associated with the occurrence of aortic complications such as aneurysms. More recently, with the advent of digital PET/CT, study of the cranial arteries (i.e., temporal, occipital, maxillary and vertebral arteries) has become possible, further increasing the diagnostic interest of this examination for the diagnosis of GCA. Despite these advantages, there are still limitations and questions regarding the use of PET/CT for the diagnosis and especially the follow-up of GCA. The aim of this review is to take stock of currently available data on the use of PET/CT for GCA diagnosis and follow-up., Competing Interests: MS was employed by the AbbVie consulting, Argenx consulting, Boehringer Ingelheim consulting, GSK consulting, Novartis consulting and research grant, Roche–Chugai consulting, CSL VIFOR consulting, Fresenius consulting. BB was employed by the Roche–Chugai personal fees for consulting, Boehringer Ingelheim consulting. AR was employed by the Novartis research grant, Novartis consulting, AbbVie consulting, Boehringer Ingelheim consulting, Chugai consulting. HD declare Grants from GSK, Consultant for NOVARTIS, Consultant for GSK, Consultant for Jonhson & Jonhson. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Thibault, Alberini, Billet, Greigert, Ramon, Devilliers, Cochet, Bonnotte and Samson.)

Purpose: To develop a new method for free-breathing 3D extracellular volume (ECV) mapping of the whole heart at 3 T., Methods: A free-breathing 3D cardiac ECV mapping method was developed at 3 T. T 1 mapping was performed before and after contrast agent injection using a free-breathing electrocardiogram-gated inversion recovery sequence with spoiled gradient echo readout. A linear tangent space alignment model-based method was used to reconstruct high-frame-rate dynamic images from (k,t)-space data sparsely sampled along a random stack-of-stars trajectory. Joint T 1 and transmit B 1 estimation were performed voxel-by-voxel for pre- and post-contrast T 1 mapping. To account for the time-varying T 1 after contrast agent injection, a linearly time-varying T 1 model was introduced for post-contrast T 1 mapping. ECV maps were generated by aligning pre- and post-contrast T 1 maps through affine transformation., Results: The feasibility of the proposed method was demonstrated using in vivo studies with six healthy volunteers at 3 T. We obtained 3D ECV maps at a spatial resolution of 1.9 × 1.9 × 4.5 mm 3 and a FOV of 308 × 308 × 144 mm 3 , with a scan time of 10.1 ± 1.4 and 10.6 ± 1.6 min before and after contrast agent injection, respectively. The ECV maps and the pre- and post-contrast T 1 maps obtained by the proposed method were in good agreement with the 2D MOLLI method both qualitatively and quantitatively., Conclusion: The proposed method allows for free-breathing 3D ECV mapping of the whole heart within a practically feasible imaging time. The estimated ECV values from the proposed method were comparable to those from the existing method., (© 2024 International Society for Magnetic Resonance in Medicine.)

Objective: This study aims to assess the surgical outcome of borderline hypoplastic left ventricle before and after the induction of the left ventricle rehabilitation strategy., Methods: A retrospective review investigated patients with borderline hypoplastic left ventricle who underwent surgical intervention between 2012 and 2022. The patient cohort was stratified into two groups based on the initiation of left ventricle rehabilitation: an early-era group (E group, 2012-2017) and a late-era group (L group, 2018-2022). Left ventricle rehabilitation was defined as palliation combined with other procedures aimed at promoting left ventricular growth such as restriction of atrial septal defect, relief of inflow/outflow obstructive lesions, and resection of endocardial fibroelastosis., Results: A total of 58 patients were included. Primary diagnosis included 12 hypoplastic left heart syndromes, 11 critical aortic valve stenosis, and others. A total of 9 patients underwent left ventricle rehabilitation, 8 of whom underwent restriction of atrial septal defect. As for clinical outcomes, 9 of 23 patients achieved biventricular repair in the E group, whereas in the L group, 27 of 35 patients achieved biventricular repair (39% vs. 77%, p = 0.004). Mortality did not differ statistically between the two groups (log-rank test p = 0.182). As for the changes after left ventricle rehabilitation, left ventricular growth was observed in 8 of 9 patients. The left ventricular end-diastolic volume index (from 11.4 to 30.1 ml/m 2 , p = 0.017) and left ventricular apex-to-right ventricular apex ratio (from 86 to 106 %, p = 0.014) significantly increased after left ventricle rehabilitation., Conclusions: The introduction of the left ventricle rehabilitation strategy resulted in an increased proportion of patients achieving biventricular repair without a concomitant increase in mortality. Left ventricle rehabilitation was associated with enhanced left ventricular growth and the formation of a well-defined left ventricle apex. Our study underscores the significance of left ventricle rehabilitation strategies facilitating successful biventricular repair. The data suggest establishing restrictive atrial communication may be a key factor in promoting left ventricular growth.

Peptide-based hydrogels are of interest to biomedical applications. Herein, we have explored the introduction of fluorinated amino acids in hydrogelator H-FQFQFK-NH 2 ( P1 ) to design a series of fluorinated peptide hydrogels and evaluate the in vitro and in vivo properties of the most promising analogues. The impact of fluorinated groups on peptide gelation, secondary structure, and self-assembly processes was assessed. We show that fluorine can significantly improve hydrogel stiffness, compared to the nonfluorinated reference P1 . For P15 (H-FQFQF( o -CF 3 )K-NH 2 ), P18 (H-FQFQF(F 5 )K-NH 2 ), and P19 (H-FQFQM(CF 3 )K-NH 2 ), microscopy studies scrutinized fiber morphologies and alignment in the network. In vitro release studies of hydrogels loaded with an opioid cargo suggested improved hydrogel stability for P15 and P18 . This improved stability was further validated in vivo , notably for P15 , giving the most significant increased gel residence time, with more than 20% of hydrogel still present 9 days post-injection, as monitored by nuclear SPECT-CT imaging.

Background: Aneurysm location is a key element in predicting the rupture risk of an intracranial aneurysm. A common impression suggests that pure ophthalmic aneurysms are under-represented in ruptured intracranial aneurysms (RIAs). The purpose of this study was to specifically evaluate the risk of rupture of ophthalmic aneurysms compared with other aneurysm locations., Methods: This multicenter study compared the frequency of ophthalmic aneurysms in a prospective cohort of RIAs admitted to 13 neuroradiology centers between January 2021 and March 2021, with a retrospective cohort of patients with unruptured intracranial aneurysms (UIAs) who underwent cerebral angiography at the same neuroradiology centers during the same time period., Results: 604 intracranial aneurysms were included in this study (355 UIAs and 249 RIAs; mean age 57 years (IQR 49-65); women 309/486, 64%). Mean aneurysm size was 6.0 mm (5.3 mm for UIAs, 7.0 mm for RIAs; P<0.0001). Aneurysm shape was irregular for 37% UIAs and 73% RIAs (P<0.0001). Ophthalmic aneurysms frequency was 14.9% of UIAs (second most common aneurysm location) and 1.2% of RIAs (second least common aneurysm location; OR 0.07 (95% CI 0.02 to 0.23), P<0.0001)., Conclusions: Ophthalmic aneurysms seem to have a low risk of rupture compared with other intracranial aneurysm locations. This calls for a re-evaluation of the benefit-risk balance when considering preventive treatment for ophthalmic aneurysms., Competing Interests: Competing interests: FC is a consultant for Medtronic, Balt Extrusion, Penumbra, Microvention, and Stryker; board member of Artedrone, and has stock options with Intradys and Collavidence. GM is a consultant for Stryker Neurovascular, Balt, Microvention Europe, and Sim and Cure, and has done paid lectures for Medtronic, Phenox, Johnson & Johnson, and Bracco. KJ is a consultant for Balt. AR is a consultant for Balt, Medtronic, Microvention, and Stryker. N-AS is a consultant for Balt, Medtronic Extrusion, and Microvention., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: α 2 γ 2 ) to adult hemoglobin (HbA: α 2 β 2 ) during development. BCL11A binds at a cognate recognition site (TGACCA) in the γ-globin gene promoter and represses its expression. DNA-binding is mediated by a triple zinc finger domain, designated ZnF456. Here, we report comprehensive investigation of ZnF456, leveraging X-ray crystallography and NMR to determine the structures in both the presence and absence of DNA. We delve into the dynamics and mode of interaction with DNA. Moreover, we discovered that the last zinc finger of BCL11A (ZnF6) plays a different role compared to ZnF4 and 5, providing a positive entropic contribution to DNA binding and γ-globin gene repression. Comprehending the DNA binding mechanism of BCL11A opens avenues for the strategic, structure-based design of novel therapeutics targeting sickle cell disease and β-thalassemia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lens epithelium-derived growth factor p75 (LEDGF/p75), member of the hepatoma-derived growth-factor-related protein (HRP) family, is a transcriptional co-activator and involved in several pathologies including HIV infection and malignancies such as MLL-rearranged leukemia. LEDGF/p75 acts by tethering proteins to the chromatin through its integrase binding domain. This chromatin interaction occurs between the PWWP domain of LEDGF/p75 and nucleosomes carrying a di- or trimethylation mark on histone H3 Lys36 (H3K36me2/3). Our aim is to rationally devise small molecule drugs capable of inhibiting such interaction. To bootstrap this development, we resorted to X-ray crystallography-based fragment screening (FBS-X). Given that the LEDGF PWWP domain crystals were not suitable for FBS-X, we employed crystals of the closely related PWWP domain of paralog HRP-2. As a result, as many as 68 diverse fragment hits were identified, providing a detailed sampling of the H3K36me2/3 pocket pharmacophore. Subsequent structure-guided fragment expansion in three directions yielded multiple compound series binding to the pocket, as verified through X-ray crystallography, nuclear magnetic resonance and differential scanning fluorimetry. Our best compounds have double-digit micromolar affinity and optimally sample the interactions available in the pocket, judging by the K d -based ligand efficiency exceeding 0.5 kcal/mol per non-hydrogen atom. Beyond π-stacking within the aromatic cage of the pocket and hydrogen bonding, the best compounds engage in a σ-hole interaction between a halogen atom and a conserved water buried deep in the pocket. Notably, the binding pocket in LEDGF PWWP is considerably smaller compared to the related PWWP1 domains of NSD2 and NSD3 which feature an additional subpocket and for which nanomolar affinity compounds have been developed recently. The absence of this subpocket in LEDGF PWWP limits the attainable affinity. Additionally, these structural differences in the H3K36me2/3 pocket across the PWWP domain family translate into a distinct selectivity of the compounds we developed. Our top-ranked compounds are interacting with both homologous LEDGF and HRP-2 PWWP domains, yet they showed no affinity for the NSD2 PWWP1 and BRPF2 PWWP domains which belong to other PWWP domain subfamilies. Nevertheless, our developed compound series provide a strong foundation for future drug discovery targeting the LEDGF PWWP domain as they can further be explored through combinatorial chemistry. Given that the affinity of H3K36me2/3 nucleosomes to LEDGF/p75 is driven by interactions within the pocket as well as with the DNA-binding residues, we suggest that future compound development should target the latter region as well. Beyond drug discovery, our compounds can be employed to devise tool compounds to investigate the mechanism of LEDGF/p75 in epigenetic regulation., 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., (Crown Copyright © 2024. Published by Elsevier Masson SAS. All rights reserved.)

Background: The appropriate duration of treatment with beta-blocker drugs after a myocardial infarction is unknown. Data are needed on the safety and efficacy of the interruption of long-term beta-blocker treatment to reduce side effects and improve quality of life in patients with a history of uncomplicated myocardial infarction., Methods: In a multicenter, open label, randomized, noninferiority trial conducted at 49 sites in France, we randomly assigned patients with a history of myocardial infarction, in a 1:1 ratio, to interruption or continuation of beta-blocker treatment. All the patients had a left ventricular ejection fraction of at least 40% while receiving long-term beta-blocker treatment and had no history of a cardiovascular event in the previous 6 months. The primary end point was a composite of death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for cardiovascular reasons at the longest follow-up (minimum, 1 year), according to an analysis of noninferiority (defined as a between-group difference of <3 percentage points for the upper boundary of the two-sided 95% confidence interval). The main secondary end point was the change in quality of life as measured by the European Quality of Life-5 Dimensions questionnaire., Results: A total of 3698 patients underwent randomization: 1846 to the interruption group and 1852 to the continuation group. The median time between the last myocardial infarction and randomization was 2.9 years (interquartile range, 1.2 to 6.4), and the median follow-up was 3.0 years (interquartile range, 2.0 to 4.0). A primary-outcome event occurred in 432 of 1812 patients (23.8%) in the interruption group and in 384 of 1821 patients (21.1%) in the continuation group (risk difference, 2.8 percentage points; 95% confidence interval [CI], <0.1 to 5.5), for a hazard ratio of 1.16 (95% CI, 1.01 to 1.33; P = 0.44 for noninferiority). Beta-blocker interruption did not seem to improve the patients' quality of life., Conclusions: In patients with a history of myocardial infarction, interruption of long-term beta-blocker treatment was not found to be noninferior to a strategy of beta-blocker continuation. (Funded by the French Ministry of Health and ACTION Study Group; ABYSS ClinicalTrials.gov number, NCT03498066; EudraCT number, 2017-003903-23.)., (Copyright © 2024 Massachusetts Medical Society.)

Objective: To clarify the association of the aortopulmonary collaterals (APCs)/venovenous collateral (VVCs) in patients with plastic bronchitis (PB) after the Fontan procedure., Methods: All patients who underwent total cavopulmonary connection from 1994 to 2022 were reviewed. APCs/VVCs were detected using angiography. The impact of APC/VVCs, as well as other variables on the onset of plastic bronchitis, was evaluated., Results: A total of 635 patients were included. Plastic bronchitis was observed in 15 (2.4%) patients, and the median duration between total cavopulmonary connection and the onset of plastic bronchitis was 1.1 years. Freedom from PB at 5 and 10 years was 97.5% and 96.5%, respectively. As for the association of PB and APCs/VVCs, patients with PB had an increased incidence of post-total cavopulmonary connection APCs (60% vs 14%, P < .001) and VVCs (53% vs 14%, P < .001). Freedom from PB was the lowest in the patients who were associated with both APCs and VVCs after total cavopulmonary connection. APCs after total cavopulmonary connection (P = .002; hazard ratio, 5.729), VVCs after total cavopulmonary connection (P = .016; hazard ratio, 3.527), and chylothorax (P = .019; hazard ratio, 3.662) were identified as independently associated factors with the onset of PB., Conclusions: The occurrence of post-Fontan APCs and VVCs was significantly associated with the development of PB. Treatment or mitigation of collaterals may represent an opportunity to prevent the development of PB, a remaining source of post-Fontan excess morbidity and mortality., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Colloidal semiconductor nanoplatelets (NPLs) have emerged as a new class of nanomaterials that can exhibit substantially distinct optical properties compared to those of isotropic quantum dots, which makes them prime candidates for new-generation optoelectronic devices. Insights into the structure and anisotropic growth of NPLs can offer a blueprint for their controlled fabrication. Here, we present an atomic-level investigation of the organic-inorganic interface structure in ultrathin and stable benzamidine ( bza )-supported ZnO NPLs prepared by the modified o ne-pot s elf- s upporting o rgano m etallic approach. High-resolution transmission electron microscopy analysis showed a well-faceted hexagonal shape of ZnO NPLs with lateral surfaces terminated by nonpolar (101̅0) facets. The basal surfaces are flat and well-formed on one side and corrugated on the other side, which indicates that the layer-by-layer growth in the thickness of the NPLs likely occurs only in one direction via the expansion of 2D islands on the surface. The ligand coordination modes were elucidated using state-of-the-art dynamic nuclear polarization (DNP)-enhanced solid-state NMR spectroscopy supported by density functional theory chemical shift calculations. Specifically, it was found that (101̅0) nonpolar facets are stabilized by neutral L-type bza -H ligands with hydrogen bond-supported η1-coordination mode, while polar (0001) and (0001̅) facets are covered by μ 2 -coordinated X-type anionic bza ligands with different conformations of aromatic rings. Moreover, the ligand packing on (101̅0) lateral facets was determined using 13 C natural abundance (∼1.1%) homonuclear dipolar correlation experiments. Overall, an in-depth understanding of the growth mechanism and the unique bimodal X-type/L-type ligand coordination shell of ZnO NPLs is provided, which will facilitate further design of anisotropic nano-objects.

Background and Aims: Cardiac resynchronization therapy (CRT) via biventricular (BIV) pacing is indicated in patients with heart failure (HF), reduced ejection fraction and prolonged QRS duration. Quadripolar leads and MultiPoint Pacing (MPP) allow multiple left ventricle (LV) sites pacing. We aimed to assess clinical benefit of MPP in patients who do not respond to standard BIV pacing., Methods: Overall 3724 patients were treated with standard BIV pacing. After 6 months, 1639 patients were considered as CRT non-responders (echo-measured relative reduction in LV end-systolic volume (LVESV) < 15%) and randomized to MPP or BIV., Results: We analysed 593 randomized patients (291 MPP, 302 BIV), who had BIV pacing >97% of time before randomization and complete 12-months clinical and echocardiographic data. The endpoint, composed by freedom from cardiac death and HF hospitalizations, and by LVESV relative reduction ≥15% between randomization and 12 months, occurred more frequently in MPP (96/291 (33.0%)) vs. BIV (71/302 (23.5%), p = 0.0103), also confirmed at multivariate analysis (hazard ratio = 1.55, 95% confidence interval = 1.02-2.34, p = 0.0402 vs. BIV). HF hospitalizations occurred less frequently in MPP (14/291 (4.81%)) vs. BIV (29/302 (9.60%), incidence rate ratio = 50%, p = 0.0245). Selecting patients with large (>30 ms) dispersion of interventricular electrical delay among the 4 LV lead dipoles, reverse remodeling was more frequent in MPP (18/51 (35.3%)) vs. BIV (11/62 (17.7%), p = 0.0335)., Conclusion: In patients who do not respond to standard CRT, despite high BIV pacing percentage, MPP is associated with lower occurrence of HF hospitalizations and higher probability of reverse LV remodeling, compared with BIV pacing., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: We aimed to compare the pulmonary artery (PA) growth between infants with univentricular hearts who underwent a ductus stenting (DS) and those who received a systemic to pulmonary shunt (SPS) as an initial palliation., Methods: All infants with ductal-dependent pulmonary blood flow who underwent initial palliation with either a DS or SPS between 2009 and 2022 in our institution were reviewed. PA development was compared between the groups using the PA index and the symmetry index., Results: A total of 130 patients were evaluated including 49 patients after DS and 81 after SPS. The most frequent primary diagnosis was tricuspid atresia in 27, followed by pulmonary atresia with intact ventricular septum in 19. At stage II palliation, PA index (P = .926), right PA index (P = .692), left PA index (P = .297), and the symmetry index (P = .650) were similar between the groups. At stage III Fontan completion, PA index (P = .115), right PA index (P = .868), and the symmetry index (P = .144) were similar between the groups. However, left PA index (60 vs 74 mm 2 /m 2 ; P = .015) was lower, and the incidence of venovenous collaterals (24.2% vs 7.8%; P = .036) was higher in the DS group compared with the SPS group. Freedom from PA interventions between stage II and III palliation was lower in the DS group compared with the SPS group (P = .009)., Conclusions: In infants with univentricular heart after DS, freedom from PA interventions after stage II was lower and the left PA index was smaller, compared with those after SPS. Long-term outcomes after the Fontan procedure should be addressed in patients after DS., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Diverting ileostomy (DS) after restorative proctocolectomy (RPC) can be omitted in selected patients. Its omission could improve functional outcomes and quality of life (QoL), as has been demonstrated in patients after proctectomy. The aim of this study was to report the impact of diverting ileostomy on functional outcomes and QoL after ileal pouch-anal anastomosis (IPAA)., Methods: This was a retrospective study including all patients operated (2015-2020) for RPC with IPAA. Functional outcome was evaluated by validated scores (LARS, Wexner, Öresland, pouch functional score [PFS] and the ileoanal pouch syndrome severity [IPSS] score). Global health-related QoL was evaluated with the SF-36. We also analysed demographic characteristics, morbidity, correlation between functional outcomes and QoL., Results: Among 179 eligible patients, 150 responded (84%): S- (no stoma = 78; 52%) and S+ (had stoma = 72; 48%). Overall morbidity and anastomotic leak rates were 46% and 9.3%, respectively without difference between the groups. Medians for the functional scores were comparable between the S- and S+ group, respectively: 18 [12.5-31] versus 18 [11-31], p = 0.48 for LARS; 9 [7-11] versus 9 [7-12], p = 0.23 for Wexner's score; 6 [3-13] versus 8 [5-11], p = 0.22 for Öresland's score, 6 [3-13] versus 6.8 [4-12], p = 0.174 for PFS score, and 40 [35-45] versus 46 [42-51], p = 0.045 for IPSS score. The SF-36 summary score was comparable between the two groups without any difference in eight specific health dimensions. After propensity score matching, results were still comparable between the two groups for all scores. Linear regression found a significant correlation between all QoL domains and all functional scores (p < 0.001)., Conclusion: DS for IPAA does not alter either functional outcomes or QoL and can be omitted in selected patients., (© 2024 The Author(s). Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Background: Failing Fontan poses a significant clinical challenge. This study aims to improve patients' outcomes by comprehensively understanding the incidence, pathophysiology, risk factors, and treatment of failing Fontan after total cavopulmonary connection., Methods: We performed a retrospective analysis of patients who underwent total cavopulmonary connection at the German Heart Center Munich between 1994 and 2022. The onset of failing Fontan was defined as: protein-losing enteropathy, plastic bronchitis, NYHA class IV, NYHA class III for > one year, unscheduled hospital admissions for heart failure symptoms, and evaluation for heart transplantation., Results: Among 634 patients, 76 patients presented with failing Fontan, and the incidence was 1.48 per 100 patient-years. Manifestations included protein-losing enteropathy (n = 34), hospital readmission (n = 28), NYHA III (n = 18), plastic bronchitis (n = 16), evaluation for heart transplantation (n = 14), and NYHA IV (n = 4). Risk factors for the onset of failing Fontan were dominant right ventricle (p = 0.010) and higher pulmonary artery pressure before total cavopulmonary connection (p = 0.004). A total of 72 interventions were performed in 59 patients, including balloon dilatation/stent implantation in the total cavopulmonary connection pathway (n = 49) and embolization of collaterals (n = 24). Heart transplantation was performed in four patients. The survival after the onset of Fontan failure was 77% at 10 years. Patients with failing Fontan revealed significantly higher zlog-NT-proBNP levels after onset compared to those without (p = 0.021)., Conclusions: The incidence of Fontan failure was 1.5 per 100 patient years. Dominant right ventricle and higher pulmonary artery pressure before total cavopulmonary connection were significant risks for the onset of failing Fontan. Zlog-NT-proBNP is only a late marker of Fontan failure.

The subgenus Tillandsia (Bromeliaceae) belongs to one of the fastest radiating clades in the plant kingdom and is characterized by the repeated evolution of Crassulacean acid metabolism (CAM). Despite its complex genetic basis, this water-conserving trait has evolved independently across many plant families and is regarded as a key innovation trait and driver of ecological diversification in Bromeliaceae. By producing high-quality genome assemblies of a Tillandsia species pair displaying divergent photosynthetic phenotypes, and combining genome-wide investigations of synteny, transposable element (TE) dynamics, sequence evolution, gene family evolution, and temporal differential expression, we were able to pinpoint the genomic drivers of CAM evolution in Tillandsia. Several large-scale rearrangements associated with karyotype changes between the 2 genomes and a highly dynamic TE landscape shaped the genomes of Tillandsia. However, our analyses show that rewiring of photosynthetic metabolism is mainly obtained through regulatory evolution rather than coding sequence evolution, as CAM-related genes are differentially expressed across a 24-h cycle between the 2 species but are not candidates of positive selection. Gene orthology analyses reveal that CAM-related gene families manifesting differential expression underwent accelerated gene family expansion in the constitutive CAM species, further supporting the view of gene family evolution as a driver of CAM evolution., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Embodied cognition asserts a symbiotic relationship between cognitive processes and the physical body, raising an intriguing question: could personality traits be intertwined with the biomechanical performance of the lower limb? This study aimed to explore this connection by examining how personality traits, assessed using the Myers-Briggs Type Indicator (MBTI), relate to lower limb rebound power (RP) measured through the five-repetition rebound jump test. Eighty participants completed two sessions: a biomechanical analysis of hopping using an Optojump® system to measure contact time, flight time, and RP, and a personality traits assessment categorizing traits across four MBTI axes: extraversion-introversion (favorite world); sensing-intuition (information processing preference); thinking-feeling (decision making); and judging-perceiving (structure). Participant characteristics did not significantly differ across MBTI axes (p≥0.07), minimizing potential confounding factors. Notably, individuals classified as intuitive showed significantly longer flight times (p = 0.02) and larger RP (p = 0.007) compared to sensing individuals, suggesting a greater reliance on the fast stretch-shortening cycle and showcasing superior use of their lower limb structures as springs. This suggests potential implications for sports performance, with intuition individuals possibly excelling in plyometric sports. However, no significant associations were found between biomechanical performance and the other three MBTI axes (p≥0.12), challenging the initial hypothesis. This research provides initial insights into the nuanced relationship between personality traits and movement patterns, indicating the potential for tailored physical interventions to enhance adherence and optimize responses in training programs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gindre et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

MANAGING MEDULLARY THYROID CARCINOMA IN 2024: Medullary thyroid carcinoma is a rare neuroendocrine thyroid cancer with a heterogeneous prognosis which has the particularity of being associated with a RET gene mutation, germline in 20-25% of cases in the context of multiple endocrine neoplasia type 2 (NEM2), and somatic in 70% of sporadic cases. It is often diagnosed on a thyroid nodule or in the context of genetic screening. Calcitonin is a biological marker, used for diagnosis, monitoring of therapeutic response and prognostic evaluation. The only curative treatment is surgery for localized disease. The extent must be carefully assessed, particularly in terms of calcitonin levels and imaging, and carried out by an expert surgeon. The prognosis of locally advanced or metastatic disease is highly heterogeneous. Histological factors, such as high grade, or biological factors, such as calcitonin doubling time, can help assess prognosis. The development of multi-kinase inhibitors cabonzantinib and vandetanib, and RET-targeted inhibitors selpercatinib, has completely changed the therapeutic arsenal for advanced disease, but their prescription is reserved to progressive disease with high tumor volume or to symptomatic disease inaccessible to local treatment in expert centers from the ENDOCAN-TUTHYREF network. Active surveillance is the alternative of choice for slowly progressing disease., Competing Interests: Liens d’intérêts H. Lasolle, F. Borson-Chazot, T. Gauduchon, M. Haissaguerre, F. Illouz, J.-C. Lifante, C. Lussey-Lepoutre, D. Prunier, C. Sajous et R. Varnier déclarent ne pas avoir de liens d’intérêts. J. Hadoux déclare avoir des liens d’intérêts pour grants/research support de la part du laboratoire Lilly; pour des honoraires versés par les laboratoires Lilly, Ipsen, Bayer, PharmaMAr, Roche, HRA pharma, AAA et Eisai. Cet article fait partie du supplément Prise en charge des cancers thyroïdiens en 2024 : avancées diagnostiques et thérapeutiques réalisé avec le soutien institutionnel de Lilly., (Copyright © 2024 Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.)

Importance: Neurodevelopmental outcomes of very preterm children exposed to tocolytics are not well described., Objective: To investigate whether tocolysis administered after spontaneous preterm labor is associated with neurodevelopmental outcomes at 5.5 years and to assess whether the type of tocolytic drug is associated with neurodevelopmental outcomes among infants exposed., Design, Setting, and Participants: This prospective, national, population-based cohort study used data from the French Etude Épidémiologique sur les Petits Âges Gestationnels-2 cohort. Children who were alive and participated in an assessment at 5.5 years and whose mothers experienced spontaneous preterm labor without an infectious context and delivered at 24 to 31 weeks were eligible for this study. Recruitment occurred from March to December 2011. Follow-up at age 5.5 years was conducted from September 2016 to December 2017. Data analysis was performed from July 2023 through April 2024., Exposures: The primary analysis examined tocolytics (yes vs no), and the secondary analysis examined the type of tocolytic (atosiban vs calcium channel blockers [CCBs])., Main Outcome and Measure: The composite outcome neurodevelopmental disabilities included cerebral palsy; visual, hearing, and cognitive deficiencies; developmental coordination disorders; or behavioral problems., Results: A total of 1055 mothers (mean [SD] age, 29.2 [5.7] years) had preterm labor without fever and gave birth to 1320 children (704 male [weighted percentage, 53.3%; 95% CI, 50.6%-56.1%]; mean [SD] gestational age, 28.8 [2.0] weeks). Overall, 776 mothers (weighted percentage, 73.5%; 95% CI, 70.8%-76.2%) received tocolytics; 136 mothers (weighted percentage, 17.9%; 95% CI, 15.3%-20.8%) received only a CCB, and 295 mothers (weighted percentage, 37.6%; 95% CI, 34.2%-41.0%) received only atosiban. From modified Poisson regression with propensity score matching, the risk of overall neurodevelopmental disabilities (mild, moderate, or severe) at 5.5 years did not differ between preterm children exposed and not exposed to tocolytics (relative risk [RR], 1.11; 95% CI, 0.85-1.45; P = .44) or in preterm infants exposed to atosiban compared with those exposed to CCBs (RR, 0.94; 95% CI, 0.67-1.32; P = .71)., Conclusions and Relevance: In this study, tocolytics were not associated with neurodevelopmental disabilities among very preterm children surviving at 5.5 years.

Sunscreens are mainly characterized by their sun-protection factor (SPF), which is measured according to the in vivo gold standard ISO 24444. Although the SPF concept is simple, SPF values are difficult to measure, due to the rather high variability caused by the complex interaction of light and skin. For half a century, there have been attempts to correlate the costly and ethically controversial in vivo procedure with a non-invasive (in vitro) method. After decades of development, alternative non-invasive SPF methods are expected to become available as ISO standards in early 2025. In particular, sunscreen manufacturers who use zinc oxide (ZnO) in higher concentrations (conc.) (10-25%) in their formulations, are concerned that these new in vitro methods would not confirm the SPF-values on their labels that have been determined in vivo, according to ISO 24444. This brief review reveals that sunscreen formulations with high conc. of ZnO often yield SPF in vitro values that are lower than the SPF in vivo values. This can be explained by the fact that in vitro methods have been developed for conventional emulsions products with organic UV filters, but not for highly concentrated ZnO-alone sunscreens. Fortunately, there seems to be a fix for this problem. There is a difference in density between ordinary emulsions with organic filters (density of the residual oil phase ~ 1.0 g/ml) and highly concentrated ZnO-alone formulations (~ 1.3-1.7 g/ml). As the application of current standards is weight-based, this makes the film on the PMMA plate much thinner, which is likely to lead to lower SPF in vitro values. Preliminary experiments show that using the same volume on the PMMA plates instead of the same weight as organic UV filters gives a much better correlation between in vitro and in vivo SPF results. A recent evaluation of three samples of highly concentrated ZnO sunscreens by the Dutch NVWA seems to confirm these findings. Further experimental evidence is required to fully understand this phenomenon and to adapt the in vitro method for higher conc. ZnO formulations accordingly., (© 2024. The Author(s).)

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacts multiple anatomical sites. Whether this is due to the virus itself or is a secondary effect caused by the influx and activation of immune cells is not known. Positron emission tomography (PET) with immunoglobulins can provide insights into which sites and cells are activated in a living animal. Our aim is to use two nanobodies as tools to monitor (1) the distribution of antigen presenting cells (APC) by virtue of their Mafa-DR expression profile, (2) virus-infected cells and viral particles using a nanobody against the SARS-CoV-2 spike protein. Two [ 89 Zr]-labeled nanobodies that target the SARS-CoV-2 spike protein and major histocompatability complex (MHC) class II antigens (Mafa-DR), respectively, are used to monitor their distribution during an experimental SARS-CoV-2 infection in a nonhuman primate model. Scans are obtained before infection and on Day 3 and 10 post infection (pi) in two macaques each. The [ 89 Zr]anti-SARS-CoV-2 spike nanobody localized to SARS-CoV-2-associated lung lesions and the nasal mucosa, while the [ 89 Zr]anti-human leukocyte antigen (HLA)-DR nanobody was predominantly found in non-affected lung tissue after infection. We also detected, pi, upregulation of the Mafa-DR signal, indicative of recruitment of professional APCs, in the superior sagittal sinus. [ 89 Zr]-labeled nanobodies show recruitment of macrophages/monocytes in non-lesional lung tissue in cynomolgus macaques after experimental infection with SARS-CoV-2, as well as accumulation of the spike protein in both lung lesions and the nasal mucosa during infection. These results show the possibility of in vivo monitoring the quality and quantity of immune responses during the initial stages of an infection., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Premise: Cladoxylopsids, one of the first lineages with complex organization to rise from the plexus of structurally simple plants that comprised the earliest euphyllophyte floras, are moniliformopsid euphyllophytes. They formed Earth's earliest forests by the Middle Devonian and are thought to have given rise to the equisetopsids and probably some fern lineages. The Lower Devonian (Emsian) Battery Point Formation (Quebec, Canada) contains previously unrecognized cladoxylopsids preserved anatomically. One of these provides new data on structural evolution among euphyllophytes and is described here., Methods: The anatomy and morphology of permineralized axes of the new plant were studied with light and electron microscopy on sections produced using the cellulose acetate peel technique. Morphological comparisons and phylogenetic analysis were used for taxonomic placement of the plant., Results: The plant represents a new species, Paracladoxylon kespekianum Chu et Tomescu, gen. et sp. nov., that has tracheids with modern-looking bordered pits and the complex cauline vascular architecture characteristic of the genus Cladoxylon. Its dissected ultimate appendages have complex regular taxis and a pattern of vascularization that suggests bilateral symmetry., Conclusions: Paracladoxylon kespekianum is one of the largest Early Devonian euphyllophytes, among the oldest representatives of the cladoxylopsid group, and older than any species of the closely related Cladoxylon by at least 35 million years. It is also one of the oldest anatomically preserved representatives of the cladoxylopsid group. Its anatomical organization pushes the rise of complex vascular architecture among moniliformopsid euphyllophytes deeper in time than previously recognized., (© 2024 Botanical Society of America.)

HLA-C*07:01:126 differs from HLA-C*07:01:01:01 by one nucleotide substitution in codon 328 in exon 7., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-A*24:02:169 differs from HLA-A*24:02:01:01 by one nucleotide substitution in codon -23 in exon 1., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-C*01:262 differs from HLA-C*01:02:01:01 by one nucleotide substitution in codon 150 in exon 3., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In 2021, the EAU Guidelines implemented a novel, expert opinion-based follow-up scheme, with a three-risk-category system for clear cell (cc) and non-cc renal cell carcinoma (non-ccRCC) after surgery with curative intent. We aimed to validate the novel follow-up scheme and provide data-driven recurrence estimates according to risk groups, to confirm or implement the oncologic surveillance strategy., Methods: We identified 5,320 patients from a prospectively maintained database involving 28 French referral centers. The risk of recurrence, as either loco-regional or distant, was evaluated with the Kaplan-Meier method for each group (low- intermediate- or high-risk) according to ccRCC or non-ccRCC histology. The noncumulative distribution of recurrences was graphically investigated through the LOWESS smoother., Results: Two thousand two hundred ninety-three (58%), 926 (23%), and 738 (19%) had low-, intermediate, and high-risk ccRCC, and 683 (50%), 297 (22%), and 383 (28%) had low-, intermediate, and high-risk non-ccRCC, respectively. Median follow-up for survivors was 46 months. Overall, 661 patients experienced recurrence. Over time, the noncumulative risk of recurrence was approximately 10% for low-risk cc-RCC, non-ccRCC, and intermediate-risk non-ccRCC, with non-significant difference among the three recurrence functions (P=0.9). At 5-year, time point after which imaging should be de-intensified to biennial, the noncumulative risks of recurrence were: for intermediate risk ccRCC and non-ccRCC: 15% and 11%, respectively; for high-risk ccRCC and non-ccRCC: 24% and 8%, respectively. Among high-risk non-ccRCC patients there were 9 recurrences at 3-month. There was no significant difference between the recurrence function of high-risk non-ccRCC patients with negative imaging at 3-month and the one of intermediate-risk ccRCC (P=0.3)., Conclusions: Given the relatively low recurrence risk of patients with intermediate-risk non-ccRCC, those individuals could be followed up with a similar strategy to the low-risk category. Similarly, patients with high-risk non-ccRCC with negative imaging at 3-month, could be followed up similarly to intermediate-risk ccRCC after the 3-month time point.

Even the most stringent environmental law cannot protect a river if its tributaries remain exposed to pollution and other threats upstream. Excluding a subset of watercourses from legal protection therefore threatens to alter freshwater ecosystems across entire river networks and the services they provide, such as drinking water and flood regulation. Considerable attention has been devoted to defining the scope of environmental laws protecting watercourses. Yet how these definitions are implemented through regulatory mapping, the cartography of waterbodies that legally qualify as watercourses and are thus protected, has not been examined outside of the United States. Here, we demonstrate the consequences of regulatory mapping on the extent of river networks that are protected, using France as a case study. By assembling the first map of France's watercourses protected under the Water Law, we estimate that a quarter of previously mapped hydrographic segments were excluded from protection and found stark geographical variations in the extent of protected ecosystems. Headwater and nonperennial segments are disproportionately excluded by 28% compared to their prevalence (67%) in the overall hydrographic network, with potentially far-reaching implications for biodiversity and people. We expect regulatory frameworks in most countries to be equally susceptible to local interpretation of legal definitions.

Background: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Nirsevimab, an RSV-neutralising monoclonal antibody, was approved for use in the EU in 2022, and a national immunisation campaign began in France in September, 2023. We aimed to assess the effectiveness of nirsevimab in reducing paediatric emergency department visits (and subsequent hospitalisations) for all-cause bronchiolitis and RSV-associated bronchiolitis., Methods: In this case-control study in a paediatric emergency department in Paris, France, we included all infants aged 12 months or younger who attended the department between Oct 14, 2023, and Feb 29, 2024, and whose nirsevimab status was known. Infants were classed as cases if they had all-cause bronchiolitis; all other infants were classed as controls. The primary outcome was the effectiveness of nirsevimab against paediatric emergency department visits for all-cause bronchiolitis during the 2023-24 RSV season. Secondary outcomes were paediatric emergency department visits for RSV-associated bronchiolitis; hospitalisations for all-cause bronchiolitis, RSV-associated bronchiolitis, and severe RSV-associated bronchiolitis requiring supplemental oxygen or feeding by nasogastric tube; and severe RSV-associated bronchiolitis requiring admission to the paediatric intensive care unit. Effectiveness estimates were adjusted for age, week of paediatric emergency department visit, and sex., Findings: Our study included 2786 infants, 864 with all-cause bronchiolitis (cases) and 1922 without bronchiolitis (controls). 178 (21%) of the 864 cases had received nirsevimab, and 305 (35%) cases were hospitalised for all-cause bronchiolitis. 200 (72%) of the 277 cases tested for RSV were positive, of whom 22 (11%) had received nirsevimab. 701 (36%) of 1922 infants in the control group had received nirsevimab. The effectiveness of nirsevimab against paediatric emergency department visits for all-cause bronchiolitis was 47% (95% CI 33-58). Nirsevimab effectiveness was 83% (71-90) against paediatric emergency department visits for RSV-associated bronchiolitis, 59% (42-71) against hospitalisations for all-cause bronchiolitis, 83% (72-90) against hospitalisations for RSV-associated bronchiolitis (91% [78-96] against those necessitating supplement oxygen and 88% [74-95] against those necessitating feeding via a nasogastric tube). Nirsevimab did not significantly reduce admissions to the paediatric intensive care unit (67% [95% CI -100 to 95])., Interpretation: During the first French national immunisation campaign, a single dose of nirsevimab effectively reduced paediatric emergency department visits (both all-cause visits and visits related to RSV-associated bronchiolitis) and subsequent hospitalisations., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Hidrocystoma is thought to be a benign retention cyst of sweat ductal units. The lesion is usually located in the periorbital skin; however, lesions with similar histopathological features are rarely observed in extra-facial sites. Herein, we present four cases of hidrocystoma-like tumours in extra-facial skin sites that harboured a RET or ALK rearrangement. This study features a 67-year-old female with a 10 mm-sized digital tumour (Case 1), a 62-year-old male with an 8 mm-sized clavicular tumour (Case 2), a 61-year-old male with a 19 mm-sized digital tumour (Case 3), and an 11-year-old female with a 10 mm-size lower leg tumour (Case 4) as well as five control cases (Cases 5-9) of classical periorbital hidrocystoma. In Cases 1-4, multicystic tumours comprising a two-cell layer of inner cuboidal ductoglandular (p63- and SOX10+/-) and outer flat myoepithelial (p63+ and SOX10+) cells were observed. The inner ductoglandular tumour cells exhibited micropapillary projections and Roman bridging structures. No apparent atypical cells were observed. NCOA4::RET in Cases 1 and 3, CCDC6::RET in Case 2, and SLC12A2::ALK in Case 4 were revealed by next-generation sequencing or Sanger sequencing. In contrast, control cases of classical hidrocystoma (Cases 5-9) did not show intracystic proliferation, abundant cytoplasm, ALK immunoreactivity, or NCOA4::RET detection in the tumour cells. RET/ALK-rearranged hidrocystoma-like tumours are tumour entities that can be distinguished from classical hidrocystoma. This RET/ALK-rearranged neoplasm is benign and is frequently observed in the digits. Future studies will establish the concept, detailed clinicopathological characteristics, and genetic variations of hidrocystoma-like tumours., (Copyright © 2024 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Closely related species often use the same genes to adapt to similar environments. However, we know little about why such genes possess increased adaptive potential and whether this is conserved across deeper evolutionary lineages. Adaptation to climate presents a natural laboratory to test these ideas, as even distantly related species must contend with similar stresses. Here, we re-analyse genomic data from thousands of individuals from 25 plant species as diverged as lodgepole pine and Arabidopsis (~300 Myr). We test for genetic repeatability based on within-species associations between allele frequencies in genes and variation in 21 climate variables. Our results demonstrate significant statistical evidence for genetic repeatability across deep time that is not expected under randomness, identifying a suite of 108 gene families (orthogroups) and gene functions that repeatedly drive local adaptation to climate. This set includes many orthogroups with well-known functions in abiotic stress response. Using gene co-expression networks to quantify pleiotropy, we find that orthogroups with stronger evidence for repeatability exhibit greater network centrality and broader expression across tissues (higher pleiotropy), contrary to the 'cost of complexity' theory. These gene families may be important in helping wild and crop species cope with future climate change, representing important candidates for future study., (© 2024. The Author(s).)

Background: We aimed to determine the epidemiology and outcomes of unplanned extubation (UE), both accidental and self-extubation, in ICU., Methods: A multicentre prospective cohort study was conducted in 47 French ICUs. The number of mechanical ventilation (MV) days, and planned and unplanned extubation were recorded in each center over a minimum period of three consecutive months to evaluate UE incidence. Patient characteristics, UE environmental factors, and outcomes were compared based on the UE mechanism (accidental or self-extubation). Self-extubation outcomes were compared with planned extubation using a propensity-matched population. Finally, risk factors for extubation failure (re-intubation before day 7) were determined following self-extubation., Results: During the 12-month inclusion period, we found a pooled UE incidence of 1.0 per 100 MV days. UE accounted for 9% of all endotracheal removals. Of the 605 UE, 88% were self-extubation and 12% were accidental-extubations. The latter had a worse prognosis than self-extubation (34% vs. 8% ICU-mortality, p < 0.001). Self-extubation did not increase mortality compared with planned extubation (8% vs. 11%, p = 0.075). Regardless of the type of extubation, planned or unplanned, extubation failure was independently associated with a poor outcome. Cancer, higher respiratory rate, lower PaO 2 /FiO 2 at the time of extubation, weaning process not-ongoing, and immediate post-extubation respiratory failure were independent predictors of failed self-extubation., Conclusion: Unplanned extubation, mostly represented by self-extubation, is common in ICU and accounts for 9% of all endotracheal extubations. While accidental extubations are a serious and infrequent adverse event, self-extubation does not increase mortality compared to planned extubation., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

In hospitalized children, height should be measured. When world health organization (WHO) height measurement gold standards is impossible, the ideal height estimation technique is still unclear. We conducted an international prospective study in eight different pediatric intensive care units to assess the accuracy, precision, practicability, safety, and inter-rater reliability of 12 different height estimation techniques, based on body segment measurement extrapolation, or other calculations using previous or projected heights. All extrapolation techniques were performed on each child, and later compared to their WHO gold standard heights. A total of 476 patients were enrolled. In the < 2-year subgroup, board length use and growth chart extrapolation performed best. In the ≥ 2-year subgroup, growth chart extrapolation and parents' report were the most accurate, followed by height measurement alongside the body with a tape measure. In both groups, body segment extrapolations were poorly predictive and showed mean bias and limits of agreement that varied a lot with age. Most body segment-based techniques presented with frequent measurement difficulties, but children's safety was rarely compromised. The inter-rater reliability of body segment measurement was low in the < 2-year subgroup.Conclusions: To accurately estimate height in hospitalized children, health care professionals should integrate the accuracy, precision, practicability, and reliability of each measurement technique to select the most appropriate one. Body segment-based techniques were the least accurate and should probably not be used. Simple techniques like growth chart extrapolation, or measurement alongside the body (and length board measurement in the youngest) should be implemented in daily practice.Trial Registration: The study protocol was registered (12 th April 2019) on the clinical-trial.gov website (NCT03913247)., (© 2024. The Author(s).)

Background and Objective: Prostate multiparametric magnetic resonance imaging (MRI) shows high sensitivity for International Society of Urological Pathology grade group (GG) ≥2 cancers. Many artificial intelligence algorithms have shown promising results in diagnosing clinically significant prostate cancer on MRI. To assess a region-of-interest-based machine-learning algorithm aimed at characterising GG ≥2 prostate cancer on multiparametric MRI., Methods: The lesions targeted at biopsy in the MRI-FIRST dataset were retrospectively delineated and assessed using a previously developed algorithm. The Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2) score assigned prospectively before biopsy and the algorithm score calculated retrospectively in the regions of interest were compared for diagnosing GG ≥2 cancer, using the areas under the curve (AUCs), and sensitivities and specificities calculated with predefined thresholds (PIRADSv2 scores ≥3 and ≥4; algorithm scores yielding 90% sensitivity in the training database). Ten predefined biopsy strategies were assessed retrospectively., Key Findings and Limitations: After excluding 19 patients, we analysed 232 patients imaged on 16 different scanners; 85 had GG ≥2 cancer at biopsy. At patient level, AUCs of the algorithm and PI-RADSv2 were 77% (95% confidence interval [CI]: 70-82) and 80% (CI: 74-85; p = 0.36), respectively. The algorithm's sensitivity and specificity were 86% (CI: 76-93) and 65% (CI: 54-73), respectively. PI-RADSv2 sensitivities and specificities were 95% (CI: 89-100) and 38% (CI: 26-47), and 89% (CI: 79-96) and 47% (CI: 35-57) for thresholds of ≥3 and ≥4, respectively. Using the PI-RADSv2 score to trigger a biopsy would have avoided 26-34% of biopsies while missing 5-11% of GG ≥2 cancers. Combining prostate-specific antigen density, the PI-RADSv2 and algorithm's scores would have avoided 44-47% of biopsies while missing 6-9% of GG ≥2 cancers. Limitations include the retrospective nature of the study and a lack of PI-RADS version 2.1 assessment., Conclusions and Clinical Implications: The algorithm provided robust results in the multicentre multiscanner MRI-FIRST database and could help select patients for biopsy., Patient Summary: An artificial intelligence-based algorithm aimed at diagnosing aggressive cancers on prostate magnetic resonance imaging showed results similar to expert human assessment in a prospectively acquired multicentre test database., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the health status and recovery of women after mid-urethral sling (MUS) revision in response to complications., Design: Cross-sectional study using a questionnaire sent to women from a registry., Setting: Twenty-two French surgical centres., Population: A total of 287 women from the VIGI-MESH registry responded, having undergone MUS revision for complications., Methods: Our sample of women were compared against a representative set of French women taken from the Eurostat database. Multivariate analysis was performed to identify clinical predictors for successful MUS revision. A qualitative analysis was carried out on free-text comments., Main Outcome Measures: Health status, defined by the Minimum European Health Module, and recovery, assessed by Patient Global Impression of Improvement., Results: The response rate was 76% (287/378), with 49% of the women (141/287, 95% CI 43%-55%) reporting good health status, which was 8 points lower than that expected from the comparator French set (57%, 95% CI 55%-58%). Overall, 53% (147/275, 95% CI 47%-59%) of the women reported feeling much better after MUS revision. Just over one-third (35%, 95/275, 95% CI 29%-40%) of respondents reported poor health with little or no improvement. Multivariate analysis showed that being operated on for pain at revision was associated with worse self-perceived health than being operated on for exposure (OR 0.36, 95% CI 0.14-0.95); women with pre-existing comorbidity reported a poorer health status following MUS revision (OR 0.22, 95% CI 0.13-0.38)., Conclusions: Our results suggest that half of the women recovered good health status after MUS revision, whereas a proportion appeared to be seriously affected by an MUS complication despite the revision., (© 2024 John Wiley & Sons Ltd.)

Aims: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2-fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions., Methods and Results: Five patients were male and the median age was 79 years (ranges: 59-95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases., Conclusion: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Objectives: Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies., Methods: Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose., Results: 110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors., Conclusions: This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Purpose: The aim of this study was to develop and train a machine learning (ML) algorithm to create a clinical decision support tool (i.e., ML-driven probability calculator) to be used in clinical practice to estimate recurrence rates following an arthroscopic Bankart repair (ABR)., Methods: Data from 14 previously published studies were collected. Inclusion criteria were (1) patients treated with ABR without remplissage for traumatic anterior shoulder instability and (2) a minimum of 2 years follow-up. Risk factors associated with recurrence were identified using bivariate logistic regression analysis. Subsequently, four ML algorithms were developed and internally validated. The predictive performance was assessed using discrimination, calibration and the Brier score., Results: In total, 5591 patients underwent ABR with a recurrence rate of 15.4% (n = 862). Age <35 years, participation in contact and collision sports, bony Bankart lesions and full-thickness rotator cuff tears increased the risk of recurrence (all p < 0.05). A single shoulder dislocation (compared to multiple dislocations) lowered the risk of recurrence (p < 0.05). Due to the unavailability of certain variables in some patients, a portion of the patient data had to be excluded before pooling the data set to create the algorithm. A total of 797 patients were included providing information on risk factors associated with recurrence. The discrimination (area under the receiver operating curve) ranged between 0.54 and 0.57 for prediction of recurrence., Conclusion: ML was not able to predict the recurrence following ABR with the current available predictors. Despite a global coordinated effort, the heterogeneity of clinical data limited the predictive capabilities of the algorithm, emphasizing the need for standardized data collection methods in future studies., Level of Evidence: Level IV, retrospective cohort study., (© 2024 The Author(s). Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)