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Objectives: To assess laser–tissue interactions through ablation, coagulation, and carbonisation characteristics in a non‐perfused porcine kidney model between three pulsed lasers: holmium (Ho): yttrium‐aluminium‐garnet (YAG), thulium fiber laser (TFL), and pulsed thulium (p‐Tm):YAG. Materials and Methods: A 150‐W Ho:YAG, a 60‐W TFL, and a 100‐W p‐Tm:YAG lasers were compared. The laser settings that can be set identically between the three lasers and be clinically relevant for prostate laser enucleation were identified and used on fresh, unfrozen porcine kidneys. Laser incisions were performed using stripped laser fibers of 365 and 550 μm, set at distances of 0 and 1 mm from the tissue surface at a constant speed of 2 mm/s. Histological analysis evaluated shape, depth, width of the incision, axial coagulation depth, and presence of carbonisation. Results: Incision depths, widths, and coagulation zones were greater with Ho:YAG and p‐Tm:YAG lasers than TFL. Although no carbonisation was found with the Ho:YAG and p‐Tm:YAG lasers, it was common with TFL, especially at high frequencies. The shapes of the incisions and coagulation zones were more regular and homogeneous with the p‐Tm:YAG laser and TFL than with Ho:YAG laser. Regardless of the laser used, short pulse durations resulted in deeper incisions than long pulse durations. Concerning the distance, we found that to be effective, TFL had to be used in contact with the tissue. Finally, 365‐μm fibers resulted in deeper incisions, while 550‐μm fibers led to wider incisions and larger coagulation zones. Conclusion: Histological analysis revealed greater tissue penetration with the p‐Tm:YAG laser compared to the TFL, while remaining less than with Ho:YAG. Its coagulation properties seem interesting insofar as it provides homogeneous coagulation without carbonisation, while incisions remained uniform without tissue laceration. Thus, the p‐Tm:YAG laser appears to be an effective alternative to Ho:YAG and TFL lasers in prostate surgery. [ABSTRACT FROM AUTHOR]

This paper investigates linkage to care following community‐based screening for hepatitis B virus (HBV) in rural Senegal. HBV‐positive participants who completed a biological and clinical examination to assess liver disease and treatment eligibility were referred to a regional hospital (if eligible for treatment), invited to join the Sen‐B research cohort study (adults with detectable viral load) or referred to their local health centre (all others). Logistic regressions were conducted to investigate factors associated with (i) uptake of the scheduled post‐screening examination, and (ii) HBV management initiation. Obstacles to HBV management were identified using thematic analysis of in‐depth patient interviews. Of the 206 HBV‐positive participants, 163 (79.1%) underwent the examination; 47 of the 163 (28.8%) initiated HBV management. Women, people not migrating for >6 months/year, individuals living in households with more agricultural and monetary resources, with other HBV‐positive participants, and beneficiaries of the national cash transfer program, were all more likely to undergo the examination. The likelihood of joining the Sen‐B cohort increased with household monetary resources, but decreased with agricultural resources. Initiation of HBV management in local health centre was higher among participants with a non‐agricultural economic activity. Individuals reported wariness and confusion about HBV management content and rationale at various stages of the care continuum, in particular with respect to venous blood sampling and management without treatment. In conclusion, HBV community‐based test‐and‐treat strategies are feasible, but early loss to follow‐up must be addressed through simplified, affordable management and community support and sensitization. [ABSTRACT FROM AUTHOR]

Nutrient availability is a key determinant of tumor cell behavior. While nutrient‐rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non‐derepressible 2 (GCN2; also known as eIF‐2‐alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53‐mediated apoptosis in patient‐derived models of colon adenocarcinoma (COAD). In nutrient‐rich conditions, a cell‐autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl‐tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2–MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first‐line chemotherapy oxaliplatin, on patient‐derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co‐inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically stressed COAD cells. [ABSTRACT FROM AUTHOR]

Tick‐borne encephalitis (TBE) virus is the most prevalent tick‐transmitted orthoflavivirus in Europe. Due to the nonspecific nature of its symptoms, TBE is primarily diagnosed by ELISA‐based detection of specific antibodies in the patient serum. However, cross‐reactivity between orthoflaviviruses complicates the diagnosis. Specificity issues may be mitigated by serum neutralization assays (SNT), although the handling of clinically relevant orthoflaviviruses requires biosafety level (BSL) 3 conditions and they have highly divergent viral kinetics and cell tropisms. In the present study, we established a reporter virus particle (RVP)‐based SNT in which the infectivity is measured by luminescence and that can be performed under BSL‐2 conditions. The RVP‐based SNT for TBEV exhibited a highly significant correlation with the traditional virus‐based SNT (R2 = 0.8637, p < 0.0001). The RVP‐based assay demonstrated a sensitivity of 92.3% (95% CI: 79.7%–97.4%) and specificity of 100% (95% CI: 81.6%–100%). We also tested the cross‐reactivity of serum samples in RVP‐based assays against other orthoflaviviruses (yellow fever virus, dengue virus type 2, Zika virus, West Nile virus and Japanese encephalitis virus). Interestingly, all serum samples which had tested TBEV‐positive by ELISA but negative by RVP‐based SNT were reactive for antibodies against other orthoflaviviruses. Thus, the RVP‐based seroneutralization assay provides an added value in clinical diagnostics as well as in epidemiological studies. [ABSTRACT FROM AUTHOR]

Electrostrictive materials exhibit a strain that is proportional to the square of the induced polarization. In linear dielectrics where the permittivity is constant, this electromechanical strain is also proportional to the square of the electric field. However, under increasing amplitudes of the driving field, the electromechanical strain sometimes saturates; the electrostrictive coefficients therefore appear to depend on the amplitude of the electric field used to measure them. Here, a methodology showing that this apparent field dependence is a consequence of neglecting higher‐order electromechanical phenomena is presented. When these are taken into account, not only do the electrostrictive coefficients remain constant but the signs of the high‐order coefficients enable the prediction of the saturation behavior from a single measurement. This approach is illustrated on both classical and non‐classical (so‐called "giant") electrostrictors. [ABSTRACT FROM AUTHOR]

Climate change is projected to increase the frequency and intensity of extreme heat events, and may increase humidity levels, leading to coupled thermal and hydric stress. However, how humidity modulates the impacts of heat stress on species and their interactions is currently unknown. Using an insect host‐parasitoid interaction: the Indian meal moth, Plodia interpunctella, and its endoparasitoid wasp, Venturia canescens, we investigated how humidity interacted with heat stress duration, applied at different host developmental stages, to affect life history traits. Hosts parasitized as 4th instar larvae and unparasitized hosts were maintained in high‐ (60.8% RH) or low‐humidity (32.5% RH) at constant 28°C. They were then exposed to a 38°C thermal stress with a duration of 0 (no heat stress), 6 or 72 h in either the 4th or 5th host instar. Neither humidity nor heat stress duration affected emergence of unparasitized hosts, but increasing heat stress duration during the 4th instar decreased parasitoid emergence irrespective of humidity. When applied during the 5th instar, increasing heat duration decreased parasitoid emergence under low humidity, but no effect of heat stress was found under high humidity. Moreover, experiencing longer heat stress in the 4th instar increased host larval development time and decreased body size under high humidity, but this effect differed under low humidity; increasing heat duration in the 5th instar decreased parasitoid body sizes only under low humidity. Larval stage and heat stress duration directly affected parasitized host survival time, with a concomitant indirect reduction of parasitoid sizes. We show that humidity modifies key life history responses of hosts and parasitoids to heat stress in species‐specific ways, highlighting the potential importance of humidity in regulating host‐parasitoid interactions and their population dynamics. Finally, we emphasize that interactions between environmental stressors need to be considered in climate change research. [ABSTRACT FROM AUTHOR]

Background: Misalignment or double‐contouring artifacts can appear in high‐resolution 3D cone beam computed tomography (CBCT) images, potentially indicating geometric accuracy issues in the projection data. Such artifacts may go unnoticed in low‐resolution images and could be associated with changes in the focal spot (FS) position. Purpose: High‐resolution 3D‐CBCT imaging by a mobile imaging device with a large gantry clearance offers more versatility for clinical workflows in image‐guided brachytherapy (IGBT), intraoperative radiation therapy (IORT), and spinal, as well as maxillofacial surgery. However, misalignment or double‐contouring artifacts hinder workflow advancements in these domains. This paper introduces intrinsic calibration and geometrical correction methods as extensions to a well‐established technique for addressing geometrical deviations resulting from factors such as gravity or mechanical inconsistencies. These extensions cover shifts and drifts of the FS depending on FS size selection, temperature, tube current, and tube potential. The proposed methods effectively mitigate artifacts in high‐resolution CBCT images stemming from geometrical inaccuracies in projection data, without requiring additional equipment like a pinhole device. Methods: Geometrical offsets and drifts of the x‐ray tube FS were characterized on a mobile multi‐purpose imaging system, the ImagingRing‐m. A pinhole‐like experiment was simulated by adjusting the movable collimation unit to a small rectangular aperture within the FS size range. The influence of filament selection, that is, FS size, temperature, the relatively low tube currents, as well as tube potential settings have been studied on two different monobloc types sharing the same x‐ray tube insert. The Catphan 504 and an Alderson head phantom were used to assess resulting image artifacts. Results: Switching the FS size to one different from what was used for geometrical (gravitation, mechanical variations) calibration induced the most notable position changes of the x‐ray FS, resulting in double‐contouring artifacts and blurring of high‐resolution 3D‐CBCT images. Incorporating these shifts into a geometrical correction method effectively minimized these artifacts. Thermal drifts exhibited the second largest geometrical changes, comparable to FS size shifts across the thermal operating conditions of the x‐ray system. The proposed thermal drift compensation markedly reduced thermal drift effects. Tube current and potential had little impact within the range of available tube currents, eliminating the need for compensation in current applications. Conclusions: Augmenting the geometrical calibration pipeline with proposed FS drift compensations yielded significant enhancements in image quality for high‐resolution reconstructions. While compensation for thermal effects posed challenges, it proved achievable. The roles of tube current and potential were found to be negligible. [ABSTRACT FROM AUTHOR]

We report data on six kidney or heart recipients who were administered daratumumab to treat or prevent antibody‐mediated rejection (ABMR). To date, data are scarce concerning the use of daratumumab in solid organ transplantation and most reports show a decrease in donor‐specific antigen (DSA) levels and an improvement in ABMR using a multiple myeloma daratumumab administration scheme, that is, with sequential systematic administration. Here, we report on the efficacy of daratumumab 1/ in reducing the histological signs of ABMR, 2/ in reducing the ability of DSA to bind to donor cells in vitro through negativation of flow cytometry crossmatching, 3/ in preferentially being directed towards antibodies sharing epitopes, suggesting that daratumumab may specifically target activated plasma cells, 4/ and when administered as a single dose. This last point suggests, for the first time, that, as for rituximab in auto‐immune diseases, the scheme for daratumumab administration could be different for targeting DSA‐producing plasma cells than for tumour cells. [ABSTRACT FROM AUTHOR]

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River ice breakups carry the potential for high flows and flooding and are of great interest to accurately predict. A challenge in forecasting these events is the management of the massive amounts of data associated with an ice season. This study couples ontological and machine learning models in a new hybrid modeling framework to predict spring breakup on a national scale. The Ice Season Ontology sorts the data and allows for a user‐friendly means of analyzing any ice season, providing insight on which variables are most and least central. With this, a refined variable selection is able to be made for machine learning models. The most successful developed model, a random forest, produced highly accurate forecasts when applied to a national scale case study, with a mean absolute error of 10.85 days and an R2 of.884. This new modeling framework provides a means for decision‐making support for river bound communities and a new methodology for modeling applications in other fields. [ABSTRACT FROM AUTHOR]

In May 2019, a measles outbreak occurred in the French subregion of Loire‐Atlantique, particularly affecting Roma settlements. Various obstacles hindered the implementation of postexposure measures among Roma population, resulting in the spread of the cases to other settlements. Suspected cases of measles were immediately investigated and concerned settlements were visited for measles–mumps–rubella (MMR) vaccination. From July 1 to September 3, 2019, a first and then a second Health Reserve team helped for vaccination on the affected and then also the measles‐free settlements. Vaccination uptake was monitored with the use of the department's vaccination center immunization registry. Genotyping of selected samples was performed for comparison with viruses circulating at the same time in France and Romania. As of September 16 2019, 109 cases of measles were confirmed among Roma population, including 99 (91%) children under 15 years. Of the 85 people eligible for vaccination, 60 (71%) had not been vaccinated and 23 (27%) had an unknown vaccination status. Sequence comparison revealed that 28/29 sequenced D8 strains were 100% identical to the strain responsible for a large number of cases throughout France in 2019, and to two sequences reported in Romania among sporadic cases. The vaccination campaign resulted in 1136 people on 35 settlements receiving at least one dose of MMR vaccine and in the increase of one‐dose MMR vaccine coverage at 24 months from 43% (23/53) to 91% (48/53). With measles transmission continuing in Europe, efforts must be made to meet immunization coverage targets, particularly in hard‐to‐reach communities where outbreaks may be difficult to control. [ABSTRACT FROM AUTHOR]

Objective: Normal interictal [18F]FDG‐PET can be predicted from the corresponding T1w MRI with Generative Adversarial Networks (GANs). A technique we call SIPCOM (Subtraction Interictal PET Co‐registered to MRI) can then be used to compare epilepsy patients' predicted and clinical PET. We assessed the ability of SIPCOM to identify the Resection Zone (RZ) in patients with drug‐resistant epilepsy (DRE) with reference to visual and statistical parametric mapping (SPM) analysis. Methods: Patients with complete presurgical work‐up and subsequent SEEG and cortectomy were included. RZ localisation, the reference region, was assigned to one of eighteen anatomical brain regions. SIPCOM was implemented using healthy controls to train a GAN. To compare, the clinical PET coregistered to MRI was visually assessed by two trained readers, and a standard SPM analysis was performed. Results: Twenty patients aged 17‐50 (32 ± 7.8) years were included, 14 (70%) with temporal lobe epilepsy (TLE). Eight (40%) were MRI‐negative. After surgery, 14 patients (70%) had a good outcome (Engel I‐II). RZ localisation rate was 60% with SIPCOM vs 35% using SPM (P = 0.015) and vs 85% using visual analysis (P = 0.54). Results were similar for Engel I‐II patients, the RZ localisation rate was 64% with SIPCOM vs 36% with SPM. With SIPCOM localisation was correct in 67% in MRI‐positive vs 50% in MRI‐negative patients, and 64% in TLE vs 43% in extra‐TLE. The average number of false‐positive clusters was 2.2 ± 1.3 using SIPCOM vs 2.3 ± 3.1 using SPM. All RZs localized with SPM were correctly localized with SIPCOM. In one case, PET and MRI were visually reported as negative, but both SIPCOM and SPM localized the RZ. Significance: SIPCOM performed better than the reference computer‐assisted method (SPM) for RZ detection in a group of operated DRE patients. SIPCOM's impact on epilepsy management needs to be prospectively validated. [ABSTRACT FROM AUTHOR]

This article discusses two novel tumors classified as extraventricular neurocytomas (EVN) that were found to have NTRK2 fusions instead of the usual FGFR1 alterations. The first case involved a 23-year-old woman with migraines and epileptic seizures, while the second case involved a 15-year-old girl with intracerebral calcifications. Both cases underwent total removal of the tumors and showed positive staining for synaptophysin and olig2. The study suggests that these findings have implications for diagnosis, therapy, and terminology, and further research is needed to better understand these tumors. [Extracted from the article]

Summary: Water stress can cause declines in plant function that persist after rehydration. Recent work has defined 'resilience' traits characterizing leaf resistance to persistent damage from drought, but whether these traits predict resilience in whole‐plant function is unknown. It is also unknown whether the coordination between resilience and 'resistance' – the ability to maintain function during drought – observed globally occurs within ecosystems.For eight rainforest species, we dehydrated and subsequently rehydrated leaves, and measured water stress thresholds for declines in rehydration capacity and maximum quantum yield of photosystem II (Fv/Fm). We tested correlations with embolism resistance and dry season water potentials (ΨMD), and calculated safety margins for damage (ΨMD – thresholds) and tested correlations with drought resilience in sap flow and growth.Ψ thresholds for persistent declines in Fv/Fm, indicating resilience, were positively correlated with ΨMD and thresholds for leaf vein embolism. Safety margins for persistent declines in Fv/Fm, but not rehydration capacity, were positively correlated with drought resilience in sap flow.Correlations between resistance and resilience suggest that species' differences in performance during drought are perpetuated after drought, potentially accelerating shifts in forest composition. Resilience to photochemical damage emerged as a promising functional trait to characterize whole‐plant drought resilience. [ABSTRACT FROM AUTHOR]

We obtain optimal estimates of the Poincaré constant of central balls on manifolds with finitely many ends. Surprisingly enough, the Poincaré constant is determined by the second largest end. The proof is based on the argument by Kusuoka–Stroock where the heat kernel estimates on the central balls play an essential role. For this purpose, we extend earlier heat kernel estimates obtained by the authors to a larger class of parabolic manifolds with ends. [ABSTRACT FROM AUTHOR]

The sequence of key water potential thresholds from the onset of water stress to mortality, and the timing of stomatal closure with regard to leaf xylem embolism formation are essential to characterizing plant adaptive strategies to drought. This constitutes a critical knowledge gap for tropical rainforest species, which may be less vulnerable to drought than previously thought.We recorded key leaf and stem water potential thresholds, leaf hydraulic safety margins (HSMleaf), leaf stomatal safety margins (SSMleaf) and estimated native embolism levels during a normal‐intensity dry season across 18 neotropical rainforest tree species. We also solved a sequence of key water potential thresholds. Additionally, we provide a cross‐biome analysis of SSMleaf encompassing 97 species from four major biomes based on a literature survey.In the studied rainforest species, leaf turgor loss point, used as a surrogate for stomatal closure, typically occurred before the onset of leaf xylem embolism. Most species exhibited positive HSMleaf and SSMleaf, with contrasting values across species and nearly absent embolism levels during the dry season irrespective of the experienced midday leaf water potentials. Our results point out that leaf xylem embolism is not routine for Neotropical rainforest tree species.Based on our proposal of the water potential sequence for tropical rainforest trees, we argue that leaf xylem embolism is a rare event for these species. This was supported by the literature survey, indicating that across biomes, most woody species have rather large SSMleaf and that leaves of tropical rainforest trees are not necessarily more vulnerable than in other biomes. However, we found evidence that some tropical rainforest species may be more vulnerable than others to ongoing climate change. Our data provide an opportunity to parametrize tree‐based or land‐surface models for tropical rainforests. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

This paper aims at proving the local boundedness and continuity of solutions of the heat equation in the context of Dirichlet spaces under some rather weak additional assumptions. We consider symmetric local regular Dirichlet forms, which satisfy mild assumptions concerning (1) the existence of cut‐off functions, (2) a local ultracontractivity hypothesis, and (3) a weak off‐diagonal upper bound. In this setting, local weak solutions of the heat equation, and their time derivatives, are shown to be locally bounded; they are further locally continuous, if the semigroup admits a locally continuous density function. Applications of the results are provided including discussions on the existence of locally bounded heat kernel; L∞$L^\infty$ structure results for ancient (local weak) solutions of the heat equation. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to perform a systematic review and meta‐analysis regarding the prevalence of traumatic dental injuries (TDI) in emergency dental services. Methods: Seven electronic and two grey literature databases were searched, up to December 2021, for studies that reported the TDI prevalence among dental emergencies. The Joanna Briggs Institute critical appraisal checklist for prevalence studies, and The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach were used to assess the risk of bias and quality of evidence respectively. The R software was used to perform a proportion meta‐analysis on a random‐effects model to estimate the pooled prevalence and respective 95% CI. Results: From a total of 1476 studies identified after excluding duplicates, 38 met the inclusion criteria, and another five were identified through hand searching, summing 43 included observational studies with a total sample of 209099 individuals searching for emergency dental care. The overall pooled prevalence of TDI was 15.4% (95% CI: 11%‐21%, I² = 100%). Paediatric dental emergency services and age group from 0 to 21 years presented the highest prevalence, 29% (95% CI: 22%‐38%, I² = 99.5%) and 24% (95% CI: 15%‐35%, I² = 98%) respectively. Conclusions: The overall pooled prevalence of TDI in emergency dental services was 15.4%, and 24% in the age group under 21 years. Considering the impact of prompt and correct emergency care in the long‐term prognosis of TDI, such knowledge is relevant to organize emergency healthcare and support public policies in this area. [ABSTRACT FROM AUTHOR]

Introduction: Alcohol use disorder (AUD) is associated with a significant disease burden in France, where alcohol use is deeply rooted in culture. However, the treatment gap is large because of several barriers, including stigmatisation and drinkers' apprehension about total abstinence. However, standardised and evidence‐based interventions based on controlled‐drinking for people with AUD are lacking. We aimed to assess the effectiveness of a novel community‐based French therapeutic patient education (TPE) program for people with AUD named Choizitaconso. Methods: A before‐after non‐randomised quasi‐experimental study, named ETHER, was designed and implemented with people living with AUD, over a period of 6 months. The primary outcome was percentage change in the number of alcohol‐related harms experienced. Secondary outcomes were percentage changes in psycho‐social patient‐reported and community‐validated outcomes. Participants in the intervention group (n = 34) benefited from the 10‐week TPE program Choizitaconso, while the comparison group (n = 58) received standard care. The Kruskall–Wallis and chi‐squared or Fisher's exact tests were used to compare before‐after changes in variables in both groups. Linear regression models were used to test for the effect of study group on each outcome and to test for the effect of alcohol consumption as a confounder. Results: At 6 months, all outcomes but one either remained stable or numerically improved in both groups. Internalised stigma significantly improved in the intervention group (p = 0.026) but not in the comparison group (p = 0.207), with a significant group effect (p = 0.014). Discussion and Conclusions: This study demonstrates the effectiveness of the Choizitaconso TPE program on community‐validated outcomes, especially internalised stigma. [ABSTRACT FROM AUTHOR]

Background: Patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) often require repeat sinus surgery. Mepolizumab reduced the need for sinus surgery in the SYNAPSE trial; this analysis sought to provide a more in‐depth assessment of surgery endpoints in SYNAPSE. Methods: SYNAPSE was a double‐blind Phase III trial (NCT03085797) in adults with recurrent, refractory, severe, CRSwNP eligible for repeat sinus surgery despite standard of care treatments and previous surgery. Patients were randomized (1:1) to mepolizumab 100 mg subcutaneously or placebo, plus standard of care, every 4 weeks for 52 weeks. Time to first inclusion on a waiting list for sinus surgery and time to first actual sinus surgery (both up to week 52) were assessed; the latter endpoint was also analyzed post hoc according to time since last sinus surgery before study screening and baseline blood eosinophil count. Results: Among 407 patients (mepolizumab: 206; placebo: 201), mepolizumab versus placebo reduced the risk of being included on a waiting list for sinus surgery (week 52 Kaplan–Meier probability estimate [95% confidence interval]: 13.9% [9.8%, 19.5%] vs. 28.5% [22.7%, 35.4%]). Mepolizumab versus placebo reduced the risk of sinus surgery irrespective of time (<3 vs ≥3 years) since patients' last sinus surgery prior to study screening (hazard ratios [95% confidence intervals] 0.28 [0.09, 0.84] and 0.50 [0.26, 0.98], respectively) and baseline blood eosinophil count. Conclusions: Mepolizumab reduced the risk of further sinus surgery in patients with recurrent, refractory, severe CRSwNP, irrespective of the patient baseline characteristics assessed. [ABSTRACT FROM AUTHOR]

The increased importance of RNA‐based therapeutics comes with a need to develop next‐generation stimuli‐responsive systems capable of binding, transporting and releasing RNA oligomers. In this work, we describe triazolium‐based amphiphiles capable of siRNA binding and enzyme‐responsive release of the nucleic acid payload. In aqueous medium, the amphiphile self‐assembles into nanocarriers that can disintegrate upon the addition of esterase. Key to the molecular design is a self‐immolative linker that is anchored to the triazolium moiety and acts as a positively‐charged polar head group. We demonstrate that addition of esterase leads to a degradation cascade of the linker, leaving the neutral triazole compound unable to form complexes and therefore releasing the negatively‐charged siRNA. The reported molecular design and overall approach may have broad utility beyond this proof‐of‐principle study, because the underlying CuAAC "click" chemistry allows bringing together three groups very efficiently as well as cleaving off one of the three groups under the mild action of an esterase enzyme. [ABSTRACT FROM AUTHOR]

The use of nucleic acids as templates, which can trigger the self‐assembly of their own vectors represent an emerging, simple and versatile, approach toward the self‐fabrication of tailored nucleic acids delivery vectors. However, the structure‐activity relationships governing this complex templated self‐assembly process that accompanies the complexation of nucleic acids remains poorly understood. Herein, the class of arginine‐rich dynamic covalent polymers (DCPs) composed of different monomers varying the number and position of arginines were studied. The combinations that lead to nucleic acid complexation, in saline buffer, using different templates, from short siRNA to long DNA, are described. Finally, a successful peptidic DCP featuring six‐arginine repeating unit that promote the safe and effective delivery of siRNA in live cancer cells was identified. [ABSTRACT FROM AUTHOR]

Purpose: Signal detection is a crucial step in the discovery of post‐marketing adverse drug reactions. There is a growing interest in using routinely collected data to complement established spontaneous report analyses. This work aims to systematically review the methods for drug safety signal detection using routinely collected healthcare data and their performance, both in general and for specific types of drugs and outcomes. Methods: We conducted a systematic review following the PRISMA guidelines, and registered a protocol in PROSPERO. MEDLINE, EMBASE, PubMed, Web of Science, Scopus, and the Cochrane Library were searched until July 13, 2021. Results: The review included 101 articles, among which there were 39 methodological works, 25 performance assessment papers, and 24 observational studies. Methods included adaptations from those used with spontaneous reports, traditional epidemiological designs, methods specific to signal detection with real‐world data. More recently, implementations of machine learning have been studied in the literature. Twenty‐five studies evaluated method performances, 16 of them using the area under the curve (AUC) for a range of positive and negative controls as their main measure. Despite the likelihood that performance measurement could vary by drug‐event pair, only 10 studies reported performance stratified by drugs and outcomes, in a heterogeneous manner. The replicability of the performance assessment results was limited due to lack of transparency in reporting and the lack of a gold standard reference set. Conclusions: A variety of methods have been described in the literature for signal detection with routinely collected data. No method showed superior performance in all papers and across all drugs and outcomes, performance assessment and reporting were heterogeneous. However, there is limited evidence that self‐controlled designs, high dimensional propensity scores, and machine learning can achieve higher performances than other methods. [ABSTRACT FROM AUTHOR]

Pathogenic variants of collagen type IV alpha 1 and 2 (COL4A1/COL4A2) genes cause various phenotypic anomalies, including intracerebral hemorrhage and a wide spectrum of developmental anomalies. Only 20% of fetuses referred for COL4A1/COL4A2 molecular screening (fetuses with a suspected intracerebral hemorrhage) carry a pathogenic variant in these genes, raising questions regarding the causative anomaly in the remaining 80% of these fetuses. We examined, following termination of pregnancy or in-utero fetal death, a series of 113 unrelated fetuses referred for COL4A1/COL4A2 molecular screening, in which targeted sequencing was negative. Using exome sequencing data and a gene-based collapsing test, we searched for enrichment of rare qualifying variants in our fetal cohort in comparison to the Genome Aggregation Database (gnomAD) control cohort (n = 71 702). Qualifying variants in pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) were overrepresented in our cohort, reaching genome-wide significance (P = 2.11 × 10-7 ). Heterozygous PDHA1 loss-of-function variants were identified in three female fetuses. Among these three cases, we observed microcephaly, ventriculomegaly, germinolytic pseudocysts, agenesis/dysgenesis of the corpus callosum and white-matter anomalies that initially suggested cerebral hypoxic-ischemic and hemorrhagic lesions. However, a careful a-posteriori reanalysis of imaging and postmortem data showed that the observed lesions were also consistent with those observed in fetuses carrying PDHA1 pathogenic variants, strongly suggesting that these two phenotypes may overlap. Exome sequencing should therefore be performed in fetuses referred for COL4A1/COL4A2 molecular screening which are screen-negative, with particular attention paid to the PDHA1 gene. © 2022 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

The I CIC- i rearranged sarcoma was introduced into the 2021 World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS), by homology of its soft-tissue counterpart.1 In the CNS, I CIC i fusions mainly implicate I DUX4 i or I NUTM1 i genes but non- I CIC i fusions (such as I ATXN1::DUX4 i and I ATXN1::NUTM1 i ) have been recently described.1-3 However, DNA-methylation profiling of all I CIC- i and non- I CIC- i fused CNS mesenchymal tumours showed that all cases clustered together.2 In soft tissue, it has been evidenced that whatever the fusion partner, the I CIC i translocation induces an oncogenic activation of the PEA3 family transcription factors, including ETV4.1 Consequently, ETV4 immunohistochemistry (IHC) may represent a specific biomarker for all I CIC- i rearranged sarcomas, whereas NUT immunoexpression is only observed in I CIC::NUTM1 i -fused sarcomas.1 In the CNS, the diagnosis of I CIC- i rearranged sarcoma may be challenging for neuropathologists, and a common diagnostic biomarker of all fusions may help to identify this rare tumour type. Our work is the first to evaluate the sensitivity and specificity of ETV4 in a large cohort of molecularly defined CNS tumours. ETV4 immunohistostaining is a sensitive and specific diagnostic biomarker for CIC-rearranged sarcoma of the central nervous system. [Extracted from the article]

Small Extracellular Vesicles (sEVs) are 50–200 nm in diameter vesicles delimited by a lipid bilayer, formed within the endosomal network or derived from the plasma membrane. They are secreted in various biological fluids, including airway nasal mucus. The goal of this work was to understand the role of sEVs present in the mucus (mu‐sEVs) produced by human nasal epithelial cells (HNECs) in SARS‐CoV‐2 infection. We show that uninfected HNECs produce mu‐sEVs containing SARS‐CoV‐2 receptor ACE2 and activated protease TMPRSS2. mu‐sEVs cleave prefusion viral Spike proteins at the S1/S2 boundary, resulting in higher proportions of prefusion S proteins exposing their receptor binding domain in an 'open' conformation, thereby facilitating receptor binding at the cell surface. We show that the role of nasal mu‐sEVs is to complete prefusion Spike priming performed by intracellular furin during viral egress from infected cells. This effect is mediated by vesicular TMPRSS2 activity, rendering SARS‐CoV‐2 virions prone to entry into target cells using the 'early', TMPRSS2‐dependent pathway instead of the 'late', cathepsin‐dependent route. These results indicate that prefusion Spike priming by mu‐sEVs in the nasal cavity plays a role in viral tropism. They also show that nasal mucus does not protect from SARS‐CoV‐2 infection, but instead facilitates it. [ABSTRACT FROM AUTHOR]

Background and purpose: A dose‐dependent association between the use of cyproterone acetate (CPA) and intracranial meningioma has been identified but data for other potent progestogens are scarce. The association was assessed between intracranial meningioma surgery and exposure to three potent progestogens: CPA (≥25 mg/day), nomegestrol acetate (NOMAC) (3.75–5 mg/day) and chlormadinone acetate (CMA) (2–10 mg/day). Methods: In this nationwide population‐based case–control study, cases underwent surgery for intracranial meningioma in France from 2009 to 2018. They were matched to five control subjects for sex, year of birth and area of residence. Progestogen exposure was defined as progestogen use within the year before surgery for cases or the same date for their controls. Results: In total, 25,216 cases were included (75% women, median age 58 years). Progestogen exposure was noted for 9.9% of cases (2497/25,216) and 1.9% (2382/126,080) of controls, with an odds ratio (OR) of 6.7 (95% confidence interval [CI] 6.3–7.1). The OR was 1.2 (1.0–1.4) for short‐term use (<1 year) and 9.5 (8.8–10.2) for prolonged use. A strong association was identified for prolonged use of CPA (OR = 22.7, 95% CI 19.5–26.4), NOMAC (OR = 6.5, 95% CI 5.8–7.2) and CMA (OR = 4.7, 95% CI 4.5–5.3). Progestogen exposure increased the risk of meningioma for all histological grades and anatomical sites, particularly for the anterior and middle skull base: OR = 35.7 (95% CI 26.5–48.2) and 23.9 (95% CI 17.8–32.2) for CPA. The estimated number of attributable cases was 2124 (95% CI 2028–2220) (212/year). Conclusion: A strong association between prolonged exposure to potent progestogens and surgery for meningioma was observed. The risk increased from CMA to NOMAC to CPA. Individuals should be informed of this risk. This study highlights a strong association between prolonged use of nomegestrol and chlormadinone acetate (two potent progestogens) and intracranial meningioma, although weaker than that of cyproterone acetate. The estimated number of cases was higher than 2000 in France over 10 years. [ABSTRACT FROM AUTHOR]

Objective: Epileptic spasms (ES) are common in tuberous sclerosis complex (TSC). However, the underlying network alterations and relationship with epileptogenic tubers are poorly understood. We examined interictal functional connectivity (FC) using stereo‐electroencephalography (SEEG) in patients with TSC to investigate the relationship between tubers, epileptogenicity, and ES. Methods: We analyzed 18 patients with TSC who underwent SEEG (mean age = 11.5 years). The dominant tuber (DT) was defined as the most epileptogenic tuber using the epileptogenicity index. Epileptogenic zone (EZ) organization was quantitatively separated into focal (isolated DT) and complex (all other patterns). Using a 20‐min interictal recording, FC was estimated with nonlinear regression, h2. We calculated (1) intrazone FC within all sampled tubers and normal‐appearing cortical zones, respectively; and (2) interzone FC involving connections between DT, other tubers, and normal cortex. The relationship between FC and (1) presence of ES as a current seizure type at the time of SEEG, (2) EZ organization, and (3) epileptogenicity was analyzed using a mixed generalized linear model. Spike rate and distance between zones were considered in the model as covariates. Results: Six patients had ES as a current seizure type at time of SEEG. ES patients had a greater number of tubers with a fluid‐attenuated inversion recovery hypointense center (p <.001), and none had TSC1 mutations. The presence of ES was independently associated with increased FC within both intrazone (p =.033) and interzone (p =.011) networks. Post hoc analyses identified that increased FC was associated with ES across tuber and nontuber networks. EZ organization and epileptogenicity biomarkers were not associated with FC. Significance: Increased cortical synchrony among both tuber and nontuber networks is characteristic of patients with ES and independent of both EZ organization and tuber epileptogenicity. This further supports the prospect of FC biomarkers aiding treatment paradigms in TSC. [ABSTRACT FROM AUTHOR]

Aim: Rosette‐forming glioneuronal tumour (RGNT) is a rare central nervous system (CNS) World Health Organization (WHO) grade 1 brain neoplasm. According to the WHO 2021, essential diagnostic criteria are a 'biphasic histomorphology with neurocytic and a glial component, and uniform neurocytes forming rosettes and/or perivascular pseudorosettes associated with synaptophysin expression' and/or DNA methylation profile of RGNT whereas 'FGFR1 mutation with co‐occurring PIK3CA and/or NF1 mutation' are desirable criteria. Material and methods: We report a series of 46 cases fulfilling the essential pathological diagnostic criteria for RGNT. FGFR1 and PIK3CA hotspot mutations were searched for by multiplexed digital PCR in all cases, whereas DNA methylation profiling and/or PIK3R1 and NF1 alterations were analysed in a subset of cases. Results: Three groups were observed. The first one included 21 intracranial midline tumours demonstrating FGFR1 mutation associated with PIK3CA or PIK3R1 (n = 19) or NF1 (n = 1) or PIK3CA and NF1 (n = 1) mutation. By DNA methylation profiling, eight cases were classified as RGNT (they demonstrated FGFR1 and PIK3CA or PIK3R1 mutations). Group 2 comprised 11 cases associated with one single FGFR1 mutation. Group 3 included six cases classified as low‐grade glioma (LGG) other than RGNT (one‐sixth showed FGFR1 mutation and one a FGFR1 and NF1 mutation) and eight cases without FGFR1 mutation. Groups 2 and 3 were enriched in lateral and spinal cases. Conclusions: We suggest adding FGFR1 mutation and intracranial midline location as essential diagnostic criteria. When DNA methylation profiling is not available, a RGNT diagnosis remains certain in cases demonstrating characteristic pathological features and FGFR1 mutation associated with either PIK3CA or PIK3R1 mutation. [ABSTRACT FROM AUTHOR]

Polyurethane (PU) foams are very common materials that have found many applications over the years. Their use is constantly improving due to their unique physical properties and easy blowing which does not require the addition of a blowing agent. Greener routes have been explored in the recent years to replace isocyanates. One of the most promising routes is leading to polyhydroxyurethanes (PHU). However, with PHUs, external blowing agent are usually required to obtain a foam. Thus, the work focuses on PHU foam synthesis using in situ reaction to produce NIPU foam. Hence, the aminolysis of thiocyclic carbonate triggers Pearson reaction between released thiols and cyclic carbonates which serves as a chemical blowing agent. [ABSTRACT FROM AUTHOR]

Ynamides are useful and versatile building blocks in organic synthesis, from which 1,1,4,4‐tetracyanobutadienes (TCBD) can be prepared for application in molecular electronics. However, their insertion onto multi‐functional molecular scaffold remains a synthetic challenge. In this work, we report the two‐steps synthesis in good isolated yield (64 % overall, 89 % stepwise) of a tetraphenylethylene (TPE) bearing four ynamides, and its further one‐step conversion into the tetra‐TCBD derivative through a [2+2] cycloaddition‐retroelectrocyclization sequence. The concomitant formation of the four ynamides required a specific optimisation of the reaction conditions. Although a poor fluorescent emitter in solution, the tetra‐TCBD compound displayed near‐infrared luminescence in the solid state, which is an attractive optoelectronic feature when considering future applications in molecular electronic devices. [ABSTRACT FROM AUTHOR]

Background: Variants of COL4A1/COL4A2 genes have been reported in fetal intracranial hemorrhage (ICH) cases but their prevalence and characteristics have not been established in a large series of fetuses. Fetal neonatal alloimmune thrombocytopenia is a major acquired ICH factor but the prevalence and characteristics of inherited platelet disorder (IPD) gene variants leading to thrombocytopenia are unknown. Herein, we screened COL4A1/COL4A2 and IPD genes in a large series of ICH fetuses. Methods: A cohort of 194 consecutive ICH fetuses were first screened for COL4A1/COL4A2 variants. We manually curated a list of 64 genes involved in IPD and investigated them in COL4A1/COL4A2 negative fetuses, using exome sequencing data from 101 of these fetuses. Result: Pathogenic variants of COL4A1/COL4A2 genes were identified in 36 fetuses (19%). They occurred de novo in 70% of the 32 fetuses for whom parental DNA was available. Pathogenic variants in two megakaryopoiesis genes (MPL and MECOM genes) were identified in two families with recurrent and severe fetal ICH, with variable extraneurological pathological features. Conclusion: Our study emphasizes the genetic heterogeneity of fetal ICH and the need to screen both COL4A1/COL4A2 and IPD genes in the etiological investigation of fetal ICH to allow proper genetic counseling. Key points: What's already known about this topic? COL4A1/COL4A2 pathogenic variants have been reported in several fetal intracranial hemorrhage (ICH) case reports but their prevalence and characteristics in a large series of fetal ICH is lacking.Fetal neonatal alloimmune thrombocytopeniais a well‐known cause of thrombocytopenia and ICH in infants and fetuses but very little is known regarding the role in fetal ICH of variants of inherited platelet disorder genes leading to thrombocytopenia. What does this study add? Fetal ICH is a highly heterogeneous condition with COL4A1/COL4A2 pathogenic variants accounting for 19% of cases with a very high de novo rate.Albeit rare, pathogenic variants of megakaryopoiesis genes are associated with ICH and screening of these genes should be performed in fetal ICH etiological investigation. [ABSTRACT FROM AUTHOR]

The dry and wet seasons in the Neotropics have strong effects on soil water and nutrient availability, as well as on forest dynamics. Despite these major effects on forest ecology, little is known on how leaf traits vary throughout the seasons in tropical rainforest trees.Here, we investigated the influence of seasonal variations in climate and soil characteristics on leaf trait variation in two tropical tree species. We measured two leaf traits, thickness and water mass per area, in 401 individuals of two species of Symphonia (Clusiaceae) in the Paracou research station in French Guiana tropical lowland rainforest.We found a significant effect of seasonal variation on these two leaf traits. Soil relative extractable water was a strong environmental predictor of leaf trait variation in response to seasonal variation. Reduced soil water availability during the dry season was associated with increased leaf thickness and water mass per area, possibly as a result of stomatal closure.Our findings advocate the need to account for environmental seasonality when studying leaf traits in seasonal ecosystems such as tropical forests. [ABSTRACT FROM AUTHOR]

Climate impacts are not always easily discerned in wild populations as detecting climate change signals in populations is challenged by stochastic noise associated with natural climate variability, variability in biotic and abiotic processes, and observation error in demographic rates. Detection of the impact of climate change on populations requires making a formal distinction between signals in the population associated with long‐term climate trends from those generated by stochastic noise. The time of emergence (ToE) identifies when the signal of anthropogenic climate change can be quantitatively distinguished from natural climate variability. This concept has been applied extensively in the climate sciences, but has not been explored in the context of population dynamics. Here, we outline an approach to detecting climate‐driven signals in populations based on an assessment of when climate change drives population dynamics beyond the envelope characteristic of stochastic variations in an unperturbed state. Specifically, we present a theoretical assessment of the time of emergence of climate‐driven signals in population dynamics (ToEpop). We identify the dependence of ToEpop on the magnitude of both trends and variability in climate and also explore the effect of intrinsic demographic controls on ToEpop. We demonstrate that different life histories (fast species vs. slow species), demographic processes (survival, reproduction), and the relationships between climate and demographic rates yield population dynamics that filter climate trends and variability differently. We illustrate empirically how to detect the point in time when anthropogenic signals in populations emerge from stochastic noise for a species threatened by climate change: the emperor penguin. Finally, we propose six testable hypotheses and a road map for future research. [ABSTRACT FROM AUTHOR]

Objective: Nodular heterotopias (NHs) are malformations of cortical development associated with drug‐resistant focal epilepsy with frequent poor surgical outcome. The epileptogenic network is complex and can involve the nodule, the overlying cortex, or both. Single‐pulse electrical stimulation (SPES) during stereo‐electroencephalography (SEEG) allows the investigation of functional connectivity between the stimulated and responsive cortices by eliciting cortico‐cortical evoked potentials (CCEPs). We used SPES to analyze the NH connectome and its relation to the epileptogenic network organization. Methods: We retrospectively studied 12 patients with NH who underwent 1 Hz or 0.2 Hz SPES of NH during SEEG. Outbound connectivity (regions where CCEPs were elicited by NH stimulation) and inbound connectivity (regions where stimulation elicited CCEPs in the NH) were searched. SEEG channels were then classified as "heterotopic" (located within the NH), "connected" (located in normotopic cortex and showing connectivity with the NH), and "unconnected." We used the epileptogenicity index (EI) to quantify implication of channels in the seizure‐onset zone and to classify seizures as heterotopic, normotopic, and normo‐heterotopic. Results: One hundred thirty‐five outbound and 72 inbound connections were found. Three patients showed connectivity between hippocampus and NH, and seven patients showed strong internodular connectivity. A total of 39 seizures were analyzed: 23 normo‐heterotopic, 12 normotopic, and 4 heterotopic. Logistic regression found that "connected" channels were significantly (p = 8.4e‐05) more likely to be epileptogenic than "unconnected" channels (odds ratio 4.71, 95% confidence interval (CI) [2.17, 10.21]) and heterotopic channels were also significantly (p =.024) more epileptogenic than "unconnected" channels (odds ratio 3.29, 95% CI [1.17, 9.23]). Significance: SPES reveals widespread connectivity between NH and normotopic regions. Those connected regions show higher epileptogenicity. SPES might be useful to assess NH epileptogenic network. [ABSTRACT FROM AUTHOR]

This study reports the effectiveness of three injections of BNT162b2 anti‐SARS‐CoV‐2 mRNA vaccine in 141 Allo‐HSCT recipients with a median follow‐up of 6 months post‐third shot. We demonstrate a long‐term high protection of Allo‐HSCT recipients since only 2 infections and one death related to COVID‐19 occurred. [ABSTRACT FROM AUTHOR]

Aims: We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low‐grade epilepsy‐associated neuroepithelial tumours (LEATs) with a prominent oligodendroglioma‐like component, in order to classify them according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumours. Methods: Centralised pathological examination was performed as well as targeted molecular analysis of v‐Raf murine sarcoma viral oncogene homologue B (BRAF) and fibroblast growth factor receptor 1 (FGFR1) by multiplexed digital polymerase chain reaction (mdPCR). DNA methylation profiling was performed in cases with sufficient DNA. In cases with no genetic alteration by mdPCR and sufficient material, RNA sequencing was done. Results: We first reclassified our cohort into three groups: ganglioglioma (GG, n = 14), dysembryoplastic neuroepithelial tumours (DNTs, n = 19) and glioneuronal tumours/paediatric‐type low‐grade glioma (LGG) not otherwise specified (GNT/PLGG NOS, n = 39). mdPCR found an alteration in 38/72 cases. Subsequent RNA sequencing revealed a fusion transcript involving BRAF, FGFR1/2/3 or neurotrophic tyrosine kinase receptor type 2 [NTRK2] in 9/25 cases. DNA methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed two clusters: Cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG–DNT methylation class (MC), with haematopoietic progenitor cell antigen (CD34) negativity and FGRF1 alterations; Cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG–GG MC MC, with BRAF V600E mutation and CD34 positivity. The tumours reclassified as GNT/PLGG NOS were equally distributed across both clusters. Interestingly, all polymorphous low‐grade neuroepithelial tumour of the young belonged to Cluster 2, whereas diffuse LGG mitogen‐activated protein kinase (MAPK) pathway‐altered were equally distributed among the two clusters. This led us to build an algorithm to classify LEATs with a prominent oligodendroglioma‐like component. Conclusions: Integrated histomolecular diagnosis of LEATs with a prominent oligodendroglioma‐like component remains challenging. Because these tumours can be split into two major clusters of biological significance, the clinicopathological relevance of the four types recognised by the WHO CNS5 within this spectrum of tumours is questionable. [ABSTRACT FROM AUTHOR]

Objectives: Atrophic rhinitis (AR) and empty nose syndrome (ENS) are chronic diseases characterized by a paradoxical nasal obstruction. These rare syndromes tend to occur after nasal surgery of the inferior turbinates in ENS and can be idiopathic in AR. Medical treatments alone are often insufficient. Surgical options are challenging and numerous resorbable and nonresorbable implants have been described in small series, with as many surgical techniques described. Whereas current surgical procedures are for risk of extrusions, graft rejections or poor lasting results, the use of GlassBONE™ (Sodimed®, Avignon, France), a bioactive glass, for a vestibular approach in AR and ENS has never been reported for this indication. Methods: We described an original technique of nasal submucoperiosteal bilateral ceramic glass implantation in two patients with AR and ENS. Results: The two cases presented a postoperative satisfying endoscopic and sinus CT‐scan results with filling of the nasal cavities, with less crusts and a complete wound healing. They had no short‐term complications. Conclusion: This innovative approach is easily feasible and could be an option considered for the surgical management of AR and ENS. Level of evidence: 4. [ABSTRACT FROM AUTHOR]

FET:CREB fusions have been described in a variety of tumors from various phenotypes. Recently, these fusion transcripts were reported in intracranial tumors, variably named intracranial mesenchymal myxoid tumors or angiomatoid fibrous histiocytomas. Controversy remains concerning the terminology for these tumors. Here, we report 11 cases of central nervous system mesenchymal tumors with proven FET:CREB fusion. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor or Sarcoma Classifier (v11b4/v12.2). However, by using unsupervised t‐SNE and hierarchical clustering analyses, six of the cases constituted a distinct cluster. The remaining four tumors showed no obvious relation to any of the other referenced classes but were close to the clusters of extra‐CNS angiomatoid fibrous histiocytomas (n = 1), clear cell sarcomas (n = 1), or solitary fibrous tumors (n = 2). Our findings confirm that intracranial FET:CREB‐fused tumors do not represent a single molecular tumor entity, although most samples clustered close to each other, indicating the existence of a distinct epigenetic group that could potentially be partially masked by the low number of cases included. Further analyses are needed to characterize intracranial FET:CREB fused‐defined tumors in more detail. [ABSTRACT FROM AUTHOR]

An increasing number of empirical studies aim to quantify individual variation in demographic parameters because these patterns are key for evolutionary and ecological processes. Advanced approaches to estimate individual heterogeneity are now using a multivariate normal distribution with correlated individual random effects to account for the latent correlations among different demographic parameters occurring within individuals. Despite the frequent use of multivariate mixed models, we lack an assessment of their reliability when applied to Bernoulli variables.Using simulations, we estimated the reliability of multivariate mixed effect models for estimating correlated fixed individual heterogeneity in demographic parameters modelled with a Bernoulli distribution. We evaluated both bias and precision of the estimates across a range of scenarios that investigate the effects of life‐history strategy, levels of individual heterogeneity and presence of temporal variation and state dependence. We also compared estimates across different sampling designs to assess the importance of study duration, number of individuals monitored and detection probability.In many simulated scenarios, the estimates for the correlated random effects were biased and imprecise, which highlight the challenge in estimating correlated random effects for Bernoulli variables. The amount of fixed among‐individual heterogeneity was frequently overestimated, and the absolute value of the correlation between random effects was almost always underestimated. Simulations also showed contrasting performances of mixed models depending on the scenario considered. Generally, estimation bias decreases and precision increases with slower pace of life, large fixed individual heterogeneity and large sample size.We provide guidelines for the empirical investigation of individual heterogeneity using correlated random effects according to the life‐history strategy of the species, as well as, the volume and structure of the data available to the researcher. Caution is warranted when interpreting results regarding correlated individual random effects in demographic parameters modelled with a Bernoulli distribution. Because bias varies with sampling design and life history, comparisons of individual heterogeneity among species is challenging. The issue addressed here is not specific to demography, making this warning relevant for all research areas, including behavioural and evolutionary studies. [ABSTRACT FROM AUTHOR]

The familial structure of a population and the relatedness of its individuals are determined by its demography. There is, however, no general method to infer kinship directly from the life cycle of a structured population. Yet, this question is central to fields such as ecology, evolution and conservation, especially in contexts where there is a strong interdependence between familial structure and population dynamics. Here, we give a general formula to compute, from any matrix population model, the expected number of arbitrary kin (sisters, nieces, cousins, etc) of a focal individual ego, structured by the class of ego and of its kin. Central to our approach are classic but little‐used tools known as genealogical matrices. Our method can be used to obtain both individual‐based and population‐wide metrics of kinship, as we illustrate. It also makes it possible to analyse the sensitivity of the kinship structure to the traits implemented in the model. [ABSTRACT FROM AUTHOR]

Medication review, clinical pharmacy, medication error, medication reconciliation, orthopaedic surgery CONCLUSION One strategy for preventing hospital MEs and preventable ADEs is to identify high-risk patients so that physicians or pharmacists can consider the patients' level of risk when deciding on the drug surveillance strategy. ME is defined as 'any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer'. Keywords: clinical pharmacy; medication error; medication reconciliation; medication review; orthopaedic surgery EN clinical pharmacy medication error medication reconciliation medication review orthopaedic surgery 504 509 6 11/26/21 20211201 NES 211201 INTRODUCTION Medication errors (MEs) and adverse drug events (ADEs) are major public health issues in hospitals because of their consequences for patient morbidity-mortality and their economic costs. [Extracted from the article]

Aim: To systematically summarise the current evidence of employing clinical decision support algorithms (CDSAs) using non‐invasive parameters for sepsis prediction in neonates. Methods: A comprehensive search in PubMed, CENTRAL and EMBASE was conducted. Screening, data extraction and risk of bias were performed by two authors. The certainty of the evidence was assessed using GRADE. PROSPERO ID: CRD42020205143. Results: After abstract and full‐text screening, 36 studies comprising 18,096 infants were included. Most CDSAs evaluated heart rate (HR)‐based parameters. Two publications derived from one randomised‐controlled trial assessing HR characteristics reported significant reduction in 30‐day septicaemia‐related mortality. Thirty‐four non‐randomised studies found promising yet inconclusive results. Conclusion: Heart rate‐based parameters are reliable components of CDSAs for sepsis prediction, particularly in combination with additional vital signs and demographics. However, inconclusive evidence and limited standardisation restricts clinical implementation of CDSAs outside of a controlled research environment. Further experimentation and comparison of parameter combinations and testing of new CDSAs are warranted. [ABSTRACT FROM AUTHOR]

Objective: The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes. Methods: We performed a gene‐based collapsing test of rare protein‐truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of 2 publicly available large‐scale databases, gnomAD and TOPMed. Western blotting was used to investigate the functional consequences of variants. Clinical and magnetic resonance imaging features of mutated patients were characterized. Results: We showed that LAMB1 truncating variants escaping nonsense‐mediated messenger RNA decay are strongly overrepresented in CSVD patients, reaching genome‐wide significance (p < 5 × 10−8). Using 2 antibodies recognizing the N‐ and C‐terminal parts of LAMB1, we showed that truncated forms of LAMB1 are expressed in the endogenous fibroblasts of patients and trapped in the cytosol. These variants are associated with a novel phenotype characterized by the association of a hippocampal type episodic memory defect and a diffuse vascular leukoencephalopathy. Interpretation: These findings are important for diagnosis and clinical care, to avoid unnecessary and sometimes invasive investigations, and also from a mechanistic point of view to understand the role of extracellular matrix proteins in neuronal homeostasis. ANN NEUROL 2021;90:962–975 [ABSTRACT FROM AUTHOR]