Search

Europe frequently experiences a wide range of extreme events and natural hazards, including heatwaves, extreme precipitation, droughts, cold spells, windstorms, and storm surges. Many of these events do not occur as single extreme events but rather show a multivariate character, known as compound events. We investigate the interactions between extreme weather events, their characteristics, and changes in their intensity and frequency, as well as uncertainties in the past, present, and future. We also explore their impacts on various socio-economic sectors in Germany and central Europe. This contribution highlights several case studies with special focus on 2018, a year marked by an exceptional sequence of compound events across large parts of Europe, resulting in severe impacts on human lives, ecosystems, and infrastructure. We provide new insights into the drivers of spatially and temporally compound events, such as heat and drought, and heavy precipitation combined with extreme winds, and their adverse effects on ecosystems and society, using large-scale atmospheric patterns. We also examine the interannual influence of droughts on surface water and the impact of water scarcity and heatwaves on agriculture and forests. We assess projected changes in compound events at different current and future global surface temperature levels, demonstrating the need for improved quantification of future extreme events to support adaptation planning. Finally, we address research gaps and future directions, stressing the importance of defining composite events primarily in terms of their impacts prior to their statistical characterisation.

Objective: Our study focused on the development and evaluation of the SAPIENS (Specific Anatomical Printed-3D-model In Education and New Surgical Simulations) as a valid tool for otologic surgical education., Methods: Twenty junior otolaryngologist surgeons in training were enrolled in the study. Each participant was invited to perform dissection of three different temporal bones. 1)Transparent 3-D printed model; 2)Opaque 3-D model; 3)fresh frozen human temporal bone. Following their drilling experience, participants answered to two specific questionnaires. The first was a questionnaire developed by Mowry et al. to evaluate 3D models in its general characteristics of anatomy and dissection, while the second one was a questionnaire specifically designed to compare the 3-D printed models with the human fresh frozen temporal bone., Results: The average total score of the questionnaire was calculated as 53.2/61 in transparent 3-D model and 55.4/61 in the opaque 3-D model. These values indicate that the 3D printed models closely resemble the human TB in terms of anatomy and dissection. Comparisons of the 3D model and human TB were rated as very similar in all surgical steps. The total score was 4/5 in the transparent 3-D model and 4.2/5 in the opaque 3-D model., Conclusion: We have designed and developed a 3D-printed model of the temporal bone that closely resembles the human temporal bone. The SAPIENS 3-D printed temporal bone model could be considered a valuable tool for advancing oto-surgical education due to its similarity to the human temporal bone in terms of anatomy and dissection., Competing Interests: Declarations. Competing interests: The author Jerome R. Lechien was not involved with the peer review process of this article., (© 2025. The Author(s).)

Purpose: The posterior cruciate-retaining (CR) design offers rotational freedom but risks abnormal kinematics and instability. The medial pivot (MP) design mimics native joint motion with a high-conformity medial and flat lateral interface. Within clinical studies, the MP design outclassed the CR design, but biomechanical studies are lacking. This study investigates the tibiofemoral and patellofemoral kinematics of both implant designs compared to native kinematics., Methods: Eight fresh-frozen cadaveric knee specimens underwent total knee arthroplasty using MP and CR designs. Testing was performed in a dynamic knee rig simulating active knee flexion (30-130°) under muscle load. Biomechanical assessments included tibial rotation, tibiofemoral translation, patellar tilt/shift, patellofemoral contact/pressure patterns and quadriceps force. Functional regressions were used to analyse the effects of the component designs on the native situation., Results: The MP design exhibited increased tibial rotation (130° flexion: MP 9.4° vs. CR 6.6°) and lateral anterior tibial translation during flexion (130° flexion: MP 25.8 mm vs. CR 22.6 mm). Both designs showed no significant differences in patellar tilt or shift and similar patellofemoral pressure (CR 3.2 MPa, MP 3.4 MPa) and contact patterns (CR 213.8 mm 2 vs. MP 230.4 mm 2 ). The MP design required lower quadriceps force, particularly in deep flexion (NS 452.6 N, CR 407.8 N and MP 367.3 N)., Conclusion: The MP design provides a more native-like knee kinematic profile than the CR design, with a more pronounced MP motion pattern and reduced quadriceps loading., Level of Evidence: Not applicable., (© 2025 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.)

Objective: The objective was to assess Potsic, EAONO/JOS, STAMCO, and ChOLE cholesteatoma staging systems in a large homogenous pediatric cohort with long-term follow-up and propose an evidence-based improved version., Study Design: Cohort study., Setting: Retrospective study in a tertiary referral center., Methods: Children with congenital or acquired cholesteatoma who underwent surgery between 2008 and 2015 and had a minimum of five years follow-up were included. ROC areas under curve (AUCs) were performed for the residual disease proportion, total number of surgeries, hearing, and C-index for recurrence proportion at the last follow-up., Results: Data from 271 ears with cholesteatoma were collected. Mean age at diagnosis was 7.9 years and 77 (28%) were congenital. Almost all patients (99%) had a canal wall up approach. The mean follow-up was 97.8 months. The Potsic classification, initially designed for congenital cholesteatoma, had the highest AUCs for residual disease rate and for number of surgeries outcomes (respectively 0.73 [0.67-0.78] and 0.71 [0.66-0.77]). For recurrence rate, all the classifications' C-index were low (<0.7). For postoperative hearing, STAMCO ossicular subscore had the highest AUC (0.73 [0.67-0.79]). The Mod-Pot staging system (modified Potsic), including stapes superstructure status and anterior epitympanum or supratubal involvement, improved the Potsic performance especially for postoperative hearing with AUC 0.73 [0.67-0.80], p < 0.001., Conclusion: The Potsic, ChOLE, EAONO/JOS, and STAMCO cholesteatoma classifications may be used in children, but in this specific population, their contribution remains limited to predict outcome. The Mod-Pot classification improved the performance of pediatric cholesteatoma classification while remaining simple and intuitive., Level of Evidence: 3 Laryngoscope, 135:908-919, 2025., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Surrogate end points are commonly used to estimate treatment efficacy in clinical studies of chronic lymphocytic leukemia (CLL). This patient- and trial-level analysis describes the correlation between progression-free survival (PFS) and minimal residual disease (MRD) with overall survival (OS) in first-line trials for CLL., Patients and Methods: First, patient-level correlation was confirmed using source data from 12 frontline German CLL Study Group (GCLLSG)-trials. Additionally, a joint-frailty copula model was fitted to validate correlation in the setting of targeted therapies (TT). Second, a meta-analysis of first-line phase III trials in CLL from 2008 to 2024 was performed. Treatment effect correlation was quantified from seven GCLLSG and nine published trials, using hazard ratios (HRs) for time-to-event and odds ratios for binary end points., Results: The GCLLSG analysis set comprised 4,237 patients. Patient-level correlation for PFS/OS was strong with Spearman Rho >0.9. The joint-frailty copula indicated a weak correlation for chemotherapy/chemoimmunotherapy (C/CIT) with a tau of 0.52 (95% CI, 0.49 to 0.55) while the correlation was strong for TT (tau, 0.91 [95% CI, 0.89 to 0.93). The meta-analysis set contained a total of 8,065 patients including 5,198 (64%) patients treated with C/CIT and 2,867 (36%) treated with TT. Treatment-effect correlation of the HRs for PFS and OS was R = 0.75 (95% CI, 0.74 to 0.76, R 2 = 0.56) while correlation of end-of-treatment MRD with PFS and OS was R = 0.88 (95% CI, -0.87 to 0.89; R 2 = 0.78) and 0.71 (95% CI, 0.69 to 0.73; R 2 = 0.5), respectively., Conclusion: Patient-level correlation was confirmed in the setting of TTs while treatment-effect correlation between PFS and OS remains uncertain. MRD response status showed a high treatment-effect correlation with PFS but not OS, with the caveat of a limited number of randomized trials with available MRD data.

Purpose: The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies., Methods: The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression to receive ibrutinib (n = 182) at a daily dose of 420 mg or placebo (n = 181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group. The final analysis included event-free survival, progression-free survival, time to next treatment, overall survival, and safety assessments., Results: Ibrutinib significantly delayed progression to symptomatic disease ( P < .001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases ( P = .562) at a median observation time of 69.3 months. Five-year survival rates were excellent: 93.3% (95% CI, 89.3 to 97.3) in the ibrutinib group, 93.6% (95% CI, 89.5 to 97.7) in the placebo group, and 97.9% (95% CI, 95.6 to 100) in the watch-and-wait cohort. Estimated 10-year survival rates from diagnosis were 86.5% (95% CI, 78.7 to 94.3, placebo), 89.8% (95% CI, 83.3 to 96.3, ibrutinib), and 95.3% (95% CI, 91.1 to 99.4, watch and wait). In the ibrutinib group, one of 12 deaths was CLL-associated, compared with four of 14 fatal cases of CLL progression or Richter transformation in the placebo group. Adverse and serious adverse events occurred in 99.4% and 60% of both treatment groups, respectively. The safety profile indicated increased cardiovascular toxicity in the ibrutinib group., Conclusion: Ibrutinib treatment in early-stage CLL delayed disease progression compared with placebo. However, with the given observation time and few deaths, no survival benefit was demonstrated. In the era of targeted therapies, watch and wait remains the standard of care irrespective of risk factors.

Introduction: Hearing impairment concerns a relevant percentage of individuals with Osteogenesis Imperfecta (OI). When looking at the current literature, the percentage of affected individuals with OI varies greatly from 32 to 58% of patients having mild OI and 21% to 27% of patients having moderate to severe OI. Little is known about the German population with OI., Method: The goal of this study was to detect how many patients with OI, who visited the annual meeting of the German Association for Osteogenesis Imperfecta in 2023, proved to have a hearing impairment. In this prospective, cross-sectional study, each included individual obtained ear microscopy, audiometry, stapedius reflexes, tympanometry, and OAEs. Furthermore, each patient was asked a set of questions concerning the medical history., Results: Of the included patients, 33% had hearing impairment. A significant difference was found for the mean air-bone gap (ABG) as well as the hearing threshold of the right ears. The difference was found between OI type III and IV (p = 0.0127) for the mean ABG and OI type I and IV (p = 0.0138) as well as III and IV (p = 0.0281) for the hearing threshold. Spearman's rank correlation showed a high correlation between age and hearing threshold. Of the patients between 40 and 50 years old, 56% had hearing loss., Conclusion: Hearing loss in individuals with OI is still a relevant problem, especially age-related in OI type I. Audiometry should be performed at least when individuals experience subjective hearing loss. The implementation of a screening starting at 40 years should be discussed and studied., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest. The authors have no relevant financial or non-financial interests to disclose. Institutional review board statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of University Hospital, LMU Munich (protocol code 22–0357 and date of approval 17.05.2022). Informed consent statement: Informed consent was obtained from all subjects involved in the study., (© 2024. The Author(s).)

The phase 2 CLL2-BZAG trial tested a measurable residual disease (MRD)-guided combination treatment of zanubrutinib, venetoclax and obinutuzumab after an optional bendamustine debulking in patients with relapsed/refractory CLL. In total, 42 patients were enrolled and two patients with ≤2 induction cycles were excluded from the analysis population per protocol. Patients had a median of one prior therapy (range 1-5), 18 patients (45%) had already received a BTK inhibitor (BTKi), seven patients (17.5%) venetoclax, and of these, five (12.5%) had received both. Fifteen patients (37.5%) had a TP53 mutation/deletion and 31 (77.5%) had unmutated IGHV. With a median observation time of 21.5 months (range 8.0-35.3) the most common adverse events were COVID-19 (n=26 patients), diarrhea (n=15), infusion-related reactions (n=15), thrombocytopenia (n=14), nausea (n=12), fatigue (n=12) and neutropenia (n=12). Two patients had fatal adverse events (COVID-19, fungal pneumonia secondary to COVID-19). After six months of the triple combination all patients responded and 21 (52.5%, 95% confidence interval 36.1%-68.5%) showed uMRD in peripheral blood. In many patients remissions deepened over time with a best uMRD rate of 85%. The best uMRD rate was similar in patients with TP53 aberrations (80%) and patients previously exposed to venetoclax/BTKi (80%). The estimated progression-free and overall survival rates at 18 months were 96% and 96.8%. No patient has yet required a subsequent treatment. In summary, the MRD-guided triple combination of zanubrutinib, venetoclax and obinutuzumab induced deep remissions in a relapsed CLL population enriched for patients previously treated with a BTKi/venetoclax. ClinicalTrials.gov NCT04515238., (Copyright © 2025 American Society of Hematology.)

The medulla is the part of the Drosophila optic lobe with the greatest neuronal diversity, in which the identity of each neuronal type is specified in progenitors and newborn neurons via the integration of temporal, spatial, and Notch-driven patterning mechanisms. This identity is maintained in differentiating and adult neurons by the expression of neuronal type-specific combinations of terminal selectors, which are transcription factors expressed continuously during development and in the adult that are thought to control all neuronal type-specific gene expression. However, how the patterning mechanisms establish terminal selector expression is unknown. We have previously characterized the temporal and Notch origin of medulla neurons. Here we have used single-cell mRNA-sequencing to characterize their spatial origins and identified two new spatial subdomains. Together, this makes the medulla the first complex brain structure for which the patterning mechanisms specifying the identity of each neuronal type are known. This knowledge allowed us to identify correlations between patterning information, terminal selector expression and neuronal features. Our results suggest that different subsets of the patterning information accessible to a given neuronal type control the expression of each of its terminal selectors and of modules of terminal features, including neurotransmitter identity. Therefore, the evolution of new neuronal types could rely on the acquisition of modules of neuronal features predetermined by their developmental origin., Competing Interests: Declaration of Interests: The authors declare no competing interests.

Background: The results of pulmonary vein isolation (PVI) are limited by arrhythmia recurrence, which is most often due to failure to effectuate a durable contiguous circumferential transmural lesion around the pulmonary vein ostia., Objective: We sought to determine if enhancing the index ablation line through the use of multiple cryoballoon diameters would be superior to standard ablation with bonus freeze., Methods: We enrolled 226 consecutive patients referred for cryoballoon-based PVI. Patients underwent PVI either with the 28-mm Arctic Front Advance (Medtronic, Minneapolis, Mn) cryoballoon using two 4-minute freezes (standard group) or with the POLARx FIT (Boston Scientific, Marlborough, Ma) cryoballoon using 3-minute freezes in both the 28- and 31-mm-diameter configurations (double stack group). Patients were followed for up to 1 year. The primary outcome was atrial tachyarrhythmia recurrence, with peri-procedural complications, cardioversion, emergency department visit, hospitalization, and repeat ablation being secondary outcomes., Results: A total of 226 patients were included (70% male; 47% with persistent atrial fibrillation [AF]). Patients in the double stack group had a significantly greater freedom from recurrent AF/atrial tachycardia/atrial flutter at 1 year (87.2% vs 68.9%; hazard ratio 0.41; 95% confidence interval 0.24-0.71; P=.008). Periprocedural complications were similar between the groups (5.2% vs 3.4%; P=.50). At 1 year, there was no difference in cardioversion (12.8% vs 20.3%; P=.20), emergency department visit (9.0% vs 15.5%; P=.22), or all-cause hospitalization (1.3% vs 2.7%; P=.66). Significantly less patients treated with double stack underwent repeat ablation (1.3% vs 13.5%; P=.002)., Conclusion: In a mixed cohort of patients with paroxysmal and persistent AF, cryoballoon ablation using the double stack technique is associated with lower rates of AF recurrence, aggregate healthcare utilisation, and lower rates of repeat ablation., Competing Interests: Disclosures Dr Andrade reports personal fees from Medtronic, Boston Scientific, J&J MedTech Kardium, and Abbott. Dr Deyell reports grants and personal fees from J&J MedTech, and Kardium. Dr Macle reports personal fees from Medtronic and grants and personal fees from St. Jude Medical/Abbott and J&J MedTech. The rest of the authors have nothing to disclose., (Copyright © 2025 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Precision medicine involves a paradigm shift toward personalized data-driven clinical decisions. The concept of a medical "digital twin" has recently become popular to designate digital representations of patients as a support for a wide range of data science applications. However, the concept is ambiguous when it comes to practical implementations. Here, we propose a medical digital twin framework with a data-centric approach. We argue that a single digital representation of patients cannot support all the data uses of digital twins for technical and regulatory reasons. Instead, we propose a data architecture leveraging three main families of digital representations: (1) multimodal dashboards integrating various raw health records at points of care to assist with perception and documentation, (2) virtual patients, which provide nonsensitive data for collective secondary uses, and (3) individual predictions that support clinical decisions. For a given patient, multiple digital representations may be generated according to the different clinical pathways the patient goes through, each tailored to balance the trade-offs associated with the respective intended uses. Therefore, our proposed framework conceives the medical digital twin as a data architecture leveraging several digital representations of patients along clinical pathways., (© Stanislas Demuth, Jérôme De Sèze, Gilles Edan, Tjalf Ziemssen, Françoise Simon, Pierre-Antoine Gourraud. Originally published in JMIR Medical Informatics (https://medinform.jmir.org).)

Live-cell microscopy routinely provides massive amounts of time-lapse images of complex cellular systems under various physiological or therapeutic conditions. However, this wealth of data remains difficult to interpret in terms of causal effects. Here, we describe CausalXtract, a flexible computational pipeline that discovers causal and possibly time-lagged effects from morphodynamic features and cell-cell interactions in live-cell imaging data. CausalXtract methodology combines network-based and information-based frameworks, which is shown to discover causal effects overlooked by classical Granger and Schreiber causality approaches. We showcase the use of CausalXtract to uncover novel causal effects in a tumor-on-chip cellular ecosystem under therapeutically relevant conditions. In particular, we find that cancer-associated fibroblasts directly inhibit cancer cell apoptosis, independently from anticancer treatment. CausalXtract uncovers also multiple antagonistic effects at different time delays. Hence, CausalXtract provides a unique computational tool to interpret live-cell imaging data for a range of fundamental and translational research applications., Competing Interests: FS, MC, TT, LD, VC, NL, AM, MP, EM, HI No competing interests declared, (© 2024, Simon, Comes, Tocci et al.)

We present measurements of the atmospheric depth of the shower maximum X&#95;{max}, inferred for the first time on an event-by-event level using the surface detector of the Pierre Auger Observatory. Using deep learning, we were able to extend measurements of the X&#95;{max} distributions up to energies of 100 EeV (10^{20}  eV), not yet revealed by current measurements, providing new insights into the mass composition of cosmic rays at extreme energies. Gaining a 10-fold increase in statistics compared to the fluorescence detector data, we find evidence that the rate of change of the average X&#95;{max} with the logarithm of energy features three breaks at 6.5±0.6(stat)±1(syst)  EeV, 11±2(stat)±1(syst)  EeV, and 31±5(stat)±3(syst)  EeV, in the vicinity to the three prominent features (ankle, instep, suppression) of the cosmic-ray flux. The energy evolution of the mean and standard deviation of the measured X&#95;{max} distributions indicates that the mass composition becomes increasingly heavier and purer, thus being incompatible with a large fraction of light nuclei between 50 and 100 EeV.

Background: Graphite Furnace-Atomic Absorption Spectrometry (GF-AAS) is a powerful technique for trace element analysis, offering high sensitivity and precision. However, its effectiveness is limited by sample preparation challenges for solid samples like soils and microplastics. Traditional methods include sample preparation, such as digestion, which is time-consuming and involves reagents, like acids, contributing to measurement uncertainty and higher carbon footprints. Slurry sampling allows direct analysis of suspensions, offering a more efficient alternative. However, maintaining suspension stability is challenging, requiring robust autosampler systems to streamline the process and enhance analytical performance., Results: We present a novel autosampler extension for slurry sample introduction into GF-AAS. This system ensures suspension stability with a stirring device and closed vessels to prevent evaporation and contamination, incorporating a cooling unit to reduce solvent and analyte losses. It installs and removes in minutes without additional connections. Validation with cadmium analysis in BAM-U110 (Soil) and BAM-H010 (ABS) showed high reliability. For BAM-U110 (Soil), we achieved recovery rates of 94 % ± 13 % in water suspension. The recovery rate for BAM-H010 (ABS) was 104 % ± 11 % in acetonitrile suspension. These results demonstrate the system's robustness, versatility, and accuracy for different matrices., Significance: The autosampler extension helps solve key problems in trace element analysis of solid samples, making the process faster and more accurate. It works well with complex materials, making it useful for areas like microplastic or nanoparticle analysis. This improvement also helps meet regulations for monitoring environmental and polymer samples, offering a reliable and flexible tool for high-throughput analysis with fewer errors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The Drosophila visual system is a powerful model to study the development of neural circuits. Lobula columnar neurons-LCNs are visual output neurons that encode visual features relevant to natural behavior. There are ~20 classes of LCNs forming non-overlapping synaptic optic glomeruli in the brain. To address their origin, we used single-cell mRNA sequencing to define the transcriptome of LCN subtypes and identified lines that are expressed throughout their development. We show that LCNs originate from stem cells in four distinct brain regions exhibiting different modes of neurogenesis, including the ventral and dorsal tips of the outer proliferation center, the ventral superficial inner proliferation center and the central brain. We show that this convergence of similar neurons illustrates the complexity of generating neuronal diversity, and likely reflects the evolutionary origin of each subtype that detects a specific visual feature and might influence behaviors specific to each species., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Sarcopenia corresponds to a decrease in muscle mass and strength. CCL5 is a new myokine whose expression, along with the CCR5 receptor, is increased in sarcopenic muscle. Therefore, we evaluated whether CCL5 and CCR5 induce a sarcopenic-like effect on skeletal muscle tissue and cultured muscle cells. Electroporation in the tibialis anterior (TA) muscle of mice was used to overexpress CCL5. The TA muscles were analyzed by measuring the fiber diameter, the content of sarcomeric proteins, and the gene expression of E3-ligases. C 2 C 12 myotubes and single-isolated flexor digitorum brevis (FDB) fibers were also treated with recombinant CCL5 (rCCL5). The participation of CCR5 was evaluated using the antagonist maraviroc (MVC). Protein and structural analyses were performed. The results showed that TA overexpression of CCL5 led to sarcopenia by reducing muscle strength and mass, muscle-fiber diameter, and sarcomeric protein content, and by upregulating E3-ligases. The same sarcopenic phenotype was observed in myotubes and FDB fibers. We showed increased reactive oxygen species (ROS) production and carbonylated proteins, denoting oxidative stress induced by CCL5. When the CCR5 was antagonized, the effects produced by rCCL5 were prevented. In conclusion, we report for the first time that CCL5 is a novel myokine that exerts a sarcopenic-like effect through the CCR5 receptor.

We report measurements of time-dependent CP asymmetries in B^{0}→K&#95;{S}^{0}π^{0}γ decays based on a data sample of (388±6)×10^{6}  BB[over ¯] events collected at the ϒ(4S) resonance with the Belle II detector. The Belle II experiment operates at the SuperKEKB asymmetric-energy e^{+}e^{-} collider. We measure decay-time distributions to determine CP -violating parameters S and C. We determine these parameters for two ranges of K&#95;{S}^{0}π^{0} invariant mass: m(K&#95;{S}^{0}π^{0})∈(0.8,1.0)  GeV/c^{2}, which is dominated by B^{0}→K^{*0}(→K&#95;{S}^{0}π^{0})γ decays, and a complementary region m(K&#95;{S}^{0}π^{0})∈(0.6,0.8)∪(1.0,1.8)  GeV/c^{2}. Our results have improved precision as compared to previous measurements and are consistent with theory predictions.

How specification mechanisms that generate neural diversity translate into specific neuronal targeting, connectivity, and function in the adult brain is not understood. In the medulla region of the Drosophila optic lobe, neural progenitors generate different neurons in a fixed order by sequentially expressing a series of temporal transcription factors as they age. Then, Notch signaling in intermediate progenitors further diversifies neuronal progeny. By establishing the birth order of medulla neurons, we found that their temporal identity correlates with the depth of neuropil targeting in the adult brain, for both local interneurons and projection neurons. We show that this temporal identity-dependent targeting of projection neurons unfolds early in development and is genetically determined. By leveraging the Electron Microscopy reconstruction of the adult fly brain, we determined the synapse location of medulla neurons in the different optic lobe neuropils and find that it is significantly associated with both their temporal identity and Notch status. Moreover, we show that all the putative medulla neurons with the same predicted function share similar neuropil synapse location, indicating that ensembles of neuropil layers encode specific visual functions. In conclusion, we show that temporal identity and Notch status of medulla neurons can predict their neuropil synapse location and visual function, linking their developmental patterning with their specific connectivity and functional features in the adult brain., Competing Interests: Declaration of Interests The authors declare no competing interests.

The analysis of per- and polyfluoroalkyl substances (PFAS) via sum parameters like extractable organic fluorine (EOF) in combination with high resolution-continuum source-graphite furnace molecular absorption spectrometry (HR-CS-GFMAS) is highly promising regarding fluorine sensitivity and selectivity. However, the HR-CS-GFMAS method includes several drying and heating steps which can lead to losses of volatile PFAS before the molecular formation step using e.g., GaF formation. Hence, the method leads to a strong discrimination of PFAS within the EOF depending on their physical/chemical properties and is therefore associated with reduced accuracy. To reduce this discrepancy and to indicate realistic PFAS pollution values, an optimization of the HR-CS-GFMAS method for PFAS analysis is needed. Hence, we determined fluorine response factors of several PFAS with different physical/chemical properties upon application of systematic optimization steps. We could therefore improve the method's sensitivity for PFAS analysis using a modifier drying pre-treatment step followed by a sequential injection of sample solutions. The highest improvement in sensitivity of volatile PFAS was shown upon addition of a Mg modifier during drying pre-treatment. Thereby, during optimization the relative standard deviation of fluorine response factors could be reduced from 55 % (initial method) to 27 % (optimized method) leading to a more accurate determination of organofluorine sum parameters. The method provides an instrumental LOD and LOQ of β(F) 1.71 μg/L and 5.13 μg/L, respectively. Further validation aimed to investigate several matrix effects with respect to water matrices. Here, substance-specific behavior was observed. For example, perfluorooctanoic acid (PFOA) which was used as calibrator, showed signal suppressions upon high chloride concentrations (>50 mg/L). Hence, a thorough separation of Cl from analytes during sample preparation is needed for accurate sum parameter analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The aim of this article was to systematically review the literature on the pediatric population surgically treated for cholesteatoma and describe the applied post-operative follow-up strategies., Methods: A systematic review was conducted following the Primary Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement recommendations. After running the selected search string in PubMed, Scopus and Google Scholar, studies in English, reporting on surgically treated pediatric cholesteatoma patients (age younger or equal to 18 year-old) were retrieved. Both primary and revision cholesteatoma surgeries were included. Articles lacking specific data on post-surgical follow-up and case series with less than 10 patients were excluded., Results: Nineteen papers, published between 2000 and 2023, were included for final analysis. Fourteen studies were retrospective and five prospective, for a total of 1319 patients and 1349 operated ears. Male to female ratio was 1.8:1, with a mean age at surgery of 10.4 years (range 1-18). The mean length of the follow-up after surgery was 4.4 ± 1.7 years (range 1-6.9). Clinical follow-up was detailed in 9 studies (47%) with otomicroscopy being the most common evaluation. In most articles (n = 8, 50%), MRI alone was utilized for radiological follow-up, while in 3 studies (19%), CT scans were employed exclusively. In 5 studies (31%), MRI was combined with CT scans. The timing of radiological investigations varied widely (ranging from 6 months to 3 years). A second-look strategy was reported in 14 studies (74%)., Conclusion: This systematic review highlights the heterogeneity of the follow-up strategies applied to pediatric patients after cholesteatoma surgery, both in terms of timing and types of investigations., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Indolent mature B-cell neoplasms are a group of diseases in which recent therapeutic advances have led to an improved overall survival (OS) extending beyond several years. While cause of celebration for patients and caregivers, the increasingly long observation periods necessary to capture treatment effects are complicating trial design and possibly hindering swift access to more effective therapies. Surrogate endpoints are a tool with the potential of earlier study readouts, however, their validity needs to be proven in each individual disease and therapeutic setting. The validation of surrogate endpoints and available data for mature B-cell neoplasms are discussed within this perspective article, followed by an outlook on the potential of precise tools such as measurable residual disease assessment as novel surrogate candidates., Competing Interests: Competing interests: F.S. reports speaker honoraria from AstraZeneca and travel support from Lilly pharmaceuticals, as well as research funding by AstraZeneca (institution). O.A.-S. reports advisory board participation with Ascentage, AstraZeneca, AbbVie, Gilead, Janssen, and Roche; received speaker honoraria from Adaptive, AstraZeneca, AbbVie, BeiGene, Gilead, Janssen, and Roche; and received research funding from BeiGene, AbbVie, Janssen, and Roche. JFS reports honoraria from Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; consultancy fees from Hoffmann-La Roche, TG Therapeutics, Bristol Myers Squibb; participating on a data safety monitoring board or advisory board with Genor Bio, Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; speakers bureau with Hoffmann-La Roche, AbbVie, and BeiGene; and research funding from F Hoffmann-La Roche and AbbVie. B.E. reports grants and personal fees from F. Hoffmann-La Roche Ltd, AbbVie, AstraZeneca, BeiGene, and Janssen; reports personal fees from Celgene, Novartis, ArQule, Gilead, Oxford Biomedica (United Kingdom), Adaptive Biotechnologies, and Hexal., (© 2024. The Author(s).)