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Abstract Crustal fault zones, holding promise as potential geothermal reservoirs, remain largely untapped and unexplored. Located in the southern Massif Central, France, the Margeride fault zone (MFZ) varies in thickness (lateral extension perpendicular to the fault plane) from 100 m to over 2500 m. Reactivated several times under different stress regimes since the Variscan orogeny, this zone is characterized by an intense alteration and fracturing. As a result, the multiple reactivation of the fault zone has maintained permeability, leading to favourable conditions for fluid circulation. Structural measurements and geological cross sections were used to precisely constrain thickness and geometry of the fault zone. North of the MFZ, the Coren thermal spring indicates reservoir temperatures of about 200–250 °C, hinting at the possible existence of a temperature anomaly. To investigate this geothermal potential, 3D numerical models simulating fluid circulation within a fault zone were conducted. Various configurations were explored, altering fault zone thickness and permeability for two key geometries. The first geometry, which manipulated the width of the fault zone along its length, demonstrated a direct correlation between fault zone thickness and amplitude of thermal anomaly. Thinner faults ( 500 m) tended to develop a single, substantial positive thermal anomaly. In the second examined geometry, where fault zone thickness increased longitudinally, a consistent positive temperature anomaly emerged at the thickest section of the fault zone. Depending on the permeability value, an additional anomaly may develop but will migrate laterally towards the thinnest part of the fault zone. This multi-disciplinary approach, combining numerical modelling and field measurements, presents a predictive methodology applicable to geothermal exploration in analogous basement domains. In our case, it has shown that the northern end of the Margeride fault zone could represent an area that needs to be explored further to assert its high geothermal potential. Our numerical models will increase understanding of how fault width and geometry impact the geothermal potential of the Margeride fault zone and similar areas in crystalline basement.

Abstract Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that plays an essential role during brain development. Using genetically engineered mouse model and primary neuronal cells, we identify the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensures proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlight a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

Abstract Prime Editing can rewrite genes in living cells by allowing point mutations, deletions, or insertion of small DNA sequences with high precision. However, its safe and efficient delivery into human stem cells remains a technical challenge. In this report, we engineer Nanoscribes, virus-like particles that encapsidate ribonucleoprotein complexes of the Prime Editing system and allow their delivery into recipient cells. We identify key features that unlock the potential of Nanoscribes, including the use of multiple fusogens, the improvement of pegRNAs structures, their encoding by a Pol II system and the optimization of Prime-Editors. Nanoscribes edit HEK293T with an efficiency of 68% at the HEK3 locus with increased fidelity over DNA-transfection and support pegRNA-multiplexing. Importantly, Nanoscribes permit editing of myoblasts, hiPSCs and hiPSCs-derived hematopoietic stem cells with an editing efficiency up to 25%. Nanoscribes is an asset for development of next generation genome editing approaches using VLPs.

Abstract Background Sepsis-associated encephalopathy (SAE) may be worsened by early systemic insults. We aimed to investigate the association of early systemic insults with outcomes of critically ill patients with severe SAE. Methods We performed a retrospective analysis using data from the French OUTCOMEREA prospective multicenter database. We included patients hospitalized in intensive care unit (ICU) for at least 48 h with severe SAE (defined by a score on the Glasgow Coma Scale (GCS) ≤ 13 and severe sepsis or septic shock (SEPSIS 2.0 criteria)) requiring invasive ventilation and who had no primary brain injury. We analyzed early systemic insults (abnormal glycemia ( 200 mmHg), carbon dioxide abnormalities ( 13. Results We included 995 patients with severe SAE, of whom 883 (89%) exhibited at least one early systemic insult that persisted through day 3. Compared to non-survivors, survivors had significantly less early systemic insults (hypoglycemia, hypotension, hypothermia, and anemia) within the first 48 h of ICU admission. The absence of correction of the following systemic insults at day 3 was independently associated with mortality: blood pressure (adjusted hazard ratio (aHR) = 1.77, 95% confidence interval (CI) 1.34–2.34), oxygenation (aHR = 1.78, 95% CI 1.20–2.63), temperature (aHR = 1.46, 95% CI 1.12–1.91) and glycemia (aHR = 1.41, 95% CI 1.10–1.80). Persistent abnormal blood pressure, temperature and glycemia at day 3 were associated with decreased chances of awakening. Conclusions In patients with severe SAE, the persistence of systemic insults within the first three days of ICU admission is associated with increased mortality and decreased chances of awakening.

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in individuals with obesity. Sexual dimorphism is present in MASLD. A noninvasive test to diagnose the severity of the disease, in particular the presence of Metabolic dysfunction-associated steatohepatitis (MASH), is lacking. This European multicenter prospective study uses a blood test based on mid-infrared (MIR) metabolic fingerprinting of individuals with severe or morbid obesity to diagnose MASH. Three hundred eighty-two individuals with severe or morbid obesity undergoing bariatric surgery were enrolled prospectively. Liver biopsies were obtained during surgery and assessed centrally. An algorithm was defined to calculate a score from the recorded MIR spectrum and to establish a diagnostic threshold to classify patients with MASH. Among the women (n = 217), MASH was diagnosed in 14.3% of cases. For women, the performance in terms of AUC were 0.83 and 0.82 in the calibration and validation groups, respectively. For a threshold of 0.1817, sensitivities were 86% and 70%, specificities were 81% and 75%, PPV were 43% and 32%, NPV were 97% and 94% and ACC were 82% and 74% for the calibration and validation groups, respectively. For men (n = 78; MASH: 33.3%), the performance of the spectral model was poor. The metabolic fingerprint obtained by MIR spectroscopy can rule out MASH in women with severe or morbid obesity. Its value in men needs new studies. Trial registration: ClinicalTrials.gov identifier: ClinicalTrials.gov identifier: NCT03978247 (04/06/2019)

Abstract A serious issue with geothermal power plants is the loss of production and decline in power plant efficiency. Scaling, also known as mineral precipitation, is one of the frequently-observed issue that causes this loss and decreasing efficiency. It is heavily observed in the production wells when the geothermal fluid rises from the depths due to a change in the fluid’s physical and chemical properties. Scaling issue in geothermal power plants result in significant output losses and lower plant effectiveness. In rare instances, it might even result in the power plant being shut down. The chemistry of the geothermal fluid, non-condensable gases, pH, temperature and pressure changes in the process from production to reinjection, power plant type and design, and sometimes the materials used can also play an active role in the scaling that will occur in a geothermal system. ICP–MS was used to evaluate the chemical properties of the fluids. On the other hand, XRD, XRF and SEM were used to investigate the chemical and mineralogical compositions of the scale samples in analytical methods. For the numerical approach, PhreeqC and GWELL codes were used to follow the chemical reactivity of the geothermal fluid in Tuzla production well. The novelty of this study is to determine potential degassing point and to characterize the mineralogical assemblage formed in the well because of the fluid composition, temperature and pressure variations. During production, geothermal fluids degas in the wellbore. This causes a drastic modification of the chemistry of the Tuzla fluids. This is why it is focused the calculations on the nature of the minerals that are able to precipitate inside the well. According to simulation results, the degassing point is estimated to be about 105 m depth, consistent with the field observations. If a small quantity of precipitated minerals is predicted before the boiling point, degassing significantly changes the fluid chemistry, and the model predicts the deposition of calcite along with smaller elements including galena, barite, and quartz. The simulation results are consistent with the mineral composition of scaling collected in the well.

Abstract Background Synchronous malignant histiocytoses are rare conditions that occur concurrently with another hematologic neoplasm. Most reported cases are associated with B-cell lymphoproliferative disorders, while associations with T-cell hemopathies are less common. These two diseases may share mutations and/or cytogenetic anomalies, which can lead to malignant proliferations. In such cases, the term “secondary malignant histiocytosis” can be applied. Case description A 26-year-old patient was diagnosed with anaplastic lymphoma kinase negative anaplastic large cell lymphoma [ALK-ALCL] associated with synchronous malignant histiocytosis. Neoplastic cells were distinguished by the exclusivity of the rearrangement of TCR genes within the lymphoma cells, whereas mutations in the KRAS and TP53 genes affected mono-histiocytic cells. However, these two cells populations shared common chromosomal abnormalities. First line treatment protocol included Brentuximab vedotin, cyclophosphamide, doxorubicin, and methylprednisolone. Despite a partial clinical and biological response after cycle 1 of treatment, the patient was refractory at the end of cycle 2. Patient died in the intensive care unit from a multiple-organ failure related to lymphohistiocytic hemophagocytosis. Conclusion This case represents the first documented instance of synchronous malignant histiocytosis associated with anaplastic large cell lymphoma. Notably, the uniqueness of this case lies in the absence of TCR rearrangement in the histiocytic cells, despite the presence of shared chromosomal abnormalities with the lymphomatous cells indicating a common origin for both neoplastic proliferations. Considering the rarity of such occurrences, the use of histiocytosis targeted therapy alongside conventional lymphoma treatment warrants consideration in such a context.

Abstract Mice have evolved a new dental plan with two additional cusps on the upper molar, while hamsters were retaining the ancestral plan. By comparing the dynamics of molar development with transcriptome time series, we found at least three early changes in mouse upper molar development. Together, they redirect spatio-temporal dynamics to ultimately form two additional cusps. The mouse lower molar has undergone much more limited phenotypic evolution. Nevertheless, its developmental trajectory evolved as much as that of the upper molar and co-evolved with it. Among the coevolving changes, some are clearly involved in the new upper molar phenotype. We found a similar level of coevolution in bat limbs. In conclusion, our study reveals how serial organ morphology has adapted through organ-specific developmental changes, as expected, but also through shared changes that have organ-specific effects on the final phenotype. This highlights the important role of developmental system drift in one organ to accommodate adaptation in another.

Abstract Prolonged contact between a corrosive liquid and metal alloys can cause progressive dealloying. For one such process as liquid-metal dealloying (LMD), phase field models have been developed to understand the mechanisms leading to complex morphologies. However, the LMD governing equations in these models often involve coupled non-linear partial differential equations (PDE), which are challenging to solve numerically. In particular, numerical stiffness in the PDEs requires an extremely refined time step size (on the order of 10−12 s or smaller). This computational bottleneck is especially problematic when running LMD simulation until a late time horizon is required. This motivates the development of surrogate models capable of leaping forward in time, by skipping several consecutive time steps at-once. In this paper, we propose a U-shaped adaptive Fourier neural operator (U-AFNO), a machine learning (ML) based model inspired by recent advances in neural operator learning. U-AFNO employs U-Nets for extracting and reconstructing local features within the physical fields, and passes the latent space through a vision transformer (ViT) implemented in the Fourier space (AFNO). We use U-AFNOs to learn the dynamics of mapping the field at a current time step into a later time step. We also identify global quantities of interest (QoI) describing the corrosion process (e.g., the deformation of the liquid-metal interface, lost metal, etc.) and show that our proposed U-AFNO model is able to accurately predict the field dynamics, in spite of the chaotic nature of LMD. Most notably, our model reproduces the key microstructure statistics and QoIs with a level of accuracy on par with the high-fidelity numerical solver, while achieving a significant 11, 200 × speed-up on a high-resolution grid when comparing the computational expense per time step. Finally, we also investigate the opportunity of using hybrid simulations, in which we alternate forward leaps in time using the U-AFNO with high-fidelity time stepping. We demonstrate that while advantageous for some surrogate model design choices, our proposed U-AFNO model in fully auto-regressive settings consistently outperforms hybrid schemes.

Abstract: There is a scarcity of data on the tumor B-cell receptor (BCR) repertoire and lymphoid microenvironment in primary mediastinal B-cell lymphoma (PMBL). We applied 5ʹ rapid amplification of complimentary DNA ends (5′RACE) to tumor RNA samples from 137 patients with PMBL with available gene expression profiling and next-generation sequencing data. We obtained 5′RACE results for 75 of the 137 (54.7%) patients with the following clinical characteristics: median age (range), 33 years (18-64); female, 53.3%; performance status score 0 to 1, 86.7%; stage I to II, 57.3%; first-line treatment with anti-CD20 plus doxorubicin-based chemotherapy, 100%. Among the 60 biopsies that expressed a productive BCR, we highlighted a strong somatic hypermutation profile, defined as 81.1% and >78.6% of all complementarity-determining region 3 sequences for IgVH and IgVL, respectively. When compared with other patients, this subgroup had similar clinical characteristics but a greater median allele frequency for all somatic variants, a decreased BCR diversity, and greater expression of PDL1/PDL2 and MS4A1 genes, suggesting greater tumoral infiltration. We confirmed this poorer prognosis in a multivariate model and in an independent validation cohort in which 6 of 37 (16%) PMBL patients exhibited HCD (PFS: HR, 12; OS: HR, 17).

Abstract: Activated protein C (APC) is a pleiotropic plasma protease with diverse functions derived from its anticoagulant, anti-inflammatory, and cytoprotective activities. The selective uncoupling and/or modulation of these APC activities by antibodies may have therapeutic benefit in diseases such as traumatic bleeding, hemophilia, sepsis, and ischemia. TPP-26870 is an antibody that targets a nonactive site of APC for the selective modulation of APC activities. To optimize the potency of TPP-26870, variants with single amino acid mutation in the complementarity-determining regions (CDRs) were screened, and 21 variants with improved affinity constant were identified. Interestingly, the affinity maturation of TPP-26870 did not merely generate a panel of variants with higher potency in functional assays. Functional data demonstrated that the pleiotropic functions of APC were very sensitive to epitope-CDR interactions. Single amino acid mutations within the CDRs of TPP-26870 were sufficient to elicit divergent antagonistic and agonistic effects on the various APC functional activities. These include prolonged in vitro APC plasma half-life, increased inhibition of anticoagulant activity, and agonistic enhancement of histone H3 cleavage, while having less impact on protease-activated receptor 1 cleavage, compared with TPP-26870. This study illustrates that APC is highly sensitive to non–active site targeting that can lead to unpredictable changes in its activity profile of this pleiotropic enzyme. Furthermore, this study demonstrates the ability to modify APC functions to advance the potential development of APC-targeted antibodies as therapeutics for the treatment of diseases including trauma bleeding, hemophilia, ischemia, and sepsis.

Abstract High mortality and low response rates in lung cancer patients call for novel therapeutic targets. Data mining of whole-genome genetic dependency screens suggest Cell Division Cycle 40 (CDC40) to be an essential protein for lung cancer cell survival. We characterized CDC40 knockdown effects in multiple lung cancer cell lines, revealing induced cell cycle defects that resulted in strong growth inhibition and activation of apoptosis. Global transcriptional and splicing changes were also investigated, where CDC40 knockdown resulted in perturbation of splicing- and translation-related genes as well as more transcripts with intron retention. In the transcript of the cell cycle regulatory protein CDCA5, CDC40 knockdown was shown to induce retention of the first intron, leading to an increase in the unspliced CDCA5 transcript and subsequent decrease in CDCA5 protein expression. Additionally, protein–protein interactions of CDC40 were explored and spliceosome components were found to be its main binding partners, further highlighting the role of CDC40 in splicing. CDC40 mutation analysis suggests that it may be difficult to disrupt key interactions using small molecules within a large complex. Our results demonstrate that CDC40 is essential for lung cancer cell growth, and that its inhibition may represent a viable therapeutic strategy for lung cancer.

Abstract Our study explores the complex dynamics of the integrated stress response (ISR) axis, highlighting PIM2 kinase’s critical role and its interaction with the BCL2 protein family, uncovering key mechanisms of cell survival and tumor progression. Elevated PIM2 expression, a marker of various cancers, often correlates with disease aggressiveness. Using a model of normal and malignant plasma cells, we show that inhibiting PIM2 kinase inhibits phosphorylated BAD production and activates ISR-mediated NOXA expression. This shift towards MCL1 dependence underscores the synergy achieved through combined PIM/MCL1 inhibition, driven largely by ISR-mediated NOXA expression. In mouse xenograft models, dual targeting of PIM2 and MCL1 effectively controls tumor growth—a response reversed by ISR-specific inhibition and upregulation of genes linked to tumor cell dissemination. This work elucidates the molecular intricacies of PIM2 inhibition and its implications for cancer therapy, especially in tumors with elevated PIM2 expression.

Abstract Current temporal studies of DNA replication are either low-resolution or require complex cell synchronisation and/or sorting procedures. Here we introduce Nanotiming, a single-molecule, nanopore sequencing-based method producing high-resolution, telomere-to-telomere replication timing (RT) profiles of eukaryotic genomes by interrogating changes in intracellular dTTP concentration during S phase through competition with its analogue bromodeoxyuridine triphosphate (BrdUTP) for incorporation into replicating DNA. This solely demands the labelling of asynchronously growing cells with an innocuous dose of BrdU during one doubling time followed by BrdU quantification along nanopore reads. We demonstrate in S. cerevisiae model eukaryote that Nanotiming reproduces RT profiles generated by reference methods both in wild-type and mutant cells inactivated for known RT determinants. Nanotiming is simple, accurate, inexpensive, amenable to large-scale analyses, and has the unique ability to access RT of individual telomeres, revealing that Rif1 iconic telomere regulator selectively delays replication of telomeres associated with specific subtelomeric elements.

Abstract Background Advances in secondary stroke prevention, including direct oral anticoagulants (DOACs), dual antiplatelet therapies (DAPT), and cardiovascular risk management, have changed costs over the past decade. This study aimed to evaluate annual treatment costs and trends in drug-based secondary prophylaxis after ischemic strokes. Methods Annual treatment costs were evaluated using the net costs per defined daily dosage (DDD) of discharge medications for ischemic stroke patients treated in 2020 at the University Hospital Frankfurt, Germany. Evaluated drugs included acetylsalicylic acid, adenosine diphosphate inhibitors, DOACs, vitamin K antagonists, lipid-lowering drugs (LLD), antihypertensives (AHT), and oral antidiabetics (OD). Kruskal–Wallis test examined intergroup differences in substance groups and stroke etiologies. DDD development between 2004 and 2021 was further evaluated for significant trend changes using an interrupted time series analysis. Results The study included 422 patients (70.5 ± 12.9 years, 43.1% female). Etiologies divided into large-artery atherosclerosis (29.9%), cardioembolic (25.6%), cryptogenic (26.8%), and small-vessel disease (17.8%). The total estimated annual drug expenditure was € 241,808; of which 51.6% was due to DOACs (median € 1157 [Q1–Q3:1157–1157], p

Resonant inelastic X-ray scattering (RIXS) is an ideal X-ray spectroscopy method to push the combination of energy and time resolutions to the Fourier transform ultimate limit, because it is unaffected by the core-hole lifetime energy broadening. Also, in pump–probe experiments the interaction time is made very short by the same core-hole lifetime. RIXS is very photon hungry so it takes great advantage from high-repetition-rate pulsed X-ray sources like the European XFEL. The Heisenberg RIXS instrument is designed for RIXS experiments in the soft X-ray range with energy resolution approaching the Fourier and the Heisenberg limits. It is based on a spherical grating with variable line spacing and a position-sensitive 2D detector. Initially, two gratings were installed to adequately cover the whole photon energy range. With optimized spot size on the sample and small pixel detector the energy resolution can be better than 40 meV (90 meV) at any photon energy below 1000 eV with the high-resolution (high-transmission) grating. At the SCS instrument of the European XFEL the spectrometer can be easily positioned thanks to air pads on a high-quality floor, allowing the scattering angle to be continuously adjusted over the 65–145° range. It can be coupled to two different sample interaction chambers, one for liquid jets and one for solids, each state-of-the-art equipped and compatible for optical laser pumping in collinear geometry. The measured performances, in terms of energy resolution and count rate on the detector, closely match design expectations. The Heisenberg RIXS instrument has been open to public users since the summer of 2022.

Background: Tendon transfers of the latissimus dorsi transfer (LDT) or the lower trapezius transfer (LTT) are treatment options for irreparable posterosuperior irreparable rotator cuff tears (PSIRCT). There is still no consensus on which type of tendon transfer is superior in the treatment of PSIRCT. Due to the differences in the anatomy and biomechanics, we hypothesize that there are different clinical situations in which either LDT or LTT should be preferred. The aim of this study was to evaluate the clinical and radiological outcomes of LDT and LTT in patients with PSIRCT to establish a clinical algorithm for the treatment decision. Materials and methods: This is a retrospective, single-center observational study. Included were patients who underwent arthroscopically assisted LDT (aaLDT) or arthroscopically assisted LTT (aaLTT) for PSIRCT. In all patients, range of motion (ROM), external rotation strength, visual analog scale of pain and subjective shoulder value were determined pre- and postoperatively. Constant–Murley score was evaluated at the final follow-up. The complication rate, failure of the tendon transfer, and revision rate were analyzed. Results: In total, 29 aaLDT (age 64 years, median follow-up time 45 months) and 8 aaLTT (age 54 years, median follow-up time 34 months) were included. Active ROM, visual analog scale and subjective shoulder value was significantly improved in both cohorts. At follow-up, the median Constant–Murley score was 73 (aaLDT) and 77 (aaLTT), respectively. The failure rate, including revision surgery, was 14% (aaLDT) and 13% (aaLTT), respectively. Low functional findings preoperatively were correlated to a lower functional outcome at follow-up in both groups. Painful loss of anterior elevation and loss of external rotation had no significant impact on functional outcomes in aaLDT. Conclusion: Following the treatment algorithm based on the clinical examination, clinical outcome parameters, active ROM and pain could be significantly improved. A good preoperative function was associated with a good clinical outcome in both transfers. A low failure and revision rate supports the good decision-making of the algorithm presented.

Abstract Background Subclinical depressive symptoms increase the risk of developing Alzheimer’s disease (AD). The neurobiological mechanisms underlying this link may involve stress system dysfunction, notably related to the hippocampus which is particularly sensitive to AD. We aimed to investigate the links between blood stress markers and changes in brain regions involved in the stress response in older adults with or without subclinical depressive symptoms. Methods This cross-sectional study was conducted using baseline data from the Age-Well trial. Cognitively unimpaired (CU) older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15-item Geriatric Depression Scale) were included in the analyses. Blood cortisol, epinephrine and norepinephrine were measured; as well as the resting-state functional connectivity (rs-FC) between, and gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields. Blood stress markers levels and neuroimaging measures were compared between groups; then regression analyses were conducted between these measures. Results DepS participants showed higher plasma epinephrine levels, which was associated with greater rs-FC between the CA1 and Subiculum hippocampal subfields and the hypothalamus. Lower GM volume in the CA1 and DG/CA2-3–4 subfields was also found in DepS. No between-group differences were observed for blood cortisol and norepinephrine. Conclusions Our findings show that subclinical depressive symptoms are associated with increased sympatho-adrenomedullary axis activity, together with lower GM volume in a hippocampal subfield (i.e., CA1) particularly sensitive to AD. While causation cannot be inferred, these results suggest that screening and treating subclinical depressive symptoms in CU older adults could reduce AD risk. Trial registration ClinicalTrials.gov Identifier: NCT02977819, Registration Date: 2016–11-25.

Abstract Wind turbines used to combat climate change pose a green-green dilemma when endangered and protected wildlife species are killed by collisions with rotating blades. Here, we investigated the geographic origin of bats killed by wind turbines along an east-west transect in France to determine the spatial extent of this conflict in Western Europe. We analysed stable hydrogen isotopes in the fur keratin of 60 common noctule bats ( Nyctalus noctula ) killed by wind turbines during summer migration in four regions of France to predict their geographic origin using models based on precipitation isoscapes. We first separated migratory from regional individuals based on fur isotope ratios of local bats. Across all regions, 71.7% of common noctules killed by turbines were of regional and 28.3% of distant origin, the latter being predominantly females from northeastern Europe. We observed a higher proportion of migratory individuals from western sites compared to eastern sites. Our study suggests that wind-turbine-related losses of common noctule bats may impact distant breeding populations across whole Europe, confirming that migratory bats are highly vulnerable to wind turbines and that effective conservation measures, such as temporary curtailment of turbine operation, should be mandatory to protect them from colliding with the rotating blades of wind turbines.

As the 7th Earth Explorer Mission within the ESA Earth Observation Program, BIOMASS will be the first spaceborne P-band polarimetric interferometric SAR (PolInSAR) mission, dedicated to global forest remote sensing. Compared with airborne PolInSAR, BIOMASS PolInSAR faces several intrinsic limitations, including the reduced number of baselines, low bandwidth of 6 MHz, and the 3-day repeat-pass acquisition mode. In this study, the capabilities of three-baseline PolInSAR in BIOMASS configuration and the spaceborne system-induced impacts are systematically evaluated. First, the BIOMASS data were simulated using the airborne P-band SAR acquisitions collected over two different tropical forests in Paracou, French Guiana, and Mondah, Gabon. Second, the forest height was retrieved using a three-baseline algorithm based on polarimetric coherence optimization with multi-baseline joint diagonalization. Finally, the impacts of spaceborne PolInSAR were quantified and analyzed. The results show that the performance of PolInSAR inversion in the spaceborne configuration decreases compared to that of the original airborne data. However, the three-baseline method still yields acceptable results, with a root-mean-square error ranging from 4.92 to 6.07 m and a correlation coefficient (R2) from 0.32 to 0.85, within hectare-scale forest height statistics. This study demonstrates that the limited bandwidth of BIOMASS has a certain impact on refined forest structure parameter retrieval, while the three-baseline PolInSAR method remains effective for large-scale forest mapping, with accuracy meeting the design requirements of the BIOMASS mission.

Temnospondyli appeared in the early Carboniferous, became extinct in the Early Cretaceous and reached high diversity especially during the Permian and Triassic. After the end-Permian mass extinction, almost only Stereospondyli survived (with the exception of the dissorophoid Micropholis). This clade radiated and gave rise to several successful groups: Plagiosauroidea, Trematosauroidea, Metoposauroidea, Capitosauria, and Brachyopoidea. While Brachyopoidea survived into the Early Cretaceous, the other groups were thought to have gradually disappeared during the Late Triassic, going extinct before the Rhaetian. This hypothesis was supported by the lack of unambiguously dated Rhaetian localities with Stereospondyli fossils. This gap was filled by the discovery of the Bonenburg clay pit in North Rhine-Westphalia (Germany). This locality has been unequivocally dated to the late middle Rhaetian and had yielded a temnospondyl fossil assigned to Capitosauria. Here we describe further Stereospondyli fossils from Bonenburg, including diagnostic bones such as a dentary, a pterygoid, a parietal, and eight other bones in different states of preservation. These fossils belong to at least two taxa of Capitosauria and one taxon of Plagiosauridae and represent the geologically youngest remains of both clades. The specimens are described morphologically, and for the long bones, a clavicle fragment, and an unidentified dermal bone, histological analysis was used to further confirm the morphological analysis. These results shed light on the extinction of two major groups of Stereospondyli, documenting that some non-brachyopoid temnospondyls survived until the end of the Triassic.

Abstract In the aim of designing and developing a novel saponin-based adjuvant system, we combined the QS21 saponin with low microgram amounts of the fully synthetic TLR4 agonist, E6020, in cholesterol-containing liposomes. The resulting adjuvant system, termed SPA14, appeared as a long-term stable and homogeneous suspension of mostly unilamellar and a few multilamellar vesicles, with an average hydrodynamic diameter of 93 nm, when formulated in citrate buffer at pH 6.0-6.5. When compared in an in vitro human innate immunity construct to AS01B, the QS21/MPL® liposomal adjuvant system of GSK, and with QS21-Liposomes used as benchmarks, SPA14 displayed the strongest immunostimulatory potential based on antigen-presenting cell (APC) activation and cytokine secretion, which was essentially driven by the highly active E6020 agonist in this assay. When tested as an adjuvant in vivo with human cytomegalovirus glycoprotein B (gB) and pentamer complex (PC) as test antigens, SPA14 was generally well tolerated and as active as AS01B for the induction of long-lasting CMV-neutralizing antibodies in mice and non-human primates (NHPs). Both adjuvants promoted the induction of Th-1 responses based on IgG2c production in mice and IFN-γ production in mice and NHPs, but in mice, a higher level of Th-2 cytokines (IL-5) and higher IgG1 over IgG2c secreting cells ratios were obtained with SPA14 indicating that the adjuvant profile of SPA14 could be less Th-1 biased than that of AS01B. From a developability standpoint, SPA14 could be manufactured by a simple and scalable ethanol injection method, owing to the high solubility in ethanol of all its lipidic components, including E6020. Furthermore, E6020 is a single molecule, well-characterized fully synthetic TLR4 agonist constructed in eight synthetic steps from entirely crystalline starting materials and intermediates via an optimized high-yield synthetic route. Overall, our data suggest that SPA14 is a viable, easy-to-manufacture, potent novel adjuvant system that could be broadly applicable as a ready-to-mix adjuvant in the form of a long-term stable liquid formulation.

Abstract It is generally accepted that a weakening of the North Atlantic thermohaline circulation caused the Younger Dryas cooling. Although the role of seasonality was emphasized previously, this aspect is rarely considered yet, and it remains elusive how this impacted hydroclimate during winters and summers across Central Europe. Here, we coupled biomarker-based δ18O and δ2H from Bergsee in southern Germany to reconstruct deuterium excess as a proxy for evaporation history from the Bølling-Allerød to the Preboreal. We compared this dataset with other biomarker isotope records in Central Europe. They are all lacking a strong isotopic depletion during the Younger Dryas, which is best explained by the summer sensitivity of the biomarker proxies: As Younger Dryas summers were relatively warm, there is an absence of the strong winter cooling signals recorded in annual water isotope records like Greenland or Lake Steißlingen. Lake evaporation at Bergsee together with other paleohydrological reconstructions draw a coherent picture of the Late Glacial hydroclimate, with strong evidence for warm and dry Younger Dryas summers. Rather than a southward shift of the Westerlies during winter, we suggest that a recently proposed feedback mechanism between North Atlantic sea ice extend, strong winter cooling and summer atmospheric blocking serves as a suitable explanation for summer dryness. Additional confidence to the robustness of these biomarker records is provided by the overall agreement of paleohydrological fluctuations during the Preboreal.

Abstract Background Folate receptor alpha (FRα) overexpression is seen in many cancers. Radioligand therapy (RLT) has emerged as a promising tool to target FRα and has been investigated previously, but further progression was limited due to high kidney retention and, subsequently, toxicity. To circumvent this, we present here the development of a [131I]I-GMIB-conjugated anti-human FRα (hFRα) single-domain antibody (sdAb), with intrinsically fast renal clearance and concomitant low kidney retention. We report the hit-to-lead development of an anti-hFRα sdAb. We evaluated its potential in vitro and assessed its targeting ability using SPECT imaging in hFRα-knockin and tumour-bearing mice. The toxicity and therapeutic efficacy of the [131I]I-GMIB-sdAb were investigated in mouse models. Results The lead anti-hFRα sdAb 2BD42 was developed with picomolar affinities, low koff, and radiolabelled using [131I]I with yields of > 41% and purity > 99%. [131I]I-GMIB-2BD42 retained tumour uptake (> 5%IA/g at 1 h p.i. and > 1.5%IA/g at 24 h p.i.) and fast kidney clearance (

Abstract Background The harmonious operation of many insect societies depends upon colony-wide dissemination of a non-volatile pheromone produced by a single queen, which informs workers of her presence. This represents a major challenge in large colonies. Honeybee colonies, which can exceed 60,000 bees, are believed to solve this challenge using ‘messenger’ workers that actively relay the queen pheromone throughout the hive. However, little is known about the structure and effectiveness of the underlying relay network or the biology of messaging. Results Here, we combine automated tracking with modelling to address these outstanding questions. We find that both queen movement and worker messaging play fundamental roles in queen pheromone dissemination. Fine-grained analyses of worker behaviour confirmed the existence of active messaging, as physical contacts with the queen caused workers to move faster and straighter, thereby accelerating pheromone transmission. Finally, we show that messaging follows a stereotypical developmental trajectory, resulting in an age-dependent hierarchical relay network, with the most intense messaging observed between three and five days of age, when workers undergo a suite of physiological changes associated with queen rearing. Conclusions These results suggest that the individuals that contribute most to advertising the presence of the queen are also the ones that control queen production.

Abstract Background Urine biomarkers are crucial for monitoring patient responses in treating urological pathologies, including non-muscle invasive bladder cancer (NMIBC). Yet, analysing urine biomarkers poses several challenges, including ensuring specimen stability during transportation and analytical processing. This prospective feasibility study aimed to investigate how urinary leukocytes and proteins are impacted by storing and refrigerating urine. Methods Stability of leukocytes from four healthy donors (HD) spiked into urine supernatants was analyzed for up to 72 h at 4°C. Urine samples from five NMIBC patients undergoing BCG treatment were divided into two portions, followed by either immediate processing or overnight refrigeration. Urinary cell content and soluble factors were analyzed by multiparameter flow cytometry and Luminex®, respectively. Results We confirmed the stability of healthy donor peripheral blood leukocytes spiked into cell-free urine supernatants from healthy donors or untreated bladder cancer patients for up to 72 h under refrigeration at + 5℃. Additionally, we conducted immune cell and proteomic analysis from urine samples obtained from five NMIBC patients receiving Bacillus Calmette-Guérin (BCG) therapy either processed immediately or after overnight refrigeration. We successfully demonstrated that leukocyte and protein composition remain stable in refrigerated urine from BCG-treated NMIBC for 24 h. This included granulocytes, monocytes, and T cells, as well as total protein, creatinine and 46 additional individual immune-related mediators. Conclusions This work demonstrates the compatibility of refrigerated urine shipment from the collection sites to analytical laboratories with both immunophenotyping and proteomic analysis and establishes clear logistical benefits for numerous clinical settings focused on monitoring patient immune responses in the urine matrix.

Abstract Background Periodontitis is an inflammatory disease causing destruction of periodontal tissues. Controlling inflammation is crucial for periodontitis treatment. Prohibitins (PHBs) are emerging targets in the treatment of inflammatory diseases. To identify compounds that would alleviate periodontitis, several small molecules that directly target PHBs and display various pharmacological activities were screened to decrease Porphyromonas gingivalis induced inflammation. Indeed, IN44, a new PHB ligand that has been shown to inhibit STAT3 and NF-kB signaling, suggesting that it may alleviate periodontitis. This study aimed to assess IN44’s impact on inflammation elicited by P. gingivalis. Methods In vitro, IN44 cytotoxicity was tested on periodontal cells with AlamarBlue and Live/Dead assays. Its effect on cytokines and mitochondrial ROS production were evaluated using ELISA and Mitosox assay. In mouse, systemic inflammation and experimental periodontitis were induced to assess IN44’s therapeutic effects. Results In vitro, IN44 (50 µM) showed no cytotoxicity on periodontal cells. It significantly reduced pro-inflammatory cytokine secretion and mitochondrial ROS in P. gingivalis-infected epithelial cells. Proteome analysis on infected epithelial cells revealed modulation of HSP60 and Akt expression by IN44. In vivo, IN44 demonstrated anti-inflammatory effects in a mouse model of systemic inflammation induced by P. gingivalis, and it improved periodontal healing. Conclusion These findings suggest that PHBs may warrant consideration as therapeutic targets for periodontitis and possibly other inflammatory disorders.

Abstract Background Echinococcosis is an infectious parasitic disease that is extremely harmful to human health. Albendazole is provided free of charge to patients requiring medication under the central government finance transfer payment scheme for echinococcosis control and prevention in China. Our aim is to monitor the state of patient medication and its therapeutic impact, which will help improve medication compliance and the therapeutic effect. Methods Random cluster sampling was used to select 10 echinococcosis-endemic counties in China, and all albendazole-treated patients in these counties were investigated. The chi-square and Kruskal–Wallis tests were used to compare two or more rates or constituent ratios, and multiple logistic regression analysis was used to identify the influencing factors. The records of patients were reviewed to obtain the initial diagnosis results as well as the most recent follow-up results and time, and efficacy was assessed. Results We examined 899 patient files treated with albendazole in 10 endemic counties. Of the 582 evaluable files, 7.9% did not take albendazole, and 69.2% did not take albendazole regularly. Only 22.9% took albendazole regularly. Of the 536 patients who took albendazole, 242 exhibited adverse reactions. Patients who were Tibetan, herdsmen, received no formal education, used emulsion, and exhibited adverse reactions demonstrated poor compliance. A total of 174 patients with cystic echinococcosis received their most recent imaging follow-up results within one year of the investigation date. Among them, 9 patients met the criteria for cure, accounting for 5.2%; 56 patients showed effectiveness, accounting for 32.2%; 105 patients were deemed ineffective, accounting for 59.8%; 5 patients experienced recurrence, accounting for 2.9%. Conclusions Albendazole medication compliance in patients with echinococcosis is not ideal. We must prioritize health education and promotion for Tibetans, herdsmen, and those without formal education. Patients who adhered to their medication regimen achieved higher rates of cure and effectiveness. To improve medication compliance and efficacy, it is particularly important to improve communication and medication guidance for patients receiving emulsions and those with adverse reactions after taking albendazole. Simultaneously strengthen patients' attention to follow-up and re-examination. Graphical Abstract

Abstract Background Positron emission tomography is widely used to study biological processes without disrupting normal physiological functions. Traditional radiotracer synthesis and industrial market is focused on producing large batches of 18F-labelled tracers, especially [18F]FDG. Accessibility to smaller quantity of diverse radiopharmaceuticals is a key to enable a more personalised approach in nuclear medicine. A novel microfluidic module, iMiDEV™, has earlier been shown to be a versatile labelling platform as it has been used in the production of Na[18F]F and various 11C- and 68 Ga-labelled tracers. In the current study our aim was to utilise iMiDEV™ in the synthesis of fluorine-18-labelled radiotracers, specifically [18F]DPA-714, [18F]LBT-999 and [18F]fallypride. Results [18F]DPA-714, [18F]LBT-999 and [18F]fallypride have been produced in up to 24%, 12% and 11% radiochemical yield, respectively, using the microfluidics based iMiDEV™ labelling platform. Activity yields at the end of synthesis were 3.6 GBq, 2.1 GBq and 2.3 GBq, respectively. All individual synthesis steps were studied for efficient activity transfer and labelling and the optimised synthesis sequence was fully automated. Conclusion In this paper, we have demonstrated fully automated production of different 18F-tracers of clinical relevance with moderate to good yields using microfluidic iMiDEV™ platform. Our work is a step towards more personalised, dose-on-demand manufacturing of PET radiopharmaceuticals.

Abstract Improved surgical skill is generally associated with improved patient outcomes, although assessment is subjective, labour intensive, and requires domain‐specific expertise. Automated data‐driven metrics can alleviate these difficulties, as demonstrated by existing machine learning instrument tracking models. However, these models are tested on limited datasets of laparoscopic surgery, with a focus on isolated tasks and robotic surgery. Here, a new public dataset is introduced: the nasal phase of simulated endoscopic pituitary surgery. Simulated surgery allows for a realistic yet repeatable environment, meaning the insights gained from automated assessment can be used by novice surgeons to hone their skills on the simulator before moving to real surgery. Pituitary Real‐time INstrument Tracking Network (PRINTNet) has been created as a baseline model for this automated assessment. Consisting of DeepLabV3 for classification and segmentation, StrongSORT for tracking, and the NVIDIA Holoscan for real‐time performance, PRINTNet achieved 71.9% multiple object tracking precision running at 22 frames per second. Using this tracking output, a multilayer perceptron achieved 87% accuracy in predicting surgical skill level (novice or expert), with the ‘ratio of total procedure time to instrument visible time’ correlated with higher surgical skill. The new publicly available dataset can be found at https://doi.org/10.5522/04/26511049.

Abstract Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with heterogeneous clinical manifestations which significantly impacts the daily lives of patients. Herein, we aimed to (i) investigate patients’ perspectives on and experience with SLE; (ii) identify meaningful aspects of health (MAHs) and concepts of interest (COIs) in SLE that could be evaluated using digital clinical measures (DCMs); and (iii) identify target DCMs for their assessment. Methods A mixed-methods, multistep approach was deployed for (i) exploring patients’ experience with SLE through a social media listening study and focused group discussions with patients; (ii) mapping patients’ experiences to define MAHs and identify COIs measurable using DCMs; (iii) selecting DCMs for the target COIs; and (iv) identifying types of wearable sensors for measuring COIs in the patients. Results Six MAHs related to physical behavior and sleep were identified: difficulty in ambulating, lack of energy, inability to perform activities of daily living, difficulty engaging in sustained walking, inability to perform leisure activities and exercise, and lack of restful sleep. Measurable COIs represented walking (fatigue and pain) and sleep (sleep and pain) characteristics. Five and six DCMs related to stepping behavior and sleep quality, respectively, were identified. Several wearable sensors are available to derive DCMs for physical behavior and sleep; however, patients showed a strong preference for a wrist-worn actigraphy sensor. Conclusion We identified DCMs for physical behavior and sleep that are relevant and meaningful to patients with SLE, measurable in a real-world environment with wearable sensors, and have the potential to aid personalized patient care.

Abstract The bioluminescent European brittle star Amphiura filiformis produces blue light at the arm-spine level thanks to a biochemical reaction involving coelenterazine as substrate and a Renilla-like luciferase as an enzyme. This echinoderm light production depends on a trophic acquisition of the coelenterazine substrate. Without an exogenous supply of coelenterazine, this species loses its luminous capabilities. Moreover, this species was recently shown not to produce coelenterazine storage forms. As an infaunal suspensive feeder, A. filiformis is assumed to find enough substrate to maintain its bioluminescence capabilities efficiently. To date, no studies have investigated the putative source of coelenterazine in the brittle star diet. A combined analysis using listing based on visual observations and metabarcoding on the planktonic communities highlights planktonic species known as light emitters using coelenterazine. Besides, the A. filiformis stomach content was analyzed seasonally via metabarcoding technique, and coelenterazine-related preys were underlined. Results provide evidence of the presence of preys containing coelenterazine in the fjord environment and within the stomach content of the ophiuroid throughout the year. The results are consistent with the demonstration of the trophic acquisition of luminous capabilities in A. filiformis and give a new step by underlying the constant presence of coelenterazine suppliers throughout the year for the luminescence reaction occurring within this species.

Abstract Background We previously published the protocol and statistical analysis plan for a randomized controlled trial of Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation: the PROMIZING study in Trials ( https://doi.org/10.1186/s13063-023-07163-w ). This update summarizes changes made to the statistical analysis plan for the trial since the publication of the original protocol and statistical analysis plan. Methods/design The Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation (PROMIZING) study is a multi-center, open-label, randomized controlled trial designed to determine if ventilation with proportional assist ventilation with load-adjustable gain factors will result in a shorter duration of time spent on mechanical ventilation compared to ventilation with pressure support ventilation for patients with acute respiratory failure. The statistical analysis plan for the trial was incorporated into the original publication of the protocol in Trials ( https://doi.org/10.1186/s13063-023-07163-w ) and was based on version 5.0 of the study protocol and version 1.0 of the statistical analysis plan (SAP), which included plans for both frequentist and Bayesian analyses. We have since updated the SAP to refine the Bayesian analysis plan, update the multistate model diagram, and include plans for a cluster analysis to determine if there is heterogeneity of treatment effect. This update summarizes the changes made and their rationale and provides a refined SAP for the PROMIZING trial with additional background information, in adherence with guidelines for the prospective reporting of SAPs for randomized controlled trials. Trial registration ClinicalTrials.gov Identifier: NCT02447692 prospectively registered May 19, 2015.

Abstract Key message Based on experimental and simulated data for maritime pine (Pinus pinaster Ait.) in a genomic selection context, our study reveals that the often-highlighted equivalence between genome-based and pedigree-based prediction accuracies of breeding values is associated with a zero accuracy of genome-based prediction within families, which can be attributed to the still insufficient size of the genomic training sets for conifers. Context Genomic selection is a promising approach for forest tree breeding. However, its advantage in terms of prediction accuracy over conventional pedigree-based methods is unclear and within-family accuracy is rarely assessed. Aims We used a pedigree-based model (ABLUP) with corrected pedigree data as a baseline reference for assessing the prediction accuracy of genome-based model (GBLUP) at the global and within-family levels in maritime pine (Pinus pinaster Ait). Methods We considered 39 full-sib families, each comprising 10 to 40 individuals, to constitute an experimental population of 833 individuals. A stochastic simulation model was also developed to explore other scenarios of heritability, training set size, and marker density. Results Prediction accuracies with GBLUP and ABLUP were similar, and within-family accuracy with GBLUP was on average zero with large variation between families. Simulations revealed that the number of individuals in the training set was the principal factor limiting GBLUP accuracy in our study and likely in many forest tree breeding programmes. Accurate within-family prediction is possible if 40–65 individuals per full-sib family are included in the genomic training set, from a total of 1600–2000 individuals in the training set. Conclusions The increase in the number of individuals per family in the training set lead to a significant advantage of GBLUP over ABLUP in terms of prediction accuracy and more clearly justify the switch to genome-based prediction and selection in forest trees.

The “Enhanced perceptual functioning model” and the “Veridical mapping model” have been proposed to explain the presence and nature of special abilities in autism. Here， we propose an important update to these two models， by combining them with autistic idiosyncratic language development. The “special abilities” of individuals with autism are achieved by redirecting language analyzers toward structured， yet socially unbiased material， which explains how these special skills extend language processing to materials beyond language. Calendar calculation serves as a test of this theory， in which language analyzers are redirected to calendars， a possible consequence of non-social learning. Non-social learning itself results from the bifurcation caused by the absence of social bias in overall information processing. The longitudinal and operational properties of calendar calculation are analogous to the language learning and processing characteristics of neurotypical populations. Combining the “hijacking” of human language analyzer and directing it towards non-communicative， language-like material provides a concise explanation for the common features of most autistic special abilities and integrates and enriches the “Veridical mapping model”.

Persons with prototypical autism often present unique strengths that traditional intelligence assessments overlook， together with absence of oral language at the preschool age. Here， we propose a strengths-based approach in understanding and engaging with non-verbal autistic children. It emphasizes recognizing unique intellectual abilities often masked by communication challenges and conventional understanding of repetitive behaviors. By observing these children’s interests in structured objects， patterns， and screens， caregivers and clinicians can gain insights into their cognitive potential. We then present methods to leverage autistic strengths to support wellbeing of the families， including using “lateral tutorship” —a non-intrusive， side-by-side engagement method—as a way to connect with autistic children， respecting and utilizing their intrinsic learning style.

Abstract Introduction In contrast with patients receiving therapy for retinal disease during clinical trials, those treated in routine clinical practice experience various challenges (including administrative, clinic, social, and patient-related factors) that can often result in high patient and clinic burden, and contribute to suboptimal visual outcomes. The objective of this study was to understand the challenges associated with clinical management of diabetic macular edema from the perspectives of patients, healthcare providers, and clinic staff, and identify opportunities to improve eye care for people with diabetes. Methods We conducted a survey of patients with diabetic macular edema, providers, and clinic staff in 78 clinics across 24 countries on six continents, representing a diverse range of individuals, healthcare systems, settings, and reimbursement models. Surveys comprised a series of single- and multiple-response questions completed anonymously. Data gathered included patient personal characteristics, challenges with appointment attendance, treatment experiences, and opportunities to improve support. Provider and clinic staff surveys asked similar questions about their perspectives; and clinic characteristics were also captured. Results Overall, 5681 surveys were gathered: 3752 from patients with diabetic macular edema, 680 from providers, and 1249 from clinic staff. Too many appointments, too short treatment intervals, difficulties in traveling to the clinic or arranging adequate support to travel, out-of-pocket costs, office/parking fees, and long waiting times were noted by all as contributing to increase the burden on the patient and caregiver. Patients generally desired more in-depth discussions with their provider, which would help with information exchange and better expectation-setting. Conclusions The wealth of systematic data generated by this global survey highlights the breadth and scale of challenges associated with the clinical management of patients with diabetic macular edema. Addressing the opportunities for improvement raised by patients, providers, and clinic staff could increase patient adherence to treatment, reduce appointment burden, and improve clinic capacity.

Abstract Introduction Neovascular age-related macular degeneration is a global public-health concern, associated with a considerable burden to individuals, healthcare systems, and society. The objective of this study was to understand different perspectives on the challenges associated with the clinical management of neovascular age-related macular degeneration, which could elucidate measures to comprehensively improve clinical care and outcomes. Methods A survey was carried out of patients with neovascular age-related macular degeneration, their providers, and clinic staff in 77 clinics across 24 countries on six continents, from a diverse range of healthcare systems, settings, and reimbursement models. Surveys comprised a series of single/multiple-response questions completed anonymously. Data gathered included patient personal characteristics, appointment attendance challenges, treatment experiences, and opportunities to improve support. Provider and clinic staff surveys asked similar questions about their perspectives; clinic characteristics were also captured. Results There were 6425 responses; 4558 patients with neovascular age-related macular degeneration, 659 providers, and 1208 clinic staff. Challenges identified included concern about patient burden to family/friends, high frequency of treatment, difficulties in traveling to appointments, long waiting times, and insufficient comprehension of neovascular age-related macular degeneration. Participants identified logistical (improved financial assistance with treatment and out-of-pocket costs, and appointment reminders), operational (addressing clinic set up to reduce waiting times and improving the amount of time providers spend with patients), and educational (improving quality and provision of patient information and expectation-setting) opportunities to improve care. Conclusions The wealth of data generated by this global survey highlights the breadth of challenges associated with clinical management of patients with neovascular age-related macular degeneration. Addressing the opportunities raised could improve patient adherence to treatment and potentially outcomes, reduce appointment burden, and increase clinic capacity.

Abstract In this neuropathological study, we investigated neuroinflammation surrounding recent and old cerebral microbleeds (CMBs) and cerebral microinfarcts (CMIs) in 18 cases of cerebral amyloid angiopathy (CAA). We used several serial stainings and immunolabellings to identify microvascular lesions, define their recent or old stage, and characterize neuroinflammatory response (scavenging activity and astrogliosis). We found that both CMBs and CMIs induce a neuroinflammatory response, which was more pronounced in old lesion than recent. Astrogliosis and scavenging activity were differentially prominent according to the ischemic/hemorrhagic nature of the lesion. Our findings provide insights into the pathophysiology of microvascular injuries in CAA.

Abstract Background Few studies have assessed the participation of the spine in arm elevation. The primary aim of this exploratory study was to specify spinal movements during unilateral arm elevation. Methods We used an EOS imaging system to assess 2D global posture (Sagittal Vertical Axis [SVA], T1 and T9 tilt and Central Sacral Line [CSL]) and segmental spine curves (C3-C7 in the sagittal plane only, and T1-T6, T7-T12 and L1-L5 in the sagittal and frontal planes) for four different left arm elevation levels: in the sagittal (Sa) plane (30°Sa: reference position, 140°Sa and 180°Sa), and in the scapular (Sc) plane (180°Sc), in ten right-handed asymptomatic participants (5 women; mean age 24.6 SD 3.0 years]. In addition, we estimated C1, head and pelvic orientation and head and pelvic linear displacement. We used Bayesian statistics (BF10 > 3 indicates a significant variation: moderate, strong, very strong or extreme evidence). Results From 140°Sa to 180°Sa or Sc, the significant decrease in SVA and the T1-T9 tilt angles indicated a global backward spine bending (moderate to very strong evidence). The significant reversal of the C3-C7 lordosis at 30°Sa (-1.34 [2.53]°) to kyphosis at 180°Sa (13.88 [3.53]°, strong evidence) and 180°Sc (11.85 [2.75]°, extreme evidence) and the significant decrease in the T7-T12 kyphosis (26.58 [2.84]°at 30°Sa to 16.40 [2.65]° at 180°Sa and 17.60 [2.78]° at 180°Sc [all extreme evidence]) showed a global spine straightening. We found significant pelvic anteversion between 30°Sa and 140°Sa (moderate evidence) and persistent right spine bending and leftward head displacement (extreme evidence). The change in C1 orientation (extreme evidence) showed an atlanto-occipital extension. Conclusion Simple unconstrained movements of unilateral arm elevation involve the whole spine, pelvis and head, including significant backward spinal bending, a reduction in the low cervical spine lordosis and the thoracic kyphosis, and atlanto-occipital extension.

Abstract Background Assessing health-related quality of life (HRQoL) is a widely employed method in orthopedics to evaluate patient well-being and measure the effectiveness of surgical interventions. Understanding the relationship between specific baseline factors and preoperative HRQoL can help clinicians identify patients at risk for low quality of life and thus, develop preventive strategies that adequately address individual patient needs. The objective was to assess associations between baseline factors and preoperative HRQoL in patients undergoing arthroscopic rotator cuff repair (ARCR). Methods This study is part of a multicenter prospective Swiss cohort study that included patients undergoing ARCR between June 2020 and November 2021. Data were derived from baseline and surgery forms. HRQoL was assessed using the European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) questionnaire to calculate EQ-5D index and EQ VAS scores. Univariable and multivariable linear regression models examined associations between the 21 factors and preoperative HRQoL. Final models were determined using stepwise backward regression. Results A total of 973 included patients (mean age [SD], 57.3 [9.4] years; 611 men [63%]) had a mean [SD] EQ-5D index and EQ VAS of 0.70 [0.23] and 68.7 [19.8], respectively. Being male (regression coefficient (β), 0.05; 95% CI [0.02–0.08]), having a higher age (β, 0.02; 95% CI [0.01–0.03]) and higher education levels (e.g., university, college: β, 0.11; 95% CI [0.06–0.16]) were associated with a higher EQ-5D index. Increased body mass index (β, -0.02; 95% CI [-0.04 to -0.01]) and worse sleep quality (β, -0.03; 95% CI [-0.04 to -0.03]) were associated with a lower EQ-5D index. Factors negatively associated with overall EQ VAS health were depression (e.g., moderate: β, -12.70; 95% CI [-16.18 to -9.21]), presence of at least one comorbidity (β, -3.71; 95% CI [-5.91 to -1.52]), and pain (β, -1.81; 95% CI [-2.36 to -1.26]). Conclusion Our results suggest that preoperative HRQoL is highly associated with sociodemographic and patient-related factors. Specifically addressing these factors may improve orthopedic care.

Abstract In this work, we demonstrate that quantizing gravity on a null hypersurface leads to the emergence of a CFT associated with each null ray. This result stems from the ultralocal nature of null physics and is derived through a canonical analysis of the Raychaudhuri equation, interpreted as a constraint generating null time reparametrizations. The CFT exhibits a non-zero central charge, providing a mechanism for the quantum emergence of time in gravitational systems and an associated choice of vacuum state. Our analysis reveals that the central charge quantifies the degrees of freedom along each null ray. Throughout our investigation, the area element of a cut plays a crucial role, necessitating its treatment as a quantum operator due to its dynamic nature in phase space or because of quantum backreaction. Furthermore, we show that the total central charge diverges in a perturbative analysis due to the infinite number of null generators. This divergence is resolved if there is a discrete spectrum for the area form operator. We introduce the concept of ‘embadons’ to denote these localized geometric units of area, the fundamental building blocks of geometry at a mesoscopic quantum gravity scale.

Abstract Reaching net-zero carbon emissions requires large shares of intermittent renewable energy and the electrification of end-use consumption, such as heating, making the future energy system highly dependent on weather variability and climate change. Weather exhibits fluctuations on temporal scales ranging from sub-hourly to yearly while climate variations occur on decadal scales. To investigate the intricate interplay between weather patterns, climate variations, and power systems, we developed a database of time series of wind and solar power generation, hydropower inflow, heating and cooling demand using an internally consistent modeling framework. Here we focused on the European continent and generated country level time series extending between 1940 and 2100. Our database can be used for analyses aimed at understanding and addressing the challenges posed by the evolving energy landscape in the face of deep decarbonization and climate change.

Abstract Background Clinical supervision by psychiatric liaison clinicians is frequently provided in medical settings such as oncology and palliative care, but rarely in endocrinology. Consequently, the specific psychosocial issues faced by endocrinologists in their daily clinical practice and how they deal with them remain largely unknown. We aimed to explore individual supervisions of endocrinologists to gain insight into what kind of clinical situations they present, how they react to them and how this is worked through in supervision. Methods The data set consisted of eight audio-recorded first supervision sessions of endocrinologists conducted by liaison psychiatry clinicians, which were transformed into written core stories accounting for key components of each session. A secondary analysis of these core stories was conducted using an interpretative approach, focusing on (i) the types of clinical situations and (ii) the supervisees’ counter-attitudes towards patients. Additionally, particular attention was given to how the supervisors worked through these elements. Results Endocrinologists presented patients who did not adhere to treatment, behaved inexplicably, or held moral values that differed from their own. Challenged by these situations, supervisees experienced negative emotions (e.g., anxiety, irritation, guilt), associated with behavioral reactions (e.g., avoidance) and/or defensive stances (e.g., denial, rationalization). In half of the supervisions, addressing these difficulties allowed supervisees to link key characteristics of the patient interaction with their own unresolved issues; in the other half, supervisees were less inclined to confront themselves with their own contributions to the patient interaction and the supervisor adopted a more active stance, making specific contributions (e.g. support, advise). Conclusions The findings call for training programs addressing “difficult” patients and advocate for closer collaboration between endocrinologists and liaison psychiatry clinicians.

Abstract Under global warming, summer precipitation over East China was projected to increase by current state-of-the-art climate models, but a large inter-model spread exists. Here we try to reduce the projection uncertainty by imposing constraints. Our procedure consists of first decomposing the projected future precipitation into inter-model principal components. The two leading modes (region-wide uniform monopole and north-south dipole, accounting for 55% of variability), by emergent constraints, are then linked to the simulation of historical precipitation in the northwest Pacific and the tropical Pacific (constraining areas). This allows us to reduce the uncertainties by 23% and obtain a smaller increase of projected precipitation in East China, relative to previous multi-model ensemble projections. Quasi-uniform increases, although weak, are obtained for the first mode, while the second mode shows a contrast pattern with a decrease in the south and an increase in the north, which both contribute to the spatial structure of constrainted projection. It is also shown that the emergent relations of both modes are physically consistent, with an enhancement of future zonal land-sea thermal contrast and a La Niña-like pattern, respectively. The use of emergent constraints inspires more confidence in the future regional precipitation projection and helps policymakers and stakeholders adjust their management policies.

Abstract African trypanosomes are important parasites in sub-Saharan Africa that undergo a quorum-sensing dependent development to morphologically ‘stumpy forms’ in mammalian hosts to favour transmission by tsetse flies. However, some trypanosome clades have simplified their lifecycle by escaping dependence on tsetse allowing an expanded geographic range, with direct transmission between hosts achieved via blood-feeding biting flies and vampire bats (Trypanosoma brucei evansi, causing ‘surra’) or through sexual transmission (Trypanosoma brucei equiperdum, causing ‘dourine’). Concomitantly, stumpy formation is reduced and the isolates are described as monomorphic, with infections spread widely in Africa, Asia, South America and parts of Europe. Here, using genomic analysis of distinct field isolates, we identify molecular changes that accompany the loss of the stumpy formation in monomorphic clades. Using CRISPR-mediated allelic replacement, mutations in two exemplar genes (Tb927.2.4020; Tb927.5.2580) are confirmed to reduce stumpy formation whereas another (Tb927.11.3400) is implicated in altered motility. Using laboratory selection we identify downregulation of RNA regulators as important in the initial development of monomorphism. This identifies a trajectory of events that simplify the life cycle in emergent and established monomorphic trypanosomes, with impact on disease spread, vector control strategies, geographical range and virulence.

Abstract Background Mycobacterium abscessus is an emerging pathogen causing severe pulmonary infections, particularly in individuals with underlying conditions, such as cystic fibrosis or chronic obstructive pulmonary disease. Macrolides, such as clarithromycin (CLR) or azithromycin (AZM), represent the cornerstone of antibiotherapy against the M. abscessus species. However, prolonged exposure to these macrolides can induce of Erm(41)-mediated resistance, limiting their spectrum of activity and leading to therapeutic failure. Therefore, inhibiting Erm(41) could thwart this resistance mechanism to maintain macrolide susceptibility, thus increasing the rate of treatment success. In our previous study, the Erm(41) methyltransferase was identified as a possible target enzyme of Cyclipostins and Cyclophostin compounds (CyC). Methods Herein, we exploited this feature to evaluate the in vitro activity of CLR and AZM in combination with different CyC via the checkerboard assay on macrolide-susceptible and induced macrolide-resistant M. abscessus strains selected in vitro following exposure CLR and AZM. Results Our results emphasize the use of the CyC to prevent/overcome Erm(41)‑induced resistance and to restore macrolide susceptibility. Conclusion This work should expand our therapeutic arsenal in the fight against a antibioticresistant mycobacterial species and could provide the opportunity to revisit the therapeutic regimen for combating M. abscessus pulmonary infections in patients, and particularly in erm(41)-positive strains.