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Abstract Richter transformation (RT) is an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia. Here we investigated the anti-CD3/anti-CD19 T-cell-engager blinatumomab after R-CHOP (i.e. rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with untreated RT of diffuse large B-cell lymphoma histology (NCT03931642). In this multicentre phase 2 study, patients without complete response (CR) after two cycles of R-CHOP were eligible to receive an 8-week blinatumomab induction via continuous vein infusion with stepwise dosing until 112 μg/day. The primary endpoint was the CR rate after blinatumomab induction and secondary endpoint included safety, response duration, progression-free and overall survival. Thirty-nine patients started the first cycle of R-CHOP, 25 of whom received blinatumomab. After blinatumomab induction, five (20%) patients achieved CR, four (16%) achieved partial response, and six (24%) were stable. Considering the entire strategy, the overall response rate in the full-analysis-set was 46% (n = 18), with CR in 14 (36%) patients. The most common treatment-emergent adverse events of all grades in the blinatumomab-safety-set included fever (36%), anaemia (24%), and lymphopaenia (24%). Cytokine release syndrome (grade 1/2) was observed in 16% and neurotoxicity in 20% of patients. Blinatumomab demonstrated encouraging anti-tumour activity (the trial met its primary endpoint) and acceptable toxicity in patients with RT.

Abstract Objectives Detection of liver metastases is crucial for guiding oncological management. Computed tomography through iterative reconstructions is widely used in this indication but has certain limitations. Deep learning image reconstructions (DLIR) use deep neural networks to achieve a significant noise reduction compared to iterative reconstructions. While reports have demonstrated improvements in image quality, their impact on liver metastases detection remains unclear. Our main objective was to determine whether DLIR affects the number of detected liver metastasis. Our secondary objective was to compare metastases conspicuity between the two reconstruction methods. Methods CT images of 121 patients with liver metastases were reconstructed using a 50% adaptive statistical iterative reconstruction (50%-ASiR-V), and three levels of DLIR (DLIR-low, DLIR-medium, and DLIR-high). For each reconstruction, two double-blinded radiologists counted up to a maximum of ten metastases. Visibility and contour definitions were also assessed. Comparisons between methods for continuous parameters were performed using mixed models. Results A higher number of metastases was detected by one reader with DLIR-high: 7 (2–10) (median (Q₁–Q₃); total 733) versus 5 (2–10), respectively for DLIR-medium, DLIR-low, and ASiR-V (p

Nach aktueller Rechtsprechung ist die Begutachtung der Schuldfähigkeit und Massnahmenindikation Personen mit Facharzttitel für Psychiatrie und Psychotherapie vorbehalten. Der damit verbundene Ausschluss von Psycholog:innen ist angesichts der Entwicklungen in den letzten zehn Jahren nicht gerechtfertigt. Die Autor:innen zeigen auf, unter welchen Weiterbildungsbedingungen Psycholog:innen als Sachverständige geeignet sind. -- Selon la jurisprudence actuelle, seuls des personnes détenant un titre de médecin spécialiste en psychiatrie et psychothérapie sont autorisés à réaliser les expertises en matière de responsabilité et d'indication de mesures. L'exclusion des psychologues, qui en découle, ne se justifie pas au vu des évolutions de ces dix dernières années. Les auteur·e·s démontrent les formations continues nécessaires pour que des psychologues soient apte à effectuer de telles expertises.

Many post-secondary institutions have implemented mandatory reporting (MR) requiring employees to report knowledge of sexual misconduct. Understanding employee perceptions (e.g., benefits/drawbacks) and experiences (e.g., reporting disclosure) is important given this responsibility. Accordingly, this study analyzes responses from a recent survey that polled faculty and staff concerning MR ("N" = 125). Findings indicate that most employees fall under a MR policy, are aware of their obligations, and will comply with them. While majority approval was evident for MR, employees also identified drawbacks (e.g., reduced victim autonomy). One in five employees in this sample have made a report. Additional perceptions, experiences, and attitudes toward MR varied, based on institutional-level factors and socio-demographic characteristics.

Ice aprons are defined as very small ice bodies covering steep rock slopes. They have only been the subject of increased scientific interest for a few years, despite the fact that they are a condition for mountaineering and obvious elements in the high-alpine landscapes. However, very little is known about their distribution, evolution and physical characteristics. In this paper, we review the existing knowledge on ice aprons, which have almost exclusively been investigated in the Mont-Blanc massif, Western Alps. We supplement this review with novel results from recent surveys of ice aprons. We used a wide array of methodologies, from remote sensing (multi-source imagery) to in situ (stakes and thermal monitoring) and laboratory (radiocarbon dating and texture analysis) glaciological investigations. In the Mont-Blanc massif, ice aprons occupy 4.2 km2 within the alpine permafrost zone. Temperature measured at the ice–rock interface is indeed largely negative. Thinness of ice aprons coupled with the cold context implies a quasi-stationary shear regime without basal Sliding. Only ice at the surface can possibly melt in warm periods. After a shrinking period from the end of the Little Ice Age to the mid-to-late-1960s, ice aprons experienced a short period of expansion, followed by an accelerated shrinkage since the beginning of the 21st century. This shrinkage now favours rockfall triggering and poses a serious threat to a glaciological heritage since ice aprons host several-thousand-year-old ice. Finally, we synthesize this information to assess the existing definition of ice aprons, and propose some future research directions.

Water takes part in most physical processes that shape mountainous periglacial landscapes and initiation of mass-wasting processes. An observed increase in rockfall activity in high mountain regions was previously linked to permafrost degradation, and water that infiltrates into rock fractures is one of the likely drivers of processes related to thawing and destabilization. However, there is very little knowledge of the quantity and timing of water availability for infiltration into steep rock slopes. This knowledge gap originates from the complex meteorological, hydrological, and thermal processes that control snowmelt, as well as challenging access and data acquisition in extreme alpine environments. Here we use field measurements and numerical modeling to simulate the energy balance and hydrological fluxes on a steep high-elevation permafrost-affected rock slope at Aiguille du Midi (3842 m a.s.l, France), in the Mont Blanc massif. Our results provide new information about water balance at the surface of steep rock slopes. Model results suggest that only ∼ 25 % of the snowfall accumulates in our study site; the remaining ∼ 75 % is likely transported downslope by wind and gravity. The snowpack thickness was found to decrease with surface slopes between 40 and 70∘. We found that among all water fluxes, sublimation is the main process of snowpack mass loss at our study site. Snowmelt occurs between spring and late summer, but most of it may not reach the rock surface due to refreezing and the formation of an impermeable ice layer at the base of the snowpack, which was observed at the field site. The annual snowmelt that is available for infiltration (i.e., effective snowmelt) is highly variable in the simulated years 1959–2021, and its onset occurs mostly between May and August and ends before October. By applying the model to a range of altitudes, we show that effective snowmelt is the main source of water for infiltration above 3600 m a.s.l.; below, direct rainfall on the snow-free surface is the dominant source. This change from snowmelt- to rainfall-dominated water input leads to an abrupt, nonlinear increase in water availability at altitudes below 3600 m a.s.l and may point to higher sensitivity of permafrost-affected rock slopes to climate change at these altitudes.

Abstract Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Glomerular hyperfiltration and albuminuria subject the proximal tubule (PT) to a subsequent elevation of workload, growth, and hypoxia. Hypoxia plays an ambiguous role in the development and progression of DKD and shall be clarified in our study. PT-von-Hippel-Lindau (Vhl)-deleted mouse model in combination with streptozotocin (STZ)-induced type I diabetes mellitus (DM) was phenotyped. In contrary to PT-Vhl-deleted STZ-induced type 1 DM mice, proteinuria and glomerular hyperfiltration occurred in diabetic control mice the latter due to higher nitric oxide synthase 1 and sodium and glucose transporter expression. PT Vhl deletion and DKD share common alterations in gene expression profiles, including glomerular and tubular morphology, and tubular transport and metabolism. Compared to diabetic control mice, the most significantly altered in PT Vhl-deleted STZ-induced type 1 DM mice were Ldc-1, regulating cellular oxygen consumption rate, and Zbtb16, inhibiting autophagy. Alignment of altered genes in heat maps uncovered that Vhl deletion prior to STZ-induced DM preconditioned the kidney against DKD. HIF-1α stabilization leading to histone modification and chromatin remodeling resets most genes altered upon DKD towards the control level. These data demonstrate that PT HIF-1α stabilization is a hallmark of early DKD and that targeting hypoxia prior to the onset of type 1 DM normalizes renal cell homeostasis and prevents DKD development.

Arbuscular mycorrhizal fungi (AMF) are soil microorganisms living in symbiosis with most terrestrial plants. They are known to improve plant tolerance to numerous abiotic and biotic stresses through the systemic induction of resistance mechanisms. With the aim of developing more sustainable agriculture, reducing the use of chemical inputs is becoming a major concern. After providing an overview on AMF history, phylogeny, development cycle and symbiosis benefits, the current review aims to explore the potential of AMF as biostimulants and/or biocontrol agents. Nowadays, AMF inoculums are already increasingly used as biostimulants, improving mineral nutrient plant acquisition. However, their role as a promising tool in the biocontrol market, as an alternative to chemical phytosanitary products, is underexplored and underdiscussed. Thus, in the current review, we will address the mechanisms of mycorrhized plant resistance to biotic stresses induced by AMF, and highlight the various factors in favor of inoculum application, but also the challenges that remain to be overcome.

The fracture of nickel–titanium (Ni-Ti) instruments during root canal instrumentation leads to compromised outcomes in endodontic treatments. Despite the significant impact of instrument facture during a root canal treatment, there is still no universally accepted method to address this complication. Several previous studies have shown the ability of a Neodymium: Yttrium–Aluminum–Perovskite (Nd: YAP) laser to cut endodontic files. This study aims to determine safe irradiation conditions for a clinical procedure involving the use of a Neodymium: Yttrium–Aluminum–Perovskite (Nd: YAP) laser for removing fractured nickel–titanium files in root canals. A total of 54 extracted permanent human teeth (n = 54) were used. This study involved nine distinct groups, each employing different irradiation conditions. Groups 1 s, 3 s, 5 s, 10 s, and 15 s simply consist of irradiation for 1, 3, 5, 10, and 15 s, respectively. After identifying the longest and safest duration time, four additional groups were proposed (labeled A, B, C, and D). Group A was composed of three series of irradiations of 5 s each separated by a rest time of 30 s (L5s + 30 s RT). Group B consisted of three series of irradiations of 5 s each separated by a rest time of 60 s (L5s + 60 s RT). Group C consisted of two series of irradiations of 5 s each separated by a rest time of 30 s (L5s + 30 s RT), and group D consisted of two series of irradiations of 5 s each separated by a rest time of 5 s (L5s + 5 s RT). In all groups, during the rest time, continuous irrigation with 2.5 mL of sodium hypochlorite (3% NaOCl) was carried out. The variation in temperature during irradiation was registered with a thermocouple during irradiation with different protocols. The mean and standard deviation of the temperature increase was noted. The calculation of the temperature was made as the Δ of the highest recorded temperature at the root surface minus (−) that recorded at baseline (37°). Additionally, scanning electron microscopy (SEM) was used after irradiation in all groups in order to assess the morphological changes in the root dentinal walls. The Nd: YAP laser irradiation parameters were a power of 3W, an energy of 300 mJ per pulse, a fiber diameter of 200 µm, a pulsed mode of irradiation with a frequency of 10 Hz, a pulse duration of 150 µs, and an energy density of 955.41 J/cm2. Our results show that the safest protocol for bypassing and/or removing broken instruments involves three series of irradiation of 5 s each with a rest time of 30 s between each series. Furthermore, our results suggest that continuous irradiation for 10 s or more may be harmful for periodontal tissue.

In this study, various chemical treatments were performed on clay-rich media to investigate their effects on hydrogen adsorption performance. We unequivocally demonstrated that acid-treated samples exhibited significant structural changes compared with those treated with alkali solutions. Gas adsorption isotherms and powder X-ray diffraction analyses clearly revealed that the acid treatment of clayey materials not only increased their surface area, but also enhanced hydrogen sorption uptake, increased interstratification, and reduced particle size. Most importantly, we succeeded in rationalizing the improvement in hydrogen uptake by sequentially applying purification, followed by acid treatment.

The ground thermal regime and permafrost development have an important influence on geomorphological processes in periglacial regions and ultimately landscape development. About 10 % of unstable rock slopes in Norway are potentially underlain by widespread permafrost. Permafrost thaw and degradation may play a role in slope destabilisation, and more knowledge about rock wall permafrost in Norway is needed to investigate possible links between the ground thermal regime, geomorphological activity and natural hazards. We assess spatio-temporal permafrost variations in selected rock walls in Norway over the last 120 years. Ground temperature is modelled using the two-dimensional ground heat flux model CryoGrid 2D along nine profiles crossing instrumented rock walls in Norway. The simulation results show the distribution of permafrost is sporadic to continuous along the modelled profiles. Results suggest that ground temperature at 20 m depth in steep rock faces increased by 0.2 ∘C per decade on average since the 1980s, and rates of change increase with elevation within a single rock wall section. Heat flow direction is primarily vertical within mountains in Norway. Nevertheless, narrow ridges may still be sensitive to even small differences in ground surface temperature and may have horizontal heat fluxes. This study further demonstrates how rock wall temperature increase rates and rock wall permafrost distribution are influenced by factors such as surface air temperature uncertainties; surface offsets arising from the incoming shortwave solar radiation; snow conditions on, above and below rock walls; and rock wall geometry and size together with adjacent blockfield-covered plateaus or glaciers.

Abstract The success of cancer immunotherapy depends in part on the strength of antigen recognition by T cells. Here, we characterize the T cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities of 371 CD8 T cell clones specific for neoantigens, tumor-associated antigens (TAAs) or viral antigens isolated from tumors or blood of patients and healthy donors. T cells from tumors exhibit stronger functional and structural avidity than their blood counterparts. Relative to TAA, neoantigen-specific T cells are of higher structural avidity and, consistently, are preferentially detected in tumors. Effective tumor infiltration in mice models is associated with high structural avidity and CXCR3 expression. Based on TCR biophysicochemical properties, we derive and apply an in silico model predicting TCR structural avidity and validate the enrichment in high avidity T cells in patients’ tumors. These observations indicate a direct relationship between neoantigen recognition, T cell functionality and tumor infiltration. These results delineate a rational approach to identify potent T cells for personalized cancer immunotherapy.

Abstract Background APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. Methods Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. Results Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. Discussion Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.

The Swiss Guestbook Project aims to preserve and study visitors’ books produced in Switzerland and neighboring Savoy before 1914. Situated at the interface between a qualitative and quantitative approach, the visitors’ book presents a series of methodological problems, particularly concerning the reliability of the data but also the importance that should be given to the texts. In this article, we briefly present the project and the current state of research before discussing two case studies. The first concerns the Monte-Rosa and Riffelhaus hotels in Zermatt between 1854 and 1866. In the second, we compare the cross-data of three books from the Chamonix valley in 1854. Our calculations of the number and origin of travelers demonstrate the contributions and limitations of these documents as statistical sources, while the analysis of the texts allows us to better understand their relevance to the development of mountaineering knowledge.

We would like to present two cases of middle-aged men found dead outdoors, in relatively low temperatures, whose postmortem brain CT scan exhibited unusual findings. Both cases presented traumatic injuries, mainly cerebral (bleeds, contusions). The first case involved a 55-year-old man, found dead in front of his house, mostly covered by snow, with an ambient temperature reaching − 1.8 °C. Before the autopsy, a native (without contrast) postmortem CT scan was performed which revealed a linear delimitation between the anterior and posterior regions of the brain, along with hypodensity in the anterior region, compatible with an advanced state of decomposition. The second case involved a 77-year-old man, found dead on the bottom of a cliff where his car was found. Temperatures recorded then approached 9 °C. However, a technical glitch in the cooling cell during the storage of the corpse was reported. The subsequent postmortem CT scan performed before the autopsy showed a grossly circular zone of hypodensity across the periphery of the brain with a centro-peripheral and right-left gradient. Furthermore, macroscopic and microscopic examinations of the brain didn’t reveal any pathological findings concerning the density differences observed on imaging in both cases. These two cases seem to highlight the processes through which the cold might affect brain tissue and his appearance on imaging, which could consequently represent a potential pitfall in postmortem forensic investigations. We intend to encourage further studies on this topic, to allow correct interpretation of such CT scan findings in forensic cases, and to open the debate about the possible causes of this phenomenon.

Background: Following a traumatic event, 40–80% of the patients with acute stress disorder (ASD) will develop post-traumatic stress disorder (PTSD), 67% at 6 months. Alpha1-blockers are effective in treating some symptoms of PTSD but their usefulness in acute stress situations remains unclear. We hypothesized that reducing noradrenergic hyperactivity with an alpha1-blocker during the acute phase after a traumatic event could prevent the transition to PTSD in patients with ASD. Objective: To investigate the efficacy and safety of a 1-month course of alpha1-blocker (prazosin) to prevent the transition to PTSD in patients with ASD at 6 months. Method: In a monocentric open-label prospective pilot study, 15 patients with ASD were included within 3–7 days of exposure to a traumatic event. After enrolment, they received prazosin LP at home at bedtime at 2.5 mg/day for 7 days and then 5 mg/day for 21 days. Incidence of PTSD was assessed at 6 months using the Clinician Administrated PTSD Scale (CAPS). Results: At 6 months, 22% of patients who completed the study (2/9) met the diagnostic criteria for PTSD. This rate was significantly lower than that observed in previous studies (67%; p = .047). The treatment was well tolerated and there were no serious adverse events. Conclusions: These preliminary findings indicating the safety of prazosin and suggesting its potential to prevent the development of PTSD in ASD require to be replicated in large-scale randomized placebo-controlled studies. Trial registration: The study was pre-registered on a public database (www.clinicalTrials.gov identifier: NCT03045016).

Mixing in a reactor can be achieved mechanically or by the injection of a gas. This can be done by injecting a gas towards the bottom of the tank. The induced flow recirculation and then the stirring quality depends on the bubbles morphology, rising velocity and frequency detachment. This study focus on the case where the stirred fluid exhibits a yield stress. It is in line with previous studies on the gas cavity at the injection point [1], the induced flow recirculation [2] and the numerical simulation [3]. Here we quantified the bubbles diameters, aspect ratios and velocities as a function of the air flow rate, rheological parameters and tank size. Scaling laws and correlations based on the characteristic dimensionless numbers governing the flow have been proposed and validated experimentally. It was found that bubble frequencies and consequently bubble volumes and velocities are mainly governed by the balance between inertial and buoyancy forces. However, viscous and yield stress effects play an important role along buoyancy and inertial in defining the bubble aspect ratios. Weakly inertial flows are characterized by elongated bubbles while high inertial flows produce almost spherical bubbles. These experimental results are of practical interest for the design of reactor or digester where yield stress fluids have to be stirred.

Objectives. To determine the ferritin inter-assay differences between three “Conformité Européenne” (CE) marked tests, the impact on reference intervals (RI), and the proportion of individuals with iron deficiency (ID), we used plasma and serum from healthy blood donors (HBD) recruited in three different Switzerland regions. Design and Methods. Heparinized plasma and serum from HBD were obtained from three different transfusion centers in Switzerland (Fribourg, Geneva, and Neuchatel). One hundred forty samples were recruited per center and per matrix, with a gender ratio of 50%, for a total of 420 HBD samples available per matrix. On both matrices, ferritin concentrations were quantified by three different laboratories using electrochemiluminescence (ECL), latex immunoturbidimetric assay (LIA), and luminescent oxygen channeling immunoassay (LOCI) assays, respectively. The degree of agreement between matrices and between the three sites/methods was assessed by Passing–Bablok and we evaluated the proportion of individuals deemed to have ID per method. Results. Overall, no difference between serum and heparinized plasma ferritin values was observed according to Passing–Bablok analyses (proportional bias range: 1.0–3.0%; maximum constant bias: 1.84 µg/L). Significant median ferritin differences (p < 0.001 according to Kruskal–Wallis test) were observed between the three methods (i.e., 83.6 µg/L, 103.5 µg/L, and 62.1 µg/L for ECL, LIA, and LOCI in heparinized plasma, respectively), with proportional bias varying significantly between ±16% and ±32% on serum and from ±14% to ±35% on plasma with no sign of gender-related differences. Affecting the lower end of RI, the proportion of ID per method substantially varied between 4.76% (20/420) for ECL, 2.86% (12/420) for LIA, and 9.05% (38/420) for LOCI. Conclusions. Serum and heparinized plasma are exchangeable for ferritin assessment. However, the order of magnitude of ferritin differences across methods and HBD recruitment sites could lead to diagnostic errors if uniform RI were considered. Challenging the recently proposed use of uniform ferritin thresholds, our results highlight the importance of method- and region-specific RI for ferritin due to insufficient inter-assay harmonization. Failing to do so significantly impacts ID diagnosis.

There is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate diverse and unexplored symbioses. Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here, we applied highly purified phage T4, free from bacterial by-products and endotoxins to mammalian cells and analyzed the cellular responses using luciferase reporter and antibody microarray assays. Phage preparations were applied in vitro to either A549 lung epithelial cells, MDCK-I kidney cells, or primary mouse bone marrow derived macrophages with the phage-free supernatant serving as a comparative control. Highly purified T4 phages were rapidly internalized by mammalian cells and accumulated within macropinosomes but did not activate the inflammatory DNA response TLR9 or cGAS-STING pathways. Following 8 hours of incubation with T4 phage, whole cell lysates were analyzed via antibody microarray that detected expression and phosphorylation levels of human signaling proteins. T4 phage application led to the activation of AKT-dependent pathways, resulting in an increase in cell metabolism, survival, and actin reorganization, the last being critical for macropinocytosis and potentially regulating a positive feedback loop to drive further phage internalization. T4 phages additionally down-regulated CDK1 and its downstream effectors, leading to an inhibition of cell cycle progression and an increase in cellular growth through a prolonged G1 phase. These interactions demonstrate that highly purified T4 phages do not activate DNA-mediated inflammatory pathways but do trigger protein phosphorylation cascades that promote cellular growth and survival. We conclude that mammalian cells are internalizing bacteriophages as a resource to promote cellular growth and metabolism.