Virtual reality cricothyrotomy - a case-control study on gamification in emergency education.

BACKGROUND: Cricothyrotomy is an invasive and rare emergency intervention to secure the airway in a "cannot intubate, cannot ventilate" situation. This leads to lack of routine. Cricothyrotomy is performed only hesitantly. Therefore, we aim to improve teaching by including a virtual reality (VR) cricothyrotomy as a learning tool. METHODS: We programmed the VR cricothyrotomy in the C# programming language on the open-source Unity platform. We could include 149 students that we randomly assigned to either a study group (VR cricothyrotomy) or control group (educational video). We asked the study group to subjectively rate the VR cricothyrotomy. To evaluate our intervention (VR cricothyrotomy) we took the time participants needed to perform a cricothyrotomy on a plastic model of a trachea and evaluated the correct procedural steps. RESULTS: The majority of students that performed the VR simulation agreed that they improved in speed (81%) and procedural steps (92%). All participants completed the cricothyrotomy in 47s ± 16s and reached a total score of 8.7 ± 0.7 of 9 possible points. We saw no significant difference in time needed to perform a cricothyrotomy between study and control group (p > 0.05). However, the total score of correct procedural steps was significantly higher in the study group than in the control group (p < 0.05). CONCLUSIONS: Virtual reality is an innovative learning tool to improve teaching of emergency procedures. The VR cricothyrotomy subjectively and objectively improved correct procedural steps. Digitized education fills an educational gap between pure haptic experience and theoretical knowledge. This is of great value when focusing on extension of factual knowledge. TRIAL REGISTRATION: DRKS00031736, registered on the 20th April 2023.

Bubble accumulation and its role in the evolution of magma reservoirs in the upper crust.

Volcanic eruptions transfer huge amounts of gas to the atmosphere. In particular, the sulfur released during large silicic explosive eruptions can induce global cooling. A fundamental goal in volcanology, therefore, is to assess the potential for eruption of the large volumes of crystal-poor, silicic magma that are stored at shallow depths in the crust, and to obtain theoretical bounds for the amount of volatiles that can be released during these eruptions. It is puzzling that highly evolved, crystal-poor silicic magmas are more likely to generate volcanic rocks than plutonic rocks. This observation suggests that such magmas are more prone to erupting than are their crystal-rich counterparts. Moreover, well studied examples of largely crystal-poor eruptions (for example, Katmai, Taupo and Minoan) often exhibit a release of sulfur that is 10 to 20 times higher than the amount of sulfur estimated to be stored in the melt. Here we argue that these two observations rest on how the magmatic volatile phase (MVP) behaves as it rises buoyantly in zoned magma reservoirs. By investigating the fluid dynamics that controls the transport of the MVP in crystal-rich and crystal-poor magmas, we show how the interplay between capillary stresses and the viscosity contrast between the MVP and the host melt results in a counterintuitive dynamics, whereby the MVP tends to migrate efficiently in crystal-rich parts of a magma reservoir and accumulate in crystal-poor regions. The accumulation of low-density bubbles of MVP in crystal-poor magmas has implications for the eruptive potential of such magmas, and is the likely source of the excess sulfur released during explosive eruptions.

FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma.

BACKGROUND: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study.

BACKGROUND: Claudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells. PATIENTS AND METHODS: Patients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile. RESULTS: From September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent. CONCLUSIONS: Zolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials. CLINICALTRIALS.GOV NUMBER: NCT01197885.

The Danish STR sequence database: duplicate typing of 363 Danes with the ForenSeq™ DNA Signature Prep Kit.

Some STR loci have internal sequence variations, which are not revealed by the standard STR typing methods used in forensic genetics (PCR and fragment length analysis by capillary electrophoresis (CE)). Typing of STRs with next-generation sequencing (NGS) uncovers the sequence variation in the repeat region and in the flanking regions. In this study, 363 Danish individuals were typed for 56 STRs (26 autosomal STRs, 24 Y-STRs, and 6 X-STRs) using the ForenSeq™ DNA Signature Prep Kit to establish a Danish STR sequence database. Increased allelic diversity was observed in 34 STRs by the PCR-NGS assay. The largest increases were found in DYS389II and D12S391, where the numbers of sequenced alleles were around four times larger than the numbers of alleles determined by repeat length alone. Thirteen SNPs and one InDel were identified in the flanking regions of 12 STRs. Furthermore, 36 single positions and five longer stretches in the STR flanking regions were found to have dubious genotyping quality. The combined match probability of the 26 autosomal STRs was 10,000 times larger using the PCR-NGS assay than by using PCR-CE. The typical paternity indices for trios and duos were 500 and 100 times larger, respectively, than those obtained with PCR-CE. The assay also amplified 94 SNPs selected for human identification. Eleven of these loci were not in Hardy-Weinberg equilibrium in the Danish population, most likely because the minimum threshold for allele calling (30 reads) in the ForenSeq™ Universal Analysis Software was too low and frequent allele dropouts were not detected.

Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases.

The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.

Influence of the substrate material on the knife-edge based profiling of tightly focused light beams.

The performance of the knife-edge method as a beam profiling technique for tightly focused light beams depends on several parameters, such as the material and height of the knife-pad as well as the polarization and wavelength of the focused light beam under study. Here we demonstrate that the choice of the substrate the knife-pads are fabricated on has a crucial influence on the reconstructed beam projections as well. We employ an analytical model for the interaction of the knife-pad with the beam and report good agreement between our numerical and experimental results. Moreover, we simplify the analytical model and demonstrate, in which way the underlying physical effects lead to the apparent polarization dependent beam shifts and changes of the beamwidth for different substrate materials and heights of the knife-pad.

Characterization of the XIAP-Inhibiting Proanthocyanidin Fraction of the Aerial Parts of Ephedra sinica.

The X-linked inhibitor of apoptosis protein is a cellular protein that inhibits the activity of mammalian caspases and promotes resistance to apoptosis. The ethanol extract of the aerial parts of Ephedra sinica has been identified to possess inhibitory activity of the X-linked inhibitor of apoptosis protein by an in vitro fluorescence polarization assay using the BIR3 domain of the X-linked inhibitor of apoptosis protein. Bioactivity-guided fractionation identified proanthocyanidin-enriched fractions as the active principles. The most active fraction showed an IC50 value of 27.3 µg/mL (CI95: 25.9-28.9 µg/mL) corresponding to 9.6 µM (CI95: 9.1-10.1 µM) calculated by the use of the determined average molecular weight of 2853.5. Samples were analyzed by a thiolytic degradation/HPLC-MS assay, UHPLC-HRMS, and 1D NMR.The thiolytic degradation/HPLC-MS assay revealed a mean degree of polymerization of 9.5 ± 0.2 units (calculated average MW 2853.5) for the active fraction and 11.4 ± 0.6 units (calculated average MW 3437.0) for the most related inactive fraction. Chemical characterization identified (epi)gallocatechin (76.6 ± 1.0 % active; 80.7 ± 2.7 % inactive sample) and (epi)catechin units as building blocks. Interestingly, the investigated proanthocyanidins turned out to be a complex mixture of double linked A-type (binding 2-O-7″, 4-6″) and single linked B-type units.This study identified oligomeric proanthocyanidins as active principles of E. sinica in vitro by a fluorescence polarization assay and via protein fragment complementation analysis.

Medical, psychological and socio-economic implications of chronic hand eczema: a cross-sectional study.

BACKGROUND: Hand eczema (HE) is a common skin disease with major medical psychological and socio-economic implications. Onset and prognosis of HE are determined by individual as well as environmental factors. So far, most epidemiological data on HE have been reported from Scandinavian and recently German studies. OBJECTIVE: To investigate the characteristics and medical care of patients with chronic HE (CHE) in Switzerland, and identify risk factors. METHODS: In this cross-sectional study, data from patients with chronic HE were obtained by means of medical history, dermatological examination and patient questionnaires. Multiple logistic regression analysis was applied to identify risk factors for high severity and dermatology life quality index (DLQI). RESULTS: In seven dermatology departments, 199 patients (mean age 40.4 years, 50.8% female) with CHE (mean duration 6.6 years) were enrolled. Moderate to severe HE was reported by 70.9% of patients, and was associated with age <30 or >50 years, localization of lesions and pruritus. Because of the CHE, 37.3% of patients were on sick leave over the past 12 months, 14.8% had changed or lost their job. Practically all patients applied topical therapy, 21% were treated with alitretinoin, and 21% with psoralen plus UVA light (PUVA). The effects on the health-related quality of life was moderate to large in 33.7% and 39.4% of CHE patients, respectively. Factors associated with a high impact on DLQI (mean 9.7 ± 5.8) were female sex, lesions on back of the hands and pruritus as well as mechanical skin irritation and wearing gloves. CONCLUSION: In agreement with recent studies, the Swiss data demonstrate the high impact of CHE on medical well-being, patient quality of life and work ability. As it is associated with an intense use of health care services, high rate of sick leave, job loss and change, CHE may cause a high socio-economic burden.

In human basophils, IL-3 selectively induces RANKL expression that is modulated by IgER-dependent and IgER-independent stimuli.

BACKGROUND: Receptor activator of NF-κB ligand (RANKL) is expressed as either surface (hRANKL1, hRANKL2) or soluble (hRANKL3) form. RANKL is involved in multifaceted processes of immunoregulation and bone resorption such as they occur in rheumatoid arthritis (RA). Interestingly, activated basophils, which are effector cells in allergic inflammation, contribute to the progress of collagen-induced arthritis (CIA), a mouse model for RA. Here, we investigate under which conditions human basophils express RANKL. METHODS: Among other stimuli, basophils were cultured with IL-3 alone. Alternatively, as a secondary stimulus, IgER-dependent or IgER-independent agents were added simultaneously either with IL-3 or after prolonged IL-3 culturing. Expression of RANKL protein and mRNA was analyzed by flow cytometry, ELISA, and real-time PCR. A coculture system was applied to investigate biological activity of basophil-derived RANKL. RESULTS: We show that in human basophils, IL-3 but no other stimulus induces de novo expression of soluble and surface RANKL, of which the latter enhances survival of MoDC. Upon simultaneous stimulation, IgER cross-linking reduces surface RANKL expression, while IgER-independent stimuli have no effect. This is in contrast to consecutive stimulation, as triggering with both IgER-dependent and IgER-independent stimuli enhances RANKL expression, particularly in its soluble form. Real-time PCR analysis shows that RANKL expression is mainly regulated at the mRNA level. CONCLUSION: This study identifies IL-3 as a potent inducer of RANKL expression in human basophils, suggesting them to interact with bone physiology and activation of immune cells. IgER-dependent and IgER-independent stimuli modulate the IL-3-mediated RANKL expression in a time- and stimulus-dependent fashion.

Validation and application of sub-2 µm core-shell UHPLC-UV-ESI-Orbitrap MS for identification and quantification of ß-carotene and selected cleavage products with preceding solid-phase extraction.

A validated ultrahigh-performance liquid chromatography method using 1.7 µm core-shell particles is presented for the identification and quantification of ß-carotene (BC) and related cleavage products (CPs) in primary cell culture media. Besides BC, apo-4'-, apo-8'-, apo-10'-, and apo-12'-carotenals, as well as 5,6-epoxy-ß-carotene, were selected as target analytes. Detection was performed via an 80-Hz diode array detector and an electrospray ionization-linear quadrupole ion trap-Orbitrap XL mass spectrometer, both hyphenated in series. Total analysis time was below 6 min with peak widths <12 s. Addition of trifluoroacetic acid and tetrahydrofuran to the mobile phase allowed for the mass spectrometric detection of BC and related CPs and reduced peak tailing due to improved solubility of hydrophobic analytes. Intra-day and inter-day precision for UV and mass spectrometric detection were ≤1.5 % for retention times and ≤5.1 % for peak areas. Instrumental linearity was confirmed by Mandel's fitting test between 0.25 (or 1.00 µg/mL) and 5.00 µg/mL for UV detection. The higher sensitivity of mass spectrometric detection allowed for the coverage of three concentration domains between 0.025 and 5.00 µg/mL in linearity testing. Homoscedasticity was confirmed between 0.10 and 5.00 µg/mL for Orbitrap XL MS. The limits of quantification were between 52.6 and 889.4 ng/mL for UV detection and between 19.3 and 102.4 ng/L for mass spectrometric detection. Offline solid-phase extraction from culture media fortified with BC and CPs provided intra- and inter-day recoveries between 65.8 and 102.4 % with coefficients of variation ≤6.2 %. Primary rat hepatocyte cultures treated with BC and subjected to different oxidative stress conditions contained 5,6-epoxy-BC and apo-4'-carotenal besides residual BC. Apparently, 5,6-epoxy-BC was formed in the medium via autoxidation of BC by ambient oxygen.

[Long-term treatment of schizophrenia spectrum disorders: focus on pharmacotherapy]. / Pharmakologische Langzeitbehandlung schizophrener Erkrankungen.

Schizophrenia spectrum disorders (SSD) constitute a group of psychiatric illnesses which frequently lead to persisting mental impairment. Although some patients show a clinical course with few episodes and good long-term outcome, the course of the disease is often chronic and unfavorable. Long-term treatment (LTT) of SSD pertains to the postacute stabilization period and the remission period following pharmacological and psychosocial therapy of an acute illness episode. This article provides an overview of treatment recommendations concerning long-term pharmacotherapy, dealing with side effects, treatment of non-response and therapy resistance and the treatment of psychiatric comorbidities. Furthermore, an overview of non-pharmacological treatment options is presented. An integrated therapeutic setting combining evidence-based pharmacotherapy, psychosocial interventions, and supportive therapies is recommended for optimal LTT of SSD. Considering the limited financial resources available in the healthcare system, one of the major challenges is to provide patients with access to the evidence-based treatment options available.

High-altitude glacier archives lost due to climate change-related melting.

Global warming has caused widespread surface lowering of mountain glaciers. By comparing two firn cores collected in 2018 and 2020 from Corbassière glacier in Switzerland, we demonstrate how vulnerable these precious archives of past environmental conditions have become. Within two years, the soluble impurity records were destroyed by melting. The glacier is now irrevocably lost as an archive for reconstructing major atmospheric aerosol components.

Corrections to the knife-edge based reconstruction scheme of tightly focused light beams.

The knife-edge method is an established technique for profiling light beams. It was shown, that this technique even works for tightly focused beams, if the material and geometry of the probing knife-edges are chosen carefully. Furthermore, it was also reported recently that this method fails, when the knife-edges are made from pure materials. The artifacts introduced in the reconstructed beam shape and position depend strongly on the edge and input beam parameters, because the knife-edge is excited by the incoming beam. Here we show, that the actual beam shape and spot size of tightly focused beams can still be derived from knife-edge measurements for pure edge materials and different edge thicknesses by adapting the analysis method of the experimental data taking into account the interaction of the beam with the edge.

Changes in incidence, survival and mortality of prostate cancer in Europe and the United States in the PSA era: additional diagnoses and avoided deaths.

BACKGROUND: We describe changes in prostate cancer incidence, survival and mortality and the resulting impact in additional diagnoses and avoided deaths in European areas and the United States. METHODS: Using data from 12 European cancer registries and the Surveillance, Epidemiology and End Results program, we describe changes in prostate cancer epidemiology between the beginning of the PSA era (USA: 1985-1989, Europe: 1990-1994) and 2002-2006 among patients aged 40-64, 65-74, and 75+. Additionally, we examine changes in yearly numbers of diagnoses and deaths and variation in male life expectancy. RESULTS: Incidence and survival, particularly among patients aged <75, increased dramatically, yet both remain (with few exceptions in incidence) lower in Europe than in the United States. Mortality reductions, ongoing since the mid/late 1990 s, were more consistent in the United States, had a distressingly small absolute impact among patients aged 40-64 and the largest absolute impact among those aged 75+. Overall ratios of additional diagnoses/avoided deaths varied between 3.6 and 27.6, suggesting large differences in the actual impact of prostate cancer incidence and mortality changes. Ten years of remaining life expectancy was reached between 68 and 76 years. CONCLUSION: Policies reflecting variation in population life expectancy, testing preferences, decision aids and guidelines for surveillance-based management are urgently needed.

Are ratings on the positive and negative syndrome scale for schizophrenia biased by personality traits?

OBJECTIVE: The aim of this study was to estimate the potential bias by personality traits for ratings on the Positive and Negative Syndrome Scale (PANSS). METHODS: Personality dimensions (five factor model), personality traits (SCID-II) and PANSS scores were assessed prospectively in 45 patients with schizophrenia spectrum disorders (SSD). RESULTS: Borderline (r=0.34; p=0.021), avoidant (r=0.66; p<0.001) and depressive (r=0.51; p<0.001) personality traits were significantly correlated with the PANSS total score. There were significant correlations for all PANSS subscores with the exemption of PANSS positive. In multivariate analyses, the final models for PANSS total score and PANSS depressive explained a total of 45.3% and 54.3% of the variance. Avoidant traits could lead to a difference of 13.1 (95% CI: 5.6-20.7) points regarding PANSS total score, depressive traits could cause differences of 4.8 points (95% CI: 2.2-7.3) for PANSS depressive subscore. CONCLUSION: Although PANSS positive subscore and PANSS excited component are relatively robust against bias by personality traits, PANSS total score and the remaining subscores are affected to a clinically relevant degree. Outcome studies in SSD patients should control for personality traits.

In-situ alignment of 3D printed anisotropic hard magnets.

Within this work, we demonstrate in-situ alignment of the easy axis single-crystal magnetic particles inside a polymer matrix using fused filament fabrication. Two different magnetic materials are investigated: (i) Strontium hexaferrite inside a PA6 matrix, fill grade: 49 vol% and (ii) Samarium iron nitride inside a PA12 matrix, fill grade: 44 vol%. In the presence of the external alignment field, the strontium hexaferrite particles inside the PA6 matrix can be well aligned with a ratio of remnant magnetization to saturation magnetization in an easy axis of 0.7. No significant alignment for samarium iron nitride could be achieved. The results show the feasibility to fabricate magnets with arbitrary and locally defined easy axis using fused filament fabrication since the permanent magnets (or alternatively an electromagnet) can be mounted on a rotatable platform.