Basophil Activation to Gluten and Non-Gluten Proteins in Wheat-Dependent Exercise-Induced Anaphylaxis

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a cofactor-induced wheat allergy. Gluten proteins, especially ω5-gliadins, are known as major allergens, but partially hydrolyzed wheat proteins (HWPs) also play a role. Our study investigated the link between the molecular composition of gluten or HWP and allergenicity. Saline extracts of gluten (G), gluten with reduced content of ω5-gliadins (G-ω5), slightly treated HWPs (sHWPs), and extensively treated HWPs (eHWPs) were prepared as allergen test solutions and their allergenicity assessed using the skin prick test and basophil activation test (BAT) on twelve patients with WDEIA and ten controls. Complementary sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE), high-performance liquid chromatography (HPLC), and mass spectrometry (MS) analyses revealed that non-gluten proteins, mainly α-amylase/trypsin inhibitors (ATIs), were predominant in the allergen test solutions of G, G-ω5, and sHWPs. Only eHWPs contained gliadins and glutenins as major fraction. All allergen test solutions induced significantly higher %CD63+ basophils/anti-FcεRI ratios in patients compared with controls. BAT using sHWPs yielded 100% sensitivity and 83% specificity at optimal cut-off and may be useful as another tool in WDEIA diagnosis. Our findings indicate that non-gluten proteins carrying yet unidentified allergenic epitopes appear to be relevant in WDEIA. Further research is needed to clarify the role of nutritional ATIs in WDEIA and identify specific mechanisms of immune activation

Considering medical students’ perception, concerns and needs for e-exam during COVID-19: a promising approach to improve subject specific e-exams

The COVID-19 pandemic forced a rapid shift to digital strategies including e-exams in medical schools. However, there are significant concerns, predominately from student perspectives, and further data is required to successfully establish e-assessment in the medical curricula. The objective of the study was to examine medical students’ perceptions, concerns, and needs regarding e-assessment to establish a comprehensive e-exam based on these and previous findings and to evaluate its effectiveness in terms of examinee perceptions and further needs. During the 2021 summer term, a cross-sectional study using qualitative and quantitative methods was conducted among all 1077 students at the School of Medicine, Technical University of Munich. They were asked to provide information regarding their characteristics, preferred exam format, e-assessment perception, concerns, and needs in an online questionnaire. Based on these findings, a pilot e-exam including an e-exam preparation for the students were established and subsequently evaluated among 125 pilot e-exam examinees under study consideration via an online-questionnaire. Of the 317 pre-exam participants (73.2% female), 70.3% preferred in-person exams and showed concerns about the technological framework, privacy, and examination requirements. Qualitative analysis showed that these concerns lead to additional exam stress and fear of failure. The 34 (79.4% female) participants who participated in the evaluation survey showed a significantly more positive e-exam perception. The fairness of the platform, the independence from an internet connection, the organization including the e-exam preparation, and the consideration of participant needs were discussed as particularly positive in the open-ended comments. In both surveys, participants requested uniform platforms and processes for all subjects. This study provides evidence for a positive, complementary role of student participation in a successful e-exam implementation. Furthermore, when establishing an e-exam format in the medical curricula, e-exam training, equal accessibility, availability offline, and all-round fairness should be considered

The dissociative subtype of PTSD in trauma-exposed individuals: a latent class analysis and examination of clinical covariates

Background A dissociative subtype of posttraumatic stress disorder (D-PTSD) was introduced into the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) but latent profiles and clinical correlates of D-PTSD remain controversial. Objective The aims of our study were to identify subgroups of individuals with distinct patterns of PTSD symptoms, including dissociative symptoms, by means of latent class analyses (LCA), to compare these results with the categorization of D-PTSD vs. PTSD without dissociative features according to the CAPS-5 interview, and to explore whether D-PTSD is associated with higher PTSD severity, difficulties in emotion regulation, and depressive symptoms. Method A German sample of treatment-seeking individuals was investigated (N = 352). We conducted an LCA on the basis of symptoms of PTSD and dissociation as assessed by the CAPS-5. Moreover, severity of PTSD (PCL-5), difficulties in emotion regulation (DERS), and depressive symptoms (BDI-II) were compared between patients with D-PTSD according to the CAPS-5 interview and patients without dissociative symptoms. Results LCA results suggested a 5-class model with one subgroup showing the highest probability to fulfill criteria for the dissociative subtype and high scores on both BDI and DERS. Significantly higher scores on the DERS, BDI and PCL-5 were found in the D-PTSD group diagnosed with the CAPS-5 (n = 75; 35.7%). Sexual trauma was also reported more often by this subgroup. When comparing the dissociative subtype to the LCA results, only a partial overlap could be found. Conclusions Our findings suggest that patients with D-PTSD have significantly more problems with emotion regulation, more depressive symptoms, and more severe PTSD-symptoms. Given the results of our LCA, we conclude that the dissociative subtype seems to be more complex than D-PTSD as diagnosed by means of the CAPS-5

Comparison of Functional and Clinical Outcomes between Minimally-Invasive and Conventional Approaches after Total Hip Replacement

Background: Total Hip Arthroplasty (THA) is one of the most commonly performed and successful orthopaedic surgeries. At the same time, the issue about the best surgical approach for THA remains controversial. This systematic review aims to evaluate the current evidence for the use of Minimally-Invasive Surgery (MIS) in THA. Methods: A systematic literature search of PubMed, Medline and Embase was conducted. Randomised controlled trials, comparative studies, and cohort studies were included in this systematic review. Main outcome measurements included incision length, blood loss, operating time, length of stay, complications, postoperative pain on a Visual Analogue Scale (VAS), Short Form 36/12 Health Survey (SF 36/12), Harris Hip Score (HHS) and cup inclination. Results: A total of 30 studies met the inclusion criteria. There was no significant difference between MIS and conventional approaches for THA with regards to complication rates and implant inclination angle. The average operating time in 10/24 (41%) studies was significantly (p<0.05) longer in the MIS group. MIS THA lead to an improvement, patient-centered results with reduced blood loss in 9/16 (56%), reduced use of analgesics in 4/4 (100%) and reduced myoglobin correlated muscle trauma in 3/4 (75%) of the analysed studies. Additionally, 10/10 (100%) studies reported less postoperative pain after MIS THA, 16/19 (84%) studies detected an improved postoperative Harris Hip score and 7/7 (100%) studies an improved SF36/12 score respectively. This resulted a reduced length of stay in 10/10 (100%) of the studies when compared to THA utilizing a conventional approach. Conclusion: MIS in THA is nowadays no longer seen as just cosmetically attractive but rather as a real improvement for the clinical outcome. There is evidence for improved patient related outcome following MIS THA

The plant specific CDKB1-CYCB1 complex mediates homologous recombination repair in Arabidopsis

Upon DNA damage, cyclin-dependent kinases (CDKs) are typically inhibited to block cell division. In many organisms, however, it has been found that CDK activity is required for DNA repair, especially for homology-dependent repair (HR), resulting in the conundrum how mitotic arrest and repair can be reconciled. Here, we show that Arabidopsis thaliana solves this dilemma by a division of labor strategy. We identify the plant-specific B1-type CDKs (CDKB1s) and the class of B1-type cyclins (CYCB1s) as major regulators of HR in plants. We find that RADIATION SENSITIVE 51 (RAD51), a core mediator of HR, is a substrate of CDKB1-CYCB1 complexes. Conversely, mutants in CDKB1 and CYCB1 fail to recruit RAD51 to damaged DNA. CYCB1; 1 is specifically activated after DNA damage and we show that this activation is directly controlled by SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1), a transcription factor that acts similarly to p53 in animals. Thus, while the major mitotic cell-cycle activity is blocked after DNA damage, CDKB1-CYCB1 complexes are specifically activated to mediate HR

Effectiveness and safety of vedolizumab in inflammatory bowel disease patients aged 60 and over: an observational multicenter UK experience.

BACKGROUND: The GEMINI trials established the efficacy of vedolizumab in moderate-to-severe inflammatory bowel disease (IBD) and demonstrated a favorable safety profile, suggesting it may be advantageous in older patients at greater risk of treatment-related complications. However, there is a paucity of data exploring the outcomes of vedolizumab in this group. Our objective was to determine the clinical effectiveness and safety of vedolizumab in older IBD patients within a real-world multicenter UK cohort. METHODS: A retrospective review of electronic records across 6 UK hospitals was undertaken to evaluate the clinical effectiveness and safety outcomes of vedolizumab in IBD patients aged ≥60 at start of therapy. Rates of clinical response, remission and corticosteroid-free remission were assessed at weeks 14 and 52, using validated clinical indices, and were compared to historical controls from real-world vedolizumab-treated cohorts unstratified by age. RESULTS: Of 74 patients aged 60 years or above (median 66 years), 48 were included in our effectiveness analysis (29 ulcerative colitis, 19 Crohn's disease). Rates of clinical response, remission and corticosteroid-free remission at week 14 were 64%, 48% and 30%, respectively. By week 52, the rates of clinical response, remission, and corticosteroid-free remission were 52%, 38%, and 32%, respectively. Six (8%) patients experienced adverse effects. Effectiveness and safety outcomes were comparable to those of age-unstratified vedolizumab-treated cohorts. CONCLUSION: Our 1-year outcome data suggests that vedolizumab is safe and effective in older IBD patients and broadly comparable to cohorts unselected by age

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1R132H are still ambiguous. The present study demonstrates that IDH1R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD+ levels upon IDH1R132H transduction. However, in astrocytes IDH1R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1R132H cells utilize NAD+ to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas.publishedVersio

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements