Standardized Production of Anti-Desmoglein 3 Antibody AK23 for Translational Pemphigus Vulgaris Research.

Antibody-mediated receptor activation is successfully used to develop medical treatments. If the activation induces a pathological response, such antibodies are also excellent tools for defining molecular mechanisms of target receptor malfunction and designing rescue therapies. Prominent examples are naturally occurring autoantibodies inducing the severe blistering disease pemphigus vulgaris (PV). In the great majority of patients, the antibodies bind to the adhesion receptor desmoglein 3 (Dsg3) and interfere with cell signaling to provoke severe blistering in the mucous membranes and/or skin. The identification of a comprehensive causative signaling network downstream of antibody-targeted Dsg3 receptors (e.g., shown by pharmacological activators or inhibitors) is currently being discussed as a basis to develop urgently needed first-line treatments for PV patients. Although polyclonal PV IgG antibodies have been used as proof of principle for pathological signal activation, monospecific anti-Dsg3 antibodies are necessary and have been developed to identify pathological Dsg3 receptor-mediated signal transduction. The experimental monospecific PV antibody AK23, produced from hybridoma cells, was extensively tested in our laboratory in both in vitro and in vivo models for PV and proved to recapitulate the clinicopathological features of PV when generated using the standardized production and purification protocols described herein. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Bovine IgG stripping from FBS and quality control Basic Protocol 2: AK23 hybridoma expansion and IgG production Basic Protocol 3: AK23 IgG purification Basic Protocol 4: AK23 IgG quality control Support Protocol 1: Detection of endotoxin levels Support Protocol 2: Detection and removal of mycoplasma

Anterior cruciate ligament repair using dynamic intraligamentary stabilization grants 88.5% survival at minimum follow-up of 5 years.

PURPOSE The aim of this study was to report on the revision rates and clinical outcomes following dynamic intraligamentary stabilization (DIS) at a minimum follow-up of 5 years and to investigate which preoperative or intraoperative characteristics could influence revision rates or clinical scores. METHODS The authors retrospectively assessed all 609 knees that underwent ACL repair using DIS at a single centre. At a minimum follow-up of 5 years, patients were assessed using the Lysholm, International Knee Documentation Committee (IKDC) and Tegner scores, as well as passive flexion and extension. RESULTS At a follow-up of 5.1 ± 0.3 years (range, 5-10), of the 609 patients, 428 patients were available for clinical assessment. Anterior tibial translation decreased from 9.7 ± 2.1 to 7.8 ± 1.9 mm, and side-to-side difference decreased from 4.3 ± 2.3 to 1.5 ± 1.8 mm. The postoperative Lysholm score was 96.9 ± 5.6, subjective IKDC was 95.6 ± 6.1 and Tegner scores ranged from 4 to 11, of which 51% of patients had a score of 7 or more. The estimated survival rate was 86% for the first half of the cohort and increased to 91% for the second half of the cohort. CONCLUSION At a minimum follow-up of 5 years following ACL repair using DIS, it was found that it grants satisfactory clinical outcomes and that surgeons should inform patients who have predispositions about the higher risk of revision. LEVEL OF EVIDENCE Level IV retrospective study

High-resolution ice-core analyses identify the Eldgjá eruption and a cluster of Icelandic and trans-continental tephras between 936 and 943 CE.

The Eldgjá eruption is the largest basalt lava flood of the Common Era. It has been linked to amajor ice‐core sulfur (S) spike in 939–940 CE and Northern Hemisphere summer cooling in 940 CE. Despite itsmagnitude and potential climate impacts, uncertainties remain concerning the eruption timeline, atmosphericdispersal of emitted volatiles, and coincident volcanism in Iceland and elsewhere. Here, we present acomprehensive analysis of Greenland ice‐cores from 936 to 943 CE, revealing a complex volatile record andcryptotephra with numerous geochemical populations. Transitional alkali basalt tephra matching Eldgjá arefound in 939–940 CE, while tholeiitic basalt shards present in 936/937 CE and 940/941 CE are compatible withcontemporaneous Icelandic eruptions from Grímsvötn and Bárðarbunga‐Veiðivötn systems (including V‐Sv tephra). We also find four silicic tephra populations, one of which we link to the Jala Pumice of Ceboruco(Mexico) at 941 ± 1 CE. Triple S isotopes, Δ33S, spanning 936–940 CE are indicative of upper tropospheric/lower stratospheric transport of aerosol sourced from the Icelandic fissure eruptions

Überprüfung des Weiss-Harter-Modells in einem prospektiven Studiendesign: Die Relevanz der wahrgenommenen sozialen Unterstützung für die körperliche Aktivität von Kindern und Jugendlichen

To counteract low physical activity levels in children and adolescents, it is crucial to understand the relevant psychological processes that can promote physical activity in this age group. The Weiss-Harter model focuses on self-esteem as a central construct for physical activity promotion in youth, which mediates the effects of perceived competence and perceived social support on enjoyment and physical activity. However, in two cross-sectional studies, an adapted model was found to have a better model fit in which perceived social support has additional direct effects on physical activity and enjoyment. The purpose of the present study was to compare the original Weiss-Harter model and the adapted model in a prospective study design. Data were based on two assessment waves of the German Motorik-Modul-Study involving 1107 participants (603 female) with a mean age of 13.98 years (SD = 2.03). Participants filled out questionnaires on perceived competence, perceived social support, self-esteem, enjoyment, and moderate-vigorous physical activity (MVPA) during the first assessment. MVPA was again assessed about five years later allowing to test whether the models could predict (1) future MVPA and (2) the difference of MVPA from the first to the second assessment. For both research questions, the original Weiss-Harter model (Model 1a: χ2 = 812.44; df = 95; p < 0.01; CFI = 0.905; RMSEA = 0.083; Model 2a: χ2 = 755.29; df = 95; p < 0.01; CFI = 0.910; RMSEA = 0.079) had a worse fit than the adapted model (Model 1b: χ2 = 512.19; df = 93; p < 0.01; CFI = 0.943; RMSEA = 0.065; Model 2b: χ2 = 513.25; df = 93; p < 0.01; CFI = 0.943; RMSEA = 0.064). The results of this study highlight the role of perceived social support for youth MVPA

Pulsed-field vs. cryoballoon vs. radiofrequency ablation: a propensity score matched comparison of one-year outcomes after pulmonary vein isolation in patients with paroxysmal atrial fibrillation.

BACKGROUND Pulsed-field ablation (PFA) has shown favourable data in terms of safety and procedural efficiency for pulmonary vein isolation (PVI). We sought to compare procedural and 1-year follow-up data of patients with paroxysmal atrial fibrillation (AF) undergoing PVI using PFA, cryoballoon ablation (CBA) and radiofrequency ablation (RFA). METHODS Consecutive patients with paroxysmal AF undergoing a first PVI with PFA at our institution were included. For comparison, patients with paroxysmal AF undergoing a first PVI with CBA and RFA were selected using a 1:2:2 propensity score matching. The PFA group followed the standard 32-applications lesion-set protocol, the CBA group a time-to-effect plus 2-min strategy, and the RFA group the CLOSE protocol. Patients were followed with 7d-Holter ECGs 3, 6, and 12 months after ablation. The primary endpoint was recurrence of atrial tachyarrhythmia (ATa) following a blanking period of 3 months. RESULTS A total of 200 patients were included (PFA n = 40; CBA n = 80; RFA n = 80). Median procedure times were shortest with CBA (75 min) followed by PFA (94 min) and RFA (182 min; p < 0.001). Fluoroscopy dose was lowest with RFA (1.6Gycm2) followed by PFA (5.0Gycm2) and CBA (5.7Gycm2; p < 0.001). After a 1-year follow-up, freedom from ATa recurrence was 85.0% with PFA, 66.2% with CBA and 73.8% with RFA (p = 0.12 PFA vs. CBA; p = 0.27 PFA vs. RFA). CONCLUSION In a propensity score matched analysis of patients with paroxysmal AF, freedom from any ATa 1 year after PVI using PFA was favourable and at least as good as for PVI with CBA or RFA

Influence of the Level of Compliance with Preventive Maintenance Therapy upon the Prevalence of Peri-Implant Diseases: A cross-sectional study.

BACKGROUND A study was made to evaluate peri-implant conditions in compliers and erratic compliers with peri-implant maintenance therapy (PIMT), and to assess the role of site-specific confounders. METHODS Erratic PIMT compliers (EC) were defined as presenting attendance < 2x/year, while regular compliers (RC) attended ≥ 2x/year. Generalized estimating equations (GEE) were employed to perform a multivariable multilevel analysis in which the peri-implant condition was established as dependent variable. RESULTS Overall, 86 non-smoker patients (42 RC and 44 EC) attending the department of periodontology of the Universitat Internacional de Catalunya were recruited consecutively on a cross-sectional basis. The mean period of loading was 9.5y. An implant placed in an erratic patient has 88% higher probability of presenting peri-implant diseases versus RC. Furthermore, the probability of diagnosis of peri-implantitis was significantly higher in EC vs RC (OR 5.26; 95% CI: 1.51 - 18.29) (p = 0.009). Among other factors, history of periodontitis, non-hygienic prosthesis, period of implant loading and Modified Plaque Index (MPI) at implant level were shown to significantly increase the risk of peri-implantitis diagnosis. Although not associated with peri-implantitis diagnosis risk, keratinized mucosa (KM) width and vestibular depth (VD) were significantly associated to plaque accumulation (mPI). CONCLUSIONS Compliance with PIMT was found to be significantly associated with peri-implant status. In this sense, attending PIMT < 2x/year may not be sufficient to prevent peri-implantitis. These outcomes should be limited to a non-smokers population. This article is protected by copyright. All rights reserved

The Therapy Intensity Level scale for traumatic brain injury: clinimetric assessment on neuro-monitored patients across 52 European intensive care units.

Intracranial pressure (ICP) data from traumatic brain injury (TBI) patients in the intensive care unit (ICU) cannot be interpreted appropriately without accounting for the effect of administered therapy intensity level (TIL) on ICP. A 15-point scale was originally proposed in 1987 to quantify the hourly intensity of ICP-targeted treatment. This scale was subsequently modified &ndash; through expert consensus &ndash; during the development of TBI Common Data Elements to address statistical limitations and improve usability. The latest, 38-point scale (hereafter referred to as TIL) permits integrated scoring for a 24-hour period and has a five-category, condensed version (TIL(Basic)) based on qualitative assessment. Here, we perform a total- and component-score analysis of TIL and TIL(Basic) to: (1) validate the scales across the wide variation in contemporary ICP management, (2) compare their performance against that of predecessors, and (3) derive guidelines for proper scale use. From the observational Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study, we extract clinical data from a prospective cohort of ICP-monitored TBI patients (n=873) from 52 ICUs across 19 countries. We calculate daily TIL and TIL(Basic) scores (TIL24 and TIL(Basic)24, respectively) from each patient&rsquo;s first week of ICU stay. We also calculate summary TIL and TIL(Basic) scores by taking the first-week maximum (TILmax and TIL(Basic)max) and first-week median (TILmedian and TIL(Basic)median) of TIL24 and TIL(Basic)24 scores for each patient. We find that, across all measures of construct and criterion validity, the latest TIL scale performs significantly greater than or similarly to all alternative scales (including TIL(Basic)) and integrates the widest range of modern ICP treatments. TILmedian outperforms both TILmax and summarised ICP values in detecting refractory intracranial hypertension (RICH) during ICU stay. The RICH detection thresholds which maximise the sum of sensitivity and specificity are TILmedian&ge;7.5 and TILmax&ge;14. The TIL24 threshold which maximises the sum of sensitivity and specificity in the detection of surgical ICP control is TIL24&ge;9. The median scores of each TIL component therapy over increasing TIL24 reflect a credible staircase approach to treatment intensity escalation, from head positioning to surgical ICP control, as well as considerable variability in the use of cerebrospinal fluid drainage and decompressive craniectomy. Since TIL(Basic)max suffers from a strong statistical ceiling effect and only covers 17% (95% CI: 16&ndash;18%) of the information in TILmax, TIL(Basic) should not be used instead of TIL for rating maximum treatment intensity. TIL(Basic)24 and TIL(Basic)median can be suitable replacements for TIL24 and TILmedian, respectively (with up to 33% [95% CI: 31&ndash;35%] information coverage) when TIL assessment is infeasible. Accordingly, we derive numerical ranges for categorising TIL24 scores into TIL(Basic)24 scores. In conclusion, our results validate TIL across a spectrum of ICP management and monitoring approaches. TIL is a more sensitive surrogate for pathophysiology than ICP..

Atypical language organization following perinatal infarctions of the left hemisphere is associated with structural changes in right-hemispheric grey matter.

AIM To assess how atypical language organization after early left-hemispheric brain lesions affects grey matter in the contralesional hemisphere. METHOD This was a cross-sectional study with between-group comparisons of 14 patients (six female, 8-26 years) with perinatal left-hemispheric brain lesions (two arterial ischemic strokes, 11 periventricular haemorrhagic infarctions, one without classification) and 14 typically developing age-matched controls (TDC) with functional magnetic resonance imaging (fMRI) documented left-hemispheric language organization (six female, 8-28 years). MRI data were analysed with SPM12, CAT12, and custom scripts. Language lateralization indices were determined by fMRI within a prefrontal mask and right-hemispheric grey matter group differences by voxel-based morphometry (VBM). RESULTS FMRI revealed left-dominance in seven patients with typical language organization (TYP) and right-dominance in seven patients with atypical language organization (ATYP) of 14 patients. VBM analysis of all patients versus controls showed grey matter reductions in the middle temporal gyrus of patients. A comparison between the two patient subgroups revealed an increase of grey matter in the middle frontal gyrus in the ATYP group. Voxel-based regression analysis confirmed that grey matter increases in the middle frontal gyrus were correlated with atypical language organization. INTERPRETATION Compatible with a non-specific lesion effect, we found areas of grey matter reduction in patients as compared to TDC. The grey matter increase in the middle frontal gyrus seems to reflect a specific compensatory effect in patients with atypical language organization

How to integrate CD19 specific chimeric antigen receptor T cells with other CD19 targeting agents in diffuse large B-cell lymphoma?

About one third of patients with diffuse large B-cell lymphoma (DLBCL) have a relapsing/refractory (R/R) disease after first line chemo-immunotherapy, with particularly poor outcomes observed in patients with primary refractory disease and early relapse. CD19 specific chimeric antigen receptor (CAR) T cell therapy is a game changer that results in durable and complete response rates in almost half of the patients with R/R DLBCL. Other emerging CD19-targeting therapies include monoclonal antibodies, bispecific antibodies and targeting antibody-drug conjugates, which also show encouraging results. However, the timing and sequencing of different anti-CD19-targeting agents and how they might interfere with subsequent CAR T cell treatment is still unclear. In this review, we summarize the results of the pivotal clinical trials as well as evidence from real-world series of the use of different CD19-targeting approved agents. We discuss the effect of various therapies on CD19 expression and its implications for treatment sequencing