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Hypothesis And/or Background: Extensive, irreparable rotator cuff tears remain a surgical challenge and multiple treatment options are proposed and currently in use. To biomechanically compare superior glenohumeral translation, subacromial contact pressures, and area in a box-shaped reconstruction using the long head of the biceps tendon (LHBT) in an irreparable supraspinatus tendon tear model., Methods: Seven cadaveric shoulders (mean age 61 years; range 32-84 years; standard deviation 22.3) were tested with a custom testing rig used to evaluate superior translation; subacromial contact pressures; and areas at 0°, 30°, and 60° of glenohumeral abduction. Conditions tested included the native state; a complete tear of the supraspinatus tendon; a wide box-shaped, double-bundle LHBT superior capsular reconstruction (BS-SCR); and a narrow BS-SCR., Results: Compared with the wide BS-SCR, the narrow BS-SCR had statistically significantly lower median contact pressure at 30° and 60°. The subacromial contact area showed a statistically significant difference at 0° (P = .001) and 30° (P = .004) for the narrow BS-SCR compared with the wide BS-SCR. At an abduction angle of 0°, the narrow BS-SCR could restore superior translation significantly better compared with the wide construct. For all angles, the wide and narrow BS-SCR increased the median subacromial distance statistically significantly. The contact areas in 30° and 60° of abduction were higher for all scenarios, both peaking in the intact state in 30° with approximately 600 mm 2 ., Conclusions: In comparison to a wide BS-SCR, a narrow BS-SCR using the LHBT has biomechanical advantages in regard to subacromial contact pressures, the subacromial contact areas, as well as the acromiohumeral distance. The width of the reconstruction, therefore, has a direct influence on the success of the technique., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Estimates of the incidence of hyperkalemia in patients with chronic kidney disease (CKD) vary widely. Our objective was to estimate hyperkalemia incidence in patients with CKD from routine clinical care, including by level of kidney damage or function and among important patient subgroups., Study Design: Retrospective cohort study., Setting & Participants: 1,771,900 patients with stage 1-4 CKD identified from the US Optum De-Identified electronic health records database., Exposures or Predictors: Impaired kidney damage or function level at baseline based on urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR), respectively, and selected patient subgroups., Outcomes: Hyperkalemia: 2 elevated serum potassium values (≥5.5 mmol/L) from the inpatient setting (2-24 hours apart) or outpatient setting (maximum 7 days apart), or 1 elevated serum potassium value plus pharmacotherapy initiation or hyperkalemia diagnosis (maximum 3 days apart)., Analytical Approach: Incidence rates of hyperkalemia were calculated. Estimates were stratified by UACR and eGFR level at baseline and patient subgroups., Results: Over a mean follow-up of 3.9 years, the incidence of hyperkalemia was 3.37 events/100 person-years (95% confidence intervals, 3.36-3.38). Higher incidence rates were observed with increased UACR and lower eGFR. Highest rates were observed with UACR ≥3,500 (up to 19.1/100 person-years) irrespective of decreased eGFR level. High rates also occurred in patients with type 2 diabetes mellitus (T2DM, 5.43/100 person-years), heart failure (8.7/100 person-years), and those prescribed steroidal mineralocorticoid receptor antagonists (sMRAs, 7.7/100 person-years)., Limitations: Potential misclassification of variables from possible medical coding errors; potential data incompleteness issues if patients received care at institutions not included in Optum., Conclusions: Hyperkalemia is a frequent occurrence in CKD, particularly in patients with T2DM, heart failure, or prescribed sMRAs, indicating the need for regular serum potassium and UACR monitoring in this patient population to help mitigate risk., (© 2024 The Authors.)

Introduction: The aim of this study was to evaluate the range of motion (ROM), elbow function and predictors for good elbow function after conservative treatment of non-displaced radial head fractures., Material and Methods: All patients with non-displaced radial head fractures (displacement < 2 mm), that were diagnosed between January 1st 2017 and December 31st 2021 in a level I trauma center, were included in this retrospective case series and the charts were evaluated for ROM and elbow function. Elbow function was categorized as "good" or "bad" depending on the ROM measured defined by Morrey et al. Overall, 73 patients (33 male, 40 female) with an average age of 38 years (+/- 13 years) could be included., Results: Conservative treatment had good clinical results for ROM and elbow function. After 6 weeks mean flexion was 131° (SD 13°), extension 8° (SD 7°), Pronation 83° (SD 11°) and Supination 83° (SD 13). Patients with a good elbow function after one week showed a good elbow function after completing the treatment., Conclusions: A clinical assessment after one week should always be performed and the study showed that it is a good predictor for good elbow function. In cases of bad elbow function further controls should be considered., (© 2024. The Author(s).)

The transcellular propagation of the aberrantly modified protein tau along the functional brain network is a key hallmark of Alzheimer's disease and related tauopathies. Inoculation-based tau propagation models can recapitulate the stereotypical spread of tau and reproduce various types of tau inclusions linked to specific tauopathy, albeit with varying degrees of fidelity. With this systematic review, we underscore the significance of judicious selection and meticulous functional, biochemical, and biophysical characterization of various tau inocula. Furthermore, we highlight the necessity of choosing suitable animal models and inoculation sites, along with the critical need for validation of fibrillary pathology using confirmatory staining, to accurately recapitulate disease-specific inclusions. As a practical guide, we put forth a framework for establishing a benchmark of inoculation-based tau propagation models that holds promise for use in preclinical testing of disease-modifying drugs., (© 2024. The Author(s).)

The posttranslational modifier ubiquitin regulates most cellular processes. Its ability to form polymeric chains of distinct linkages is key to its diverse functionality. Yet, we still lack the experimental tools to induce linkage-specific polyubiquitylation of a protein of interest in cells. Here, we introduce a set of engineered ubiquitin protein ligases and matching ubiquitin acceptor tags for the rapid, inducible linear (M1-), K48-, or K63-linked polyubiquitylation of proteins in yeast and mammalian cells. By applying the so-called "Ubiquiton" system to proteasomal targeting and the endocytic pathway, we validate this tool for soluble cytoplasmic and nuclear as well as chromatin-associated and integral membrane proteins and demonstrate how it can be used to control the localization and stability of its targets. We expect that the Ubiquiton system will serve as a versatile, broadly applicable research tool to explore the signaling functions of polyubiquitin chains in many biological contexts., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective As population-based studies describing the characteristics of patients with refractory chronic cough (RCC) are sparse, the objective of this descriptive study was to identify and describe such patients using an algorithm developed for administrative claims databases and requiring validation in future. Methods We identified adults with chronic cough (N = 782,121) from Optum Clinformatics™ Data Mart as individuals with a 'cough event' (primary cough event; based on ICD codes/relevant prescriptions) and ≥2 cough events in the 56-180 preceding days. We applied several exclusion criteria to identify potential RCC cases and stratified them into probable, possible, and unlikely RCC cohorts by the number of cough events during 1-year follow up (≥3, 1-2 or 0 events, respectively). Patient characteristics were described during the year before the primary cough event and follow up. Results 16.8% (n = 131,772) of patients with chronic cough were potential RCC cases: 25.8% probable, 35.9% possible and 38.3% unlikely. The majority were female (66.4-70.5%); median age was 53-60 years. The most common comorbidities and cough-associated complications at baseline were: allergic rhinitis (30.7-39.1%), hypertension (37.3-47.7%), gastro-oesophageal reflux disease (23.7-34.3%), asthma (18.1-27.3%), insomnia (6.3-8.3%) and stress incontinence (2.5-3.9%). Among probable RCC cases, use of several medications was higher during follow up versus baseline: 52.7% versus 49.0% (cough treatments), 73.3% versus 69.0% (respiratory drugs), 40.5% versus 34.2% (gastrointestinal drugs) and 58.8% versus 56.1% (psychotherapeutics). Conclusion Our algorithm requires validation but provides a starting point to identify patients with RCC in claims databases in future studies., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SvBW and PV are employees of Bayer AG (Germany). RH and PVP were employees of Bayer AG (Germany) at the time the study was carried out. KA has served as a consultant and speaker for Merck and Vindico, Axdev, Lyra Pharmaceuticals, and Bellus Pharmaceuticals. PP declares no conflicts of interest.

Prion diseases are characterized by prion protein (PrP) transmissible aggregation and neurodegeneration, which has been linked to oxidative stress. The physiological function of PrP seems related to sequestering of redox-active Cu 2+ , and Cu 2+ dyshomeostasis is observed in prion disease brain. It is unclear whether Cu 2+ contributes to PrP aggregation, recently shown to be mediated by PrP condensation. This study indicates that Cu 2+ promotes PrP condensation in live cells at the cell surface and in vitro through copartitioning. Molecularly, Cu 2+ inhibited PrP β-structure and hydrophobic residues exposure. Oxidation, induced by H 2 O 2 , triggered liquid-to-solid transition of PrP:Cu 2+ condensates and promoted amyloid-like PrP aggregation. In cells, overexpression of PrP C initially protected against Cu 2+ cytotoxicity but led to PrP C aggregation upon extended copper exposure. Our data suggest that PrP condensates function as a buffer for copper that prevents copper toxicity but can transition into PrP aggregation at prolonged oxidative stress.

The stereotypical progression of Tau pathology during Alzheimer disease has been attributed to trans-neuronal spreading of misfolded Tau proteins, followed by prion-like templated aggregation of Tau. The nature of Tau and the cellular mechanisms of Tau spreading are still under debate. We hypothesized that Tau's propensity for aggregation would correlate with its ability to spread across synapses and propagate pathology. To study the progressive propagation of Tau proteins in brain regions relevant for Alzheimer disease, we used mice expressing near-physiological levels of full-length human Tau protein carrying pro-aggregant (TauΔK280, Tau ΔK ) or anti-aggregant (TauΔK280-PP, Tau ΔK-PP ) mutations in the entorhinal cortex (EC). To enhance Tau expression in the EC, we performed EC injections of adeno-associated virus (AAV) particles encoding Tau ΔK or Tau ΔK-PP . The brains of injected and non-injected EC/Tau ΔK and EC/Tau ΔK-PP mice were studied by immunohistological and biochemical techniques to detect Tau propagation to dentate gyrus (DG) neurons and Tau-induced pathological changes. Pro- and anti-aggregant mice had comparable low transgene expression (~0.2 times endogenous mouse Tau). They accumulated human Tau at similar rates and only in expressing EC neurons, including their axonal projections of the perforant path and presynaptic terminals in the molecular layer of the DG. Pro-aggregant EC/Tau ΔK mice showed misfolded Tau and synaptic protein alterations in EC neurons, not observed in anti-aggregant EC/Tau ΔK-PP mice. Additional AAV-mediated expression of Tau ΔK or Tau ΔK-PP in EC/Tau ΔK or EC/Tau ΔK-PP mice, respectively, increased the human Tau expression to ~0.65 times endogenous mouse Tau, with comparable spreading of Tau ΔK and Tau ΔK-PP throughout the EC. There was a low level of transcellular propagation of Tau protein, without pathological phosphorylation or misfolding, as judged by diagnostic antibodies. Additionally, Tau ΔK but not Tau ΔK-PP expression induced hippocampal astrogliosis. Low levels of pro- or anti-aggregant full-length Tau show equivalent distributions in EC neurons, independent of their aggregation propensity. Increasing the expression via AAV induce local Tau misfolding in the EC neurons, synaptotoxicity, and astrogliosis and lead to a low level of detectable trans-neuronal spreading of Tau. This depends on its concentration in the EC, but, contrary to expectations, does not depend on Tau's aggregation propensity/misfolding and does not lead to templated misfolding in recipient neurons., (© 2023. The Author(s).)

So far there are no clear recommendations for postoperative follow-up treatment of elbow injuries and individual concepts are often chosen. Due to the susceptibility for posttraumatic or postoperative impaired movement up to stiffness of the elbow joint, early mobilization plays a crucial role. Therefore, mid-term to long-term immobilization should be avoided. In addition to the necessary cryotherapy and compression therapy for swelling and pain control in the initial period, early actively assisted mobilization now has an important role. Additionally, active flexion and extension in an overhead position, so-called overhead motion, was recently established. After a short initial immobilization in a cast, mostly 3-5 days, the cast is changed to a dynamic movement orthosis, which when possible enables a free range of motion. Care is taken that varus and valgus loading is avoided. In general loading is avoided for the first 6 weeks, followed by a stepwise increase of loading up to maximum loading. In most cases return to sport is possible after 3 months. After implantation of an elbow prosthesis a maximum loading of 5 kg for single loading and 1 kg for repetitive loading are recommended., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)