Interleukin-17A promotes parietal cell atrophy by inducing apoptosis

Background & Aims: Atrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined. We investigated the role of interleukin-17A (IL-17A) in causing parietal cell atrophy. Methods: A mouse model of autoimmune atrophic gastritis was used to examine IL-17A production during early and late stages of disease. Organoids derived from corpus glands were used to determine the direct effects of IL-17A on gastric epithelial cells. Immunofluorescent staining was used to examine IL-17A receptors and the direct effect of signaling on parietal cells. Mice were infected with an IL-17A-producing adenovirus to determine the effects of IL-17A on parietal cells in vivo. Finally, IL-17A neutralizing antibodies were administered to mice with active atrophic gastritis to evaluate the effects on parietal cell atrophy and metaplasia. Results: Increased IL-17A correlated with disease severity in mice with chronic atrophic gastritis. IL-17A caused caspase-dependent gastric organoid degeneration, which could not be rescued with a necroptosis inhibitor. Parietal cells expressed IL-17A receptors and IL-17A treatment induced apoptosis in parietal cells. Overexpressing IL-17A in vivo induced caspase-3 activation and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining in parietal cells. Finally, IL-17A neutralizing antibody decreased parietal cell atrophy and metaplasia in mice with chronic atrophic gastritis. Conclusions: These data identify IL-17A as a cytokine that promotes parietal cell apoptosis during atrophic gastritis, a precursor lesion for gastric cancer. Keywords: IL-17A, Atrophy, Metaplasia, Apoptosi

ICD Shock, Not Ventricular Fibrillation, Causes Elevation of High Sensitive Troponin T after Defibrillation Threshold Testing-The Prospective, Randomized, Multicentre TropShock-Trial

Background The placement of an implantable cardioverter defibrillator (ICD) has become routine practice to protect high risk patients from sudden cardiac death. However, implantation-related myocardial micro-damage and its relation to different implantation strategies are poorly characterized. Methods A total of 194 ICD recipients (64 +/- 12 years, 83% male, 95% primary prevention of sudden cardiac death, 35% cardiac resynchronization therapy) were randomly assigned to one of three implantation strategies: (1) ICD implantation without any defibrillation threshold (DFT) testing,(2) estimation of the DFT without arrhythmia induction (modified "upper limit of vulnerability (ULV) testing") or (3) traditional safety margin testing including ventricular arrhythmia induction. High-sensitive Troponin T (hsTnT) levels were determined prior to the implantation and 6 hours after. Results All three groups showed a postoperative increase of hsTnT. The mean delta was 0.031 +/- 0.032 ng/ml for patients without DFT testing, 0.080 +/- 0.067 ng/ml for the modified ULV-testing and 0.064 +/- 0.056 ng/ml for patients with traditional safety margin testing. Delta hsTnT was significantly larger in both of the groups with intraoperative ICD testing compared to the non-testing strategy (p<0.001 each). There was no statistical difference in delta hsTnT between the two groups with intraoperative ICD testing (p = 0.179). Conclusion High-sensitive Troponin T release during ICD implantation is significantly higher in patients with intraoperative ICD testing using shock applications compared to those without testing. Shock applications, with or without arrhythmia induction, did not result in a significantly different delta hsTnT. Hence, the ICD shock itself and not ventricular fibrillation seems to cause myocardial micro-damage

Selecting patients with HER2-low Breast Cancer: getting out of the tangle

The promising effect of antibody–drug conjugates on breast cancer with low expression of HER2 (HER2-low) raises many questions regarding the optimal selection of patients for this treatment. A key question is whether HER2 immunohistochemistry, an assay optimised to detect HER2 amplification, is reliable enough to assess HER2 protein levels to select patients with HER2-low breast cancer in daily pathology practices worldwide. Moreover, whether this assessment can be performed with sufficient reproducibility between pathologists in daily practices is debatable. Herein, we address the historical track record of the CAP-ASCO HER2 Guidelines, the reported limited reproducibility by pathologists of HER2 immunohistochemistry in the non-amplified cases, and the performance variation of different antibodies. Based on this summary, we propose solutions to improve the robustness to enable reliable identification of patients with HER2-low breast cancer

Colchicine for primary prevention of atrial fibrillation after open-heart surgery: Systematic review and meta-analysis

Background Atrial fibrillation occurs frequently after open-heart surgery. It is associated with increased morbidity and mortality, longer hospital stays, and increased healthcare costs. Prophylactic administration of colchicine may mitigate post-operative atrial fibrillation (POAF). Methods We searched PubMed, ClinicalTrials.gov and CENTRAL databases to identify randomized controlled trials (RCTs) that; (1) compared prophylactic use of colchicine to placebo, or usual care, in patients with sinus rhythm who underwent elective open-heart surgery and (2) reported POAF-incidence. We excluded trials focused on incidence of atrial fibrillation after percutaneous interventions or colchicine treatment of diagnosed pericarditis or post-pericardiotomy-syndrome. A random-effects model was used to pool data for POAF-incidence as the primary outcome and for drug-related adverse effects, major adverse events (death and stroke), and hospital length-of-stay as secondary outcomes. Results We included five RCTs (1412 patients). Colchicine treatment reduced POAF-events by 30% versus placebo or usual care (18% vs. 27%, risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.84, p = 0.0002). Adverse drug-related effects, especially gastrointestinal intolerance, increased with colchicine; (21% vs. 8.2%, RR 2.52, 95% CI 1.62 to 3.93, p < 0.0001). However, major adverse events were unchanged (3.2% vs. 3.2%, RR 0.96, 95% CI 0.48 to 1.95, p = 0.92). Length-of-stay decreased by 1.2 days with colchicine (95% CI -1.89 to − 0.44, p = 0.002). Conclusion Colchicine demonstrated superior efficacy versus usual care for prevention of atrial fibrillation after cardiac surgery. Moreover, colchicine treatment was associated with shorter hospital stays. These benefits outweigh increased risk of adverse drug-related effects; although further work is needed to minimize gastrointestinal effects

Biomarker-based diagnosis of pacemaker and implantable cardioverter defibrillator pocket infections: A prospective, multicentre, case control evaluation

Background: The use of cardiac implantable electronic devices (CIED) has risen steadily, yet the rate of cardiac device infections (CDI) has disproportionately increased. Amongst all cardiac device infections, the pocket infection is the most challenging diagnosis. Therefore, we aimed to improve diagnosis of such pocket infection by identifying relevant biomarkers. Methods: We enrolled 25 consecutive patients with invasively and microbiologically confirmed pocket infection. None of the patients had any confounding conditions. Pre-operative levels of 14 biomarkers were compared in infected and control (n = 50) patients. Our selected biomarkers included white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT), lipopolysaccharide binding protein, high-sensitivity C-reactive protein (HS-CRP), polymorphonuclear-elastase, presepsin, various interleukins, tumor necrosis factor a (TNF-a), and granulocyte macrophage colony-stimulating factor (GM-CSF). Results: Of the 25 patients with isolated pocket infection (70 13years, 76% male, 40% ICDs), none presented with leukocytosis. In contrast, they had higher serum levels of HS-CRP (p = 0.019) and PCT (p = 0.010) than control patients. Median PCT-level was 0.06 ng/mL (IQR 0.03-0.07 ng/mL) in the study group versus 0.03 ng/mL (IQR 0.02-0.04 ng/mL) in controls. An optimized PCT cut-off value of 0.05 ng/mL suggests pocket infection with a sensitivity of 60% and specificity of 82%. In addition TNF-alpha- and GM-CSF-levels were lower in the study group. Other biomarkers did not differ between groups. Conclusion: Diagnosis of isolated pocket infections requires clinical awareness, physical examination, evaluation of blood cultures and echocardiography assessment. Nevertheless, measurement of PCT- and HS-CRP-levels can aid diagnosis. However, no conclusion can be drawn from normal WBC-values

Smartphone-based cardiac implantable electronic device remote monitoring: improved compliance and connectivity

Aims: Remote monitoring (RM) is the standard of care for follow up of patients with cardiac implantable electronic devices. The aim of this study was to compare smartphone-based RM (SM-RM) using patient applications (myMerlinPulse™ app) with traditional bedside monitor RM (BM-RM). Methods and results: The retrospective study included de-identified US patients who received either SM-RM or BM-RM capable of implantable cardioverter defibrillators or cardiac resynchronization therapy defibrillators (Abbott, USA). Patients in SM-RM and BM-RM groups were propensity-score matched on age and gender, device type, implant year, and month. Compliance with RM was quantified as the proportion of patients enrolling in the RM system (Merlin.net™) and transmitting data at least once. Connectivity was measured by the median number of days between consecutive transmissions per patient. Of the initial 9714 patients with SM-RM and 26 679 patients with BM-RM, 9397 patients from each group were matched. Remote monitoring compliance was higher in SM-RM; significantly more patients with SM-RM were enrolled in RM compared with BM-RM (94.4 vs. 85.0%, P &lt; 0.001), similar number of patients in the SM-RM group paired their device (95.1 vs. 95.0%, P = 0.77), but more SM-RM patients transmitted at least once (98.1 vs. 94.3%, P &lt; 0.001). Connectivity was significantly higher in the SM-RM, with patients transmitting data every 1.2 (1.1, 1.7) vs. every 1.7 (1.5, 2.0) days with BM-RM (P &lt; 0.001) and remained better over time. Significantly more SM-RM patients utilized patient-initiated transmissions compared with BM-RM (55.6 vs. 28.1%, P &lt; 0.001). Conclusion: In this large real-world study, patients with SM-RM demonstrated improved compliance and connectivity compared with BM-RM

Highdicom: A Python library for standardized encoding of image annotations and machine learning model outputs in pathology and radiology

Machine learning is revolutionizing image-based diagnostics in pathology and radiology. ML models have shown promising results in research settings, but their lack of interoperability has been a major barrier for clinical integration and evaluation. The DICOM a standard specifies Information Object Definitions and Services for the representation and communication of digital images and related information, including image-derived annotations and analysis results. However, the complexity of the standard represents an obstacle for its adoption in the ML community and creates a need for software libraries and tools that simplify working with data sets in DICOM format. Here we present the highdicom library, which provides a high-level application programming interface for the Python programming language that abstracts low-level details of the standard and enables encoding and decoding of image-derived information in DICOM format in a few lines of Python code. The highdicom library ties into the extensive Python ecosystem for image processing and machine learning. Simultaneously, by simplifying creation and parsing of DICOM-compliant files, highdicom achieves interoperability with the medical imaging systems that hold the data used to train and run ML models, and ultimately communicate and store model outputs for clinical use. We demonstrate through experiments with slide microscopy and computed tomography imaging, that, by bridging these two ecosystems, highdicom enables developers to train and evaluate state-of-the-art ML models in pathology and radiology while remaining compliant with the DICOM standard and interoperable with clinical systems at all stages. To promote standardization of ML research and streamline the ML model development and deployment process, we made the library available free and open-source