The spectrum of cardiovascular complications related to immune-checkpoint inhibitor treatment : Including myocarditis and the new entity of non inflammatory left ventricular dysfunction.

BACKGROUND: The full range of cardiovascular complications related to the use of Immune checkpoint inhibitors (ICI) is not fully understood. We aim to describe the spectrum of cardiovascular adverse events (cvAEs) by presenting our real-world experience of the diagnosis and management of these complications. METHODS: Two thousand six hundred and forty-seven (2647) patients were started on ICI treatment between 2014 and 2020. Data from 110 patients referred to the cardio-oncology service with a suspected cvAE was collected prospectively and analysed. RESULTS: Eighty-nine patients (3.4%) were confirmed to have cvAEs while on ICI therapy. Myocarditis was the most frequent event (33/89), followed by tachyarrhythmia (27/89), non-inflammatory left ventricular dysfunction (NILVD) (15/89) and pericarditis (7/89). Results from myocarditis and non-inflammatory left ventricular dysfunction cohorts were compared. Myocarditis and NILVD showed significant differences in respect toof troponin elevation, cardiac magnetic resonance abnormalities and ventricular function. Dual ICI therapy and other immune related adverse events were more frequently associated with myocarditis than NILVD. There was a significant difference in the median time from starting ICI treatment to presentation with myocarditis versus NILVD (12 vs 26 weeks p = 0.049). Through early recognition of myocarditis, prompt treatment with steroids and interruption of ICI, there were no cardiovascular in-hospital deaths. NILVD did not require steroid treatment and ICI could be restarted safely. CONCLUSIONS: The full spectrum of cardiovascular complications in patients with immune checkpoint inhibitors is much broader than initially described. Myocarditis remains the most frequent cvAE related to ICI treatment. A novel type of myocardial injury was observed and defined as Atrial tachyarrhythmias and NILVD were also frequent in this cohort. NILVD has a This differs fromdifferent presentation from ICI-related myocarditis, mainly usually presenting afterby the lack of inflammatory features on CMR and biomarkers and a later presentation in time

Optimal Consensus set for nD Fixed Width Annulus Fitting

International audienceThis paper presents a method for fitting a nD fixed width spherical shell to a given set of nD points in an image in the presence of noise by maximizing the number of inliers, namely the consensus set. We present an algorithm, that provides the optimal solution(s) within a time complexity O(N n+1 log N) for dimension n, N being the number of points. Our algorithm guarantees optimal solution(s) and has lower complexity than previous known methods

HIV Infection among Men Who Have Sex with Men in Kampala, Uganda–A Respondent Driven Sampling Survey

Uganda's generalized HIV epidemic is well described, including an estimated adult male HIV prevalence in Kampala of 4.5%, but no data are available on the prevalence of and risk factors for HIV infection among men who have sex with men (MSM).From May 2008 to February 2009, we used respondent-driven sampling to recruit MSM ≥18 years old in Kampala who reported anal sex with another man in the previous three months. We collected demographic and HIV-related behavioral data through audio computer-assisted self-administered interviews. Laboratory testing included biomarkers for HIV and other sexually transmitted infections. We obtained population estimates adjusted for the non-random sampling frame using RDSAT and STATA. 300 MSM were surveyed over 11 waves; median age was 25 years (interquartile range, 21-29 years). Overall HIV prevalence was 13.7% (95% confidence interval [CI] 7.9%-20.1%), and was higher among MSM ≥25 years (22.4%) than among MSM aged 18-24 years (3.9%, odds ratio [OR] 5.69, 95% CI 2.02-16.02). In multivariate analysis, MSM ≥25 years (adjusted OR [aOR] 4.32, 95% CI 1.33-13.98) and those reporting ever having been exposed to homophobic abuse (verbal, moral, sexual, or physical abuse; aOR 5.38, 95% CI 1.95-14.79) were significantly more likely to be HIV infected.MSM in Kampala are at substantially higher risk for HIV than the general adult male population. MSM reporting a lifetime history of homophobic abuse are at increased risk of being HIV infected. Legal challenges and stigma must be overcome to provide access to tailored HIV prevention and care services

Cross-cultural adaptation and validation of the VISA-A questionnaire for German-speaking Achilles tendinopathy patients

<p>Abstract</p> <p>Background</p> <p>Achilles tendinopathy is the predominant overuse injury in runners. To further investigate this overload injury in transverse and longitudinal studies a valid, responsive and reliable outcome measure is demanded. Most questionnaires have been developed for English-speaking populations. This is also true for the VISA-A score, so far representing the only valid, reliable, and disease specific questionnaire for Achilles tendinopathy. To internationally compare research results, to perform multinational studies or to exclude bias originating from subpopulations speaking different languages within one country an equivalent instrument is demanded in different languages. The aim of this study was therefore to cross-cultural adapt and validate the VISA-A questionnaire for German-speaking Achilles tendinopathy patients.</p> <p>Methods</p> <p>According to the "guidelines for the process of cross-cultural adaptation of self-report measures" the VISA-A score was cross-culturally adapted into German (VISA-A-G) using six steps: Translation, synthesis, back translation, expert committee review, pretesting (n = 77), and appraisal of the adaptation process by an advisory committee determining the adequacy of the cross-cultural adaptation. The resulting VISA-A-G was then subjected to an analysis of reliability, validity, and internal consistency in 30 Achilles tendinopathy patients and 79 asymptomatic people. Concurrent validity was tested against a generic tendon grading system (Percy and Conochie) and against a classification system for the effect of pain on athletic performance (Curwin and Stanish).</p> <p>Results</p> <p>The "advisory committee" determined the VISA-A-G questionnaire as been translated "acceptable". The VISA-A-G questionnaire showed moderate to excellent test-retest reliability (ICC = 0.60 to 0.97). Concurrent validity showed good coherence when correlated with the grading system of Curwin and Stanish (rho = -0.95) and for the Percy and Conochie grade of severity (rho 0.95). Internal consistency (Cronbach's alpha) for the total VISA-A-G scores of the patients was calculated to be 0.737.</p> <p>Conclusion</p> <p>The VISA-A questionnaire was successfully cross-cultural adapted and validated for use in German speaking populations. The psychometric properties of the VISA-A-G questionnaire are similar to those of the original English version. It therefore can be recommended as a sufficiently robust tool for future measuring clinical severity of Achilles tendinopathy in German speaking patients.</p

Web-based monitoring tools for Resistive Plate Chambers in the CMS experiment at CERN

The Resistive Plate Chambers (RPC) are used in the CMS experiment at the trigger level and also in the standard offline muon reconstruction. In order to guarantee the quality of the data collected and to monitor online the detector performance, a set of tools has been developed in CMS which is heavily used in the RPC system. The Web-based monitoring (WBM) is a set of java servlets that allows users to check the performance of the hardware during data taking, providing distributions and history plots of all the parameters. The functionalities of the RPC WBM monitoring tools are presented along with studies of the detector performance as a function of growing luminosity and environmental conditions that are tracked over time

Radiation background with the CMS RPCs at the LHC

The Resistive Plate Chambers (RPCs) are employed in the CMS Experiment at the LHC as dedicated trigger system both in the barrel and in the endcap. This article presents results of the radiation background measurements performed with the 2011 and 2012 proton-proton collision data collected by CMS. Emphasis is given to the measurements of the background distribution inside the RPCs. The expected background rates during the future running of the LHC are estimated both from extrapolated measurements and from simulation

Male mice with deleted Wolframin (Wfs1) gene have reduced fertility

Background: Wolfram Syndrome (WS) is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO) male mice have reduced fertility and, if so, to examine possible causes. Methods: Wfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt) male mice were mated with wt female mice. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analysed. Serum testosterone and FSH concentrations were also measured. Results: The pregnancy rate in wt females mated with Wfs1KO males was significantly lower than in the control group (15% vs. 32%; p < 0.05), but there was no significant difference in litter size. Analysis of male fertility showed that, in the Wfs1KO group, eight males out of 13 had pups whereas in the control group all 13 males had at least one litter. Sperm motility was not affected in Wfs1KO mice, but Wfs1KO males had less proximal bent tails (14.4 +/- 1.2% vs. 21.5 +/- 1.3 p < 0.05) and less abnormal sperm heads (22.8 +/- 1.8 vs. 31.5 +/- 3.5, p < 0.05) than wt males. Testes histology revealed significantly reduced number of spermatogonia (23.9 +/- 4.9 vs. 38.1 +/- 2.8; p < 0.05) and Sertoli cells (6.4 +/- 0.5 vs. 9.2 +/- 1.0; p < 0.05) in Wfs1KO mice. Serum testosterone and FSH concentrations did not differ between the two groups. Conclusion: The impaired fertility of Wfs1KO male mice is most likely due to changes in sperm morphology and reduced number of spermatogenic cells. The exact mechanism through which the Wfs1 gene influences sperm morphology needs to be clarified in further studies

The Medical Action Ontology: A tool for annotating and analyzing treatments and clinical management of human disease

\ua9 2023Background: Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology specifically designed to organize medical procedures, therapies, and interventions. Methods: MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology. Findings: MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases. Conclusions: MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO). Funding: NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04

Are Trp53 rescue of Brca1 embryonic lethality and Trp53/Brca1 breast cancer association related?

Brca1 is involved in multiple biological pathways including DNA damage repair, transcriptional regulation, and cell-cycle progression. A complex pattern of interactions of Brca1 with Trp53 has also emerged. Xu and coworkers found that haploid loss of Trp53 significantly reduces the embryonic lethality observed in mice with a homozygous in-frame deletion of Brca1 exon 11. They report that widespread apoptosis correlates with the embryonic lethality resulting from this homozygous Δ11 Brca1 mutation. A mechanism responsible for Brca1-associated carcinogenesis is proposed. These experiments extend our knowledge of a complex Brca1/Trp53 relationship. However, the precise mechanisms through which Brca1 interacts with Trp53 to suppress mammary tumor formation have yet to be elucidated