Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia: Systematic Review and Meta‐Analysis of Randomized Controlled Trials

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The risk of osteoporosis in patients with liver cirrhosis: A meta-analysis of literature studies

Objective Data about the association between cirrhosis and osteoporosis are contrasting. Thus, we have performed a meta-analysis of literature studies on this topic. Design MEDLINE, Cochrane library, EMBASE, Scopus and Web of Science databases have been searched to retrieve all articles of interest. Data on prevalence of osteoporosis, bone mineral density (BMD) and bone turnover laboratory parameters were compared among cirrhotic patients and control subjects without cirrhosis. Patients Studies on patients with liver cirrhosis screened for the presence of osteoporosis were included. Results Six case-control studies (372 cirrhotic patients and 1579 controls) were included. The prevalence of osteoporosis was higher in cirrhotic patients than in controls (34·7% vs 12·8%, OR: 2·52, 95%CI: 1·11, 5·69; P = 0·03, I2 = 81%; P = 0·005). Accordingly, a reduced lumbar spine BMD (MD: -0·13, 95%CI: -0·24, -0·02; P = 0·02, I2 = 93%; P < 0·00001) and z-score (MD: -1·06, 95%CI: -1·79, -0·34; P = 0·004, I2 = 95%; P < 0·00001) were found in cirrhotic patients as compared with controls. In contrast, no significant differences were reported in femoral neck BMD and z-score. Interestingly, bone turnover laboratory parameters widely confirmed these results showing higher levels of ALP and D-Pyr, accompanied by reduced levels of IGF-1, PTH and 25-OH-D in cirrhotic patients as compared with controls. Conclusions Despite the high heterogeneity among studies, data showed an increased prevalence of osteoporosis in patients with cirrhosis. This information suggests the need of an accurate screening of bone mineral density in patients with liver cirrhosis to plan an adequate osteoporosis managemen

Methylation reactions, the redox balance and atherothrombosis: the search for a link with hydrogen sulfide

It is now clear that homocysteine (Hcy) is irreversibly degraded to hydrogen sulfide (H(2)S), an endogenous gasotransmitter that causes in vivo platelet activation via upregulation of phospholipase A2 and downstream boost of the arachidonate cascade. This mechanism involves a transsulfuration pathway. Based on these new data, clinical and experimental models on the relationships between Hcy and folate pathways in vascular disease and information on the Hcy controversy have been reanalyzed in the present review. Most interventional trials focused on Hcy lowering by folate administration did not exclude patients routinely taking the arachidonate inhibitor aspirin. This may have influenced the results of some of these trials. It is also clear that nutritional intake of folate affects several enzymatic reactions of the methionine-Hcy cycle and associated one-carbon metabolism and, thereby, both methylation reactions and redox balance. Hence, it is conceivable that the abnormally high Hcy levels seen in pathologic states reflect a poorly elucidated perturbation of such reactions and of such balance. While it is unknown whether there is an interplay between H2S, methylation reactions, and redox balance, measuring the sole reduction of blood Hcy that follows folate administration may well be an oversimplified approach to a complex biologic perturbation. The need to investigate this complex framework is thoroughly discussed in this article

Functional analysis of peripheral and intratumoral neoantigen-specific TCRs identified in a patient with melanoma

Background Neoantigens derived from somatic mutations correlate with therapeutic responses mediated by treatment with immune checkpoint inhibitors. Neoantigens are therefore highly attractive targets for the development of therapeutic approaches in personalized medicine, although many aspects of their quality and associated immune responses are not yet well understood. In a case study of metastatic malignant melanoma, we aimed to perform an in-depth characterization of neoantigens and respective T-cell responses in the context of immune checkpoint modulation. Methods Three neoantigens, which we identified either by immunopeptidomics or in silico prediction, were investigated using binding affinity analyses and structural simulations. We isolated seven T-cell receptors (TCRs) from the patient’s immune repertoire recognizing these antigens. TCRs were compared in vitro by multiparametric analyses including functional avidity, multicytokine secretion, and cross-reactivity screenings. A xenograft mouse model served to study in vivo functionality of selected TCRs. We investigated the patient’s TCR repertoire in blood and different tumor-related tissues over 3 years using TCR beta deep sequencing. Results Selected mutated peptide ligands with proven immunogenicity showed similar binding affinities to the human leukocyte antigen complex and comparable disparity to their wild-type counterparts in molecular dynamic simulations. Nevertheless, isolated TCRs recognizing these antigens demonstrated distinct patterns in functionality and frequency. TCRs with lower functional avidity showed at least equal antitumor immune responses in vivo. Moreover, they occurred at high frequencies and particularly demonstrated long-term persistence within tumor tissues, lymph nodes and various blood samples associated with a reduced activation pattern on primary in vitro stimulation. Conclusions We performed a so far unique fine characterization of neoantigen-specific T-cell responses revealing defined reactivity patterns of neoantigen-specific TCRs. Our data highlight qualitative differences of these TCRs associated with function and longevity of respective T cells. Such features need to be considered for further optimization of neoantigen targeting including adoptive T-cell therapies using TCR-transgenic T cells

Virological COVID-19 surveillance in Bavaria, Germany suggests no SARS-CoV-2 spread prior to the first German case in January 2020

The Bavarian Influenza Sentinel (BIS) monitors the annual influenza season by combining virological and epidemiological data. The 2019/2020 influenza season overlapped with the beginning COVID-19 pandemic thus allowing to investigate whether there was an unnoticed spread of SARS-CoV-2 among outpatients with acute respiratory infections in the community prior to the first COVID-19 cluster in Bavaria. Therefore, we retrospectively analysed oropharyngeal swabs obtained in BIS between calendar week (CW) 39 in 2019 and CW 14 in 2020 for the presence of SARS-CoV-2 RNA by RT-PCR. 610 of all 1376 BIS swabs-contained sufficient material to test for SARS-CoV-2, among them 260 oropharyngeal swabs which were collected prior to the first notified German COVID-19 case in CW 04/2020. In none of these swabs SARS-CoV-2 RNA was detected suggesting no SARS-CoV-2 spread prior to late January 2020 in Bavaria

DataSheet_1_Intramuscular vaccination against SARS-CoV-2 transiently induces neutralizing IgG rather than IgA in the saliva.pdf

The mucosal immunity is crucial for restricting SARS-CoV-2 at its entry site. Intramuscularly applied vaccines against SARS-CoV-2 stimulate high levels of neutralizing Abs in serum, but the impact of these intramuscular vaccinations on features of mucosal immunity is less clear. Here, we analyzed kinetic and functional properties of anti-SARS-CoV-2 Abs in the saliva after vaccination with BNT162b2. We analyzed a total of 24 healthy donors longitudinally for up to 16 months. We found that specific IgG appeared in the saliva after the second vaccination, declined thereafter and reappeared after the third vaccination. Adjusting serum and saliva for the same IgG concentration revealed a strong correlation between the reactivity in these two compartments. Reactivity to VoCs correlated strongly as seen by ELISAs against RBD variants and by live-virus neutralizing assays against replication-competent viruses. For further functional analysis, we purified IgG and IgA from serum and saliva. In vaccinated donors we found neutralizing activity towards authentic virus in the IgG, but not in the IgA fraction of the saliva. In contrast, IgA with neutralizing activity appeared in the saliva only after breakthrough infection. In serum, we found neutralizing activity in both the IgA and IgG fractions. Together, we show that intramuscular mRNA vaccination transiently induces a mucosal immunity that is mediated by IgG and thus differs from the mucosal immunity after infection. Waning of specific mucosal IgG might be linked to susceptibility for breakthrough infection.</p