Liver involvement and mortality in COVID-19: A retrospective analysis from the CORACLE study group

INTRODUCTION: liver abnormalities are common in COVID-19 patients and associated with higher morbidity and mortality. We aimed to investigate clinical significance and effect on the mortality of abnormal liver function tests (ALFTs) in COVID-19 patients. METHODS: we retrospectively evaluated in a multicentre study all patients admitted with confirmed diagnosis of COVID-19. RESULTS: 434 patients were included in this analysis. Among overall patients, 311 (71.6%) had normal baseline ALT levels. 123 patients showed overall abnormal liver function tests (ALFTs) at baseline [101 ALFTs <2x UNL and 22 ≥2 UNL]. Overall in-hospital mortality was 14% and mean duration of hospitalization was 10.5 days. Hypertension (50.5%), cardiovascular diseases (39.6%), diabetes (23%) were frequent comorbidities and 53.7% of patients had ARDS. At multivariate analysis, the presence of ARDS at baseline (OR=6.11; 95% CI: 3.03–12.32; p<0.000); cardiovascular diseases (OR=4; 95% CI: 2.05–7.81; p<0.000); dementia (OR=3.93; 95%CI:1.87–8.26; p<0.000) and no smoking (OR=4.6; 95% CI: 1.45–14.61; p=0.010) resulted significantly predictive of in-hospital mortality. The presence of ALFTs at baseline was not significantly associated with mortality (OR=3.44; 95% CI=0.81–14.58; p=0.094). CONCLUSION: ALFTs was frequently observed in COVID-19 patients, but the overall in-hospital mortality was mainly determined by the severity of illness, comorbidities and presence of ARDS

YAP contributes to DNA methylation remodeling upon mouse embryonic stem cell differentiation

The Yes-associated protein YAP, one of the major effectors of the Hippo pathway together with its related protein TAZ, mediates a range of cellular processes from proliferation and death to morphogenesis. YAP and TAZ regulate a large number of target genes, acting as co-activators of DNA-binding transcription factors or as negative regulators of transcription by interacting with the nucleosome remodeling and histone deacetylase complexes. YAP is expressed in self-renewing embryonic stem cells (ESCs), although it is still debated whether it plays any crucial roles in the control of either stemness or differentiation. Here we show that the transient downregulation of YAP in mouse ESCs perturbs cellular homeostasis, leading to the inability to differentiate properly. Bisulfite genomic sequencing revealed that this transient knockdown caused a genome-wide alteration of the DNA methylation remodeling that takes place during the early steps of differentiation, suggesting that the phenotype we observed might be due to the dysregulation of some of the mechanisms involved in regulation of ESC exit from pluripotency. By gene expression analysis we identified two molecules which could have a role in the altered genome-wide methylation profile: the long non-coding RNA Ephemeron, whose rapid upregulation is crucial for ESCs transition into epiblast, and the methyltransferase-like protein Dnmt3l, which, during the embryo development, cooperates with Dnmt3a and Dnmt3b to contribute to the de novo DNA methylation that governs early steps of ESC differentiation. These data suggest a new role for YAP in the governance of the epigenetic dynamics of exit from pluripotency

Enhanced immunological recovery with early start of antiretroviral therapy during acute or early HIV infection–results of Italian Network of ACuTe HIV InfectiON (INACTION) retrospective study

ABSTRACT Background: Viral load peak and immune activation occur shortly after exposure during acute or early HIV infection (AEHI). We aimed to define the benefit of early start of antiretroviral treatment (ART) during AEHI in terms of immunological recovery, virological suppression, and treatment discontinuation. Setting: Patients diagnosed with AEHI (Fiebig stages I-V) during 2008-2014 from an analysis of 20 Italian centers. Methods: This was an observational, retrospective, and multicenter study. We investigated the ef- fect of early ART (defined as initiation within 3 months from AEHI diagnosis) on time to virolog- ical suppression, optimal immunological recovery (defined as CD4 count ≥ 500/μL, CD4 ≥ 30%, and CD4/CD8 ≥ 1), and first-line ART regimen discontinuation by Cox regression analysis. Results: There were 321 patients with AEHI included in the study (82.9% in Fiebig stage III-V). At diagnosis, the median viral load was 5.67 log10 copies/mL and the median CD4 count was 456 cells/μL. Overall, 70.6% of patients started early ART (median time from HIV diagnosis to ART initiation 12 days, IQR 6-27). Higher baseline viral load and AEHI diagnosis during 2012-2014 were independently associated with early ART. HBV co-infection, baseline CD4/CD8 ≥ 1, lower baseline HIV-RNA, and AEHI diagnosis in recent years (2012-2014) were independently associ- ated with a shorter time to virological suppression. Early ART emerged as an independent predic- tor of optimal immunological recovery after adjustment for baseline CD4 (absolute and percent- age count) and CD4/CD8 ratio. The only independent predictor of first-line ART discontinuation was an initial ART regimen including &gt; 3 drugs. Conclusions: In a large cohort of well-characterized patients with AEHI, we confirmed the ben- eficial role of early ART on CD4+ T-cell recovery and on rates of CD4/CD8 ratio normalization. Moreover, we recognized baseline CD4/CD8 ratio as an independent factor influencing time to virological response in the setting of AEHI, thus giving new insights into research of immunolog- ical markers associated with virological control

Outcomes and Predictors of Mortality in Patients With KPC-Kp Infections Treated With Meropenem Vaborbactam: An Observational Multicenter Study

Background Meropenem-vaborbactam is a recent and promising option for the treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections, including those resistant to ceftazidime-avibactam.Methods We conducted a retrospective analysis of observational data from 19 Italian hospitals on use and outcomes of patients treated with meropenem-vaborbactam for at least &gt;= 24 hours for KPC-Kp infections. Crude and propensity-weighted multiple Cox regression models were performed to ascertain risk factors independently associated with 30-day mortality.Results The cohort included 342 adults with bloodstream infections (n = 172) and nonbacteremic infections (n = 170), of which 107 were lower respiratory tract infections, 30 were complicated urinary tract infections, and 33 were infections involving other sites. Most infections (62.3%) were managed with meropenem-vaborbactam monotherapy, or in combination with at least 1 other active drug (usually fosfomycin, tigecycline, or gentamicin) (37.7%). The 30-day mortality rate was 31.6% (108/342). In multiple Cox regression model, 30-day mortality was independently associated with septic shock at infection onset, Charlson comorbidity index &gt;= 3, dialysis, concomitant COVID-19, and INCREMENT score &gt;= 8. Administration of meropenem-vaborbactam within 48 hours from infection onset was a negative predictor of mortality. All predictors, except administration of meropenem-vaborbactam within 48 hours, remained significant when the multiple Cox regression model was repeated after adjustment for the propensity score for receipt of combination therapy.Conclusions Despite the limits of a retrospective study, the data derived from this multicenter cohort provide additional evidence on the efficacy of meropenem-vaborbactam in treating severe KPC-Kp infections, even when used as monotherapy

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk