Gain of function of mutant p53: The mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation

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A Moderate Walking Test Predicts Survival in Women With Cardiovascular Disease

Introduction: Cardiovascular disease (CVD) is the principal cause of death in U.S. women. Peak oxygen uptake is strongly related to mortality and CVD. This study aimed to investigate the association between estimated peak oxygen uptake, determined using a moderate 1-km walking test, and all-cause mortality in female patients with stable CVD. Methods: Of the 482 women in our registry between 1997 and 2020, we included 430 participants in the analysis (aged 67 [34-88] years). A Cox proportional hazard model was used to determine the variables significantly associated with mortality. On the basis of the peak oxygen uptake estimated using the 1-km walking test, the sample was subdivided into tertiles, and mortality risk was calculated. The discriminatory accuracy of peak oxygen uptake in estimating survival was assessed by receiver operating characteristic curves. All results were adjusted for demographic and clinical covariates. Results: A total of 135 deaths from any cause occurred over a median of 10.4 years (IQR=4.4-16.4), with an average annual mortality of 4.2%. Estimated peak oxygen uptake was a stronger predictor of all-cause mortality than demographic and clinical variables (c-statistic-0.767; 95% CI=0.72, 0.81; p<0.0001). The survival rate decreased from the highest tertile of fitness to the lowest. Compared with the lowest group, hazard ratios (95% CIs) for the second and third tertiles were 0.55 (0.37, 0.83) and 0.29 (0.16, 0.51), respectively (p for trend <0.0001). Conclusions: Higher peak oxygen uptake levels were associated with a lower risk of all-cause mortality. The indirect estimation of peak oxygen uptake using the 1-km walking test is feasible and can be applied for risk stratification among female patients undergoing secondary prevention programs

Biochemical and cellular studies of three human 3‐phosphoglycerate dehydrogenase variants responsible for pathological reduced L‐serine levels

In the brain, the non-essential amino acid L-serine is produced through the phosphorylated pathway (PP) starting from the glycolytic intermediate 3-phosphoglycerate: among the different roles played by this amino acid, it can be converted into D-serine and glycine, the two main co-agonists of NMDA receptors. In humans, the enzymes of the PP, namely phosphoglycerate dehydrogenase (hPHGDH, which catalyzes the first and rate-limiting step of this pathway), 3-phosphoserine aminotransferase, and 3-phosphoserine phosphatase are likely organized in the cytosol as a metabolic assembly (a "serinosome"). The hPHGDH deficiency is a pathological condition biochemically characterized by reduced levels of L-serine in plasma and cerebrospinal fluid and clinically identified by severe neurological impairment. Here, three single-point variants responsible for hPHGDH deficiency and Neu-Laxova syndrome have been studied. Their biochemical characterization shows that V261M, V425M, and V490M substitutions alter either the kinetic (both maximal activity and Km for 3-phosphoglycerate in the physiological direction) and the structural properties (secondary, tertiary, and quaternary structure, favoring aggregation) of hPHGDH. All the three variants have been successfully ectopically expressed in U251 cells, thus the pathological effect is not due to hindered expression level. At the cellular level, mistargeting and aggregation phenomena have been observed in cells transiently expressing the pathological protein variants, as well as a reduced L-serine cellular level. Previous studies demonstrated that the pharmacological supplementation of L-serine in hPHGDH deficiencies could ameliorate some of the related symptoms: our results now suggest the use of additional and alternative therapeutic approaches

Impact of Improvement in Walking Speed on Hospitalization and Mortality in Females with Cardiovascular Disease

Cardiovascular disease (CVD) is the principal cause of death in women. Walking speed (WS) is strongly related with mortality and CVD. The rate of all-cause hospitalization or death was assessed in 290 female outpatients with CVD after participation in a cardiac rehabilitation/secondary prevention program (CR/SP) and associated with the WS maintained during a moderate 1 km treadmill-walk. Three-year mortality rates were 57%, 44%, and 29% for the slow (2.1 ± 0.4 km/h), moderate (3.1 ± 0.3 km/h), and fast (4.3 ± 0.6 km/h) walkers, respectively, with adjusted hazard ratios (HRs) of 0.78 (p = 0.24) and 0.55 (p = 0.03) for moderate and fast walkers compared to the slow walkers. In addition, hospitalization or death was examined four to six years after enrollment as a function of the change in the WS of 176 patients re-assessed during the third year after baseline. The rates of hospitalization or death were higher across tertiles of reduced WS, with 35%, 50%, and 53% for the high (1.5 ± 0.3 km/h), intermediate (0.7 ± 0.2 km/h), and low tertiles (0.2 ± 0.2 km/h). Adjusted HRs were 0.79 (p = 0.38) for the intermediate and 0.47 (p = 0.02) for the high tertile compared to the low improvement tertile. Improved walking speed was associated with a graded decrease in hospitalization or death from any cause in women undergoing CR/SP

Intrinsic generation time of the SARS-CoV-2 Omicron variant: an observational study of household transmission

Background Starting from the final months of 2021, the SARS-CoV-2 Omicron variant expanded globally, swiftly replacing Delta, the variant that was dominant at the time. Many uncertainties remain about the epidemiology of Omicron; here, we aim to estimate its generation time.Methods We used a Bayesian approach to analyze 23,122 SARS-CoV-2 infected individuals clustered in 8903 households as determined from contact tracing operations in Reggio Emilia, Italy, throughout January 2022. We estimated the distribution of the intrinsic generation time (the time between the infection dates of an infector and its secondary cases in a fully susceptible population), realized household generation time, realized serial interval (time between symptom onset of an infector and its secondary cases), and contribution of pre-symptomatic transmission.Findings We estimated a mean intrinsic generation time of 6.84 days (95% credible intervals, CrI, 5.72-8.60), and a mean realized household generation time of 3.59 days (95%CrI: 3.55-3.60). The household serial interval was 2.38 days (95%CrI 2.30-2.47) with about 51% (95%CrI 45-56%) of infections caused by symptomatic individuals being generated before symptom onset.Interpretation These results indicate that the intrinsic generation time of the SARS-CoV-2 Omicron variant might not have shortened as compared to previous estimates on ancestral lineages, Alpha and Delta, in the same geographic setting. Like for previous lineages, pre-symptomatic transmission appears to play a key role for Omicron transmission. Estimates in this study may be useful to design quarantine, isolation and contact tracing protocols and to support surveillance (e.g., for the accurate computation of reproduction numbers).Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/

The impact of chest CT body composition parameters on clinical outcomes in COVID-19 patients

We assessed the impact of chest CT body composition parameters on outcomes and disease severity at hospital presentation of COVID-19 patients, focusing also on the possible mediation of body composition in the relationship between age and death in these patients. Chest CT scans performed at hospital presentation by consecutive COVID-19 patients (02/27/2020-03/13/2020) were retrospectively reviewed to obtain pectoralis muscle density and total, visceral, and intermuscular adipose tissue areas (TAT, VAT, IMAT) at the level of T7-T8 vertebrae. Primary outcomes were: hospitalization, mechanical ventilation (MV) and/or death, death alone. Secondary outcomes were: C-reactive protein (CRP), oxygen saturation (SO2), CT disease extension at hospital presentation. The mediation of body composition in the effect of age on death was explored. Of the 318 patients included in the study (median age 65.7 years, females 37.7%), 205 (64.5%) were hospitalized, 68 (21.4%) needed MV, and 58 (18.2%) died. Increased muscle density was a protective factor while increased TAT, VAT, and IMAT were risk factors for hospitalization and MV/death. All these parameters except TAT had borderline effects on death alone. All parameters were associated with SO2 and extension of lung parenchymal involvement at CT; VAT was associated with CRP. Approximately 3% of the effect of age on death was mediated by decreased muscle density. In conclusion, low muscle quality and ectopic fat accumulation were associated with COVID-19 outcomes, VAT was associated with baseline inflammation. Low muscle quality partly mediated the effect of age on mortality.We assessed the impact of chest CT body composition parameters on outcomes and disease severity at hospital presentation of COVID-19 patients, focusing also on the possible mediation of body composition in the relationship between age and death in these patients. Chest CT scans performed at hospital presentation by consecutive COVID-19 patients (02/ 27/2020-03/13/2020) were retrospectively reviewed to obtain pectoralis muscle density and total, visceral, and intermuscular adipose tissue areas (TAT, VAT, IMAT) at the level of T7-T8 vertebrae. Primary outcomes were: hospitalization, mechanical ventilation (MV) and/or death, death alone. Secondary outcomes were: C-reactive protein (CRP), oxygen saturation (SO2), CT disease extension at hospital presentation. The mediation of body composition in the effect of age on death was explored. Of the 318 patients included in the study (median age 65.7 years, females 37.7%), 205 (64.5%) were hospitalized, 68 (21.4%) needed MV, and 58 (18.2%) died. Increased muscle density was a protective factor while increased TAT, VAT, and IMAT were risk factors for hospitalization and MV/death. All these parameters except TAT had borderline effects on death alone. All parameters were associated with SO2 and extension of lung parenchymal involvement at CT; VAT was associated with CRP. Approximately 3% of the effect of age on death was mediated by decreased muscle density. In conclusion, low muscle quality and ectopic fat accumulation were associated with COVID-19 outcomes, VAT was associated with baseline inflammation. Low muscle quality partly mediated the effect of age on mortality

Erratum to: Changes in patterns of uveitis at a tertiary referral center in Northern Italy: analysis of 990 consecutive cases

Erratum to: Changes in patterns of uveitis at a tertiary referral center in Northern Italy: analysis of 990 consecutive case