New score to predict COVID-19 progression in vaccine and early treatment era: the COVID-19 Sardinian Progression Score (CSPS).

BACKGROUND: Several scores aimed at predicting COVID-19 progression have been proposed. As the variables vaccination and early SARS-CoV-2 treatment were systematically excluded from the prognostic scores, the present study's objective was to develop a new model adapted to the current epidemiological scenario. METHODS: We included all patients evaluated by the Infectious Disease Unit in Sassari, with SARS-CoV-2 infection and without signs of respiratory failure at the first evaluation (P/F > 300). Disease progression was defined by the prescription of supplemental oxygen. In addition, variables related to demographics, vaccines, comorbidities, symptoms, CT scans, blood tests, and therapies were collected. Multivariate logistic regression modelling was performed to determine factors associated with progression; any variable with significant univariate test or clinical relevance was selected as a candidate for multivariate analysis. Hosmer-Lemeshow (HL) goodness of fit statistic was calculated. Odds ratio values were used to derive an integer score for developing an easy-to-use progression risk score. The discrimination performance of the risk index was determined using the AUC, and the best cut-off point, according to the Youden index, sensitivity, specificity, predictive value, and likelihood ratio, was chosen. RESULTS: 1145 patients [median (IQR) age 74 (62-83) years; 53.5% males] were enrolled; 336 (29.3%) had disease progression. Patients with a clinical progression were older and showed more comorbidities; furthermore, they were less vaccinated and exposed to preventive therapy. In the multivariate logistic regression analysis, age ≥ 60 years, COPD, dementia, haematological tumours, heart failure, exposure to no or one vaccine dose, fever, dyspnoea, GGO, consolidation, ferritin, De Ritis ≥ 1.2, LDH, and no exposure to early anti-SARS-CoV-2 treatment were associated with disease progression. The final risk score ranged from 0 to 45. The ROC curve analysis showed an AUC of 0.92 (95% CI 0.90-0.93) with a 93.7% specificity and 72.9% sensitivity. Low risk was defined when the cut-off value was less than 23. Three risk levels were identified: low (0-23 points), medium (24-35), and high (≥ 36). CONCLUSIONS: The proportion of patients with progression increases with high scores: the assessment of the risk could be helpful for clinicians to plan appropriate therapeutic strategies.

Long-acting combination of cabotegravir plus rilpivirine: A picture of potential eligible and ineligible HIV-positive individuals from the Italian ARCA cohort.

OBJECTIVES: We aimed to evaluate the prevalence and characteristics of people living with HIV (PLWH) eligible for the long-acting injectable (LAI) regimen with cabotegravir (CAB) and rilpivirine (RPV), in comparison with ineligible individuals. METHODS: This was an observational, cross-sectional study from the ARCA cohort, including virologically suppressed PLWH with at least one genotypic resistance testing (GRT) for reverse transcriptase and integrase from plasma and/or PBMCs. Eligibility criteria for LAI CAB+RPV were: negative HBsAg, absence of previous virological failures and/or resistance-associated mutations for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and/or integrase strand transfer inhibitors. Potential differences between eligible and ineligible individuals were investigated by univariable and multivariable analyses. RESULTS: A total of 514 individuals were included: 377 (73.3%) were male, median age was 51 (IQR: 43-58), on ART for 9 years (IQR: 4-17), virologically suppressed for 63 months (IQR: 35-105). Eligible individuals for CAB+RPV were 229 (44.5%, 95%CI: 40.8-48.8); compared with ineligible individuals, they received a lower number of previous regimens (aOR 0.76, 95% CI 0.71-0.83, P < 0.001) and were on current NNRTIs (aOR 2.16, 95% CI 1.38-3.37, P = 0.001). CONCLUSIONS: Less than half of virologically suppressed PLWH in the ARCA cohort were potentially eligible for CAB+RPV. They seem to be "less complicated" with shorter exposure to ART and preferably already on NNRTIs.

Living with HIV and Getting Vaccinated: A Narrative Review.

After 40 years of its appearance, human immunodeficiency virus (HIV) infection remains a leading public health challenge worldwide. Since the introduction of antiretroviral treatment (ART), HIV infection has become a chronic condition, and people living with HIV could have life expectancies close to those of the general population. People with HIV often have an increased risk of infection or experience more severe morbidity following exposure to vaccine-preventable diseases. Nowadays, several vaccines are available against bacteria and viruses. However, national and international vaccination guidelines for people with HIV are heterogeneous, and not every vaccine is included. For these reasons, we aimed to perform a narrative review about the vaccinations available for adults living with HIV, reporting the most updated studies performed for each vaccine among this population. We performed a comprehensive literature search through electronic databases (Pubmed-MEDLINE and Embase) and search engines (Google Scholar). We included English peer-reviewed publications (articles and reviews) on HIV and vaccination. Despite widespread use and guideline recommendations, few vaccine trials have been conducted in people with HIV. In addition, not all vaccines are recommended for people with HIV, especially for those with low CD4 cells count. Clinicians should carefully collect the history of vaccinations and patients' acceptance and preferences and regularly check the presence of antibodies for vaccine-preventable pathogens.

Is the 4C Score Still a Valid Item to Predict In-Hospital Mortality in People with SARS-CoV-2 Infections in the Omicron Variant Era?

Since the start of the SARS-CoV-2 pandemic, several scores have been proposed to identify infected individuals at a higher risk of progression and death. The most famous is the 4C score. However, it was developed in early 2020. Our study aimed to evaluate the accuracy of the 4C score during the wave in which the Omicron variant was prevalent. An observational study was conducted at an Italian University Hospital between 1 January and 31 July 2022. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability of the 4C score to predict mortality. Overall, 1186 people were recruited, of which 160 (13.5%) died. According to the 4C score, 177 (11.6%) were classified as having a low risk of mortality, 302 (25.5%) were intermediate, 596 (50.3%) were high, and 151 (12.7%) were very high. The ROC curve of the 4C score showed an AUC (95% CI) value of 0.78 (0.74−0.82). At the criterion value of > 10, the sensitivity was 76.2% and the specificity was 62.67%. Similar to previous studies, the 4C mortality score performed well in our sample, and it is still a useful tool for clinicians to identify patients with a high risk of progression. However, clinicians must be aware that the mortality rate reported in the original studies was higher than that observed in our study.

Reduced risk of death in people with SARS-CoV-2 infection treated with remdesivir: a nested case-control study.

INTRODUCTION: Since the start of the SARS-CoV-2 pandemic, several treatment options have been proposed (e.g. steroids, heparin, antivirals and monoclonal antibodies). Remdesivir was the first antiviral approved for the treatment of COVID-19, even though controversial evidence exists concerning the efficacy. Therefore, we aimed to conduct a study to evaluate whether the use of remdesivir was associated with lower mortality in patients with COVID-19. METHODS: We conducted a nested case-control study of a retrospective cohort collecting medical records of people with SARS-CoV-2 infection admitted in the infectious Disease Unit of Sassari University Hospital (S.C. Clinica di Malattie Infettive, AOU di Sassari, Italy), or in the Infectious Disease Unit of Foggia (AOU "Ospedali Riuniti" Foggia), between 1 July 2020 and 10 November 2021. The outcome considered was death; thus, we matched death (cases) to survivors (controls) by sex and age (1:1). RESULTS: We included in the study 342 patients, with 171 deaths (cases) and 171 survivors (controls). Remdesivir was administered to 60 people in the control group and to 18 people in the case group (35.1% vs. 10.5%, p < .0001). In the multivariate analysis, treatment with remdesivir and heparin was associated with lower mortality (OR: 0.19 [95% CI :0.10-0.38], p <.0001; OR: 0.39 [95% CI: 0.21-0.74] p = .004, respectively). On the contrary, diabetes, oxygen therapy and CPAP/NIV were associated with higher mortality. CONCLUSION: Our study showed lower mortality in people with SARS-CoV-2 infection treated with remdesivir.

Safety and efficacy of molnupiravir in SARS-CoV-2-infected patients: A real-life experience.

Since the start of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, several treatments have been proposed to cure coronavirus disease 2019 (COVID-19) and prevent it. Molnupiravir is a ribonucleoside prodrug of N-hydroxycytidine with an in vitro and in vivo activity against SARS-CoV-2. We conducted a retrospective cohort study that included all people treated with molnupiravir between January 10, 2022, and March 31, 2022, at the University Hospital of Sassari. Molnupiravir was prescribed, according to the Italian Agency of Drug indications, to patients with recent symptom onset (≤5 days), no need for oxygen supplementation, and with a high risk of disease progression for the presence of chronic diseases. We included 192 people with a mean age of 70.4 ± 15.4 years, with 144 (75%) patients over 60 years. During the follow-up, 20 (10.4%) patients showed a disease progression. At the multivariate analysis, older age, having neurological disease, having dyspnea at the onset of the symptoms, and acquiring SARS-CoV-2 infection during hospital admission were associated with an increased risk of progression. In contrast, an early start of treatment was associated with a reduced risk of disease progression. Molnupiravir was also extremely safe since 13 (6.8%) adverse events were reported, with only one interruption. Our study shows that monlupiravir confirmed its efficacy and safety in a real-life cohort that included a high percentage of elderly people with a high comorbidity burden.

How Little Do We Know about HIV and STIs Prevention? Results from a Web-Based Survey among the General Population.

BACKGROUND: Prevention campaigns have led to a significant decrease in new HIV diagnoses in Western Europe, while other sexual transmitted infections (STIs) have shown an opposite trend. Several educational programs are promoted among young students, whereas informational campaigns addressing the general population are scarce. We aimed to investigate the level of awareness regarding STIs among the general population. METHODS: We proposed a questionnaire regarding STIs and HIV to the general population in Italy. We assigned 1 point to correct, 0.5 point to partially correct, and 0 point to wrong answers. We collected data about age, sex, region of origin, level of education and whether they were health workers. RESULTS: Overall, 2183 people answered the questionnaire, of which 555 aged over 50 years old. Being male, older than 50 years old, retired or unemployed, not educated, and no regular use of condoms were associated with lower scores. Only 16% of participants knew the Undetectable = Untransmittable (U = U) campaign. Overall, 2131 (97.6%) people think more educational campaigns should be offered. Of interest, 80% said the questionnaire led them to learn more about HIV and STIs. CONCLUSION: Our study reveals several gaps in general population awareness about HIV and STIs, especially among people aged over 50 years old. Most participants stated that the questionnaire was a learning opportunity. These data suggest that improvement of knowledge could start from easy-to-dispose medium, such as surveys and questionnaires delivered through social media. Furthermore, particular attention should be paid to population segmentation and campaign tailoring to enhance interventions effectiveness. Our data reinforce the need for more informational and educational campaigns tailored to the specific segments of the population.

Impact of Early SARS-CoV-2 Antiviral Therapy on Disease Progression.

Since the start of the SARS-CoV-2 pandemic, several treatments have been proposed to prevent the progression of the disease. Currently, three antiviral (molnupiravir, nirmaltrevir/r, remdesivir) and two monoclonal antibodies (casirivimab/imdevimab and sotrovimab) are available in Italy. Therefore, we aimed to evaluate the presence of risk factors associated with disease progression. We conducted a retrospective cohort study, including all patients with a confirmed diagnosis of SARS-CoV-2 evaluated between 01/01/2022 ad 10/05/2022 by our Unit of Infectious Diseases in Sassari. We defined disease progression as the necessity of starting O2 therapy. According to AIFA (Italian Medicines Agency) indications, preventive treatment was prescribed in patients with recent symptoms onset (≤five days), no need for oxygen supplementation, and risk factors for disease progression. Subgroup differences in quantitative variables were evaluated using Student's t-test. Pearson chi-square or Fisher's exact tests were used to assess differences for qualitative variables. Multivariate logistic regression modelling was performed to determine factors associated with progression. A two-tailed p-value less than 0.05 was considered statistically significant. All statistical analyses were performed with STATA version 17 (StataCorp, College Station, TX, USA). We included 1145 people with SARS-CoV-2 diagnosis, of which 336 (29.3%) developed severe disease with oxygen supplementation. In multivariate logistic regression analysis, age, dementia, haematologic tumors, heart failure, dyspnoea or fever at first evaluation, having ground glass opacities or consolidation at the first CT scan, and bacteria coinfection were associated with an increased risk of disease progression. Vaccination (at least two doses) and early treatment with antiviral or monoclonal antibodies were associated with a lower risk of disease progression. In conclusion, our study showed that vaccination and early treatment with antiviral and/or monoclonal antibodies significantly reduce the risk of disease progression.

The Presence of Polysaccharides, Glycerol, and Polyethyleneimine in Hydrogel Enhances the Performance of the Glucose Biosensor.

The use of amperometric biosensors has attracted particular attention in recent years, both from researchers and from companies, as they have proven to be low-cost, reliable, and very sensitive devices, with a wide range of uses in different matrices. The continuous development of amperometric biosensors, since their use involves an enzyme, is specifically aimed at keeping and increasing the catalytic properties of the loaded protein, so as to be able to use the same device over time. The present study aimed to investigate the impact of glycerol and polysaccharides, in the presence of polycationic substances to constitute a hydrogel, in enhancing the enzymatic and analytic performance of a glucose biosensor. Initially, it was possible to verify how the deposition of the starch-based hydrogel, in addition to allowing the electropolymerization of the poly(p-phenylenediamine) polymer and the maintenance of its ability to shield the ascorbic acid, did not substantially limit the permeability towards hydrogen peroxide. Moreover, different biosensor designs, loading a mixture containing all the components (alone or in combination) and the enzyme, were tested in order to evaluate the changes of the apparent enzyme kinetic parameters, such as VMAX and KM, and analytical response in terms of Linear Region Slope, highlighting how the presence of all components (starch, glycerol, and polyethyleneimine) were able to substantially enhance the performance of the biosensors. The surface analysis of the biosensors was performed by scanning electron microscope (SEM). More, it was shown that the same performances were kept unchanged for seven days, proving the suitability of this biosensor design for short- and mid-term use.

Oxidative stress-induced Akt downregulation mediates green tea toxicity towards prostate cancer cells.

Green tea consumption has been shown to possess cancer chemopreventive activity. Polyphenol E (PE) is a widely used standardized green tea extract formulation. This study was designed to investigate the impact of PE on prostate cancer cells (PC3), analyze the potential signals involved and elucidate whether anti- or pro-oxidant effects may be implicated. Treatment of PC3 cells with 30 and 100µg/ml PE significantly decreased cell viability and proliferation. At the tested concentrations, PE did not exert any antioxidant activity, eliciting instead a pro-oxidant effect at concentrations 30 and 100µg/ml, which was consistent with the observed PE cytotoxicity. PE-induced cell death was associated with mitochondrial dysfunction and downregulation of Akt activation, thus suggesting their implication in the PE-elicited cell dysfunction. Cell exposure to the ROS scavenger N-Acetyl Cysteine prevented PE-induced ROS increase, pAkt impairment, and cell death, clearly indicating the causative role of ROS in the observed phenomena. Failure of PE to induce PC3 damage in cells overexpressing Akt further confirms its implication in the PE-elicited cell death. Our findings showed an association between the antiproliferative and the pro-oxidant effect elicited by PE on PC3 cells and delineates a molecular signaling pattern potentially implicated in the toxicity of PE towards prostate cancer cells.

Sex-specific pharmacological modulation of autophagic process in human umbilical artery smooth muscle cells.

Sex has largely been neglected in cell studies. Therefore, we investigated the occurrence of sexual dimorphism in human umbilical artery smooth muscle cells (HUASMCs). In particular, we investigated the existence of sex differences in basal and in drug-induced autophagy, a process involved in cardiovascular diseases. HUASMCs were isolated from healthy and normal weight male and female newborns (MHUASMCs and FHUASMCs, respectively). Expression of the primary molecules involved in the autophagic process [beclin-1 and microtubule-associated protein 1 light chain 3 (LC3)], and PmTOR were detected using western blotting in basal conditions, after serum starvation, rapamycin and verapamil treatments. The level of constitutive autophagy, measured as the LC3II/I ratio, was similar in male and female HUASMCs in the basal condition. Serum starvation promoted autophagy in both cell types, but the increase was more pronounced in FHUASMCs, while 250nM rapamycin induced autophagy only in female cells. Moreover, the level of verapamil-induced autophagy was not different between the two sexes. Notably, in the basal condition, Beclin-1 was more elevated in MHUASMCs than in FHUASMCs, and the difference disappeared after serum starvation and exposure to rapamycin. After exposure to verapamil, the differences in Beclin-1 increased, with more elevated expression levels in female cells. PmTor did not differ in basal conditions, but it was significantly down-regulated by starvation only in FHUASMCs and by rapamycin both in male and female cells. Finally, a strong negative correlation was observed between the newborn's weight and basal autophagy in female cells and between the newborn's weight and the LC3II/I ratio in male verapamil-treated cells. These results indicate that sex-differences begin in utero, are parameter-specific and drug specific suggesting that HUASMCs are a suitable model for the screening of drugs and to study the influence of sex. The sex differences in the autophagy suggest sexually different pharmacodynamics effects of verapamil and rapamycin.

Human umbilical endothelial cells (HUVECs) have a sex: characterisation of the phenotype of male and female cells.

BACKGROUND: Human umbilical endothelial cells (HUVECs) are widely used to study the endothelial physiology and pathology that might be involved in sex and gender differences detected at the cardiovascular level. This study evaluated whether HUVECs are sexually dimorphic in their morphological, proliferative and migratory properties and in the gene and protein expression of oestrogen and androgen receptors and nitric oxide synthase 3 (NOS3). Moreover, because autophagy is influenced by sex, its degree was analysed in male and female HUVECs (MHUVECs and FHUVECs). METHODS: Umbilical cords from healthy, normal weight male and female neonates born to healthy non-obese and non-smoking women were studied. HUVEC morphology was analysed by electron microscopy, and their function was investigated by proliferation, viability, wound healing and chemotaxis assays. Gene and protein expression for oestrogen and androgen receptors and for NOS3 were evaluated by real-time PCR and Western blotting, respectively, and the expression of the primary molecules involved in autophagy regulation [protein kinase B (Akt), mammalian target of rapamycin (mTOR), beclin-1 and microtubule-associated protein 1 light chain 3 (LC3)] were detected by Western blotting. RESULTS: Cell proliferation, migration NOS3 mRNA and protein expression were significantly higher in FHUVECs than in MHUVECs. Conversely, beclin-1 and the LC3-II/LC3-I ratio were higher in MHUVECs than in FHUVECs, indicating that male cells are more autophagic than female cells. The expression of oestrogen and androgen receptor genes and proteins, the protein expression of Akt and mTOR and cellular size and shape were not influenced by sex. Body weights of male and female neonates were not significantly different, but the weight of male babies positively correlated with the weight of the mother, suggesting that the mother's weight may exert a different influence on male and female babies. CONCLUSIONS: The results indicate that sex differences exist in prenatal life and are parameter-specific, suggesting that HUVECs of both sexes should be used as an in vitro model to increase the quality and the translational value of research. The sex differences observed in HUVECs could be relevant in explaining the diseases of adulthood because endothelial dysfunction has a crucial role in the pathogenesis of cardiovascular diseases, diabetes mellitus, neurodegeneration and immune disease.

Glutamyl cycle in the rat liver appears to be sex-gender specific.

Numerous studies show sexually dimorphic responses of drug metabolizing enzymes in the liver, but it is less clear whether xenobiotic detoxification mediated by glutathione is sex-gender specific. Therefore, we investigated whether sex-gender differences exist in the biosynthesis and metabolism of GSH in the rat liver. Livers were obtained from Sprague-Dawley rats of both sexes for measurement of glutathione, its precursors and metabolites by capillary electrophoresis, whereas H(2)S and malondialdehyde were measured by colorimetric assays. The expression of glutamylcysteine ligase (GCL), the key enzyme in glutathione synthesis was detected by Western blotting and immunohistochemistry. It was observed that L-methionine, glutathione, taurine and malondialdehyde (a marker of lipid peroxidation) were similar in livers from both sexes, while L-cysteine levels were significantly higher and H(2)S was lower in female rat livers. Furthermore, L-methionine and L-cysteine, L-cysteine and glutathione, L-cysteine and taurine were positively associated only in male livers. Finally, the female liver expressed less GCL than the male liver. These data suggest that the glutamyl cycle in the liver is sexually dimorphic. This difference could be linked to the increased sensitivity of females to drugs and xenobiotics.

Sex and gender aspects in anesthetics and pain medication.

The influence of sex and gender on anesthesia and analgesic therapy remains poorly understood, nevertheless the numerous physiological and pharmacological differences present between men and women. Although in anesthesiology sex-gender aspects have attracted little attention, it has been reported that women have a greater sensitivity to the non-depolarizing neuroblocking agents, whereas males are more sensitive than females to propofol. It has been suggested that men wake slower than women after general anesthesia and have less postoperative nausea and vomiting. Sexual hormones seem to be of importance in the onset of differences. Nevertheless, in the last years, sex-gender influences on pain and analgesia have become a hot topic and data regarding sex-gender differences in response to pharmacologic and non-pharmacologic pain treatments are still scanty, inconsistent, and non-univocal. In particular, females seem to be more sensitive than males to opioid receptor agonists. Women may experience respiratory depression and other adverse effects more easily if they are given the same doses as males. Evidently, there is an obvious need for more research, which should include psychological and social factors in experimental preclinical and clinical paradigms in view of their importance on pain mechanism, in order to individualize analgesia to optimize pain relief.