Post-marketing surveillance study of the DTaP2-IPV-HB-Hib (Hexyon) vaccine administered in preterm infants in the Apulia region, Italy, in 2017.

Recommendations in many countries state that preterm infants (PTIs) should receive the same routine immunization schedule and timing as for full-term births, according to their chronological age. Data regarding hexavalent vaccine safety in PTIs are still limited. We conducted a post-marketing surveillance study of the DTaP2-IPV-HB-Hib vaccine administered to PTIs in Apulia region, Italy. We identified PTIs by selecting the hospital discharge records of infants born between January and June 2017 using the DRG and ICD-9-CM codes for preterm birth, and we matched these data with records included in the regional immunization registry. We analyzed coverage and timeliness of vaccination. To investigate adverse events (AEs) after the first dose, we interviewed via phone the parents of PTIs vaccinated with at least one dose of the DTaP2-IPV-HB-Hib vaccine. At the time of our analysis (31.12.2017), 866/936 (92.5%) PTIs received the first dose of hexavalent vaccine and 539/936 (57.6%) were vaccinated by the third month of age, as recommended; 700/866 (80.8%) received the DTaP2-IPV-HB-Hib vaccine. The parents of 339 PTIs vaccinated with the DTaP2-IPV-HB-Hib vaccine reported local pain as the most common reaction (35.7% of the children). Erythema, swelling, induration and nodule were also reported in about 25% of the children. Systemic adverse events were generally rarer than local reactions. No serious AEs were reported. Our findings showed that more than 40% of PTIs received delayed hexavalent vaccination. This study showed a reassuring safety profile of the vaccine in the preterm population and may be considered as a pilot for further real-world studies

Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression

The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury

Alterations of clock gene RNA expression in brain Regions of a triple transgenic model of Alzheimer's Disease

A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer's disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas¾suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem¾of 6- and 18-month-old Non-Tg and 3×Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Rorα, Csnk1ɛ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis

Local deprivation status and seasonal influenza vaccination coverage in adults ≥65 years residing in the Foggia municipality, Italy, 2009-2016

IntroductionIn Italy, vaccination against seasonal influenza has been recommended for the elderly since 1980, but coverage is still far below the WHO minimum target level of 75%. Effective interventions to improve influenza vaccination should understand which socioeconomic determinants may cause inequalities in vaccine uptake. This study aimed at assessing differences in vaccination coverage among people ≥65 years of age residing in the Foggia municipality, Italy, by socioeconomic status. MethodsA Socio-Economic-Health Deprivation Index (SEHDI) was constructed using a multivariate analysis model. Resident population, for census block, was classified in 5 deprivation groups. Differences in demographic and socioeconomic indicators, the standardized mortality ratios (SMRs), and the average vaccination coverage among deprivation groups were evaluated with the linear F-test. The association between census variables and influenza vaccination coverage, in each deprivation group, was assessed using the Pearson bivariate correlation. Results The SEHDI allowed to identify factors related to ageing, housing, household size and composition, and education. Forty percent of people residing in the Foggia municipality lived in conditions of socioeconomic and health deprivation. Belonging to families with 3 or 4 members was associated with increased coverage rates. In the most deprived group, vaccination uptake was positively associated with the dependency ratio.ConclusionsThe results of this study have shown that there is still large room for improving influenza vaccination coverage among subjects belonging to the most deprived areas. Surveillance of trends in influenza vaccine uptake by socioeconomic groups is a feasible contribution to implementing effective, tailored to the frail older persons, vaccine utilization programs

Successful surgical repair of left ventricular pseudoaneurysm in a patient with subacute ST-elevation myocardial infarction.

We report a successful surgical repair of left ventricular pseudoaneurysm in a patient with subacute ST-elevation myocardial infarction (STEMI). In the case of expansion of the infarct related ventricular wall, early (within 24 hours) or late (3-5 days after STEMI) cardiac rupture should be always borne in mind in order to proceed to life saving prompt surgical repair

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with high toxicity and resistance, suggesting that new combinatorial strategies are needed to improve its therapeutic index. In our study, we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different 3D-self-assembled spheroid models, suggesting the ability of the combined approach to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced DNA damage in combination treatment by reducing the mRNA expression of ERCC Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular concentration via upregulation at transcriptional level of CDDP influx channel copper transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export. Valproic acid also induced a dose-dependent downregulation of epidermal growth factor receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also in vivo in both heterotopic and orthotopic models, demonstrating that the combined treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall, the introduction of a safe and generic drug such as VPA into the conventional treatment for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants further clinical evaluation. A phase II clinical trial exploring the combination of VPA and CDDP/CX in R/M HNSCC patients is currently ongoing in our institute

BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment.

DNA double-strand breaks (DSBs) are toxic DNA lesions, which, if not properly repaired, may lead to genomic instability, cell death and senescence. Damage-induced long non-coding RNAs (dilncRNAs) are transcribed from broken DNA ends and contribute to DNA damage response (DDR) signaling. Here we show that dilncRNAs play a role in DSB repair by homologous recombination (HR) by contributing to the recruitment of the HR proteins BRCA1, BRCA2, and RAD51, without affecting DNA-end resection. In S/G2-phase cells, dilncRNAs pair to the resected DNA ends and form DNA:RNA hybrids, which are recognized by BRCA1. We also show that BRCA2 directly interacts with RNase H2, mediates its localization to DSBs in the S/G2 cell-cycle phase, and controls DNA:RNA hybrid levels at DSBs. These results demonstrate that regulated DNA:RNA hybrid levels at DSBs contribute to HR-mediated repair

Safety of heterologous ChAdOx1-S/BNT162b2 primary schedule versus homologous BNT162b2 vaccination: Insights from an Italian post-marketing study, 2021

During COVID-19 vaccination campaign, possible ChAdOx1-S-associated risks of thrombosis with thrombocytopenia syndrome led to implement ChAdOx1-S/BNT162b2 heterologous vaccination, despite the limited information on its reactogenicity and safety. We conducted a prospective observational post-marketing surveillance study to assess the safety of this heterologous schedule. A casually selected sample of recipients (n: 85; age: 18–60 years) of ChAdOx1-S/BNT162b2 at the vaccination hub of the Foggia Hospital, Italy, was matched with an equal sample of recipients of homologous BNT162b2. Safety was evaluated 7 days, 1 month and 14 weeks after the primary vaccination series using an adapted version of the “V-safe active surveillance for COVID-19 vaccine safety” CDC standardized questionnaire. After 7 days, local reactions were highly frequent (>80%) in both groups, and systemic reactions were less common (<70%). Moderate or severe pain at the injection site (OR = 3.62; 95%CI, 1.45–9.33), moderate/severe fatigue (OR = 3.40; 95%CI, 1.22–9.49), moderate/severe headache (OR = 4.72; 95%CI, 1.37–16.23), intake of antipyretics (OR = 3.05; 95 CI%, 1.35–6.88), inability to perform daily activities and work (OR = 2.64; 95%CI, 1.24–5.62) were significantly more common with heterologous than homologous vaccination. No significant difference in self-reported health status was recorded 1 month or 14 weeks after the second dose with BNT162b2 or ChAdOx1-S/BNT162b2. Our study confirms the safety of both heterologous and homologous vaccination, with a slight increase in some short-term adverse events for the heterologous regimen. Therefore, administering a second dose of a mRNA vaccine to the recipients of a previous dose of viral vector vaccine may have represented an advantageous strategy to improve flexibility and to accelerate the vaccination campaign

Association of socio-economic deprivation with COVID-19 incidence and fatality during the first wave of the pandemic in Italy: lessons learned from a local register-based study

Abstract Background COVID-19 has been characterised by its global and rapid spread, with high infection, hospitalisation, and mortality rates worldwide. However, the course of the pandemic showed differences in chronology and intensity in different geographical areas and countries, probably due to a multitude of factors. Among these, socio-economic deprivation has been supposed to play a substantial role, although available evidence is not fully in agreement. Our study aimed to assess incidence and fatality rates of COVID-19 across the levels of socio-economic deprivation during the first epidemic wave (March–May 2020) in the Italian Province of Foggia, Apulia Region. Methods Based on the data of the regional active surveillance platform, we performed a retrospective epidemiological study among all COVID-19 confirmed cases that occurred in the Apulian District of Foggia, Italy, from March 1st to May 5th, 2020. Geocoded addresses were linked to the individual Census Tract (CT) of residence. Effects of socio-economic condition were calculated by means of the Socio-Economic and Health-related Deprivation Index (SEHDI) on COVID-19 incidence and fatality. Results Of the 1054 confirmed COVID-19 cases, 537 (50.9%) were men, 682 (64.7%) were 0–64 years old, and 338 (32.1%) had pre-existing comorbidities. COVID-19 incidence was higher in the less deprived areas (p  65 years (p < 0.001), cases having a connection with a nursing home (p < 0.05) or having at least 1 comorbidity (p < 0.001). On the other hand, a significant protection for healthcare workers was apparent (p < 0.001). Conclusions Our findings show that deprivation alone does not affect COVID-19 incidence and fatality burden, suggesting that the burden of disease is driven by a complexity of factors not yet fully understood. Better knowledge is needed to identify subgroups at higher risk and implement effective preventive strategies