Impact of Caffeine on Ethanol-Induced Stimulation and Sensitization: Changes in ERK and DARPP-32 Phosphorylation in Nucleus Accumbens

Background: Caffeine is frequently consumed with ethanol to reduce the impairing effects induced by ethanol, including psychomotor slowing or incoordination. Both drugs modulate dopamine (DA)-related markers in accumbens (Acb), and Acb DA is involved in voluntary locomotion and locomotor sensitization. The present study determined whether caffeine can affect locomotion induced by acute and repeated ethanol administration in adult male CD-1 mice. Methods: Acute administration of caffeine (7.5 to 30.0 mg/kg) was evaluated for its effects on acute ethanol-induced (1.5 to 3.5 g/kg) changes in open-field horizontal locomotion, supported rearing, and rearing not supported by the wall. DA receptor-dependent phosphorylation markers were assessed: extracellular signal-regulated kinase (pERK), and dopamine-and cAMP-regulated phosphoprotein Mr32kDa phosphorylated at threonine 75 site (pDARPP-32-Thr75) in Acb core and shell. Acutely administered caffeine was also evaluated in ethanol-sensitized (1.5 g/kg) mice. Results: Acute ethanol decreased both types of rearing. Caffeine increased supported rearing but did not block ethanol -induced decreases in rearing. Both substances increased horizontal locomotion in a biphasic manner, and caffeine potentiated ethanol-induced locomotion. Although ethanol administered repeatedly induced sensitization of locomotion and unsupported rearing, acute administration of caffeine to ethanol-sensitized mice in an ethanol-free state resulted in blunted stimulant effects compared with those seen in ethanol-naïve mice. Ethanol increased pERK immunoreactivity in both subregions of the Acb, but coadministration with caffeine blunted this increase. There were no effects on pDARPP-32(Thr75) immunoreactivity. Conclusions: The present results demonstrated that, after the first administration, caffeine potentiated the stimulating actions of ethanol, but did not counteract its suppressant or ataxic effects. Moreover, our results show that caffeine has less activating effects in ethanol-sensitized animals

Comparing the effects of combined numerical and visuospatial psychoeducational trainings conducted by curricular teachers and external trainers. Preliminary evidence across kindergarteners

The aim of this study was to verify the efficacy of two pencil-and-paper trainings empowering numerical and visuo-spatial abilities in Italian five-year-old kindergarteners. Specifically, the trainings were respectively carried out by the curricular teacher or by an external trainer. The former received a specific training in order to use the psychoeducational programmes with her pupils, whereas the latter received a specific education about the role of numerical and visuo-spatial abilities for school achievement and she was also trained to use psychoeducational trainings in kindergarten schools. At pre-test and post-test nonverbal functions and numeracy knowledge were assessed through a battery of standardized tests. The results show that both the numerical psychoeducational programme and the visuo-spatial one are useful tools to enhance mathematical achievements in kindergarteners. However, when the trainings were proposed by the external trainer, the efficacy of the psychoeducational programmes was more significant. These outcomes seem to be related both to the expertise and the novelty effect of the external trainer on the classroom

Shimura varieties in the Torelli locus via Galois coverings of elliptic curves

We study Shimura subvarieties of $\mathsf{A}_g$ obtained from families of Galois coverings $f: C \rightarrow C'$ where $C'$ is a smooth complex projective curve of genus $g' \geq 1$ and $g= g(C)$. We give the complete list of all such families that satisfy a simple sufficient condition that ensures that the closure of the image of the family via the Torelli map yields a Shimura subvariety of $\mathsf{A}_g$ for $g' =1,2$ and for all $g \geq 2,4$ and for $g' > 2$ and $g \leq 9$. In a previous work of the first and second author together with A. Ghigi [FGP] similar computations were done in the case $g'=0$. Here we find 6 families of Galois coverings, all with $g' = 1$ and $g=2,3,4$ and we show that these are the only families with $g'=1$ satisfying this sufficient condition. We show that among these examples two families yield new Shimura subvarieties of $\mathsf{A}_g$, while the other examples arise from certain Shimura subvarieties of $\mathsf{A}_g$ already obtained as families of Galois coverings of $\mathbb{P}^1$ in [FGP]. Finally we prove that if a family satisfies this sufficient condition with $g'\geq 1$, then $g \leq 6g'+1$.Comment: 18 pages, to appear in Geometriae Dedicat

A Multi-Center Study Investigating Long COVID-19 in Healthcare Workers from North-Eastern Italy: Prevalence, Risk Factors and the Impact of Pre-Existing Humoral Immunity—ORCHESTRA Project

: Introduction: The impact of long-COVID-19 syndrome is rather variable, since it is influenced by several residual confounders. This study aimed to investigate the prevalence of long COVID-19 in healthcare workers (HCWs) from four university hospitals in north-eastern Italy: Trieste, Padua, Verona, and Modena-Reggio Emilia. Methods: During the period June 2022-August 2022, HCWs were surveyed for past COVID-19 infections, medical history, and any acute as well as post-COVID-19 symptoms. The prevalence of long COVID-19 was estimated at 30-60 days or 61+ days since first negative swab following first and second COVID-19 episode. Furthermore, the risk of long COVID-19 was investigated by multivariable logistic regression. Results were expressed as the adjusted odds ratio (aOR) with a 95% confidence interval (95%CI). Results: 5432 HCWs returned a usable questionnaire: 2401 were infected with SARS-CoV-2 at least once, 230 were infected at least twice, and 8 were infected three times. The prevalence of long COVID-19 after a primary COVID-19 infection was 24.0% at 30-60 days versus 16.3% at 61+ days, and 10.5% against 5.5% after the second SARS-CoV-2 event. The most frequent symptoms after a first COVID-19 event were asthenia (30.3%), followed by myalgia (13.7%), cough (12.4%), dyspnea (10.2%), concentration deficit (8.1%), headache (7.3%), and anosmia (6.5%), in decreasing order of prevalence. The risk of long COVID-19 at 30-60 days was significantly higher in HCWs hospitalized for COVID-19 (aOR = 3.34; 95%CI: 1.62; 6.89), those infected with SARS-CoV-2 during the early pandemic waves-namely the Wuhan (aOR = 2.16; 95%CI: 1.14; 4.09) or Alpha (aOR= 2.05; 95%CI: 1.25; 3.38) transmission periods-and progressively increasing with viral shedding time (VST), especially 15+ days (aOR = 3.20; 95%CI: 2.07; 4.94). Further determinants of long COVID-19 at 30-60 days since primary COVID-19 event were female sex (aOR = 1.91; 95%CI: 1.30; 2.80), age >40 years, abnormal BMI, or administrative services (reference category). In contrast, HCWs vaccinated with two doses before their primary infection (aOR = 0.57; 95%CI: 0.34; 0.94), undergraduate students, or postgraduate medical trainees were less likely to experience long COVID-19 at 30-60 days. Apart from pandemic waves, the main determinants of long COVID-19 at 30-60 days were confirmed at 61+ days. Conclusions: The risk of long COVID-19 following primary infection increased with the severity of acute disease and VST, especially during the initial pandemic waves, when more virulent viral strains were circulating, and susceptibility to SARS-CoV-2 was higher since most HCWs had not been infected yet, COVID-19 vaccines were still not available, and/or vaccination coverage was still building up. The risk of long COVID-19 therefore decreased inversely with humoral immunity at the individual level. Nevertheless, the prevalence of long COVID-19 was remarkably lower after SARS-CoV-2 reinfections regardless of vaccination status, suggesting that hybrid humoral immunity did not increase protection against the syndrome compared to immunity mounted by either natural infection or vaccination separately. Since the risk of long COVID-19 is currently low with Omicron and patients who developed the syndrome following SARS-CoV-2 infection in the early pandemic waves tend to return to a state of full health with time, a cost-effective approach to screen post-COVID-19 symptoms during the Omicron time could be restricted to vulnerable individuals developing severe disease and/or with prolonged VST

New insights on occupational exposure and bladder cancer risk: a pooled analysis of two Italian case-control studies.

Purpose: The main risk factor for bladder cancer (BC) is cigarette smoking, but also occupational exposure to carcinogens is relevant, causing about 4-10% of BC. We aimed at investigating the association between BC risk, occupations held in the past and exposure to occupational carcinogens, also assessing whether these associations were influenced by tumor grade. Methods: We pooled data from two Italian case-control studies on male BC, analyzing 893 cases and 978 controls. Occupations were classified using the International Standard Classification of Occupations and exposure to carcinogens was assigned using a validated Job Exposure Matrix. Logistic regression approach was used as well as a semi- Bayesian model, based on a priori information on exposure. Results: A significantly increased BC risk was found for chemical engineering technicians, postmen, and lathe operators, but only for the latter the association remained significant after Bayesian control for type I error. Among carcinogens, cadmium and trichloroethylene were associated with BC. When analyzing data by grade, exposure to these carcinogens was associated with low-grade BC only. Conclusions: Our results suggest that monitoring workplaces to prevent exposure to carcinogenic agents is still an important task, which should be still given adequate importance in public health

Determinants of anti-S immune response at 6 months after COVID-19 vaccination in a multicentric European cohort of healthcare workers – ORCHESTRA project

Background: The duration of immune response to COVID-19 vaccination is of major interest. Our aim was to analyze the determinants of anti-SARS-CoV-2 IgG titer at 6 months after 2-dose vaccination in an international cohort of vaccinated healthcare workers (HCWs). Methods: We analyzed data on levels of anti-SARS-CoV-2 Spike antibodies and sociodemographic and clinical characteristics of 6,327 vaccinated HCWs from 8 centers from Germany, Italy, Romania and Slovakia. Time between 1st dose and serology ranged 150-210 days. Serological levels were log-transformed to account for the skewness of the distribution and normalized by dividing them by center-specific standard errors, obtaining standardized values. We fitted center-specific multivariate regression models to estimate the cohort-specific relative risks (RR) of an increase of 1 standard deviation of log antibody level and corresponding 95% confidence interval (CI), and finally combined them in random-effects meta-analyses. Results: A 6-month serological response was detected in 99.6% of HCWs. Female sex (RR 1.10, 95%CI 1.00-1.21), past infection (RR 2.26, 95%CI 1.73-2.95) and two vaccine doses (RR 1.50, 95%CI 1.22-1.84) predicted higher IgG titer, contrary to interval since last dose (RR for 10-day increase 0.94, 95%CI 0.91-0.97) and age (RR for 10-year increase 0.87, 95%CI 0.83-0.92). M-RNA-based vaccines (p<0.001) and heterologous vaccination (RR 2.46, 95%CI 1.87-3.24, one cohort) were associated with increased antibody levels. Conclusions: Female gender, young age, past infection, two vaccine doses, and m-RNA and heterologous vaccination predicted higher antibody level at 6 months. These results corroborate previous findings and offer valuable data for comparison with trends observed with longer follow-ups

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis