Comprehensive Analysis of HERV Transcriptome in HIV+ Cells: Absence of HML2 Activation and General Downregulation of Individual HERV Loci

Human endogenous retrovirus (HERV) expression is currently studied for its possible activation by HIV infection. In this context, the HERV-K(HML2) group is the most investigated: it has been proposed that HIV-1 infection can prompt HML2 transcription, and that HML2 proteins can affect HIV-1 replication, either complementing HIV or possibly influencing antiretroviral therapy. However, little information is available on the expression of other HERV groups in HIV infection. In the present study, we used a bioinformatics pipeline to investigate the transcriptional modulation of approximately 3250 well-characterized HERV loci, comparing their expression in a public RNA-seq profile, including a HIV-1-infected and a control T cell culture. In our pilot study, we found approximately 200 HERV loci belonging to 35 HERV groups that were expressed in one or both conditions, with transcripts per million (TPM) values from 1 to >500. Intriguingly, HML2 elements constituted only the 3% of expressed HERV loci, and in most cases (160) HERV expression was downregulated in the HIV-infected culture, showing from a 1- to 14-fold decrease as compared to uninfected cells. HERV transcriptome has been inferred de novo and employed to predict a total of about 950 HERV open reading frames (ORFs). These have been validated according to the coding potential and estimated abundance of the corresponding transcripts, leading to a set of 57 putative proteins potentially encoded by 23 HERV loci. Analysis showed that some individual loci have a coding potential that deserves further investigation. Among them, a HML6 provirus at locus 19q13.43 was predicted to produce a transcript showing the highest TPM among HERV-derived transcripts, being upregulated in HIV+ cells and inferred to produce Gag and Env puteins with possible biological activity

household transmission and disease transmissibility of a large hav outbreak in lazio italy 2016 2017

Abstract A major outbreak of Hepatitis A Virus (HAV) has swept through Europe between mid-2016 and 2017, mainly within the community of men who have sex with men (MSM). Over the same period, about 1,000 outbreak-related cases of acute Hepatitis A (AHA) were recorded in Lazio region, Italy. We calibrated a Bayesian model to reconstruct likely transmission events within all 44 households where multiple infections were recorded, representing a total of 103 cases from the HAV outbreak in Lazio. Based on information on the observed times of symptom onset, we estimated for the probability distribution function of the HAV generation time and used it to compute the effective and instantaneous reproduction numbers for the considered outbreak from the overall epidemic curve (N = 998 cases). We estimated a mean generation time of 30.2 days (95%CI: 25.2-33.0) and an effective reproduction number of about 1.63 (95% CI: 1.35-1.94). Transmissibility peaked in January 2017, shortly before targeted awareness and vaccination campaigns were put in place by health authorities; however, transmission remained above the epidemic threshold until June 2017. Within households, children (0-15) and young adults (16-30) infected preferentially individuals of the same age class, whereas transmission within older age groups was substantially homogeneous. These results suggest that the implemented interventions were able to slow down HAV transmission, but not to bring it rapidly to a halt. According to our estimates of the HAV transmissibility, about 50% of the at-risk persons should be immunized to prevent similar outbreaks in the future. Our results also indicate spillover from community transmission to household members, suggesting the opportunity of vaccinating household contacts of cases to prevent further spread of the epidemics

Full-length genome sequence of a dengue serotype 1 virus isolate from a traveler returning from Democratic Republic of Congo to Italy, July 2019.

Abstract We report the full-genome sequence of a Dengue serotype-1 virus (DENV-1) isolated from a traveller returning in July 2019 to Italy from Democratic Republic of Congo (DRC), which is currently affected by Ebola and measles outbreaks. The sequence shows high similarity with two 2013 strains isolated in Angola and China

Broad-spectrum coronavirus 3C-like protease peptidomimetic inhibitors effectively block SARS-CoV-2 replication in cells: Design, synthesis, biological evaluation, and X-ray structure determination

Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2–P1 residues, allowing the development of broad-spectrum inhibitors. The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2–P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the β-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low μM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics

Vox clamantis in deserto: a survey among Italian psychiatrists on defensive medicine and professional liability

Due to recent events, professional liability for psychiatrists in Italy is currently a matter of lively debate. Specifically, overwhelming pressure on psychiatrists’ duties has been brought by regulatory developments, such as the closure of forensic psychiatric hospitals, with the consequent return of offenders to community-based care, and the mental health consequences of the pandemic. According to Italian courts, psychiatrists are not only responsible for diagnostic and therapeutic appropriateness but also for the effects of their interventions on patients, and their behaviors. The aim of this study was to explore the attitude and behaviors of Italian psychiatrists regarding defensive medicine and professional liability. A total sample of 254 psychiatrists was surveyed by means of a quantitative online questionnaire. Most psychiatrists reported practicing defensive medicine (no. 153/254, 60.2%) and felt that their position of guarantee compromised their work in healthcare for patients (no. 138/253, 54.3%). Age correlated inversely with acknowledgment of defensive practices (r = −0.245, p < 0.001), with younger physicians more prone to defensive medicine (p = 0.013), particularly for patients at risk of suicide or violence. Psychiatrists in ‘closed’ settings (hospital wards, residential and rehabilitation centers, mental health service units in prison) reported more malpractice claims (p = 0.037) and complaints (p = 0.031), as well as a greater propensity to act defensively. In the treatment of patients with violent behavior, suicidal ideation, dual diagnoses, and criminal convictions, defensive practices were associated more with perceived legal risks (r = 0.306, p < 0.001) than actual legal involvement (p > 0.05). Anxiety, anger, and restlessness were common reactions to legal complaints, involving no. 50/254 (19.7%) respondents, with 40% reporting impaired functioning. Most psychiatrists (no. 175/253, 68.9%) were concerned about both civil and criminal laws regarding their professional responsibility, but many were not fully informed about recent legislative regulations and younger physicians resulted scarcely trained in risk management (p < 0.001). In conclusion, our findings suggest that defensive medicine is a common phenomenon among psychiatrists and their position of guarantee drives this attitude. Education on legal implications and risk management should be provided starting from the university and continuing over time, to improve the knowledge of young and senior doctors on professional liability and inform their decision-making processes. This would also reduce defensive practices and improve the quality of healthcare. Considering the concerns of younger physicians, as well as of professionals working in acute and high-intensity medical care facilities, there is also an urgent need for a revision of the medical liability to ensure the sustainability of the National Health Service

Characterization of the patterns of drug-resistance mutations in newly diagnosed HIV-1 infected patients naïve to the antiretroviral drugs

<p>Abstract</p> <p>Background</p> <p>The transmission of HIV-1 drug-resistant strains in drug naive patients may seriously compromise the efficacy of a first-line antiretroviral treatment. To better define this problem, a study in a cohort of newly diagnosed HIV-1 infected individuals has been conducted. This study is aimed to assess the prevalence and the patterns of the mutations recently associated with transmitted drug resistance in the reverse transcriptase (RT) and in protease (PR) of HIV-1.</p> <p>Methods</p> <p>Prevalence of transmitted drug resistant strains is determined in 255 newly diagnosed HIV-1 infected patients enrolled in different counselling and testing (CT) centres in Central Italy; the Avidity Index (AI) on the first available serum sample is also used to estimate time since infection. Logistic regression models are used to determine factors associated with infection by drug resistant HIV-1 strains.</p> <p>Results</p> <p>The prevalence of HIV-1 strains with at least one major drug resistance mutation is 5.9% (15/255); moreover, 3.9% (10/255) of patients is infected with HIV nucleoside reverse transcriptase inhibitor (NRTI)-resistant viruses, 3.5% (9/255) with HIV non-NRTI-resistant viruses and 0.4% (1/255) with HIV protease inhibitor (PI)-resistant viruses. Most importantly, almost half (60.0%) of patients carries HIV-1 resistant strains with more than one major drug resistance mutation. In addition, patients who had acquired HIV through homosexual intercourses are more likely to harbour a virus with at least one primary resistance mutation (OR 7.7; 95% CI: 1.7–35.0, P = 0.008).</p> <p>Conclusion</p> <p>The prevalence of drug resistant HIV-1 strains among newly diagnosed individuals in Central Italy is consistent with the data from other European countries. Nevertheless, the presence of drug-resistance HIV-1 mutations in complex patterns highlights an additional potential risk for public health and strongly supports the extension of wide genotyping to newly diagnosed HIV-1 infected patients.</p

Determinants of access to experimental antiretroviral drugs in an Italian cohort of patients with HIV: a multilevel analysis

<p>Abstract</p> <p>Background</p> <p>Identification of the determinants of access to investigational drugs is important to promote equity and scientific validity in clinical research. We aimed to analyze factors associated with the use of experimental antiretrovirals in Italy.</p> <p>Methods</p> <p>We studied participants in the Italian Cohort of Antiretroviral-Naive Patients (ICoNA). All patients 18 years or older who had started cART (≥ 3 drugs including at least two NRTI) after their enrolment and during 1997-2007 were included in this analysis. We performed a random effect logistic regression analysis to take into account clustering observations within clinical units. The outcome variable was the use of an experimental antiretroviral, defined as an antiretroviral started before commercial availability, in any episode of therapy initiation/change. Use of an experimental antiretroviral obtained through a clinical trial or an expanded access program (EAP) was also analyzed separately.</p> <p>Results</p> <p>A total of 9,441 episodes of therapy initiation/change were analyzed in 3,752 patients. 392 episodes (360 patients) involved an experimental antiretroviral. In multivariable analysis, factors associated with the overall use of experimental antiretrovirals were: number of experienced drugs (≥ 8 drugs versus "naive": adjusted odds ratio [AOR] = 3.71) or failed antiretrovirals(3-4 drugs and ≥ 5 drugs versus 0-2 drugs: AOR = 1.42 and 2.38 respectively); calendar year (AOR = 0.80 per year) and plasma HIV-RNA copies/ml at therapy change (≥ 4 log versus < 2 log: AOR = 1.55). The probability of taking an experimental antiretroviral through a trial was significantly lower for patients suffering from liver co-morbidity(AOR = 0.65) and for those who experienced 3-4 drugs (vs naive) (AOR = 0.55), while it increased for multi-treated patients(AOR = 2.60). The probability to start an experimental antiretroviral trough an EAP progressively increased with the increasing number of experienced and of failed drugs and also increased for patients with liver co-morbidity (AOR = 1.44; p = 0.053). and for male homosexuals (vs heterosexuals: AOR = 1.67). Variability of the random effect associated to clinical units was statistically significant (p < 0.001) although no association was found with specific characteristics of clinical unit examined.</p> <p>Conclusions</p> <p>Among patients with HIV infection in Italy, access to experimental antiretrovirals seems to be influenced mainly by exhaustion of treatment options and not by socio-demographic factors.</p

Bollettino Sismico Italiano: Analisys of Early Aftershocks of the 2016 MW 6.0 Amatrice, MW 5.9 Visso and MW 6.5 Norcia earthquakes in Central Italy

The Amatrice-Visso-Norcia seismic sequence is the most important of the last 30 years in Italy. The seismic sequence started on 24 August, 2016 and still is ongoing in central Apennines. At the end of February 2017 more than 57,000 events were located, 80,000 events up to the end of September 2017 (Fig. 1). The mainshocks of the sequence occurred on 24 August 2016 (Mw 6.0 and Mw 5.4), 26 October 2016 (Mw 5.4 and Mw 5.9), 30 October 2016 (Mw 6.5), 18 January 2017 (four earthquakes Mw≥ 5.0). In this seismic sequence, all the waveforms recorded by temporary stations deployed by the SISMIKO emergency group (stations T12**; Moretti et al., 2016) where available in real- time at the surveillance room of INGV. Because of the high level of seismicity and the dense seismic network installed in the region, more than 150 events per day were located at the end of February 2017; still 60 events per day were located up to the end of August 2017.The Amatrice-Visso-Norcia is the most important seismic sequence since 2015, the time when the analysis procedures of the BSI group (Bollettino Sismico Italiano) were revised (Nardi et al., 2015). BSI is now available every four months on the web: bulletins contain revised earthquakes (location and magnitude) with ML≥ 1.5, quasi-real time revision of ML≥ 3.5 earthquakes and phase arrivals from waveforms recorded on seismic stations available from the European Integrated Data Archive (EIDA), (Mazza et al., 2012). These last procedures allow the integration of signals from temporary seismic stations (Moretti et al., 2014) installed by the emergency group SISMIKO (Moretti and Sismiko working group, 2016), even when they are not in real time transmission, if they are rapidly archived in EIDA, together with real time signals from the seismic stations of the permanent INGV network. The analysis strategy of the BSI group for the Amatrice -Visso - Norcia seismic sequence (AVN.s.s in the following) was to select the earthquakes located in the box with min/max latitude: 42.2/43.2 - and min/max longitude: 12.4/14.1 to prepare a special volume of BSI on the seismic sequence.PublishedTrieste, Italy1SR. TERREMOTI - Servizi e ricerca per la Societ

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p &lt; .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p &lt; .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come