The Stability of Social and Behavioral Rhythms and Unexpected Low Rate of Relevant Depressive Symptoms in Old Adults during the COVID-19 Pandemic.

Background: The disruption of social rhythms was found to be associated with depressive disorders during the COVID-19 pandemic; lower rates of these disorders were surprisingly found in old adults. The present study aims to verify the stability of social rhythms during lockdown in a sample of elderly people. Methods: Controlled cohort study (secondary analyses) of a previous randomized-controlled trial with the first evaluation in April 2019 (T0) and then 48 weeks later (T1) during the lockdown. The regulation of social and behavioral rhythms was measured through the Brief Social Rhythms Scale (BSRS); the Patient Health Questionnaire-9 (PHQ9) was adopted to detect relevant depressive symptoms. Results: 93 elderlies (73.36 ± 4.97 years old, 50.5% females) were evaluated at T0 and T1. Neither the total score of BSRS nor any of the 10 items showed a statistically significant difference comparing the two survey periods. The frequency of relevant depressive symptoms was 5.3% at T0 and 6.4% at T1 (OR = 0.8, CI95% 0.2-24). Conclusions: Among elderlies who did not show an increased risk of depression during the lockdown, social and behavioral rhythms remained exceptionally stable during the same period. Considering previous evidence about rhythms dysregulation preceding depression, their stability may be considered a factor of resilience.

Humoral responses to wild type and ancient BA.1 SARS-CoV-2 variant after heterologous priming vaccination with ChAdOx1 nCoV-19 and BNT162b2 booster dose.

Several countries have recommended a booster dose of Pfizer BNT162b2 vaccine for subjects under the age of 60, who have already received the first dose of ChAdOx1. This is due to several ChAdOx1 vaccine-associated adverse vascular events and thrombocytopenia. Neutralization assay and quantitative IgG anti-SARS-CoV-2 Spike antibody (anti-S-IgG) were conducted to investigate the long-term responses to vaccine treatment in a cohort of Sardinian participants, who have received heterologous Prime-Boost Vaccination via ChAdOx1 vector vaccine and a booster dose via BNT162b2. The obtained results were compared with those of a cohort of healthcare workers (HCW) who received homologous BNT162b2 (BNT/BNT/BNT) vaccination. One month (T2) and five months after the second and before the third dose (T3), anti-spike antibody or neutralizing titers in the subjects vaccinated with ChAdOx1-S/BNT162b2 were significantly higher than those who experienced the ChAdOx1-S/ChAdOx1-S or BNT162b2/BNT162b2 schedule. These results suggest that a ChAdOx1-S/BNT162b2 regimen provides a more robust antibody response than either of the homologous regimens. However, the anti-spike antibodies or neutralizing titers after the third injection (mRNA vaccine) of ChAdOx1-S as a second dose and BNT162b2 were not statistically different. Homologous and heterologous vaccination provided a strong antibody response. Neutralizing activities were also described against the Omicron BA.1 variant in a sub-group (40) representative of the three vaccination regimens among our cohort.

Decision trees for early prediction of inadequate immune response to coronavirus infections: a pilot study on COVID-19.

Introduction: Few artificial intelligence models exist to predict severe forms of COVID-19. Most rely on post-infection laboratory data, hindering early treatment for high-risk individuals. Methods: This study developed a machine learning model to predict inherent risk of severe symptoms after contracting SARS-CoV-2. Using a Decision Tree trained on 153 Alpha variant patients, demographic, clinical and immunogenetic markers were considered. Model performance was assessed on Alpha and Delta variant datasets. Key risk factors included age, gender, absence of KIR2DS2 gene (alone or with HLA-C C1 group alleles), presence of 14-bp polymorphism in HLA-G gene, presence of KIR2DS5 gene, and presence of KIR telomeric region A/A. Results: The model achieved 83.01% accuracy for Alpha variant and 78.57% for Delta variant, with True Positive Rates of 80.82 and 77.78%, and True Negative Rates of 85.00% and 79.17%, respectively. The model showed high sensitivity in identifying individuals at risk. Discussion: The present study demonstrates the potential of AI algorithms, combined with demographic, epidemiologic, and immunogenetic data, in identifying individuals at high risk of severe COVID-19 and facilitating early treatment. Further studies are required for routine clinical integration.

Decision trees to evaluate the risk of developing multiple sclerosis.

Introduction: Multiple sclerosis (MS) is a persistent neurological condition impacting the central nervous system (CNS). The precise cause of multiple sclerosis is still uncertain; however, it is thought to arise from a blend of genetic and environmental factors. MS diagnosis includes assessing medical history, conducting neurological exams, performing magnetic resonance imaging (MRI) scans, and analyzing cerebrospinal fluid. While there is currently no cure for MS, numerous treatments exist to address symptoms, decelerate disease progression, and enhance the quality of life for individuals with MS. Methods: This paper introduces a novel machine learning (ML) algorithm utilizing decision trees to address a key objective: creating a predictive tool for assessing the likelihood of MS development. It achieves this by combining prevalent demographic risk factors, specifically gender, with crucial immunogenetic risk markers, such as the alleles responsible for human leukocyte antigen (HLA) class I molecules and the killer immunoglobulin-like receptors (KIR) genes responsible for natural killer lymphocyte receptors. Results: The study included 619 healthy controls and 299 patients affected by MS, all of whom originated from Sardinia. The gender feature has been disregarded due to its substantial bias in influencing the classification outcomes. By solely considering immunogenetic risk markers, the algorithm demonstrates an ability to accurately identify 73.24% of MS patients and 66.07% of individuals without the disease. Discussion: Given its notable performance, this system has the potential to support clinicians in monitoring the relatives of MS patients and identifying individuals who are at an increased risk of developing the disease.

A review of the main genetic factors influencing the course of COVID-19 in Sardinia: the role of human leukocyte antigen-G.

Introduction: A large number of risk and protective factors have been identified during the SARS-CoV-2 pandemic which may influence the outcome of COVID-19. Among these, recent studies have explored the role of HLA-G molecules and their immunomodulatory effects in COVID-19, but there are very few reports exploring the genetic basis of these manifestations. The present study aims to investigate how host genetic factors, including HLA-G gene polymorphisms and sHLA-G, can affect SARS-CoV-2 infection. Materials and Methods: We compared the immune-genetic and phenotypic characteristics between COVID-19 patients (n = 381) with varying degrees of severity of the disease and 420 healthy controls from Sardinia (Italy). Results: HLA-G locus analysis showed that the extended haplotype HLA-G*01:01:01:01/UTR-1 was more prevalent in both COVID-19 patients and controls. In particular, this extended haplotype was more common among patients with mild symptoms than those with severe symptoms [22.7% vs 15.7%, OR = 0.634 (95% CI 0.440 - 0.913); P = 0.016]. Furthermore, the most significant HLA-G 3'UTR polymorphism (rs371194629) shows that the HLA-G 3'UTR Del/Del genotype frequency decreases gradually from 27.6% in paucisymptomatic patients to 15.9% in patients with severe symptoms (X2 = 7.095, P = 0.029), reaching the lowest frequency (7.0%) in ICU patients (X2 = 11.257, P = 0.004). However, no significant differences were observed for the soluble HLA-G levels in patients and controls. Finally, we showed that SARS-CoV-2 infection in the Sardinian population is also influenced by other genetic factors such as ß-thalassemia trait (rs11549407C>T in the HBB gene), KIR2DS2/HLA-C C1+ group combination and the HLA-B*58:01, C*07:01, DRB1*03:01 haplotype which exert a protective effect [P = 0.005, P = 0.001 and P = 0.026 respectively]. Conversely, the Neanderthal LZTFL1 gene variant (rs35044562A>G) shows a detrimental consequence on the disease course [P = 0.001]. However, by using a logistic regression model, HLA-G 3'UTR Del/Del genotype was independent from the other significant variables [ORM = 0.4 (95% CI 0.2 - 0.7), PM = 6.5 x 10-4]. Conclusion: Our results reveal novel genetic variants which could potentially serve as biomarkers for disease prognosis and treatment, highlighting the importance of considering genetic factors in the management of COVID-19 patients.

COVID-19 Vaccine Hesitancy among Italian Healthcare Workers: Latent Profiles and Their Relationships to Predictors and Outcome.

Vaccine hesitancy and conspiracy beliefs among healthcare workers (HCWs) represent operational priorities that require urgent attention. Identifying and classifying specific subpopulation of hesitancy is crucial to customize educational and intervention strategies to enhance the acceptance and uptake rate of vaccination. Thus, the main purpose of our study was to empirically identify latent profiles of vaccine hesitancy among Italian HCWs adopting a person-centered approach and investigating their relationships with antecedents and intention to get a fourth dose of COVID-19 vaccine. We conducted latent profile analyses (LPA) to identify different configurations of vaccine hesitancy based on five antecedents of vaccination: confidence, complacency, constraints, calculation, and collective responsibility among a sample of Italian HCWs (n = 573). LPA revealed four distinct profiles: believer (61.5%), middler (24.7%), hesitant (9.00%), and rejecter (4.7%). Having conspiracy beliefs was associated with a greater likelihood of membership in all but believer. Finally, the likelihood of intention to get a fourth dose of COVID-19 vaccine was lowest in the rejector and hesitant profiles. Theoretical contributions and implications for practice are discussed.

The double-sided of human leukocyte antigen-G molecules in type 1 autoimmune hepatitis.

The immunomodulatory effects of HLA-G expression and its role in cancers, human liver infections and liver transplantation are well documented, but so far, there are only a few reports addressing autoimmune liver diseases, particularly autoimmune hepatitis (AIH). Method and materials: We analyzed the genetic and phenotypic characteristics of HLA-G in 205 type 1 AIH patients (AIH-1) and a population of 210 healthy controls from Sardinia (Italy). Results: Analysis of the HLA-G locus showed no substantial differences in allele frequencies between patients and the healthy control population. The HLA-G UTR-1 haplotype was the most prevalent in both AIH-1 patients and controls (40.24% and 34.29%). Strong linkage was found between the HLA-G UTR-1 haplotype and HLA-DRB1*03:01 in AIH-1 patients but not controls (D' = 0.92 vs D' = 0.50 respectively; P = 1.3x10-8). Soluble HLA-G (sHLA-G) levels were significantly lower in AIH-1 patients compared to controls [13.9 (11.6 - 17.4) U/mL vs 21.3 (16.5 - 27.8) U/mL; P = 0.011]. Twenty-four patients with mild or moderate inflammatory involvement, as assessed from liver biopsy, showed much higher sHLA-G levels compared to the 28 patients with severe liver inflammation [33.5 (23.6 - 44.8) U/mL vs 8.8 (6.1 - 14.5) U/mL; P = 0.003]. Finally, immunohistochemistry analysis of 52 liver biopsies from AIH-1 patients did not show expression of HLA-G molecules in the liver parenchyma. However, a percentage of 69.2% (36/52) revealed widespread expression of HLA-G both in the cytoplasm and the membrane of plasma cells labeled with anti-HLA-G monoclonal antibodies. Conclusion: This study highlights the positive immunomodulatory effect of HLA-G molecules on the clinical course of AIH-1 and how this improvement closely correlates with plasma levels of sHLA-G. However, our results open the debate on the ambiguous role of HLA-G molecules expressed by plasma cells, which are pathognomonic features of AIH-1.

Differences in lethality and diffusion of Covid-19 in countries using different kinds of vaccines.

To verify if lethality and diffusivity of Covid-19 correlated with percentage of people vaccinated in different countries and whether results on these indicators were comparable under different types of vaccines. A linear regression analysis was conducted between vaccines/inhabitant, new cases/inhabitants and ratio deaths/cases. A comparison between the three indicators was carried out in countries subdivided by kind of vaccine. The proportion of vaccinations/inhabitants correlates negatively with proportion of deaths × 100 cases (R = -3.90, p < 0.0001), but didn't on incidence of new cases. Countries with prevalence of mRNA vaccines were similar to others on incidence of new cases; but a lower lethality of Sars-Cov2 was found than in countries with prevalence of viral vehicle vaccines (F = 6.064, p = 0.0174) but didn't against countries with prevalence of inactivated vaccines. The higher is the proportion of vaccine/inhabitant in a given country, the less is the fraction of infected people who die.

Evaluation of humoral and cellular response to third dose of BNT162b2 mRNA COVID-19 vaccine in patients treated with B-cell depleting therapy.

OBJECTIVE: to investigate the responses to mRNA COVID-19 vaccines in a cohort of immunosuppressed patients affected by immune-mediated inflammatory diseases (IMID). METHODS: we have measured humoral and cellular immunity using quantitative IgG anti-SARS-CoV-2 Spike antibody (anti-S-IgG), neutralization assays and specific interferon-gamma (IFN-g) release assay (IGRA) before and after the third dose of BNT162b2. The response of those on anti-CD20 (n = 18) was then compared with healthy controls (HC, n = 18) and IMID naïve to anti-CD20 drugs (n = 13). RESULTS: a third BNT162b2 dose is highly immunogenic in IMID patients naïve to anti-CD20, as 100% of the subjects seroconverted compared to the 55% in anti-CD20. The rate of IGRA response was of 79% in anti-CD20, 50% in IMID naïve to anti-CD20, 100% in HC. Among those who have seroconverted, IMID patients had significantly reduced anti-S-IgG and neutralization titers compared to HC, whereas no significant difference was observed when comparing anti-CD20 and HC. Furthermore, 13% of anti-CD20 and 7.7% of IMID were simultaneously negative for both neutralizing antibodies and IGRA after three doses. CONCLUSION: these data draw attention to the immunogenicity of COVID-19 vaccination in treated IMID, taking specific groups into consideration for vaccination program.

A Protective HLA Extended Haplotype Outweighs the Major COVID-19 Risk Factor Inherited From Neanderthals in the Sardinian Population.

Sardinia has one of the lowest incidences of hospitalization and related mortality in Europe and yet a very high frequency of the Neanderthal risk locus variant on chromosome 3 (rs35044562), considered to be a major risk factor for a severe SARS-CoV-2 disease course. We evaluated 358 SARS-CoV-2 patients and 314 healthy Sardinian controls. One hundred and twenty patients were asymptomatic, 90 were pauci-symptomatic, 108 presented a moderate disease course and 40 were severely ill. All patients were analyzed for the Neanderthal-derived genetic variants reported as being protective (rs1156361) or causative (rs35044562) for severe illness. The ß°39 C>T Thalassemia variant (rs11549407), HLA haplotypes, KIR genes, KIRs and their HLA class I ligand combinations were also investigated. Our findings revealed an increased risk for severe disease in Sardinian patients carrying the rs35044562 high risk variant [OR 5.32 (95% CI 2.53 - 12.01), p = 0.000]. Conversely, the protective effect of the HLA-A*02:01, B*18:01, DRB*03:01 three-loci extended haplotype in the Sardinian population was shown to efficiently contrast the high risk of a severe and devastating outcome of the infection predicted for carriers of the Neanderthal locus [OR 15.47 (95% CI 5.8 - 41.0), p < 0.0001]. This result suggests that the balance between risk and protective immunogenetic factors plays an important role in the evolution of COVID-19. A better understanding of these mechanisms may well turn out to be the biggest advantage in the race for the development of more efficient drugs and vaccines.

Neutralizing Antibodies Responses against SARS-CoV-2 in a Sardinian Cohort Group Up to 9 Months after BNT162b2 Vaccination.

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, has caused over 460 million cases of infection and over 6 million deaths worldwide. The pandemic has called for science, technology, and innovation to provide solutions and, due to an incredible scientific and financial global effort, several prophylactic and therapeutic apparatuses such as monoclonal antibodies and vaccines were developed in less than one year to address this emergency. After SARS-CoV-2 infection, serum neutralizing antibodies are produced by B cells and studies on virus-neutralizing antibodies' kinetics are pivotal. The process of protective immunity and the duration of this kind of protection against COVID-19 remain to be clarified. We tested 136 sera from 3 groups of individuals, some of them providing multiple sequential sera (1-healthy, no previous CoV2-infected, vaccinated; 2-healthy, previous CoV2 infected, vaccinated; 3-healed, previous CoV2-infected, not vaccinated) to assess the kinetics of antibodies (Abs) neutralizing activity. We found that SARS-CoV-2 infection elicits moderate neutralizing antibody activity in most individuals; neither age nor gender appear to have any influence on Abs responses. The BNT162b2 vaccine, when administered in two doses, induces high antibodies titre endowed with potent neutralizing activity against bare SARS-CoV-2 in in vitro neutralizing assay. The residual neutralization capability and the kinetic of waning immunity were also evaluated over 9 months after the second dose in a reference group of subjects. Neutralization titre showed a decline in all subjects and the median level of S-protein IgG, over 270 days after the second vaccination dose, was below 10 AU/mL in 53% of serum tested.

Covid-19 vaccines work but other factors play a relevant role: a data analysis on spread and mortality in 24 countries.

BACKGROUND: The aim was to outline a methodology to monitor the impact of vaccinations in different countries comparing at two different times within countries and between countries the frequency of new cases and Covid-19 related deaths and the percentage of vaccinations conducted. DESIGN AND METHODS: The 25 countries with the largest increase in SARS-CoV-2 cases on 8 August 2021 were evaluated. In each nation was calculated the proportion of Covid-19 deaths divided per new cases x 100 and the proportion of new cases per 1.000 inhabitants on 10 January 2021 (before vaccinations' distribution) and 8 August 2021 (when large percentage of the population had been vaccinated in many countries). RESULTS: The study shows that in the countries with the highest number of cases as of 8 August 2021, the proportion of vaccinations carried out in the population correlates negatively with both the proportion between Covid-19 dead people x100 infected people and with the rate of new cases. However, the proportion of vaccinations does not correlate with the differences in the two same indicators considered in the weeks observed, thus additional factors seem to play an important role. CONCLUSIONS: This work indicates that mass vaccination is associated with a lower spread of the pandemic and, to greater extent, with a lowering of mortality in infected people.

Previous functional social and behavioral rhythms affect resilience to COVID-19-related stress among old adults.

BACKGROUND: Functioning of Social Behavioral Rhythms (SBRs) may affect resilience toward stressful events across different age groups. However, the impact of SBRs on the coronavirus disease of 2019 (COVID-19) in elder people is yet to ascertain, representing the aim of the present report. DESIGN AND METHODS: Follow-up of a peer-reviewed randomized controlled trial on exercise on old adults (³65 years), concurrent to the onset of the pandemic-related lockdown. Post-RCT evaluations occurred after further 12 and 36 weeks since the beginning of the lockdown phase. People with Major Depressive Episode (MDE) at week-48 (follow-up endpoint) were deemed as cases, people without such condition were considered controls. MDE was ascertained using the Patient Health Questionnaire-9 (PHQ-9); SBRs functioning at week 12 onward, through the Brief Symptom Rating Scale (BSRS). RESULTS: Seventy-nine individuals (53.2%, females) entered the RCT-follow-up phase. The frequency of MDE did not significantly change before versus during lockdown (OR 2.60, CI95%=0.87-9.13). People with BSRS>1 standard deviation of the whole sample score at week-12 had an inflated risk of DE during lockdown (OR=5.6, 95%CI: 1.5-21.4) compared to those with lower BSRS scores. Such odd hold after excluding individuals with MDD at week-12. The post-hoc analysis could be potentially affected by selection bias. CONCLUSIONS: Overall, older adults were resilient during the first phase of the pandemic when functioning of pre-lockdown was still preserved, in contrast to the subsequent evaluations when the impairment of daily rhythms was associated with impaired reliance.

Evaluation of antibody response to BNT162b2 mRNA COVID-19 vaccine in patients affected by immune-mediated inflammatory diseases up to 5 months after vaccination.

SARS-CoV-2 vaccination with mRNA product BNT162b2 elicited high immunogenicity in healthy subjects in trials. This study aims to better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). We enrolled patients and healthy healthcare workers control group (HCW) that underwent mRNA BNT162b2 vaccination and measured the serum IgG anti-S-RBD response at booster dose (T1), one month after booster dose (T2) and up to 5 months (T3). Demographic, disease-specific and vaccination data were recorded. Vaccination response of 551 participants naïve to SARS-CoV-2 infection were included in HCW and 102 in the IMID group, analyzing separately those on anti-CD20. At T2 all naïve HCW developed anti-S-RBD-IgG, while 94% of IMID responded (p < 0.001). IMID patients had a significantly different level of IgG than HCW at both T1 (p = 0.031), T2 (p < 0.001), while there was no significant difference at T3. There were no statistically significant differences according to the IMID type or to ongoing treatment with immunosuppressants, corticosteroids or biological drugs other than anti-CD20. The proportion and magnitude of response was significantly lower in IMID treated with anti-CD20 drugs. There was a correlation with age at T1 and at T2 but not at T3, stronger in patients than in HCW. Immune response close after BNT162b2 vaccination is reduced in patients with IMID, but there is no significant difference at 5 months. The measured reduction is related to age and the disease itself rather than treatments, with the exception of anti-CD20 drugs.

Evaluation of Antibody Response to Heterologous Prime-Boost Vaccination with ChAdOx1 nCoV-19 and BNT162b2: An Observational Study.

In several countries, thrombotic events after vaccination with ChAdOx1 nCoV-19 have led to heterologous messenger RNA (mRNA) boosting. We tested the antibody response to SARS-CoV-2 spike protein four weeks after heterologous priming with the ChAdOx1 (ChAd) vector vaccine followed by boosting with BNT162b2(ChAd/BNT), comparing data of homologous regimen (BNT/BNT, ChAd/ChAd) subjects positive for SARS-CoV-2 after the first dose of BNT162b2 (BNT1dose/CoV2) and convalescent COVID-19. METHODS: healthy subjects naïve for SARS-CoV-2 infection were assessed for serum IgG anti-S-RBD response 21 days after priming (T1), 4 (TFULL) and 15 (T15W) weeks after booster dose. RESULTS: The median IgG anti-S-RBD levels at TFULL of Chad/BNT group were significantly higher than the BNT/BNT group and ChAd/ChAd. Those of BNT/BNT group were significantly higher than ChAd/ChAd. IgG anti-S-RBD of BNT1dose/CoV2 group were similar to BNT/BNT, ChAd/BNT and ChAd/Chad group. The levels among COVID-19 convalescents were significantly lower than ChAd/BNT, BNT/BNT, ChAd/Chad and BNT1dose/CoV2. The proportion of subjects reaching an anti-S-RBD titer >75 AU/mL, correlated with high neutralizing titer, was 94% in ChAd/BNT and BNT/BNT, 60% in BNT1dose/CoV2, 25% in ChAd/ChAd and 4.2% in convalescents. At T15W the titer of ChAd/BNT was still significantly higher than other vaccine schedules, while the anti-S-RBD decline was reduced for ChAd/ChAd and similar for other combinations. CONCLUSION: Our data highlight the magnitude of IgG anti-S-RBD response in ChAd/BNT dosing, supporting the current national guidelines for heterologous boosting.

Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection.

BACKGROUND: The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study's focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. METHODS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. RESULTS: Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1-2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3-0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3-0.7), PM = 0.0005, PMC = 0.005]. CONCLUSIONS: The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.

The COVID-19 incidence in Italian regions correlates with low temperature, mobility and PM10 pollution but lethality only with low temperature.

BACKGROUND: The aim was to verify whether the density of particulate matter (PM10), the climate, and the mobility of people can influence the pandemic in the 19 regions and in the two autonomous Italian provinces as incidence rate and lethality. DESIGN AND METHODS: The incidence rates per 100,000 inhabitants and the case fatality ratio (CFR) (dependent variables) in all Italian regions were calculated in January 2021 at John Hopkins University Coronavirus Center. The independent variables were: Minimum average temperatures in the same month (January) of 2020; average pollution of PM10 in the air in each region in the last year available reported on a 0-10 scale to 0 = total absence of PM10 to 10 maximum pollutions; number of places in hotels occupied per inhabitants in 2020. Linear regression and Multiple Regression Analysis were carried out. RESULTS: The spread of the COVID-19 in the Italian regions seems to be related to pollution of PM10, the number of beds occupied in hotels (as an index of mobility and temperature (indirect correlation). On the contrary, the CFR correlates inversely with temperature but not with pollution. Measuring the concomitant effect of two independent variables by means of Multiple Regression Analysis, temperature and pollution show a synergistic effect on COVID-19 incidence. CONCLUSIONS: The study seems to confirm the literature on the influence of temperature on the lethality of COVID-19 but adds the new results of an inverse relationship between the spread of the virus and low temperature in regions between the Mediterranean area (which includes southern Italy and Sicily and Sardinia islands) and the cold European temperate zone which includes the northern regions under the Alps. A new date also concerns the summation effect of the risk between cold weather and PM10 air pollution was found. Due to several methodic weaknesses, the study has an exploratory than conclusive relevance.

Delta-globin gene expression improves sickle cell disease in a humanised mouse model.

Sickle cell disease (SCD) is a widespread genetic disease associated with severe disability and multi-organ damage, resulting in a reduced life expectancy. None of the existing clinical treatments provide a solution for all patients. Gene therapy and fetal haemoglobin (HbF) reactivation through genetic approaches have obtained promising, but early, results in patients. Furthermore, the search for active molecules to increase HbF is still ongoing. The delta-globin gene produces the delta-globin of haemoglobin A2 (HbA2). Although expressed at a low level, HbA2 is fully functional and could be a valid anti-sickling agent in SCD. To evaluate the therapeutic potential of a strategy aimed to over-express the delta-globin gene in vivo, we crossed transgenic mice carrying a single copy of the delta-globin gene, genetically modified to be expressed at a higher level (activated), with a humanised mouse model of SCD. The activated delta-globin gene gives rise to a consistent production of HbA2, effectively improving the SCD phenotype. For the first time in vivo, these results demonstrate the therapeutic potential of delta-globin, which could lead to novel approaches to the cure of SCD.

Undetected infectives in the Covid-19 pandemic.

OBJECTIVES: Epidemiological investigations and mathematical models have revealed that the rapid diffusion of Covid-19 can mostly be attributed to undetected infective individuals who continue to circulate and spread the disease: finding their number would be of great importance in the control of the epidemic. METHODS: The dynamics of an infection can be described by the SIR model, which divides the population into susceptible (S), infective I, and removed R subjects. In particular, we exploited the Kermack-McKendrick epidemic model, which can be applied when the population is much larger than the fraction of infected subjects. RESULTS: We proved that the fraction of undetected infectives, compared to the total number of infected subjects, is given by 1-1R0, where R0 is the basic reproduction number. The mean value R0=2.102.09-2.11 for the Covid-19 epidemic in three Italian regions yielded a percentage of undetected infectives of 52.4% (52.2%-52.6%) compared to the total number of infectives. CONCLUSIONS: Our results, straightforwardly obtained from the SIR model, highlight the role of undetected carriers in the transmission and spread of the SARS-CoV-2 infection. Such evidence strongly recommends careful monitoring of the infective population and ongoing adjustment of preventive measures for disease control until a vaccine becomes available for most of the population.

Gastrointestinal coronavirus disease 2019: epidemiology, clinical features, pathogenesis, prevention, and management.

INTRODUCTION: The new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019. Some authors reported pieces of evidence that patients with SARS-CoV-2 infection could have direct involvement of the gastrointestinal tract, and in symptomatic cases, gastrointestinal symptoms (diarrhea, nausea/vomiting, abdominal pain) could be very common. AREA COVERED: In this article, we reviewed current-published data of the gastrointestinal aspects involved in SARS-CoV-2 infection, including prevalence and incidence of specific symptoms, the presumptive biological mechanism of GI infection, prognosis, clinical management, and public health-related concerns on the possible risk of oral-fecal transmission. EXPERT OPINION: Different clues point to direct virus infection and replication in mucosal cells of the gastrointestinal tract. In vitro studies showed that SARS-CoV-2 could enter into the gastrointestinal epithelial cells by the Angiotensin-Converting enzyme two membrane receptor. These findings, coupled with the identification of viral RNA found in stools of patients, clearly suggest that direct involvement of the gastrointestinal tract is very likely. This can justify most of the gastrointestinal symptoms but also suggest a risk for an oral-fecal route for transmission, additionally or alternatively to the main respiratory route.