Danon disease in a Sardinian family: different aspects of the same mutation-a case report

Background Danon disease (DD) is a rare X-linked disorder due to mutations in the lysosome-associated membrane protein 2 gene. It is characterized by a clinical triad of hypertrophic cardiomyopathy, skeletal myopathy, and a variable degree of intellectual disability. Case summary In this case series, we describe a mother and her son affected by DD, highlighting consistent clinical severity despite the expected variability related to gender. The mother (Case 1) presented isolated cardiac involvement, with an arrhythmogenic phenotype that evolved into severe heart failure requiring heart transplantation (HT). Danon disease was diagnosed 1 year after this event. Her son (Case 2) showed an earlier age onset of symptoms with complete atrioventricular block and fast progression of cardiac disease. Diagnosis was established 2 years after clinical presentation. He is currently listed for HT. Discussion In both of our patients, diagnostic delay was extremely long and could have been avoided by emphasizing the relevant clinical red flags. Patients affected by DD may present clinical heterogeneity in terms of natural history, age of onset, and cardiac and extracardiac involvement, even in the same family. Early diagnosis that phenotypic sex differences may impact is a crucial factor in managing patients with DD. Considering the rapid progression of cardiac disease and the poor prognosis, early diagnosis is important and close surveillance should be mandatory during follow-up

Does Patient Compliance Influence Wearable Cardioverter Defibrillator Effectiveness? A Single-Center Experience

The study was designed to assess patient adherence to wearable cardioverter defibrillator as an indicator of device effectiveness. The patient training is not widely properly standardized. We enrolled 25 patients with a wearable cardioverter defibrillator to prevent sudden cardiac death between June 2020 and August 2022. Among them, 84% were male with a median age of 63.6 years. The indication was an ischemic (44%) and a non-ischemic (56%) disease. The patients were followed-up until the decision to upgrade to an implantable device was taken. We trained the patients according to our suggested protocol. The median wear time was 90 days, and the median daily wear time was 23.5 h, similar throughout sex, age, and indication groups. In total, 24% of the participants underwent cardioverter defibrillator implantation. Between the device-implanted and non-implanted groups, left ventricular ejection fraction and left ventricular indexed end-diastolic volume were significantly different (EF 35.8 & PLUSMN; 12 vs. 46.4 & PLUSMN; 8.5%, p = 0.028, iEDV 108 & PLUSMN; 52 vs. 70.7 & PLUSMN; 21.1 mL/m(2), p = 0.024). We did not find any differences in cardiac magnetic resonance data, even though all patients who underwent device implantation had late gadolinium enhancement spots. Our results support standardized patient training to obtain great patient adherence to the instructions to the wearable device and therefore its effectiveness

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

Is the Inversion in the Trend of the Lethality of the COVID-19 in the Two Hemispheres due to the Difference in Seasons and Weather?

The climate has an influence on the COVID-19 virus lethality. The aim of this study is to verify if the summer weather coincided with the decrease of the Case Fatality Ratio (CFR) in Europe and if, on the contrary, an inverse trend was observed in Australia and New Zealand. To verify our hypothesis, we considered the largest European countries (Germany, UK, France, Italy, and Spain), plus Belgium and the Netherlands. Furthermore, we compared these countries with Australia and New Zealand. For each country considered, we have calculated the CFR from the beginning of the pandemic to May 6th and from May 6th to September 21st (late summer in Europe, late winter in the southern hemisphere). The CFRs were calculated from the John Hopkins University database. According to the results, in all European countries, a progressive decrease in CFR is observed. A diametrically opposite result is found in Australia where, on the contrary, the CFR is much higher at the end of September (at the end of winter) than on May 6th (mid-autumn), and the risk of dying if we count the infection is higher in September. In New Zealand, there are no statistically significant differences between the two surveys. The present study was based on public access macro data

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

The Effect of Exposure to SARS-CoV-2 Vaccination and Infection on Humoral and Cellular Immunity in a Cohort of Patients with Immune-Mediated Diseases: A Pilot Study

Immunization against COVID-19 is needed in patients with immune-mediated inflammatory diseases (IMIDs). However, data on long-term immunity kinetics remain scarce. This study aimed to compare the humoral and cellular response to COVID-19 in patients with immune-mediated inflammatory diseases (IMIDs) compared to healthy controls. We compared the humoral and cellular response to SARS-Cov-2 elicited by vaccination and/or infection in a prospective cohort of 20 IMID patients compared with a group of 21 healthcare workers (HCWs). We assessed immunity before and after the third and fourth dose of BNT162b2 or after COVID-19 infection using quantitative IgG anti-SARS-CoV-2 Spike antibody (anti-S-IgG), neutralization assay, and specific interferon-gamma (IFN-g) release assay (IGRA). The responses were compared with those of healthy controls. The two groups were similar in age and total exposure, becoming infected for the first time, mainly after the third dose. Neutralizing antibodies and IGRA were negative in 9.5% of IMID patients but not in any HCWs. No significant difference was found between neutralization titers to BA.1 in the IMID and the HCW groups. The study highlights the SARS-CoV-2 immunological responses in healthy controls and IMID patients, suggesting that the combined stimuli of vaccination and infection in IMID patients could promote a more profound immunological response

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

The Impact of the COVID-19 Pandemic on the Mental Health of Healthcare Workers in Italy: Analyzing the Role of Individual and Workplace-Level Factors in the Reopening Phase After Lockdown

IntroductionItaly is one of the high-income countries hit hardest by Covid-19. During the first months of the pandemic, Italian healthcare workers were praised by media and the public for their efforts to face the emergency, although with limited knowledge and resources. However, healthcare workers soon had to face new challenges at a time when the national health system was working hard to recover. This study focuses on this difficult period to assess the impact of the COVID-19 pandemic on the mental health of Italian healthcare workers. Materials and MethodsHealthcare workers from all Italian regions [n = 5,502] completed an online questionnaire during the reopening phase after the first wave lockdown. We assessed a set of individual-level factors (e.g., stigma and violence against HCWs) and a set of workplace-level factors (e.g., trust in the workplace capacity to handle COVID-19) that were especially relevant in this context. The primary outcomes assessed were score >= 15 on the Patient Health Questionnaire-9 and score >= 4 on the General Health Questionnaire-12, indicators of clinically significant depressive symptoms and psychological distress, respectively. Logistic regression analyses were performed on depressive symptoms and psychological distress for each individual- and workplace-level factor adjusting for gender, age, and profession. ResultsClinically significant depressive symptoms were observed in 7.5% and psychological distress in 37.9% of HCWs. 30.5% of healthcare workers reported having felt stigmatized or discriminated, while 5.7% reported having experienced violence. Feeling stigmatized or discriminated and experiencing violence due to being a healthcare worker were strongly associated with clinically significant depressive symptoms [OR 2.98, 95%CI 2.36-3.77 and OR 4.72 95%CI 3.41-6.54] and psychological distress [OR 2.30, 95%CI 2.01-2.64 and OR 2.85 95%CI 2.16-3.75]. Numerous workplace-level factors, e.g., trust in the workplace capacity to handle COVID-19 [OR 2.43, 95%CI 1.92-3.07] and close contact with a co-worker who died of COVID-19 [OR 2.05, 95%CI 1.56-2.70] were also associated with clinically significant depressive symptoms. Similar results were found for psychological distress. ConclusionsOur study emphasizes the need to address discrimination and violence against healthcare professionals and improve healthcare work environments to strengthen the national health system's capacity to manage future emergencies

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