Changes in blood serum parameters in farmed rainbow trout (Oncorhynchus mykiss) during a piscine lactococcosis outbreak.

The aquaculture sector plays a vital role in global food security, yet it grapples with significant challenges posed by infectious diseases. Piscine lactococcosis is one of the significant threats in rainbow trout aquaculture due to its potential to cause severe economic losses through mortalities, reduced growth rates, and increased susceptibility to other pathogens. It poses challenges in disease management strategies, impacting the sustainability and profitability of rainbow trout farming. The current study focuses on the variations in serum blood parameters of farmed rainbow trout Oncorhynchus mykiss during a lactococcosis outbreak caused by Lactococcus garvieae. Blood samples were collected for biochemical analysis, fish were examined for parasites and bacteria, and DNA from bacterial colonies was PCR-amplified and sequenced for identification. Overall, 13 biochemical parameters, including proteins, enzymes, lipids, chemicals, and minerals, were measured in serum blood samples from both diseased and healthy fish. The results indicate significant alterations in the levels of these parameters during the outbreak, highlighting the impact of infections on the blood profile of farmed rainbow trout. Urea levels were significantly higher in diseased fish compared to controls, and creatinine, phosphorus, and magnesium also showed similar trends. Alanine aminotransferase and total protein levels were higher in control fish. Chloride levels differed significantly between groups. Iron levels were higher in controls and lower in diseased fish. No significant differences were found in other parameters. This study reveals significant changes in serum blood parameters of rainbow trout during a lactococcosis outbreak caused by L. garvieae. These changes highlight the potential of these parameters as tools for monitoring health status, stress, and aquaculture management. Continuous monitoring can provide valuable insights into disease severity and overall fish health, aiding in the development of improved management practices. The presented data contribute to understanding the pathophysiology of piscine lactococcosis and developing effective mitigation strategies for farmed rainbow trout.

Effects of Biodanza® SRT on Motor, Cognitive, and Behavioral Symptoms in Patients with Parkinson's Disease: A Randomized Controlled Study.

Rolando Toro's Biodanza (SRT) is a therapeutic strategy that uses movement, music, and emotions to induce integrative living experiences. The present study aims to explore the efficacy of a three-month SRT intervention on motor, cognitive, and behavioral symptoms in patients with Parkinson's disease (PD). This study employed a randomized between-group design. Twenty-eight non-demented PD patients were enrolled in this study. Out of these, fourteen patients were assigned to the active treatment group using the Biodanza SRT system and fourteen to the untreated control group. The study group attended 2 h SRT classes once a week, completing twelve lessons in twelve weeks. All patients underwent: (i) a neurological examination to measure the severity of motor symptoms, balance, mobility, and risk of falls, and (ii) a neuropsychological battery to assess cognitive status, apathy, depressive symptomatology, and perceived quality of life (QoL), at study entry (T0) and at twelve weeks (T1, end of dance training). At T1, we observed a significant improvement in motor (i.e., severity of motor symptoms and balance) and cognitive parameters (i.e., working memory and delayed verbal memory) in all treated patients compared with the controls. Furthermore, a significant improvement in the social support dimension was found in all treated patients compared to the controls. A trend toward increased apathy was found in untreated patients at T1. The three-month Biodanza intervention significantly ameliorated the motor parameters of PD patients, with a parallel improvement in cognitive and QoL status. Hence, Biodanza intervention can, in the short term, represent a useful personalized medical intervention for the management of Parkinson's disease.

Perceptions and Expectations of Youth Regarding the Respect for Their Rights in the Hospital.

Information obtained from children themselves regarding the characteristics of the ideal hospital that ensure well-being during a hospital stay is scarce. Here, we report the opinions, perceptions, and expectations of 700 children and adolescents about their experiences, assessed through a mixed-method research approach with age-appropriate questionnaires, three open-ended questions, and an analysis of optional pictorial and textual narratives. Most children indicated that, while they acknowledged the expertise of hospital staff, they also noted several shortcomings, e.g., insufficiently understandable medical information as well as emotional and cognitive support. The continuity of schooling and the right to suffer as little as possible were also critical issues. Adolescents valued in particular the quality of care and services provided, the hospital's adherence to equality and non-discrimination rights, and protection systems but negatively perceived several aspects related to play and participation. Significant differences in the co-occurrences of the most frequently used text terms with the keywords "hospital" and "child/adolescent" between age groups highlight variations in the way patients perceive and articulate their experiences within the hospital setting depending on the cognitive processes linked to age. In drawings, prevailing attention was placed on the physical context of the hospital room, with figures expressing mostly negative emotions. Specifically, in this regard, the main emotion in children was sadness, and, in adolescents, it was fear. Overall, these insights are pivotal in the context of our research objectives as they shed light on the nuanced preferences, needs, and perspectives of children and adolescents during their hospital stays. Recognizing the identified shortcomings, we propose recommendations emphasizing the improvement of medical communication clarity, enhancement of emotional and cognitive support, and the improvement of programs to avoid instructional gaps during hospital stays. Addressing these specific needs is critical for a more comprehensive approach to pediatric healthcare provision.

Development of collagenous scaffolds for wound healing: characterization and in vivo analysis.

The development of wound dressings from biomaterials has been the subject of research due to their unique structural and functional characteristics. Proteins from animal origin, such as collagen and chitosan, act as promising materials for applications in injuries and chronic wounds, functioning as a repairing agent. This study aims to evaluate in vitro effects of scaffolds with different formulations containing bioactive compounds such as collagen, chitosan, N-acetylcysteine (NAC) and ε-poly-lysine (ε-PL). We manufactured a scaffold made of a collagen hydrogel bioconjugated with chitosan by crosslinking and addition of NAC and ε-PL. Cell viability was verified by resazurin and live/dead assays and the ultrastructure of biomaterials was evaluated by SEM. Antimicrobial sensitivity was assessed by antibiogram. The healing potential of the biomaterial was evaluated in vivo, in a model of healing of excisional wounds in mice. On the 7th day after the injury, the wounds and surrounding skin were processed for evaluation of biochemical and histological parameters associated with the inflammatory process. The results showed great cell viability and increase in porosity after crosslinking while antimicrobial action was observed in scaffolds containing NAC and ε-PL. Chitosan scaffolds bioconjugated with NAC/ε-PL showed improvement in tissue healing, with reduced lesion size and reduced inflammation. It is concluded that scaffolds crosslinked with chitosan-NAC-ε-PL have the desirable characteristics for tissue repair at low cost and could be considered promising biomaterials in the practice of regenerative medicine.

Older Age, a High Titre of Neutralising Antibodies and Therapy with Conventional DMARDs Are Associated with Protection from Breakthrough Infection in Rheumatoid Arthritis Patients after the Booster Dose of Anti-SARS-CoV-2 Vaccine.

Objectives: We aimed to analyse the incidence and severity of breakthrough infections (BIs) in rheumatoid arthritis (RA) patients after a COronaVIrus Disease 2019 (COVID-19) vaccination booster dose. Methods: We enrolled 194 RA patients and 1002 healthcare workers (HCWs) as controls. Clinical, lifestyle and demographic factors were collected at the time of the third dose, and immunogenicity analyses were carried out in a subgroup of patients at 4-6 weeks after the third dose. Results: BIs were experienced by 42% patients (82/194) with a median time since the last vaccination of 176 days. Older age (>50 years; aHR 0.38, 95% CI: 0.20-0.74), receiving conventional synthetic disease modifying antirheumatic drugs (csDMARDs) (aHR 0.52, 95%CI: 0.30-0.90) and having a titre of neutralising antibodies >20 (aHR 0.36, 95% CI: 0.12-1.07) were identified as protective factors. Conversely, anti-IL6R treatment and anti-CD20 therapy increased BI probability. BIs were mostly pauci-symptomatic, but the hospitalisation incidence was significantly higher than in HCWs (8.5% vs. 0.19%); the main risk factor was anti-CD20 therapy. Conclusions: Being older than 50 years and receiving csDMARDs were shown to be protective factors for BI, whereas anti-IL6R or anti-CD20 therapy increased the risk. Higher neutralising antibody titres were associated with a lower probability of BI. If confirmed in a larger population, the identification of a protective cut-off would allow a personalised risk-benefit therapeutic management of RA patients.

The Third Dose of BNT162b2 COVID-19 Vaccine Does Not "Boost" Disease Flares and Adverse Events in Patients with Rheumatoid Arthritis.

Data on the risk of adverse events (AEs) and disease flares in autoimmune rheumatic diseases (ARDs) after the third dose of COVID-19 vaccine are scarce. The aim of this multicenter, prospective study is to analyze the clinical and immunological safety of BNT162b2 vaccine in a cohort of rheumatoid arthritis (RA) patients followed-up from the first vaccine cycle to the third dose. The vaccine showed an overall good safety profile with no patient reporting serious AEs, and a low percentage of total AEs at both doses (40/78 (51.3%) and 13/47 (27.7%) patients after the second and third dose, respectively (p < 0.002). Flares were observed in 10.3% of patients after the end of the vaccination cycle and 12.8% after the third dose. Being vaccinated for influenza was inversely associated with the onset of AEs after the second dose, at both univariable (p = 0.013) and multivariable analysis (p = 0.027). This result could allow identification of a predictive factor of vaccine tolerance, if confirmed in larger patient populations. A higher disease activity at baseline was not associated with a higher incidence of AEs or disease flares. Effectiveness was excellent after the second dose, with only 1/78 (1.3%) mild breakthrough infection (BI) and worsened after the third dose, with 9/47 (19.2%) BI (p < 0.002), as a probable expression of the higher capacity of the Omicron variants to escape vaccine recognition.

Antiplatelet Strategies for Older Patients with Acute Coronary Syndromes: Finding Directions in a Low-Evidence Field.

Patients ≥ 75 years of age account for about one third of hospitalizations for acute coronary syndromes (ACS). Since the latest European Society of Cardiology guidelines recommend that older ACS patients use the same diagnostic and interventional strategies used by the younger ones, most elderly patients are currently treated invasively. Therefore, an appropriate dual antiplatelet therapy (DAPT) is indicated as part of the secondary prevention strategy to be implemented in such patients. The choice of the composition and duration of DAPT should be tailored on an individual basis, after careful assessment of the thrombotic and bleeding risk of each patient. Advanced age is a main risk factor for bleeding. Recent data show that in patients of high bleeding risk short DAPT (1 to 3 months) is associated with decreased bleeding complications and similar thrombotic events, as compared to standard 12-month DAPT. Clopidogrel seems the preferable P2Y12 inhibitor, due to a better safety profile than ticagrelor. When the bleeding risk is associated with a high thrombotic risk (a circumstance present in about two thirds of older ACS patients) it is important to tailor the treatment by taking into account the fact that the thrombotic risk is high during the first months after the index event and then wanes gradually over time, whereas the bleeding risk remains constant. Under these circumstances, a de-escalation strategy seems reasonable, starting with DAPT that includes aspirin and low-dose prasugrel (a more potent and reliable P2Y12 inhibitor than clopidogrel) then switching after 2-3 months to DAPT with aspirin and clopidogrel for up to 12 months.

"Without social there is no health": Social work perspectives in multidisciplinary healthcare.

The pandemic has not just affected the health sphere: strong social effects of the emergency have added to the health risk, stressing on social relations and the deterioration of people's living conditions, and making those who are already fragile more fragile. Notwithstanding, during the emergency following the COVID-19 pandemic the attention was focused, indeed understandably, on the health aspects, widening the already existing misalignment between the health interventions and the social ones. Emergency oriented efforts and resources more toward a clinical care approach (cure) than toward support for the social and the inclusion aspects (care). Reflecting on the specific area of health care that interacts with social care (and vice versa), shows how the medicalization in managing the emergency have undermined or, at least, weakened the global approach to the person and to vulnerability profiles that should inspire the socio-healthcare integration. The aim of this review is describing the relationship between the health and social systems and the effects of the COVID-19 pandemic on it: a review of studies on the role played by social work in the health sector before and during COVID-19 pandemic emergency shows how much potential there is still to be developed for social work in the health sector that acts together with the personal health services; a care that looks at the person within his or her relationships, community resources and environmental aspects requires an investment toward integration between hospital care, social services and local communities.

Booster dose of SARS-CoV-2 messenger RNA vaccines strengthens the specific immune response of patients with rheumatoid arthritis: A prospective multicenter longitudinal study.

OBJECTIVES: To characterize the kinetics of humoral and T-cell responses in rheumatoid arthritis (RA)-patients followed up to 4-6 weeks (T3) after the SARS-CoV-2 vaccine booster dose. METHODS: Health care workers (HCWs, n = 38) and patients with RA (n = 52) completing the messenger RNA vaccination schedule were enrolled at T3. In each cohort, 25 subjects were sampled after 5 weeks (T1) and 6 months (T2) from the first vaccine dose. The humoral response was assessed by measuring anti-receptor-binding domain (RBD) and neutralizing antibodies, the T-cell response by interferon-γ-release assay (IGRA), T cell cytokine production, and B cell phenotype at T3 by flow cytometry. RESULTS: Patients with RA showed a significant reduction of antibody titers from T1 to T2 and a significant increase at T3. T-cell response by IGRA persisted over time in patients with RA, whereas it increased in HCWs. Most patients with RA scored positive for anti-RBD, neutralizing antibody and T-cell responses, although the magnitude was lower than HCWs. The spike-specific-cytokine response was mainly clusters of differentiation (CD)4+ T cells restricted in both cohorts and significantly lower with reduced interleukin-2 response and CD4-antigen-responding naïve T cells in patients with RA. Unswitched memory B cells were reduced in patients with RA compared with HCWs independently of vaccination. CONCLUSION: COVID-19 vaccine booster strengthens the humoral immunity in patients with RA even with a reduced cytokine response.

Iatrogenic atrial septal defects after transseptal puncture for percutaneous left atrial appendage occlusion and their hemodynamic effects.

Background: Percutaneous left atrial appendage occlusion (LAAO) requires puncture of the interatrial septum. The immediate hemodynamic effects of iatrogenic atrial septal defects (iASD) after LAAO have not been examined so far. We aimed at evaluating these effects through invasive measurements of pressure and oxygen saturation. Moreover, we assessed the incidence of persistent iASD at three months. METHODS: Forty-eight patients scheduled for percutaneous LAAO were prospectively included in the study. Pressure and oxygen saturation were measured (1) in the right atrium (RA) before transseptal puncture, (2) in the left atrium (LA) through the transseptal sheath after transseptal puncture, (3) in the LA after removal of introducer sheath, and (4) in the RA after removal of introducer sheath. Transesophageal echocardiography was performed at three months to detect iASD. RESULTS: Pressure in the RA increased significantly after removing the introducer sheath (P = 0.034), whereas no difference was found in oxygen saturation in the RA (P = 0.623). Pressure measurement in the LA showed no significant difference after removing the introducer sheath (P = 0.718). Oxygen saturation in the LA also showed no significant difference (P = 0.129). Follow-up transesophageal echocardiogram at 3 months revealed a persistent iASD in 4 patients (8.5 %). CONCLUSIONS: Our study suggests that iASD after percutaneous LAAO does not result in significant shunts directly after the procedure, although a significant increase of mean right atrial pressure can be observed. Persistent iASDs after percutaneous LAAO seem to be relatively rare at three months.

Percutaneous left atrial appendage occlusion in a frail, high-risk, octogenarian patient population, after having undergone transcatheter aortic valve implantation.

BACKGROUND: Percutaneous left atrial appendage occlusion (LAAO) represents an alternative stroke prevention method in patients with atrial fibrillation and an increased bleeding risk, chronic kidney disease or contraindications to oral anticoagulants. Aim of our study was to evaluate the feasibility and safety of percutaneous LAAO in high-risk, frail patients having undergone transcatheter aortic valve implantation (TAVI). METHODS: Thirty-one patients having undergone TAVI and scheduled for LAAO were prospectively included in our study. RESULTS: Implantation was successful in 29 of 31 cases (93.5%).There were no patients that developed a major acute cardiovascular event, stroke, or device dislocation/embolization. There was a single case of major bleeding (3.2%) and 3 cases of acute kidney injury (9.7%). At 3 months, no patients experienced a stroke, one patient had a device-related thrombus (3.4%), one patient showed a significant peri-device leak, and one patient had a persistent iatrogenic atrial septal defect. CONCLUSIONS: Our study shows that percutaneous LAAO may represent a feasible alternative strategy for stroke prevention, that can be safely performed in high-risk, multimorbid patients with high bleeding risk or contraindications to oral anticoagulation.

Kinetics of the B- and T-Cell Immune Responses After 6 Months From SARS-CoV-2 mRNA Vaccination in Patients With Rheumatoid Arthritis.

Objective: To assess the kinetics of the humoral and cell-mediated responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in rheumatoid arthritis (RA) patients treated with different immunosuppressive therapies. Methods: Following vaccine completed schedule, health care workers (HCWs, n = 49) and RA patients (n = 35) were enrolled at 5 weeks (T1) and 6 months (T6) after the first dose of BNT162b2-mRNA vaccination. Serological response was assessed by quantifying anti-receptor-binding domain (RBD)-specific immunoglobulin G (IgG) and SARS-CoV-2 neutralizing antibodies, while cell-mediated response was assessed by a whole-blood test quantifying the interferon (IFN)-γ response to spike peptides. B-cell phenotype and IFN-γ-specific T-cell responses were evaluated by flow cytometry. Results: After 6 months, anti-RBD antibodies were still detectable in 91.4% of RA patients, although we observed a significant reduction of the titer in patients under Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)-Ig [median: 16.4 binding antibody units (BAU)/ml, interquartile range (IQR): 11.3-44.3, p < 0.0001] or tumor necrosis factor (TNF)-α inhibitors (median: 26.5 BAU/ml, IQR: 14.9-108.8, p = 0.0034) compared to controls (median: 152.7 BAU/ml, IQR: 89.3-260.3). All peripheral memory B-cell (MBC) subpopulations, in particular, the switched IgG+ MBCs (CD19+CD27+IgD-IgM-IgG+), were significantly reduced in RA subjects under CTLA-4-Ig compared to those in HCWs (p = 0.0012). In RA patients, a significantly reduced anti-RBD IgG titer was observed at T6 vs. T1, mainly in those treated with CTLA-4-Ig (p = 0.002), interleukin (IL)-6 inhibitors (p = 0.015), and disease-modifying antirheumatic drugs (DMARDs) ± corticosteroids (CCSs) (p = 0.015). In contrast, a weak nonsignificant reduction of the T-cell response was reported at T6 vs. T1. T-cell response was found in 65.7% of the RA patients at T6, with lower significant magnitude in patients under CTLA-4-Ig compared to HCWs (p < 0.0001). The SARS-CoV-2 IFN-γ-S-specific T-cell response was mainly detected in the CD4+ T-cell compartment. Conclusions: In this study, in RA patients after 6 months from COVID-19 vaccination, we show the kinetics, waning, and impairment of the humoral and, to a less extent, of the T-cell response. Similarly, a reduction of the specific response was also observed in the controls. Therefore, based on these results, a booster dose of the vaccine is crucial to increase the specific immune response regardless of the immunosuppressive therapy.

Pregnenolone-methyl-ether enhances CLIP170 and microtubule functions improving spine maturation and hippocampal deficits related to CDKL5 deficiency.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a neurodevelopmental disease characterized by severe infantile seizures and intellectual disability. The absence of CDKL5 in mice causes defective spine maturation that can at least partially explain the cognitive impairment in CDKL5 patients and CDD mouse models. The molecular basis for such defect may depend on the capacity of CDKL5 to regulate microtubule (MT) dynamics through its association with the MT-plus end tracking protein CLIP170 (cytoplasmic linker protein 170). Indeed, we here demonstrate that the absence of CDKL5 causes CLIP170 to be mainly in a closed inactive conformation that impedes its binding to MTs. Previously, the synthetic pregnenolone analogue, pregnenolone-methyl-ether (PME), was found to have a positive effect on CDKL5-related cellular and neuronal defects in vitro. Here, we show that PME induces the open active conformation of CLIP170 and promotes the entry of MTs into dendritic spines in vitro. Furthermore, the administration of PME to symptomatic Cdkl5-knock-out mice improved hippocampal-dependent behavior and restored spine maturation and the localization of MT-related proteins in the synaptic compartment. The positive effect on cognitive deficits persisted for 1 week after treatment withdrawal. Altogether, our results suggest that CDKL5 regulates spine maturation and cognitive processes through its control of CLIP170 and MT dynamics, which may represent a novel target for the development of disease-modifying therapies.

Early hemodynamic changes after transcatheter aortic valve implantation in patients with severe aortic stenosis measured by invasive pressure volume loop analysis.

Replacement of a stenotic aortic valve reduces immediately the ventricular to aortic gradient and is expected to improve diastolic and systolic left ventricular function over the long term. However, the hemodynamic changes immediately after valve implantation are so far poorly understood. Within this pilot study, we performed an invasive pressure volume loop analysis to describe the early hemodynamic changes after transcatheter aortic valve implantation (TAVI) with self-expandable prostheses. Invasive left ventricular pressure volume loop analysis was performed in 8 patients with aortic stenosis (mean 81.3 years) prior and immediately after transfemoral TAVI with a self-expandable valve system (St. Jude Medical Portico Valve). Parameters for global hemodynamics, afterload, contractility and the interaction of the cardiovascular system were analyzed. Left ventricular ejection fraction, (53.9% vs. 44.8%, p = 0.018), preload recruitable stroke work (68.5 vs. 44.8 mmHg, p = 0.012) and end-systolic elastance (3.55 vs. 2.17, p = 0.036) both marker for myocardial contractility declined significantly compared to baseline. As sign of impaired diastolic function, TAU, a preload-independent measure of isovolumic relaxation (37.3 vs. 41.8 ms, p = 0.018) and end-diastolic pressure (13.1 vs. 16.4 mmHg, p = 0.015) raised after valve implantation. Contrarily, a smaller ratio of end-systolic to arterial elastance (ventricular-arterial coupling) indicates an improvement of global cardiovascular energy efficiency (1.40 vs. 0.97 p = 0.036). Arterial elastance had a strong correlation with the number of conducted rapid ventricular pacings (Pearson correlation coefficient, r = 0.772, p = 0.025). Invasive left ventricular pressure volume loop analysis revealed impaired systolic and diastolic function in the early phase after TAVI with self-expandable valve for the treatment of severe aortic stenosis. Contrarily, we found indications for early improvement of global cardiovascular energy efficiency.

Management of acute coronary syndromes in older adults.

Older patients are underrepresented in prospective studies and randomized clinical trials of acute coronary syndromes (ACS). Over the last decade, a few specific trials have been conducted in this population, allowing more evidence-based management. Older adults are a heterogeneous, complex, and high-risk group whose management requires a multidimensional clinical approach beyond coronary anatomic variables. This review focuses on available data informing evidence-based interventional and pharmacological approaches for older adults with ACS, including guideline-directed management. Overall, an invasive approach appears to demonstrate a better benefit-risk ratio compared to a conservative one across the ACS spectrum, even considering patients' clinical complexity and multiple comorbidities. Conversely, more powerful strategies of antithrombotic therapy for secondary prevention have been associated with increased bleeding events and no benefit in terms of mortality reduction. An interdisciplinary evaluation with geriatric assessment should always be considered to achieve a holistic approach and optimize any treatment on the basis of the underlying biological vulnerability.

Loss of CDKL5 Causes Synaptic GABAergic Defects That Can Be Restored with the Neuroactive Steroid Pregnenolone-Methyl-Ether.

CDKL5 deficiency disorder (CDD) is an X-linked neurodevelopmental disorder characterised by early-onset drug-resistant epilepsy and impaired cognitive and motor skills. CDD is caused by mutations in cyclin-dependent kinase-like 5 (CDKL5), which plays a well-known role in regulating excitatory neurotransmission, while its effect on neuronal inhibition has been poorly investigated. We explored the potential role of CDKL5 in the inhibitory compartment in Cdkl5-KO male mice and primary hippocampal neurons and found that CDKL5 interacts with gephyrin and collybistin, two crucial organisers of the inhibitory postsynaptic sites. Through molecular and electrophysiological approaches, we demonstrated that CDKL5 loss causes a reduced number of gephyrin puncta and surface exposed γ2 subunit-containing GABAA receptors, impacting the frequency of miniature inhibitory postsynaptic currents, which we ascribe to a postsynaptic function of CDKL5. In line with previous data showing that CDKL5 loss impacts microtubule (MT) dynamics, we showed that treatment with pregnenolone-methyl-ether (PME), which promotes MT dynamics, rescues the above defects. The impact of CDKL5 deficiency on inhibitory neurotransmission might explain the presence of drug-resistant epilepsy and cognitive defects in CDD patients. Moreover, our results may pave the way for drug-based therapies that could bypass the need for CDKL5 and provide effective therapeutic strategies for CDD patients.

ImmunosuppressiveTherapies Differently Modulate Humoral- and T-Cell-Specific Responses to COVID-19 mRNA Vaccine in Rheumatoid Arthritis Patients.

Objective: To assess in rheumatoid arthritis (RA) patients, treated with different immunosuppressive therapies, the induction of SARS-CoV-2-specific immune response after vaccination in terms of anti-region-binding-domain (RBD)-antibody- and T-cell-specific responses against spike, and the vaccine safety in terms of clinical impact on disease activity. Methods: Health care workers (HCWs) and RA patients, having completed the BNT162b2-mRNA vaccination in the last 2 weeks, were enrolled. Serological response was evaluated by quantifying anti-RBD antibodies, while the cell-mediated response was evaluated by a whole-blood test quantifying the interferon (IFN)-γ-response to spike peptides. FACS analysis was performed to identify the cells responding to spike stimulation. RA disease activity was evaluated by clinical examination through the DAS28crp, and local and/or systemic clinical adverse events were registered. In RA patients, the ongoing therapeutic regimen was modified during the vaccination period according to the American College of Rheumatology indications. Results: We prospectively enrolled 167 HCWs and 35 RA patients. Anti-RBD-antibodies were detected in almost all patients (34/35, 97%), although the titer was significantly reduced in patients under CTLA-4-inhibitors (median: 465 BAU/mL, IQR: 103-1189, p<0.001) or IL-6-inhibitors (median: 492 BAU/mL, IQR: 161-1007, p<0.001) compared to HCWs (median: 2351 BAU/mL, IQR: 1389-3748). T-cell-specific response scored positive in most of RA patients [24/35, (69%)] with significantly lower IFN-γ levels in patients under biological therapy such as IL-6-inhibitors (median: 33.2 pg/mL, IQR: 6.1-73.9, p<0.001), CTLA-4-inhibitors (median: 10.9 pg/mL, IQR: 3.7-36.7, p<0.001), and TNF-α-inhibitors (median: 89.6 pg/mL, IQR: 17.8-224, p=0.002) compared to HCWs (median: 343 pg/mL, IQR: 188-756). A significant correlation between the anti-RBD-antibody titer and spike-IFN-γ-specific T-cell response was found in RA patients (rho=0.432, p=0.009). IFN-γ T-cell response was mediated by CD4+ and CD8+ T cells. Finally, no significant increase in disease activity was found in RA patients following vaccination. Conclusion: This study showed for the first time that antibody-specific and whole-blood spike-specific T-cell responses induced by the COVID-19 mRNA-vaccine were present in the majority of RA patients, who underwent a strategy of temporary suspension of immunosuppressive treatment during vaccine administration. However, the magnitude of specific responses was dependent on the immunosuppressive therapy administered. In RA patients, BNT162b2 vaccine was safe and disease activity remained stable.

May Bacterial Infections Trigger Bullous Pemphigoid? Case Report and Review of Literature.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease, mainly observed in the elderly. Infections have been suggested as possible disease triggers. However, infections may even heavily influence the disease clinical course and mortality. A 75-year-old woman was admitted to hospital for severe erythematosus blistering disease, accompanied by hyper-eosinophilia and hyper-IgE. The culture of bullous fluid was positive for Enterococcus faecalis, the blood culture was positive for Staphylococcus aureus, and the urine culture was positive for Proteus mirabilis and Escherichia coli. Moreover, circulating anti-BP180 IgG was present and the histopathological/ultrastructural examination of a lesional skin biopsy was compatible with BP. High eosinophil levels (up to 3170/µL) were found throughout the clinical course, while values below 1000/µL were associated with clinical improvement. The total IgE was 1273 IU/mL, and specific anti-G/V-penicillin/ampicillin IgE antibodies were positive. The patient had a complete clinical recovery in two months with methyl-prednisolone (40 then 20 mg/day) and low-dose azathioprine (50 mg/day) as a steroid-sparing agent. The steroid treatment was tapered until interruption during a one-year period and intravenous immunoglobulins have been administered for three years in order for azathioprine to also be interrupted. The patient stopped any treatment five years ago and, in this period, has always been in good health. In this case, the contemporaneous onset of different bacterial infections and BP is suggestive of bacterial infections acting as BP trigger(s), with allergic and autoimmune pathways contributing to the disease pathogenesis.

Association of Sex with Outcome in Elderly Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Worse outcomes have been reported for women, compared with men, after an acute coronary syndrome (ACS). Whether this difference persists in elderly patients undergoing similar invasive treatment has not been studied. We investigated sex-related differences in 1-year outcome of elderly acute coronary syndrome patients treated by percutaneous coronary intervention (PCI). METHODS: Patients 75 years and older successfully treated with PCI were selected among those enrolled in 3 Italian multicenter studies. Cox regression analysis was used to assess the independent predictive value of sex on outcome at 12-month follow-up. RESULTS: A total of 2035 patients (44% women) were included. Women were older and most likely to present with ST-elevation myocardial infarction (STEMI), diabetes, hypertension, and renal dysfunction; men were more frequently overweight, with multivessel coronary disease, prior myocardial infarction, and revascularizations. Overall, no sex disparity was found about all-cause (8.3% vs 7%, P = .305) and cardiovascular mortality (5.7% vs 4.1%, P = .113). Higher cardiovascular mortality was observed in women after STEMI (8.8%) vs 5%, P = .041), but not after non ST-elevation-ACS (3.5% vs 3.7%, P = .999). A sensitivity analysis excluding patients with prior coronary events (N = 1324, 48% women) showed a significantly higher cardiovascular death in women (5.4% vs 2.9%, P = .025). After adjustment for baseline clinical variables, female sex did not predict adverse outcome. CONCLUSIONS: Elderly men and women with ACS show different clinical presentation and baseline risk profile. After successful PCI, unadjusted 1-year cardiovascular mortality was significantly higher in women with STEMI and in those with a first coronary event. However, female sex did not predict cardiovascular mortality after adjustment for the different baseline variables.

Revisiting the metallothionein genes polymorphisms and the risk of oral squamous cell carcinoma in a Brazilian population / Revisando los polimorfismos de los genes de metalotioneína y el riesgo de carcinoma oral de células escamosas en una población brasileña

Background: Metallothioneins (MTs) gene polymorphisms have been associated with the ability of free radicalscavenging and detoxification of heavy metals leading to cancer development. Our aim was to revisit, in a Brazil-ian population, single-nucleotide polymorphisms (SNPs) of the MT gene family previously associated with oralsquamous cell carcinoma (OSCC).Material and Methods: A case-control investigation with 28 OSCC patients and 45 controls was conducted, usingconventional risk factors (tobacco use and alcohol consumption) as covariates. SNPs genotyping for rs8052334(MT1B), rs964372 (MT1B), and rs1610216 (MT2A) was performed by PCR-RFLP, and SNPs for rs11076161(MT1A) were analyzed by TaqMan assay.Results: The only SNP associated with increased risk for OSCC was the MT-1A AA genotype (OR = 4.7; p = 0.01).We have also evidenced for the first time a significant linkage disequilibrium between the SNPs of MT-2A andMT-1A in this population with the highest frequency (30%) of the unfavorable haplotype G/A/C/T (rs1610216 /rs11076161 / rs964372 / rs8052334) of MT gene polymorphisms (OR = 6.2; p = 0.04). Interestingly, after removingthe effects of conventional risk factors, we have uncovered the significance of the AA genotype of the rs11076161with increased odds of 19-fold higher towards OSCC development.Conclusions: This is the first demonstration that a significant linkage disequilibrium among gene polymor-phisms of the MT family may affect susceptibility to oral cancer, which is conditioned by the G/A/C/T haplotype(rs1610216/rs11076161/rs964372/ rs8052334) and the MT-1A gene polymorphism has a potential clinical utility forthe OSCC risk assessment.(AU)