Quantitative evaluation of OCT angiography images in healthy and glaucomatous subjects through a novel approach: exploring inter-image variability.

PURPOSE: This study aims to investigate inter-image intra-observer variability of macular, and optic disc (ONH) microvasculature measurements of glaucomatous and normal subjects using Swept-Source Optical Coherence Tomography Angiography (OCT-A) (OCT Topcon ImageNet 6; DRI OCT Triton, Topcon Corporation, JAPAN) - based imaging data analysis and processing with a newly made quantitative approach. METHODS: A total of 20 glaucomatous and 20 healthy eyes underwent three OCT-A scanning of the ONH and macula. Macular and papillary and peripapillary vascular networks were calculated. For each eye, eighteen scans were analyzed using a novel approach: custom MATLAB 2021b scripts were employed for imaging analyses. Grayscale distribution was performed using the histcounts MATLAB function with 51 bins. For all layers, the vascular layer coefficient of variation (vl CoV) of the three measures were performed. The vl CoV difference between the two groups was analyzed by Student t-test. RESULTS: In glaucomatous eyes, the vl CoV ranged from 4.49% to 8.54%, while in the control group from 3.58% to 8.32%. Both groups exhibited higher CoVs when assessing the optic disc. The papillary and macular microvasculature reproducibility was comparable between groups. CONCLUSIONS: Utilizing Swept-Source OCT-A images our study has identified an easy and reproducible method that appears to be fast and can assist physicians in assessing macular and ONH perfusion with less inter-image variability, particularly in the 70 µm superficial area of the optic disc. The high reliability obtained suggested that this method could be useful as early clinical biomarker.

Recurrent Kounis Syndrome: A Case Report and Literature Review.

Kounis syndrome is a condition where inflammatory cells (mostly mast cells with the contribution of macrophages and T-lymphocytes) cause an acute coronary syndrome. Kounis syndrome comes in four variants: type I in patients with normal coronary arteries; type II in patients with inactive pre-existing atheromatous disease; type III in patients with pre-existing coronary artery stenting; type IV in patients with a pre-existing coronary artery bypass. Recently, we came across a case of recurrent type I Kounis syndrome in our clinical practice. The purpose of the paper is to present our case and conduct a review using the Pubmed scientific database about the most relevant cases of recurrent Kounis syndrome. This review shows that recurrent Kounis syndrome is a rare condition and is mostly associated with Kounis syndrome type III. Recurrent Kounis syndrome may be also triggered by vaccination and it could be associated with chronic spontaneous urticaria. In the last condition, therapy is represented by second-generation anti-histamines and corticosteroids, but also by an anti-IgE monoclonal antibody (omalizumab) in the recalcitrant cases.

Association between maternal dupilumab exposure and pregnancy outcomes in patients with moderate-to-severe atopic dermatitis: A nationwide retrospective cohort study.

BACKGROUND: There is limited epidemiological evidence on outcomes associated with dupilumab exposure during pregnancy; monitoring pregnancy outcomes in large populations is required. OBJECTIVE: To investigate the potential association between exposure to dupilumab in pregnant women with atopic dermatitis and any adverse pregnancy, neonatal, congenital and post-partum outcomes. METHODS: We performed a multicentre retrospective cohort study across 19 Italian tertiary referral hospital. Childbearing women were eligible if aged 18-49 years and carried out the pregnancy between 1 October 2018 and 1 September 2022. RESULTS: We retrospectively screened records of 5062 patients receiving dupilumab regardless of age and gender, identifying 951 female atopic dermatitis patients of childbearing age, 29 of whom had been exposed to the drug during pregnancy (3%). The median duration of dupilumab treatment prior to conception was 22.5 weeks (range: 3-118). The median time of exposure to the drug during pregnancy was 6 weeks (range: 2-24). All the documented pregnancies were unplanned, and the drug was discontinued in all cases once pregnancy status was reported. The comparison of the study cohort and the control group found no significant drug-associated risk for adverse pregnancy, congenital, neonatal or post-partum outcomes. The absence of a statistically significant effect of exposure on the event was confirmed by bivariate analysis and multivariate analysis adjusted for other confounding factors. CONCLUSIONS: This cohort of pregnant patients exposed to dupilumab adds to the existing evidence concerning the safety of biologic agents in pregnancy. No safety issues were identified regarding the primary outcome assessed. In clinical practice, these data provide reassurance in case of dupilumab exposure during the first trimester. However, the continuous use of dupilumab throughout pregnancy warrants further research.

Safety of omalizumab in chronic urticaria during pregnancy: a real-life study.

BACKGROUND: Managing a pregnant patient with chronic spontaneous urticaria (CSU) is often challenging. Recent data have shown that most CSU treatments in pregnant patients are second-generation H1 antihistamines (sgAHs), while data on the safety of omalizumab are scant. OBJECTIVES: To evaluate, in a routine clinical practice setting, the efficacy and safety of omalizumab in patients with severe CSU refractory to sgAHs who either became pregnant during treatment or who started the drug during pregnancy. METHODS: We conducted a retrospective study of women aged ≥ 18 years who were pregnant, who received one or more doses of omalizumab at any time during their pregnancy or who were taking omalizumab at the time of, or in the 8 weeks before, conception. RESULTS: Twenty-nine pregnant patients were evaluated: 23 (79%) conceived a child while taking omalizumab (group A), while 6 (21%) started omalizumab treatment during pregnancy (group B). Among patients in group A, we observed 23 births (21 liveborn singletons and 1 liveborn twin pair) and 1 miscarriage. Fifteen (65%) patients discontinued omalizumab after confirming their pregnancy, while eight (35%) were exposed to omalizumab during their entire pregnancy. In group B, omalizumab was introduced at a mean (SD) 10.83 (3.60) weeks' gestation and all patients were exposed to it until the end of pregnancy. In this group, there were seven liveborn infants (five singletons and one twin pair). No adverse events, pregnancy complications or congenital anomalies in newborns were recorded in either group. CONCLUSIONS: Omalizumab for CSU treatment before and during pregnancy does not appear to have negative effects on maternal or fetal outcomes.

Don't plan, just do it: Cognitive and sensorimotor contributions to manual dexterity.

Manual dexterity is referred to as the skill to perform fine motor movements and it has been assumed to be associated to the cognitive domain, as well as the sensorimotor one. In this work, we investigated with functional near-infrared spectroscopy the cortical activations elicited by the execution of the 9-HPT, i.e., a standard test evaluating manual dexterity in which nine pegs were taken, placed into and then removed from nine holes on a board as quickly as possible. For comparison, we proposed a new active control task mainly involving the sensorimotor domain, in which the pegs must be placed and removed using the same single hole (1-HPT). Behaviorally, we found two distinct groups based on the difference between the execution time of the 9-HPT and the 1-HPT (ΔHPT). Cortical areas belonging to the network controlling reaching and grasping movements were active in both groups; however, participants showing a large ΔHPT presented significantly higher activation in prefrontal cortical areas (right BA10 and BA11) during 9-HPT and 1-HPT performance with respect to the participants with a small ΔHPT, who showed a deactivation in BA10. Unexpectedly, we observed a significant linear relationship between ΔHPT and right BA10 activity. This suggested that participants performing the 9-HPT more slowly than the 1-HPT recruited prefrontal areas implicitly exploiting the cognitive skills of planning, perhaps in search of a motor strategy to solve the test activating attentional and cognitive control processes, but this resulted not efficient and instead increased the time to accomplish a manual dexterity task.

Microbiota and IL-33/31 Axis Linkage: Implications and Therapeutic Perspectives in Atopic Dermatitis and Psoriasis.

Microbiome dysbiosis and cytokine alternations are key features of atopic dermatitis (AD) and psoriasis (PsO), two of the most prevalent and burdensome pruritic skin conditions worldwide. Interleukin (IL)-33 and IL-31 have been recognized to be major players who act synergistically in the pathogenesis and maintenance of different chronic inflammatory conditions and pruritic skin disorders, including AD and PsO, and their potential role as therapeutic targets is being thoroughly investigated. The bidirectional interplay between dysbiosis and immunological changes has been extensively studied, but there is still debate regarding which of these two factors is the actual causative culprit behind the aetiopathological process that ultimately leads to AD and PsO. We conducted a literature review on the Pubmed database assessing articles of immunology, dermatology, microbiology and allergology with the aim to strengthen the hypothesis that dysbiosis is at the origin of the IL-33/IL-31 dysregulation that contributes to the pathogenesis of AD and PsO. Finally, we discussed the therapeutic options currently in development for the treatment of these skin conditions targeting IL-31, IL-33 and/or the microbiome.

Time-of-day influences resting-state functional cortical connectivity.

Time-of-day is rarely considered during experimental protocols investigating motor behavior and neural activity. The goal of this work was to investigate differences in functional cortical connectivity at rest linked to the time of the day using functional Near-Infrared Spectroscopy (fNIRS). Since resting-state brain is shown to be a succession of cognitive, emotional, perceptual, and motor processes that can be both conscious and nonconscious, we studied self-generated thought with the goal to help in understanding brain dynamics. We used the New-York Cognition Questionnaire (NYC-Q) for retrospective introspection to explore a possible relationship between the ongoing experience and the brain at resting-state to gather information about the overall ongoing experience of subjects. We found differences in resting-state functional connectivity in the inter-hemispheric parietal cortices, which was significantly greater in the morning than in the afternoon, whilst the intra-hemispheric fronto-parietal functional connectivity was significantly greater in the afternoon than in the morning. When we administered the NYC-Q we found that the score of the question 27 ("during RS acquisition my thoughts were like a television program or film") was significantly greater in the afternoon with respect to the morning. High scores in question 27 point to a form of thought based on imagery. It is conceivable to think that the unique relationship found between NYC-Q question 27 and the fronto-parietal functional connectivity might be related to a mental imagery process during resting-state in the afternoon.

miRNAs' Cross-Involvement in Skin Allergies: A New Horizon for the Pathogenesis, Diagnosis and Therapy of Atopic Dermatitis, Allergic Contact Dermatitis and Chronic Spontaneous Urticaria.

Skin inflammation is a common underlying feature of atopic dermatitis, allergic contact dermatitis and chronic spontaneous urticaria. The pathogenetic mechanisms have not been fully elucidated. The purpose of this study was to examine whether miRNA, by regulating inflammatory mechanisms through the modulation of innate and adaptive immune responses, could play a major role in the pathogenesis of these skin conditions. We conducted a narrative review using the Pubmed and Embase scientific databases and search engines to find the most relevant miRNAs related to the pathophysiology, severity and prognosis of skin conditions. The studies show that miRNAs are involved in the pathogenesis and regulation of atopic dermatitis and can reveal an atopic predisposition or indicate disease severity. In chronic spontaneous urticaria, different miRNAs which are over-expressed during urticaria exacerbations not only play a role in the possible response to therapy or remission, but also serve as a marker of chronic autoimmune urticaria and indicate associations with other autoimmune diseases. In allergic contact dermatitis, miRNAs are upregulated in inflammatory lesions and expressed during the sensitization phase of allergic response. Several miRNAs have been identified as potential biomarkers of these chronic skin conditions, but they are also possible therapeutic targets.

The effects of systemic immunomodulatory treatments on COVID-19 outcomes in patients with atopic dermatitis: Results from the global SECURE-AD registry.

BACKGROUND: Limited data are available on the effects of systemic immunomodulatory treatments on COVID-19 outcomes in patients with atopic dermatitis (AD). OBJECTIVE: To investigate COVID-19 outcomes in patients with AD treated with or without systemic immunomodulatory treatments, using a global registry platform. METHODS: Clinicians were encouraged to report cases of COVID-19 in their patients with AD in the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Atopic Dermatitis (SECURE-AD) registry. Data entered from 1 April 2020 to 31 October 2021 were analysed using multivariable logistic regression. The primary outcome was hospitalization from COVID-19, according to AD treatment groups. RESULTS: 442 AD patients (mean age 35.9 years, 51.8% male) from 27 countries with strongly suspected or confirmed COVID-19 were included in analyses. 428 (96.8%) patients were treated with a single systemic therapy (n = 297 [67.2%]) or topical therapy only (n = 131 [29.6%]). Most patients treated with systemic therapies received dupilumab (n = 216). Fourteen patients (3.2%) received a combination of systemic therapies. Twenty-six patients (5.9%) were hospitalized. No deaths were reported. Patients treated with topical treatments had significantly higher odds of hospitalization, compared with those treated with dupilumab monotherapy (odds ratio (OR) 4.65 [95%CI 1.71-14.78]), including after adjustment for confounding variables (adjusted OR (aOR) 4.99 [95%CI 1.4-20.84]). Combination systemic therapy which did not include systemic corticosteroids was associated with increased odds of hospitalization, compared with single agent non-steroidal immunosuppressive systemic treatment (OR 8.09 [95%CI 0.4-59.96], aOR 37.57 [95%CI 1.05-871.11]). Hospitalization was most likely in patients treated with combination systemic therapy which included systemic corticosteroids (OR 40.43 [95%CI 8.16-207.49], aOR 45.75 [95%CI 4.54-616.22]). CONCLUSIONS: Overall, the risk of COVID-19 complications appears low in patients with AD, even when treated with systemic immunomodulatory agents. Dupilumab monotherapy was associated with lower hospitalization than other therapies. Combination systemic treatment, particularly combinations including systemic corticosteroids, was associated with the highest risk of severe COVID-19.

The hand motor hotspot for seed-based functional connectivity of hand motor networks at rest.

In the seed-based method for studying functional connectivity (FC), seed selection is relevant. Here, we propose a new methodological approach for resting-state FC analysis of hand motor networks using the individual hand motor hotspot (hMHS) as seed. Nineteen right-handed healthy volunteers underwent a transcranial magnetic stimulation (TMS) session and resting-state fMRI. For each subject, the hMHS in both hemispheres was identified by TMS with the contralateral abductor pollicis brevis muscle as the target, the site eliciting the highest and most reliable motor-evoked potentials. Seed regions were built on coordinates on the cortex corresponding to the individual left and right hMHSs. For comparison, the left and right Brodmann's area 4 (BA4) masks extracted from a standard atlas were used as seed. The left and right hMHSs showed FC patterns at rest mainly including sensorimotor regions, with a bilateral connectivity only for the left hMHS. The statistical contrast BA4 > hMHS for both hemispheres showed different extension and lateralization of the functionally connected cortical regions. On the contrary, no voxels survived the opposite contrast (hMHS > BA4). This suggests that detection of individual hand motor seeds by TMS allows to identify functionally connected motor networks that are more specific with respect to those obtained starting from the a priori atlas-based identification of the primary motor cortex.

Incidence and Characteristics of Adverse Events after COVID-19 Vaccination in a Population-Based Programme.

Compliance with vaccination is linked to its safety. In Italy, a plan to identify people who could be at an increased risk of adverse events (AEs) was defined so they could be vaccinated in a protected setting. We conducted an audit to describe the process of AE risk assessment and occurrence in the Reggio Emilia Province in Italy in people who received any of the four COVID-19 vaccines currently used in Italy. Incidence of AEs was calculated by dose and type of vaccine and type of setting (standard vs. protected). After 182,056 first doses were administered, 521 (0.3%) AEs were reported. Most of the AEs were non-serious (91.4%) and non-allergic (92.7%). The percentage of AEs was similar in both settings: 0.3% in the standard setting and 0.2% in the protected setting. However, the incidence of AEs was higher among those who had an allergist visit than among those who did not (IR 666.7 vs. 124.9). All deaths (1.6/100.000) occurred in standard settings and after the Pfizer and Moderna vaccines. The incidence of AEs was lower after the second dose (IR 286.2 vs. 190.3), except for mRNA vaccines, for which it was higher after the second dose (IR 169.8 vs. 251.8). Although vaccination in a protected medical setting could reassure patients with a history of allergies to be vaccinated, allergy history and other anamnestic information is not useful in predicting the risk of COVID-19 vaccine-related AEs in the general population.

Effectiveness and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps and associated comorbidities: a multicentric prospective study in real life.

BACKGROUND: Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. METHODS: We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). RESULTS: In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. CONCLUSIONS: These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Efficacy and Safety of an Antioxidant-Enriched Medical Device for Topical Use in Adults with Eczematous Dermatitis.

INTRODUCTION: Emollients reduce the severity of dermatitis-associated symptoms. Antioxidant supplementation may be helpful to control inflammatory processes and consequential skin damage. The clinical performance and safety of an emollient medical device for topical treatment enriched with antioxidant ingredients in adults with mild-to-moderate dermatitis is presented in this manuscript. METHODS: We performed a monocenter, open-label, uncontrolled clinical trial. Participants applied the product twice a day for 28 days. No other medication or moisturizer was allowed. Changes in dermatitis severity were assessed at days 14 and 28 by study investigators. Subjects self-assessed pruritus, Dermatology Life Quality Index, and product satisfaction. At the end of the study, a global evaluation of the product was done both by patient-reported outcomes and investigators' evaluations. RESULTS: Forty subjects were enrolled in the study (mean age 35 years). Treatment success was achieved in 87.5% of subjects (p < 0.0001) after 28 days. Mean Investigator's Global Assessment (IGA) and Eczema Area and Severity Index (EASI) scores decreased at days 14 and 28 (p < 0.0001). Subjects reported a reduction in pruritus severity and improvement of quality of life (p < 0.0001), along with satisfaction with the product. At the end of the study, skin condition improved in more than 90% of subjects. No safety issues were identified. CONCLUSION: The medical device studied for topical use in this clinical trial is considered safe and reduces pruritus in adults with atopic and contact dermatitis.

Mild/Moderate Asthma Network in Italy (MANI): a long-term observational study.

OBJECTIVE: The prevalence of asthma in Italy is estimated to be around 4%; it affects approximately 2,000,000 citizens, and up to 80-90% of patients have mild-to-moderate asthma. Despite the clinical relevance of mild-to-moderate asthma, longitudinal observational data are very limited, including data on disease progression (worsening vs. improvement), the response to treatment, and prognosis. Studies are needed to develop long-term, observational, real-life research in large cohorts. The primary outcomes of this study will be based on prospective observation and the epidemiological evolution of mild and moderate asthma. Secondary outcomes will include patient-reported outcomes, treatments over time, disease-related functional and inflammatory patterns, and environmental and life-style influences. METHODS: This study, called the Mild/Moderate Asthma Network of Italy (MANI), is a research initiative launched by the Italian Respiratory Society and the Italian Society of Allergology, Asthma and Clinical Immunology. MANI is a cluster-based, real world, cross-sectional, prospective, observational cohort study that includes 20,000 patients with mild-to-moderate asthma. (ClinicalTrials.gov Identifier: NCT04796844). RESULTS AND CONCLUSION: Despite advances in asthma care, several research gaps remain to be addressed through clinical research. This study will add important new knowledge about long-term disease history, the transferability of clinical research results to daily practice, the efficacy of currently recommended strategies, and their impact on the burden and evolution of the disease. ABBREVIATIONS: MANI:Mild/Moderate Asthma Network of ItalySANI:Severe Asthma Network ItalyGINA:Global Initiative for AsthmaSABA:short acting ß2-agonistsICS:inhaled corticosteroidsCRF:Case Report Form.

Quality of life in patients with allergic and immunologic skin diseases: in the eye of the beholder.

Allergic and immunologic skin diseases negatively impact the quality of life (QoL) of affected patients with detrimental consequences. Nonetheless, in everyday clinical practice the evaluation of QoL is often overlooked. Considering the increasing prevalence of atopic dermatitis, allergic contact dermatitis, hereditary angioedema, cutaneous mastocytosis, and urticaria, it is essential to determine the effects of allergic and immunologic skin diseases on QoL. A joint meeting (GET TOGETHER 2021) of the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) aimed to summarize the features of the main QoL tools used in these diseases and to describe the extent of QoL impairment as well as the impact of treatments on QoL, particularly biologic therapies. The assessment of QoL in patients with allergic and immunologic skin diseases relies on generic, organ-specific and disease-specific questionnaires. While generic and organ-specific questionnaires allow comparison between different diseases, disease-specific questionnaires are designed and validated for specific cohorts: the QoL Index for Atopic Dermatitis (QoLIAD) and the Childhood Atopic Dermatitis Impact Scale (CADIS) in atopic dermatitis, the ACD-11 in allergic contact dermatitis, the Angioedema QoL Questionnaire (AE-QoL) and the Hereditary Angioedema QoL questionnaire (HAE-QoL) in hereditary angioedema, the Mastocytosis QoL Questionnaires (MCQoL e MQLQ) in cutaneous mastocytosis, and the Chronic Urticaria QoL questionnaire (CU-Q2oL) in urticaria. Among the many factors that variably contribute to QoL impairment, pruritus can represent the leading cause of patient discomfort. Biologic therapies significantly ameliorate QoL in atopic dermatitis, hereditary angioedema, mastocytosis and chronic urticaria. In general, adequate management strategies are essential for improving QoL in patients with allergic and immunologic skin diseases.

Additive and interaction effects of working memory and motor sequence training on brain functional connectivity.

Although shared behavioral and neural mechanisms between working memory (WM) and motor sequence learning (MSL) have been suggested, the additive and interactive effects of training have not been studied. This study aimed at investigating changes in brain functional connectivity (FC) induced by sequential (WM + MSL and MSL + WM) and combined (WM × MSL) training programs. 54 healthy subjects (27 women; mean age: 30.2 ± 8.6 years) allocated to three training groups underwent twenty-four 40-min training sessions over 6 weeks and four cognitive assessments including functional MRI. A double-baseline approach was applied to account for practice effects. Test performances were compared using linear mixed-effects models and t-tests. Resting state fMRI data were analysed using FSL. Processing speed, verbal WM and manual dexterity increased following training in all groups. MSL + WM training led to additive effects in processing speed and verbal WM. Increased FC was found after training in a network including the right angular gyrus, left superior temporal sulcus, right superior parietal gyrus, bilateral middle temporal gyri and left precentral gyrus. No difference in FC was found between double baselines. Results indicate distinct patterns of resting state FC modulation related to sequential and combined WM and MSL training suggesting a relevance of the order of training performance. These observations could provide new insight for the planning of effective training/rehabilitation.