Patients with STAT1 Gain-of-function Mutations Display Increased Apoptosis which is Reversed by the JAK Inhibitor Ruxolitinib.

INTRODUCTION: The signal transducer and activator of transcription (STAT1) gain-of-function (GOF) syndrome accounts for most cases of chronic mucocutaneous candidiasis but is characterized by a broader clinical phenotype that may include bacterial, viral, or invasive fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The severity of lymphopenia may vary and influence the infectious morbidity. METHODS: In our cohort of seven STAT1-GOF patients, we investigated the mechanisms that may determine T lymphopenia, we characterized the interferon gene signature (IGS) and analyzed the effect of ruxolitinib in reverting the immune dysregulation. RESULTS: STAT1-GOF patients exhibited increased T lymphocyte apoptosis that was significantly augmented in both resting conditions and following stimulation with mitogens and IFNα, as evaluated by flow cytometry by Annexin V/ Propidium iodide assay. The JAK inhibitor ruxolitinib significantly reduced the IFNα-induced hyperphosphorylation of STAT1 and reverted the stimulation-induced T-cell apoptosis, in vitro. In two adult STAT1-GOF patients, the JAKinib treatment ameliorated chronic mucocutaneous candidiasis and lymphopenia. Most STAT1-GOF patients, particularly those who had autoimmunity, presented increased IGS that significantly decreased in the two patients during ruxolitinib treatment. CONCLUSION: In STAT1-GOF patients, T lymphocyte apoptosis is increased, and T lymphopenia may determine higher risk of severe infections. The JAKinib target therapy should be evaluated to treat severe chronic candidiasis and lymphopenia, and to downregulate the IFNs in patients with autoinflammatory or autoimmune manifestations.

Efficacy of COVID-19 mRNA vaccination in patients with autoimmune disorders: humoral and cellular immune response.

BACKGROUND: The impact of immunosuppressive therapies on the efficacy of vaccines to SARS-CoV-2 is not completely clarified. We analyzed humoral and T cell-mediated response after COVID-19 mRNA vaccine in immunosuppressed patients and patients with common variable immunodeficiency disease (CVID). PATIENTS: We enrolled 38 patients and 11 healthy sex- and age-matched controls (HC). Four patients were affected by CVID and 34 by chronic rheumatic diseases (RDs). All patients with RDs were treated by corticosteroid therapy and/or immunosuppressive treatment and/or biological drugs: 14 patients were treated with abatacept, 10 with rituximab, and 10 with tocilizumab. METHODS: Total antibody titer to SARS-CoV-2 spike protein was assessed by electrochemiluminescence immunoassay, CD4 and CD4-CD8 T cell-mediated immune response was analyzed by interferon-γ (IFN-γ) release assay, the production of IFN-γ-inducible (CXCL9 and CXCL10) and innate-immunity chemokines (MCP-1, CXCL8, and CCL5) by cytometric bead array after stimulation with different spike peptides. The expression of CD40L, CD137, IL-2, IFN-γ, and IL-17 on CD4 and CD8 T cells, evaluating their activation status, after SARS-CoV-2 spike peptides stimulation, was analyzed by intracellular flow cytometry staining. Cluster analysis identified cluster 1, namely the "high immunosuppression" cluster, and cluster 2, namely the "low immunosuppression" cluster. RESULTS: After the second dose of vaccine, only abatacept-treated patients, compared to HC, showed a reduced anti-spike antibody response (mean: 432 IU/ml ± 562 vs mean: 1479 IU/ml ± 1051: p = 0.0034), and an impaired T cell response, compared with HC. In particular, we found a significantly reduced release of IFN-γ from CD4 and CD4-CD8 stimulated T cells, compared with HC (p = 0.0016 and p = 0.0078, respectively), reduced production of CXCL10 and CXCL9 from stimulated CD4 (p = 0.0048 and p = 0.001) and CD4-CD8 T cells (p = 0.0079 and p = 0.0006). Multivariable General Linear Model analysis confirmed a relationship between abatacept exposure and impaired production of CXCL9, CXCL10, and IFN-γ from stimulated T cells. Cluster analysis confirms that cluster 1 (including abatacept and half of rituximab treated cases) showed a reduced IFN-γ response, as well as reduced monocyte-derived chemokines All groups of patients demonstrated the ability to generate specific CD4 T activated cells after spike proteins stimulation. After the third dose of vaccine, abatacept-treated patients acquired the ability to produce a strong antibody response, showing an anti-S titer significantly higher compared to that obtained after the second dose (p = 0.0047), and comparable with the anti-S titer of the other groups. CONCLUSIONS: Patients treated with abatacept showed an impaired humoral immune response to two doses of COVID-19 vaccine. The third vaccine dose has been demonstrated to be useful to induce a more robust antibody response to balance an impaired T cell-mediated one. All patients, exposed to different immunosuppressive drugs, were able to produce specific CD4-activated T cells, after spike proteins stimulation. TRIAL REGISTRATION: Local Ethical Committee NP4187.

Del Nido cardioplegia in adult cardiac surgery: Clinical outcomes in a single center all-comer study.

INTRODUCTION: The use of Del Nido Cardioplegia (DNC) has been extended in the latest years from pediatrics to adult cardiac surgery with encouraging results. We sought to investigate clinical and biochemical outcomes in adult patients who underwent cardiac surgery with different degrees of complexity who received DNC for myocardial protection. METHODS: Data on one-thousand patients were retrospectively collected from 2020 to 2022. The only exclusion criteria was off-pump adult cardiac surgery. Surgical procedures weight was categorized according EuroSCORE II in six groups: Single-CABG(G1), isolated non-CABG(mitral) (G2), isolated non-CABG(aortic) (G3), isolated non-CABG(any) (G4), 2-procedures(G5), 3/more-procedures(G6). Primary endpoint was to identify a binomial correlation between hs-TnT/CK-MB and the cross-clamp time (X-Clamp). A secondary endpoint was the comparison between the treatment groups of the vasoactive-inotropic score (VIS) and the need of mechanical circulatory support (MCS). RESULTS: A linear correlation was identified between hs-TnT and X-clamp in the overall population (rho:0.447, p< .001) and in the treatment groups (G1:rho=0.357, p< .001/G2:rho=0.455, p< .001/G3:rho=0.307, p= .001/G4:rho=0.165, p= .257/G5:rho=0.157, p= .031/G6:rho=0.226, p= .015). Similarly, a linear correlation between CK-MB and X-clamp in the overall population (rho=0.457, p< .001) and treatment group (G1:rho=0.282, p< .001/G2:rho=0.287, p= .025/G3:rho=0.211, p= .009/G4:rho=0.0878, p= .548/G5:rho=0.309, p< .001/G6: rho=0.212, p= .024) was identified. As regard for the secondary endpoint, no differences were reported between the treatment groups in terms of VIS and MCS (VIS G1:7; G2:4; G3:7; G4:7, G5:5.5, G6:6, p-value= .691) (MCS G1: 4.5%; G2:4.8%; G3:3.3%; G4:3.1%; G5:1.4%; G6:5.3%; p-value= .372). CONCLUSIONS: Del Nido Cardioplegia is a safe and useful tool in adult cardiac surgery allowing operators to achieve a stable and durable cardioplegic arrest. Despite accounting with different types of surgery, the six subgroups of our study population showed similar perioperative results.

Cross-Sectional Study of the Psychological Well-Being of Healthcare Workers in a Large European University Hospital after the COVID-19 Initial Wave.

BACKGROUND: The SARS-CoV-2 pandemic greatly impacted healthcare workers (HCWs) dedicated to caring for COVID-19 patients. The study was conducted in a large European hospital to study the psychological distress of HCWs engaged in COVID-19 wards in the early phase of the pandemic. METHODS: A questionnaire was sent to 1229 HCWs aimed at collecting the following information: 1) sociodemographic data; 2) depression, anxiety, and stress scales (DASS-21); 3) event impact scale (IES-R); 4) perceived stress scale (PSS); and 5) work interface analysis. The responses were collected through Google® forms and then statistically analyzed. Regardless of the outcome of the questionnaire, all subjects were offered psychological support voluntarily. RESULTS: Approximately two-thirds of the workers reported no symptoms according to the DASS-21 scales, while the IES-R and PSS scales showed 36% and 43%, respectively. There were no statistically significant differences in the levels of depression investigated through the different scales in the various occupational categories. Symptoms of anxiety, stress, and depression were more pronounced in women, while the highest stress levels were observed in the younger age groups. The highest scores were observed on the DAS-21 scales of anxiety and IES-R but not on the others. Only 51 workers, most of them with previous SARS-CoV-2 infection, sought clinical psychological counseling, and more than half received subsequent psychological support. CONCLUSIONS: Our results agree with most of the literature data that anxiety, depression, and stress are associated with gender (female), age (18-44 vs. over 55), and having cared for patients with COVID-19.

Home-based pulmonary rehabilitation in patients undergoing (chemo)radiation therapy for unresectable lung cancer: a prospective explorative study.

AIMS: The prevention of pulmonary toxicity is an important goal for patient candidate to radiation therapy for lung cancer. There is a lack of evidence on the role of exercise training for patients with unresectable stage III lung cancer candidated to radical treatment. The aim of this study was to evaluate the feasibility of a home-based pulmonary rehabilitation (PR) program and to identify reliable tools in terms of respiratory function, exercise capacity and quality of life. METHODS: Patients' recruitment lasted from April 2020 till February 2022. The PR program was proposed concomitantly to radiation therapy to the first 20 patients (interventional group, IG), and the other 20 patients were identified as an observational group (OG). All patients were assessed at baseline (T0) and after 8 weeks (T2) with 6 minute walking test (6MWT), modified Borg Scale (mBORG), SF-36 questionnaire (SF-36) and pulmonary function test (PFT); after 4 weeks (T1), only SF-36 was administered. RESULTS: A decrease of 13.8 m in the walked-distance was registered in the OG between T0 and T2 (p = 0.083). Instead, an increase of 56.6 m in the distance walked was recorded in the IG between T0 and T2 (p ≤ 0.001). In the OG, the mBORG scores showed a negative trend. On the contrary, in the IG, these scores showed a slight improvement. In the OG, all the items of SF-36 scores decreased between T0 and T1. In the IG, an increased trend from T0 to T2 was observed for all the items of SF-36. No clinically significant variations were detected from baseline to T2 in both groups regarding PFT. CONCLUSION: The 6MWT, mBORG and SF-36 resulted as useful tools to assess the role of a PR program. A significant gain in functional exercise capacity and a prevention of the physiological impairment of QoL during radio(chemo)therapy was registered.

A Short Cycle of Narrow-Band UVB Phototherapy in the Early Phase of Dupilumab Therapy Can Provide a Quicker Improvement of Severe Atopic Dermatitis.

BACKGROUND: Since the best clinical response to dupilumab is achieved after 12-16 weeks, a combination therapy at the beginning of the treatment could be a helpful strategy to reach a faster response in patients with severe atopic dermatitis (AD). OBJECTIVES: To quantify the benefit of a combination of dupilumab treatment with a short course of narrow-band ultraviolet B (NB-UVB) phototherapy. METHODS: In the present pilot study adult patients suffering from severe AD were enrolled with a 2:1 ratio to receive treatment with dupilumab alone or dupilumab plus NB-UVB phototherapy, for 12 weeks. After the twelfth week, all patients received dupilumab only. A follow-up visit took place after 16 weeks. Both clinician-oriented and patient-oriented scores were assessed at baseline (T0) and after 4 (T1), 12 (T2) and 16 (T3) weeks. RESULTS: Forty-five adult patients were enrolled in the study. Both treatment regimens were well tolerated and very effective on all measured scores (EASI, SCORAD, BSA, NRS of itching, NRS of sleep loss, DLQI, POEM and HADS), but the combined regimen led to a more robust clinical improvement of lesions and relief of symptoms after 4 weeks. However, after 12 and 16 weeks, the additional therapeutic effect of phototherapy weakened. CONCLUSION: NB-UVB phototherapy can provide a faster remission of severe AD in the first few weeks of dupilumab therapy.

Clinical and Spectrophotometric Evaluation of Skin Photoadaptation in Vitiligo Patients after a Short Cycle of NB-UVB Phototherapy.

BACKGROUND: The phenomenon of photoadaptation to narrow-band ultraviolet B (NB-UVB) radiation has been previously described in vitiligo and has usually been clinically measured by the assessment of the minimal erythema dose (MED) after phototesting. OBJECTIVES: To assess the photoadaptive response in vitiligo and healthy skin after NB-UVB phototherapy not only clinically, but also by spectrophotometry. MATERIALS AND METHODS: Fourteen patients affected by generalized vitiligo underwent NB-UVB phototherapy twice weekly for 12 weeks. Before and after phototherapy, a phototesting procedure was administered on vitiligo patches and adjacent healthy skin with a solar simulated radiation (SSR). Visual assessment of the MED took place after 24 h. A spectrophotometer was used to assess the a* value and the melanin index (MI*), as signs of skin erythema and pigmentation. The photoadaptation factor (MED-PF) and the a* photoadaptation factor (a*-PF) were calculated. RESULTS: After NB-UVB phototherapy, both vitiligo and healthy skin showed an increase in MED and MI* values and a reduction of skin erythema compared to baseline (p < 0.05). MED-PF data showed a photoadaptation in 10 (71.4%) vitiligo lesions and in 12 (85.7%) healthy skin areas. The assessment of the a*-PF showed a negative mean percentage value in all affected and unaffected skin areas. CONCLUSIONS: A short cycle of NB-UVB phototherapy can induce photoadaptation in vitiligo by increasing the MED and reducing skin erythema after stimulation with SSR. This is most likely due to the physical filter function induced by ultraviolet radiation.

Does treatment assignment influence the prognosis of patients with symptomatic severe aortic stenosis?

OBJECTIVE: Aortic valve replacement (AVR) is the standard therapy in patients with symptomatic aortic stenosis (AS). In high surgical risk patients, alternative therapeutic options to medical treatment (MT) such as trans-catheter aortic valve implantation (TAVI) or balloon aortic valvuloplasty (BAV) have been proposed. In this study we evaluated whether treatment assignment influences per se the prognosis of these subjects. PATIENTS AND METHODS: Criteria for treatment assignment were based on patient's clinical conditions, Logistic EuroSCORE and other co-morbidities ignored by EuroSCORE. Due to baseline clinical differences between patients with diverse treatment assignment, we used propensity score matching to achieve balance. RESULTS: 368 patients were studied: 141 underwent AVR, 127 TAVI, 49 BAV and 51 MT. 84 events (deaths for all causes) occurred during 14 months of follow-up: 11 AVR (8%), 26 TAVI (20%), 18 MT (35%), 29 BAV group (59%). Traditional Cox analysis identified treatment assignment as independent predictor of events (HR 1.82 [CI 1.10-3.25]) together with lower left ventricular ejection fraction, impaired renal function and history of heart failure. Matched Cox analysis by propensity score confirmed treatment assignment as an independent prognosticator of events (HR 1.90 [CI 1.27-2.85]), and showed similar rate events in TAVI and AVR patients, while it was significantly increased in BAV and MT patients. CONCLUSIONS: Treatment assignment may influence outcome of symptomatic patients with AS.

[Considerations on the use of meta-analyses in the orientation of knowledge and decisions in Occupational Medicine]. / Riflessioni sull'impiego della meta-analisi nell'orientamento delle conoscenze e delle decisioni in Medicina (del Lavoro).

In recent years, due to the need to elaborate the amount of information available from the scientific literature, the meta-analyses and systematic reviews have become very numerous. The meta-analyses are carried out to evaluate the association between two events when single researches haven't provided comprehensive data. On the other hand, a good meta-analysis must satisfy certain criteria, from the selection of the studies until the evaluation of the outcomes; to this purpose, the application of methods for quality assessment is a crucial point to obtain data of adequate reliability. The aim of this review is to give some introductory tools for a critical approach to meta-analyses and systematic reviews, which have become useful instruments also in occupational medicine.

[Risk assessment comparison of biomechanical overloading of the musculoskeletal system: 10 years' applied experience]. / Metodi di valutazione del rischio da sovraccarico biomeccanico all'apparato muscolo scheletrico a confronto: esperienza applicativa di dieci anni.

UNLABELLED: Risk assessment for upper extremity work related muscoloskeletal disorders by applying six methods of ergonomic: a ten years experience. The objective of this research was to verify and validate the multiple step method suggested by SIMLII guidelines and to compare results obtained by use of these methods: Washington State Standard, OCRA, HAL, RULA, OREGE and STRAIN INDEX. METHODS: 598 workstations for a total of 1800 analysis by different methods were considered, by adopting the following multiple step procedure: prelinminary evaluation by Washington State method and OCRA checklist in all the working stations, RULA or HAL as first level evaluation, OREGE or SI as second level evaluation. RESULTS: The preliminary evaluation resulted negative (risk absent) in the 75% of examined work stations and by using checklist OCRA optimal-acceptable condition was found in 58% by HAL in 92% of analysis, by RULA in 100%, by OREGE in 64%; by SI in 70% of examined working positions. We observed similar evaluation of strain among methods and main differences have been observed in posture and frequency assessment. DISCUSSION AND CONCLUSION: The preliminary evaluation by State of Washington method appears to be an adequate instrument for identify the working condition at risk. All the adopted methods were in a good agreement in two estreme situations: high risk or absent risk, expecially in absent risk conditions. Level of accordance varied on the basis of their rationale and of the role of their different components so SIML indications about the critical use of biouzechanical methods and about the possible use of more than one of them (considering working chlaracteristics) have been confirmed.

Impact of Pemphigus on Sleep Quality: A Prospective Observational Single-Center Case-Control Study.

INTRODUCTION: Pemphigus, an autoimmune disorder, significantly impacts the quality of life for those affected. OBJECTIVE: This study examined the sleep quality in patients with pemphigus, a domain for which the existing literature provides limited data without a focused analysis. METHODS: A total of 156 individuals, 52 in the case and 104 in the control group, completed several questionnaires (Pittsburgh Sleep Quality Index [PSQI], General Health Questionnaire-12 [GHQ-12], and ABQOL [Autoimmune Bullous Disease Quality of Life]). Disease severity was evaluated using the Pemphigus disease area index (PDAI index). RESULTS: The case group exhibited significantly higher levels of psychological distress, reflected in GHQ-12 scores (P = 0.00), and notably poorer sleep quality compared to controls across various parameters (sleep latency [SL], disturbances [SDi], medication [SM], daytime sleep dysfunction [DSD]), and the global PSQI score (GS)] (P = 0.00)). Significant correlations were observed between PDAI scores and sleep duration (SDu) (P = 0.01), SM (P=0.03), SL (P =0.03), and GS (P=0.00). An association was found between the equivalent steroid intake and SDu (P=0.00) as well as GS (P=0.02). No statistically significant correlation emerged between disease duration and PSQI scores. Our findings indicated a correlation between poor sleep quality and cutaneous rather than mucosal manifestations (p=0.01). Pemphigus affects sleep quality. Severe disease showed heightened SDi, correlating with higher steroid doses, and in the chronic phase, the impact seems to have been more influenced by the pro-inflammatory stage of the disease. Patients with cutaneous pemphigus exhibited reduced sleep quality compared to those with oral pemphigus. CONCLUSION: Understanding that pemphigus worsens sleep quality can be beneficial for the holistic management of individuals with this condition.

Influence of regression, its extent and tumor-infiltrating lymphocytes on sentinel node status, relapse, and survival in a 10-year retrospective study of melanoma patients.

This case-control study seeks to investigate the influence of histological findings, specifically regression, its extent and tumor-infiltrating lymphocyte (TILs), on result of sentinel lymph node (SLN) biopsy, 5-year melanoma-specific survival (MSS), and relapse-free survival (RFS). We included all patients with cutaneous melanoma who underwent SLN biopsy at the Melanoma Center of the University of Brescia, following the Italian Association of Medical Oncology National guidelines from January 2008 to August 2018. Regression and its extent (<75 or ≥75%) and the presence of TILs were reevaluated by a trained dermatopathologist, adhering to the 2017 College of American Pathologists Cancer Protocol for Skin Melanoma. These patients were followed up for 5 years. Our study uncovered significant associations between regression and male sex ( P  < 0.05), melanoma location on the trunk, upper limbs, and back ( P  = 0.001), ulceration ( P  < 0.05), lower Breslow thickness ( P  = 0.001), and the presence of lymphocytic infiltration (both brisk and nonbrisk) ( P  < 0.001). Regression and its extent, however, did not appear to affect SLN positivity ( P  = 0.315). Similarly, our data did not reveal a correlation between TILs and result of SLN biopsy ( P  = 0.256). When analyzing MSS and RFS in relation to the presence or absence of regression and TILs, no statistically significant differences were observed, thus precluding the need for logistic regression and Kaplan-Meier curve analysis. This study's findings underscore that regression and TILs do not appear to exert an influence on sentinel lymph node status, MSS, or RFS in our cohort of patients.

Inter-observer variability of right ventricular output measurement in newborn infants: an observational study.

Neonatologist Performed Echocardiography (NPE) is one of the emerging technologies used to evaluate Systemic Blood Flow (SBF) in term and preterm infants. Right Ventricular Output (RVO) can assess SBF correctly in the absence of significant interatrial or interventricular shunts, even in the presence of a large patent ductus arteriosus (PDA), but only few studies evaluated inter-observer variability in neonates. Furthermore, measuring pulmonary peak flow (PF) provides a simple screening tool for low SBF state, easier and faster to perform than RVO; no previous studies evaluated PF inter-observer variability. To describe inter-observer variability of RVO and PF measurement in neonates. We conducted a prospective observational study in term and preterm infants admitted to the Neonatal Intensive Care Unit (NICU). Echocardiographic examinations were performed by two expert neonatologists, blinded to each other. Recordings were analyzed off-line to assess RVO and PF variability between observers. We analyzed a cohort of 33 neonates, 17 of them born prematurely. Inter-observer mean difference for RVO was 22,1 mL/kg/min (p = 0.005); the biggest discrepancy was due to pulmonary valve diameter measurement (p = 0.0001). Inter-observer mean difference for PF measurement was not statistically significant. We found a statistically significant inter-observer variability for RVO measurement, consistent with previous reports; PF instead showed low inter-observer variability. For this reason, PF could be evaluated in future studies as a surrogate for RVO in both term and preterm infants, especially in emergency conditions or in presence of a poor echocardiographic window.

Evaluation of the incidence of melanoma and non-melanoma skin cancer in patients with systemic lupus erythematosus and systemic sclerosis.

BACKGROUND: The incidence of skin cancer in patients with systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) has only been investigated with retrospective studies enrolling a low number of patients. The aims of our study were to assess the incidence of skin cancer in two large cohorts of patients, one with SLE and the other with SSc and investigating possible risk factors. METHODS: Ninety SLE, 53 SSc patients and 392 control subjects were enrolled. A questionnaire including personal and medical details was fulfilled. The severity of photoaging, photosensitivity and sun exposure habits was assessed. Skin lesions were evaluated using a video-dermatoscope. Suspicious lesions were surgically removed. RESULTS: The incidence of skin cancer was not different to those of controls. However, a decrease in the incidence of basal cell carcinoma was found in patients with SLE. This finding associated negatively with photosensitivity. SSc patients with skin malignancies did not report photosensitivity and did not adopt a careful photoprotection. A positive association was found between skin cancer and diffuse cutaneous sclerosis, pitting scars, severe photoaging and treatment with Iloprost. CONCLUSIONS: Regular avoidance of sun exposure and photoprotection are effective in reducing the development of skin cancer in patients with autoimmune diseases.

Artificial Intelligence-suggested Predictive Model of Survival in Patients Treated With Stereotactic Radiotherapy for Early Lung Cancer.

BACKGROUND/AIM: Overall survival (OS)-predictive models to clinically stratify patients with stage I Non-Small Cell Lung Cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT) are still unavailable. The aim of this work was to build a predictive model of OS in this setting. PATIENTS AND METHODS: Clinical variables of patients treated in three Institutions with SBRT for stage I NSCLC were retrospectively collected into a reference cohort A (107 patients) and 2 comparative cohorts B1 (32 patients) and B2 (38 patients). A predictive model was built using Cox regression (CR) and artificial neural networks (ANN) on reference cohort A and then tested on comparative cohorts. RESULTS: Cohort B1 patients were older and with worse chronic obstructive pulmonary disease (COPD) than cohort A. Cohort B2 patients were heavier smokers but had lower Charlson Comorbidity Index (CCI). At CR analysis for cohort A, only ECOG Performance Status 0-1 and absence of previous neoplasms correlated with better OS. The model was enhanced combining ANN and CR findings. The reference cohort was divided into prognostic Group 1 (0-2 score) and Group 2 (3-9 score) to assess model's predictions on OS: grouping was close to statistical significance (p=0.081). One and 2-year OS resulted higher for Group 1, lower for Group 2. In comparative cohorts, the model successfully predicted two groups of patients with divergent OS trends: higher for Group 1 and lower for Group 2. CONCLUSION: The produced model is a relevant tool to clinically stratify SBRT candidates into prognostic groups, even when applied to different cohorts. ANN are a valuable resource, providing useful data to build a prognostic model that deserves to be validated prospectively.

Retinal microvascular alterations in patients with active rheumatoid arthritis without cardiovascular risk factors: the potential effects of T cell co-stimulation blockade.

Background: The evaluation of microvascular alterations might provide clinically useful information for patients with an increased cardiovascular (CV) risk, such as those with rheumatoid arthritis (RA), being the small artery remodeling the earliest form of target organ damage in primary CV diseases, such as arterial hypertension. The evaluation of retinal arterioles is a non-invasive technique aimed to identify an early microvascular damage, represented by the increase of the wall-to-lumen ratio (WLR) index. Abatacept (ABA), a T-cell co-stimulator blocker, is used to treat RA. A CV protective action was hypothesized for its peculiar mechanism of action in the modulation of T-cells, potentially involved in the pathogenesis of CV comorbidity. The study aimed to non-invasively investigate morphological characteristics of retinal arterioles in a cohort of RA patients treated with ABA. Materials and methods: Seventeen RA patients [median (25th-75thpercentile) age = 58 (48-64) years, baseline 28-joint Disease Activity Score DAS28-C-reactive protein (DAS28-CRP) = 4.4 (3.9-4.6), body mass index (BMI) = 24.2 (23.4-26) kg/m2, rheumatoid factor positive:52.9%, anti-citrullinated peptide autoantibodies positive:76.5%] without known CV risk factors (arterial hypertension, diabetes, hypercholesterolemia, previous CV events, smoking) were evaluated by the adaptive optics imaging system of retinal arterioles before and every 6 months of therapy with ABA (T0, T6 and T12). Office blood pressure evaluation, 24-h ambulatory blood pressure monitoring and tissue-doppler echocardiography were also performed. Results: A progressive significant reduction of the WLR of retinal arterioles was observed [T0 = 0.28 (0.25-0.30), T6 = 0.27 (0.24-0.31), T12 = 0.23 (0.23-0.26); p T0 vs. T6 = 0.414; p T6 vs. T12 = 0.02; p T0 vs. T12 = 0.009], without significant variations in other parameters. The T0-T12 reduction of WLR was correlated with that of DAS28-CRP (r:0.789; p = 0.005). Moreover, a significant reduction of diastolic office blood pressure and a trend for reduction of daily pressure measured by ambulatory monitoring were observed. Conclusion: In a cohort of RA patients without known CV risk factors, a reduction of retinal microvascular alterations was demonstrated after treatment for 12 months with ABA, in parallel with the reduction of disease activity. These results might suggest the possibility of microvascular abnormalities regression induced by the immune system modulation.

Early onset of puberty during COVID-19 pandemic lockdown: experience from two Pediatric Endocrinology Italian Centers.

OBJECTIVES: During COVID-19 pandemic lockdown, reports of evaluations for suspected precocious puberty significantly raised. We aimed to assess the increase of precocious puberty in patients referred to Pediatric Endocrinology Units of Brescia (Italy), to determine clinical characteristics of patients undergoing a GnRH stimulation test before and during lockdown and evaluate the role of environmental factors in pubertal development. METHODS: Clinical and biochemical data of patients undergoing GnRH stimulation test were collected and stratified in two groups: March 2019 - February 2020 (Period 1) and March 2020 - February 2021 (Period 2). RESULTS: A total number of 391 evaluations for suspected precocious puberty were identified in the two study periods: 183 (46.8%) first visits during Period 1, and 208 (53.2%) in Period 2. Sixty-one patients underwent a GnRH stimulation test (4.1% of first consultations) before the SARS-CoV2 pandemic, and 93 children (8.7%) after the lockdown. Thirty-four new diagnoses of central precocious puberty were registered during Period 1 (2.3%), vs. 45 new cases (4.2%) in Period 2. During lockdown patients evaluated for suspected precocious puberty underwent a stimulation test at younger age than those evaluated before pandemic (median age of 8.2 years vs. 8.4, p=0.04). In Period 2, children showed a median bone age advancement of 0.61 years vs. 1.06 of Period 1 (p=0.03). CONCLUSIONS: During the COVID-19 pandemic, we observed an increased proportion of consultations for suspected precocious puberty. These children showed lower bone age advancement than observed in pre-lockdown suggesting the influence of pandemic-related lifestyle changes on pubertal development.

Definition of the Clinical Characteristics of Patients with Moderate and Severe Atopic Dermatitis for Whom Narrow-Band UVB (NB-UVB) and Medium-Dose UVA1 Phototherapies Are Still Valuable Treatment Options at the Age of Biologics.

Narrow-band (NB) UVB and UVA1 have been successfully used for the treatment of atopic dermatitis (AD) since the 1980s, but the clinical indications for their use "at the age of biologics" remain to be assessed. From 2013 to 2017, 145 patients underwent a first treatment cycle with phototherapy. They achieved a median final EASI score of 9.90 with UVA1 and 13.70 with NB-UVB. The rates of patients achieving an IGA score of 0/1 persistent for at least 6 months were 33% with UVA1 and 28% with NB-UVB, and the rates with an EASI90 improvement were 10.9% with UVA1 and 11.0% with NB-UVB. The cut-off baseline EASI values for a good probability to achieve a 0/1 IGA were 24.4 with UVA1 and 24.7 with NB-UVB. A 0/1 IGA persistent for at least 6 months was more likely to be achieved by patients with a history of flares interspersed with periods of mild or no disease. From 2018, we only enrolled patients with the above-mentioned characteristics. The number of treated patients was lower, but the final EASI score, the rate of patients achieving IGA 0/1 persistent for at least 6 months, and EASI90 were significantly higher. Medium-dose UVA1 and NB-UVB phototherapies remain useful for the treatment of AD patients with a baseline EASI score lower than 24.4 and 24.7, respectively, and a medical history of flares followed by prolonged periods of complete or near-complete remission.

Dupilumab Treatment Efficacy and Impact on Clinical Scores, Serum Biomarkers, and Itch in Adult Patients with Atopic Dermatitis: A Retrospective Analysis.

Purpose: Dupilumab, a fully human monoclonal antibody that inhibits the signaling pathways of interleukin (IL)-4 and IL-13, has demonstrated remarkable efficacy in the treatment of atopic dermatitis (AD). Dupilumab has been reported to attenuate itch and reduce several serum markers, including blood lactate dehydrogenase (LDH), blood eosinophil count, and serum total immunoglobulin E (IgE). Patients and Methods: The present study investigated retrospectively changes in clinical scores and serum biomarker from 175 adults with moderate-to-severe AD treated with dupilumab. Clinical manifestations were assessed using eczema area and severity index (EASI) and visual analogue scale (VAS) for itch at baseline and subsequently at 16-week intervals up to a duration of 48 weeks. Total IgE, LDH and blood eosinophil count were also collected. Results: The dupilumab treatment significantly improved EASI and VAS scores and decreased serum levels of IgE, LDH, and total eosinophil count. The EASI scores were positively correlated with VAS for itch at all recorded time points, whereas serum biomarkers did not exhibit a strong correlation with EASI scores. Conclusion: These findings highlight the close relationship between the extent and severity of eczema and the intensity of itch experienced by patients and suggest that factors beyond the measured serum biomarkers play a significant role in the clinical manifestations of AD, emphasizing the complex nature of the disease.

A Twenty-Year Retrospective Analysis of Risk Assessment of Biomechanical Overload of the Upper Limbs in Multiple Occupational Settings: Comparison of Different Ergonomic Methods.

BACKGROUND: Several methods with which to assess the risk of biomechanical overload of the upper limb are described in the literature. METHODS: We retrospectively analysed the results of the risk assessment of the biomechanical overload of the upper limb in multiple settings by comparing the application of the Washington State Standard, the threshold limit values (TLV) proposed by the American Conference of Governmental Industrial Hygienists (ACGIH), based on hand-activity levels (HAL) and normalised peak force (PF), the Occupational Repetitive Actions (OCRA) checklist, the Rapid Upper-Limb Assessment (RULA), and the Strain Index and Outil de Repérage et d'Evaluation des Gestes of INRS (Institut National de Recherche et de Sécurité). RESULTS: Overall, 771 workstations were analysed for a total of 2509 risk assessments. The absence of risk demonstrated for the Washington CZCL, used as the screening method, was in good agreement with the other methods, with the sole exception of the OCRA CL, which showed at-risk conditions in a higher percentage of workstations. Differences in the assessment of the frequency of actions were observed among the methods, while their assessments of strength appeared to be more uniform. However, the greatest discrepancies were observed in the assessment of posture. CONCLUSIONS: The use of multiple assessment methods ensures a more adequate analysis of biomechanical risk, allowing researchers to investigate the factors and segments in which different methods show different specificities.