Progression of type 1 diabetes is associated with high levels of soluble PD-1 in islet autoantibody-positive children.

AIMS/HYPOTHESIS: Type 1 diabetes is an autoimmune disorder that is characterised by destruction of pancreatic beta cells by autoreactive T lymphocytes. Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb+) children to identify molecules related to type 1 diabetes progression. METHODS: We measured the levels of 14 sICM in the sera of AAb+ children (n=57) compared to those with recent-onset type 1 diabetes (n=79) and healthy children (n=44), obtained from two cohorts. AAb+ children were followed up and divided based on their progression to type 1 diabetes (AAbP) or not (AAbNP) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAbP children. RESULTS: We found that AAb+ children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb+ children who progressed to type 1 diabetes (AAbP) had higher sICM concentrations than non-progressors (AAbNP). Further, sICM levels decreased in AAbP children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; p=0.007). CONCLUSIONS/INTERPRETATION: This study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoimmune diabetes.

The Inborn Errors of Immunity-Virtual Consultation System Platform in Service for the Italian Primary Immunodeficiency Network: Results from the Validation Phase.

PURPOSE: Inborn errors of immunity (IEI) represent a heterogeneous group of rare genetically determined diseases. In some cases, patients present with complex or atypical phenotypes, not fulfilling the accepted diagnostic criteria for IEI and, thus, at high risk of misdiagnosis or diagnostic delay. This study aimed to validate a platform that, through the opinion of immunologist experts, improves the diagnostic process and the level of care of patients with atypical/complex IEI. METHODS: Here, we describe the functioning of the IEI-Virtual Consultation System (VCS), an innovative platform created by the Italian Immunodeficiency Network (IPINet). RESULTS: In the validation phase, from January 2020 to June 2021, 68 cases were entered on the IEI-VCS platform. A final diagnosis was achieved in 35/68 cases (51%, 95% CI 38.7 to 64.2). In 22 out of 35 solved cases, the diagnosis was confirmed by genetic analysis. In 3/35 cases, a diagnosis of secondary immunodeficiency was made. In the remaining 10 cases, an unequivocal clinical and immunological diagnosis was obtained, even though not substantiated by genetic analysis. CONCLUSION: From our preliminary study, the VCS represents an innovative and useful system to improve the diagnostic process of patients with complex unsolved IEI disorders, with benefits both in terms of reduction of time of diagnosis and access to the required therapies. These results may help the functioning of other international platforms for the management of complex cases.

Circulating cytokines and risk of developing hypertension: A systematic review and meta-analysis.

BACKGROUND: Immune responses play a significant role in hypertension, though the importance of key inflammatory mediators remains to be defined. We used a systematic literature review and meta-analysis to study the associations between key cytokines and incident hypertension. METHODS: We performed a systematic search of Pubmed/Medline, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL), for peer-reviewed studies published up to August 2022. Incident hypertension was defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg and/or the use of antihypertensive medications. Random effects meta-analyses were used to calculate pooled hazard ratios (HRs)/risk ratios (RRs) and 95% confidence intervals by cytokine levels (highest vs. lowest quartile). RESULTS: Only IL-6 and IL-1ß levels have evidence allowing for quantitative evaluation concerning the onset of hypertension. Six studies (10406 participants, 2932 incident cases) examined the association of IL-6 with incident hypertension. The highest versus lowest quartile of circulating IL-6 was associated with a significant HR/RR of hypertension (1.61, 95% CI: 1.00 to 2.60; I2 =87%). After adjusting for potential confounders, including body mass index (BMI), HR/RR was no longer significant (HR/RR: 1.24; 95% CI, 0.96 to 1.61; I2 = 56%). About IL-1ß, neither the crude (HR/RR: 1.03; 95% CI, 0.60 to 1.76; n = 2) nor multivariate analysis (HR/RR: 0.97, 95% CI, 0.60 to 1.56; n = 2) suggested a significant association with the risk of developing hypertension. CONCLUSIONS: A limited number of studies suggest that higher IL-6, but not IL-1ß, might be associated with the development of hypertension.

Findings from the Use of Spinal Anesthesia in the Laparoscopic Treatment of Extrauterine Pregnancy: Could It Represent an Alternative to General Anesthesia?

INTRODUCTION: Minimally invasive procedures performed in laparoscopy, such as salpingectomy for ectopic pregnancy, can be combined with a minimally invasive anesthesia. The aim of this study was to assess the feasibility and the intraoperative and postoperative outcomes of laparoscopic surgery for ectopic pregnancy under spinal anesthesia (SA) compared to general anesthesia (GA) from the point of view of the surgeon, anesthesiologist, and patient. METHODS: A retrospective cohort study was performed at DAI Materno Infantile of AOU Federico II of Naples, analyzing all medical records of women who met the inclusion criteria between April 2020 and April 2023. Eighty-two women (35 under SA in group A and 47 under GA in group B) undergone elective or emergency laparoscopic salpingectomy for ectopic tubal or ovarian pregnancy were included. RESULTS: Patients in group A reported less pain at 0 h (adjusted mean difference: -1.5; 95% CI: -2.3 to -0.7; p < 0.001) and after 6 h (adjusted mean difference: -1.1; 95% CI: -2.0 to -0.3; p = 0.01) while no statistically significant differences between the two groups at 12 and 24 h after surgery. No differences were observed among the type of analgesic and during the postoperative observation time, except for paracetamol at 0 h in group B. A faster resumption of bowel motility, patient's mobilization, and a shorter hospital stay were observed in group A compared to group B. Also greater odds of returning faster to daily activities emerged in group A (adjusted OR: 5.39; 95% CI: 1.77-16.37). A greater number of patients in group A were satisfied with the entire procedure compared to those of group B (33 [94.3%] vs. 37 [78.7%]). The general surgeon satisfaction was always very good or excellent in group A. Finally, all surgical steps were well tolerated in group A. CONCLUSION: In specific settings, SA is a feasible and safe procedure for the laparoscopic treatment of ectopic pregnancy.

Endovenous laser ablation (EVLA) for vein insufficiency: two-year results of a multicenter experience with 1940-nm laser diode and a novel optical fiber.

Thermoablative techniques currently represent, in accordance with international guidelines, the most used methods in the treatment of varicose veins. From some years, lasers with a wavelength greater than 1900 nm have been introduced for EndoVenous Laser Ablation (EVLA) treatment. However, currently, few clinical studies regarding this new technology are reported in the medical literature. The aim of this study is to evaluate outcomes at a 2-year follow-up (mid-term) of EVLA of varicose veins of the lower limbs using a 1940-nm laser and a new cylindric monoring fiber. This clinical trial was conducted as a multicenter, retrospective, non-randomized, non-blind clinical study. Ninety-three patients were enrolled for a total of one hundred consecutive procedures performed in the period between January 2021 and May 2021 in two Italian facilities. The primary efficacy endpoint was the occlusion rate of the treated vein immediately after surgery and at the follow-up (24 months). The secondary efficacy endpoint was the evaluation of the parameters of energy delivered during the procedure (power and linear energy density or LEED). The primary safety endpoints were the incidence of pain (1 day and 7 days after surgery) and the rate of intraoperative and postoperative complications. The precepted pain was evaluated with the visual analog scale (VAS). The secondary safety endpoint was the evaluation of the improvement of the patient's symptoms related to venous disease. This evaluation was conducted by recording the changes in clinical, etiologic, anatomic, and pathophysiologic (CEAP) classification. All procedures were carried out regularly on an outpatient basis, and no intraoperative complications occurred. The occlusion rate of the target veins was 100% at 7- and 30-day controls. At follow-up controls, performed at 6 months, 1 and 2 years carried out showed an occlusion rate respectively of 99% (97 to 100), 96.9% (93.6 to 100), and 95.9% (92.1 to 99.9). The secondary efficacy endpoint was the evaluation of the parameters of energy delivered during the procedure (power watt and linear energy density): As regards the power parameters, we report an average of watts of 4.5 ± 0.8 [2.5 to 6] and linear energy density delivered (LEED) of 41.2 ± 8.6 [(21.1 to 66.7)]. The pain reported (with VAS scale) on 1 day of the procedure was 2 [1; 3] and 1 [0 to 4] at 7 days. All patients showed improved symptoms related to venous disease, with reduction of the individual CEAP class to which they belong. This study demonstrates that EndoVascular Laser Ablation (EVLA) treatment of varicose veins with a wavelength > 1900 nm is safe and effective. The overall occlusion rate was high. The reported results suggest that using lower parameters, such as output power (watts) and LEED (linear energy density), do not reduce the success rate of the treatment when used over 35 J/cm.

Isolated Valve Amyloid Deposition in Aortic Stenosis: Potential Clinical and Pathophysiological Relevance.

Amyloid deposition within stenotic aortic valves (AVs) also appears frequent in the absence of cardiac amyloidosis, but its clinical and pathophysiological relevance has not been investigated. We will elucidate the rate of isolated AV amyloid deposition and its potential clinical and pathophysiological significance in aortic stenosis (AS). In 130 patients without systemic and/or cardiac amyloidosis, we collected the explanted AVs during cardiac surgery: 57 patients with calcific AS and 73 patients with AV insufficiency (41 with AV sclerosis and 32 without, who were used as controls). Amyloid deposition was found in 21 AS valves (37%), 4 sclerotic AVs (10%), and none of the controls. Patients with and without isolated AV amyloid deposition had similar clinical and echocardiographic characteristics and survival rates. Isolated AV amyloid deposition was associated with higher degrees of AV fibrosis (p = 0.0082) and calcification (p < 0.0001). Immunohistochemistry analysis suggested serum amyloid A1 (SAA1), in addition to transthyretin (TTR), as the protein possibly involved in AV amyloid deposition. Circulating SAA1 levels were within the normal range in all groups, and no difference was observed in AS patients with and without AV amyloid deposition. In vitro, AV interstitial cells (VICs) were stimulated with interleukin (IL)-1ß which induced increased SAA1-mRNA both in the control VICs (+6.4 ± 0.5, p = 0.02) and the AS VICs (+7.6 ± 0.5, p = 0.008). In conclusion, isolated AV amyloid deposition is frequent in the context of AS, but it does not appear to have potential clinical relevance. Conversely, amyloid deposition within AV leaflets, probably promoted by local inflammation, could play a role in AS pathophysiology.

Chest CT Lung Abnormalities 1 Year after COVID-19: A Systematic Review and Meta-Analysis.

Background Radiological lung sequelae may explain the persistence of respiratory complaints in post-COVID-19 condition (long-COVID). Purpose To perform a systematic review and meta-analysis of the prevalence and type of COVID-19 residual lung abnormalities at 1-year chest CT. Materials and Methods A literature search of PubMed, Web of Science, Embase, and Medline databases was performed from January 2020 to January 2023. Full-text reports of CT lung sequelae in adults (≥18 years) with confirmed COVID-19 at 1-year follow-up were included. The prevalence of any residual lung abnormality and type (fibrotic or not) was analyzed according to the Fleischner Glossary. The meta-analysis included studies with chest CT data assessable in no less than 80% of individuals. A random-effects model was used to estimate pooled prevalence. Multiple sub-group (country, journal category, methodological quality, study setting, outcomes) and meta-regression analyses were performed to identify potential sources of heterogeneity. I2 statistics estimated low (25%), moderate (26-50%) and high (>50%) heterogeneity. 95% Prediction Intervals (95% PIs) were computed to describe the expected estimates range. Results Of 22 709 records, 21 studies were reviewed (20 prospective, 9 from China, and 7 in radiology journals). The meta-analysis included 14 studies with chest CT data in 1854 of 2043 individuals (M/F: 1109/934). Estimates of lung sequelae were highly heterogeneous (7.1-96.7%), with a pooled frequency of 43.5% (I2=94%; 95% PI: 5.9%, 90.4%). This also applied to single non-fibrotic changes, including ground glass opacity, consolidations, nodules/masses, parenchymal bands, and reticulations. The prevalence range of fibrotic traction bronchiectasis/bronchiolectasis was 1.6-25.7% (I2=93%; 95% PI: 0.0%, 98.6%;); honeycombing was unremarkable (0-1.1%; I2=58%; 95% PI: 0%, 60%). Lung sequelae were unrelated to any characteristics of interest. Conclusion The prevalence of COVID-19 lung sequelae at 1-year chest CT is highly heterogeneous among studies. Heterogeneity determinants remain unknown suggesting caution in data interpretation with no convincing evidence. PROSPERO (CRD42022341258) Keywords: COVID-19 pneumonia, pulmonary fibrosis, chest CT, long-COVID, systematic review, metaanalysis See also the editorial by Parraga and Svenningsen in this issue.

Platelet Inhibition with Ticagrelor 60 mg Versus 90 mg Twice Daily in Elderly Patients with Acute Coronary Syndrome: Rationale and Design of the PLINY THE ELDER Trial.

BACKGROUND: Elderly status is steadily increasing among patients with acute coronary syndrome (ACS). Dual antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 receptor inhibitor is the cornerstone of treatment to prevent recurrent thrombotic complications in patients with ACS. However, DAPT in older patients is challenged by a concurrent heightened risk of ischemia and bleeding. The aim of this study is to evaluate the pharmacodynamic and pharmacokinetic profile of a lower dose of ticagrelor (60 mg twice daily) among elderly patients during the early phase of ACS. STUDY DESIGN: PLINY THE ELDER (PLatelet INhibition with two different doses of potent P2y12 inhibitors in THE ELDERly population) (NCT04739384) is a prospective, randomized, open-label, crossover trial to evaluate the non-inferiority of a lower dose of ticagrelor (60 mg twice daily) compared with a standard dose (90 mg twice daily) among elderly patients with ACS undergoing percutaneous coronary intervention (PCI). A total of 50 patients, aged 75 years or more, with indication to potent P2Y12 receptor inhibitors will be randomized within 3 days from PCI for the index ACS. Patients with indication to oral anticoagulant therapy, treatment with glycoprotein IIb/IIIa inhibitors, or active bleeding will be excluded. The primary endpoint is platelet reactivity determined by P2Y12 reaction units (PRU) (VerifyNow, Accumetrics, San Diego, CA, USA) after treatment with ticagrelor 60 or 90 mg twice daily for 14 days. Secondary endpoints will include other pharmacodynamic tests of ADP-induced aggregation (light transmittance aggregometry and multiple electrode aggregometry) and determination of pharmacokinetic profile (plasma levels of ticagrelor and its metabolite AR-C124910XX) by high performance liquid chromatography-tandem mass spectrometry. CONCLUSIONS: The PLINY THE ELDER trial will determine whether a lower dose of ticagrelor confers non-inferior platelet inhibition compared with the standard dose in the early phase of ACS among elderly patients undergoing PCI, informing future clinical investigation.

Prevalence and Risk Factors of Functional Gastrointestinal Disorders: A Cross-Sectional Study in Italian Infants and Young Children.

OBJECTIVES: Reports of prevalence of functional gastrointestinal disorders (FGIDs) in infants/toddlers are widely variable. Reasons for this variability are not yet fully understood. The objective of this study is to estimate the prevalence of FGIDs according to Rome IV criteria and to evaluate associated factors, in Italian infants and toddlers. METHODS: Subjects aged 0-48 months were enrolled by general pediatricians from 3 Italian regions. Parents or legal guardians were administered questionnaires including information about the child, the family, and GI symptoms according to Rome IV criteria. RESULTS: Five hundred eight infants aged 0-12 months [mean age 4.4 ± 3.4 months; females (F) 40.9%], and 268 children aged 13-48 months (mean age 30.8 ± 10.7 months; F 44.4%) were included. In infants, prevalence of FGIDs was 21.1%, and the most prevalent FGID was infant colic (9.3%). In toddlers, prevalence of FGIDs was 19.6%, with functional constipation being the most frequent disorder (16.1%). In infants, multivariable analysis found that being older, being the only child, and living in a rural environment were associated with a lower rate of FGIDs. Prevalence was, in contrast, higher in infants fed with formula. CONCLUSIONS: One out of 5 Italian infants and young children is affected by at least 1 FGID. The most frequent FGID in infants is infant colic, while in toddlers this is functional constipation. In infants, prevalence of FGIDs is lower if the subject has no siblings, and in children living in a rural environment, while formula feeding represents a risk factor for FGIDs occurrence.

Endovascular laser treatment. Comparison of lasers and fibers of different generations: study of temperatures and tissue damage produced on a porcine liver model.

The current international guidelines identify tumescent ablative techniques such as laser thermal ablation (EVLA) and radiofrequency (RFA) to be the gold standard in varicose vein surgery. New-generation lasers have been introduced, which have high wavelengths (1940 and 2000 nm) and therefore with a greater affinity for water than the old generation (980- and 1470-nm lasers). The purpose of the study was to evaluate the biological effect and the temperatures produced during the use of lasers with different wavelengths (980, 1470, and 1940 nm) and with optical fibers with different emission (radial diverging at 60° and radial with cylindrical mono-ring) on in vitro model. Porcine liver was used as an in vitro model. The laser control units used had 3 different wavelengths: 980, 1470, and 1940 nm. The optical fibers used were 2: the Corona 360 fiber (mono-ring radial fiber) and the infinite fiber (cylindrical mono-ring fiber). The laser operating parameters used included the delivery of 6 W in continuous wave (CW) mode with a standard 10 s/cm pull-back. Eleven measurements were made for each fiber and for each laser, for a total of 66 measurements. We performed measurements of the maximum transverse diameter produced with laser irradiation to evaluate the biological effectiveness of the treatment. During laser irradiation, we performed measurements of both of the temperatures reached on the external surface of the porcine tissue, near the tip of the laser catheter, and the temperatures reached inside the irradiated tissue by using a digital laser infrared thermometer with apposite probe. The calculation of the statistical significance (p-value) was obtained with the ANOVA method with two between factors. The comparison study of the maximum transverse diameter (DTM) of the lesion produced on the target tissue demonstrated the absence of statistically significant differences between the 1470-nm laser and the 1940-nm laser regardless of the type of fiber used. It was not possible to perform measurements of the maximum transverse diameter produced with the 980-nm laser as this produced no visible effect on the model. The comparison study of the temperatures developed during and immediately after the treatment instead showed higher maximum surface temperatures (TSM) and a higher thermal increase (IT) regardless of the type of fiber used in a statistically significant way (respectively, p 0.002 and 0.012) when using the 980-nm laser versus the 1940-nm laser. Comparing instead the 980-nm laser with 1470 nm, there were no differences in TI recorded during the procedure but a significantly higher VTI (p 0.029). The experiment conducted with the new generation laser, compared with those of the first and second generation, shows how this works overall at lower temperatures with the same effectiveness.

The heart to single vertebra ratio: A new objective method for radiographic assessment of cardiac silhouette size in dogs.

Vertebral heart size (VHS) is widely determined in clinical practice as an objective method to assess the cardiac silhouette dimensions. However, a key limitation is that it is difficult to determine VHS in dogs with vertebral alterations. This retrospective, method comparison, observer agreement study sought to overcome this limitation by using the heart-to-single vertebra ratio (HSVR), by evaluating the level of agreement between VHS and HSVR, as well as the intra- and inter-observer agreement for HSVR. Three independent observers retrospectively evaluated thoracic radiographs obtained over a set time period. Exclusion criteria were the presence of alterations of the thoracic spine and the inability to clearly outline the cardiac silhouette. The lengths of the vertebral bodies, from the fourth to eighth thoracic vertebra, and VHS were measured on each radiograph. The HSVR was calculated by dividing the sum of the cardiac long and short axes by the length of each vertebral body. Eighty dogs of different breeds were included in the final analysis. Lin's concordance correlation coefficients revealed strong correlations between VHS and HSVR (0.91-0.96), and the Bland-Altman plots showed low bias (0.01-0.2) between the methods. The mean absolute errors indicated low average magnitudes of error (0.11-0.28). The intraclass correlation coefficients showed good to excellent inter-observer (0.87-0.92; P = 0.000) and intra-observer (0.87-0.99; P < .001) agreement. In the authors' opinion, this new method, which is less time consuming and more objective, could offer a valuable alternative to VHS.

High levels of blood circulating immune checkpoint molecules in children with new-onset type 1 diabetes are associated with the risk of developing an additional autoimmune disease.

AIMS/HYPOTHESIS: We assessed the levels of blood circulating immune checkpoint molecules (ICMs) at diagnosis of type 1 diabetes, and determined their association with the risk of developing an additional autoimmune disorder over time. METHODS: Children with new-onset type 1 diabetes (n = 143), without biological and/or clinical signs of additional autoimmune disorders, and healthy children (n = 75) were enrolled, and blood circulating levels of 14 ICMs were measured. The children with type 1 diabetes were divided into two groups on the basis of the development of an additional autoimmune disease in the 5 years after diabetes onset. Differences in soluble ICM levels between the groups were assessed, and a Cox regression analysis was used to evaluate their association with the risk of development of an additional autoimmune disease over time. To validate the data, circulating ICMs were measured in an independent cohort of 60 children with new-onset type 1 diabetes stratified into two groups. RESULTS: We found that the levels of circulating ICMs were significantly higher in children with new-onset diabetes compared with healthy children. Further, we observed that children with type 1 diabetes who developed a second autoimmune disease over time (T1D-AAD+ children) had higher levels of soluble ICMs than children with type 1 diabetes who did not (T1D-AAD- children). Cox regression models revealed that high circulating levels of CD137/4-1BB and PD-1 molecules at diabetes diagnosis were associated with the risk of developing an additional autoimmune disease in both type 1 diabetes cohorts. CONCLUSIONS/INTERPRETATION: Our findings suggest that soluble CD137/4-1BB and PD-1 molecules may be used as prognostic biomarkers in children with type 1 diabetes, and may pave the way for novel immunological screening at diabetes onset, allowing early identification of children at higher risk of developing other autoimmune conditions over time.

Progressive Depletion of B and T Lymphocytes in Patients with Ataxia Telangiectasia: Results of the Italian Primary Immunodeficiency Network.

Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype-phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.

Systemic administration of glucocorticoids, cardiovascular complications and mortality in patients hospitalised with COVID-19, SARS, MERS or influenza: A systematic review and meta-analysis of randomised trials.

BACKGROUND: Administration of glucocorticoids might reduce mortality in patients with severe COVID-19 but have adverse cardiometabolic effects. OBJECTIVES: to investigate the effect of systemic administration of glucocorticoids on cardiovascular complications and all-cause mortality in patients hospitalised with respiratory viral infections, including COVID-19, SARS, MERS and influenza. METHODS: We identified randomised trials published prior to July 28th, 2021. The Mantel-Haenszel random effects method and the Hartung and Knapp adjustment were used to obtain pooled estimates of treatment effect with 95% confidence intervals. RESULTS: No randomised trials of glucocorticoids for SARS, MERS or influenza reported relevant outcomes. We included eleven COVID-19 randomised trials (8109 patients). Overall, compared to placebo or standard care, glucocorticoids were not associated with a reduction of in-hospital mortality (p = 0.09). In a pre-specified sub-analysis, in-hospital mortality was reduced by 19% when follow-up was restricted to 14 days from randomisation (5/11 trials, 1329 patients, p = 0.02). With longer follow-up (9/11 trials, 7874 patients), administration of glucocorticoids was associated with a trend to benefit for those requiring mechanical ventilation (RR 0.86; 95% CI 0.57-1.27) but possible harm for those not receiving oxygen at randomisation (RR 1.27; 95% CI 1.00 - 1.61), an effect that was significantly different amongst subgroups (p = 0.0359). Glucocorticoids reduced the risk of worsening renal function by 37% (4/11 trials); reported rate of other cardiovascular complications was low. CONCLUSIONS: Administration of systemic glucocorticoids to patients hospitalised with COVID-19 does not lower mortality overall but may reduce it in those requiring respiratory support and increase it in those who do not.

The impact of symptoms on daily life as perceived by patients with Charcot-Marie-Tooth type 1A disease.

INTRODUCTION: In Charcot-Marie-Tooth type 1A (CMT1A) patients, daily life is mainly influenced by mobility and ambulation dysfunctions. The aim of our work was to evaluate the perception of disturbances that mostly impact on daily life in CMT1A patients and its difference on the basis of age, gender, disability, and quality of life. METHODS: Forty-one CMT1A patients underwent neurological assessment focused on establishing clinical disability through the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and quality of life through the Short Form-36 (SF-36) questionnaire. We identified from CMT disturbances 5 categories [weakness in lower limbs (WLL), weakness in upper limbs (WUL), skeletal deformities (SD), sensory symptoms (SS), balance (B)] and patients classified the categories from the highest to the lowest impact on daily life (1: highest; 5: lowest). Ranking of the 5 categories, in the overall sample and in the different subgroups (dividing by gender, median of age and disease duration, CMTNS, domains of SF-36), was obtained and differences among subgroups were assessed using a bootstrap approach. RESULTS: Rank analysis showed that WLL was the most important disturbance on daily life whereas WUL had the lowest impact. In the older CMT1A group, the most important disturbance on daily life was B that was also the most relevant disturbance in patients with a greater disability. SD influenced daily life in younger patients. SS had less impact on daily life, with the exception of patients with a milder disability. DISCUSSION: Our findings demonstrated that the perception of disturbances that mostly impact on CMT1A patients' daily life changes over the lifetime and with degree of disability.

Performance and characteristics of the Newborn Hearing Screening Program in Campania region (Italy) between 2013 and 2019.

PURPOSE: Universal newborn hearing screening (UNHS) in the first month of life is crucial for facilitating both early hearing detection and intervention (EHDI) of significant permanent hearing impairment (PHI). In Campania region, UNHS has been introduced in 2003 by the Regional Council Resolution and started on January 2007. The aim of this paper is to update a previous article describing the performance of the program since its implementation in the period between 2013 and 2019. METHODS: A longitudinal retrospective study was carried at the Regional Reference Center III on 350,178 babies born in the analysis period. The paper reports the main results of overall coverage, referral rate, lost-to-follow-up rate,yield for PHI and shall determine various risk factor associations with hearing impairment RESULTS: In Campania region, 318,878 newborns were enrolled at I level, with a coverage rate of 91.06%, 301,818 (86.18%) Well Infant Nurseries (WIN) and 17,060 (5.35%) Neonatal Intensive Care Unit (NICU) babies. PHI was identified in 413 children, 288 (69.73%) bilaterally and 125 (30.26%) unilaterally. The overall cumulative incidence rate of PHI was 1.29 per 1000 live-born infants (95% CI 1.17-1.42) with a quite steady tendency during the whole study period. CONCLUSIONS: This study confirms the feasibility and effectiveness of UNHS in Campania region also in a setting with major socioeconomic and health organization restrictions.The program meets quality benchmarks to evaluate the progress of UNHS. Nowadays, it is possible to achieve an early diagnosis of all types of HL avoiding the consequences of hearing deprivation.

In severe obesity, subcutaneous adipose tissue cell-derived cytokines are early markers of impaired glucose tolerance and are modulated by quercetin.

BACKGROUND: Excessive adiposity provides an inflammatory environment. However, in people with severe obesity, how systemic and local adipose tissue (AT)-derived cytokines contribute to worsening glucose tolerance is not clear. METHODS: Ninty-two severely obese (SO) individuals undergoing bariatric surgery were enrolled and subjected to detailed clinical phenotyping. Following an oral glucose tolerance test, participants were included in three groups, based on the presence of normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or type 2 diabetes (T2D). Serum and subcutaneous AT (SAT) biopsies were obtained and mesenchymal stem cells (MSCs) were isolated, characterized, and differentiated in adipocytes in vitro. TNFA and PPARG mRNA levels were determined by qRT-PCR. Circulating, adipocyte- and MSC-released cytokines, chemokines, and growth factors were assessed by multiplex ELISA. RESULTS: Serum levels of IL-9, IL-13, and MIP-1ß were increased in SO individuals with T2D, as compared with those with either IGT or NGT. At variance, SAT samples obtained from SO individuals with IGT displayed levels of TNFA which were threefold higher compared to those with NGT, but not different from those with T2D. Elevated levels of TNFα were also found in differentiated adipocytes, isolated from the SAT specimens of individuals with IGT and T2D, compared to those with NGT. Consistent with the pro-inflammatory milieu, IL-1ß and IP-10 secretion was significantly higher in adipocytes from individuals with IGT and T2D. Moreover, increased levels of TNFα, both mRNA and secreted protein were detected in MSCs obtained from IGT and T2D, compared to NGT SO individuals. Exposure of T2D and IGT-derived MSCs to the anti-inflammatory flavonoid quercetin reduced TNFα levels and was paralleled by a significant decrease of the secretion of inflammatory cytokines. CONCLUSION: In severe obesity, enhanced SAT-derived inflammatory phenotype is an early step in the progression toward T2D and maybe, at least in part, attenuated by quercetin.

Reduced Annexin A1 Expression Associates with Disease Severity and Inflammation in Multiple Sclerosis Patients.

Chronic neuroinflammation is a key pathological hallmark of multiple sclerosis (MS) that suggests that resolution of inflammation by specialized proresolving molecules is dysregulated in the disease. Annexin A1 (ANXA1) is a protein induced by glucocorticoids that facilitates resolution of inflammation through several mechanisms that include an inhibition of leukocyte recruitment and activation. In this study, we investigated the ability of ANXA1 to influence T cell effector function in relapsing/remitting MS (RRMS), an autoimmune disease sustained by proinflammatory Th1/Th17 cells. Circulating expression levels of ANXA1 in naive-to-treatment RRMS subjects inversely correlated with disease score and progression. At the cellular level, there was an impaired ANXA1 production by CD4+CD25- conventional T and CD4+RORγt+ T (Th17) cells from RRMS subjects that associated with an increased migratory capacity in an in vitro model of blood brain barrier. Mechanistically, ANXA1 impaired monocyte maturation secondarily to STAT3 hyperactivation and potently reduced T cell activation, proliferation, and glycolysis. Together, these findings identify impaired disease resolution pathways in RRMS caused by dysregulated ANXA1 expression that could represent new potential therapeutic targets in RRMS.

Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials.

AIMS: Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD. METHODS AND RESULTS: In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85-1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80-0.96) and a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79-0.98), all-cause mortality (HR 0.89, 95% CI 0.81-0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76-0.94), and heart failure (HF) hospitalization (HR 0.92, 95% CI 0.86-0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82-1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83-1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo. CONCLUSION: Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.

Lanthionine, a Novel Uremic Toxin, in the Vascular Calcification of Chronic Kidney Disease: The Role of Proinflammatory Cytokines.

Vascular calcification (VC) is a risk factor for cardiovascular events and mortality in chronic kidney disease (CKD). Several components influence the occurrence of VC, among which inflammation. A novel uremic toxin, lanthionine, was shown to increase intracellular calcium in endothelial cells and may have a role in VC. A group of CKD patients was selected and divided into patients with a glomerular filtration rate (GFR) of <45 mL/min/1.73 m2 and ≥45 mL/min/1.73 m2. Total Calcium Score (TCS), based on the Agatston score, was assessed as circulating lanthionine and a panel of different cytokines. A hemodialysis patient group was also considered. Lanthionine was elevated in CKD patients, and levels increased significantly in hemodialysis patients with respect to the two CKD groups; in addition, lanthionine increased along with the increase in TCS, starting from one up to three. Interleukin IL-6, IL-8, and Eotaxin were significantly increased in patients with GFR < 45 mL/min/1.73 m2 with respect to those with GFR ≥ 45 mL/min/1.73 m2. IL-1b, IL-7, IL-8, IL-12, Eotaxin, and VEGF increased in calcified patients with respect to the non-calcified. IL-8 and Eotaxin were elevated both in the low GFR group and in the calcified group. We propose that lanthionine, but also IL-8 and Eotaxin, in particular, are a key feature of VC of CKD, with possible marker significance.