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Silicon carbide (SiC) films are grown on Si(111) using as a precursor fullerene seeded in helium supersonic beams. The regime of energy and flux distributions, achievable by changing the beam parameters, is well suited to synthesizing SiC films under well ordered conditions, because of better control of the synthesis process and of the C[sub 60] dissociative absorption. This is confirmed by the first experimental results and by morphological and structural characterization of the films produced. Further developments are briefly discussed. [ABSTRACT FROM AUTHOR]

Background: Activated Phosphoinositide 3-Kinase (PI3K) δ Syndrome (APDS), an inborn error of immunity due to upregulation of the PI3K pathway, leads to recurrent infections and immune dysregulation (lymphoproliferation and autoimmunity)., Methods: Clinical and genetic data of 28 APDS patients from 25 unrelated families were collected from fifteen Italian centers., Results: Patients were genetically confirmed with APDS-1 (n = 20) or APDS-2 (n = 8), with pathogenic mutations in the PIK3CD or PIK3R1 genes. The median age at diagnosis was 15.5 years, with a median follow-up of 74 months (range 6-384). The main presenting symptoms were respiratory tract infections alone (57%) or associated with lymphoproliferation (17%). Later, non-clonal lymphoproliferation was the leading clinical sign (86%), followed by respiratory infections (79%) and gastrointestinal complications (43%). Malignant lymphoproliferative disorders, all EBV-encoding RNA (EBER)-positive at the histological analysis, occurred in 14% of patients aged 17-19 years, highlighting the role of EBV in lymphomagenesis in this disorder. Diffuse large B-cell lymphoma was the most frequent. Immunological work-up revealed combined T/B cell abnormalities in most patients. Treatment strategies included immunosuppression and PI3K/Akt/mTOR inhibitor therapy. Rapamycin, employed in 36% of patients, showed efficacy in controlling lymphoproliferation, while selective PI3Kδ inhibitor leniolisib, administered in 32% of patients, was beneficial on both infections and immune dysregulation. Additionally, three patients underwent successful HSCT due to recurrent infections despite ongoing prophylaxis or lymphoproliferation poorly responsive to Rapamycin., Conclusions: This study underscores the clinical heterogeneity and challenging diagnosis of APDS, highlighting the importance of multidisciplinary management tailored to individual needs and further supporting leniolisib efficacy., Competing Interests: Declarations. Compliance with Ethical Standards: The study was conducted in strict adherence to the Helsinki Declaration: participants or their parents provided written informed consent for the collection and publication of any data included in this article, which was approved by the local ethical committee of each centre. Competing Interests: Authors V.L., C.C., F.C., A.To., A.Tr., R.B., M.Z., F.B., C.P. received an honorarium from Pharming Group N.V. to participate in the APDS advisory board. The other authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: The large-scale utilization of immunoglobulins in patients with inborn errors of immunity (IEIs) since 1952 prompted the discovery of their key role at high doses as immunomodulatory and anti-inflammatory therapy, in the treatment of IEI-related immune dysregulation disorders, according to labelled and off-label indications. Recent years have been dominated by a progressive imbalance between the gradual but constant increase in the use of immunoglobulins and their availability, exacerbated by the SARS-CoV-2 pandemic., Objectives: To provide pragmatic indications for a need-based application of high-dose immunoglobulins in the pediatric context., Sources: A literature search was performed using PubMed, from inception until 1st August 2023, including the following keywords: anti-inflammatory; children; high dose gammaglobulin; high dose immunoglobulin; immune dysregulation; immunomodulation; immunomodulatory; inflammation; intravenous gammaglobulin; intravenous immunoglobulin; off-label; pediatric; subcutaneous gammaglobulin; subcutaneous immunoglobulin. All article types were considered., Implications: In the light of the current imbalance between gammaglobulins' demand and availability, this review advocates the urgency of a more conscious utilization of this medical product, giving indications about benefits, risks, cost-effectiveness, and administration routes of high-dose immunoglobulins in children with hematologic, neurologic, and inflammatory immune dysregulation disorders, prompting further research towards a responsible employment of gammaglobulins and improving the therapeutical decisional process.

Multisystem inflammatory syndrome (MIS-C) is a rare condition associated with COVID-19 affecting children, characterized by severe and aberrant systemic inflammation leading to nonspecific symptoms, such as gastrointestinal, cardiac, respiratory, hematological, and neurological disorders. In the last year, we have experienced a progressive reduction in the incidence and severity of MIS-C, reflecting the worldwide trend. Thus, starting from the overall trend in the disease in different continents, we reviewed the literature, hypothesizing the potential influencing factors contributing to the reduction in cases and the severity of MIS-C, particularly the vaccination campaign, the spread of different SARS-CoV-2 variants (VOCs), and the changes in human immunological response. The decrease in the severity of MIS-C and its incidence seem to be related to a combination of different factors rather than a single cause. Maturation of an immunological memory to SARS-CoV-2 over time, the implication of mutations of key amino acids of S protein in VOCs, and the overall immune response elicited by vaccination over the loss of neutralization of vaccines to VOCs seem to play an important role in this change.

Background: Pyogenic bacteria are associated with a wide range of clinical manifestations, ranging from common and relatively mild respiratory and cutaneous infections to life-threatening localized or systemic infections, such as sepsis and profound abscesses. Despite vaccination and the widespread use of effective antibiotic treatment, severe infection is still observed in a subset of affected patients., Objectives: We aim to summarize the available data regarding inborn errors of immunity that result in a high risk of severe pyogenic infections., Sources: Case series, as well as review and original articles on human genetic susceptibility to pyogenic infections were examined., Content: We review host-associated factors resulting in inborn errors of immunity and leading to a susceptibility to pyogenic infections, including deficiency in major components of the immune system (e.g., neutrophils, complement, immunoglobulin, and spleen function) and novel monogenic disorders resulting in specific susceptibility to pyogenic infection. Specifically, innate immune system deficiency involving toll-like receptors and associated signaling typically predispose to a narrow spectrum of bacterial diseases in otherwise healthy people, making a diagnosis more difficult to suspect and confirm. More complex syndromes, such as hyper IgE syndrome, are associated with a high risk of pyogenic infections due to an impairment of the interleukin-6 or -17 signaling, demonstrating the pivotal role of these pathways in controlling bacterial infections., Implications: In clinical practice, awareness of such conditions is essential, especially in the pediatric setting, to avoid a potentially fatal diagnostic delay, set the most proper and prompt treatment, and ensure prevention of severe complications., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Inborn errors of intrinsic and innate immunity constitute the focus of a growing research field that investigates the molecular mechanisms underlying susceptibility to infections previously not considered part of the spectrum of inborn errors of immunity. These so-called nonconventional inborn errors of immunity often occur as infections caused by a narrow spectrum of microorganisms in otherwise healthy subjects., Objectives: This review aimed to provide a framework for identifying and evaluating patients with viral, bacterial, mycobacterial, and fungal infection needing further assessment for inborn errors of intrinsic and innate immunity., Sources: A literature search was performed using PubMed, from inception until 1 May 2022. The search included the following keywords: "inborn errors of immunity"; "inborn errors of innate immunity"; "primary immune deficiency"; "primary immunodeficiency"; "infections"; "infectious susceptibility"; "virus"; "pyogenic bacteria"; "mycobacteria"; "fungi". All article types were considered., Content: We review the definition of what can be considered an inborn error of immunity and how the definition changed over the last ∼25 years. We further provide criteria to rule out secondary immunodeficiencies, identify patients needing further clinical and laboratory immunological assessment, and suspect and diagnose an inborn error of intrinsic and innate immunity. These steps are proposed as part of an algorithm., Implications: Patients with unexplained life-threatening infections, including otherwise healthy subjects, should be systematically screened for known inborn errors of immunity. The early diagnosis can prevent recurrence of life-threatening infections in the patients and reduce the total burden of infectious diseases., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Treatment of refractory autoimmune cytopenias (AICs) and Evans syndrome (ES) represent a great challenge in pediatric setting, where an underlying primary immunodeficiency is recurrent. Frequently, second or third line treatments are employed, with an increased risk of toxicity and infections. The advent of novel drugs is the object of research in order to modify the management of these patients.We report a case of successful use of bortezomib in a child with 22q11.2 deletion syndrome and CVID-like phenotype with a multi-refractory severe ES. Last flares were prolonged and dominated by severe and symptomatic ITP, refractory to different courses of high dose steroid and IVIG, mofetil mycophenolate, thrombopoietin receptor agonists, sirolimus, and rituximab. Persistence of AICs in subjects with depletion of CD20 + B-cells and IgG strengthens the hypothesis about the production of autoantibodies by terminally differentiated plasma-cells, not targetable from immunosuppressants and rituximab.In the attempt to enhance plasma-cells inhibition, the child was addressed to bortezomib, with a good response at 6 month follow-up without side effects. Nowadays, the use of bortezomib in ES/AICs is based only on small retrospective studies and case reports. Despite the lack of long term follow-up, our work highlights the potential role of bortezomib in the management of pediatric patients with multi-resistant AICs secondary to immune-system impairment.

Sickle cell disease (SCD) is a condition of functional hypo-/a-splenism in which predisposition to bacterial infections is only a facet of a wide spectrum of immune-dysregulation disorders forming the clinical expression of a peculiar immunophenotype. The objective of this study was to perform an in-depth immunophenotypical characterization of SCD pediatric patients, looking for plausible correlations between immunological biomarkers, the impact of hydroxyurea (HU) treatment and clinical course. This was an observational case−control study including 43 patients. The cohort was divided into two main groups, SCD subjects (19/43) and controls (24/43), differing in the presence/absence of an SCD diagnosis. The SCD group was split up into HU+ (12/19) and HU− (7/19) subgroups, respectively receiving or not a concomitant HU treatment. The principal outcomes measured were differences in the immunophenotyping between SCD patients and controls through chi-squared tests, t-tests, and Pearson’s correlation analysis between clinical and immunological parameters. Leukocyte and neutrophil increase, T-cell depletion with prevalence of memory T-cell compartment, NK and B-naïve subset elevation with memory and CD21low B subset reduction, and IgG expansion, significantly distinguished the SCD HU− subgroup from controls, with naïve T cells, switched-memory B cells and IgG maintaining differences between the SCD HU+ group and controls (p-value of <0.05). The mean CD4+ central-memory T-cell% count was the single independent variable showing a positive correlation with vaso-occlusive crisis score in the SCD group (Pearson’s R = 0.039). We report preliminary data assessing plausible clinical implications of baseline and HU-related SCD immunophenotypical alterations, which need to be validated in larger samples, but potentially affecting hypo-/a-splenism immuno-chemoprophylactic recommendations.

Background: A steady increase in the international production and consumption of fish has positioned aquaculture as a development option. Previous literature has highlighted the potential of aquaculture to improve economic, nutritional and gender equality outcomes, however, the evidence on the effectiveness of these programmes remains unclear., Objectives: The review assessed whether aquaculture interventions increase the productivity, income, nutrition, and women's empowerment of individuals. We additionally aimed to identify barriers and facilitators that could affect the effectiveness of these interventions, and the cost-effectiveness of such programmes., Methods: We searched for experimental and quasi-experimental studies focused on low- and middle-income countries. We used standard methodological procedures expected by The Campbell Collaboration for the data collection and analysis., Results: We identified 21 impact evaluations assessing the effect of 13 aquaculture interventions in low- and lower-middle income countries. Twelve of these studies have a high risk of bias. Aquaculture interventions lead to a small increase in the production value, income, total expenditures and food consumption of participants. The limited availability of evidence prevented us from assessing other nutritional and women's empowerment outcomes. We identified barriers and facilitators affecting the programmes' set up, the participation of beneficiaries, and the level of productive activities. Insufficient cost data hindered full comparisons across programmes., Conclusions: The review suggests a lack of rigorous evidence assessing the effectiveness of aquaculture programmes. Future research could focus on evaluating nutrition and women's empowerment impacts, promoting reporting standards, and the use of cost data to continue building quality evidence around aquaculture interventions., (© 2021 International Initiative for Impact Evaluation (3ie). Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

The review aims to examine and synthesise the state of the evidence around what works to improve productivity, income, nutrition and women's empowerment outcomes of households involved in aquaculture in low- and middle-income countries. We are particularly interested in addressing the following research questions: (1) Do aquaculture interventions increase the productivity, income, nutrition and empowerment of individuals engaged in aquaculture and their households in low- and middle-income countries? (2) Do aquaculture interventions generate income and nutrition spillover effects beyond the farmers' households? (3) To what extent do the effects of aquaculture interventions vary by intervention type, population group, and location? In particular, to what extent do effects vary by gender? (4) What are the potential barriers and facilitating factors that impact the effectiveness of aquaculture interventions? (5) What is the cost-effectiveness of different aquaculture interventions focused on productivity, income, nutrition and empowerment outcomes?, (© 2021 International Initiative for Impact Evaluation (3ie). Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

Background: Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune-mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms., Objective: Aim of this study is to provide clinical-immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation., Methods: We retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA, and AIN, aged 0-18 years at onset of immune cytopenias and/or immune-dysregulation. The cohort was divided into two groups (IEI+ and IEI-), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: common variable immune deficiency (CVID; 9/19), autoimmune lymphoproliferative syndrome (ALPS; 4/19), DiGeorge syndrome (1/19), and unclassified IEI (5/19)., Results: IEI prevalence among patients with ITP, AIHA, AIN, and Evans Syndrome was respectively of 42%, 64%, 36%, and 62%. In IEI+ group the extended immunophenotyping identified the presence of statistically significant (p < .05) specific characteristics, namely T/B lymphopenia, decrease in naїve T-cells%, switched memory B-cells%, plasmablasts%, and/or immunoglobulins, increase in effector/central memory T-cells% and CD21low B-cells%. Except for DiGeorge and three ALPS patients, only 2/9 CVID patients had a molecular diagnosis for IEI: one carrying the pathogenic variant CR2:c.826delT, the likely pathogenic variant PRF1:c.272C> and the compound heterozygous TNFRSF13B variants p.Ser144Ter (pathogenic) and p.Cys193Arg (variant of uncertain significance), the other one carrying the likely pathogenic monoallelic variant TNFRSF13B:p.Ile87Asn., Conclusion: The synergy between hematologists and immunologists can improve and fasten diagnosis and management of patients with immune cytopenias through a wide focused clinical/immunophenotypical characterization, which identifies children worthy of IEI-related molecular analysis, favouring a genetic IEI diagnosis and potentially unveiling new targeted-gene variants responsible for IEI phenotype., (© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Problem: University of Washington Medicine (UW Medicine), an academic health system in Washington State, was at the epicenter of the first outbreak of the COVID-19 pandemic in the United States. The extent of emergency activation needed to adequately respond to this global pandemic was not immediately known, as the evolving situation differed significantly from any past disaster response preparations in that there was potential for exponential growth of infection, unproven mitigation strategies, serious risk to health care workers, and inadequate supply chains for critical equipment., Approach: The rapid transition of the UW Medicine system to account for projected COVID-19 and usual patient care, while balancing patient and staff safety and conservation of resources, represents an example of an adaptive disaster response., Key Insights: Although our organization's ability to meet the needs of the public was uncertain, we planned and implemented changes to space, supply management, and staffing plans to meet the influx of patients across our clinical entities. The surge management plan called for specific actions to be implemented based on the level of activity. This article describes the approach taken by UW Medicine as we braced for the storm., (Copyright © 2020 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

The role of DNA damage in PCR processivity/fidelity is a relevant topic in molecular investigation of aged/forensic samples. In order to reproduce one of the most common lesions occurring in postmortem tissues, a new protocol based on aqueous hydrolysis of the DNA was developed in vitro. Twenty-five forensic laboratories were then provided with 3.0 μg of a trial sample (TS) exhibiting, in mean, the loss of 1 base of 20, and a molecular weight below 300 bp. Each participating laboratory could freely choose any combination of methods, leading to the quantification and to the definition of the STR profile of the TS, through the documentation of each step of the analytical approaches selected. The results of the TS quantification by qPCR showed significant differences in the amount of DNA recorded by the participating laboratories using different commercial kits. These data show that only DNA quantification "relative" to the used kit (probe) is possible, being the "absolute" amount of DNA inversely related to the length of the target region (r(2) = 0.891). In addition, our results indicate that the absence of a shared stable and certified reference quantitative standard is also likely involved. STR profiling was carried out selecting five different commercial kits and amplifying the TS for a total number of 212 multiplex PCRs, thus representing an interesting overview of the different analytical protocols used by the participating laboratories. Nine laboratories decided to characterize the TS using a single kit, with a number of amplifications varying from 2 to 12, obtaining only partial STR profiles. Most of the participants determined partial or full profiles using a combination of two or more kits, and a number of amplifications varying from 2 to 27. The performance of each laboratory was described in terms of number of correctly characterized loci, dropped-out markers, unreliable genotypes, and incorrect results. The incidence of unreliable and incorrect genotypes was found to be higher for participants carrying out a limited number of amplifications, insufficient to define the correct genotypes from damaged DNA samples such as the TS. Finally, from a dataset containing about 4500 amplicons, the frequency of PCR artifacts (allele dropout, allele drop-in, and allelic imbalance) was calculated for each kit showing that the new chemistry of the kits is not able to overcome the concern of template-related factors. The results of this collaborative exercise emphasize the advantages of using a standardized degraded DNA sample in the definition of which analytical parameters are critical for the outcome of the STR profiles., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Colchicine seems to be a good drug for treating recurrences of pericarditis after conventional treatment failure, but no clinical trial has tested the effects of colchicine as first-line drug for the treatment of the first recurrence of pericarditis., Methods: A prospective, randomized, open-label design was used to investigate the safety and efficacy of colchicine therapy as adjunct to conventional therapy for the first episode of recurrent pericarditis. Eighty-four consecutive patients with a first episode of recurrent pericarditis were randomly assigned to receive conventional treatment with aspirin alone or conventional treatment plus colchicine (1.0-2.0 mg the first day and then 0.5-1.0 mg/d for 6 months). When aspirin was contraindicated, prednisone (1.0-1.5 mg/kg daily) was given for 1 month and then was gradually tapered. The primary end point was the recurrence rate. Intention-to-treat analyses were performed by treatment group., Results: During 1682 patient-months (mean follow-up, 20 months), treatment with colchicine significantly decreased the recurrence rate (actuarial rates at 18 months were 24.0% vs 50.6%; P = .02; number needed to treat = 4.0; 95% confidence interval 2.5-7.1) and symptom persistence at 72 hours (10% vs 31%; P = .03). In multivariate analysis, previous corticosteroid use was an independent risk factor for further recurrences (odds ratio, 2.89; 95% confidence interval, 1.10-8.26; P = .04). No serious adverse effects were observed., Conclusion: Colchicine therapy led to a clinically important and statistically significant benefit over conventional treatment, decreasing the recurrence rate in patients with a first episode of recurrent pericarditis.

Background: Whether an invasive or a conservative strategy should form the basis of an optimal management strategy for non-Q wave myocardial infarction is at present still subject of debate. We reported our observational experience with the long-term follow-up of patients with a first uncomplicated non-Q wave myocardial infarction and submitted to a conservative treatment strategy based on the in-hospital stress echocardiography and treadmill exercise., Methods: We studied 134 consecutive patients admitted for a first uncomplicated non-Q wave myocardial infarction between 1991 and 1994. All patients were submitted to a dipyridamole echocardiography test (DET) between 5-7 days after admission and to a treadmill test before discharge. Coronary angiography and myocardial revascularization (coronary angioplasty or coronary artery bypass grafting) were performed according to the outcomes of the stress echo and treadmill test., Results: The early and delayed follow-up results were quite good: 2.9% early hard events, 15% delayed hard events. DET negativity identified patients with a lower risk of both spontaneous and hard events. Multivariate analysis indicated the DET as the only predictive variable of spontaneous events within 1 year (p = 0.0001), of delayed spontaneous events (p = 0.0001) and of delayed hard events (p = 0.05)., Conclusions: In this study, revascularization procedures performed on the basis of stress echo result in good short- and long-term outcomes in stabilized uncomplicated non-Q wave myocardial infarction. The patients with a negative DET had a very low rate of events. DET positivity identifies a higher risk group of patients, whatever treatment they subsequently undergo.

Background: Isolated alterations of the left ventricular diastolic function have been described in diabetic insulin-dependent patients (IDDM), even in the absence of old age, hypertension, ischemic heart disease, left ventricular hypertrophy. Such alterations have been associated with microangiopathy but it is not known whether it is reversible or if there is a relation with the way the therapy is given., Methods: Fifty-five subjects have been studied, of which 15 were healthy, 30 recently diagnosed IDDM without microangiopathy and 10 IDDM with microangiopathy. All the patients were under 35 years old and did not present risk factors for coronary artery disease, hypertension or autonomic neuropathy. The maximal exercise stress test proved negative. The diastolic function was studied using the results of Doppler echocardiography of the mitral flow and of isovolumetric relaxation time, with continuous and discrete parameters., Results: The velocity of wave A and E, the relationship between them and their integrals are significantly greater in diabetics with microangiopathy than in those without it and in healthy subjects. There are no significant differences between healthy and diabetic subjects without microangiopathy using continuous parameters. Using discrete parameters diastolic damage is absent in the healthy subjects and is present in 48% of diabetics without microangiopathy and in 90% of those with it., Conclusions: Slight preclinical diastolic dysfunction is present in young recently diagnosed IDDM without microangiopathy. More severe dysfunction is present when there is also microangiopathy.