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Abstract Background Among patients with cystic fibrosis (CF), females have worse pulmonary function and survival than males, primarily due to chronic lung inflammation and infection with Pseudomonas aeruginosa (P. aeruginosa). A role for gender hormones in the causation of the CF "gender gap" has been proposed. The female gender hormone 17β-estradiol (E2) plays a complex immunomodulatory role in humans and in animal models of disease, suppressing inflammation in some situations while enhancing it in others. Helper T-cells were long thought to belong exclusively to either T helper type 1 (Th1) or type 2 (Th2) lineages. However, a distinct lineage named Th17 is now recognized that is induced by interleukin (IL)-23 to produce IL-17 and other pro-inflammatory Th17 effector molecules. Recent evidence suggests a central role for the IL-23/IL-17 pathway in the pathogenesis of CF lung inflammation. We used a mouse model to test the hypothesis that E2 aggravates the CF lung inflammation that occurs in response to airway infection with P. aeruginosa by a Th17-mediated mechanism. Results Exogenous E2 caused adult male CF mice with pneumonia due to a mucoid CF clinical isolate, the P. aeruginosa strain PA508 (PA508), to develop more severe manifestations of inflammation in both lung tissue and in bronchial alveolar lavage (BAL) fluid, with increased total white blood cell counts and differential and absolute cell counts of polymorphonuclear leukocytes (neutrophils). Inflammatory infiltrates and mucin production were increased on histology. Increased lung tissue mRNA levels for IL-23 and IL-17 were accompanied by elevated protein levels of Th17-associated pro-inflammatory mediators in BAL fluid. The burden of PA508 bacteria was increased in lung tissue homogenate and in BAL fluid, and there was a virtual elimination in lung tissue of mRNA for lactoferrin, an antimicrobial peptide active against P. aeruginosa in vitro. Conclusions Our data show that E2 increases the severity of PA508 pneumonia in adult CF male mice, and suggest two potential mechanisms: enhancement of Th17-regulated inflammation and suppression of innate antibacterial defences. Although this animal model does not recapitulate all aspects of human CF lung disease, our present findings argue for further investigation of the effects of E2 on inflammation and infection with P. aeruginosa in the CF lung.

Objective: To provide an analysis of casualties treated during medical evacuation (MEDEVAC) or/and at the Spanish Role 2 in Herat, Afghanistan, including type of weapon, injuries, and effects of protective measures.Method: A retrospective analysis was carried out concerning patients who had suffered injuries from either gunshot or explosive devices treated during MEDEVAC or/and at this facility during the period 2005-2008.Results: The total number of cases analyzed was 256. The majority of the casualties were produced by explosive devices (71%). The anatomical regions most affected were the lower limbs (48%). There was a higher New Injury Severity Score in casualties wounded by gunshot (14 +/- 1) than in those wounded by explosive devices (8.5 +/- 1.5) (p < 0.001). Surgical procedures for injuries caused by gunshots were 1.7 times more likely than for those due to explosive devices (95% confidence interval: 1.4 to 2.1). Protective devices were used only by 25% of casualties.Conclusions: The injury score indices of firearm casualties were higher than the explosive device casualties' injury score indices. The possible reasons for this finding are discussed. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the prevalence and characteristics of neuropathic pain in patients with various subtypes of spondyloarthritis (SpA), including axial SpA (axSpA), psoriatic arthritis (PsA), and undifferentiated peripheral SpA (p-SpA). Additionally, the study sought to identify potential risk factors associated with the presence or severity of neuropathic pain and to investigate its impact on clinical disease activity assessment., Methods: We conducted a cross-sectional study at two tertiary rheumatology centers, enrolling patients diagnosed with SpA. Data on demographic and clinical characteristics, comorbidities, and current therapies were collected. Neuropathic pain was assessed using the PainDETECT Questionnaire (PD-Q) and the Neuropathic Pain Symptom Inventory (NPSI). Statistical analyses included descriptive statistics, t-tests, and Pearson's correlations to evaluate the relationships between neuropathic pain scores and clinical disease activity indices., Results: The study included 177 patients. Of these, 22.2% had a PD-Q score ≥19, showing a high likelihood of neuropathic pain, while 64.9% scored ≤12, suggesting the absence of significant neuropathic components. The mean PD-Q score was 11.5 ± 10.1. Subgroup analyses showed that females had significantly higher scores for paroxysmal and evoked pain (p < 0.05), and obese patients had significantly higher scores across all NPSI subscores (p < 0.05). Moderate positive correlations were found between neuropathic pain scores and clinical disease activity indices, such as DAPSA (r = 0.46, p < 0.0001) and ASDAS-CRP (r = 0.42, p < 0.01)., Conclusions: Neuropathic pain is prevalent among patients with SpA and is significantly associated with disease activity assessments and management. This study highlights the importance of integrating neuropathic pain evaluation into the clinical assessment of SpA to tailor treatment approaches effectively and improve patient outcomes., Competing Interests: Declaration of competing interest The authors declared they do not have any conflict of interest with respect to this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: One of the main drawbacks of tunneled central venous catheters (CVCs) is catheter-related bloodstream infections (CRBSIs). Antibiotic lock therapy (ALT) can be combined with systemic antibiotics to achieve catheter salvage. Our objectives are to describe cases of CRBSI and our experience with ALT in a pediatric oncology-hematology ward., Methods: a retrospective descriptive study of pediatric CRBSI cases in a Spanish oncology-hematology unit from 2007 to 2017 was conducted. We collected demographic, clinical, and microbiological data from all patients., Results: fifty-eight CRBSIs were diagnosed in thirty-nine patients; 72.9% of these patients were male, with a median age of 42.1 months. The main underlying diseases were leukemia/lymphoma (51.7%) and solid tumors (32.7%). Thirty-five (60.3%) CRBSIs were caused by Gram-positive cocci, of which 70.6% were coagulase-negative Staphylococci , and sixteen (27.6%) were caused by Gram-negative bacilli. We treated 41/58 (71%) cases with ALT. A total of 12/17 (71%) CVCs that were not treated with adjunctive ALT were removed, compared with 13/41 (32%) that were treated with ALT (relative risk (RR), 0.449; confidence interval (CI), 95%: 0.259-0.778, p = 0.004). Major reasons to remove the CVC in the CRBSI-ALT group were local insertion/pocket site infection (23%), persistent symptoms (23%), and infectious' relapses (15%)., Conclusions: ALT was shown to be an effective approach to keeping the CVC in place, with no added adverse effects.

REHem-AR was created in 2013. The progressive implementation of neonatal screening for haemoglobinopathies in Spanish autonomous communities where the registry had not been implemented, as well as the addition of new centres during this period, has considerably increased the sample of patients covered. In this study, we update our previous publication in this area, after a follow-up of more than 5 years. An observational, descriptive, multicentre and ambispective study of adult and paediatric patients with haemoglobinopathies and rare anaemias registered in REHem was performed. The data are from a cross-sectional analysis performed on 1 June, 2023. The study population comprised 1,756 patients, of whom 1,317 had SCD, 214 had thalassaemia and 224 were diagnosed with another condition. Slightly more than one third of SCD patients (37%) were diagnosed based on neonatal bloodspot screening, and the mean age at diagnosis was 2.5 years; 71% of thalassaemia patients were diagnosed based on the presence of anaemia. Vaso-occlusive crisis and acute chest syndrome continue to be the most frequent complications in SCD. HSCT was performed in 83 patients with SCD and in 50 patients with thalassaemia. Since the previous publication, REHem-AR has grown in size by more than 500 cases. SCD and TM are less frequent in Spain than in other European countries, although the data show that rare anaemias are frequent within rare diseases. REHem-AR constitutes an important structure for following the natural history of rare anaemias and enables us to calculate investment needs for current and future treatments., (© 2024. The Author(s).)

Background: Association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years, but still remains unexplained. We recently showed that HLA-B27 expressed in wing imaginal disc from HLA-B27/human-β2 microglobulin (hβ2m) transgenic Drosophila deregulated bone morphogenetic protein (BMP) pathway by interacting physically with type I BMP receptor (BMPR1) Saxophone (Sax), leading to crossveinless phenotype., Methods: Genetic interaction was studied between activin/transforming growth factor β (TGFβ) pathway and HLA-B27/hβ2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs. In mesenteric lymph node (mLN) T cells from HLA-B27/hβ2m rat (B27 rat), physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s, phosphorylation of small mothers against decapentaplegic (SMADs) and proteins of the non-canonical BMP/TGFβ pathways induced by its ligands, and the transcript level of target genes of the TGFβ pathway, were evaluated., Results: In HLA-B27/hβ2m transgenic Drosophila, inappropriate signalling through the activin/TGFβ pathway, involving Baboon (Babo), the type I activin/TGFβ receptor, contributed to the crossveinless phenotype, in addition to deregulated BMP pathway. We identified peptides bound to HLA-B27 with the canonical binding motif in HLA-B27/hβ2m transgenic Drosophila wing imaginal disc. We demonstrated specific physical interaction, between HLA-B27/hβ2m and mammalian orthologs of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGFβ receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFβ1 was increased in T cells from B27 rats, showing evidence for deregulated TGFβ pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFβ exposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly, Tgfb1 expression was reduced in naive T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern., Conclusions: This study shows that HLA-B27 alters the TGFβ pathways in Drosophila and B27 rat. Given the importance of this pathway in CD4 + T cells differentiation and regulation, its disturbance could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and altered regulatory T cell phenotype observed in B27 rats., (© 2024. The Author(s).)

Introduction: The increase in the number of patients with hemoglobinopathies in Europe in recent decades highlights the need for more detailed epidemiological information in Spain. To fulfil this need, the Spanish Society of Pediatric Hematology and Oncology (SEHOP) sponsored the creation of a national registry of hemoglobinopathies known as REHem-AR (Spanish Registry of Hemoglobinopathies and Rare Anemias). Data from the transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) β-thalassemia cohorts are described and analyzed., Methods: We performed an observational, multicenter, and ambispective study, which included patients of any age with TDT and NTDT, registered up to December 31, 2021., Results: Among the 1741 patients included, 168 cases of thalassemia were identified (103 TDT and 65 NTDT-patients). Survival at 18 years was 93% for TDT and 100% for NTDT. Regarding management, 80 patients with TDT (77.7%) and 23 patients with NTDT (35.4%) started chelation treatment during follow-up, with deferasirox being the most widely used. A total of 76 patients within the TDT cohort presented at least 1 complication (73.8%), the most frequent being hemosiderosis and osteopenia-osteoporosis. Comparison of both cohorts revealed significant differences in the diagnosis of hepatic hemosiderosis (p = 0.00024), although these were not observed in the case of cardiac iron overload (p = 0.27)., Discussion: Our registry enabled us to describe the management of β thalassemia in Spain and to analyze the morbidity and mortality of the cohorts of patients with TDT and NTDT. Complications related to iron overload in TDT and NTDT account for most of the morbidity and mortality of the disease, which is associated with a considerable social, psychological, and economic impact, although cardiac, osteopathy and endocrinological complications requiring more attention. The convenience and simplicity of online registries make it possible to homogenize variables and periodically update data, thus providing valuable information on these diseases., (© 2024. The Author(s).)

In May 2003, Madrid established the universal newborn screening (NBS) for sickle cell disease (SCD). However, there are no studies resembling the evolution of a SCD neonate cohort followed according to national guidelines in Spain. The aim of this study is to describe the morbimortality and the stroke prevention programme in patients diagnosed by SCD NBS in Madrid. This is a multicentre, observational, prospective cohort study between 2003 and 2018; 187 patients diagnosed with SCD were included (151 HbSS, 6 HbSβ 0 , 27 HbSC, 3 HbSβ +), and median follow-up was 5.2 years (0.03-14.9). There were 5 deaths: 2 related to SCD in patients with severe genotype (HbSS/HbSβ 0 ). Overall survival reached 95% and SCD-related survival 96.8%. The most frequent events were fever without focus, vaso-occlusive crises and acute chest syndromes. Eight strokes occurred in 5 patients which led to a 90.7% stroke-free survival in severe genotype patients (first stroke rate, 0.54 per 100 patient-years). Transcranial Doppler (TCD) was performed in 95% of eligible patients; 75% of children with pathological TCD remained stroke-free. Regarding HbSS/HbSβ 0 patients, 50.1% received hydroxyurea and 9.5% haematopoietic stem cell transplantation. This study reflects the evolution of Madrid SCD cohort and provides morbimortality data similar to other developed countries., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Children with sickle cell disease (SCD) are at a high risk of invasive bacterial infections (IBI). Universal penicillin prophylaxis and vaccination, especially against Streptococcus pneumoniae, have deeply changed its epidemiology. Analysis of IBI in children with SCD in a post-13-valent pneumococcal vaccine era is limited., Methods: Twenty-eight pediatric hospitals from 5 European countries retrospectively collected IBI episodes in SCD children aged 1 month to 18 years between 2014 and 2019. IBI was defined as a positive bacterial culture or polymerase chain reaction from a normally sterile fluid: blood, cerebrospinal, joint, or pleural fluid and deep surgical specimen., Results: We recorded 169 IBI episodes. Salmonella spp. was the main isolated bacteria (n = 44, 26%), followed by Streptococcus pneumonia (Sp; n = 31, 18%) and Staphylococcus aureus (n = 20, 12%). Salmonella prevailed in osteoarticular infections and in primary bacteremia (45% and 23% of episodes, respectively) and Sp in meningitis and acute chest syndrome (88% and 50%, respectively). All Sp IBI occurred in children ≤10 years old, including 35% in children 5 to 10 years old. Twenty-seven (17%) children had complications of infection and 3 died: 2 because of Sp, and 1 because of Salmonella. The main risk factors for a severe IBI were a previous IBI and pneumococcal infection (17 Sp/51 cases)., Conclusions: In a post-13-valent pneumococcal vaccine era, Salmonella was the leading cause of bacteremia in IBI in children with SCD in Europe. Sp came second, was isolated in children ≤10 years old, and was more likely to cause severe and fatal cases., (Copyright © 2023 by the American Academy of Pediatrics.)

Sickle cell disease is a hereditary multiorgan disease that is considered rare in the EU. In 2017, the Rare Diseases Plan was implemented within the EU and 24 European Reference Networks (ERNs) were created, including the ERN on Rare Haematological Diseases (ERN-EuroBloodNet), dedicated to rare haematological diseases. This EU initiative has made it possible to accentuate existing collaborations and create new ones. The project also made it possible to list all the needs of people with rare haematological diseases not yet covered health-care providers in the EU to allow optimised care of individuals with rare pathologies, including sickle cell disease. This Viewpoint is the result of joint work within 12 EU member states (ie, Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Portugal, Spain, Sweden, and The Netherlands), all members of the ERN-EuroBloodNet. We describe the role of the ERN-EuroBloodNet to improve the overall approach to and the management of individuals with sickle cell disease in the EU through specific on the pooling of expertise, knowledge, and best practices; the development of training and education programmes; the strategy for systematic gathering and standardisation of clinical data; and its reuse in clinical research. Epidemiology and research strategies from ongoing implementation of the Rare Anaemia Disorders European Epidemiological Platform is depicted., Competing Interests: Declaration of interests MdMMP declares grant funding or contracts from EuroBloodNet Association (RADeep) and Agios Pharmaceuticals (PKDeep) and participation in an advisory board for Agios Pharmaceuticals. RC declares grant funding or contracts from Global Blood Therapeutics, EU grants in the framework of Horizon 2020 and Horizon Europe, and EuroBloodNet Association (RADeep); consulting fees from Global Blood Therapeutics and Novartis; honoraria from Physician's Education Resources and Global Blood Therapeutics; participation on a data safety monitoring board or advisory board for Vertex, Addmedica, and Novonordisk; being a member of the steering committee of the Italian Association of Pediatric Hematology Oncology and coordinator of the Red Cell Disorder Working Group. PB declares grant funding or contracts from EuroBloodNet Association (RADeep). EC declares support for the Spanish Registry of Rare Anemias, partly supported by Novartis; grant funding or contracts from Vall d'Hebrin Research Institute (Integra) and EuroBloodNet Association (RADeep); honoraria from Terumo BCT, Chiesi, and Bionest; support for attending meetings or travel to the European Hematology Association Hemoglobinopathy Working Party 2023 by the European Hematology Association and to the Sociedad Española de Hematología y Oncología Pediátricas 2022 by Novartis; and participation on a data safety monitoring board or advisory board of Novartis (Adakveo) and Vertex. AC declares grant funding or contracts from EuroBloodNet Association (RADeep) and consulting fees from Novartis. LD declares grant funding or contracts from EuroBloodNet Association (RADeep). AG declares grant funding or contracts from Bristol Myers Squibb, Novo Nordisk, and EuroBloodNet Association (RADeep) and participation on a data safety monitoring board or advisory board of Novo Nordisk and Agios Pharmaceuticals. VGV declares grant funding or contracts from EuroBloodNet Association (RADeep). AK declares grant funding or contracts from Novartis and BMS; consulting fees from Agios Pharmaceuticals, Amgen, Bristol Myers Squib/Celgene, Crispr/Vertex, Ionis Pharmaceuticals, Novartis, and Vifor; honoraria from Novartis, Bristol Myers Squib/Celgene, Chiesi, and Crisp/Vertex; and support for attending meetings or travel from Bristol Myers Squib/Celgene. JK declares grant funding or contracts from the Deutsche Kinderkrebsstiftung (German Childhood Cancer Foundation), Pfizer, and Novartis; support for attending meetings or travel for American Society of Hematology Annual Meeting 2020 with support from Art Tempi Communications; participation on a data safety monitoring board or advisory board of Novartis, Global Blood Therapeutics, and Bluebird Bio; and leadership or fiduciary role of the Konsortium Sichelzellkrankheit. SL declares consulting fees for advisory board of Novartis, BlueBird Bio, AddMedica, Global Blood Therapeutics, and Agios; honoraria from Novartis and BlueBird Bio; participation on a data safety monitoring board or advisory board of Novartis, BlueBird Bio, AddMedica, Global Blood Therapeutics, and Agios; leadership or fiduciary role at Vertex CTX001 study program steering committee, in the German National Disease Management Program, and in the German National Treatment Guideline. SR declares grant funding or contracts from EuroBloodNet Association (RADeep). GR declares participation on a data safety monitoring board or advisory board of Biovalley. MS declares payment for expert testimony from Novartis; support for attending meetings or travel to ASCAT 2022 from ERN-EuroBloodNet; leadership or fiduciary role as patient representative for the UK in the Red Cell Network, Patient and Public Voice Group. EvB declares grant funding or contracts from Agios Pharmaceuticals, Horizon Europe, Sikkelcelfonds, and EuroBloodNet Association (RADeep); honoraria from Agios and GSK; support for attending meetings or travel from European Rare Disease Research Coordination and Support Action consortium and EuroBloodNet Association (RADeep); participation on a data safety monitoring board or advisory board at Imara, BMS, Agios, and Forma therapeutics; leading the ERN-EuroBloodNet Transversal Field of Action on Clinical Trials and Research for non-oncological rare haematological diseases; and being a board member of the Benign Hematology Section of the Dutch Society for Hematology (NVVH) and chair of the Dutch Patient Registry for Sickle Cell Disease (SCORE). PK declares grant funding or contracts from EuroBloodNet Association (RADeep). BG declares grant funding or contracts from EuroBloodNet Association (RADeep). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Aims: Hereditary anemia (HA) encloses a wide group of rare inherited disorders with clinical and hematologic overlaps that complicate diagnosis., Materials and Methods: A 48-gene panel was developed to diagnose HA by Next Generation Sequencing (NGS) in a large cohort of 165 patients from 160 unrelated families., Results: Patients were divided in: A) patients who had a suspicion of a specific type of HA (n = 109), and B) patients who had a suspicion of HA but with no clear type (n = 56). Diagnostic performance was 83.5% in group A and a change of the initial diagnosis occurred in 11% of these patients. In group B, 35.7% of patients achieved a genetic diagnosis. NGS identified 6 cases of xerocytosis, 6 of pyruvate kinase (PK) deficiency, 4 of G6PD, and 1 case of phytosterolemia with no initial suspicion of these pathologies, which is clinically relevant since they have specific treatment. Five patients were found to carry variants associated to two different pathologies (4 of them combining a metabolic deficiency and a membrane defect), and 44 new variants were identified in 41 patients., Conclusion: The use of NGS is a sensitive technique to diagnose HA and it shows better performance when patients are better characterized., (Copyright © 2022 Elsevier B.V. All rights reserved.)

There is interest in understanding the relationship between naturally contaminated commodities and the potential for the production of different useful and toxic secondary metabolites (SMs). This study examined the impact of interacting abiotic stress parameters of water availability and temperature of stored naturally contaminated maize on the SM production profiles. Thus, the effect of steady-state storage water activity (aw; 0.80−0.95) and temperature (20−35 °C) conditions on SM production patterns in naturally contaminated maize was examined. The samples were analysed using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) to evaluate (a) the total number of known SMs, (b) their concentrations, and (c) changes under two-way interacting environmental stress conditions. A total of 151 metabolites were quantified. These included those produced by species of the Aspergillus, Fusarium and Penicillium genera and other unspecified ones by other fungi or bacteria. There were significant differences in the numbers of SMs produced under different sets of interacting environmental conditions. The highest total number of SMs (80+) were present in maize stored at 20−25 °C and 0.95 aw. In addition, there was a gradation of SM production with the least number of SMs (20−30) produced under the driest conditions of 0.80 aw at 20−30 °C. The only exception was at 35 °C, where different production patterns occurred. There were a total of 38 Aspergillus-related SMs, with most detected at >0.85 aw, regardless of the temperature in the 50−500 ng/g range. For Fusarium-related SMs, the pattern was different, with approx. 10−12 SMs detected under all aw × temperature conditions with >50% produced at 500 ng/g. A total of 40−45 Penicillium-related SMs (50−500 ng/g) were detected in the stored maize but predominantly at 20−25 °C and 0.95 aw. Fewer numbers of SMs were found under marginal interacting abiotic stress storage conditions in naturally contaminated maize. There were approx. eight other known fungal SM present, predominantly in low concentrations (<50 ng/g), regardless of interacting abiotic conditions. Other unspecified SMs present consisted of <20 in low concentrations. The effect of interacting abiotic stress factors for the production of different suites of SMs to take account of the different ecological niches of fungal genera may be beneficial for identifying biotechnologically useful SMs.

This study deals with the issue of beach litter pollution in the context of the Descriptor 10 of the Marine Strategy Framework Directive Good Environmental Status of EU waters and Ecological objective 10, Common indicator 22 of IMAP. Analyses of the amount, distribution and categorization of beach litter were conducted on nine beaches during 108 surveys covering the area of 206.620 m 2 in Albania, Italy and Montenegro. Our findings showed that the level of beach litter pollution on south Adriatic beaches is significantly above the adopted threshold values, with a median item numbers of 327, 258 and 234 per 100 m of beach stretch for Albania, Italy and Montenegro, respectively. It can be concluded that, when it comes to beach litter pollution, GES has not been achieved. Given the defined baseline and threshold values at the EU level, the process of reducing the total amount of marine litter in southern Adriatic Sea will be very challenging and needs urgent and specific actions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Active ageing is defined as the process of optimizing opportunities for health, participation and security in order to enhance quality of life as people age. The design of active ageing policies intersects with different overarching societal challenges, especially ageing populations, social rights and sustainability. However, there are no previous attempts to review active ageing policies in the light of these challenges and the international policy objectives and targets that are guiding the international community. The aim of this study is to systematically identify, review and analyse all national and regional policies on active ageing adopted in Italy, by applying a conceptual framework derived from main international policy initiatives in the three areas. The research was conducted in two stages. First, a case study analysis was carried out per each relevant national institution and regional government. Standardised interviews were combined with policy document search, selection and analysis. Second, we performed a policy analysis in the light of a conceptual framework adopted. This latter was composed by nine policy domains, selected and integrated from principles and objectives of three overarching international frameworks on ageing-i.e., the Regional Implementation Strategy (RIS) commitments of the Madrid International Plan of Action on Ageing (MIPAA), social rights-i.e., the European Pillar of Social Rights and sustainability-i.e., the Sustainable Development Goals (SDGs) of the Agenda 2030 for Sustainable Development. Results pointed out that out of the identified nine policy fields, the major intervention areas by Italian policy makers concerned labour market participation, life-long learning, social and economic inequalities, health and well-being. Less attention had been given to issues such as gender and equal opportunities and sustainable cities. This systematic policy review is a milestone for understanding how active ageing policies contribute to address major societal challenges and what domains need further policy development.

There are limited and controversial studies that address the role of vitamin D (vitD), a vitamin with immunomodulatory effects, in myasthenia gravis (MG), a neuromuscular autoimmune disease. We aimed to assess 25-hydroxy vitamin D (25(OH)D) levels and to evaluate possible associations with the clinical severity and other biomarkers of the disease. Serum levels of 25(OH)D, anti-acetylcholine receptor antibodies and complement factor C5a were measured in MG patients (n = 66) and healthy volunteers (HV) (n = 25). Participants were evaluated through questionnaires to determine vitD intake and sunlight exposure. Severity scores were registered for MG patients. We found an 89.4% of MG individuals with nonsufficient levels of vitD, in comparison with 68.0% in the group of HV (OR = 3.96; P = 0.024). In addition, there was an inverse correlation between 25(OH)D levels and one of the scores (P = 0.037 r = -0.26, CI 95  = -0.49 to -0.0087). However, when we compared 25(OH)D median serum levels between MG patients and HV, no statistically significant differences have been found. This is the first report of vitD status in a cohort of Argentinean MG patients, where we found that patients are more likely to have nonsufficient levels of vitD compared to healthy people and that patients with more severe disease have lower levels of vitD., (© 2021 American Society for Photobiology.)

Background: Red blood cell (RBC) transfusion remains an essential part of sickle cell disease (SCD) management but it can lead to alloimmunisation, with an increased incidence in this population. Prevention is based on RBC antigen phenotype matching, with complete RH and Kell matching being a standard of care., Materials and Methods: We performed a retrospective, single-centre study analysing alloimmunisation prevalence and risk factors in a cohort of transfused SCD patients., Results: Eighty-seven patients (96.5% of paediatric age) received 1,781 RBC units (RBCu). Complete RH and Kell matched RBCu represented a median of 100% among total transfusions per patient. Of the 87 patients, 52 (59.8%) underwent chronic transfusion therapy, whereas 35 (40.2%) were only episodically transfused. Seven patients were alloimmunised (8.4%) and eleven antibodies were detected (alloimmunisation rate: 0.62/100 units transfused). 54.6% of these antibodies corresponded to RH-Kell despite the high accomplishment of the RH-Kell matching transfusion protocol. Alloimmunised patients had a median of 90.9% RH-Kell matched transfusions vs 100% in non-alloimmunised patients, but no statistical differences were observed (p=0.127). Number of transfused RBCu (19 vs 7; p=0.023), number of episodic RBCu (8 vs 2; p=0.006), episodic to chronic RBCu ratio (0.57 vs 0.09; p=0.045), number of vaso-occlusive crises (VOC) (4 vs 2; p=0.011), and autoantibody presence (57.1 vs 0%; p<0.001) were all statistically related to alloimmunisation., Discussion: We report a low alloimmunisation prevalence (8.4%) related to a high grade of RH-Kell matching. However, deviation from 100% translates into alloimmunisation, with >50% of alloantibodies corresponding to RH-Kell. Alloimmunisation risk increases with transfusion burden, particularly during acute complications, and in patients with a higher number of VOC, probably reflecting underlying inflammation and disease severity. Further studies will be needed to elucidate additional risk factors and help prevent alloimmunisation in these patients.

Pediatric patients with sickle cell disease and thalassemia major present clinical characteristics that could lead to a higher incidence of central venous access devices-associated complications (CVAD-C). With the objective of analyzing the safety of the use of CVAD in these patients, a retrospective review including all pediatric patients with these pathologies who required the implantation of a CVAD between 2004 and 2019 was performed. In all, 54 patients with 100 CVAD (65 totally implantable venous access port with subcutaneous reservoir, 35 single-lumen or double-lumen partially tunneled catheter) were included. During 60,410 days at risk of suffering a CVAD-C, 55 complications (complication rate [CR]/1000 catheter-days at risk=0.91) were reported in 46 CVAD: 19 mechanicals (CR=0.32), 32 infectious (CR=0.53), and 4 thrombotic complications (CR=0.066). Incidence of mechanical and infectious complications was significantly higher in double-lumen partially tunneled catheter than in totally implantable venous access port with subcutaneous reservoir (P<0.001). Lower age at insertion was related with a higher incidence of any complication (odds ratio=0.88/y, P=0.02). Patients who required a stem cell transplantation (31 patients and 65 CVAD) had no significant higher incidences of CVAD-C. In conclusion, our study supports the safety of using CVAD in these patients, with a low incidence of infectious, thrombotic, and mechanical complications., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Aflatoxins (AFs) are produced by fungi in crops and can cause liver cancer. Permitted levels are legislated and batches of grain are rejected based on average concentrations. Corn grown in Southern Georgia (GA), USA, which experiences drought during the mid-silk growth period in June, is particularly susceptible to infection by Aspergillus section Flavi species which produce AFs. Previous studies showed strong association between AFs and June weather. Risk factors were developed: June maximum temperatures > 33 °C and June rainfall < 50 mm, the 30-year normals for the region. Future climate data were estimated for each year (2000-2100) and county in southern GA using the RCP 4.5 and RCP 8.5 emissions scenarios. The number of counties with June maximum temperatures > 33 °C and rainfall < 50 mm increased and then plateaued for both emissions scenarios. The percentage of years thresholds were exceeded was greater for RCP 8.5 than RCP 4.5. The spatial distribution of high-risk counties changed over time. Results suggest corn growth distribution should be changed or adaptation strategies employed like planting resistant varieties, irrigating and planting earlier. There were significantly more counties exceeding thresholds in 2010-2040 compared to 2000-2030 suggesting that adaptation strategies should be employed as soon as possible.

In the UK and Northern Europe, ripening oats can become contaminated with T-2 and HT-2 mycotoxins, produced mainly by Fusarium langsethiae. There are indicative levels related to the maximum limits for oat grain for these toxins. The objectives of this study were to examine the effect of interacting conditions of temperature (10-30 °C) and water activity (a w , 0.995-0.90) on (a) lag times prior to growth, (b) growth and (c) T-2 and HT-2 toxins by two strains of F. langsethiae isolated from oats in the UK and compare this with the type strain (Fl201059) which has been genomically sequenced, and (d) develop (and validated with published data) a probabilistic models for impacts of temperature × a w on growth and toxin production. All three strains had an optimum a w range and temperature of 0.995-0.98 and 25 °C for growth. For T-2 + HT-2 production these were 0.995 a w and 20 °C. Overall, the type strain produced higher amounts of T-2 + HT-2 with a HT-2/T-2 ratio of up to 76. Using this study data sets and those from the literature, probabilistic models were developed and validated for growth and T-2 + HT-2 toxin production in relation to temperature × a w conditions. These models, when applied in stored oats, will be beneficial in determining the conditions on the relative level of risk of contamination with these two toxins in the context of the EU indicative maximum levels., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Bread and intermediate moisture bakery products are mainly spoiled by yeasts and filamentous fungi. The inoculum load and preservation system used determines their shelf life. To extend the shelf life of such commodities, the use of chemical preservatives is the most common way to try and control the initiation of mold spoilage of bread. This study has utilized a rapid turbidimetric assay system (Bioscreen C) to examine the temporal efficacy of calcium propionate (CP) and potassium sorbate (PS) for controlling the growth of important bread spoilage fungi. The objectives were to compare the temporal growth of strains of three important spoilage fungi Hyphopichia burtonii (HB17), Paecilomyces variotii (PV11), and Penicillium roqueforti (PR06) isolated from visibly molded bread to (a) different concentrations of CP and PS (0-128 mM), (b) temperatures (25°C, 30°C), (c) water activity (a w ; 0.95, 0.97), and (d) pH (5.0, 5.5). All three abiotic factors, pH, a w, and temperature, and preservative concentrations influenced the relative growth of the species examined. In general, PS was more effective than CP in inhibiting the growth of the strains of these three species. In addition, the Time to Detection (TTD) for the efficacy of the preservatives under the interacting abiotic factors was compared. The strain of Paecilomyces variotii (PV10) was the most tolerant to the preservatives, with the shortest TTD values for both preservatives. P. roqueforti was the most sensitive with the longest TTD values under all conditions examined. These results are discussed in the context of the evolution of resistance to food-grade preservatives by such spoilage fungi in bakery products., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Garcia, Garcia-Cela, Magan, Copetti and Medina.)

Inhibition of platelet activation may reduce vaso-occlusion rates in patients with sickle cell disease (SCD). In the HESTIA4 (NCT03492931) study, 21 children with SCD received a single oral dose of the antiplatelet agent ticagrelor (0.1 mg/kg <6 months; 0.2 mg/kg ≥6 to <24 months). All patients had measurable ticagrelor plasma concentrations. Ticagrelor and active metabolite (AR-C124910XX) exposure were comparable across all groups (<6 months, ≥6 to <12 months and ≥12 to <24 months). Ticagrelor was well tolerated. Palatability was generally acceptable. These data will be used to enable dose selection for further investigations of ticagrelor efficacy and safety in children with SCD., (© 2021 Wiley Periodicals LLC.)

Objectives: The prevalence of sickle cell disease (SCD) in Spain is markedly inferior compared with other European and Mediterranean countries. However, the diagnosis of new patients with SCD is expected to increase. In this multicenter retrospective study, we analyze the hematopoietic stem cell transplantation (HSCT) results obtained in Spain., Methods: Forty-five patients who underwent a matched sibling donor (MSD) HSCT between 1999 and 2018 were included. Primary endpoint was event-free survival (EFS), and secondary endpoints included acute and chronic graft-versus-host disease (GvHD) and overall survival (OS)., Results: Bone marrow was the most frequent stem cell source (93.3%). Most patients received a conditioning regimen based on busulfan and cyclophosphamide (69%). Cumulative incidence of grade III-IV acute GvHD and chronic GvHD was 6.8% (95% CI: 2.3%-20.1%) and 5.4% (95% CI: 1.38%-19.9%), respectively. EFS and overall survival (OS) at 3 years post-HSCT were 89.4% (95% CI: 73.9%-95.9%) and 92.1% (95% CI: 77.2%-97.4%), respectively. All patients aged ≤ 5 presented 100% EFS and OS., Conclusions: An early referral to HSCT centers should be proposed early in life, before severe complications occur. MSD HSCT should be considered a curative option for all patients aged ≤ 5 years and for older pediatric patients who present complications derived from the disease., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The aim was to decipher the temporal impact of key interacting climate change (CC) abiotic factors of temperature (30 vs 37 °C), water activity (a w ; 0.985 vs 0.930) and CO 2 exposure (400 vs 1000 ppm) on (a) growth of Aspergillus flavus and effects on (b) gene expression of a structural (aflD) and key regulatory gene (aflR) involved in aflatoxin B 1 (AFB 1 ) biosynthesis and (c) AFB 1 production on a yeast extract sucrose medium over a period of 10 days. A. flavus grew and produced AFB 1 very early with toxin detected after only 48 h. Both growth and toxin production were significantly impacted by the interacting abiotic factors. The relative expression of the aflD gene was significantly influenced by temperature; aflR gene expression was mainly modulated by time. However, no clear relationship was observed for both genes with AFB 1 production over the experimental time frame. The optimum temperature for AFB 1 production was 30 °C. Maximum AFB 1 production occurred between days 4-8. Exposure to higher CO 2  conditions simulating forecasted CC conditions resulted in the amount of AFB 1  produced in elevated temperature (37 °C) being higher than with the optimum temperature (30 °C) showing a potential for increased risk for human/animal health due to higher accumulation of this toxin., (Copyright © 2020 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

Little is known on the impact that climate change (CC) may have on Aspergillus carbonarius and Ochratoxin A (OTA) contamination of grapes, especially in the Mediterranean region where in CC scenarios temperature are expected to increase by +2-5 °C and CO 2 from 400 to 800/1200 ppm. This study examined the effect of (i) current and increased temperature in the alternating 11.5 h dark/12.5 h light cycle (15-28 °C vs 18-34 °C), representative of the North Apulia area, South Italy and (ii) existing and predicted CO 2 concentrations (400 vs 1000 ppm), on growth, expression of biosynthetic genes (AcOTApks, AcOTAnrps, AcOTAhal, AcOTAp450, AcOTAbZIP) and regulatory genes of Velvet complex (laeA/veA/velB, "velvet complex") involved in OTA biosynthesis and OTA phenotypic production by three strains of A. carbonarius. The experiments made on a grape-based matrix showed that elevated CO 2 resulted in a general stimulation of growth and OTA production. These results were also supported by the up-regulation of both structural and regulatory genes involved in the OTA biosynthesis. Our work has shown for the first time that elevated CO 2 concentration in the Mediterranean region may result in an increased risk of OTA contamination in the wine production chain., (Copyright © 2019 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

Pistachio nuts are an economically important commodity produced by many countries. They can be colonized by mycotoxigenic fungi, especially Aspergillus flavus , resulting in contamination with aflatoxins (AFs) , especially aflatoxin B 1 (AFB 1 ), a Class 1a carcinogen. The objectives were to examine the effect of interactions between the two key abiotic factors, temperature and water activity (a w ) on (a) in vitro growth and AFB 1 production by four strains of A. flavus isolated from pistachio nuts, on a milled pistachio nut medium modified ionically (NaCl) and non-ionically (glycerol) in the range 20-35°C and 0.995-0.85 a w , (b) colonization of layers of raw pistachio nuts stored at different interacting temperature x a w conditions and on relative AFB 1 production and (c) develop models to produce contour maps of the optimal and marginal boundary conditions for growth and AFB 1 production by up to 4 strains of this species. On pistachio nut-based media, optimum growth of four strains of A. flavus was at 0.98-0.95 a w and 30-35°C. Optimum AFB 1 production was at 30-35°C and 0.98 a w . No significant differences in growth was found on ionic and non-ionically modified media. Colonization of layers of raw pistachio nuts was slower and contamination with AFB 1 significantly less than in in vitro studies. Contour maps based on the pooled data for up to four strains ( in vitro , in situ ) showed the optimum and marginal conditions for growth and AFB 1 production. These data can be used to identify those conditions which represent a high, intermediate or low risk of colonization and AFB 1 contamination in the pistachio nut processing chain. These results are discussed in the context of the development of appropriate intervention strategies to minimize AFB 1 contamination of this economically important commodity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Baazeem, Garcia-Cela, Medina and Magan.)

Penicillium verrucosum contaminates temperate cereals with ochratoxin A (OTA) during harvesting and storage. We examined the effect of temperature (25 vs 30  o C), CO 2  (400 vs 1000 ppm) and matric/solute stress (-2.8 vs -7.0 MPa) on (i) growth, (ii) key OTA biosynthetic genes and (iii) OTA production on a milled wheat substrate. Growth was generally faster under matric than solute stress at 25  o C, regardless of CO 2  concentrations. At 30  o C, growth of P. verrucosum was significantly reduced under solute stress in both CO 2  treatments, with no growth observed at -2.8 MPa (=0.98 water activity, a w ) and 1000 ppm CO 2 . Overall, growth patterns under solute stress was slower in elevated CO 2  than under matric stress when compared with existing conditions. The otapksPV gene expression was increased under elevated CO 2  levels in matric stress treatments. There was fewer effects on the otanrpsPV biosynthetic gene. This pattern was paralleled with the production of OTA under these conditions. This suggest that P. verrucosum is able to actively grow and survive in both soil and on crop debris under three way interacting climate-related abiotic factors. This resilience suggests that they would still be able to pose an OTA contamination risk in temperate cereals post-harvest., (Copyright © 2020 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

Active ageing (AA) policies aim to improve quality of life of older people by enabling better social participation and inclusion. Despite many international initiatives to promote AA undertaken in recent years, Italy did not systematically address this policy challenge until very recently. This paper presents the first national Plan-of-Action (PoA) (2019-2022) adopted by this country for supporting policy design and recommendation in this field. The PoA aims to create a multilevel, co-managed coordination of AA policies, by involving a network of national and regional policy makers, experts, researchers and stakeholders in civil society. The ad-hoc consultation process established for this purpose helps the recognition of different interests and expectations on AA, fostering new solutions by involvement, consultation and joint discussion of policy options. The PoA is designed to cover the traditional policy cycle, including the stages of agenda setting, policy formulation, decision-making, implementation and monitoring. At the end of the period covered by the PoA, an Italian AA Strategy will be launched to achieve systematic impact in this field, thus ensuring a long-term, sustainable impact on national and regional policy makers, civil society and research community.

Fusarium causes significant post-harvest quality losses and mycotoxin contamination in stored wheat but the colonisation dynamics of the grain and how this may be affected by the initial inoculum position in the grain mass is poorly understood. This study examined the 3D growth kinetics and mycotoxin production (deoxynivalenol and zearalenone) by F. graminearum during hyphal colonisation from different initial inoculum positions in wheat microcosms (top-centre, bottom-centre, and bottom-side) maintained at two water activities (a w ; 0.95 and 0.97). Clear jars were used to visually follow the colonisation dynamics. Fungal respiration and associated dry matter loss (DML) and ergosterol were also quantified. Colonisation dynamics was shown to be affected by the inoculation position. At the end of the colonisation process, fungal respiration and DML were driven by the inoculation position, and the latter also by the prevailing a w . Fungal biomass (ergosterol) was mainly affected by the a w . The initial inoculum position did not affect the relative mycotoxin production. There was a positive correlation between respiration and ergosterol, and between mycotoxin production and colonisation indicators. We suggest that spatially explicit predictive models can be used to better understand the colonisation patterns and mycotoxin contamination of stored cereal commodities and to aid more effective post-harvest management.