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Despite intense research towards the understanding of abiotic stress adaptation in tomato, the physiological adjustments and transcriptome modulation induced by combined salt and low nitrate (low N) conditions remain largely unknown. Here, three traditional tomato genotypes were grown under long-term single and combined stresses throughout a complete growth cycle. Physiological, molecular, and growth measurements showed extensive morphophysiological modifications under combined stress compared to the control, and single stress conditions, resulting in the highest penalty in yield and fruit size. The mRNA sequencing performed on both roots and leaves of genotype TRPO0040 indicated that the transcriptomic signature in leaves under combined stress conditions largely overlapped that of the low N treatment, whereas root transcriptomes were highly sensitive to salt stress. Differentially expressed genes were functionally interpreted using GO and KEGG enrichment analysis, which confirmed the stress and the tissue-specific changes. We also disclosed a set of genes underlying the specific response to combined conditions, including ribosome components and nitrate transporters, in leaves, and several genes involved in transport and response to stress in roots. Altogether, our results provide a comprehensive understanding of above- and below-ground physiological and molecular responses of tomato to salt stress and low N treatment, alone or in combination., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Recurrent pericarditis (RP) is defined by the European Society of Cardiology (ESC) as an instance of acute pericarditis (AP) that occurs at least 4-6 weeks after the resolution of a previous episode of the same ailment. To mitigate the risk of RP, it is advised to administer accurate and prolonged pharmacological treatment for both the initial AP and subsequent RP. ESC guidelines recommend commencing treatment for any single episode of AP, including those that contribute to RP, with non-steroidal anti-inflammatory drugs (NSAIDs) in conjunction with colchicine for several months, often followed by gradual tapering. If there is an inadequate response, corticosteroids (CS) may be introduced cautiously. However, in a minority of cases, even when NSAIDs, colchicine, and CS are administered together at the highest recommended dosages, they may prove ineffective. In such instances, treatment with immunosuppressive drugs or biologics is advised. Among biologics, interleukin (IL)-1 inhibitors have been extensively studied, although certain gaps remain. This narrative review delves into the rationale for employing IL-1 inhibitors and presents findings from existing studies regarding their efficacy, tolerability, and safety. Analysis of the literature indicates that there is currently insufficient data to ascertain the true therapeutic role of IL-1 inhibitors in managing and preventing RP. However, theoretically, drugs targeting both IL-1α and IL-1β may offer superior efficacy compared to those solely targeting IL-1β due to the significant involvement of both cytokines in inflammation. Further research is warranted to determine the comparative effectiveness of IL-1α and IL-1β inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

'Corbarino' (COR) and 'Lucariello' (LUC) belong to the family of Mediterranean long shelf-life tomato landraces, producing high quality fruits under low water input cultivation regime in their traditional cultivation area. Understanding the morpho-physiological and molecular details of the peculiar drought stress tolerance of these two genotypes may be key to their valorization as breeding material. RNA sequencing of leaf samples of COR and LUC subjected to drought stress by water withholding in a semi-controlled greenhouse identified 3089 and 2135 differentially expressed genes respectively. These included COR- and LUC-specific annotated genes, as well as genes containing single nucleotide polymorphisms as compared to reference genome. Enriched Gene Ontology categories showed that categories such as response to water, oxidoreductase activity, nucleotide salvation and lipid biosynthesis-related processes were enriched among up-regulated DEGs. By contrast, growth and photosynthesis related genes were down-regulated after drought stress, consistent with leaf gas exchange and biomass accumulation measurements. Genes encoding cell wall degrading enzymes of the pectinase family were also down-regulated in drought stress conditions and upregulated in rewatering, indicating that cell wall composition/hardness is important for drought stress responses. Globally our results contribute to understanding the transcriptomic and physiological responses of representative tomato genotypes from Southern Italy, highlighting a promising set of genes to be investigated to improve tomato tolerance to drought., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Alkalinity is an important environmental factor that affects crop production and will be exacerbated in the current climate change scenario. Thus, the presence of carbonates and high pH in soils negatively impacts nutrient assimilation and photosynthesis and causes oxidative stress. A potential strategy to improve tolerance to alkalinity could be the modification of cation exchanger (CAX) activity, given that these transporters are involved in calcium (Ca 2+ ) signaling under stresses. In this study, we used three Brassica rapa mutants (BraA.cax1a-4, BraA.cax1a-7, and BraA.cax1a-12) from the parental line 'R-o-18' that were generated by Targeting Induced Local Lesions in Genomes (TILLING) and grown under control and alkaline conditions. The objective was to assess the tolerance of these mutants to alkalinity stress. Biomass, nutrient accumulation, oxidative stress, and photosynthesis parameters were analyzed. The results showed that BraA.cax1a-7 mutation was negative for alkalinity tolerance because it reduced plant biomass, increased oxidative stress, partially inhibited antioxidant response, and lowered photosynthesis performance. Conversely, the BraA.cax1a-12 mutation increased plant biomass and Ca 2+ accumulation, reduced oxidative stress, and improved antioxidant response and photosynthesis performance. Hence, this study identifies BraA.cax1a-12 as a useful CAX1 mutation to enhance the tolerance of plants grown under alkaline conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: This Italian multicentric retrospective study aimed to investigate the possible changes in outcomes of patients undergoing surgery for gastrointestinal cancers during the COVID-19 pandemic., Method: Our primary endpoint was to determine whether the pandemic scenario increased the rate of patients with colorectal, gastroesophageal, and pancreatic cancers resected at an advanced stage in 2020 compared to 2019. Considering different cancer staging systems, we divided tumors into early stages and advanced stages, using pathological outcomes. Furthermore, to assess the impact of the COVID-19 pandemic on surgical outcomes, perioperative data of both 2020 and 2019 were also examined., Results: Overall, a total of 8250 patients, 4370 (53%) and 3880 (47%) were surgically treated during 2019 and 2020 respectively, in 62 Italian surgical Units. In 2020, the rate of patients treated with an advanced pathological stage was not different compared to 2019 (P = 0.25). Nevertheless, the analysis of quarters revealed that in the second half of 2020 the rate of advanced cancer resected, tented to be higher compared with the same months of 2019 (P = 0.05). During the pandemic year 'Charlson Comorbidity Index score of cancer patients (5.38 ± 2.08 vs 5.28 ± 2.22, P = 0.036), neoadjuvant treatments (23.9% vs. 19.5%, P < 0.001), rate of urgent diagnosis (24.2% vs 20.3%, P < 0.001), colorectal cancer urgent resection (9.4% vs. 7.37, P < 0.001), and the rate of positive nodes on the total nodes resected per surgery increased significantly (7 vs 9% - 2.02 ± 4.21 vs 2.39 ± 5.23, P < 0.001)., Conclusions: Although the SARS-CoV-2 pandemic did not influence the pathological stage of colorectal, gastroesophageal, and pancreatic cancers at the time of surgery, our study revealed that the pandemic scenario negatively impacted on several perioperative and post-operative outcomes., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We recently described C18 fatty acid acylated peptides as a new class of potent long-lasting single-chain RXFP1 agonists that displayed relaxin-like activities in vivo. Early pharmacokinetics and toxicological studies of these stearic acid acylated peptides revealed a relevant oxidative metabolism occurring in dog and minipig, and also seen at a lower extent in monkey and rat. Mass spectrometry combined to NMR spectroscopy studies revealed that the oxidation occurred, unexpectedly, on the stearic acid chain at ω-1, ω-2 and ω-3 positions. Structure-metabolism relationship studies on acylated analogues with different fatty acids lengths (C15-C20) showed that the extent of oxidation was higher with longer chains. The oxidized metabolites could be generated in vitro using liver microsomes and engineered bacterial CYPs. These systems were correlating poorly with in vivo metabolism observed across species; however, the results suggest that this biotransformation pathway might be catalyzed by some unknown CYP enzymes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Children are an important target group for influenza vaccination, but few studies have prospectively evaluated influenza vaccine efficacy (VE) in children under 3 years of age. This was a randomized Phase III trial to assess the efficacy, immunogenicity, and safety of an inactivated quadrivalent influenza vaccine (QIV) in young children (EudraCT: 2016-004904-74)., Methods: Influenza-naïve children aged 6-35 months were randomized during three influenza seasons to receive vaccination with QIV or a non-influenza control vaccine. One group of participants was revaccinated with QIV in the subsequent influenza season. The primary efficacy endpoint was the absolute VE of QIV against influenza caused by any circulating strain. Key secondary efficacy endpoints included the absolute VE of QIV against influenza due to antigenically matching strains and immunogenicity. Safety and reactogenicity were also evaluated., Results: In total, 1005 children received QIV and 995 received control vaccine. Influenza A/B infection due to any circulating influenza strain occurred less frequently in children who received QIV versus children receiving a control vaccine. The absolute VE of QIV against any circulating influenza strain was 54% (95% confidence interval [CI]: 37%, 66%). The absolute VE of QIV against antigenically matching influenza strains was 68% (95% CI: 45%, 81%). Mean hemagglutination inhibition titers for all influenza strains in the QIV group increased post-vaccination, whereas increases were minimal in the control vaccine group; results from virus neutralization and neuraminidase-inhibition assays were generally consistent with the hemagglutination inhibition assay findings. Approximately 12 months after primary vaccination with QIV, antibody titers remained higher than pre-vaccination titers for most strains. In participants who were revaccinated, QIV elicited strong antibody responses. The overall safety profile and reactogenicity of QIV was comparable with control vaccine., Conclusion: Primary vaccination with QIV was well tolerated and effective in protecting children aged 6-35 months against influenza., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Serge van de Witte and Jos Nauta declared that they are employees of Abbott Healthcare Products B.V., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Lipidation, a common strategy to improve half-life of therapeutic peptides, affects their tendency to oligomerize, their interaction with plasmatic proteins, and their catabolism. In this work, we have leveraged the use of NMR and SPR spectroscopy to elucidate oligomerization propensity and albumin interaction of different analogs of the two marketed lipidated GLP-1 agonists liraglutide and semaglutide. As most lipidated therapeutic peptides are administered by subcutaneous injection, we have also assessed in vitro their catabolism in the SC tissue using the LC-HRMS-based SCiMetPep assay. We observed that oligomerization had a shielding effect against catabolism. At the same time, binding to albumin may provide only limited protection from proteolysis due to the higher unbound peptide fraction present in the subcutaneous compartment with respect to the plasma. Finally, identification of catabolites in rat plasma after SC dosing of semaglutide showed a good correlation with the in vitro data, with Tyr 19 -Leu 20 being the major cleavage site. Early characterization of the complex interplay between oligomerization, albumin binding, and catabolism at the injection site is essential for the synthesis of lipidated peptides with good pharmacokinetic profiles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Low temperatures (0-10 °C) represent a major physiological stress for plants, negatively affecting both their growth rates and overall growth. Cold stress may induce a wide range of negative physiological effects, from oxidative stress to photosynthetic damage. We investigated the effects of low temperatures in two different model plants, Arabidopsis thaliana and Hordeum vulgare. We tested whether the oxidative pentose phosphate pathway (OPPP) is involved in the increase of reductants' levels needed to counteract oxidative stress induced by cold. The expression, occurrence, and activity of different glucose-6-phosphate dehydrogenase (G6PDH, EC 1.1.1.49) isoforms during cold stress and plant recovery from low temperatures, were measured at different growth stages from early germinated to mature pot-grown plants. Our results showed plants exhibited changes in different stress markers; ascorbate peroxidase - APX, catalase - CAT, proline, malondialdehyde, H 2 O 2, NADPH/NADP + . We found that a major role in cold acclimation for cytosolic- and peroxisome-located G6PDHs, and different roles for plastidial/chloroplastic isoforms. This suggests that G6PDH isoforms may regulate redox homeostasis in low temperatures, in order to support the increased and continued demand of reductants during both cold stress and recovery stages. Furthermore, we found a significant involvement of (6PGDH), strengthening the idea that the contribution of the whole oxidative pentose phosphate pathway (OPPP) is required to sustain reductant supply under cold stress., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Varicella vaccination confers high and long-lasting protection against chickenpox and induces robust immune responses, but an absolute correlate of protection (CoP) against varicella has not been established. This study models the relationship between varicella humoral response and protection against varicella., Methods: This was a post-hoc analysis of data from a Phase IIIb, multicenter, randomized trial (NCT00226499) conducted in ten varicella-endemic European countries. Healthy children aged 12-22 months were randomized 3:3:1 to receive one dose of measles-mumps-rubella and one dose of varicella vaccine (one-dose group) or two doses of measles-mumps-rubella-varicella vaccine (two-dose group) or two doses of measles-mumps-rubella vaccine (control group) six weeks apart. The study remained observer-blind until completion, except in countries with obligatory additional immunizations. The objective was to correlate varicella-specific antibody concentrations with protection against varicella and probability of varicella breakthrough, using Cox proportional hazards and Dunning and accelerated failure time statistical models. The analysis was guided by the Prentice framework to explore a CoP against varicella., Results: The trial included 5803 participants, 5289 in the efficacy (2266: one-dose group, 2279: two-dose group and 744: control group) and 5235 (2248, 2245 and 742 in the same groups) in the immunogenicity cohort. The trial ended in 2016 with a median follow-up time of 9.8 years. Six weeks after vaccination with one- or two-dose varicella-containing vaccine, more than 93.0% of vaccinees were seropositive for varicella-specific antibodies. Estimated vaccine efficacy correlated positively with antibody concentrations. The fourth Prentice CoP criterion was not met, due to predicted positive vaccine efficacy in seronegative participants. Further modelling showed decreased probability of moderate to severe varicella breakthrough with increasing varicella-specific antibody concentrations (ten-year probability <0.1 for antibody concentrations ≥2-fold above the seropositivity cut-off)., Conclusions: Varicella-specific antibody concentrations are a good predictor of protection, given their inverse correlation with varicella occurrence., Clinical Trial: NCT00226499., Competing Interests: Declaration of Competing Interest Md Ahsan Habib, Stephane Carryn, Ouzama Henry, Stéphanie Ravault, Paul Gillard and Michael Povey are employees of the GSK groups of companies. Md Ahsan Habib, Stephane Carryn, Ouzama Henry, Stéphanie Ravault and Paul Gillard hold shares in the GSK group of companies as part of their employee remuneration. Roman Prymula received grant support from the GSK group of companies. Susanna Esposito received grant support from Abbott and DMG companies; personal fees from MSD company; and grant support and personal fees from the GSK group of companies, Sanofi, Vifor Pharma and Janssen Pharmaceutica. Jacek Wysocki received personal fees from the GSK group of companies during the conduct of the study. Vytautas Usonis received grant from the GSK group of companies during the conduct of the study and as educational grant. All authors have no non-financial interest to declare., (Copyright © 2021 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy. Infections and vaccines have been hypothesized to play a role in triggering GBS development. These beliefs can play a role in reducing vaccination coverage. In this report, data concerning this hypothesis are discussed. It is shown that an association between vaccine administration and GBS has never been proven for most of debated vaccines, although it cannot be definitively excluded. The only exception is the influenza vaccine, at least for the preparation used in 1976. For some vaccines, such as measles/mumps/rubella, human papillomavirus, tetravalent conjugated meningococcal vaccine, and influenza, the debate between supporters and opponents of vaccination remains robust and perception of vaccines' low safety remains a barrier to achieving adequate vaccination coverage. Less than 1 case of GBS per million immunized persons might occur for these vaccines. However, in some casesimmunization actually reduces the risk of GBS development. In addition, the benefits of vaccination are clearly demonstrated by the eradication or enormous decline in the incidence of many vaccine-preventable diseases. These data highlight that the hypothesized risks of adverse events, such as GBS, cannot be considered a valid reason to avoid the administration of currently recommended vaccines., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The duration of protection provided by varicella vaccines is unclear. We assessed the 10-year vaccine efficacy of two doses of a combined measles-mumps-rubella-varicella vaccine (MMRV), one live attenuated varicella vaccine (V) dose given after one measles-mumps-rubella vaccine (MMR) dose (MMR + V), versus two MMR doses (control vaccine) for the prevention of confirmed varicella., Methods: This was a phase 3b follow-up of an observer-blinded, randomised, controlled trial. In phase a, children aged 12-22 months (at first vaccination) from Czech Republic (Czechia), Greece, Italy, Lithuania, Norway, Poland, Romania, Russia, Slovakia, and Sweden were randomly assigned by computer-generated randomisation list (3:3:1) to receive two doses of MMRV, one dose of MMR and one dose of varicella vaccine, or two doses of MMR, 42 days apart. Varicella cases were confirmed by detection of viral DNA, or epidemiological link and clinical assessment, by an independent data monitoring committee; disease severity was based on a modified Vázquez scale. Hazard ratios for MMRV and MMR + V versus MMR estimated in the per-protocol cohort using a Cox proportional hazards regression model were used to calculate vaccine efficacy and 95% CI. Serious adverse events were recorded throughout the study in all vaccinated children. Study objectives were secondary and descriptive. The trial is registered at ClinicalTrials.gov, number NCT00226499., Findings: Between Sept 1, 2005, and May 10, 2006, 5803 children (mean age 14·2 months, SD 2·5) were vaccinated. The per-protocol cohort included 2279 children from the MMRV group, 2266 from the MMR + V group, and 744 from the MMR group. From baseline to a median follow-up of 9·8 years, 76 (3%) children in the MMRV group, 469 (21%) in the MMR + V group, and 352 (47%) in the MMR group had varicella. Vaccine efficacy against all varicella was 95·4% (95% CI 94·0-96·4) for MMRV and 67·2% (62·3-71·5) for MMR + V; vaccine efficacy against moderate or severe varicella was 99·1% (97·9-99·6) for MMRV and 89·5% (86·1-92·1) for MMR + V. During phase b, serious adverse events were reported by 290 (15%) of 1961 children in the MMRV group, 317 (16%) of 1978 in the MMR + V group, and 93 (15%) of 641 in the MMR group. There were no treatment-related deaths., Interpretation: The 10-years vaccine efficacy observed, suggests that a two-dose schedule of varicella vaccine provided optimum long-term protection for the prevention of varicella by offering individual protection against all severities of disease and leading to a potential reduction in transmission, as observed in the US experience with universal mass vaccination., Funding: GlaxoSmithKline Biologicals., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS), have been associated to alterations in chromatin structure resulting in long-lasting changes in gene expression. ALS is predominantly a sporadic disease and environmental triggers may be involved in its onset. In this respect, alterations in the epigenome can provide the key to transform the genetic information into phenotype. In this paper, we demonstrate that two modifications associated with transcriptional activation, namely dimethylation of lysine 4 on H3 tail (H3K4me2) and phospho-acetylation of serine 10 and lysine 14 on H3 tail (H3K14ac-S10ph), and two modifications associated to transcriptional repression, namely trimethylation of lysine 9 on H3 tail (H3K9me3) and DNA methylation are selectively altered in cellular and animal model of ALS. These results reinforce the idea that epigenetic therapy may represent a potential and attractive approach for ALS treatment., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Mayer-Rokitansky-Küster-Hauser syndrome (MRKH; Online Mendelian Inheritance in Man #277000) is a rare disorder of the female reproductive tract. Its etiology is still unknown for most patients, although the genetic background of this condition has been intensively studied. Chromosome 16p11.2 deletion syndrome (Online Mendelian Inheritance in Man #611913) is a well known recurrent deletion syndrome that can present with various clinical phenotypes, including developmental delay, intellectual disability, autism spectrum disorder, obesity, and an increased frequency of congenital defects., Case: Herein we report a patient with 16p11.2 recurrent microdeletion in whom MRKH syndrome was diagnosed in adolescence., Summary and Conclusion: Our purpose is to underscore the possible presence of gynecological malformations in patients with 16p11.2 microdeletion and highlight the utility of a genetic evaluation in cases of MRKH syndrome., (Copyright © 2018 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

The proportion of the population ≥65 years old is about 17% today and will be about 27% in 2050 worldwide. The problem, however, is not ageing in itself, it is individual disabilities associated with ageing. This manuscript summarizes the consensus points reached during a pan-European meeting on gaps and barriers in making vaccination of adults aged 50+ a reality and on further joint actions in Europe. The shift from childhood to life-long vaccination is essential to prevent disability, morbidity and mortality in the elderly and promote healthy ageing. This vaccination shift is a major challenge in the post-truth, media-based era in countries with dwindling resources for the provision of healthcare. The challenge can be met only by adopting an innovative approach designed to shift the mindset of decision-makers from treatment to prevention. A number of key actions are required and for these actions a European multidisciplinary network including health authorities, medical doctors with different specialties, sociologists, psychologists, pharmaceutical companies and Associations of patients appears mandatory., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

For almost a century, aluminum (Al) in the form of Al oxyhydroxide (a crystalline compound), Al hydroxyphosphate (an amorphous Al phosphate hydroxide), Al phosphate, and Al potassium sulfate has been used to improve the immunogenicity of vaccines. Al is currently included in vaccines against tetanus, hepatitis A, hepatitis B, human papillomavirus, Haemophilus influenzae type b, and infections due to Streptococcus pneumoniae and Neisseria meningitidis. Official health authorities consider the inclusion of Al in most of the presently recommended vaccines to be extremely effective and sufficiently safe. However, the inclusion of Al salts in vaccines has been debated for several years because of studies that seem to indicate that chronic Al exposure through vaccine administration can interfere with cellular and metabolic processes leading to severe neurologic diseases. Children, who in their first years of life receive several vaccine doses over a reduced period of time, would be most susceptible to any risk that might be associated with vaccines or vaccine components. The main aim of this paper was to discuss the data presently available regarding Al neurotoxicity and the risk for children receiving vaccines or other pharmaceutical preparations containing Al. Analysis of the literature showed that no apparent reason exists to support the elimination of Al from vaccines for fear of neurotoxicity. The only problem that deserves attention is the suggested relationship between Al oxyhydroxide-containing vaccines and macrophagic myofaciitis or myalgic encephalomyelitis/chronic fatigue syndrome. Currently, definitive conclusions cannot be drawn on these risks and further studies must be conducted. Until then, Al remains the best solution to improve vaccine efficacy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Subcutaneous (SC) injection is the most common administration route for peptide therapeutics. Catabolism at the injection site can be a specific and major degradation pathway for many SC administered peptides. In some cases, it can significantly affect pharmacokinetics, particularly bioavailability, and have detrimental effects on the efficacy of the drug. This work describes a liquid chromatography-high resolution mass spectrometry based in vitro assay to assess peptide metabolism in the SC tissue (SCiMetPep assay). The SCiMetPep assay was developed using human, Sprague-Dawley rat and Göttingen minipig SC tissue homogenate supernatant, and allows for both determination of degradation rate (half-life) of the parent peptide and identification of metabolites generated from enzymatic proteolysis. The assay was developed and validated using known peptides including human insulin and four GLP-1 analogues (lixisenatide, exenatide, liraglutide and semaglutide). Different experimental parameters were evaluated in order to optimize the homogenization process of the SC tissue and the peptide incubation conditions. In vitro metabolism of these peptides was in good agreement with in vivo data reported in the literature. Finally, when SCiMetPep assay was applied on a series of structurally related peptides, a fairly good correlation was found between SC metabolic stability and bioavailability, suggesting that catabolism at the injection site can have a major role in the absorption, distribution, metabolism, and excretion (ADME) of peptide therapeutics. The SCiMetPep showed the ability to identify analogs with improved SC metabolic stability and hence higher bioavailability. The assay can be used in the early phases of drug discovery to identify peptide metabolic soft spots at the injection site and guide the peptide drug discovery process., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The clinical relevance of herpes zoster (HZ) and its increased incidence in recent years has prompted a search for more effective measures of prevention and therapy. A number of vaccines has been developed. For two of them, the live attenuated HZ vaccine (LAHZV) and the adjuvanted recombinant subunit HZ vaccine (SUHZV), data regarding immunogenicity, efficacy, safety and reactogenicity have been collected. This information allows us to draw some conclusions about what can be expected from their use and what is still required to definitively solve the problem of HZ prevention. The currently licensed vaccine LAHZV is only partially satisfactory in terms of efficacy, but it is safe and exhibits acceptable reactogenicity. Because LAHZV is also highly cost effective, it should be used as widely as possible until new, more effective preparations are developed. In this regard, preliminary data regarding SUHZV are very promising, although more studies are needed before it can be licensed for routine use. Other vaccines, such as the inactivated VZV vaccine, are in development. It seems likely that in the near future, more effective HZ prevention for older adults can be achieved., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rotavirus (RV) is the leading cause of severe acute gastroenteritis (GE) in infants worldwide. Several vaccines against RV were developed to reduce disease burden, hospitalization rates and health utilization costs. RV GE is a serious disease in preterm (PT) infants, and the administration of RV vaccine to these at-risk subjects at the proper time could have great clinical relevance. However, most data on the efficacy and safety of RV vaccinations were collected in healthy full-term infants, and few studies investigated PT infants. The lack of studies in PT infants may explain why neonatologists in several neonatal intensive care units (NICUs) do not follow the official recommendations, which indicate that RV vaccine may be administered in hospitals. Increasing neonatologists' knowledge on the efficacy and safety of RV vaccines and defining PT candidates for vaccination and the necessary precautions are extremely important to avoid potential vaccine virus transmission and improve RV vaccination coverage in PT infants. Further studies should analyse the impact of vaccination of PT infants of different gestational ages and various clinical histories in stable conditions in the NICU with a careful monitoring of adverse events to the vaccine and RV GE occurrence. Only data that confirm the efficacy and safety of RV vaccines in large numbers of PT infants with different characteristics will convince neonatologists to use RV vaccines in PT infants hospitalized in NICUs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Vaccination during pregnancy is increasingly being recognised internationally a useful means of preventing illness in pregnant women and their newborns. It has been used since the 1960s, when it was found that tetanus vaccine was highly effective in preventing neonatal tetanus, but interest has greatly increased over the last few years. As new data become available showing the numerous benefits of maternal immunisation and its potential for improving maternal and neonatal health in relation to a number of infectious conditions, it is being increasingly incorporated into the national vaccination programmes around the world. However, the development of new vaccines, the existence of clinical trials testing the efficacy of vaccinating pregnant women in order to protect newborns against respiratory syncytial virus and group B Streptococcus infections, and the fact that the uptake of influenza and pertussis vaccines during pregnancy is lower than expected in developed countries is making it increasingly clear that existing maternal vaccination programmes need to be strengthened. This reviews addresses the importance of integrating maternal immunisation and standard obstetrical care in order to promote vaccination administration by maternal care providers (MCPs) because the vaccination goals for pregnant women cannot be achieved without appropriate training and extending the role of MCPs as vaccinators. In order to make meaningful progress, it is necessary to develop and refine targeted messages for pregnant women concerning the benefits of maternal immunisation for themselves and their infants., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

At the beginning of this century, a number of studies suggested that in healthy children, particularly those <2years of age, influenza could have a serious and complicated course, as it frequently led to hospitalization and sometimes, albeit rarely, to death. Moreover, pre-schoolers and school-age children were found to be among the most important causes of influenza transmission to the community, as they shed the virus for a longer time than adults and had frequent contact with greater numbers of individuals through day-care and school. These findings led a number of health authorities to modify the official recommendations regarding the use of influenza vaccine in healthy children. Several factors seem to indicate that vaccination against influenza in healthy children of any age and in pregnant women could be effective in preventing the disease in the entire paediatric population and in providing herd immunity in adults and old people as well. The direct advantages of the vaccine seem greater in younger subjects, particularly those <2-3years of age. Vaccination of older children is considered effective by most experts, but high vaccination coverage of these subjects has been difficult to attain. Similar difficulties have been identified for the vaccination of pregnant women. These challenges can be overcome, at least in part, by appropriate information and accurate evaluations of available data. In addition, further studies specifically designed to clarify unresolved problems regarding vaccine use in paediatric and pregnant populations are needed to convince reluctant health authorities. More effective vaccines for younger children as well as improved availability of data regarding the optimal time period for vaccine administration in pregnant women appear relevant in this regard., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Longer life expectancy and decreasing fertility rates mean that the proportion of older people is continually increasing worldwide, and particularly in Europe. Ageing is associated with an increase in the risk and severity of infectious diseases. These diseases are also more difficult to diagnose and manage in seniors who often have at least one comorbid condition (60% of seniors have two or more conditions). Infectious diseases increase the risk of hospitalization, loss of autonomy and death in seniors. Effective vaccines are available in Europe for infectious diseases such as influenza, pneumococcal diseases, herpes zoster, diphtheria, tetanus and pertussis. Their effectiveness has been demonstrated in terms of reducing the rates of hospitalization, disability, dependency and death. The prevention of diseases in seniors also results in savings in healthcare and societal costs each year in Europe. Despite the availability of vaccines, vaccine-preventable diseases affect millions of European citizens annually, with the greatest burden of disease occurring in seniors, and the medical and economic benefits associated with are not being achieved. Vaccination coverage rates must be improved to achieve the full benefits of vaccination of seniors in Europe., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In recent years, several outbreaks due to Enterovirus D-68 (EV-D68) have been reported, and it was confirmed that the virus can cause upper and lower respiratory tract diseases and be associated with the development of neurological problems., Objectives: The main aim of this research was to study the genetic characteristics of EV-D68 strains that were circulating in Italy identified during an outbreak of an EV-D68 infection that occurred in Italy during the period March-October 2016., Study Design: A retrospective study of the circulation of different types and subtypes of EV-D68 was performed. Nasopharyngeal swabs were collected from March 2016 through October 2016 in children admitted to the Emergency Room with respiratory diseases., Results: Among 390 children, 22 (59.1% males; mean age 47 months) were found to be infected by EV-D68 and most of them were immunocompetent (72.7%). Pneumonia was diagnosed in 12 (54.5%) children. Phylogenetic analysis of the VP1 region showed that all the strains identified in this study belonged to clade B3. Within B3 subclade, the Italian EV-D68 strains were most closely related to strains detected in Southern China in 2015 as well as to strains detected in US and the Netherlands in 2016., Conclusions: These results showed that EV-D68 infections are a common cause of lower respiratory illness in pediatric age. The circulation of one EV-D68 lineage has been proven in Italy and in the European region during 2016. However, further studies are required to investigate whether some strains or lineages may possess a higher affinity for the lower airway or central nervous system., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In Italy, Hib conjugate vaccine was introduced for infants in 1999 and included in the DTaP-HBV-IPV-Hib combination in 2001, with an uptake of 83.4% in 2002, >90% by 2005, and >95% by 2011. We estimated the impact of Hib vaccination on hospitalizations for H. influenzae invasive disease in children <5years. Age-specific hospitalization rates and hospitalization risk ratios (HRRs) with 95%CI during 2001-2013 were calculated performing time-series analysis. The number of cases reported to the national surveillance of invasive bacterial diseases was compared to the number of hospitalizations between 2007-2013. Hospitalization rates declined from 2.3 in 2001 to 0.9×100,000 in 2002 (HRR=0.4, 95%CI=0.3-0.6, p<0.05) among children 1-4years and from 5.4 in 2001 to 2.4×100,000 in 2005 (HRR=0.4, 95%CI=0.2-0.9, p<0.05) among infants. During 2007-2013: 401 cases were reported, 242 were typed, 12.4% were by serotype b; 861 hospital admissions were recorded. Applying the percentage of typed b strains retrieved from the surveillance to the number of hospitalizations for invasive H. influenzae disease, an estimated 107 episodes could be attributable to serotype b. These findings provided reassuring data on the impact of Hib vaccination on the burden of hospitalization for invasive disease in Italian children., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Type 1 diabetes (T1D) is the most common chronic metabolic disorder in children. Epigenetic and environmental factors capable of altering the penetrance of major susceptibility genes or capable of increasing the penetrance of low-risk genes are currently thought to play a role in triggering autoimmunity and T1D development. This paper discusses the current knowledge of the role of viruses in T1D. Most studies that have evaluated the potential association between viral infections and T1D have indicated that it is highly likely that some of these infectious agents play a role in T1D development. However, most T1D cases are immune-mediated, and it is supposed that the initial viral infection is capable of creating, in genetically predisposed subjects, a particular condition in which chronic local inflammation occurs through the persistence of the infecting virus in pancreatic tissue and the activation of autoimmunity by means of molecular mimicry, bystander activation, or both. Theoretically, this knowledge could lead to possible prophylaxis and therapy for T1D. Further studies devoted to evaluating which infectious agents are linked to T1D and which immune mechanisms induce or protect against the disease are needed before adequate prophylactic and therapeutic measures can be developed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The involvement and the efficiency of the antioxidants scavenging system upon drought were examined by comparing traditional tomato landraces with respect to an industrial commercial genotype (Red Setter); for the first time, comprehensive analyses of physiological, biochemical and molecular parameters were investigated directly under real field conditions, in a typical agricultural environment of Southern Italy. The characterization of the responses upon drought evidenced peculiar changes in stomatal conductance, ascorbate peroxidase and catalase activities and expression in drought tolerant tomato landraces, with respect to the industrial genotype. An in silico analysis (promoter and co-expression study) coupled to a phylogenetic investigation of selected enzymes was performed, reinforcing the hypothesis of a basal activation of ROS scavenging machinery in the Mediterranean landraces. Thus our data suggest a constitutive increase in the expression and activities of specific enzymes involved in ROS detoxification that can play a pivotal role in the drought response shown by tomato landraces. Therefore, traditional landraces could represent an important source of useful genetic variability for the improvement of commercial varieties; their ROS detoxifying capabilities denote peculiar aspects worth being explored to better describe their specific stress tolerance., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: 4CMenB is immunogenic in infants and toddlers. We assessed persistence of human complement serum bactericidal activity (hSBA) following a fourth dose administered at 12, 18 or 24months and characterised the antibody response to a fifth dose administered at 4years of age., Methods: A phase 3, open label, multi-centre extension to a randomised controlled trial conducted in four countries (number of centres): Czech Republic (nineteen), Italy (four), Spain (four) and the United Kingdom (four). Four-year-old children who were either 4CMenB-naïve or had previously received a variety of 3-dose infant priming schedules and a booster vaccine as toddlers (follow-on group) were recruited. Venous blood samples were obtained to determine hSBA against four reference strains; acting as targets to assess immunity to each of the vaccine antigens, NadA (5/99), fHbp (H44/76), PorA (NZ98/254), and NHBA (M10713) at baseline (prior to vaccination, all participants) and one month following a dose of 4CMenB for all vaccine-naïve and follow-on participants primed with the 2, 3, 4 schedule, and a third of follow-on participants primed with a 2, 4, 6month schedule., Results: At baseline (prior to vaccination), the proportion of participants (n=468) with hSBA titers⩾5 was similar across all followon groups: 89-100% against 5/99; 12-35% for H44/76; 8-12% for NZ98/254 and 53-80% for M10713 compared with 5%, 0%, 0%; and 60% respectively, for the vaccine-naïve controls (n=206). Following a dose of 4CMenB at 4years of age, this increased to 100% (5/99), 97-100% (H44/76), 80-95 % (NZ98/254) and 84-100% (M10713) (n=210), compared with 89%, 70%, 24%, and 76% respectively for vaccine-naïve controls (n=192)., Conclusion: Waning of protective antibodies occurred 24–36 months after toddler booster regardless of age at boost. This was least marked against target strains 5/99 and M10713. A robust memory response occurred after a booster dose given at 4 years of age., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Multiple vaccination visits and administrations can be stressful for infants, parents and healthcare providers. Multivalent combination vaccines can deliver the required number of antigens in fewer injections and clinic visits, while vaccine co-administration can also reduce the number of visits. This non-inferiority study was undertaken to evaluate the feasibility of co-administering a combined measles-mumps-rubella-varicella (MMRV) vaccine with conjugated meningococcal C (MenC) vaccine in a large cohort of healthy Italian toddlers., Methods: Healthy subjects aged 13-15months were randomized (2:1:1) to receive single doses of either: co-administered MMRV+MenC at the same visit (MMRV+MenC group); or MMRV followed 42days later by MenC (MMRV group); or MenC followed 42days later by MMRV (MenC group). Blood samples were collected before and 43days after vaccination. Antibody titers against MMRV were measured using ELISA. Functional-anti-meningococcal-serogroup activity (rSBAMenC) was assessed using a serum bactericidal test. Solicited local and general reactions were recorded for up to 4 and 42days post-vaccination, respectively. Non-inferiority of MMRV+MenC to MMRV (post-dose-1 seroconversion rates) and MMRV+MenC to MenC (post-dose-1 seroprotection rates) was achieved if the lower limit (LL) of the 95% confidence interval (CI) for the group difference was ⩾-10% for each antigen., Results: 716 subjects were enrolled in the study. At 42days post-vaccination, the MMRV seroconversion rates were 99.3% (measles), 94.5% (mumps), 100% (rubella) and 99.7% (varicella) in the MMRV+MenC group, and 99.4%, 93.2%, 100% and 100%, respectively, in the MMRV group. The seroprotection rates against rSBA-MenC were 98.3% in the MMRV+MenC group and 99.3% in the MenC group. Non-inferiority was reached for all the vaccine antigens. The safety profiles were as expected for these vaccines., Conclusion: The immune responses elicited by co-administered MMRV+MenC were non-inferior to those elicited by MMRV or MenC alone and support vaccination of children with both vaccines at a single visit., Clinical Trials Registration: NCT01506193., (Copyright © 2016. Published by Elsevier Ltd.)

The present study was undertaken to investigate the expression, occurrence and activity of glucose 6 phosphate dehydrogenase (G6PDH - EC 1.1.1.49), the key-enzyme of the Oxidative Pentose Phosphate Pathway (OPPP), in tomato plants (Solanum lycopersicum cv. Red Setter) exposed to short- and long-term drought stress. For the first time, drought effects have been evaluated in plants under different growth conditions: in hydroponic laboratory system, and in greenhouse pots under controlled conditions; and in open field, in order to evaluate drought response in a representative agricultural environment. Interestingly, changes observed appear strictly associated to the induction of well known stress response mechanisms, such as the increase of proline synthesis, accumulation of chaperone Hsp70, and ascorbate peroxidase. Results show significant increase in total activity of G6PDH, and specifically in expression and occurrence of cytosolic isoform (cy-G6PDH) in plants grown in any cultivation system upon drought. Intriguingly, the results clearly suggest that abscissic acid (ABA) pathway and signaling cascade (protein phosphatase 2C PP2C) could be strictly related to increased G6PDH expression, occurrence and activities. We hypothesized for G6PDH a specific role as one of the main reductants' suppliers to counteract the effects of drought stress, in the light of converging evidences given by young and adult tomato plants under stress of different duration and intensity., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: The value of plasma levels of human herpesvirus 8 (HHV-8) DNA as a marker of clinical status in acquired immunodeficiency syndrome-related Kaposi's sarcoma (AIDS-KS) remains to be elucidated., Objectives: To investigate the relationship between the plasma HHV-8 DNA viral load and the clinical status of AIDS-KS., Study Design: A total of 378 blood samples were obtained from 62 patients with AIDS-KS followed longitudinally. All patients received antiretroviral therapy (ART) or anti-neoplastic therapy. The patients were divided into four groups according to their clinical status: onset disease (OD), progressive disease (PD), stable or partial remission (S/PR) and complete remission (CR)., Results: Plasma HHV-8 DNAaemia was detected in all samples obtained from patients with OD or PD (100%); in contrast, HHV-8 DNAaemia was found only in a minority of patients with CR (8%) and was invariably undetectable in patients with stable CR. HHV-8 DNA detection in plasma was strongly associated with an unfavourable outcome (odds ratio=231.9; p<0.0001). Conversely, neither the HIV-1 viral load nor peripheral CD4(+) T-cell counts were associated with the KS clinical status, though both parameters did affect HHV-8 DNAaemia levels (p<0.0001). Multivariate analysis confirmed that HHV-8 DNAaemia was strongly and independently correlated with both clinical status (p<0.05) and HIV-1 plasma viraemia (p=0.027)., Conclusions: The strong association of plasma HHV-8 DNAaemia with onset or progressive disease is compatible with an active role of replicating virus in clinically active AIDS-KS. An accurate evaluation of the plasma HHV-8 load might be useful for monitoring AIDS-KS under antiretroviral or antineoplastic therapy., (Copyright © 2016. Published by Elsevier B.V.)

This work describes a simple, sensitive and rapid liquid chromatography-high resolution mass spectrometry method for the quantitation of perhexiline and the simultaneous detection of perhexiline metabolites in C57bl/6 mice plasma. Only 5 μL of plasma was used for analysis. Pretreatment was limited to a 100-fold dilution ('dilute-and-shoot'). The analyte was detected by high resolution mass spectrometry (Orbitrap™ technology). Three scan events were performed over the entire chromatogram. Targeted single ion monitoring with data dependent acquisition was employed for perhexiline quantitation and confirmation, while full scan was used to perform untargeted detection of perhexiline phase I and phase II circulating metabolites. The calibration curve was linear (r(2)=0.990) ranging from 0.305 ng/mL (LLOQ) to 10000 ng/mL. Matrix effect was limited to 6.1%. The method was applied to a pharmacokinetic study of perhexiline in mouse plasma and the results obtained were compared to a standard sample preparation method based on protein precipitation and liquid chromatography-tandem mass spectrometry (MRM mode) detection. The new approach provided comparable results in terms of pharmacokinetics parameters estimate with a high sensitivity, additional information on perhexiline circulating metabolites and a low consumption of biological sample. The combination of the 'dilute-and-shoot' approach together with HRMS targeted and untargeted detection represents a suitable alternative to classic bioanalytical approaches in preclinical research., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Obesity may be a risk factor for increased hospitalization and deaths from infections due to respiratory pathogens. Additionally, obese patients appear to have impaired immunity after some vaccinations. To evaluate the immunogenicity, safety and tolerability of an inactivated trivalent influenza vaccine (TIV) in overweight and obese children, 28 overweight/obese pediatric patients and 23 healthy normal weight controls aged 3-14 years received a dose of TIV. Four weeks after vaccine administration, significantly higher seroprotection rates against the A/H1N1 strain were observed among overweight/obese children compared with normal weight controls (p<0.05). Four months after vaccination, similar or slightly higher seroconversion and seroprotection rates against the A/H1N1 and A/H3N2 strains were detected in overweight/obese than in normal weight children, whereas significantly higher rates of seroconversion and seroprotection against the B strain were found in overweight/obese patients than in normal weight controls (p<0.05 for seroconversion and seroprotection). Geometric mean titers (GMTs) and fold increase against B strains were significantly higher in overweight/obese patients than in normal weight controls 4 months after vaccine administration (p<0.01 for GMT values and p<0.05 for fold increase). The frequency of local and systemic reactions was similar between the groups, and there were no serious adverse events. The results of this study indicate that in overweight and obese children, antibody response to TIV administration is similar or slightly higher than that evidenced in normal weight subjects of similar age and this situation persists for at least 4 months after vaccine administration in the presence of a favorable safety profile., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

To evaluate vaccination coverage of children and adolescents with inborn errors of metabolism (IEMs) and the attitudes of their parents towards vaccination, the vaccination status of 128 patients with IEM and 128 age- and gender-matched healthy controls was established by consulting the official vaccination chart. In children with IEMs, compared with healthy controls, low vaccination rates and/or delays in administration were observed for pneumococcal conjugate, meningococcus C, measles, mumps, rubella, diphtheria-tetanus-pertussis-inactivated polio, Bacillus Calmette-Guerin, and influenza vaccines. Among the parents of IEM patients, vaccine schedule compliance was primarily driven by the doctors at the hospital's reference centres; among the parents of the healthy controls, compliance was driven by the primary care paediatricians. These results show that IEM patients demonstrate sub-optimal vaccination coverage. Further studies of the different vaccines in each IEM disorder and educational programmes aimed at physicians and parents to increase immunization coverage in these patients are urgently needed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Four species of human bocaviruses (HBoV) are currently included in the Bocavirus genus. There is satisfactory evidence demonstrating an association between HBoV1 and respiratory disease in children, and there is evidence that HBoV2 (and possibly the HBoV3 and HBoV4 species) are associated with gastroenteritis. In particular, HBoV1 has been associated with a prolonged period of persistence in the mucosa of the respiratory tract. Virus persistence does play a role in the high frequency of co-infections with proper pathogens of the upper and lower respiratory tracts. The high detection rate of multiple respiratory viruses in up to 83% of respiratory specimens and the presence of asymptomatic HBoV1 infections complicate the elucidation of the pathogenic role of the agent. Overall, a large amount of data are available concerning HBoV1, whereas little information is available about other bocavirus species. High viral loads are often associated with symptoms, and viremia may be associated with systemic manifestations such as encephalopathy. The effects and mechanisms of latency, persistence, reactivation, and reinfection are poorly understood. Thus, particularly in co-infections, the pathogenic contribution of the detected bocavirus species cannot be accurately stated. This review summarizes the current knowledge of HBoV species and provides perspectives for future clinical studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: An increasing number of children infected by enterovirus D68 (EV-D68) and affected by severe respiratory illness, muscle weakness and paralysis were described in the USA and Canada in 2014 OBJECTIVES: To investigate the potential involvement of EV-D68 in determining community-acquired pneumonia (CAP) in hospitalised children in order to acquire information concerning the clinical problems associated with EV-D68 in Italy., Study Design: This prospective study of children hospitalised for CAP in the largest Pediatric Department in Milan, Italy, was carried out between 1 June and 31 December 2014. All of the children's admission nasopharyngeal swabs were investigated for the presence of EV-D68., Results: One hundred and seventy-six children with radiographically confirmed CAP were hospitalised during the 7-month study period: 97 (55.1%) had enterovirus/rhinovirus-positive nasopharyngeal samples, including four (2.3%) positive for EV-D68. These four samples were collected between 9 and 21 October, a month in which 21 cases of CAP were recorded. Phylogenetic analysis showed that all of the sequences fell into clade B. The most severe case was diagnosed in a 14-year-old girl with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS syndrome), who died after 12 days of hospitalisation., Conclusions: EV-D68 was detected in few children with usually mild-to-moderate lower respiratory tract infection, although the disease lead to the death of a girl with a severe chronic underlying disease. Further studies capable of better defining the epidemiological, genetic and pathogenetic characteristics of the virus are required in order to be able to prepare appropriate preventive and therapeutic measures., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Although the incidence of human rhinovirus (HRV) infection is highest in young, no study has yet been published concerning the types of HRV circulating in this population, the incidence of symptomatic infections due to the different types, or duration of shedding, Objectives: This prospective study evaluated the circulation of HRV species and types, and established the incidence of asymptomatic and symptomatic infections in young children., Study Design: The study enrolled 93 healthy children aged <2 years, 88 of whom completed the follow-up of weekly household visits from November 2013 to February 2014. At each visit, a record was made of any signs and symptoms of acute infection, and a nasopharyngeal (NP) swab was taken in order to identify the HRVs by means of RT-polymerase chain reaction and to construct the phylogenetic tree of the HRV-positive cases., Results: A total of 1408 NP samples were obtained and 326 HRV infections were diagnosed (23.1%), leading to a mean number of 3.7 ± 2.3 infections per child: HRV-A in 72 cases (22.1%), HRV-B in 29 (8.9%), HRV-C in 122 (37.4%), and non-typeable HRV in 103 (31.6%). Shedding was significantly longer for HRV-A (14 days) and HRV-B (14 days) than HRV-C (7 days; p = 0.002 and p = 0.012). Most of the HRV infections (209/326, 64.1%) remained asymptomatic and, when symptomatic, were of marginal clinical relevance., Conclusions: In healthy young children, HRV infection is extremely frequent, generally asymptomatic or with a mild clinical presentation, and viral shedding is limited in time., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In this study the effects of salt stress and nitrogen assimilation have been investigated in roots of hydroponically-grown barley plants exposed to 150 mM NaCl, in presence or absence of ammonium as the sole nitrogen source. Salt stress determines a diversion of root metabolism towards the synthesis of osmolytes, such as glycine betaine and proline, and increased levels of reduced glutathione. The metabolic changes triggered by salt stress result in a decrease in both activities and protein abundance of key enzymes, namely GOGAT and PEP carboxylase, and in a slight increase in HSP70. These variations would enhance the requirement for reductants supplied by the OPPP, consistently with the observed increase in total G6PDH activity. The involvement and occurrence of the different G6PDH isoforms have been investigated, and the kinetic properties of partially purified cytosolic and plastidial G6PDHs determined. Bioinformatic analyses examining co-expression profiles of G6PDHs in Arabidopsis and barley corroborate the data presented. Moreover, the gene coding for the root P2-G6PDH isoform was fully sequenced; the biochemical properties of the corresponding protein were examined experimentally. The results are discussed in the light of the possible distinct roles and regulation of the different G6PDH isoforms during salt stress in barley roots., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Pediatric patients with severe chronic kidney disease (CKD) on conservative treatment, on dialysis, and those with renal transplantation are at a higher risk for infectious diseases as the result of impaired immune responses against infectious agents. Infections in these patients can have drastic consequences for disease morbidity and mortality. Immunization is a crucial preventive strategy for disease management in this pediatric population. However, vaccination coverage among children with CKD remains low due to safety concerns and doubts about vaccine immunogenicity and efficacy. In this study, we reviewed why children with CKD are at higher risk of infections, the importance of vaccinations among these children, barriers to vaccinations, and recommend the best vaccination schedules. Overall, vaccines have acceptable immunogenicity, efficacy, and safety profiles in children with CKD. However, in some cases, the protective antibody levels induced by vaccines and the benefits and risks of booster vaccine doses must be individually managed. Furthermore, close contacts and household members of these children should complete age-appropriate vaccination schedules to increase the child's indirect protection.

Neuromuscular diseases (NMDs) encompass a broad spectrum of conditions. Because infections may be relevant to the final prognosis of most NMDs, vaccination appears to be the simplest and most effective solution for protecting NMD patients from vaccine-preventable infections. However, very few studies have evaluated the immunogenicity, safety, tolerability, and efficacy of different vaccines in NMD patients; therefore, detailed vaccination recommendations for NMD patients are not available. Here, we present vaccination recommendations from a group of Italian Scientific Societies for optimal disease prevention in NMD patients that maintain high safety levels. We found that NMD patients can be classified into two groups according to immune function: patients with normal immunity and patients who are immunocompromised, including those who intermittently or continuously take immunosuppressive therapy. Patients with normal immunity and do not take immunosuppressive therapy can be vaccinated as healthy subjects. In contrast, immunocompromised patients, including those who take immunosuppressive therapy, should receive all inactivated vaccines as well as influenza and pneumococcal vaccines; these patients should not be administered live attenuated vaccines. In all cases, the efficacy and long-term persistence of immunity from vaccination in NMD patients can be lower than in normal subjects. Household contacts of immunocompromised NMD patients should also be vaccinated appropriately., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Neurofibromatosis 1 is a complex inherited neurocutaneous disease that is often difficult to diagnose early because of its age-dependent presentation. The diagnosis is also extremely difficult to communicate to patients and their parents because of the disease's clinical variability, unpredictable evolution, and uncertain prognosis. Since 1988, the year of publication of the last Consensus Conference statement concerning the diagnosis of neurofibromatosis 1, our understanding of the disease has naturally increased and, in addition to the availability of increasingly precise molecular analyses, some new clinical signs have been reported such as anaemic nevi, unidentified bright objects, choroidal hamartomas, and a typical neuropsychological phenotype. We critically review the current diagnostic criteria, and suggest the addition of new signs on the basis of published findings and our own clinical experience. This proposal aims to improve diagnostic power in paediatric age, securing a better and more reliable healthcare transition toward adult age. We finally recommend a new Consensus Conference in order to revise the diagnostic criteria, possibly differentiated by age of presentation., (Copyright © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Primary immunodeficiency disorders (PIDs) are a heterogeneous group of rare, congenital and genetically determined conditions caused by one or more defects of innate and/or adaptive immunity. In subjects suffering from PIDs, an unusually increased susceptibility to infections is demonstrated. As infections condition the final prognosis of most PIDs, clearly defined prophylactic practices are essential. In most cases, intravenously or subcutaneously administered immunoglobulin remains the mainstay of treatment, although antibiotics and antifungals can be added under some conditions, particularly when the infections are highly recurrent despite immunoglobulin replacement. Vaccines could also play a role, but their administration leads to different results depending on the type of PID: in some cases, immune response is not impaired, and vaccines can evoke the same protection as that usually induced in healthy subjects; in others, the immunodeficiency significantly interferes with antigen stimulation of the immune system and, depending on the type and degree of impairment, little or no protection is evoked. Moreover, particularly when live vaccines are given, significant vaccine-related adverse events can occur, including the emergence of disease from vaccine strains. The main aim of this paper is to discuss what is currently known about how and when vaccines can be used in patients with PIDs in order to facilitate physician choices and assure the best possible patient protection., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Human parechoviruses (HPeVs) are members of the large and growing family of Picornaviridae. Although 16 types have been described on the basis of the phylogenetic analyses of the VP1 encoding region, the majority of published reports relate to the HPeV types 1-8. In pediatrics, HPeV1, HPeV2 and HPeV4-8 mainly cause mild gastrointestinal or respiratory illness; only occasionally more serious diseases have been reported, including myocarditis, encephalitis, pneumonia, meningitis, flaccid paralysis, Reye syndrome and fatal neonatal infection. In contrast, HPeV3 causes severe illness in young infants, including sepsis and conditions involving the central nervous system. Currently, the most sensitive method for detecting HPeV is real-time polymerase chain reaction assays on stools, respiratory swabs, blood and cerebrospinal fluid. However, although it is known that HPeVs play a significant role in various severe pediatric infectious diseases, diagnostic assays are not routinely available in clinical practice and the involvement of HPeV is therefore substantially underestimated. Despite long-term efforts, the development of antiviral therapy against HPeVs is limited; no antiviral medication is available and the use of monoclonal antibodies is still being evaluated. More research is therefore needed to clarify the specific characteristics of this relevant group of viruses and to develop appropriate treatment strategies., (Copyright © 2014 Elsevier B.V. All rights reserved.)

It is known that the immunogenicity and efficacy of conventional inactivated influenza vaccines (IIVs) are not completely satisfactory in children. The aim of this prospective, randomised, single-blind study was to compare the immune response to, and the effectiveness and safety of, an IIV (Fluarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) administered to 68 children aged 36-59 months affected by recurrent respiratory tract infections (RRTIs) who were vaccinated with (n=33) or without (n=35) the mixed bacterial lysate OM-85 BV (Broncho-vaxom, Vifor Pharma, Geneva, Switzerland). OM-85 BV had no effect on seroconversion or seroprotection rates, geometric mean titres, or dendritic cells, which were not significantly different between the two groups. Moreover, OM-85 BV did not significantly increase the pool of the memory B cells that produce IgG and IgM antibodies against the influenza antigens. However, respiratory morbidity was significantly lower in the children treated with OM-85 BV (p<0.05), thus confirming its positive effect on the incidence of RRTIs. There was no difference in the incidence of adverse events between the two groups. These findings show that the immune response of children to influenza vaccine is not significantly influenced by the administration of OM-85 BV. However, the use of OM-85 before and at the same time as IIV seems to reduce respiratory morbidity, and seems to be safe and well tolerated., (Copyright © 2014 Elsevier Ltd. All rights reserved.)