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Although maternal antenatal transfer is the preferred option, some infants inevitably need urgent transport to a tertiary neonatal care facility after birth. This study aimed to investigate trends over time in patient characteristics and respiratory management in a large series of neonatal emergency transfers, in order to provide health caregivers an up-to-date profile of such patients and their therapeutic needs. Trends in patient characteristics and respiratory management were evaluated in 3337 transfers by the Eastern Veneto Neonatal Emergency Transport Service in 2000–2019. Joinpoint regression analysis was performed to evaluate trends and to estimate annual percentage changes (APCs). Proportions of preterm neonates increased (APC2000–2012 2.25%), then decreased (APC2012–2019 − 6.04%). Transfers at birth increased (APC2000–2013 2.69%), then decreased (APC2013–2019 − 5.76%). Proportion of neonates with cardiac and surgical diseases declined (APCs2000–2019 − 6.82% and − 3.32%), while proportion of neonates with neurologic diseases increased (APC2000–2019 8.62%). Use of nasal-continuous-positive-airway-pressure (APC2000–2019 9.72%) and high-flow-nasal-cannula (APC2007–2019 58.51%) at call, and nasal-continuous-positive-airway-pressure (APC2000–2019 13.87%) and nasal-intermittent-mandatory-ventilation (APC2000–2019 32.46%) during transfer increased. Mechanical ventilation during transfer decreased (APC2014–2019 − 10.77%). Use of oxygen concentrations at 21% increased at call and during transfer (APCs 2000–2019 2.24% and 2.44%), while oxygen concentrations above 40% decreased at call and during transfer (APCs 2000–2019 − 3.93% and − 5.12%). Conclusion: Our findings revealed a shift toward a more “gentle” approach and the reduced use of oxygen in respiratory management. Equipment and team expertise should meet the requirements of such changing patients and their therapeutic needs.

The diagnosis of asthma is currently based on clinical history, physical examination and lung function, and to date, there are no accurate objective tests either to confirm the diagnosis or to discriminate between different types of asthma. This consensus exercise reviews the state of the art in asthma diagnosis to identify opportunities for future investment based on the likelihood of their successful development, potential for widespread adoption and their perceived impact on asthma patients. Using a two-stage e-Delphi process and a summarizing workshop, a group of European asthma experts including health professionals, researchers, people with asthma and industry representatives ranked the potential impact of research investment in each technique or tool for asthma diagnosis and monitoring. After a systematic review of the literature, 21 statements were extracted and were subject of the two-stage Delphi process. Eleven statements were scored 3 or more and were further discussed and ranked in a face-to-face workshop. The three most important diagnostic/predictive tools ranked were as follows: “New biological markers of asthma (eg genomics, proteomics and metabolomics) as a tool for diagnosis and/or monitoring,” “Prediction of future asthma in preschool children with reasonable accuracy” and “Tools to measure volatile organic compounds (VOCs) in exhaled breath.”.

Assessment of problematic severe asthma in children should be performed in a step-wise manner to ensure an optimal approach. A four-step assessment scheme is proposed. First, a full diagnostic work-up is performed to exclude other diseases which mimic asthma. Secondly, a multi-disciplinary assessment is performed to identify issues that may need attention, including comorbidities. Thirdly, the pattern of inflammation is assessed, and finally steroid responsiveness is documented. Based upon these four steps an optimal individualised treatment plan is developed. In this article the many gaps in our current knowledge in all these steps are highlighted, and recommendations for current clinical practice and future research are made. The lack of good data and the heterogeneity of problematic severe asthma still limit our ability to optimise the management on an individual basis in this small, but challenging group of patients.

Background: International guidelines recommend regular treatment with inhaled glucocorticoids for children with frequent wheezing; however, prn inhaled bronchodilator alone or in combination with glucocorticoid is also often used in practice. We aimed to evaluate whether regular nebulized glucocorticoid plus a prn bronchodilator or a prn nebulized bronchodilator/glucocorticoid combination is more effective than prn bronchodilator alone in preschool children with frequent wheeze. Methods: Double-blind, double-dummy, randomized, parallel-group trial. After a 2-week run-in period, 276 symptomatic children with frequent wheeze, aged 1–4 years, were randomly assigned to three groups for a 3-month nebulized treatment: (1) 400 μg beclomethasone bid plus 2500 μg salbutamol prn; (2) placebo bid plus 800 μg beclomethasone/1600 μg salbutamol combination prn; (3) placebo bid plus 2500 μg salbutamol prn. The percentage of symptom-free days was the primary outcome measure. Secondary outcomes included symptom scores, use of relief medication and exacerbation frequency. Results: As compared with prn salbutamol (61.0 ± 24.83 [SD]), the percentage of symptom-free days was higher with regular beclomethasone (69.6%, SD 20.89; P = 0.034) but not with prn combination (64.9%, SD 24.74). Results were no different in children with or without risk factors for developing persistent asthma. The effect of prn combination was no different from that of regular beclomethasone on the primary and on several important secondary outcomes. Conclusions: Regular inhaled glucocorticoid is the most effective treatment for frequent wheezing in preschool children. However, prn bronchodilator/glucocorticoid combination might be an alternative option, but it requires further study.

The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover new antibiotics that are active against the antibiotic-resistant bacteria of current clinical concern. However, the main hurdle is diminishing economic incentives. Increased global calls to minimize the overuse of antibiotics, the cost of meeting regulatory requirements and the low prices of currently marketed antibiotics are strong deterrents to antibacterial drug development programmes. New economic models that create incentives for the discovery of new antibiotics and yet reconcile these incentives with responsible antibiotic use are long overdue. DRIVE-AB is a €9.4 million public–private consortium, funded by the EU Innovative Medicines Initiative, that aims to define a standard for the responsible use of antibiotics and to develop, test and recommend new economic models to incentivize investment in producing new anti-infective agents.

Asthma treatment might improve when inhaled steroids are titrated on airway inflammation. Fractional exhaled nitric oxide (FeNO0.05), a marker of eosinophilic airway inflammation, can be measured at home.We assessed daily FeNO0.05 telemonitoring in the management of childhood asthma.Children with atopic asthma (n = 151) were randomly assigned to two groups: FeNO0.05 plus symptom monitoring, or monitoring of symptoms only. All patients scored asthma symptoms in an electronic diary over 30 weeks; 77 received a portable nitric oxide (NO) analyzer. Data were transmitted daily to the coordinating centers. Patients were phoned every 3 weeks and their steroid dose was adapted according to FeNO0.05 and symptoms, or according to symptoms. Children were seen at 3, 12, 21, and 30 weeks for examination and lung function testing. The primary end point was the proportion of symptom-free days in the last 12 study weeks.Telemonitoring was feasible with reliable FeNO0.05 data for 86% of days, and valid diary entries for 79% of days. Both groups showed an increase in symptom-free days, improvement of FEV1 and quality of life, and a reduction in steroid dose. None of the changes from baseline differed between groups. The difference in symptom-free days over the last 12 weeks was 0.3% (P = 0.95; 95% confidence interval, -10 to 11%). There was a trend for fewer exacerbations in the FeNO0.05 group.Thirty weeks of daily FeNO0.05 and symptom telemonitoring was associated with improved asthma control and a lower steroid dose. We found no added value of daily FeNO0.05 monitoring compared with daily symptom monitoring only.

There is a lack of high-quality evidence on what treatment should be used in children with properly characterised severe, therapy-resistant asthma. Data have to be largely extrapolated from trials in children with mild asthma, and adults with severe asthma. Therapeutic options can be divided into medications used in lower doses for children with less severe asthma, and those used in other paediatric diseases but not for asthma (for example, methotrexate). In the first category are high-dose inhaled corticosteroids (ICS) (≤ 2,000 μg · day(-1) fluticasone equivalent), oral prednisolone, the anti-immunoglobulin (Ig)E antibody omalizumab, high-dose long-acting β(2)-agonists, low-dose oral theophylline and intramuscular triamcinolone. If peripheral airway inflammation is thought to be a problem, the use of fine-particle ICS or low-dose oral corticosteroids may be considered. More experimental therapies include oral macrolides, cyclosporin, cytotoxic drugs such as methotrexate and azathioprine, gold salts, intravenous infusions of Ig, subcutaneous β(2)-agonist treatment and, in those sensitised to fungi, oral antifungal therapy with itraconazole or voriconazole. Those with recurrent severe exacerbations, particularly in the context of good baseline asthma control, are particularly difficult to treat; baseline control and lung function must be optimised with the lowest possible dose of ICS, and allergen triggers and exposures minimised. The use of high-dose ICS, leukotriene receptor antagonists or both at the time of exacerbations can be considered. There is no evidence regarding which therapeutic option to recommend. Better evidence is required for all these treatment options, underscoring the need for the international and co-ordinated approach which we have previously advocated.

Although most children with asthma are easy to treat with low doses of safe medications, many remain symptomatic despite every therapeutic effort. The nomenclature regarding this group is confusing, and studies are difficult to compare due to the proliferation of terms describing poorly defined clinical entities. In this review of severe asthma in children, the term problematic severe asthma is used to describe children with any combination of chronic symptoms, acute severe exacerbations and persistent airflow limitation despite the prescription of multiple therapies. The approach to problematic severe asthma may vary with the age of the child, but, in general, three steps need to be taken in order to separate difficult-to-treat from severe therapy-resistant asthma. First, confirmation that the problem is really due to asthma requires a complete diagnostic re-evaluation. Secondly, the paediatrician needs to systematically exclude comorbidity, as well as personal or family psychosocial disorders. The third step is to re-evaluate medication adherence, inhaler technique and the child's environment. There is a clear need for a common international approach, since there is currently no uniform agreement regarding how best to approach children with problematic severe asthma. An essential first step is proper attention to basic care.

Several epidemiologic studies have suggested an association between childhood asthma and exposure to disinfection by-products (DBPs) in the swimming pool environment. In August 2007 a group of clinicians, epidemiologists, exposure scientists, pool operations experts, and analytical chemists met to discuss the literature on childhood asthma and swimming pools, and to develop recommendations for future research. In a review based on the results of that workshop, the authors state that current evidence, while suggestive, is inconclusive for an association with childhood asthma, and they point to several substantial data gaps that must be filled [EHP 117:500–507; Weisel et al.]. The authors articulate several variables that must be measured in more detail to properly characterize inhalation exposure to chemicals around pools. The review calls for a comprehensive assessment of a substantially larger number of chemicals in the pool area than the limited number of DBPs studied to date. Earlier epidemiologic studies suggested trichloramine as a DBP of interest, but one 2007 study revealed previously unknown volatile DBPs in the air surrounding swimming pools. The frequency and extent of exposure to chemicals around pools also must be studied. In research to date, only simple exposure indices have been used, including whether the pool was indoors or outdoors, specific disinfection treatment, whether the child swam in or was simply present at an indoor pool, and cumulative duration of swimming. But to evaluate the breathing rate and DBP dose delivered to the lungs, more detailed, validated assessments of activity levels are needed. To obtain these data, the authors recommend that future studies use prospective questionnaires in which participants report their pool use and activity levels over time as they occur. The authors also point to the need for studies that define asthma cases in a rigorous, reproducible way, utilizing the International Study of Asthma and Allergy in Children questionnaire. Previous studies have often used clinical diagnoses, but this may be insufficient for epidemiologic studies because asthma is a heterogeneous disease with no single reliable diagnostic test. Additional needs include development and validation of new biomarkers for asthmatic reactivity and studies designed to refine guidelines for proper pool maintenance and disinfection to reduce levels of DBPs. The authors conclude this research area requires studies across multiple disciplines. Once chemicals of interest are identified, studies of the mechanisms behind the possible association—such as oxidative stress, inflammation, and changes in lung permeability—may be useful. But long-range prospective studies starting in early childhood will be needed to better gauge the relationship between swimming pools and childhood asthma. Absent conclusive studies, the authors say children’s exposures should be minimized. Pool managers must be well educated about pool chemistry so they can understand the potential dangers of disinfectants and DBPs. Swimmers, too, must be educated about the need for proper pool hygiene (for example, showering before swimming and not urinating in the pool), as swimmer hygiene can affect the formation of DBPs and the amount of disinfectant used.

Background The PERSEO study (psychiatric emergency study and epidemiology) is a naturalistic, observational clinical survey in Italian acute hospital psychiatric units, called SPDCs (Servizio Psichiatrico Diagnosi e Cura; in English, the psychiatric service for diagnosis and management). The aims of this paper are: (i) to describe the epidemiological and clinical characteristics of patients, including sociodemographic features, risk factors, life habits and psychiatric diagnoses; and (ii) to assess the clinical management, subjective wellbeing and attitudes toward medications. Methods A total of 62 SPDCs distributed throughout Italy participated in the study and 2521 patients were enrolled over the 5-month study period. Results Almost half of patients (46%) showed an aggressive behaviour at admission to ward, but they engaged more commonly in verbal aggression (38%), than in aggression toward other people (20%). A total of 78% of patients had a psychiatric diagnosis at admission, most frequently schizophrenia (36%), followed by depression (16%) and personality disorders (14%), and no relevant changes in the diagnoses pattern were observed during hospital stay. Benzodiazepines were the most commonly prescribed drugs, regardless of diagnosis, at all time points. Overall, up to 83% of patients were treated with neuroleptic drugs and up to 27% received more than one neuroleptic either during hospital stay or at discharge. Atypical and conventional antipsychotics were equally prescribed for schizophrenia (59 vs 65% during stay and 59 vs 60% at discharge), while atypical drugs were preferred in schizoaffective psychoses (72 vs 49% during stay and 70 vs 46% at discharge) and depression (41 vs 32% during stay and 44 vs 25% at discharge). Atypical neuroleptics were slightly preferred to conventional ones at hospital discharge (52 vs 44%). Polypharmacy was in general widely used. Patient attitudes toward medications were on average positive and self-reported compliance increased during hospital stay. Conclusion Results confirm the widespread use of antipsychotics and the increasing trend in atypical drugs prescription, in both psychiatric in- and outpatients.

Background & Aims Premenopausal women who are HCV positive (HCV+) have failing ovarian function, which is likely to impact their fertility. Thus, we investigated the reproductive history, risk of infertility, and pregnancy outcomes in women of childbearing age who were HCV+. Methods Three different groups were studied: (1) Clinical cohort: 100 women who were HCV+ and also had chronic liver disease (CLD), age matched with 50 women who were HBV+ with CLD and with 100 healthy women; all women were consecutively observed in three gastroenterology units in hospitals in Italy; (2) 1,998 women who were HCV+ and enrolled in the Italian Platform for the Study of Viral Hepatitis Therapies (PITER); (3) 6,085 women, who were mono-infected with HCV, and 20,415 women, who were HCV−, from a large de-identified insurance database from the USA. Measurements: total fertility rate (TFR) defined as the average number of children that a woman would bear during her lifetime. To define the reproductive stage of each participant, levels of anti-Müllerian hormone (AMH) and 17β-estradiol were measured. Results Clinical cohort: women who were either HCV+ or HBV+ had similar CLD severity and age at first pregnancy. Based on a multivariate analysis, women who were HCV+ had a higher risk of miscarriage than those who were HBV+ (odds ratio [OR] 6,905; 95% CI 1.771–26.926). Among women who were HCV+, incidence of miscarriage was correlated with median AMH level (1.0 ng/ml). Achieving a sustained virologic response (SVR) after antiviral treatment reduced the risk of miscarriage (OR 0.255; 95% CI 0.090–0.723). In the PITER-HCV cohort, miscarriage occurred in 42.0% of women (44.6% had multiple miscarriages). TFR for women who were HCV+ and between 15 and 49 years of age was 0.7 vs. 1.37 of Italian population of the same age range. In the US cohort: compared with women who were HCV−, women who were HCV+ positive were significantly more likely to have infertility (OR 2.439; 95% CI 2.130–2.794), premature birth (OR 1.34; 95% CI 1.060–1.690), gestational diabetes (OR 1.24; 95% CI 1.020–1.510), and pre-eclampsia (OR 1.206; 95% CI 0.935–1.556), and were less likely to have a live birth (OR 0.754; 95% CI 0.622–0.913). Conclusions Ovarian senescence in women of childbearing age who are HCV+ is associated with a lower chance of live birth, greater risk of infertility, gestational diabetes, pre-eclampsia and miscarriage. Such risks could be positively influenced by successful HCV cure. Lay summary Most new cases of HCV infection are among people who inject drugs, many of whom are young women in their childbearing years. Women of reproductive age who are HCV+ display markers of ovarian senescence. This is associated with an increased burden in terms of infertility and adverse pregnancy outcomes, including stillbirth, miscarriage, fewer live births, and gestational diabetes. Early viral suppression with therapy is likely to mitigate these risks.

Rationale: Lung ultrasound is useful in critically ill patients with acute respiratory failure. Given its characteristics, it could also be useful in extremely preterm infants with evolving chronic respiratory failure, as we lack accurate imaging tools to monitor them. Objectives: To verify if lung ultrasound can monitor lung aeration and function and has good reliability to predict bronchopulmonary dysplasia in extremely preterm neonates. Methods: A multicenter, international, prospective, longitudinal, cohort, diagnostic accuracy study consecutively enrolling inborn neonates with gestational age 3016 weeks or younger. Lung ultrasound was performed on the 1, 7, 14, and 28 days of life, and lung ultrasound scores were calculated and correlated with simultaneous blood gases and work of breathing score. Gestational age-adjusted lung ultrasound scores were created, verified in multivariate models, and subjected to receiver operator characteristics (ROC) analyses to predict bronchopulmonary dysplasia at 36 weeks postmenstrual age. Measurements and Main Results: Mean lung ultrasound scores are different between infants developing (n572) or not developing (n575) bronchopulmonary dysplasia (P,0.001 at any time point). Lung ultrasound scores significantly correlate with oxygenation metrics and work of breathing at any time point (P always,0.0001). Gestational age-adjusted lung ultrasound scores significantly predict bronchopulmonary dysplasia at 7 (area under ROC curve, 0.826-0.833; P,0.0001) and 14 (area under ROC curve, 0.834-0.858; P,0.0001) days of life. Bronchopulmonary dysplasia severity and gestational age-adjusted lung ultrasound scores are significantly correlated at 7 and 14 days (P always,0.0001). Conclusions: Lung ultrasound scores allow monitoring of lung aeration and function in extremely preterm infants. Gestational age-adjusted scores significantly predict the occurrence of bronchopulmonary dysplasia, starting from the seventh day of life.

Summary Background Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. Methods NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov ( NCT02790996 ). Findings Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). Interpretation In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. Funding EU Seventh Framework Programme for research, technological development and demonstration.

In Italy, two clinical practice guidelines for the diagnosis and treatment of bronchiolitis were published in October 2014 and December 2015. We evaluated prescriptions for bronchiolitis in children aged 0–24 months before (December 2012–December 2014), in between (December 2014–December 2015) and after (December 2015–December 2018) the guidelines publications. Data were retrieved from the Pedianet database; the measured outcomes were prescriptions rates of antibiotics, corticosteroids, β2-agonists, and other respiratory drugs. In 1011 out of 1581 episodes, patients received at least one treatment, with a total of 2003 prescriptions. The rate of treated bronchiolitis decreased from 66% to 57% (p p = 0.013). Overall antibiotic prescriptions rate did not change, with 31.6% of the patients still receiving them. Our results confirm unnecessary non-evidence-based treatments in the primary care setting, with few changes after the guidelines publications.

BackgroundThe thermal servo-controlled systems are routinely used in neonatal intensive care units (NICUs) to accurately manage patient temperature, but their role during the immediate postnatal phase has not been previously assessed.ObjectiveTo compare two modalities of thermal management (with and without the use of a servo-controlled system) immediately after birth.Study design and settingMulticentre, unblinded, randomised trial conducted 15 Italian tertiary hospitals.ParticipantsInfants with estimated birth weight +6weeks.InterventionThermal management with or without a thermal servo-controlled system during stabilisation in the delivery room.Primary outcomeProportion of normothermia at NICU admission (axillary temperature 36.5°C–37.5°C).ResultsAt NICU admission, normothermia was achieved in 89/225 neonates (39.6%) with the thermal servo-controlled system and 95/225 neonates (42.2%) without the thermal servo-controlled system (risk ratio 0.94, 95% CI 0.75 to 1.17). Thermal servo-controlled system was associated with increased mild hypothermia (36°C–36.4°C) (risk ratio 1.48, 95% CI 1.09 to 2.01).ConclusionsIn very low birthweight infants, thermal management with the servo-controlled system conferred no advantage in maintaining normothermia at NICU admission, while it was associated with increased mild hypothermia. Thermal management of preterm infants immediately after birth remains a challenge.Trial registration numberNCT03844204

Respiratory syncytial virus (RSV) is the leading global cause of respiratory infections in infants and the second most frequent cause of death during the first year of life. This highly contagious seasonal virus is responsible for approximately 3 million hospitalizations and 120,000 deaths annually among children under the age of 5 years. Bronchiolitis is the most common severe manifestation; however, RSV infections are associated with an increased long-term risk for recurring wheezing and the development of asthma. There is an unmet need for new agents and a universal strategy to prevent RSV infections starting at the time of birth. RSV is active between November and April in Italy, and prevention strategies must ensure that all neonates and infants under 1 year of age are protected during the endemic season, regardless of gestational age at birth and timing of birth relative to the epidemic season. Approaches under development include maternal vaccines to protect neonates during their first months, monoclonal antibodies to provide immediate protection lasting up to 5 months, and pediatric vaccines for longer-lasting protection. Meanwhile, improvements are needed in infection surveillance and reporting to improve case identification and better characterize seasonal trends in infections along the Italian peninsula. Rapid diagnostic tests and confirmatory laboratory testing should be used for the differential diagnosis of respiratory pathogens in children. Stakeholders and policymakers must develop access pathways once new agents are available to reduce the burden of infections and hospitalizations.

European Union (EU) and global sustainability policies emphasize the need to replace contentious pesticides with safe, efficient, and cost-effective alternatives to ensure sustainable food production. However, R&D for alternatives to contentious pesticides are lagging behind and need to be broadened. Here, we discuss how RNAi-based technology can contribute to pesticide risk reduction.

While research on reshoring generally focuses on the host-country to explain why a company brings its previously offshored activities back home, this paper stresses the relevance also of the home-country context. Specifically, relying on the IMP (Industrial Marketing & Purchasing) perspective we show how offshoring and reshoring processes and decisions are both enabled and constrained by the micro-interactions and interdependencies in the industrial networks stretching over the home-country and the host-country. This work relies on a longitudinal case study about an Italian manufacturing firm to develop a model indicating how offshoring/reshoring is a long-term process which unfolds depending both on the focal firm's strategy and on its interplay with the embedding network. Next to this interactive process perspective, we contribute to the literature on reshoring and the global factory also the concept of “selective reshoring”, whereby companies bring back a very specific sub-set of activities, which were previously fine-sliced and offshored, and re-embed these activities in their local home context. The more flexible and selective nature of this relocation of activities between different supply markets depends both on the firm's strategy and on the structure, overlap and evolution of the network elements located in the home- and host-country contexts.

Background Many preschool children develop recurrent respiratory tract infections (RRI). Strategies to prevent RRI include the use of immunomodulators as pidotimod or probiotics, but there is limited evidence of their efficacy on clinical features or on urine metabolic profile. Objective To evaluate whether pidotimod and/or bifidobacteria can reduce RRI morbidity and influence the urine metabolic profile in preschool children. Materials and methods Children aged 3–6 years with RRI were enrolled in a four-arm, exploratory, prospective, randomized, double-blinded, placebo-controlled trial. Patients were randomly assigned to receive pidotimod plus bifidobacteria, pidotimod plus placebo, bifidobacteria plus placebo or double placebo for the first 10 days of each month over 4 consecutive months. Respiratory symptoms and infections were recorded with a daily diary by parents during the study. Metabolomic analyses on urine samples collected before and after treatment were performed. Results Compared to placebo, children receiving pidotimod, alone or with bifidobacteria, had more symptom-free days (69 versus 44, p = 0.003; and 65 versus 44, p = 0.02, respectively) and a lower percentage of days with common cold (17% versus 37%, p = 0.005; and 15% versus 37%, p = 0.004, respectively). The metabolomic analysis showed that children treated with Pidotimod (alone or in combination with bifidobacteria) present, respect to children treated with placebo, a biochemical profile characterized by compounds related to the pathway of steroids hormones, hippuric acid and tryptophan. No significant difference in the metabolic profile was found between children receiving bifidobacteria alone and controls. Conclusions Preschool children with RRI treated with pidotimod have better clinical outcomes and a different urine metabolomic profile than subjects receiving placebo. Further investigations are needed to clarify the connection between pidotimod and gut microbiome.

Background: Sickle cell disease (SCD) is a chronic multisystem disorder requiring comprehensive care that includes newborn screening (NBS) as the first step of care. Italy still lacks a national SCD NBS program and policy on blood disorders. Pilot single-center screening programs and a regional targeted screening have been implemented so far, but more evidence is needed in order to impact health policies. Population and methods: NBS was offered to parents of newborns in gynecology clinics in Padova and Monza, tertiary care university hospitals in northern Italy. High-performance liquid chromatography (HPLC) was performed as the first test on samples collected on Guthrie cards. Molecular analysis of the beta-globin gene was performed on positive samples. Results: A total of 5466 newborns were enrolled; for 5439, informed consents were obtained. A similar family origin was seen in the two centers (65% Italians, 9% mixed couples, 26% immigrants). Compared with SCD NBS programs in the United States and Europe, our results show a similar incidence of SCD patients and carriers. All SCD patients had a Sub-Saharan family background; HbS carriers were 15% Caucasians (Italian, Albanians) and 10% from other areas (North Africa–India–South America); carriers of other hemoglobin variants were mainly (47%) from other areas. Conclusions: Our results demonstrate the feasibility of a multicentric NBS program for SCD, give information on HbS epidemiology in two Northern Italian Areas, and support previous European recommendation for a universal NBS program for SCD in Italy: a high incidence of patients and carriers has been detected, with a high percentage of Caucasian carriers, impossible to identify in a targeted NBS.

Plant pathogenic fungi are the largest group of disease-causing agents on crop plants and represent a persistent and significant threat to agriculture worldwide. Conventional approaches based on the use of pesticides raise social concern for the impact on the environment and human health and alternative control methods are urgently needed. The rapid improvement and extensive implementation of RNA interference (RNAi) technology for various model and non-model organisms has provided the initial framework to adapt this post-transcriptional gene silencing technology for the management of fungal pathogens. Recent studies showed that the exogenous application of double-stranded RNA (dsRNA) molecules on plants targeting fungal growth and virulence-related genes provided disease attenuation of pathogens like Botrytis cinerea, Sclerotinia sclerotiorum and Fusarium graminearum in different hosts. Such results highlight that the exogenous RNAi holds great potential for RNAi-mediated plant pathogenic fungal disease control. Production of dsRNA can be possible by using either in-vitro or in-vivo synthesis. In this review, we describe exogenous RNAi involved in plant pathogenic fungi and discuss dsRNA production, formulation, and RNAi delivery methods. Potential challenges that are faced while developing a RNAi strategy for fungal pathogens, such as off-target and epigenetic effects, with their possible solutions are also discussed.

This Article examines the potential stakeholder-related obstacles hindering the implementation of mechanisms to re-ignite the development of novel antibiotics. Proposed economic models and incentives to drive such development include: Public Funding of Research and Development (“R&D”), Tax Incentives, Milestone Prizes, End Payments, Intellectual Property (“IP”) and Exclusivity Extensions, Pricing and Reimbursement Incentives, Product Development Partnerships (“PDPs”), and the Options Market for Antibiotics model. Drawing on personal experience and understanding of the antibiotic field, as well as stakeholder consultation and numerous expert meetings within the DRIVE-AB project and Uppsala Health Summit 2015, the Authors identify obstacles attributable to the following actors: Universities and Research Institutes, Small and Medium-sized Enterprises (“SMEs”), Large Pharmaceutical Companies, Marketing Approval Regulators, Payors, Healthcare Providers, National Healthcare Authorities, Patients, and Supranational Institutions.The analysis also proposes a characterization and ranking of the difficulty associated with implementing the reviewed mechanisms. Public Funding of R&D, Pricing and Reimbursement Incentives, and PDPs are mechanisms expected to meet highly systemic barriers (i.e., obstacles across the entire antibiotic value chain), imposing greater implementation challenges in that they require convincing and involving several motivationally diverse actors in order to have much effect.

Background Antibiotic innovation has dwindled to dangerously low levels in the past 30 years. Since resistance continues to evolve, this innovation deficit can have perilous consequences on patients. A number of new incentives have been suggested to stimulate greater antibacterial drug innovation. To design effective solutions, a greater understanding is needed of actual antibiotic discovery and development costs and timelines. Small and medium-sized enterprises (SMEs) undertake most discovery and early phase development for antibiotics and other drugs. This paper attempts to gather a better understanding of SMEs’ targets, costs, and durations related to discovery and early phase development of antibacterial therapies. Methods DRIVE-AB, a project focused on developing new economic incentives to stimulate antibacterial innovation, held a European stakeholder meeting in February 2015. All SMEs invited to this meeting (n = 44) were subsequently sent a survey to gather more data regarding their areas of activity, completed and expected development costs and timelines, and business models. Results Twenty-five companies responded to the survey. Respondents were primarily small companies each focusing on developing 1 to 3 new antibiotics, focused on pathogens of public health importance. Most have not yet completed any clinical trials. They have reported ranges of discovery and development out-of-pocket costs that appear to be less expensive than other studies of general pharmaceutical research and development (R&D) costs. The duration ranges reported for completing each phase of R&D are highly variable when compared to previously published general pharmaceutical innovation average durations. However, our sample population is small and may not be fully representative of all relevant antibiotic SMEs. Conclusions The data collected by this study provide important insights and estimates about R&D in European SMEs focusing on antibiotics, which can be combined with other data to design incentives to stimulate antibacterial innovation. The variation implies that costs and durations are difficult to generalize due to the unique characteristics of each antibiotic project and depend on individual business strategies and circumstances.

Background Very few studies have explored the distinguishing features of severe asthma in childhood in Europe, and only one study was conducted in Southern Europe. The aim of this study was to provide a detailed characterization of children with severe asthma treated in specialized pediatric asthma centers across Italy. Methods We conducted a web-based data collection of family, environmental, clinical and laboratory characteristics of 41 patients aged 6–17 years with severe asthma, defined according to the recent guidelines of the European Respiratory Society and the American Thoracic Society, and 78 age-matched peers with non-severe persistent asthma. The patients have been enrolled from 16 hospital-based pediatric pulmonology and allergy centers in Northern, Central, and Southern Italy. Logistic regression analysis assessed the relationship between patients’ characteristics and severe asthma or non-severe persistent asthma. Results Features independently and significantly associated with severe asthma included lifetime sensitization to food allergens [Odds ratio (OR), 4.73; 95 % Confidence Interval (CI), 1.21–18.53; p = 0.03], lifetime hospitalization for asthma (OR, 3.71; 95 % CI, 1.11–12.33; p = 0.03), emergency-department visits for asthma during the past year (OR = 11.98; 95 % CI, 2.70–53.11; p = 0.001), and symptoms triggered by physical activity (OR = 12.78; 95 % CI, 2.66–61.40; p = 0.001). Quality-of-life score was worse in patients with severe asthma than in subjects with non-severe persistent asthma (5.9 versus 6.6, p = 0.005). Self-perception of wellbeing was compromised in more than 40 % of patients in both groups. Children with severe asthma had lower spirometric z scores than non-severe asthmatic peers (all p

Introduction Chronic hepatitis C is the main cause of death in patients with end-stage liver disease. Prognosis depends on the increase of fibrosis, whose progression is twice as rapid in men as in women. Aim of the study was to evaluate the effects of reproductive stage on fibrosis severity in women and to compare these findings with age-matched men. Materials and Methods A retrospective study of 710 consecutive patients with biopsy-proven chronic hepatitis C was conducted, using data from a clinical database of two tertiary Italian care centers. Four age-matched groups of men served as controls. Data about demographics, biochemistry, liver biopsy and ultrasonography were analyzed. Contributing factors were assessed by multivariate logistic regression analysis. Results Liver fibrosis was more advanced in the early menopausal than in the fully reproductive (P

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems. Part of the conceptual work presented has received support from the European commission FP7 projects AIRProm (Grant Agreement FP7 270194), BioSHaRE-EU (Grant Agreement FP7 261433), MeDALL (Grant Agreement FP7 264357), SYNERGY-COPD (Grant Agreement) and U-BIOPRED (Grant Agreement IMI 115010). JB, JMA, AC-T, FK, MLK, SP, CP and CA were supported by MeDALL; PJS, IMA and KFC were supported by U-BIOPRED; JR and AA were supported by SYNERGY-COPD; CB was supported by AIRProm; AC-T was supported by BioSHaRE-EU

Background: Montelukast has been shown to be effective in controlling the increase in exhaled NO in asthmatic children re-exposed to house dust mite (HDM).This study compared the effect of low dose inhaled budesonide and oral montelukast in preventing the expected relapse of airway inflammation and reactivity in a group of 24 mild asthmatic children allergic to HDM after a brief period of exposure to relevant allergens. Methods: Lung function, bronchial hyperresponsiveness (BHR) to methacholine (PC20), fractional exhaled nitric oxide (FeNO) levels and sputum eosinophilia were evaluated. Results: Pulmonary function remained stable. The BHR was unchanged after exposure in the group treated with budesonide, whereas a significant increase (P ¼ 0.028) was observed in the patients receiving montelukast. No significant difference was observed in FeNO levels after exposure to mite antigen in the two groups. In both the groups of asthmatic children we observed a significant increase in sputum eosinophil % after the exposure to mite antigen. Conclusions: The significant increase in BHR level observed in the group of children receiving montelukast suggests a more comprehensive effect as disease controller by inhaled steroids than by leukotriene antagonist in allergic asthmatic children re-exposed to relevant allergens.

Acute bronchiolitis is the leading cause of lower respiratory t ract infection and hospitalization in children less than 1y ear of age worldwide. It is usually a mild disease, but some children may develop severe symptoms, requiring hospital admission and ventilatory support in the ICU. Infants with pre-existing risk factors (prematurity, bronchopulmonary dysplasia, congenital heart diseases and immunodeficiency) may be predisposed to a severe form of the disease. Clinical diagnosis of bronchiolitis is manly based on medical history and physical examination (rhinorrhea, cough, crackles, wheezing and signs of respiratory distress). Etiological diagnosis, with antigen or genome detection to identify viruses involved, may have a role in reducing hospital transmission of the infection. Criteria for hospitalization include low oxygen saturation (