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INTRODUCTION AND OBJECTIVE: Community-acquired pneumonia (CAP) is one of the most common reasons of prescribing antibiotics for children, often with overuse of broad-spectrum antibiotics. The aim of this study is to describe the antibiotic prescriptions for Italian children with CAP, at the primary care level. STUDY DESIGN: Retrospective cohort study conducted among children 3 months-14 years of age with CAP, enrolled in Pedianet (http://www.pedianet.it) from January 1, 2009 to December 31, 2018. Antibiotic treatment was defined as narrow-spectrum (NS-ABT) if amoxicillin and broad-spectrum (BS-ABT) if amoxicillin/clavulanic acid, cephalosporins or any combination. Crude and adjusted logistic regressions for the odds of receiving NS-ABT were conducted (all episodes of CAP and per patient). A P value

Background Acute otitis media (AOM) and pharyngitis are very common infections in children and adolescents. Italy is one of the European countries with the highest rate of antibiotic prescriptions. The aim of this study is to describe first-line treatment approaches for AOM and pharyngitis in primary care settings in Italy over six years, including the prevalence of ‘wait and see’ for AOM, where prescription of antibiotics is delayed 48 h from presentation, and differences in prescribing for pharyngitis when diagnostic tests are used. Methods The study is a secondary data analysis using Pedianet, a database including data at outpatient level from children aged 0–14 in Italy. Prescriptions per antibiotic group, per age group and per calendar year were described as percentages. “Wait and see” approach rate was described for AOM and pharyngitis prescriptions were further grouped according to the diagnostic test performed and test results. Results We identified 120,338 children followed by 125 family pediatricians between January 2010 and December 2015 for a total of 923,780 person-years of follow-up. Among them 30,394 (mean age 44 months) had at least one AOM diagnosis (n = 54,943) and 52,341 (mean age 5 years) had at least one pharyngitis diagnosis (n = 126,098). 82.5% of AOM diagnoses were treated with an antibiotic within 48 h (mainly amoxicillin and amoxicillin/clavulanate) and the “wait and see” approach was adopted only in 17.5% of cases. The trend over time shows an increase in broad spectrum antibiotic prescriptions in the last year (2015). 79,620 (63%) cases of pharyngitis were treated and among GABHS pharyngitis confirmed by rapid test 56% were treated with amoxicillin. The ones not test confirmed were treated mainly with broad spectrum antibiotics. Conclusions Despite guidance to use the ‘wait and see’ approach in the age group analyzed, this strategy is not often used for AOM, as previously noted in other studies in hospital settings. Broad-spectrum antibiotic prescription was more frequent when pharyngitis was not confirmed by rapid test, in keeping with evidence from other studies that diagnostic uncertainty leads to overuse of antibiotics. Electronic supplementary material The online version of this article (10.1186/s13052-019-0696-9) contains supplementary material, which is available to authorized users.

Background: In Italy, the bacterial lysate OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral®, Vaxoral®) is registered for the prophylaxis of recurrent respiratory tract infections (RTIs) in adults and children above one year of age, but there are limited data on its use in the paediatric population. We aim to estimate the impact of OM-85 treatment on RTIs and antibiotic prescriptions in children. Methods: This study included children aged 1 to 14 years enrolled in Pedianet, a paediatric general practice research database, from January 2007 to June 2017, having at least one prescription of OM-85. Children with less than 12 months of follow-up before (PRE period) and after (POST period) the OM-85 prescription were excluded. The frequency of antibiotic prescriptions and the frequency of RTI episodes in the PRE and POST periods were compared through the post-hoc test. Subgroup analysis was performed in children with recurrent RTIs. Results: 1091 children received 1382 OM-85 prescriptions for a total follow-up of 619,525.5 person-years. Overall, antibiotic prescriptions decreased from a mean of 2.8 (SD (standard deviation) 2.7) prescriptions in the PRE period to a mean of 2.2 (SD 2.6) prescriptions in the POST period (p &lt, 0.0001). RTIs decreased from a mean of 3.4 (SD 2.9) episodes in the PRE period to a mean of 2.5 (SD 2.6) episodes in the POST period (p &lt, 0.0001). No change in antibiotic class was noted, and co-amoxiclav remained the preferred therapy in 28% of cases, followed by amoxicillin. These results were confirmed among children with recurrent RTIs. Conclusions: OM-85 is effective in preventing both antibiotic prescriptions and RTIs in children.

Healthcare utilisation databases, and other secondary data sources, have been used with growing frequency to assess health outcomes and healthcare interventions worldwide. Their increased popularity as a research tool is due to their timely availability, the large patient populations covered, low cost, and applicability for studying real-world clinical practice. Despite the need to measure Italian National Health Service performance both at regional and national levels, the wealth of good quality electronic data and the high standards of scientific research in this field, healthcare research and public health policies seem to progress along orthogonal dimensions in Italy. The main barriers to the development of evidence-based public health include the lack of understanding of evidence-based methodologies by policy makers, and of involvement of researchers in the policy process. The CRACK programme was launched by some academics from the Lombardy Region. By extensively using electronically stored data, epidemiologists, biostatisticians, pharmacologists and clinicians applied methods and evidence to several issues of healthcare research. The CRACK programme was based on their intention to remove barriers that thwart the process of bridging methods and findings from scientific journals to public health practice. This paper briefly describes aim, articulation and management of the CRACK programme, and discusses why it might find articulated application in Italy.

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.

Background Pregnant women who suffer from depressive disorders are likely to be treated with antidepressant (AD) medications. Recent meta-analyses underlined the possible relation between AD use and several neonatal outcomes, although the underlying mechanisms remains unclear. Methods To summarise and evaluate the associations between AD use in pregnancy and neonatal outcomes, we conducted an umbrella review of meta-analyses of observational studies published up to December 2019 in PubMed and Embase. Summary risk estimates for the associations between use of AD as a whole, or specific AD classes and drugs, and the risk of neonatal outcomes were reported. Results Our review included 22 meta-analyses investigating 69 associations. However, none were supported by convincing evidence. Highly suggestive evidence regarded the associations between (i) any time AD exposure and the risk of preterm birth (relative risk, 1.68; 95% confidence interval 1.52, 1.86), (ii) any time exposure to selective serotonin reuptake inhibitors (SSRIs) and the risk of preterm birth (1.43; 1.22, 1.37) and (iii) respiratory distress (1.33; 1.14, 1.55), and (iv) SSRI exposure during the first trimester of pregnancy and the risk of cardiovascular malformations (1.25; 1.13, 1.39). Suggestive evidence was obtained for any time AD exposure on 1-min low Apgar score (absolute average difference, −0.34; −0.53, −0.14). Conclusions Overall, the effects of AD exposure during pregnancy on neonatal outcomes have been extensively studied, but few of the associations are graded as high quality evidence. More prospective studies and large collaborations with comprehensive standardised reporting of analyses are needed.

Objective Several factors affect adherence to antihypertensive drug treatment, but whether these factors include a sex difference is unclear. Aim of the study was to compare persistence with antihypertensive drug therapy between men and women in a large cohort of patients. Methods The 60 526 residents of the Italian Lombardy Region aged 40-80 years newly treated with antihypertensive drugs during 2010 were identified and followed for 1 year after the first prescription. Discontinuation of treatment was defined as lack of prescription renewal for at least 90 days. Log-binomial regression models were fitted to estimate the risk ratio of treatment discontinuation in relation to sex. Other than for the whole population, analyses were stratified according to age, comorbidity status and the initial antihypertensive treatment strategy. Results Thirty-seven percent of the patients discontinued the drug treatment during follow-up. Compared with women, men had a 10% lower risk of discontinuation of drug treatment (95% confidence interval: 8-12). Persistence on antihypertensive treatment was better in men than in women, this being the case in both younger (40-64 years) and older patients (65-80 years), in patients starting treatment with any major antihypertensive drug and in patients who had a low comorbidity status. There was no evidence that men and women had a different risk of treatment discontinuation when their comorbidity status was worse, or initial antihypertensive treatment was based on drug combinations. Conclusion Our data show that in a real-life setting, men are more persistent to antihypertensive drug therapy than women.

Background According to recent polling, public trust in the healthcare sector remains low relative to other industries globally. The implications of low healthcare trust permeate throughout the industry in a number of ways, most visibly by discouraging therapy compliance. Methods This study investigated four putative determinants of trust in healthcare-related scenarios: individuals vs. collective groups as communicators of healthcare advice; expert vs. laypeople as providers of healthcare communication; public vs. private healthcare sector; and positive vs. negative information. Two hundred seventy-four participants were recruited via Prolific Academic and were presented with four statements in random order, related to a positive reflection of the public healthcare sector, a negative reflection of the public healthcare sector, a positive reflection of the private healthcare sector and a negative reflection of the private healthcare sector. According to these reflection, participants were repeatedly asked to rate the system on its trustworthiness. Trust outcomes were constructed using a four-dimension framework, consisting of benevolence, reliability, competence and predictability. Results Claims relating to the public sector had a significantly stronger impact on benevolence and reliability than claims relating to the private sector; claims from individuals had a significantly stronger impact on all trust variables than claims from collectives; and claims from laypeople had a significantly greater impact on reliability and competence ratings than claims from experts. Conclusions The findings in this study offer insight into the patterns with which trust decisions are made in healthcare contexts. More importantly, this research offers a novel perspective of how different factors interact to affect the various facets of trust. These results provide a foundation for future study in this evolving area, and offer insights into designing effective communication strategies that cultivate greater levels of individual trust in the healthcare sector.

Background: Limited evidence is available on the safety and efficacy of antimicrobials during pregnancy, with even less according to the trimester of their use. Objective: This study aimed to evaluate the association between exposure to antibiotics therapy (AT) during pregnancy and short-term neonatal outcomes. Methods: We considered 773,237 deliveries that occurred between 2007–2017 in the Lombardy region of Italy. We evaluated the risk of neonatal outcomes among infants that were born to mothers who underwent AT during pregnancy. The odds ratios and the hazard ratios, with the 95% confidence intervals, were estimated respectively for early (first/second trimester) and late (third trimester) exposure. The propensity score was used to account for potential confounders. We also performed subgroup analysis for the class of AT. Results: We identified 132,024 and 76,921 singletons that were exposed to AT during early and late pregnancy, respectively. Infants born to mothers with early exposure had 17, 11, and 16% increased risk of preterm birth, low birth weight, and low Apgar score, respectively. Infants that were exposed in late pregnancy had 25, 11, and 13% increased risk of preterm birth, low birth weight, and low Apgar score, respectively. The results were consistent in the subgroup analysis. Conclusion: Our results suggested an increased risk of several neonatal outcomes in women exposed to ATs during pregnancy, albeit we were not able to assess to what extent the observed effects were due to the infection itself. To reduce the risk of neonatal outcomes, women that are prescribed AT during pregnancy should be closely monitored.

BACKGROUND Recent evidence suggests that neutralizing antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 may persist over time; however, knowledge regarding pediatric subjects is limited. METHODS A single-center, prospective observational study was conducted on 57 family clusters of coronavirus disease 2019, including children of neonatal and pediatric age attending the University Hospital of Padua (Italy). For each patient, blood samples were collected for both the quantification of nAbs through a plaque reduction neutralizing test and the detection of antinucleocapsid-spike protein immunoglobulin G and/or immunoglobulin M. RESULTS We analyzed 283 blood samples collected from 152 confirmed coronavirus disease 2019 cases (82 parents and 70 children or older siblings of median age of 8 years, interquartile range: 4–13), presenting asymptomatic or with mildly symptomatic disease. Despite the decrease of immunoglobulin G over time, nAbs were found to persist up to 7 to 8 months in children, whereas adults recorded a modest declining trend. Interestingly, children aged CONCLUSIONS Mild and asymptomatic severe acute respiratory syndrome coronavirus 2 infections in family clusters elicited higher nAbs among children.

Objective Methodological challenges for investigating the changes in healthcare utilization during COVID-19 pandemic must be considered for obtaining unbiased estimates. Study design and setting A population-based study in the Lombardy region (Italy) measured the association between the level of epidemic restrictions (increasing exposure during pre-epidemic, post-lockdown, and lockdown periods) and the recommended healthcare (outcome) for patients with schizophrenia, heart failure, chronic obstructive pulmonary disease, breast cancer and pregnancy women. Two designs are applied: the self-controlled case series (SCCS) and the usual cohort design. Adjustments for between-patients unmeasured confounders and seasonality of medical services delivering were performed. Results Compared with pre-epidemic, reductions in delivering recommended healthcare during lockdown up to 73% (95% confidence interval: 63%-80%) for timeliness of breast cancer surgery, and up to 20% (16%-23%) for appropriated gynaecologic visit during pregnancy were obtained from SCCS and cohort design, respectively. Healthcare provision came back to pre-epidemic levels during the post-lockdown, with the exception of schizophrenic patients for whom the SCCS showed a reduction in continuity of care of 11% (11%-12%). Conclusion Strategies for investigating the changes in healthcare utilization during pandemic must be implemented. Recommendations for taking into account sources of systematic uncertainty are discussed and illustrated by using motivating examples.

BackgroundThe immune response plays a pivotal role in dictating the clinical outcome in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected adults, but it is still poorly investigated in the pediatric population.MethodsOf 209 enrolled subjects, 155 patients were confirmed by PCR and/or serology as having coronavirus disease 2019 (COVID-19). Blood samples were obtained at a median of 2.8 (interquartile, 2.1–3.7) and 6.1 (5.3–7.2) months after baseline (symptom onset and/or first positive virus detection). The immune profiles of activation, senescence, exhaustion, and regulatory cells were analyzed by flow cytometry. Neutralizing antibodies (nAbs) were detected by a plaque reduction neutralization test. In available nasopharyngeal swabs at baseline, SARS-CoV-2 levels were quantified by digital droplet PCR (ddPCR).ResultsOverall, COVID-19 patients had higher levels of immune activation, exhaustion, and regulatory cells compared to non-COVID-19 subjects. Within the COVID-19 group, activated and senescent cells were higher in adults than in children and inversely correlated with the nAbs levels. Conversely, Tregs and Bregs regulatory cells were higher in COVID-19 children compared to adults and positively correlated with nAbs. Higher immune activation still persisted in adults after 6 months of infection, while children maintained higher levels of regulatory cells. SARS-CoV-2 levels did not differ among age classes.ConclusionsAdults displayed higher immune activation and lower production of anti-SARS-CoV-2 nAbs than children. The different immune response was not related to different viral load. The higher expression of regulatory cells in children may contribute to reduce the immune activation, thus leading to a greater specific response against the virus.

Almost 25% of lung cancers (LCs) occur in never-smokers. LC inflammatory profile, based on plasma C-reactive protein levels (CRP), predicts mortality, independently by smoking-status. We hypothesized that: CRP could be associated with tumor immune contexture (TIC) in never-smokers and both these two parameters may improve their prognosis. Sixty-eight never-smokers LC patients with high or low CRP were selected. The programmed cell death protein 1 (PD-1) and its ligand (PD-L1), the human leukocyte antigens (HLA-DR and HLA-I), CD8, CD4, CD3, CD33, CD163, and CD68 were evaluated by immunohistochemistry on surgical samples given TIC evaluation. The classification model based on TIC scores was generated by Classification and Regression Tree analysis. Tumor mutational burden was evaluated by targeted next-generation sequencing. Exclusively high CRP (H-CRP) subset showed PD-L1 expression in 35% of LC as well as lower HLA-I and HLA-DR in their stromal cells. CD3, CD4, CD8, HLA-I, HLA-DR tumor cells staining were associated with a &ldquo, low inflammatory profile&rdquo, subset. CRP and LC immune profiles drive clinical outcome: 5-year survival 88% against 8% was associated with low and high-risk profiles (p &lt, 0.0001). Clinical outcome prediction in never-smoker LC patients may be improved by both CRP and tumor immune contexture evaluation.

Introduction Acute otitis media (AOM) is the most common childhood disease leading to antibiotic use. More than 80% of children under three years of age experience at least one episode, and about one-third of these report significant recurrence of episodes. In recent years, several studies reported that normal nasopharyngeal flora inhibits growth of common otopathogens, suggesting that maintenance of an “adequate” nasopharyngeal flora might prevent occurrence of upper respiratory tract infections, including AOM. This study aims to determine whether five-month treatment with Streptococcus salivarius 24SMB and Streptococcus oralis 89a nasal spray prevents recurrence of AOM and prescription of antibiotics in children with diagnosis of recurrent AOM. Methods Observational prospective cohort study including children aged 1–6 years with diagnosis of recurrent AOM registered with 31 Italian family pediatricians. 81 children were enrolled in the study from September 2016 to the end of the five therapeutic cycles of the Streptococcus salivarius 24SMB and Streptococcus oralis 89a supplied 7 days each month for 5 consecutive months. For each treated child, one untreated control was randomly selected, 1:1 matched for gender, age, and follow-up. Results 158 children (79 treated and 70 untreated) were included into the analysis (mean age, 3.9 years; 47% female). Univariate analysis showed a statistically significant 34% (95% CI 1%–56%) reduction in number of AOM episodes in treated children compared with those not treated. Significantly fewer antibiotics were dispensed among treated children (24%, 95% CI 1%–41%). Conclusions Our findings suggest that intermittent treatment of children with diagnosis of recurrent AOM with nasal spray containing Streptococcus salivarius 24SMB and Streptococcus oralis 89a for a period of five months might be effective in preventing antibiotic use associated with recurrent episodes of AOM. Additional larger studies to address this important clinical problem are recommended.

Background The Multicentric Italian Lung Detection (MILD) trial demonstrated that prolonged low-dose computed tomography (LDCT) screening could achieve a 39% reduction in lung cancer (LC) mortality. We have here evaluated the long-term results of annual vs. biennial LDCT and the impact of screening intensity on overall and LC-specific mortality at 10 years. Patients and methods Between 2005 and 2018, the MILD trial prospectively randomised the 2376 screening arm participants to annual (n = 1190) or biennial (n = 1186) LDCT, for a median screening period of 6.2 years and 23,083 person-years of follow-up. The primary outcomes were 10-year overall and LC-specific mortality, and the secondary end-points were the frequency of advanced-stage and interval LCs. Results The biennial LDCT arm showed a similar overall mortality (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.57–1.12) and LC-specific mortality at 10 years (HR 1.10, 95% CI 0.59–2.05), as compared with the annual LDCT arm. Biennial screening saved 44% of follow-up LDCTs in subjects with negative baseline LDCT, and 38% of LDCTs in all participants, with no increase in the occurrence of stage II-IV or interval LCs. Conclusions The MILD trial provides original evidence that prolonged screening beyond five years with biennial LDCT can achieve an LC mortality reduction comparable to annual LDCT, in subjects with a negative baseline examination.

Background: Blood level of C-reactive protein (CRP) at diagnosis is a well-know prognostic bio-marker in different primary tumors, but its role has not been investigated in resectable lung metastases. The aim of our study is to assess the predictive value of baseline (CRP0) and 3rd postoperative day (CRP3) levels on long-term survival of patients undergoing lung metastasectomy. Methods: A total of 846 consecutive patients underwent the first pulmonary resection for lung metastases between January 2003 and December 2015, including 611 (72%) single surgical procedures, 235 (28%) multiple metastasectomies, 501 (59%) epithelial primary tumors, 276 (33%) sarcomas, 66 (8%) melanomas, 286 (33.8%) with 0 risk factors (CRP0 ≤ 2 and CRP3 ≤ 84 mg/L) and 560 (66.2%) with ≥ 1 risk factor (CRP 0 > 2 and/or CRP 3 > 84 mg/L). Results: Cumulative 5-year survival was 57% in patients with low CRP (0 risk factors) versus 43% in high CRP (≥ 1 risk factor, p < 0.0002), 62% versus 50% respectively for epithelial tumors (p < 0.0140), and 51% versus 34% for sarcomas (p < 0.0111). Multivariable Cox analysis confirmed a mortality hazard ratio of 2.5 at 1-year and 1.5 at 5-years in patients with high CRP. Conclusions: Baseline and postoperative CRP levels predict survival of patients with resectable lung metastases. These data provide a rationale for prospective clinical trials testing the efficacy of anti-inflammatory or immune-modulating agents as “adjuvant” therapy after lung metastasectomy, in patients with elevated pre- and/or postoperative CRP levels.

Background and aims To validate a set of indicators for monitoring the quality of care of patients with diabetes in ‘real-life’ practice through its relationship with measurable clinical outcomes and healthcare costs. Methods and results A population-based cohort study was carried out by including the 20,635 patients, residents in the Lombardy Region (Italy), who in the year 2012 were newly taken-in-care for diabetes. Adherence with clinical recommendations (i.e., controls for glycated haemoglobin, lipid profile, urine albumin excretion and serum creatinine) was recorded during the first year after the patient was taken-in-care, and categorized according whether he/she complied with none or almost none (0 or 1), just some (2) or all or almost all (3 or 4) the recommendations, respectively denoted as poor, intermediate and high adherence. Short- and long-term complications of diabetes, and healthcare cost incurred by the National Health Service, were assessed during follow-up. Compared with patients with poor adherence, those with intermediate and high adherence respectively showed (i) a delay in outcome occurrence of 13 days (95% CI, -2 to 27) and 23 days (9 to 38), and (ii) a lower healthcare cost of 54 € and 77 €. In average, a gain of 18 Euros and 15 Euros for each day free from diabetic complication by increasing adherence respectively from poor to intermediate and from poor to high were observed. Conclusion Close control of patients with diabetes through regular clinical examinations must be considered the cornerstone of national guidance, national audits, and quality improvement incentive schemes.

Acute healthcare services are extremely important, particularly during the COVID-19 pandemic, as healthcare demand has rapidly intensified, and resources have become insufficient. Studies on specific prepandemic hospitalization and emergency department visit (EDV) trends in proximity to death are limited. We examined time-trend specificities based on sex, age, and cause of death in the last 2 years of life. Datasets containing all hospitalizations and EDVs of elderly residents in Friuli-Venezia Giulia, Italy (N = 411,812), who died between 2002 and 2014 at ≥ 65 years, have been collected. We performed subgroup change-point analysis of monthly trends in the 2 years preceding death according to sex, age at death (65–74, 75–84, 85–94, and ≥ 95 years), and main cause of death (cancer, cardiovascular, or respiratory disease). The proportion of decedents (N = 142,834) accessing acute healthcare services increased exponentially in proximity to death (hospitalizations = 4.7, EDVs = 3.9 months before death). This was inversely related to age, with changes among the youngest and eldest decedents at 6.6 and 3.5 months for hospitalizations and at 4.6 and 3.3 months for EDVs, respectively. Healthcare use among cancer patients intensified earlier in life (hospitalizations = 6.8, EDVs = 5.8 months before death). Decedents from respiratory diseases were most likely to access hospital-based services during the last month of life. No sex-based differences were found. The greater use of acute healthcare services among younger decedents and cancer patients suggests that policies potentiating primary care support targeting these at-risk groups may reduce pressure on hospital-based services.

Introduction: Gastroesophageal reflux disease (GERD) as well as its treatment with acid-suppressive medications have been considered possible risk factors for the development of asthma, but few studies have disentangled the role of GERD with that of its treatment. The present study aimed at estimating the association of treated and untreated GERD in the first year of life with the risk of asthma. Methods: Retrospective cohort study including all children born between 2004 and 2015 registered in Pedianet, an Italian primary care database. We analyzed the association of children exposed to GERD (both treated and untreated) in the first year of life with the risk of developing clinically assessed asthma (clinical asthma) after 3 years. Secondary outcomes included asthma identified by anti-asthmatic medications (treated asthma) and wheezing after 3 years. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated comparing children with and without GERD, stratifying by treatment with acid-suppressive medications. Results: Out of 86,381 children, 1652 (1.9%) were affected by GERD in the first year of life, of which 871 (53%) were treated with acid-suppressive medications. Compared with controls, children with GERD were at increased risk of clinical asthma (HR: 1.40, 95% CI 1.15–1.70). Risks were similar between treated and untreated GERD (p = 0.41). Comparable results were found for treated asthma, but no risk increase was seen for wheezing. Discussion: Early-life GERD was associated with subsequent childhood asthma. Similar risks among children with treated and untreated GERD suggest that acid-suppressive medications are unlikely to play a major role in the development asthma.

Antenatal care (ANC) aims of monitoring wellbeing of mother and foetus during pregnancy. We validate a set of indicators aimed of measuring the quality of ANC of women on low-risk, uncomplicated pregnancy through their relationship with maternal and neonatal outcomes. We conducted a population-based cohort study including 122,563 deliveries that occurred between 2015 and 2017 in the Lombardy Region, Italy. Promptness and appropriateness of number and timing of gynaecological visits, ultrasounds and laboratory tests were evaluated. We assessed several maternal and neonatal outcomes. Log-binomial regression models were used to estimate prevalence ratio (PR), and corresponding 95% confidence interval (95% CI), for the exposure&rarr, outcome association. Compared with women who adhered with recommendations, those who were no adherent had a significant higher prevalence of maternal intensive care units admission (PR: 3.1, 95%CI: 1.2&ndash, 7.9, and 2.7, 1.1&ndash, 7.0 respectively for promptness of gynaecological visits, and appropriateness of ultrasound examinations), low Apgar score (1.6, 1.1&ndash, 1.2, 1.9, 1.3&ndash, 2.7, and 2.1, 1.5&ndash, 2.8 respectively for appropriateness and promptness of gynaecological visits, and appropriateness of ultrasound examinations), and low birth weight (1.8, 1.5&ndash, 2.3 for appropriateness of laboratory test examinations). Benefits for mothers and newborn are expected from improving adherence to guidelines-driven recommendations regarding antenatal care even for low-risk, uncomplicated pregnancies.

Background MyDiabetesPlan is a web-based, interactive patient decision aid that facilitates patient-centred, diabetes-specific, goal-setting and shared decision-making (SDM) with interprofessional health care teams. Objective Assess the feasibility of (1) conducting a cluster randomized controlled trial (RCT) and (2) integrating MyDiabetesPlan into interprofessional primary care clinics. Methods We conducted a cluster RCT in 10 interprofessional primary care clinics with patients living with diabetes and at least two other comorbidities; half of the clinics were assigned to MyDiabetesPlan and half were assigned to usual care. To assess recruitment, retention, and resource use, we used RCT conduct logs and financial account summaries. To assess intervention fidelity, we used RCT conduct logs and website usage logs. To identify barriers and facilitators to integration of MyDiabetesPlan into clinical care across the IP team, we used audiotapes of clinical encounters in the intervention groups. Results One thousand five hundred and ninety-seven potentially eligible patients were identified through searches of electronic medical records, of which 1113 patients met the eligibility criteria upon detailed chart review. A total of 425 patients were randomly selected; of these, 213 were able to participate and were allocated (intervention: n = 102; control: n = 111), for a recruitment rate of 50.1%. One hundred and fifty-one patients completed the study, for a retention rate of 70.9%. A total of 5745 personnel-hours and $6104 CAD were attributed to recruitment and retention activities. A total of 179 appointments occurred (out of 204 expected appointments—two per participant over the 12-month study period; 87.7%). Forty (36%), 25 (23%), and 32 (29%) patients completed MyDiabetesPlan at least twice, once, and zero times, respectively. Mean time for completion of MyDiabetesPlan by the clinician and the patient during initial appointments was 37 min. From the clinical encounter transcripts, we identified diverse strategies used by clinicians and patients to integrate MyDiabetesPlan into the appointment, characterized by rapport building and individualization. Barriers to use included clinician-related, patient-related, and technical factors. Conclusion An interprofessional approach to SDM using a decision aid was feasible. Lower than expected numbers of diabetes-specific appointments and use of MyDiabetesPlan were observed. Addressing facilitators and barriers identified in this study will promote more seamless integration into clinical care. Trial registration Clinicaltrials.gov Identifier: NCT02379078. Date of Registration: February 11, 2015. Protocol version: Version 1; February 26, 2015.

ObjectivesTo develop a population-based risk stratification model (COVID-19 Vulnerability Score) for predicting severe/fatal clinical manifestations of SARS-CoV-2 infection, using the multiple source information provided by the healthcare utilisation databases of the Italian National Health Service.DesignRetrospective observational cohort study.SettingPopulation-based study using the healthcare utilisation database from five Italian regions.ParticipantsBeneficiaries of the National Health Service, aged 18–79 years, who had the residentship in the five participating regions. Residents in a nursing home were not included. The model was built from the 7 655 502 residents of Lombardy region.Main outcome measureThe score included gender, age and 29 conditions/diseases selected from a list of 61 conditions which independently predicted the primary outcome, that is, severe (intensive care unit admission) or fatal manifestation of COVID-19 experienced during the first epidemic wave (until June 2020). The score performance was validated by applying the model to several validation sets, that is, Lombardy population (second epidemic wave), and the other four Italian regions (entire 2020) for a total of about 15.4 million individuals and 7031 outcomes. Predictive performance was assessed by discrimination (areas under the receiver operating characteristic curve) and calibration (plot of observed vs predicted outcomes).ResultsWe observed a clear positive trend towards increasing outcome incidence as the score increased. The areas under the receiver operating characteristic curve of the COVID-19 Vulnerability Score ranged from 0.85 to 0.88, which compared favourably with the areas of generic scores such as the Charlson Comorbidity Score (0.60). A remarkable performance of the score on the calibration of observed and predicted outcome probability was also observed.ConclusionsA score based on data used for public health management accurately predicted the occurrence of severe/fatal manifestations of COVID-19. Use of this score may help health decision-makers to more accurately identify high-risk citizens who need early preventive or treatment interventions.

Duchenne muscular dystrophy cardiomyopathy (DMD-DCM) is characterized by progressive ventricular dilation and dysfunction that can begin at any age and worsens over time. Thanks to the lengthening of life expectancy due to better management of respiratory involvement, end-stage heart failure (HF) is becoming the main cause of death for DMD patients. Therefore, from the time of DMD diagnosis, every effort should be focused to early detect the onset and the worsening of the DMD-DCM, with the aim of starting and modulating the therapy to slow the progression of cardiac dysfunction. In cardiac evaluation, biomarkers, electrocardiograms, and echocardiograms must be considered, but cardiac magnetic resonance (CMR) is now acquiring a leading role due to its sensitivity in the earlier identification of cardiac involvement. The management of DMD-DCM at end stage is a difficult challenge that requires a multidisciplinary team composed of clinical cardiologists, electrophysiologists, cardiac surgeons, neuromuscular specialists, and psychologists. Because of the lack of specific drugs for DMD, we will review the actual cardiovascular armamentarium including drugs used for HF.

Background IPD and pneumonia are associated with high mortality and healthcare resource utilization (HCRU). This analysis assessed incidence, HCRU and costs of IPD and pneumonia following PCV13 introduction in 2010 in Veneto. Methods IPD, unspecified invasive disease episodes, outpatient pneumococcal and unspecified pneumonia episodes were identified in Pedianet, a pediatric primary care database from 2010-2017. HCRU includes primary care and specialist visits, antibiotic prescriptions, diagnostics, ER visits and hospitalizations. Incidence rates (IRs) were numbers of episodes/1,000 person-years. Standardized regional incidence rates (SRIRs) were calculated by standardizing IRs with regional population data by age and year. Regional expenditures (€/1,000 person-years) were calculated by multiplying SRIRs with average costs per episode. Interrupted time series (ITS) analyses assessed trends in annual IRs in the early and late PCV13 (2010-2013, 2014-2017) periods. Results During 2010-2017, IPD and unspecified invasive disease incidence decreased from 0.40 to 0.31/1,000 person-years. While incidence was numerically lower in 2017 than in 2010, ITS analysis did not detect a significant trend in the early (coef=1.97; p = 0.63) or late PCV13 (coef=0.50; p = 0.90) periods. Average cost per episode was €4206 and average regional expenditure was €171/1,000 person-year. SRIR for outpatient pneumonia decreased from 13.35 to 5.48/1,000 person-year during 2010 to 2017. Pneumonia episodes were associated with 0.29 ER visits and 0.15 short stay and 0.06 long stay hospitalization. Average cost per episode was €345, majority of which was associated with ER visits (€50.8) and hospitalizations (€243.9). Regional expenditures decreased from €12852.31 to €5351.98/1,000 person-year. Conclusions IPD and unspecified invasive disease burden did not change significantly following PCV13 introduction, while disease burden declined for outpatient pneumococcal and unspecified pneumonia. Key messages IPD and unspecified invasive disease burden did not change significantly following PCV13 introduction. Disease burden declined for outpatient pneumococcal and unspecified pneumonia following PCV13.

This study aimed to illustrate and account for immortal time bias in pregnancy observational investigations, using the relationship between late use of antibiotics and risk of preterm birth as an example. We conducted a population-based cohort study including 549,082 deliveries between 2007 and 2017 in Lombardy, Italy. We evaluated the risk of preterm births, low birth weight, small for gestational age, and low Apgar score associated with antibiotic dispensing during the third trimester of pregnancy. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of the outcomes, considering the use of antibiotics as time-fixed (with biased classification of exposure person-time) and time-varying (with proper classification of exposure person-time) exposure. There were 23,638 (4.3%) premature deliveries. There was no association between time-fixed exposure to antibiotics and preterm delivery (adjusted HR 0.96, 95% CI 0.92 to 1.01) but an increased risk of preterm birth when time-varying exposure to antibiotics was considered (1.27, 1.21 to 1.34). The same trend was found for low birth weight and low Apgar score. Immortal time bias is a common and sneaky trap in observational studies involving exposure in late pregnancy. This bias could be easily avoided with suitable design and analysis.

Background Acute Otitis Media (AOM) causes substantial healthcare resource utilization (HCRU) in children. This analysis assessed AOM HCRU and costs following PCV13 introduction in 2010 in Veneto. Methods AOM episodes in children Results Simple AOM episodes were associated with 1.03 primary care visits and 1.52 antibiotic prescriptions on average. Only 2.4% and 0.18% of simple AOM episodes included an ER visit, and a hospitalization respectively. Recurrent AOM episodes were associated with 1.06 primary care visits and 1.62 antibiotic prescriptions. Annual costs per episode were €50 for simple AOM and €54.2 for recurrent AOM, majority of which were associated with primary care visits and antibiotic prescriptions. Average antibiotic prescription costs were €14.2 for simple AOM and €16 for recurrent AOM. During 2010 and 2017, SRIRs declined from 100 to 72/1000 person-year for simple AOM and from 13 to 11/1,000 person-year for recurrent AOM. Regional expenditures decreased from €4702.7 to €3358.5/1,000 person-year for simple AOM and from €672.4 to €572.6/1000 person-year for recurrent AOM. Conclusions SRIRs and regional expenditures declined for simple and recurrent AOM after PCV13 introduction. Primary care visits and antibiotic prescriptions account for the majority of expenditures. Key messages SRIRs and regional expenditures declined for simple and recurrent AOM after PCV13 introduction. Primary care visits and antibiotic prescriptions account for the majority of expenditures.

Aim of our study was to assess the relationship between adherence with antihypertensive drugs and the risk of death in frail versus nonfrail old individuals. Using the database of the Lombardy Region (Italy), we identified 1 283 602 residents aged ≥65 years (mean age 76) who had ≥3 prescriptions of antihypertensive drugs between 2011 and 2012. A nested case-control design was applied, with cases being the cohort members who died during the observation period (7 years). Logistic regression was used to model the association of interest, with adjustment for potential confounders. Adherence was measured by the proportion of the follow-up covered by prescriptions, and the analysis was separately performed in patients with a good, medium, poor, and very poor clinical status, as assessed by a score that has been shown to be a sensitive predictor of death in the Italian population. The 7-year death probability increased from 16% (good) to 64% (very poor) clinical status. Compared with patients with very low adherence with antihypertensive treatment (75% of time covered by prescriptions) exhibited a lower risk of all-cause mortality in each group, the difference decreasing progressively (−44%, −43%, −40%, and −33%) from the good to the very poor clinical status. Adherence with antihypertensive drug treatment was also associated with a lower risk of cardiovascular mortality. Adherence with antihypertensive appears to be protective in frail old patients, but the benefit is less marked than in patients with a good clinical status.

Background and objectivesHospital readmissions are a frequent complication of pneumonia. Most data regarding readmissions are obtained from the United States, whereas few data are available from the European healthcare utilization (HCU) systems. In a large cohort of Italian patients with a previous hospitalization for pneumonia, our aim was to evaluate the incidence and predictors of early readmissions due to pneumonia.MethodsThis is a observational retrospective, population based, cohort study. Data were retrieved from the HCU databases of the Italian Lombardy region. 203,768 patients were hospitalized for pneumonia between 2003 and 2012. The outcome was the first rehospitalization for pneumonia. The patients were followed up after the index hospital admission to estimate the hazard ratio, and relative 95% confidence interval, of the outcome associated with the risk factors that we had identified.Results7,275 patients (3.6%) had an early pneumonia readmission. Male gender, age ≥70 years, length of stay of the first admission and a higher burden of comorbidities were significantly associated with the outcome. Chronic use of antidepressants, antiarrhythmics, glucocorticoids and drugs for obstructive airway diseases were also more frequently prescribed in patients requiring rehospitalization. Previous use of inhaled broncodilators, including both beta2-agonists and anticholinergics, but not inhaled steroids, were associated with an increased risk of hospital readmission.ConclusionsFrail elderly patients with multiple comorbidities and complex drug regimens were at higher risk of early rehospitalization and, thus, may require closer follow-up and prevention strategies.

Nation-wide information about medication use in pregnancy is lacking for Italy, and no study has so far investigated the prescribed medications which pregnant women deliberately avoid. In this study, we map medication use patterns in pregnancy, as well as the extent and type of prescribed medications which are purposely avoided by pregnant women in Italy. This is a sub-study within the &ldquo, Multinational Medication Use in Pregnancy Study&rdquo, &mdash, a cross-sectional, web-based study conducted in Italy from 7 November 2011 to 7 January 2012. Using an anonymous electronic questionnaire, we collected data from pregnant women and new mothers on medication use and deliberate avoidance during pregnancy and maternal characteristics. The sample included 926 women residing in Italy. The point prevalence of total medication use was 71.2%. Whereas 61.4% and 12.4% of women reported medication use for the treatment of short and longer-term illnesses, respectively, only 8.8% reported medication use for the treatment of both a short and a longer-term illness in pregnancy. We found no substantial differences in estimates across various geographical areas of Italy. Overall, 26.6% of women reported to have deliberately avoided a prescribed medication in pregnancy&mdash, most often nimesulide or ketoprofen, but also antibiotics. We conclude that prenatal exposure to medication is common among women in Italy, but estimates are lower than in other Western countries. Intentional avoidance of important medications by pregnant women raises concerns about the safeguarding of maternal&ndash, child health.

Aim To provide information on the balance between the cardiovascular (CV) benefit and the diabetogenic harm of statin therapy in the current clinical practice. Methods All the 115,939 residents (older than 50 years) in the Italian Lombardy Region newly treated with statins between 2003 and 2005, were followed from the first statin prescription until 2012 to identify those experiencing a macrovascular complication and those with at least one sign suggestive of new onset diabetes. The proportion of days of follow-up covered by statin prescriptions measured adherence with statins. Hazard ratio, and relative 95% confidence interval (CI), for the two considered outcomes associated with statin adherence, were separately estimated (proportional hazard models). Number needed to treat (NNT) and number needed to harm (NNH), i.e., number of individuals who must be treated with statins in order to prevent a macrovascular complication, or to generate a new onset diabetes, respectively, were calculated to evaluate the balance between CV benefit and diabetogenic harm of statin therapy. Results Compared to those at very low adherence with statins, patients at high adherence showed a significant reduction of macrovascular risk (28%, 95% CI: 23%–33%) and a greater risk of developing diabetic condition (67%, 50%-86%). In the whole cohort, the NNT was 26, whereas the NNH 65. NNT was lower than NNH also in all considered strata of age, gender, clinical profile. Conclusions This large cohort investigation provides real-world evidence that the balance between CV benefit and diabetogenic harm of statin therapy is largely favourable to treatment benefits.

Birth cohort studies are the most appropriate type of design to determine the causal relationship between potential risk factors during the prenatal or postnatal period and the health status of the newborn up to childhood and potentially adulthood. To date, there has been a growth in interest regarding observational population-based studies which are performed to provide answers to specific research questions for defined populations, for instance, assessing the exposure to environmental pollutants or drugs on the risk of developing a disease. Birth cohorts based on the recruitment and active follow-up of mothers and children allow the collection of biological material, and specific clinical and genetic information. However, they require a considerable amount of time and resources and, besides being usually of limited size, they are exposed to the risk of the loss of subjects to follow-up, with decreased statistical power and possible selection bias. For these reasons, linking the medical birth register with administrative health records for mothers and babies is increasingly being used in countries with a universal healthcare system, allowing researchers to identify large and unselected populations from birth, and to reconstruct relevant traits and care pathways of mothers and newborns. This Special Issue of the International Journal of Environmental Research and Public Health focuses on the current state of knowledge on perinatal and postnatal exposures and adverse pregnancy, maternal, fetal and neonatal outcomes through population-based birth cohort studies, with a specific focus on real-word data. The 12 accepted articles covered a wide range of themes that can be addressed specifically through birth cohort study design; however, only three were based on real word data with record-linkage to health administrative databases. In particular, two papers have addressed the topic of socioeconomic status considering several indicators both at the individual and contextual level. Two papers focused on inflammatory bowel diseases, both as an outcome of perinatal and antibiotic exposure in early life and as a condition associated with asthma, among children identified in a birth cohort based on a Regional Medical Birth Register. Three articles focused on medication use during pregnancy and its impact on maternal and fetal health. The effect of exposure to prenatal environmental risk factors on perinatal and childhood outcomes has been considered in two papers. Two papers analyzed ad hoc nationwide prospective birth cohorts set in Japan and UK. Finally, we included a systematic review with meta-analysis to evaluate the relation between growth restriction at birth and congenital heart defects. We think that this Special Issue may contribute to enriching the discussion of future challenges, opportunities, strengths and limitations for all research topics that can be investigated using a population-based birth cohort study design.

Introduction: Nimesulide is the most prescribed non-steroidal anti-inflammatory drug in Italy, and it is currently marketed in about 50 countries worldwide. The association between the use of nimesulide in early pregnancy and the risk of birth defects was investigated in a large cohort of pregnant women from Italy. Methods: Data were from the healthcare utilization databases of the Italian region of Lombardy. The cohort of 353,081 newborns occurring in Lombardy during the period 2005–2010 was investigated. Exposure to nimesulide during the first trimester of pregnancy, and congenital malformations detected at presentation and within 90 days after birth (outcome), were investigated. Exposure–outcome association was measured by the ratio between the prevalence of congenital malformations among users and non-users of nimesulide. Propensity score stratification was used to control for potential confounders, including maternal medical comorbidities, concomitant medications and sociodemographic characteristics. Results: The 627 (0.18%) women who filled prescriptions for nimesulide in the first trimester of pregnancy had a 2.6-fold risk of having children with congenital urinary tract anomalies compared to those who did not (adjusted prevalence ratio 2.6; 95% CI 1.2–5.7). Weaker and non-significant evidence for congenital malformations as a whole was found (adjusted prevalence ratio 1.2, 95% CI 0.9–1.6). Conclusion: Our study suggests that the use of nimesulide in early pregnancy may result in a greater risk of having births with congenital urinary tract anomalies. Funding: This study was funded by grants from the Italian Ministry of the Education, University and Research (’Fondo d’Ateneo per la Ricerca’ portion, year 2015)

Background Clinical dental evaluations are considered complex and costly measurements that epidemiological surveillance studies of multiple simultaneous chronic diseases currently require, for example National Health Surveys (ENS). Accordingly, simpler and more affordable methods need to be validated. The aim of this study was to assess the validity of the self-report on the total number of teeth in the general Chilean adult population. Methods A substudy was conducted on ENS 2016–2017 participants. A stratified random sample of 101 of them was subjected to a telephone questionnaire. This information was then compared with the results obtained from the oral examination performed by a trained nurse during a home visit. Spearman correlations, intraclass correlation coefficients and the Bland-Altman method were used to analyse the data. Results In men, the average number of teeth recorded during the oral examination coincided with the number of teeth in the self-report (22 teeth). In women, the total teeth average was 18 and 19 teeth according to the examination and self-report, respectively. For the total number of participants, a strong and significant Spearman correlation was obtained (ρ = 0.93); in men and women, the Spearman correlation observed was also strong and significant (ρ = 0.90 and ρ = 0.96 respectively). The value of the intraclass correlation coefficient indicated a significant concordance (CCI = 0.96) in both men and women (CCI = 0.93 and 0.98 respectively). A tendency to greater correlation was observed as the number of teeth decreased. Conclusions The number of teeth self-reported by the subjects in this study correlated with the number of teeth recorded in the clinical examination. Self-report is a valid method to determine the number of teeth in national health surveys.

Background Untreated depression and antidepressant use during pregnancy may have negative consequences for births. There are still conflicting data on the potential harmful effects of prenatal antidepressant treatment on child health. Objective To investigate the relationship between the use of antidepressant medication during pregnancy and selected neonatal outcomes. Methods A population-based cohort study including 9825 deliveries exposed to an antidepressant between 9 months before last menstrual date through to delivery, from January 2005 to December 2010 in the Lombardy region of Italy, was conducted. We evaluated the prevalence ratio (PR) of low Apgar score, small for gestational age, intrauterine hypoxia and birth asphyxia, neonatal convulsion, and other respiratory conditions, among infants born to mothers exposed to an antidepressant during pregnancy using log-binomial regression analysis. Fine stratification was applied to the propensity score to account for all potential confounders. Sensitivity and subgroup analyses restricted to specific types of antidepressant, time of exposure, and women with vaginal deliveries and full-term births were also performed. Results A total of 33.4% of women filled at least one prescription during pregnancy. Compared to infants born to mothers with exposure to antidepressants only before pregnancy, those with exposure to antidepressants during pregnancy had an increased prevalence ratio of a low Apgar score (PR, 1.63, 95% CI, 1.01-2.61), intrauterine hypoxia and birth asphyxia (aPR, 1.37, 1.08-1.73), neonatal convulsion (aPR, 2.81, 1.07-7.36), and other respiratory condition (aPR, 1.24, 1.00-1.52). Results were similar in the sensitivity and subgroup analyses. Conclusions Use of antidepressants during pregnancy may have an increased risk for several neonatal outcomes. KEY POINTS In this population-based cohort study, we found a significant increase in the prevalence ratio of low Apgar score, intrauterine hypoxia and birth asphyxia, neonatal convulsion, and other respiratory conditions among who were exposed in utero to antidepressant drugs. These effects seem to be attributable to the treatment rather than to the disease itself. Further researches are needed to evaluate the longer-term developmental outcomes.

Enormous progress has been made globally in the use of evidence derived from patients’ clinical information as they access their routine medical care. The value of real-world data lies in their complementary nature compared with data from randomised controlled trials: less detailed information on drug efficacy but longer observational periods and larger, more heterogeneous study populations reflecting clinical practice because individuals are included who would not usually be recruited in trials. Real-world data can be collected in various types of electronic sources, such as electronic health records, claims databases and drug or disease registries. These data sources vary in nature from country to country, according to national healthcare system structures and national policies. In Italy, a growing number of healthcare databases have been used to evaluate post-marketing drug utilisation and safety in the last two decades. The aim of this narrative review is to describe the available Italian sources of real-world data and their contribution to generating post-marketing evidence on drug use and safety. We also discuss the strengths and limitations of the most commonly used Italian healthcare databases in addressing various research questions concerning drug utilisation, comparative effectiveness and safety studies, as well as health technology assessment and other areas.

Aims: Women with pre-existing diabetes should plan for optimal care of the disease before, during and after pregnancy. The aim of this study was to assess the quality of diabetes mellitus monitoring and care before, during and after pregnancy in a large cohort of women. Methods: 1913 diabetic women resident in the Lombardy Region (Italy) who experienced at least a birth between 2011 and 2015 and exhibited signs of diabetes ≥2 years before delivery were identified using the healthcare utilization database. Antidiabetic care was defined via outpatient examinations (i.e., assessments of glycated haemoglobin, lipid profile, urine albumin excretion and serum creatinine, and dilated eye exams) and use of antidiabetic drugs. Differences in adherence to recommendations before, during and after pregnancy were assessed by the non-parametric McNemar's test among the whole cohort and among the subgroup with type 1 diabetes. Results: Adherence to recommendations was very poor before pregnancy, ranging from 13% to 42% for dilated eye and serum creatinine exam, respectively. During pregnancy, a significant portion of women increased adherence to all recommendations (e.g., glycated haemoglobin from 20% to 47%, p-value < 0.001), with the exception of lipid profile control. After pregnancy, adherence dropped to pre-pregnancy levels. A similar trend was observed in the use of antidiabetic drugs. Although women with type 1 diabetes showed better adherence across all periods, the same patterns emerged. Conclusions: Besides an improvement in the indicators of clinical adherence during pregnancy, the management of diabetes among pregnant women remains sub-optimal both before and after the birth.

Background The National Lung Screening Trial showed that lung cancer (LC) screening by three annual rounds of low-dose computed tomography (LDCT) reduces LC mortality. We evaluated the benefit of prolonged LDCT screening beyond 5 years, and its impact on overall and LC specific mortality at 10 years. Design The Multicentric Italian Lung Detection (MILD) trial prospectively randomized 4099 participants, to a screening arm (n = 2376), with further randomization to annual (n = 1190) or biennial (n = 1186) LDCT for a median period of 6 years, or control arm (n = 1723) without intervention. Between 2005 and 2018, 39 293 person-years of follow-up were accumulated. The primary outcomes were 10-year overall and LC specific mortality. Landmark analysis was used to test the long-term effect of LC screening, beyond 5 years by exclusion of LCs and deaths that occurred in the first 5 years. Results The LDCT arm showed a 39% reduced risk of LC mortality at 10 years [hazard ratio (HR) 0.61; 95% confidence interval (CI) 0.39–0.95], compared with control arm, and a 20% reduction of overall mortality (HR 0.80; 95% CI 0.62–1.03). LDCT benefit improved beyond the 5th year of screening, with a 58% reduced risk of LC mortality (HR 0.42; 95% CI 0.22–0.79), and 32% reduction of overall mortality (HR 0.68; 95% CI 0.49–0.94). Conclusions The MILD trial provides additional evidence that prolonged screening beyond 5 years can enhance the benefit of early detection and achieve a greater overall and LC mortality reduction compared with NLST trial. ClinicalTrials.gov identifier NCT02837809.

The optical axis of a Nasmyth telescope should be perpendicular to the Elevation axis and pass through the rotational center of the Tertiary mirror turret rotator. Realized by aligning a laser beam to the rotational center of the two field derotators. A high precision Pentaprism mounted on the Tertiary mirror rotator deviates the laser beam by 90° defining the optical axis onto which the Primary and Secondary mirrors are mounted and aligned. We present method, procedure, tools and results for two examples of Nasmyth Telescopes; the 4.1m SOAR and the LSST's 1.2m Auxiliary Telescope.

The Southern Astrophysical Research (SOAR) 4.1m telescope, located in Cerro Pachon, Chile, has an active optics system that uses a Shack Hartmann wave front sensor to achieve optimal image correction and focus. This Calibration Wave Front Sensor (CWFS) has two detectors, one to acquire the star and the other to sense the wave front. In 2012 the acquisition camera failed, being replaced temporarily by an SBIG camera. We describe here a project to repair and upgrade the CWFS, extending the lifetime of this critical telescope component. The upgrade includes two new detectors and modifications to the existing software in order to communicate with the new cameras. Also, new mechanical supports were fabricated to mount the new cameras, and a new field flattener was designed for the acquisition camera. A laboratory rig with all the components was setup so to carry out extensive testing before installation on the telescope.

DCM is the leading cause of death in Duchenne patients. LVADs are considered as therapeutic options as DT in advanced HF. The aim of our study was to evaluate LV remodeling of Duchenne after LVADs and chronic therapy. Demographic and echocardiographic data of 8 Duchenne patients implanted with LVADs were reviewed and analyzed. All measures were collected before LVAD implantation, after 1 month and 1 year. All patients were affected by end-stage DCM, and mean age at implantation was 16.9 ± 2.9 years. Patients were treated with maximal medical therapy. One-year post-implantation HR decreased from a mean of 110 ± 19 bpm to 82 ± 2 bpm (P = .002), and a significant decrease in LV volumes and diameters LVEDD P = .03, LVESD P = .02, EDV P = .01, and ESV P = .02) was noticed together with a significant increase in EF (P = .0036). However, RWT did not change over time, showing an eccentric remodeling pattern pre- and post-LVADs. Our data showed that cardiac atrophy is persistent in Duchenne cardiomyopathy despite the improvement of LV function secondary to a significant ventricular unloading due to LVADs coupled with chronic therapy.

Duchenne muscular dystrophy (DMD) cardiomyopathy (DCM) is characterized by a hypokinetic, dilated phenotype progressively increasing with age. Regular cardiac care is crucial in DMD care. Early recognition and prophylactic use of angiotensin converting enzyme inhibitors (ACEi) are the main stay therapeutic strategy to delay incidence of DMD-DCM. Pharmacological treatment to improve symptoms and left ventricle (LV) systolic function, have been widely implemented in the past years. Because of lack of DMD specific drugs, actual indications for established DCM include current treatment for heart failure (HF). This review focuses on current HF strategies to identify, characterize, and treat DMD-DCM.

Lamin A/C (LMNA) encodes for two nuclear intermediate filament proteins. Mutations in LMNA cause a highly heterogeneous group of diseases predominantly leading to muscular or cardiac disease, lipodystrophy syndromes, peripheral neuropathy, and accelerated aging disorders. Cardiac involvement includes progressive arrhythmias (brady/tachyarrhythmias, sudden cardiac death). Furthermore, cardiomyocyte damage often progresses into dilated cardiomyopathy (DCM), rarely described in the pediatric age group. Neuromuscular manifestations are even rarer in children. We report on six pediatric patients with LMNA mutations: patient 1 was operated on for aortic coarctation, non-compact left ventricle, atrial fibrillation (AF) preceding the diagnosis of DCM; patient 2 was operated on for ventricular septal defect (VSD), developed after years malignant arrhythmias preceding the progression to DCM (left ventricular non-compaction with LV dysfunction); patient 3 had ectopic atrial tachycardia as first manifestation of a DCM; patients 4 and 5 had no major arrhythmic events but only dilated ascending aorta, mildly dilated LV with mild hypertrabeculation of the lateral wall and a normally functioning but dilated left ventricle, respectively; patient 6 showed aortic coarctation, supraventricular tachycardia. Paroxysmal AF occurred in patients 1, 2, and 3 (50% of cases). Our series highlight the coexistence of congenital heart defects (CHDs) and aortic involvement with laminopathies in four of our patients: consisting of aortic coarctation (two patients), aortic root dilatation (one patient), and VSD (one patient). Aortic changes in laminopathies have been reported only once in an adult patient. This is the first report in the pediatric setting, and no associations with CHD have been previously described.

Morbidity and mortality in Down syndrome (DS) are mainly related to congenital heart defects (CHDs). While CHDs with high prevalence in DS (typical CHDs), such as endocardial cushion defects, have been extensively described, little is known about the impact of less common CHDs (atypical CHDs), such as aortic coarctation and univentricular hearts. In our single-center study, we analyzed, in observational, retrospective manner, data regarding cardiac features, surgical management, and outcomes of a cohort of DS patients. Literature review was performed to investigate previously reported studies on atypical CHDs in DS. Patients with CHDs were subclassified as having typical or atypical CHDs. Statistical analysis was performed for comparison between the groups. The study population encompassed 859 DS patients, 72.2% with CHDs, of which 4.7% were atypical. Statistical analysis showed a significant excess in multiple surgeries, all-cause mortality and cardiac mortality in patients with atypical CHDs (p = .0067, p = .0038, p = .0001, respectively). According to the Kaplan-Meier method, survival at 10 and 40 years was significantly higher in typical CHDs (99 and 98% vs. 91 and 84%, log rank

Aiming to break the software monoliths that traditional approaches usually produce as artifacts, solutions that are based on microservices consist of heterogeneous and independent software platforms to manage applications and data. In this scenario, the term polyglot persistence has been introduced to characterize software solutions where the involved microservices rely on different data storage technologies. Especially in Fog Computing where data are expected to efficiently flow among nodes – usually from the edge to the cloud – the polyglot persistence could have a negative impact since a combination of data replication and transformation is required. The goal of this paper is to study the challenges in data management in Fog Computing when microservices are adopted, and to present a solution which combines the advantages of the physical copy approach performed by network file systems to provide a fast data movement and the ability of the logical copy approach to transform the data. The resulting mix is demonstrated to reduce the time of creating the replica up to 70%.

Background Multimorbidity is a growing concern for healthcare systems, with many countries experiencing demographic transition to older population profiles. A simple multisource comorbidity score (MCS) has been recently developed and validated. A very large real-world investigation was conducted with the aim of measuring inequalities in the MCS distribution across Italy. Methods Beneficiaries of the Italian National Health Service aged 50–85 years who in 2018 were resident in one of the 10 participant regions formed the study population (15.7 million of the 24.9 million overall resident in Italy). MCS was assigned to each beneficiary by categorizing the individual sum of the comorbid values (i.e. the weights corresponding to the comorbid conditions of which the individual suffered) into one of the six categories denoting a progressive worsening comorbidity status. MCS distributions in women and men across geographic partitions were compared. Results Compared with beneficiaries from northern Italy, those from centre and south showed worse comorbidity profile for both women and men. MCS median age (i.e. the age above which half of the beneficiaries suffered at least one comorbidity) ranged from 60 (centre and south) to 68 years (north) in women and from 63 (centre and south) to 68 years (north) in men. The percentage of comorbid population was lower than 50% for northern population, whereas it was around 60% for central and southern ones. Conclusion MCS allowed of capturing geographic variability of multimorbidity prevalence, thus showing up its value for addressing health policy in order to guide national health planning.

Increasingly rational use of phosphate fertilizers by agriculture is important, especially in Brazil, due to its importance for global food security and its high dependence on phosphate fertilizers for crop production. Thus, correlation and calibration researches with soil available phosphorus (P) extractants to improve the recommendation and the use of P are extremely important. Our objectives were (i) to determine soil P recovery rates and critical levels by the extractants Mehlich-1 (M1), Mehlich-3 (M3), and Ion Exchange Resin (RTI); (ii) to adjust predictive models of P recovery rates and critical levels for each extractant, as a function of soil properties related to the soil P buffer capacity, and (iii) to adjust the an interpretation table of soil P availability by M3 taking into account soil P buffer capacity indices. A pot experiment under greenhouse condition was conducted, in which the treatments were generated by the combination of a factorial 12 × 6, being 12 soil samples collected at a layer of 0.00-0.20 m, and six doses of P. The experimental units were constituted by plastic pots with capacity for 2.0 dm3 of soil, in which four hybrid corn plants (Zea mays L.) were cultivated for 45 d. The experimental design was a randomized complete block with four replicates. After cultivation, soil samples were collected from each experimental unit, and the determination of soil available P was performed by the extractants. The remaining P and the clay content were the soil properties that best correlated with the P recovery rates and P critical levels in the soil by the M1 and M3. The IER did not show sensitivity to soil P buffer capacity. The M3 had a discontinuous loss of extraction capacity with increasing soil P buffer capacity. Therefore, it is recommended the use of M3 as P extractant in soils with different characteristics, but a measure of soil P buffer capacity such as remaining P or clay content have to be used.

Background Heterotaxy syndrome (HS) is a group of congenital disorders characterized by abnormal arrangement of thoraco-abdominal organs across the left-right axis of the body, classified as right (RAI) and left atrial isomerism (LAI)·We investigated the long-term survival and phenotypic spectrum in our HS cohort. Results are compared to literature data. Methods This is a single centre, observational, both retro and prospective study. Cardiac features, surgical management and abdominal ultrasound (US) of all HS patients were reviewed or investigated if missing. We evaluated all anatomical data and their clinical impact on survival, arrhythmias, infections, and heart transplant (HT). Results 136 patients were classified as RAI (81) and LAI (55). Long-term survival and freedom from HT reached 69.8% and 87.8% at 40 years in RAI and LAI, respectively. Multivariate analysis showed that LAI is an independent predictor for pacemaker implantation (p = 0.019). Splenic status varied in both groups: in RAI, abdominal US showed asplenia, polysplenia and normal spleen in 48%, 4% and 32% of patients, respectively, whereas in LAI polysplenia, asplenia and normal spleen occurred in 64%, 4% and 16% of cases, respectively. Conclusions Mortality was significantly lower (9%) compared to literature (50%). Although patients with RAI experienced a higher mortality, no independent predictors were found. We demonstrated that the obsolete cardiac definition of "asplenia" and "polysplenia" instead of RAI and LAI is misleading, because of the high variability of the splenic phenotype among patients of both groups.

Background: Early nutrition affects the risk of atopy and infections through modifications of intestinal microbiota. The Prebiotics in the Prevention of Atopy (PIPA) study was a 24-month randomised, double-blind, placebo-controlled trial. It aimed to evaluate the effects of a galacto-oligosaccharide/polydextrose (GOS/PDX)-formula (PF) on atopic dermatitis (AD) and common infections in infants who were born to atopic parents and to investigate the relationship among early nutrition, gut microbiota and clinical outcomes. Methods: A total of 201 and 199 infants were randomized to receive a PF and standard formula (SF), respectively; 140 infants remained on exclusive breastfeeding (BF). Results: The cumulative incidence of AD and its intensity and duration were not statistically different among the three groups. The number of infants with at least one episode of respiratory infection (RI) and the mean number of episodes until 48 weeks of age were significantly lower in the PF group than in the SF group. The number of patients with recurrent RIs and incidence of wheezing lower RIs until 96 weeks were lower in the PF group than the SF group, but similar to the BF group. Bifidobacteria and Clostridium cluster I colonization increased over time in the PF group but decreased in the SF and BF groups. Bifidobacteria had a protective role in RIs, whereas Clostridium cluster I was associated with atopy protection. Conclusion: The early administration of PF protects against RIs and mediates a species-specific modulation of the intestinal microbiota. Trial registration: clinicaltrial.gov Identifier: NCT02116452.

BACKGROUND. Statins, are to date the most effective drugs for the treatment of hypercholesterolemia, and their important protective role in the prevention of cardiovascular (CV) morbidity and mortality is well-established [1]. Since people aged between 60 and 79 years were well represented in many trials, this applies also to elderly patients [2]. However, it does not apply to patients aged 80 years or older, because (i) none or few octogenarians have been included in outcome-based trials and (ii) evidence on the protective effects of statins among them is limited to only few observational studies with inconsistent results [3,4]. This represents an important limitation because the increasing life expectancy makes octogenarians the fastest growing subgroup of the population and, furthermore, this highly advanced aged subgroup accounts for a considerable portion of the overall CV events, hospitalizations and deaths [5]. AIM. To assess whether in individuals aged 80 years or older adherence to statins is accompanied by a reduced risk of all-cause mortality and major cardiovascular events. METHODS. A nested case–control study was carried out including a cohort of patients aged 80 years or older, who were under treatment with statins between 2008 and 2009, using the administrative databases of Lombardy region (Italy). Cases were the cohort members who experienced death or hospitalization for stroke, myocardial infarction or heart failure from the initial prescription until 2012. Up to five controls were randomly selected for each case. Logistic regression was fitted to estimate the odds ratio (OR), and its 95% confidence interval (CI), for the considered outcomes in relation to the adherence to therapy with statins, measured by the proportion of days covered (PDC). Four categories of adherence were employed (i.e., =75%), using the lowest one (