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Phytoestrogens are present in high concentration in soybeans. Therefore, hormonal effects may occur in infants fed soy formula (SF). The aim of this study was to evaluate the hormonal effects of long-term SF feeding in a selected group of children who were fed SF (Isomil) for more than 6 mo early in life. We enrolled 50 children (30 boys and 20 girls), median age 29 mo (range 7 mo-12 y). Every child had a physical examination with particular attention paid to signs and symptoms of precocious puberty. In addition, the following were evaluated: bone density (mineralometry with double photon absorptiometry) in children aged 3 y; bone age (X-ray of carpus and metacarpus according to Tanner) in all of the children; bone metabolism urinary markers, i.e., urinary deoxypyridinoline (by chemiluminescence), calcium, creatine, phosphorus (by colorimetry), in all the children; and serum levels of bone alkaline phosphatase (by immunoenzymeassay), osteocalcin, 17-[Beta]-estradiol (by RIA) and parathyroid hormone (by chemiluminescence) in all the children. The same variables were evaluated in 20 normal children of the same age and sex (controls) who were not fed any soy. No abnormalities were seen in the evaluated variables. None of the enrolled children presented signs or symptoms of precocious puberty; weight and height were within the normal range; and bone age was in the normal range. Serum levels of bone alkaline phosphatase, osteocalcin, 17-[Beta]-estradiol and parathyroid hormone and the levels of the urinary markers of bone metabolism (deoxypyridinoline, calcium, creatine and phosphorus) were in the normal range. Of the 20 children aged 3 y, 8 (40%) had mineralometry values that were in the range for sex and age. The preliminary data of the present study suggest that prolonged SF feeding does not induce estrogenic effects for the evaluated variables. To confirm these preliminary data, further studies, which are in progress in our department, on a larger cohort of children fed SF for a prolonged period are required.

Peripheral blood mononuclear cells (PBMNCs) are reported to prevent major amputation and healing in no-option critical limb ischemia (NO-CLI). The aim of this study is to evaluate PBMNC treatment in comparison to standard treatment in NO-CLI patients with diabetic foot ulcers (DFUs). The study included 76 NO-CLI patients admitted to our centers because of CLI with DFUs. All patients were treated with the same standard care (control group), but 38 patients were also treated with autologous PBMNC implants. Major amputations, overall mortality, and number of healed patients were evaluated as the primary endpoint. Only 4 out 38 amputations (10.5%) were observed in the PBMNC group, while 15 out of 38 amputations (39.5%) were recorded in the control group ( p = 0.0037). The Kaplan-Meier curves and the log-rank test results showed a significantly lower amputation rate in the PBMNCs group vs. the control group ( p = 0.000). At two years follow-up, nearly 80% of the PBMNCs group was still alive vs. only 20% of the control group ( p = 0.000). In the PBMNC group, 33 patients healed (86.6%) while only one patient healed in the control group ( p = 0.000). PBMNCs showed a positive clinical outcome at two years follow-up in patients with DFUs and NO-CLI, significantly reducing the amputation rate and improving survival and wound healing. According to our study results, intramuscular and peri-lesional injection of autologous PBMNCs could prevent amputations in NO-CLI diabetic patients.

Background: Several aspects of the association between exposure to air pollution and risk of lung cancer remain unclear., Objective: We aimed at performing a meta-analysis of high-quality cohort studies on exposure to particulate matter (PM) 10 and PM2.5 and risk of lung cancer., Methods: We identified cohort studies published since 2004, that reported risk estimates of lung cancer for exposure to PM2.5 and PM10 adjusted for tobacco smoking and socioeconomic status, and conducted a meta-analysis based on random-effects models, including stratification by outcome, sex, country, tobacco smoking, and age., Results: Results on PM2.5 exposure were available from 15 studies; the summary relative risk (RR) for an increase of 10 μg/m 3 was 1.16 (95% confidence interval [CI] 1.09, 1.23). The corresponding RR for PM10 exposure was 1.23 (95 CI 1.05, 1.40; seven studies). A higher risk was suggested in studies based on lung cancer mortality and in studies conducted in East Asia, while no difference was shown according to sex, smoking status or age. There was no suggestion of publication bias., Conclusions: Our meta-analysis supported the hypothesis of an association between exposure to PM2.5 or PM10 and risk of lung cancer, and provided evidence that the magnitude of the risk might be higher than previously estimated, and might be modified by outcome and geographic region., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Infection with Human Immunodeficiency Virus (HIV) is highly prevalent worldwide, especially in Sub-Saharan Africa, where anaemia is also widespread. HIV infection is known to be associated with anaemia and various other haematologic alterations, but little data on correlation with immunological and virologic conditions in treatment-naïve patients and impact on mortality are available. Our study aims to investigate hematologic features in HIV-infected individuals in Malawi and Mozambique and assesses possible correlations with early morality., Material and Methods: We conducted a retrospective analysis of baseline data (general details, nutritional status, full blood count and HIV infection progress data) and 12 months follow-up status for HIV+ adult patients in 22 health facilities in Malawi (11 sites) and Mozambique (11 sites) run by DREAM program. Anagraphic details, anthropometric characteristics, full blood count, CD4+ count and Viral Load data were collected from electronical medical records (EMR) for all the HIV-positive, treatment-naïve patients starting care in the sites in the period January 2007 -December 2016. Follow-up status after one year since enrolment in care was also considered. All the data extracted from the EMR were included in a dataset and then analysed. Univariate and multivariate analysis were conducted through logistical regression to investigate associations, and survival analysis analysed in a Cox regression model., Results: On the whole, 22.657 patients were included; severe and moderate anaemia were observed in 1.174 (8,2%) and 4.703 (21,9%) patients respectively. Gender, nutritional status, CD4+ count, and viral load (VL) were associated with anaemia, leukopenia, and thrombocytopenia. Among 21.166 fully evaluable patients, 8.494 (40,1%) had at least one cytopenia. Any cytopenia was present in 1/3 of patients with normal nutritional status and less advanced HIV infection, and it wouldn't be diagnosed in a basic HIV care setting. During the first year of treatment, 1.725 subjects (7,6% of the entire sample) died. Anaemia, lower Red blood cells and platelets counts correlated with mortality in the first year of care, independently by body mass index, haemoglobin, CD4+ count and VL., Conclusions: Notwithstanding anaemia is known to be associated with HIV infection at diagnosis, full blood count is not routinely performed in many African countries. Our results emphasize that including the study of a broader set of parameters in the routine HIV care services in Sub-Saharan Africa would provide significant clinical information able to predict other alterations and poor outcomes., Competing Interests: The authors have declared that no competing interests exist.

Objective: To provide an overview of the currently available risk prediction models (RPMs) for cardiovascular diseases (CVDs), diabetes and hypertension, and to compare their effectiveness in proper recognition of patients at risk of developing these diseases., Design: Umbrella systematic review., Data Sources: PubMed, Scopus, Cochrane Library., Eligibility Criteria: Systematic reviews or meta-analysis examining and comparing performances of RPMs for CVDs, hypertension or diabetes in healthy adult (18-65 years old) population, published in English language., Data Extraction and Synthesis: Data were extracted according to the following parameters: number of studies included, intervention (RPMs applied/assessed), comparison, performance, validation and outcomes. A narrative synthesis was performed. Data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Study Selection: 3612 studies were identified. After title/abstract screening and removal of duplicate articles, 37 studies met the eligibility criteria. After reading the full text, 13 were deemed relevant for inclusion. Three further papers from the reference lists of these articles were then added., Study Appraisal: The methodological quality of the included studies was assessed using the AMSTAR tool., Risk of Bias in Individual Studies: Risk of Bias evaluation was carried out using the ROBIS tool., Results: Sixteen studies met the inclusion criteria: six focused on diabetes, two on hypertension and eight on CVDs. Globally, prediction models for diabetes and hypertension showed no significant difference in effectiveness. Conversely, some promising differences among prediction tools were highlighted for CVDs. The Ankle-Brachial Index, in association with the Framingham tool, and QRISK scores provided some evidence of a certain superiority compared with Framingham alone., Limitations: Due to the significant heterogeneity of the studies, it was not possible to perform a meta-analysis. The electronic search was limited to studies in English and to three major international databases (MEDLINE/PubMed, Scopus and Cochrane Library), with additional works derived from the reference list of other studies; grey literature with unpublished documents was not included in the search. Furthermore, no assessment of potential adverse effects of RPMs was carried out., Conclusions: Consistent evidence is available only for CVD prediction: the Framingham score, alone or in combination with the Ankle-Brachial Index, and the QRISK score can be confirmed as the gold standard. Further efforts should not be concentrated on creating new scores, but rather on performing external validation of the existing ones, in particular on high-risk groups. Benefits could be further improved by supplementing existing models with information on lifestyle, personal habits, family and employment history, social network relationships, income and education., Prospero Registration Number: CRD42018088012., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

While associations between exposure to air pollutants and increased morbidity and mortality are well established, few rigorous studies on this issue are available. The aim of the current study is to implement a new approach to the spatial analysis of mortality and morbidity, based on testing for the presence of the same association in other areas of similar size. Additionally, we perform a case study in Val d'Agri (VA), an area of Basilicata Region, Southern Italy, where oil and natural gas extraction began in 1998. In order to examine the spatial distribution of morbidity and mortality in the region of interest, Hospital discharge (2001-2013) and mortality (2003-2014) rates for the main environment-related diseases were calculated. In addition, a comparison between the period 1980-1998 and the period 1999-2014 was performed for cardiovascular disease mortality. For the period under study, a neutral scenario emerged for cancer and respiratory diseases, where we found no differences in morbidity and mortality as compared to the national benchmark. In some cases significantly lower values (as compared to the nation-wide benchmark) were found. Conversely, a slight excess in morbidity and mortality (as compared to the nation-wide benchmark) emerged for cardiovascular diseases. Still, this excess was common to a number of municipalities in the surroundings of VA, and appeared to be already present in 1980. Higher rates of cardiovascular diseases, lower rates of neoplastic disorders no differences in mortality for respiratory causes (as compared to the nation-wide benchmark) were found in multiple areas of the region, and were therefore not specific to VA. In summary, our data do not support the hypothesis of a role of industrial activities related to oil extraction in VA in determining mortality and morbidity patterns and trends.

Background: Vaccine-preventable invasive bacterial diseases (IBDs) caused by Neisseria meningitidis (Nm), Streptococcus pneumoniae (Sp), and Haemophilus influenzae (Hi) have been notified in Italy since 2007 without assessing reporting completeness., Methods: Our study compared the number of cases of IBDs identified from the Italian Hospital Discharge Records (HDRs), using specific diagnostic ICD-9-CM codes, with those notified to the National Surveillance System (NSS) from 2007 to 2016. A multinomial logistic regression model was used to impute the aetiology of all discharges with a diagnosis of unspecified bacterial meningitis., Results: Over a 10-year period, 14,243 hospital discharges with diagnosis of IBD were estimated in Italy (12,671 with specified aetiology and 1,572 with imputed aetiology). Among those, 2,513 (17.6%) were caused by Nm, 10,441 (73.3%) by Sp, and 1289 (9.1%) by Hi. Most invasive meningococcal diseases were coded as meningitis (72.3%), while Hi and Sp were more frequently coded as septicaemia (51.6% and 60.4%, respectively). The highest mean annual incidence rate was found for IBD caused by Sp (1.74 per 100,000), followed by Nm (0.42 per 100,000) and by Hi (0.21 per 100,000). Comparing NSS with HDR data, we found an initially high underreporting of all IBDs, and particularly for Hi. Data from the two systems overlapped in more recent years, due to an improved reporting completeness. The increasing IBD incidence observed in NSS data was not confirmed by HDR data trends, although with pathogen-related differences with Hi cases rising in both data sources, suggesting that is mainly due to an improved disease notification rather than to a true incidence increase., Conclusions: Comparing surveillance data with other data sources is useful to better interpret observed trends of notifiable diseases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The use of engineered nanomaterials (ENM) has grown after the turn of the 21st century. Also, the production of ENM has globally grown, and exposure of workers especially via the lungs to ENM has increased. This review tackles with effects of ENM on workers' health because occupational environment is the main source of exposure to ENM. Assessment of exposure to ENM is demanding, and today there are no occupational exposure level (OEL) for ENM. This is partly due to challenges of such measurements, and in part to the unknown causality between ENM metrics and effects. There are also marked gaps in systematic knowledge on ENM hazards. Human health surveys of exposed workers, or human field studies have not identified specific effects of ENM linking them with a specific exposure. There is, however, a consensus that material characteristics such as size, and chemistry influence effects of ENM. Available data suggest that multiwalled carbon nanotubes (MWCNT) affect the immunological system and cause inflammation of the lungs, or signs of asthma whereas carbon nanofibers (CNF) may cause interstitial fibrosis. Metallic and metal oxide nanoparticles together with MWCNT induce genotoxicity, and a given type of MWCNT has been identified as a possible human carcinogen. Currently, lack of understanding of mechanisms of effects of ENM renders assessment of hazards and risks of ENM material-by-material a necessity. The so called "omics" approaches utilizing ENM-induced alterations in gene and protein expression may be useful in the development of a new paradigm for ENM hazard and risk assessment. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials., (© 2018 Wiley Periodicals, Inc.)

Background: Transplacental passage of IgGs is impaired in HIV + pregnant women, possibly determining an inadequate immunological protection in their children. We aimed to determine the impact of maternal immunological IgG profile and immunoactivation status on the efficiency of transplacental passage of IgG subclasses in HIV + mothers., Methods: 16 mother/infants pairs were studied in Malawi. Mothers received antiretroviral therapy (ART) from the third trimester of pregnancy. Determinations of pre-ART levels of maternal sCD14, of IgG subclasses in mothers at delivery and in their 1-month-old infants, were performed using commercial ELISA kits., Results: At delivery, after a median of 10 weeks of ART, 12/16 mothers were hypergammaglobulinemic, with IgG levels (20.5 mg/ml, 95% CI:18.8-26.8) directly correlated to the plasmatic levels of sCD14 (r = 0.640, p = 0.014). IgG1 levels (17.9 mg/ml) accounted for 82% of IgG, IgG3 and IgG4 levels were in the normal range. A profound deficit of IgG2 was observed both in mothers (0.60 mg/ml) and in infants (0.14 mg/ml). Placental transfer ratio (range 0.16-0.42) did not show a selective impairment between the different IgG subclasses. The transplacental passage of all IgG subclasses was decreased in the presence of maternal IgG over 16 mg/ml (significantly for IgG1, p = 0.031) and of high levels of sCD14 (p = 0.063)., Conclusions: Transplacental passage was reduced for all IgG subclasses and inversely correlated to high levels of maternal IgGs and to the degree of immunoactivation. The profound depression of IgG2 in mothers suggests that IgG2 neonatal levels mostly reflect the maternal deficit rather than a selective impairment of IgG2 transfer.

Objectives: Nevirapine is used in developing countries for the treatment of HIV infection, but its use is associated with rare serious adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recently, an association between rs5010528 in the human leucocyte antigen (HLA)-C locus and SJS/TEN susceptibility has been described in sub-Saharan populations. Our aim was to verify this association in a population of nevirapine-treated patients from Mozambique., Methods: The rs5010528 SNP was analysed by direct sequencing in 27 patients who had developed SJS/TEN and 75 patients who did not develop adverse reactions after nevirapine treatment. A case-control association study was conducted. A multivariate analysis was performed in order to evaluate the role of HLA-C also in relation to other susceptibility genetic factors (CYP2B6, TRAF3IP2, HCP5, PSORS1C1 and GSTM1 genes)., Results: rs5010528 was significantly associated with a higher risk of developing SJS/TEN; the variant allele was more frequent in cases than in controls, conferring a high risk of developing this adverse reaction in carriers (OR = 5.72 and P = 0.0002 at genotype level, OR = 3.51 and P = 0.0002 at allelic level). The multivariate analysis showed that the HLA-C SNP, CYP2B6 (rs28399499), TRAF3IP2 (rs76228616) and GSTM1 (null genotype) can explain 25% of the susceptibility to this reaction, with the HLA-C SNP as the most significant contributor (P = 0.02 and OR = 5.64)., Conclusions: Our study confirmed the association of the rs5010528 SNP in the HLA-C region with susceptibility to developing SJS/TEN in a population from Mozambique, suggesting that it could be a good genomic biomarker for SJS/TEN susceptibility in different sub-Saharan populations.

Competing Interests: No Conflict of Interest is declared

Background: Vaccination has determined a dramatic decline in morbidity and mortality from infectious diseases over the last century. However, low perceived risk of the infectious threat and increased concern about vaccines' safety led to a reduction in vaccine coverage, with increased risk of disease outbreaks., Methods: Annual surveillance data of nationally communicable infectious diseases in Italy between 1900 and 2015 were used to derive trends in morbidity and mortality rates before and after vaccine introduction, focusing particularly on the effect of vaccination programs. Autoregressive integrated moving average models were applied to ten vaccine-preventable diseases: diphtheria, tetanus, poliomyelitis, hepatitis B, pertussis, measles, mumps, rubella, chickenpox, and invasive meningococcal disease. Results of these models referring to data before the immunization programs were projected on the vaccination period to estimate expected cases. The difference between observed and projected cases provided estimates of cases avoided by vaccination., Results: The temporal trend for each disease started with high incidence rates, followed by a period of persisting reduction. After vaccine introduction, and particularly after the recommendation for universal use among children, the current rates were much lower than those forecasted without vaccination, both in the whole population and among the 0-to-4 year olds, which is, generally, the most susceptible age class. Assuming that the difference between incidence rates before and after vaccination programs was attributable only to vaccine, more than 4 million cases were prevented, and nearly 35% of them among children in the early years of life. Diphtheria was the disease with the highest number of prevented cases, followed by mumps, chickenpox and measles., Conclusions: Universal vaccination programs represent the most effective prevention tool against infectious diseases, having a major impact on human health. Health authorities should make any effort to strengthen public confidence in vaccines, highlighting scientific evidence of vaccination benefits., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To identify all systematic reviews investigating the role of maternal and fetal biomarkers for predicting spontaneous preterm birth (SPTB)., Methods: Medline and Web of Sciences databases were searched electronically. Studies exploring the association between maternal biomarkers and spontaneous delivery were considered suitable for inclusion. A synthesis of the systematic reviews was performed with the umbrella methodology. Statistical measures of association (Odd ratio, OR, relative risk, RR) and predictive accuracy (sensitivity, specificity, positive and negative likelihood ratios were used to synthesize results of the included studies., Results: 21,614 articles were identified, 542 were assessed with respect to their eligibility for inclusion and 14 systematic reviews included. Cervical fibronectin was the biomarkers which showed the highest strength of association with the occurrence of SPTB (delivery within 24 h OR 7, 95%CI 3-17; delivery <7 days (OR 12, 95%CI 8-16). Maternal serum alpha fetoprotein, was associated with an OR of 4 and 3 for early and late SPTB. C-reactive protein had an OR of 2 (95%CI 1-2) and 8 (95%CI 4-16) when detected in maternal plasma and amniotic fluid, respectively. Among cytokines, interleukin-6 had an OR and an LR + for SPTB of 2 and 12 when detected in maternal serum., Conclusions: Cervical fetal fibronectin, alpha fetoprotein, C- reactive protein and interleukin 6 can have an overall good diagnostic accuracy in identifying pregnancies at risk of SPTB. Large prospective studies in different sub-set of women are needed to ascertain whether the combination of different serological and imaging marker can improve antenatal prediction of this condition.

Introduction: The elderly, who suffer from multiple chronic diseases, represent a substantial proportion of Emergency Department (ED) frequent users, thus contributing to ED overcrowding, although they could benefit from other health care facilities, if those were available. The aim of this study was to evaluate and characterize hospital visits of older patients (age 65 or greater) to the ED of a university teaching hospital in Rome from the 1st of January to the 31st of December 2014, in order to identify clinical and social characteristics potentially associated with "elderly frequent users"., Material and Methods: A retrospective study was performed during the calendar year 2014 (1st January 2014 - 31st December 2014) analyzing all ED admissions to the University Hospital of Rome Tor Vergata. Variables collected included age, triage code, arrival data, discharge diagnosis, and visit outcome. We performed a risk analysis using univariate binary logistic regression models., Results: A total number of 38,016 patients accessed the ED, generating 46,820 accesses during the study period, with an average of 1.23 accesses for patient. The elderly population represented a quarter of the total ED population and had an increased risk of frequent use (OR 1.5: CI 1.4-1.7) and hospitalization (OR 3.8: CI 3.7-4). Moreover, they showed a greater diagnostic complexity, as demonstrated by the higher incidence of yellow and red priority codes compared to other ED populations (OR 3.1: CI 2.9-3.2)., Discussion: Older patients presented clinical and social characteristics related to the definition of "elderly frail frequent users". The fact that a larger number of hospitalizations occurred in such patients is indirect evidence of frailty in this specific population, suggesting that hospital admissions may be an inappropriate response to frailty, especially when continued care is not established., Conclusion: Enhancement of continuity of care, establishment of a tracking system for those who are at greater risk of visiting the ED and evaluating fragile individuals should be the highest priority in addressing ED frequent usage by the elderly., Competing Interests: The authors have declared that no competing interest exist.

Aim of this paper is to describe the protocol of the study "Impact of a Community-based Program on Prevention and Mitigation of Frailty in community-dwelling older adults" developed in the framework of the European Innovation Partnership on Active and Healthy Ageing. This proposal has been developed by the Partnership Action groups on frailty, fall prevention and polypharmacy in older. The proposal wants to assess the impact of community-based programs aimed to counteract three main outcomes related to frailty: hospitalization, institutionalization and death. Bringing together researchers from seven European countries, the proposal aims to achieve the critical mass and the geographical extension enough to provide information useful to all older European citizens. An observational study will be carried out to calculate the incidence of the different outcomes in relation to the various interventions that will be assessed; results will be compared with data coming from already established national, regional and local dataset using the observed/expected approach. The sample will be made up by at least 2000 citizens for each outcome. All the citizens will be assessed at the baseline with two multidimensional questionnaires: the RISC questionnaire and the Short Functional Geriatric Evaluation questionnaire. The outcomes will be assessed every six-twelve months.

In times of economic crisis and a national healthcare system that absorbs more than 7% of the gross domestic product, there is a need to "rethink" healthcare practice. EHealth is part of this process of improving accessibility to services, use of available resources and coordination of program choices, and is an indispensable tool for implementing this cultural and management revolution. How realistic is it, today, to think of implementing a digitalized healthcare practice network? To settle this question is essential for today's national healthcare system.

Background: Cow's milk allergy is a common disease of infancy and early childhood. If the baby is not breast-fed, a substitute for cow's milk formula is necessary., Objective: The aim of this study was to investigate, in vitro and in vivo, the allergenicity of mare's milk in a population of selected children with severe IgE-mediated cow's milk allergy., Methods: Twenty-five children (17 male and 8 female) aged 19 to 72 months (median age 34 months) with IgE-mediated cow's milk allergy were selected for this study. All the children underwent skin prick tests with cow's milk and mare's milk and double-blind placebo-controlled oral food challenge (DBPCOFC) with fresh cow's milk, fresh mare's milk, and, as placebo, a soy formula (Isomil, Abbott, Campoverde, Italy). We performed immunoblotting of cow's and mare's milk developed with IgE from allergic children., Results: All the children showed strong positive skin test responses to cow's milk (4+); 2 children had positive skin test responses to mare's milk (2+). All children had positive DBPCOFCs to cow's milk; one child had a positive DBPCOFC to mare's milk. No children reacted to the placebo (Isomil). In the cow's milk, some proteins are able to strongly react with human IgE; when the sera are tested with mare's milk, the bands corresponding to the same proteins are recognized by a lower percentage of sera., Conclusion: These data suggest that mare's milk can be regarded as a good substitute of cow's milk in most children with severe IgE-mediated cow's milk allergy. It would be prudent, however, to confirm its tolerability by a supervised titrated oral challenge test.