Medical conditions of children and young people with Down syndrome.

BACKGROUND: The life expectancy of people with Down syndrome (DS) has significantly increased in the last decades. We describe the congenital malformations and main comorbidities of a cohort of children and young people with DS and analyse their differences according to age and gender groups. METHODS: This retrospective cross-sectional study was conducted at DS centre of Bambino Gesù Children's Hospital in Rome (Italy). The period for reviewing all electronic health records ran from July 2016 to September 2017. We collected data on clinical conditions and compared them with the general paediatric population. Moreover, we compared the main comorbidities, dental diseases and body mass index data between age groups. RESULTS: Seven hundred sixty-three children and young people with DS included in this study were aged 7.45 ± 5.49 years. Gender distribution included 58.19% male patients. The majority of our population (71.04%) came from central regions of Italy. Respiratory diseases (19%), congenital heart defects (72.23%), malocclusions (58.62%), astigmatism (20.31%), farsightedness (16.51%), near-sightedness (12.19%) and autoimmune hypothyroidism (3.28%) were more frequent in our population compared with the typical paediatric population. Upper respiratory tract infections and underweight were significantly more frequent in the youngest children, whereas dental diseases, refractive errors, obesity and autoimmune hypothyroidism increased over age. CONCLUSIONS: Children and young people with DS present a high prevalence of potentially treatable medical conditions making multidisciplinary teams a mandatory need for this population.

Nitrous oxide occupational exposure in conscious sedation procedures in dental ambulatories: a pilot retrospective observational study in an Italian pediatric hospital.

BACKGROUND: Nitrous oxide has a proven clinical efficacy in conscious sedation. At certain environmental concentrations it may pose a health risk to chronically exposed healthcare workers. The present pilot study aims at evaluating the exposure to nitrous oxide of dental ambulatory personnel of a pediatric hospital. METHODS: A descriptive study design was conducted in two phases: a bibliographic analysis on the environmental safety policies and a gas concentration analysis in the dental ambulatories of a pediatric hospital, detected every 6 months from December 2013 to February 2017 according to law provisions. The surveys were carried out using for gas analysis a photoacoustic spectrometer Innova-B&K "Multi-gas monitor model 1312" and Innova-B&K "Multi-sampler model 1309". The biological analysis and monitoring have been carried out on staff urine. RESULTS: The analyses were performed during 11 dental outpatient sessions on pediatric patients. All the patients were submitted to the same dental procedures, conservative care and dental extractions. The pediatric patients were 47 (23 males, 24 females; age range 3-17 years; mean age 6,63, SD ± 2,69) for a mean of 4,27 (SD ± 1,49) per session., The mean environmental concentration of nitrous oxide during the sessions was 24.7 ppm (SD ±16,16). A correlation was found between urinary nitrous oxide concentration of dentists (Pearson's correlation 0.786; p = 0.007) and dental assistants urines (Pearson's correlation 0.918; p < 0.001) and environmental concentrations of nitrous oxide. Weak negative correlations were found between age and sex of patients and environmental concentrations of nitrous oxide. The mean values of the biological monitoring data referring to all the outpatient sessions are lower than the reference values foreseen in accordance to the regulations in force on nitrous oxide concentration. CONCLUSIONS: The mean environmental concentration values recorded in our study are below the limit of 50 ppm considered as a reference point, a value lower than those reported in other similar surveys. The results of the present study provide a contribution to the need to implement technical standards, criteria and system requirements for the dental ambulatories, to date not yet completely defined, and cannot be assimilated to the ones established for the surgical rooms.

Strategies to control antibiotic resistance: results from a survey in Italian children's hospitals.

BACKGROUND: Antimicrobial stewardship programs and comprehensive infection control programs represent the main strategies to limit the emergence and transmission of multi-drug resistant bacteria in hospital settings. The purpose of this study was to describe strategies implemented in Italian children's hospitals for controlling antibiotic resistance. STUDY DESIGN: Cross sectional multicenter study. METHODS: Four tertiary care Italian children's hospitals were invited to participate in a survey aimed at collecting information on activities implemented as of December 2015 using a self-administered online questionnaire. The questionnaire was divided in three sections focalizing on: i) policies for prevention and control of hospital-acquired infection, ii) prevention and control of multi-drug resistant bacteria, and iii) antibiotic prescribing policies and Antimicrobial stewardship programs. Questionnaires were compiled between May and July 2016. RESULTS: All hospitals had multidisciplinary infection control committee, procedures on hand hygiene, isolation measures, disinfection/sterilization, waste disposal and prevention on infections associated to invasive procedures. All sites screened patients for multi-drug resistant bacteria colonization in selected units, and adopted contact precautions for colonized patients. Screening during hospitalization, or in case of infections in the same ward were not universally implemented. All hospitals had policies on surgical prophylaxis, while policies on medical prophylaxis and treatment of bacterial infections varied among sites. Two sites recommended to review the appropriateness of antibiotic prescribing after 48-72 hours and one recommended de-escalation therapy. CONCLUSIONS: This study highlighted several areas of improvement, such as actions for screening patients in case of occurrence of multi-drug resistant bacteria, antimicrobial stewardship programs and implementation of policies targeting antibiotic prescriptions for therapeutic purposes and medical prophylaxis.

Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma.

Background: A major limitation of circulating tumor DNA (ctDNA) for somatic mutation detection has been the low level of ctDNA found in a subset of cancer patients. We investigated whether using a combined isolation of exosomal RNA (exoRNA) and cell-free DNA (cfDNA) could improve blood-based liquid biopsy for EGFR mutation detection in non-small-cell lung cancer (NSCLC) patients. Patients and methods: Matched pretreatment tumor and plasma were collected from 84 patients enrolled in TIGER-X (NCT01526928), a phase 1/2 study of rociletinib in mutant EGFR NSCLC patients. The combined isolated exoRNA and cfDNA (exoNA) was analyzed blinded for mutations using a targeted next-generation sequencing panel (EXO1000) and compared with existing data from the same samples using analysis of ctDNA by BEAMing. Results: For exoNA, the sensitivity was 98% for detection of activating EGFR mutations and 90% for EGFR T790M. The corresponding sensitivities for ctDNA by BEAMing were 82% for activating mutations and 84% for T790M. In a subgroup of patients with intrathoracic metastatic disease (M0/M1a; n = 21), the sensitivity increased from 26% to 74% for activating mutations (P = 0.003) and from 19% to 31% for T790M (P = 0.5) when using exoNA for detection. Conclusions: Combining exoRNA and ctDNA increased the sensitivity for EGFR mutation detection in plasma, with the largest improvement seen in the subgroup of M0/M1a disease patients known to have low levels of ctDNA and poses challenges for mutation detection on ctDNA alone. Clinical Trials: NCT01526928.

Incidence of surgical site infections in children: active surveillance in an Italian academic children's hospital.

BACKGROUND: Surgical Site Infections (SSIs) account for 16-34% of all health-care associated infections. This study aimed to assess the incidence rate of SSIs in children who underwent surgical procedures in an academic children's hospital in Italy. STUDY DESIGN: Prospective cohort study. METHODS: We actively followed-up 0-17 year old children at 30 days of surgical procedures without implants conducted during one index week per quarter, from the second quarter of 2014, to the first quarter of 2016 (8 index weeks in total). Follow up data were collected by telephone interview, or derived by clinical records if patients were still hospitalized. SSIs were defined according to case definitions of Centers for Diseases Control, Atlanta, USA. We calculated cumulative incidence of SSIs per 100 surgical procedures, by patient characteristics, procedure characteristics, and quarter. To investigate variables associated with SSIs, we compared characteristics of procedures with SSIs with those of procedures without SSIs. RESULTS: Over the study period, SSI incidence was 1.0% (19 cases/1,830 surgical procedures). SSI incidence was significantly lower after ear, nose and throat procedures compared to all other procedures, and significantly decreased over time. Duration of surgery was a risk factor for SSIs; patients with SSIs had a significantly longer total length of stay (LOS), due to a prolonged post-operative LOS. CONCLUSION: As reported in adults, this study confirms that SSIs are associated with longer hospitalizations in children. Active surveillance of SSIs is an important component of the overall strategy to reduce the incidence of these infections in children.

Advancement in the routine identification of anaerobic bacteria by MALDI-TOF mass spectrometry.

We evaluated matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) Biotyper as a tool for the identification of anaerobic bacteria compared with 500 base-pair (bp) 16S ribosomal ribonucleic acid (rRNA) gene sequencing analysis, which is considered to be the "gold standard" method. A total of 484 anaerobic bacteria were retrieved from the clinical specimens of 318 pediatric patients. Molecular identification resulted in 18 genera and 51 species. The most prevalent genus was Clostridium (76.85 %), with 70 % C. difficile isolates. The concordance and sensitivity determined by MALDI-TOF MS for C. difficile, the most prevalent species isolated, was 94.08 %, whereas the specificity was 100 %. For the other anaerobes, the sensitivity and specificity were 94.07 % and 81.82 %, respectively, with a concordance of 93.15 %. Low performance was observed for Propionibacterium acnes and Fusobacterium nucleatum, for which a dedicated pretreatment procedure should likely be set up. MALDI-TOF MS was shown to be a valid alternative for the fast and reliable identification of the most clinically relevant anaerobic bacteria; moreover, it is less time-consuming, the cost for reagents is minimized, and it does not require dedicated personnel.

Proactive evaluation of clinical risk: a FMECA analysis in pediatric chemotherapy.

In 2010-2011, we used FMECA to prospectively assess risk-management in chemotherapy of children with cancer, in a third level Italian children's Hospital (Ospedale Pediatrico Bambino Gesù; OPBG). We designed a flow chart representing the entire process; we described potential failure points for each step of the process, as well as their potential underlying causes. We calculated the risk priority number (RPN) of each failure point based on the severity of the failure, the frequency of occurrence, and the likelihood of detecting the failure prior to completion of the process. All FMECA activities were supported by a web-based tool. The highest RPN values were observed for failure points of the paper-based chemotherapy medication orders sent from clinicians to Pharmacy, the transcription of the orders into the Pharmacy paper-based work-sheet for medication preparation, and the selection of medications to be used for chemotherapy preparation. Causes of these failures were mostly related to illegible or incomplete handwriting. As a consequence of these results, the implementation of an electronic ordering process for children's chemotherapy medications was proposed as risk-reducing action.

Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities.

Defects at the level of pre-mRNA splicing are a common source of genetic mutation but such mutations are not always easy to identify from DNA sequence data alone. Clinical practice has only recently begun to incorporate analysis for this type of abnormality. Some base changes at the DNA level currently viewed as unclassified variants or missense mutations may influence RNA splicing. To address this problem for fibrillin 1 (FBN1) gene missense mutations we have carried out RNA analysis and in silico analysis with splice site prediction programs on 40 cases with 36 different mutations. Direct analysis of RNA from blood was performed by cDNA preparation, PCR amplification of specific FBN1 fragments, gel electrophoresis and sequencing of the PCR products. Of the 36 missense base changes, direct RNA analysis identified 2 which caused an abnormality of splicing. In silico analysis using five splice site prediction programs did not always accurately predict the splicing seen by direct RNA analysis. In conclusion, some apparent missense mutations have an effect on splicing which can be identified by direct RNA analysis, however, in silico analysis of splice sites is not always accurate, should be carried out with more than one prediction program and results should be used with caution.

Incidence and risk factors of bacterial sepsis and invasive fungal infection in neonates and infants requiring major surgery: an Italian multicentre prospective study.

BACKGROUND: Limited data are currently available on the incidence rates and risk factors for bacterial sepsis and invasive fungal infections (IFIs) among neonates and infants undergoing major surgery. AIM: To assess the incidence of bacterial sepsis and IFI, fungal colonization, risk factors for sepsis, and mortality in neonates and infants aged <3 months undergoing major surgery. METHODS: A multicentre prospective study was conducted involving 13 level-3 neonatal intensive care units in Italy, enrolling all infants aged ≤3 months undergoing major surgery. FINDINGS: From 2018 to 2021, 541 patients were enrolled. During hospitalization, 248 patients had a bacterial infection, and 23 patients had a fungal infection. Eighty-four patients were colonized by fungal strains. Overall, in-hospital mortality was 2.8%, but this was higher in infected than in uninfected infants (P = 0.034). In multivariate analysis, antibiotic exposure before surgery, ultrasound-guided or surgical placement of vascular catheters, vascular catheterization duration, and gestational age ≤28 weeks were all associated with bacterial sepsis. The risk of IFI was markedly higher in colonized infants (odds ratio (OR): 8.20; P < 0.001) and was linearly associated with the duration of vascular catheterization. Fungal colonization in infants with abdominal surgery increased the probability of IFI 11-fold (OR: 11.1; P < 0.001). CONCLUSION: Preventive strategies such as early removal of vascular catheters and the fluconazole prophylaxis should be considered to prevent bacterial and fungal sepsis in infants undergoing abdominal surgery, and even more so in those with fungal colonization.

Prolonged in-hospital exposure to an infant with active pulmonary tuberculosis.

Active pulmonary tuberculosis was diagnosed in a 4-month-old infant 16 days after hospitalization; 186 exposed individuals were traced and one conversion detected. Although the risk of tuberculosis transmission in paediatric hospitals is low, paediatricians in low-incidence countries should maintain a high level of alert for timely identification of cases.

Acute toxic exposures in children: analysis of a three year registry managed by a Pediatric poison control Center in Italy.

INTRODUCTION: Acute pediatric poisoning is an emerging health and social problem. The aim of this study is to describe the characteristics of a large pediatric cohort exposed to xenobiotics, through the analysis of a Pediatric Poison Control Center (PPCc) registry. METHODS: This study, conducted in the Pediatric Hospital Bambino Gesù of Rome, a reference National Pediatric Hospital, collected data of children whose parents or caregivers contacted the PPCc by phone (group "P"), or who presented to the Emergency Department (group "ED"), during the three-year period 2014-2016. Data were prospectively and systematically collected in a pre-set electronic registry. Comparisons among age groups were performed and multivariable logistic regression models used to investigate associations with outcomes (hospital referral for "P", and hospital admission for "ED"group). RESULTS: We collected data of 1611 children on group P and 1075 on group ED. Both groups were exposed to both pharmaceutical and non-pharmaceutical agents. Pharmaceutical agent exposure increased with age and the most common route of exposure was oral. Only 10% among P group were symptomatic children, with gastrointestinal symptoms. Among the ED patients, 30% were symptomatic children mostly with gastrointestinal (55.4%) and neurologic symptoms (23.8%). Intentional exposure (abuse substance and suicide attempt), which involved 7.7% of patients, was associated with older age and Hospital admission. CONCLUSIONS: Our study describes the characteristics of xenobiotics exposures in different paediatric age groups, highlighting the impact of both pharmacological and intentional exposure. Furthermore, our study shows the utility of a specific PPCc, either through Phone support or by direct access to ED. PPCc phone counselling could avoid unnecessary access to the ED, a relevant achievement, particularly in the time of a pandemic.

Point prevalence study of antibiotic use in a paediatric hospital in Italy.

A survey aimed to describe the prevalence of antibiotic use in hospitalised children was conducted in June 2007, in Bambino Gesù Children's Hospital in Rome which has the highest annual number of inpatients among paediatric hospitals in Italy. Data were collected by reviewing medical charts of all patients hospitalised for >48 hours. A total of 412 hospitalised children were evaluated; their median age was 42.3 months, and 55.6% were males. Antibiotics were prescribed to 181 of the 412 patients (43.9%). The prevalence was lowest (37.7%) in medical wards, higher (51.1%) in intensive care units and highest (52.2%) in surgical wards. Of the patients treated with antibiotics in surgical wards, 71% received the treatment as prophylaxis. The most frequently prescribed antibiotics were ceftazidime and the combination of amoxicillin and clavulanic acid. The observed prevalence of antibiotic use was within the range recently reported from other paediatric hospitals in Europe; however, it is advisable to collect data from all over the country in order to identify priority areas and design interventions. These results also highlight the need to implement guidelines for surgical prophylaxis in children, and to further investigate reasons for prescription of parenteral antibiotic therapy in paediatric hospitals.

Human NDE1 splicing and mammalian brain development.

Exploring genetic and molecular differences between humans and other close species may be the key to explain the uniqueness of our brain and the selective pressures under which it evolves. Recent discoveries unveiled the involvement of Nuclear distribution factor E-homolog 1 (NDE1) in human cerebral cortical neurogenesis and suggested a role in brain evolution; however the evolutionary changes involved have not been investigated. NDE1 has a different gene structure in human and mouse resulting in the production of diverse splicing isoforms. In particular, mouse uses the terminal exon 8 T, while Human uses terminal exon 9, which is absent in rodents. Through chimeric minigenes splicing assay we investigated the unique elements regulating NDE1 terminal exon choice. We found that selection of the terminal exon is regulated in a cell dependent manner and relies on gain/loss of splicing regulatory sequences across the exons. Our results show how evolutionary changes in cis as well as trans acting signals have played a fundamental role in determining NDE1 species specific splicing isoforms supporting the notion that alternative splicing plays a central role in human genome evolution, and possibly human cognitive predominance.

Functional splicing assay shows a pathogenic intronic mutation in neurofibromatosis type 1 (NF1) due to intronic sequence exonization.

Genomic variations with no apparent effect ("neutral polymorphisms") may have a significant effect on splicing. The effect of this type of mutation is difficult to spot, unless a functional assay is undertaken. In our study, DNA sequencing of a patient with clinically defined neurofibromatosis type 1 (NF1) showed only a single polymorphism in intron 30 due to an A>G transition 279 nucleotides from the 3' splice site. Using a minigene splicing assay we conclusively show that this change produces a cryptic exon with a 3' SS defined by the nucleotide change and the unexpected activation of a very weak 5'SS. Further site directed mutagenesis studies aimed at identifying the signals involved in the cryptic exon inclusion were carried out. Interestingly we find that particular characteristics of the cryptic 5' SS are essential for its inclusion. Significantly an additional single nucleotide change disrupting the cryptic 5'ss consensus sequence rescues the effect of the pathogenetic mutation resulting in normal splicing.

[Troponin I and B-type Natriuretic Peptide (BNP) as biomarkers for the prediction of cardiotoxicity in patients with breast cancer treated with adjuvant anthracyclines and trastuzumab]. / Troponina I e Peptide Natriuretico Cerebrale (BNP) come biomarcatori predittivi di cardiotossicità nelle pazienti affette da carcinoma della mammella in terapia adiuvante con antracicline e trastuzumab.

Adjuvant trastuzumab with chemotherapy is the treatment of choice for patients with human epidermal growth factor receptor positive (HER2+) breast cancer and improves the outcome of patients with early breast cancer. However, it is potentially cardiotoxic and there are no validated methods of early detection of cardiotoxicity from trastuzumab following anthracycline-based chemotherapy. Currently, changes in left ventricular ejection fraction (LVEF) are assessed but this approach has limited sensitivity and specificity. Early identification of patients at risk for cardiotoxic effects is a primary goal for both cardiologists and oncologists. Plasma markers such as b-type natriuretic peptide (BNP - an index of elevated filling pressure) and troponin I (TnI - an index of cardiomyocyte damage) may be used to identify the risk of developing cardiac dysfunction during treatment. In this review, we discuss if TnI and/or BNP could be used to help the prevention or treatment of cardiac dysfunction at the earliest possible time.

Improvement of diastolic function after reversal of left ventricular hypertrophy induced by long-term antihypertensive treatment with tertatolol.

In 15 previously untreated hypertensive subjects with left ventricular (LV) hypertrophy who responded favorably (supine blood pressure less than or equal to 140/90 mm Hg) to antihypertensive treatment with a nonselective beta-blocking agent, tertatolol, the effects of reversal of LV hypertrophy on systolic and diastolic function were assessed. Patients underwent echocardiographic and radionuclide studies in control conditions (phase 1), after 1 month of blood pressure normalization (phase 2), after reversal of LV hypertrophy or at least a 20% reduction of LV mass compared to basal value (phase 3) and finally, after a 1-month washout (phase 4). In phase 2, blood pressure (130 +/- 2/85 +/- 1 vs 148 +/- 4/104 +/- 1 mm Hg) and heart rate (59 +/- 1 vs 76 +/- 2 beats/min) decreased (both p less than 0.01); LV mass remained unchanged. There were improvements in peak filling rate (end-diastolic volume/s) (2.4 +/- 0.1 vs 2.0 +/- 0.1), ejection fraction (65 +/- 1 vs 61 +/- 1%) and their ratio (stroke counts/s) (3.7 +/- 0.2 vs 3.2 +/- 0.1) (all p less than 0.05). In phase 3, blood pressure and heart rate were unchanged and reversal of LV hypertrophy was accompanied by a further increase in peak filling rate (2.9 +/- 0.1), ejection fraction (69 +/- 1%) and their ratio (4.1 +/- 0.1) compared to phase 2 (all p less than 0.01). Finally, in phase 4 blood pressure and heart rate returned to the basal value, but peak filling rate (2.7 +/- 0.1) and ejection fraction (65 +/- 1%), although reduced compared to phase 3, were still higher than phase 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of long-term antihypertensive treatment with tertatolol on diastolic function in hypertensive patients with and without left ventricular hypertrophy.

UNLABELLED: We assessed the effects of long-term antihypertensive treatment with 5 mg tertatolol, a noncardioselective beta-blocker, on left ventricular hypertrophy (LVH) and diastolic function. Fifteen hypertensive patients were selected as good responders to previous treatment with tertatolol (supine blood pressure less than 140/90 mm Hg). They were divided into 2 groups: group 1 with LVH (n = 6) and group 2 without LVH (n = 9). After a one month wash-out period, all patients received 5 mg tertatolol once daily. In case of uncontrolled blood pressure (BP), the dose was doubled after 2 weeks in 10 patients. BP control was obtained in all patients. M-mode echocardiography and Doppler-echocardiography were performed under controlled conditions after BP normalization and after 6 months of treatment. Long-term BP normalization significantly reduced left ventricular mass index (LVMI) in group 1 (from 137 +/- 3 to 121 +/- 3 g/m2, P less than .01), but not in group 2 (from 120 +/- 3 to 114 +/- 4 g/m2, P = NS). After 2 weeks of effective therapy, the ratio between early and late diastolic peak flow velocity across the mitral valve (E/A ratio), significantly increased in both groups (from 0.72 +/- 0.04 to 0.87 +/- 0.06 in group 1, P less than .05; and from 1.13 +/- 0.06 to 1.26 +/- 0.07 in group 2, P less than .05). After 6 months, together with the reduction of LVMI, a further increase of E/A ratio was only observed in group 1 (to 1.30 +/- 0.12, P less than .05). IN CONCLUSION: (1) LVH contributes to left ventricular diastolic dysfunction in hypertensive patients since its reversal is able to improve diastolic filling, and (2) effective antihypertensive treatment with tertatolol improves diastolic function independently from its effect on LV mass.

[Regulation of coronary circulation in patients with hypertensive cardiopathy: role of ventricular mechanoreceptors]. / La regolazione della circolazione coronarica nel paziente con cardiopatia ipertensiva: ruolo dei meccanocettori ventricolari.

In order to assess the involvement of the cardiopulmonary receptors in the regulation of the coronary circulation, changes in coronary resistance produced by the application of a -10 mmHg pressure to the lower body were studied in 6 healthy subjects and 6 patients with arterial hypertension and left ventricular hypertrophy. The results show that the inhibition of the ventricular receptors significantly increases coronary resistance and that this reflex response is eliminated in hypertensive patients with ventricular hypertrophy. The results show that the inhibition of the ventricular receptors significantly increases coronary resistance and that this reflex response is eliminated in hypertensive patients with ventricular hypertrophy.

[Coronary effects of left ventricular hypertrophy associated with hypertension]. / Effets coronariens de l'hypertrophie ventriculaire gauche associée à l'hypertension.

Left ventricular hypertrophy secondary to hypertension has been associated with a reduction of maximum coronary flow per unit mass as shown by the increase in the minimal threshold of coronary vascular resistance per gramme. This phenomenon has usually been attributed to an increase in muscle mass with absent or inadequate vascular compensation. However, chronic hypertension may induce a function reduction in coronary flow. In particular, it has been recently shown that coronary vascular resistances are influenced by a cardio-cardiac reflex involving the baroreceptor response. Left ventricular hypertrophy could alter the function of the ventricular receptors and favourise myocardial ischemia by preventing the adaptation of coronary flow to myocardial metabolic demands.