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Objective. Human Papillomavirus (HPV)-induced oropharyngeal squamous cell carcinoma (OPSCC) represents an increasing tumor entity with typical clinical and histopathological features, associated with a rising incidence and improved prognosis (1). Detection of HPV-DNA is the most widely used method to diagnose HPV infection in clinical samples. Commercially available diagnostic assays show variable sensitivity and specificity and no international standards have been proposed yet (2). The main purpose of this preliminary study was to evaluate the reliability of EasyPap Direct HPV DNA Test (Ulisse BioMed) on formalin-fixed paraffin-embedded samples (FFPE), despite this test has been designed to work in vaginal mucus, where preliminary data showed a sensitivity of 97%. The test is real-time PCR based, it does not require DNA extraction and it can perform high-risk HPV genotyping. Kit performances have been compared with a commercial kit which requires DNA extraction. Materials and Methods. This pilot study included 38 cases of OPSCC that were surgically treated in our institute. Tumor samples were fixed in buffered formalin, embedded in paraffin and stored at room temperature for 1-13 years (mean storage period 4 ± 4 years). In order to confirm histology and lesion grade, all samples were reviewed by hematoxylin-eosin staining. DNA extraction has been performed starting from FFPE samples through QIAamp® DNA FFPE Tissue Kit (Qiagen, Hilden, Germany) and HPV has been typed through Real Time PCR HPV sign® Pyro Mark System Q96 IDTM (CE-IVD Diatech Pharmacogentetics Iesi Italy). We found 16 cases positive for HPV16, 1 case positive for HPV35 and 21 HPV negative samples. In order to perform HPV detection through EasyPap Direct HPV DNA test, samples underwent deparaffinization with xylene and rehydration with ethanol. Genotyping data were compared to those obtained with Qiagen kit. Results. EasyPap Direct HPV DNA test identified 16 HPVpositive cases and 22 HPV negative cases. Genotyping data showed that 15 samples were HPV16 and 1 sample was HPV35 positive. Concordance analysis showed an agreement- coefficient Kappa Cohen K=0.95 IC95% [0.84-1.00] (excellent agreement, Fleiss classification). The sensibility and specificity of the EasyPap HPV DNA test was 94.1% (95%, confidence interval 80.1%-98.8%) and 100% (95%, confidence interval 88.6%-100%), respectively. The positive predictive value was 100% (95%, confidence interval 88.6%-100%) and the negative predictive value was 95.5% (95% confidence interval, 81.9%-99.3%). Conclusions. Hitherto it was well known that DNA extraction contributes to increase the sensitivity of PCR-based HPV test starting from FFPE tissue samples (3). Despite small sample size has been analyzed, preliminary data obtained through EasyPap Direct HPV DNA test successfully showed that high sensitivity and specificity can be achieved without DNA extraction, with a remarkable decrease of assay cost and time. These results lead us to perform large scale EasyPap testing.

OBJECTIVE. Human Papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx (HPV-OPSCC) usually originates from the reticulated epithelium lining the crypts of Waldeyer’s ring. The increasing epidemiologic evidence of this type of tumors and the peculiar positive prognosis, suggested to introduce a dedicated staging system (1). The 8th edition of the American Joint Committe on Cancer (AJCC) staging manual presented a new classification to discriminate HPV-related cancers based on p16 over-expression, since it demonstrated to be an important biomarker (2). The detection of HPV-DNA could not be used as a defining factor due to its cost and lack of universal applicability. The main purpose of this preliminary study was to evaluate the concordance between the results of immunohistochemistry for p16 overexpression and the HPV-DNA detection performed with a commercial kit as control. MATERIALS AND METHODS. We retrospectively collected 32 cases of OPSCC diagnosed in 2016 at the Academic Hospital of Cattinara in Trieste, whose samples had been tested with Real Time PCR (Pyro Mark System Q96 IDTM - CE-IVD Diatech Pharmacogentetics Iesi Italy). The study was performed using tumor samples fixed in buffered formalin, embedded in paraffin and stored at room temperature for 6 to 18 months. All samples were selected by a pathologist based on sections stained with hematoxylin and eosin to confirm the adequacy of the tissue. The samples were tested for p16 by immunohistochemistry (CINtech® p16 Histology E6H4 ROCHE) and the positivity was assessed when nuclear expression was ≥+2/+3 intensity and ≥75% distribution according to the 8th edition of the AJCC staging manual. In the context of oropharyngeal cancer, the optimal cut-off for p16 overexpression is ≥+2/+3 intensity (+/- cytoplasmic staining) with ≥75% distribution. RESULTS. Seven cases were excluded because of lack of histological stored material for p16 immunohistochemical analysis (only cytological specimen). Among the remaining 25 cases, there were 5 HPV-positive and 20 HPV-negative tumors. The sensibility and specificity of the p16 immunostaining was equal to 100% (95%, confidence interval 83.4%-100%) and 100% (95%, confidence interval 83.4%-97.8%), respectively; the positive predictive value was 100% (95%, confidence interval 83.4%-100%) and the negative predictive value 100% (95% confidence interval, 83.4%-100%). CONCLUSIONS. In agreement with the literature, p16 overexpression demonstrated to be a reliable parameter to identify the cases of OPSCC in which performing an in-depth analysis by means the detection of HPV-DNA would be indicated. Indeed, it is widely known that the association of p16 immunostaining and HPV-DNA detection by quantitative PCR increases the prognostic discriminator (3). We intend to carry on this study adopting a prospective design increasing the sample size and the test accuracy.

l cancro di intervallo (CI) è un’entità patologica che viene descritta solo nell’ambito dei programmi di screening organizzato. Si intende per CI un carcinoma successivo ad un processo di screening negativo e comparso prima del passaggio di screening successivo. Qualsiasi sia la motivazione della loro genesi, i CI rappresentano un insuccesso del programma di screening che, in teoria, mira a diagnosticare tutti i carcinomi in fase di screening, e a non consentire la comparsa di CI. L’analisi dei CI (loro frequenza di comparsa nel tempo, caratteristiche morfologiche e cliniche, revisione della precedente mammografia di screening) è un momento fondamentale della valutazione di performance dello screening.Per questo motivo a 10 anni dall’attivazione del programma di Screening a Trieste, si è voluto confrontare i fattori prognostici dei carcinomi screening-detected (CSD) e dei (CI), alla luce dell’ampio dibattito in letteratura riguardo la maggior aggressività di questi ultimi.

Gli indicatori relativi ai tempi di attesa sono difficili da rispettare, come recentemente evidenziato al XIII Convegno ONS 2015 . Per questo motivo è fondamentale identificare in quale momento della gestione dei carcinomi screening-detected si concentrino i ritardi e stabilirne le cause (se attribuibili alla paziente o all’organizzazione del programma o intrinseci al tipo di lesione) così da proporre mirate modifiche migliorative. Metodi: L’analisi riguarda 146 carcinomi screening-detected consecutivi (biennio 2013-2014). Sono stati misurati i tempi tra le varie fasi diagnostiche (Mammografia di I° livello, Richiamo II° livello, I° approfondimento cito/microistologico, Comunicazione diagnosi) e i tempi chirurgici (Visita chirurgica, Intervento chirurgico, Referto istologico con marcatori biologici, Visita oncologica). Per ogni fase sono stati calcolati i tempi medi/mediani rappresentati tramite box plot e giustificati gli outliers.Risultati: La latenza nella presa in carico chirurgica è legato alla complessità degli esami preoperatori (3) (tempo mediano tra richiamo al II° livello ed intervento: 53 giorni (se unico esame pre-operatorio) vs 73 (se più di un esame pre-operatorio, p

Background: Spontaneous reporting of suspected adverse drug reactions (ADR) is considered the eornerstone of pharrnacovigilance as it allows to assess the risklbenefit ratio of alI marketed drugs. Regional health service has arranged numerous initiatives aimed at promoting the culture of pharrnacovigilance and the participation of ali health care professiona!s. Aim: To describe the evolution of spontaneous reporting in the EmiliaRomagna Region (ERR) in the period 2001-2010 through qualitative (e.g. proper compìlation of the report form) and quantitative indicators (number of annua! reports for Local Health Authority, source of the report, etc). Metbod: Data of regìonal spontaneous reporting 2001-2010 were extracted from the National Network of Pharrnacovigilance of the Italian Drug Agency (AIFA). Drugs were classified according to the ATC classification (Anatomical Therapeutic Chemica! Classification System). For the analysis of adverse drug reactions the dictionary of terminology of Regulatory Agencies MedDRA was used. Results: The contributìon of the Region in the decade was approximately lO % of the national amount (9,633 out of 99,321), with 8 reports per 100 physicians and 230 per million inhabitants. The number of national and regional reports progressively decreased from 200 1 onwards and then retumed to grow in recent years. Strong differences between the individuai Local Health Authorities were identified. The reports concerned more females than males (FIM ratio 1.3: l) and age classes 0-2 and 60-80 years. Hospital doctors were the main source of reports, followed by generai physicians while it is still negligible the contribution by nurses and pharmacists. 2,556 reports (26.5 %) were c1assified as serious and 125 cases were lethal (4.9 % of serious ADRs and 1.3 % of ali regional reports). Iomeprol, amoxicillinlclavulanic acid, lenalidomide and ticlopidine were the most reported suspected drngs. Several serious cases involved vaccines. Discussion: ERR contributes most to the national pharmacovigilance system. Several initiatives launched in recent years allowed to involve in the spontaneous reporting system nurses and pharmacists who in the past underestimated the importance of monitoring the safety of drngs, but there is considerable room for improvement. Generai practitioners lost their major role in spontaneous reporting, probably due to the loss of patenes of drugs and also for the marketing of new drugs made for hospital use only. Conclusion: The pharmacovigilance system of ERR participates in the periodic signal analysis, therefore the quality of the data and the number of reports are essenti al for the emergence of these signals that allow to reevaluate the safety profile of marketed drugs in the primary interest of public health.

Background: Kawasaki Disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) are pediatric diseases characterized by systemic inflammation and vascular injury, potentially leading to coronary artery lesions (CALs). Data on vascular injury occurring during acute COVID-19 (AC19) in children are still lacking. The aim of our study was to investigate endothelial injury in KD-, MIS-C- and AC19-dosing circulating endothelial cells (CECs). Methods: We conducted a multicenter prospective study. CECs were enumerated by CellSearch technology through the immunomagnetic capture of CD146-positive cells from whole blood. Results: We enrolled 9 KD, 20 MIS-C and 10 AC19. During the acute stage, the AC19 and KD patients had higher CECs levels than the MIS-C patients. From the acute to subacute phase, a significant CEC increase was observed in the KD patients, while a mild decrease was detected in the MIS-C patients. Cellular clusters/syncytia were more common in the KD patients. No correlation between CECs and CALs were found in the MIS-C patients. The incidence of CALs in the KD group was too low to investigate this correlation. Conclusions: Our study suggests a possible role of CECs as biomarkers of systemic inflammation and endothelial dysfunction in KD and MIS-C and different mechanisms of vascular injury in these diseases. Further larger studies are needed.

Objectives: To investigate the experiences by distance learning (DL) method during the first wave of the SARS-CoV-2 pandemic in Italy, and to search for correlations with purported experiences and respective levels of social determinants of health (SDH). Study design and methods: Cross-sectional online survey, investigating various SDH and parents’ attitude towards DL, proposed 6 months after the beginning of the pandemic to a sample population of parents with school-aged children throughout Italy. Results: A total of 3791 questionnaires were analyzed. Non-Italian parents complained more frequently of difficulties in providing support to their children in DL due to poor digital skills (p = 0.01), lack of good-quality digital equipment (p = 0.01), problems with the Italian language (p < 0.001), and a lower level of education (p < 0.001). When parents lived apart, greater difficulties in concentration in children using DL (p = 0.05) and a lower parental capacity to support DL (p = 0.002) were reported. Adequate digital structures appeared related to living in owned compared to rented property, higher levels of parental education, and better familial financial situations. Conclusions: Students from families with financial difficulties and low levels of parental education, or even those living in houses for rent or having separated parents, may be disadvantaged in an educational context since the introduction of DL.

Visceral Leishmaniasis (VL) is a vector-borne disease caused by an intracellular protozoa of the genus Leishmania that can be lethal if not treated. VL is caused by Leishmania donovani in Asia and in Eastern Africa, where the pathogens’ reservoir is represented by humans, and by Leishmania infantum in Latin America and in the Mediterranean area, where VL is a zoonotic disease and dog is the main reservoir. A part of the infected individuals become symptomatic, with irregular fever, splenomegaly, anemia or pancytopenia, and weakness, whereas others are asymptomatic. VL treatment has made progress in the last decades with the use of new drugs such as liposomal amphotericin B, and with new therapeutic regimens including monotherapy or a combination of drugs, aiming at shorter treatment duration and avoiding the development of resistance. However, the same treatment protocol may not be effective all over the world, due to differences in the infecting Leishmania species, so depending on the geographical area. This narrative review presents a comprehensive description of the clinical picture of VL, especially in children, the diagnostic approach, and some insight into the most used pharmacological therapies available worldwide.

Bronchiolitis is the most common lower respiratory tract infection in infants. According to evidence-based guidelines, diagnosis is clinical, there is no need for routine use of laboratory or instrumental tests and therapy is primarily supportive, based on oxygen and adequate fluid supplementation. Nevertheless, unnecessary diagnostic tests and pharmacological treatments are still very common. The aim of this retrospective cohort study was to evaluate how the management of bronchiolitis has changed in the last ten years in a Tertiary Care Center in Italy, assessing adherence to national guidelines. Considering the publication of the Italian inter-society consensus document in 2014, we compared patients admitted in the prior four epidemic seasons with patients admitted in the latter six epidemic seasons. The comparison between the two groups showed a significant reduction in the prescription of systemic corticosteroids (58.9% vs. 41.8%, p &lt, 0.001), nebulized epinephrine (73.8% vs. 38.3%, p &lt, 0.001) and antibiotics (59.5% vs. 42.3%, p &lt, 0.001), together with a drastic decrease in the use of chest X-ray (92.2% vs. 54.4%, p &lt, 0.001). On the contrary, the use of inhaled salbutamol remained substantially stable over time (39.4% vs. 37.6%, p = 0.505). Despite the encouraging results, further efforts are needed to limit the prescription of ineffective therapies like antibiotics and inhaled salbutamol.

Urinary tract infections (UTIs) are among the most common bacterial infections in children, and Escherichia coli is the main pathogen responsible. Several guidelines, including the recently updated Italian guidelines, recommend amoxicillin-clavulanic acid (AMC) as a first-line antibiotic therapy in children with febrile UTIs. Given the current increasing rates of antibiotic resistance worldwide, this study aimed to investigate the three-year trend in the resistance rate of E. coli isolated from pediatric urine cultures (UCs) in a metropolitan area of northern Italy. We conducted a retrospective review of E. coli-positive, non-repetitive UCs collected in children aged from 1 month to 14 years, regardless of a diagnosis of UTI, catheter colonization, urine contamination, or asymptomatic bacteriuria. During the study period, the rate of resistance to AMC significantly increased from 17.6% to 40.2% (p < 0.001). Ciprofloxacin doubled its resistance rate from 9.1% to 16.3% (p = 0.007). The prevalence of multidrug-resistant E. coli rose from 3.9% to 9.2% (p = 0.015). The rate of resistance to other considered antibiotics remained stable, as did the prevalence of extended spectrum beta-lactamases and extensively resistant E. coli among isolates. These findings call into question the use of AMC as a first-line therapy for pediatric UTIs in our population, despite the indications of recent Italian guidelines.

Respiratory syncytial virus (RSV) represents the main cause of acute respiratory tract infections in children worldwide and is the leading cause of hospitalization in infants. RSV infection is a self-limiting condition and does not require antibiotics. However hospitalized infants with clinical bronchiolitis often receive antibiotics for fear of bacteria coinfection, especially when chest radiography is performed due to similar radiographic appearance of infiltrate and atelectasis. This may lead to unnecessary antibiotic prescription, additional cost, and increased risk of development of resistance. Despite the considerable burden of RSV bronchiolitis, to date, only symptomatic treatment is available, and there are no commercially available vaccines. The only licensed passive immunoprophylaxis is palivizumab. The high cost of this monoclonal antibody (mAb) has led to limiting its prescription only for high-risk children: infants with chronic lung disease, congenital heart disease, neuromuscular disorders, immunodeficiencies, and extreme preterm birth. Nevertheless, it has been shown that the majority of hospitalized RSV-infected children do not fully meet the criteria for immune prophylaxis. While waiting for an effective vaccine, passive immune prophylaxis in children is mandatory. There are a growing number of RSV passive immunization candidates under development intended for RSV prevention in all infants. In this review, we describe the state-of-the-art of palivizumab’s usage and summarize the clinical and preclinical trials regarding the development of mAbs with a better cost-effectiveness ratio.

SARS-CoV-2 pandemic restrictions have deeply altered the common respiratory illnesses burden. The aim of this paper was to clarify how these measures may have influenced bronchiolitis epidemiology, exploring possible explanations. We studied 342 infants hospitalized for bronchiolitis at our center from four different epidemic seasons (October–April 2017–2018, 2018–2019, 2019–2020 and 2020–2021). March–April hospitalization rate, RSV (respiratory syncytial virus) infection, pediatric intensive care unit (PICU) admission and oxygen therapy administration data were compared among different seasons to outline any changes during the SARS-CoV-2 outbreak. In March–April, 30 (23.1%), 28 (24.6%) and 5 (5.1%) infants were hospitalized for bronchiolitis, respectively, in 2017–2018, 2018–2019 and 2019–2020, with a lower rate in March–April 2020 (p < 0.001). No hospitalizations for bronchiolitis occurred during the epidemic season of 2020–2021. No significant differences in RSV infections, oxygen therapy administration and PICU admissions across seasons were outlined. In conclusion, we report a severe decrease in hospitalizations for bronchiolitis at our center throughout the entire SARS-CoV-2 outbreak rather than only during the lockdown periods. This seems to suggest a pivotal role for the systematic implementation of cost-effective non-pharmaceutical interventions (NPIs) such as compulsory face masks and hand hygiene, which were deployed for the entire pandemic, in reducing the circulation of infectious agents.

Human cytomegalovirus (hCMV) is one of the most common causes of congenital infection in the post-rubella era, representing a major public health concern. Although most cases are asymptomatic in the neonatal period, congenital CMV (cCMV) disease can result in permanent impairment of cognitive development and represents the leading cause of non-genetic sensorineural hearing loss. Moreover, even if hCMV mostly causes asymptomatic or pauci-symptomatic infections in immunocompetent hosts, it may lead to severe and life-threatening disease in immunocompromised patients. Since immunity reduces the severity of disease, in the last years, the development of an effective and safe hCMV vaccine has been of great interest to pharmacologic researchers. Both hCMV live vaccines—e.g., live-attenuated, chimeric, viral-based—and non-living ones—subunit, RNA-based, virus-like particles, plasmid-based DNA—have been investigated. Encouraging data are emerging from clinical trials, but a hCMV vaccine has not been licensed yet. Major difficulties in the development of a satisfactory vaccine include hCMV’s capacity to evade the immune response, unclear immune correlates for protection, low number of available animal models, and insufficient general awareness. Moreover, there is a need to determine which may be the best target populations for vaccine administration. The aim of the present paper is to examine the status of hCMV vaccines undergoing clinical trials and understand barriers limiting their development.

Human Adenoviruses (HAdV) are known to be potentially associated with strong inflammatory responses and morbidity in pediatric patients. Although most of the primary infections are self-limiting, the severity of clinical presentation, the elevation of the white blood cell count and inflammatory markers often mimic a bacterial infection and lead to an inappropriate use of antibiotics. In infections caused by HAdV, rapid antigen detection kits are advisable but not employed routinely; costs and feasibility of rapid syndromic molecular diagnosis may limit its use in the in-hospital setting; lymphocyte cultures and two-sampled serology are time consuming and impractical when considering the use of antibiotics. In this review, we aim to describe the principal diagnostic tools and the immune response in HAdV infections and evaluate whether markers based on the response of the host may help early recognition of HAdV and avoid inappropriate antimicrobial prescriptions in acute airway infections.

SARS-CoV-2 infection in children can trigger cardiovascular manifestations potentially requiring an intensive treatment and defining a new entity named Multisystem Inflammatory Syndrome in Children (MIS-C), whose features partially overlap with Kawasaki Disease (KD). A cross-sectional study including all diagnoses of MIS-C and KD from April 2020 to May 2021 in our metropolitan area was conducted evaluating clinical, laboratory (including immunological response, cytokines, and markers of myocardial damage), and cardiac (coronary and non-coronary) features at onset of the diseases. Evolution of ventricular dysfunction, valve regurgitations, and coronary lesions was documented. The severity of the disease was also considered based on the need for inotropic support and ICU admission. Twenty-four MIS-C were diagnosed (14 boys, median age 82 months): 13/24 cases (54.17%) presented left ventricular dysfunction, 12/24 (50%) required inotropic support, and 10/24 (41.67%) developed coronary anomalies (CALs). All patients received steroids and IVIG at a median time of 5 days (IQR1:4, IQR3:6.5) from onset of fever and heart function normalized 6 days (IQR1: 5, IQR3: 7) after therapy, while CALs persisted in one. One patient (12.5%) required infliximab because of refractory disease and still presented CALs 18 days after therapy. During the same study period, 15 KD were diagnosed: none had ventricular dysfunction, while 7/15 (46.67%) developed CALs. Three out of 15 patients (20%) still presented CALs 46 days from onset. Compared to KD, MIS-C pts have significantly higher IL8 and similar lymphocytes subpopulations. Despite a more severe presentation and initial cardiac findings compared to KD, the myocardial injury in MIS-C has a rapid response to immunomodulatory treatment (median time 6 days), in terms of ventricular function, valve regurgitations, and troponin. Incidence of CALs is similar at onset, but it tends to regress in most of the cases of MIS-C differently than in KD where CALs persist in up to 40% in the subacute stage after treatment.

Purpose Monitoring mutation status in circulating free DNA (cfDNA) during target therapy could hold significant clinical importance in non-small cell lung cancer (NSCLC). Our aim is to establish if EGFR mutational status change on cfDNA has predictive value that can impact clinical management of NSCLC patients care. Methods This study included 30 patients with EGFR-mutated NSCLC. Blood samples were collected at diagnosis (T0) and in 19 patients during therapy (T1). Results Concordance between T0 and T1 EGFR mutation status for patients evaluable for both samples (n = 19) was 79%, with a sensitivity of 100% (95% CI: 55.5–100.0) and specificity of 60.0% (95% CI: 26.2–86.8). For the patients in oncological therapy with targeted drug and with T1 sample available (n = 18), survival outcomes were evaluated. For both mutation-negative T0 and T1 patients, 12-month progression-free survival (PFS) was 66.7% (95% CI: 27.2–100.0) and 12-month overall survival (OS) was 100% (95% CI: 1.00–1.00); for patients mutated both at T0 and T1, PFS was 22.2% (95% CI: 6.5–75.4%) and OS was 55.6% (95% CI: 20.4–96.1%). Conclusion EGFR mutation status can be assessed using cfDNA for routine purposes and longitudinal assessment of plasma mutation is an easy approach to monitor the therapeutic response or resistance onset.

Respiratory syncytial virus (RSV) is the main cause of acute respiratory tract infections in infants and it also induces significant disease in the elderly. The clinical course may be severe, especially in high-risk populations (infants and elderly), with a large number of deaths in developing countries and of intensive care hospitalizations worldwide. To date, prevention strategies against RSV infection is based on hygienic measures and passive immunization with humanized monoclonal antibodies, limited to selected high-risk children due to their high costs. The development of a safe and effective vaccine is a global health need and an important objective of research in this field. A growing number of RSV vaccine candidates in different formats (particle-based vaccines, vector-based vaccines, subunit vaccines and live-attenuated vaccines) are being developed and are now at different stages, many of them already being in the clinical stage. While waiting for commercially available safe and effective vaccines, immune prophylaxis in selected groups of high-risk populations is still mandatory. This review summarizes the state-of-the-art of the RSV vaccine research and its implications for clinical practice, focusing on the characteristics of the vaccines that reached the clinical stage of development.

Mycoplasma pneumoniae (MP) is one of the main causes of both upper and lower respiratory infections in school-aged children, accounting for up to 40% of community-acquired pneumonia. Younger children are also affected, and extrapulmonary manifestations have been recently reported in the pediatric population. We carried out a retrospective analysis of MP-positive patients admitted to the Pediatric Emergency Unit of S. Orsola Malpighi University Hospital in Bologna, the largest tertiary pediatric referral center in the Emilia–Romagna region, Northern Italy, between 2012 and 2020. We identified 145 patients with MP infection (82 males and 63 females), 27% of which were younger than 2 years; the median age was 5 years (interquartile range 1–9). The clinical presentation partially differed between age groups. School-aged children were more likely to have a chest X-ray-confirmed pneumonia (p = 0.013), while younger children required oxygen therapy more often (p = 0.048). Seventy-four children (51%) showed extrapulmonary manifestations, mainly gastrointestinal (30%) and dermatological (14%). Neurological symptoms were more frequent in children older than 6 years (p = 0.006). The rate of other extrapulmonary manifestations did not differ significantly between age groups. This study shows that MP infection is a frequent cause of pediatric hospitalization, including of children younger than 2 years. Clinicians should be aware of the variable clinical expressions of MP, including extrapulmonary manifestations, to achieve a correct diagnosis and determine appropriate treatment.

Several different socio-economic factors have caused a large portion of the population to adopt unhealthy eating habits that can undermine healthcare systems, unless current trends are inverted towards more sustainable lifestyle models. Even though a dietary plan inspired by the principles of the Mediterranean Diet is associated with numerous health benefits and has been demonstrated to exert a preventive effect towards numerous pathologies, including obesity, its use is decreasing and it is now being supplanted by different nutritional models that are often generated by cultural and social changes. Directing governments’ political actions towards spreading adherence to the Mediterranean Diet’s principles as much as possible among the population could help to tackle the obesity epidemic, especially in childhood. This document intends to reiterate the importance of acting in certain age groups to stop the spread of obesity and proceeds with a critical review of the regulatory instruments used so far, bearing in mind the importance of the scientific evidence that led to the consideration of the Mediterranean Diet as not just a food model, but also as the most appropriate regime for disease prevention, a sort of complete lifestyle plan for the pursuit of healthcare sustainability.

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Objective To describe clinical presentation, electrocardiographic, and echocardiographic characteristics of carditis at the time of diagnosis of acute rheumatic fever (ARF) over a 13-year period. Study design A single-center retrospective chart analysis was conducted involving all consecutive patients diagnosed with ARF between 2003 and 2015. Patient age, sex, clinical characteristics, recent medical history for group A streptococcal pharyngotonsillitis and antibiotic treatment, and laboratory, echocardiographic, and electrocardiographic findings were recorded. Results Of 98 patients (62 boys, mean age 8.81 ± 3.04 years), 59 (60.2%) reported a positive history of pharyngotonsillitis; 48 (49%) had received antibiotic (mean duration of treatment of 5.9 ± 3.1 days), and, among these, 28 (58.3%) had carditis. Carditis was the second most frequent finding, subclinical in 27% of patients. Mitral regurgitation was present in 49 of 56 patients (87.5%) and aortic regurgitation in 36/56 (64.3%) no stenosis was documented. Conclusions ARF is still present in high-income countries and can develop despite primary prophylaxis, especially when given for a short course. Our findings highlight the need for 10 days of antistreptococcal treatment to prevent ARF. Echocardiography is important because 27% of cases with carditis were subclinical.

Acute bronchiolitis represents the leading cause of hospitalization in infants. Together with a respiratory syncytial virus, rhinovirus (RV) is one of the most common pathogens associated with bronchiolitis, and its genetic diversity (>150 types) makes the recurrence of RV infections each year quite typical. The frequency of RV infection and co-infection with other viruses and its impact on the clinical course of bronchiolitis have been studied by several authors with controversial results. Some studies demonstrate that multiple virus infections result in more severe clinical presentation and a higher risk of complications, whereas other studies suggest no influence on clinical course. Moreover, RV bronchiolitis has been reported to potentially contribute to the development of long-term sequelae, such as recurrent wheezing and asthma, in the pediatric population. In the present review, we summarize the most recent findings of the role of RV infection in children with acute bronchiolitis, its impact on subsequent asthma development, and the implication in clinical practice.

Respiratory Syncytial Virus (RSV) is a ubiquitous and highly contagious virus belonging to the Paramyxoviridae family. RSV is the most common cause of bronchiolitis and hospitalization during the first year of life and it might be associated with an increased risk of recurrent wheeze, asthma as well as with decreased respiratory function in school-aged children. The treatment of RSV bronchiolitis is primarily supportive and no specific etiological therapy is routinely used, thus prevention plays an essential role. Since there is currently no vaccine against RSV, preventive strategies are based on environmental prophylaxis together with passive immunization using a monoclonal antibody (palivizumab) in selected patients prone to develop severe RSV disease.Environmental prophylaxis is essentially based on frequently and correctly done handwashing, cleaning of contaminated surfaces and avoidance of direct contact with people with cold-like symptoms. Parental smoking should be avoided as tobacco smoke exposure has been associated with an increased risk and severity of bronchiolitis. Finally, breastfeeding for at least six months decreases the morbidity of these children and should be encouraged. Moreover, preventive strategies should be adopted in the management of hospitalized infants to minimize the incidence of RSV nosocomial infections. These measures include cohorting of RSV positive cases, handwashing, using gloves, gowns and masks in case of contact with infected infants, cleaning of surfaces, stethoscopes and other medical instruments. Palivizumab is a humanized monoclonal antibody specific for the surface fusion F protein of the RSV virus that blocks viral replication. It has been shown to reduce the hospitalization rate and death in patients with coexisting conditions (prematurity, congenital heart disease, chronic lung disease, immunodeficiency) at high risk of severe RSV infection. In the following paragraphs we report the most updated evidences for the environmental prophylaxis and we summarize current recommendations about targeted palivizumab immunisation and ongoing trials on RSV vaccine development.

Rhinovirus (RV) is an RNA virus that causes more than 50% of upper respiratory tract infections in humans worldwide. Together with Respiratory Syncytial Virus, RV is one of the leading causes of viral bronchiolitis in infants and the most common virus associated with wheezing in children aged between one and two years. Because of its tremendous genetic diversity (>150 serotypes), the recurrence of RV infections each year is quite typical. Furthermore, because of its broad clinical spectrum, the clinical variability as well as the pathogenesis of RV infection are nowadays the subjects of an in-depth examination and have been the subject of several studies in the literature. In fact, the virus is responsible for direct cell cytotoxicity in only a small way, and it is now clearer than ever that it may act indirectly by triggering the release of active mediators by structural and inflammatory airway cells, causing the onset and/or the acute exacerbation of asthmatic events in predisposed children. In the present review, we aim to summarize the RV infection’s epidemiology, pathogenetic hypotheses, and available treatment options as well as its correlation with respiratory morbidity and mortality in the pediatric population.

OBJECTIVE: Progestogens are widely used to treat a large number of common conditions. We aimed to investigate a potential signal concerning progestogens and paraesthesia. METHODS: Data were obtained from the VigiBase, the WHO Global Individual Case Safety Reports (ICSR) database, which is maintained by the Uppsala Monitoring Centre. We collected all suspected reports of paraesthesia associated with oral progestogens, reported between January 1972 and June 2012 and classified in VigiBase according to WHO-Adverse Reaction Terminology critical term 'paraesthesia'. A disproportionality analysis was conducted using the Information Component (IC) and the standard deviation (IC025) as a measure. RESULTS: Out of the total number of reports collected in the VigiBase (7,332,991), paraesthesia was associated with progestogen therapy in 920 reports, coming from 22 countries. Progestogens had the highest number of suspected reports (n = 864) than the other Anatomical Therapeutic Chemical (ATC) considered. Only norethisterone was associated with paraesthesia with positive IC (0.47) and IC025 (0.02). CONCLUSIONS: Norethisterone-associated paraesthesia appears to be a rare outcome. However, the widespread use of progestogens in medical practice suggests that it is a complaint that can affect a large number of women. Since paraesthesia can be caused by several drugs, clinicians should consider that it may be also caused by norethisterone.

BACKGROUND:: Benign nodular hepatic regenerating lesions such as focal nodular hyperplasia (FNH) have been reported as rare complications of the antineoplastic therapy received during infancy. Little is known about the risk factors associated with the onset of these lesions and their diagnostic management. METHODS:: We have analyzed a series of benign hepatic nodular lesions occurring in children previously treated for malignant tumors in our institution in a period of 11 years. An extensive description of the imaging presentation of the lesions has been provided to facilitate the differential diagnosis, and a risk factor analysis has been conducted. RESULTS:: A total of 14 diagnoses (10 FNH and 4 hemangiomas) of benign nodular hepatic lesions have been found. Hematopoietic stem cell transplantation is the most important statistically independent risk factor associated with the development of these lesions, especially for FNH. No malignant transformation of nodules has been recorded during a median follow-up time of 4 years. CONCLUSIONS:: In our experience, FNH is the most frequent benign nodular hepatic lesions occurring after treatment for childhood cancer. Hematopoietic stem cell transplantation is the most important risk factor to be taken in account. After a secure diagnosis of these benign lesions, only a close imaging follow-up is recommended.

BACKGROUND: The risk of myocardial infarction, macular oedema and bone fractures associated with thiazolidinediones (TZDs) has been extensively investigated. OBJECTIVE: The aim of the study was to verify if the analysis of a large spontaneous reporting database could generate early signals on these adverse drug reactions (ADRs) associated with TZDs. METHODS: A case/non-case study, restricted to antidiabetic drugs, was performed on spontaneous reports of ADRs (2005-2008) in the US FDA Adverse Event Reporting System (AERS). The method was applied to TZDs, both as a drug class and as single agents. The reporting odds ratio (ROR) with 95% CI was calculated as a measure of disproportionality in the whole dataset and in a quarter-by-quarter analysis. RESULTS: TZD use was registered in 49 589 out of 301 950 drug-reaction pairs (16%), with significant disproportionality for myocardial infarction (ROR 4.71; 95% CI 4.40, 5.05), macular oedema (3.88; 2.79, 5.39) and bone fractures (1.73; 1.53, 1.96). Separate analysis of the two TZDs showed that only rosiglitazone was associated with myocardial infarction (7.86; 7.34, 8.34) and macular oedema (5.55; 3.94, 7.79), whereas pioglitazone was associated with multiple site fractures (2.00; 1.70, 2.35), in particular upper and lower limb and pelvic fractures. The quarter-by-quarter analysis identified disproportionality for myocardial infarction (3.13; 2.38, 4.10) and bone fractures since January-March 2005 (2.70; 1.04, 2.78). CONCLUSIONS: The frequency of reporting of myocardial infarction, macular oedema and fractures was significantly higher for TZDs in comparison with other antidiabetic drugs, with large intraclass differences. Both myocardial infarction and bone fracture signals appeared before major publications on these safety issues.

Acute myeloid leukemia is a heterogeneous group of diseases accounting for 15-20% of all tumors diagnosed in children under 15 years of age. The past few decades have yielded remarkable improvements in long-term outcomes for children with acute myeloid leukemia. A better risk-group stratification of patients based upon clinical and biologic features, a more effective use of anti-leukemic agents and enormous improvements in supportive care have increased the probability of cure by approximately 60%. The increase in our understanding of the biology of this disease has resulted in the development of molecularly targeted therapies that are potentially more effective and less toxic than the standard approaches. We here review novel molecularly targeted drugs for the treatment of childhood acute myeloid leukemia such as monoclonal antibodies, inhibitors of signalling molecules, proteasome inhibitors and epigenetic agents. For these recently patented agents, we also provide a detailed analysis of the published preclinical data and the clinical trials that have been completed.

Objective: To describe the evolution of adverse drug reactions (ADRs) spontaneously reporting in the Emilia-Romagna region (ERR) in the period 2001 - 2010 through qualitative and quantitative indicators following local educational and editorial initiatives. Methods: Data of regional spontaneous reporting from 1 January 2001 to 31 December 2010 were obtained from the Pharmacovigilance National Network of the Italian Medicines Agency. Drugs were classified according to the Anatomical Therapeutic Chemical classification. ADRs were coded using the Medical Dictionary for Regulatory Activities Terminology. Results: The overall contribution of the ERR was 9.7% of the total national number of reports (9631 out of 99,319) with a rate of 8 reports per 100 physicians and 230 per million inhabitants. Reports concerned more females and more patients aged 0 - 2 and 60 - 80 years. Differences between the individual local health authorities were identified in rate of ADR reporting. Hospital doctors were the main source of reports followed by general physicians. Out of 2555 serious reports, 124 cases were lethal (4.9% of serious ADRs and 1.3% of all regional reports). Conclusion: The results represent a useful trend analysis of the post-marketing surveillance and suggest that, although the pharmacovigilance system has succeeded in reaching a stable and lasting flow of information in ERR, there is considerable place for improvement.

PURPOSE: Underreporting is a major limitation of spontaneous reporting systems for suspected adverse drug reactions (ADRs). Several interventions to increase the ADR reporting rate have been proposed, but their efficacy remains poorly investigated. METHODS: This was a questionnaire study aimed at assessing the knowledge, attitudes, and behavior of general practitioners (GPs) regarding ADR reporting and at evaluating whether a monthly e-mail-based newsletter on drug safety could affect the rate and the quality of the ADR reports submitted by these GPs. Three local health authorities (LHAs) of the Emilia-Romagna region were chosen on the basis of their ADR reporting rate during the period preceding the study: Rimini (high), Ferrara (average), and Piacenza (low reporting rate). All GPs (n = 737) associated with these three LHAs were recruited. The pooled number of ADR reports sent by GPs in the remaining seven LHAs of the region was used as controls. The study covered a period of 3 years and was divided into: (1) identification of the reasons leading to underreporting through a questionnaire (Phase I); (2) the intervention, i.e., sending a newsletter for a 10-month period (Phase II); (3) evaluation of the intervention outcomes during the 10 months following the period in which the newsletter had been received (Phase III). RESULTS: Among GPs involved, 22.8 % returned the questionnaire. Over 94 % of the respondents considered the spontaneous reporting of suspected ADRs to be part of their professional obligations, but only 6.5 % had submitted at least one report in the previous 6 months. Following the completion of Phase II, the overall number of reports coming from the LHAs subjected to the intervention rose by 49.2 % compared to 2009, while the number of reports coming from the control LHAs increased by 8.8 %. Rimini and Piacenza showed a 200 % increase in the number of ADR reports submitted by GPs, while the number of ADR reported submitted by the control group decreased by 25.5 %. In 2011, the number of overall ADRs reports from the LHAs subjected to the intervention decreased by 6.8 %; this decrease reached 50.0 % of the GPs. Control HLAs showed an overall decline of 4.3 %, while the total number of ADRs from GPs increased by 63.3 %. Ferrara was excluded from the analysis due to confounding factors. CONCLUSIONS: The periodic e-mail update on the safety of drugs represents an effective and inexpensive way to raise the awareness of GPs on the importance of spontaneous ADR reporting. Since the outcome of the intervention seemed to disappear after the intervention was stopped, there appears to be a need to adopt a policy of regular updates and educational strategies for health professionals.

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia with specific epidemiological, pathogenetic and clinical features. Its frequency varies widely among nations, with a decreased incidence among 'Nordic' origin populations. The molecular hallmark of the disease is the presence of a balanced reciprocal translocation resulting in the PML/RAR-alpha gene fusion, which represents the target of the all-trans retinoic acid (ATRA) therapy. The introduction of ATRA in conjunction with anthracyclines marked a turning point in the treatment of APL, previously associated with a significant morbidity and mortality. Nowadays the standard front-line therapy for pediatric APL includes ATRA in every phase of the treatment, resulting in a complete remission rate of 90-95%. Here we provide an overview of the role of ATRA in the treatment of pediatric APL, summarizing the most relevant clinical results of recent decades and investigating future therapeutic perspectives for children with APL.

Background Posterior reversible encephalopathy syndrome (PRES) is a severe neurological complication after pediatric allogeneic hematopoietic stem cell transplantation (allo-HSCT). Seizures are a common manifestation of PRES. Status epilepticus (SE) is a potentially life-threatening event rarely described in this condition. The aim of this study was to describe the clinical and electroencephalographic features of SE as a manifestation of PRES in children after allo-HSCT. Procedure We retrospectively identified episodes of SE as a consequence of PRES out of 211 children who received allo-HSCT in the period January 2000 to June 2008. Results PRES was diagnosed in 11 patients. We identified 12 episodes of SE associated to PRES in 10 patients. Nonconvulsive SE (NCSE) involving posterior regions of the brain (confirmed by EEG monitoring) was observed in four cases; convulsive SE (CSE) was observed in eight cases. Gaze deviation, oculoclonic movements, nystagmus, and altered mental status were the main clinical signs during NCSE and preceded CSE in 5/8 cases. Most patients needed intensive care management. A complete normalization of neurological examination and EEG pattern was observed in all patients after SE and withdrawal of causative agent. Follow-up MRI showed complete resolution of brain edema in all patients. Conclusions Our experience shows that SE is more frequent than previously reported and is often the main manifestation of PRES after pediatric allo-HSCT. Looking for suggestive clinical signs as well as routine use of EEG monitoring may allow prompt recognition of SE and therapy of both SE and PRES. Pediatr Blood Cancer 2012; 58: 785–790. © 2011 Wiley Periodicals, Inc.

Purpose: We evaluated the incidence, prevalence, and patterns of triptan use with a special focus on patients who also received cardiovascular drugs, considered as a deviation from appropriate triptan use. Methods: We collected data on prescriptions reimbursed in between 2006 and 2008 in an Italian region. Patients receiving at least one prescription of triptans from January to December 2007 were divided in two populations: new users (without triptan prescriptions in 2006), and already in treatment. All patients were followed for 12 months in terms of both triptan use and cardiovascular coprescriptions. Results: One-year prevalence of triptan use was 0.8%, whereas the incidence was 0.4%. New users accounted for 47.5% of total users (34,915). The percentages of very frequent users (>120 and >180 dosage unit per year) were about double among those already in treatment (26.6% and 15.3%, respectively) and new users (1% and 0.3%; p < 0.01). Patients starting with the lowest dose of tablet formulation were more likely to interrupt therapy after their first prescription (p < 0.01). Many users aged >65 received concomitant cardiovascular therapies: 36.6% among new users and 64.3% for already in treatment (p < 0.01). In both groups, about 5% of elderly patients received coprescriptions, suggesting a high deviation from appropriate triptan use. Conclusions: A higher percentage of very frequent users was detected in patients already in treatment compared with new users. Moreover, the percentage of nonnegligible triptan recipients were in age groups for which the drug is not recommended by the product label (≤18 years and >65) and who had cardiovascular coprescriptions suggestive of vasoconstrictive risk. © 2011 Springer-Verlag.

Focal nodular hyperplasia (FNH) is a benign hepatic lesion very rarely described in the pediatric population. It has been reported more frequently in patients treated for pediatric cancers with chemotherapy or hematopoietic stem cell transplantation. The use of high dosage of alkylating agents, the occurrence of venous occlusive disease, graft-versus-host disease, and other variables linked to the hematopoietic stem cell transplantation procedure can represent risk factors for the development of FNH in the pediatric age. The discovery of hepatic nodules in the follow-up of patients treated for malignancies suggests recurrence of disease and raises a diagnostic dilemma. Here we describe possible risk factors, clinical and radiological findings of eight pediatric patients who developed focal nodular hyperplasia after hematopoietic stem cell transplantation. The aim of this report is to provide useful diagnostic tools to facilitate accurate diagnosis of FNH and suggest a correct management of this benign lesion during postcancer follow-up. © 2011 Springer-Verlag.

Introduzione. Il profilo di sicurezza dei glitazoni, rosiglitazone e pioglitazone, è attualmente sotto indagine da parte delle agenzie regolatorie internazionali, FDA ed EMA. Diversi studi successivi alla loro commercializzazione hanno fatto emergere possibili associazioni tra questi farmaci e reazioni avverse gravi. Nel giugno 2007 Nissen ha pubblicato una metanalisi che evidenziava un aumento di eventi cardiovascolari per il rosiglitazone, rischio confermato da studi successivi. Altri studi clinici suggeriscono possibili associazioni anche con danni oculari e ossei. Il presente studio ha l'obiettivo di delineare il profilo di sicurezza dei glitazoni per ciò che riguarda l'infarto miocardico, l'edema maculare e il rischio di fratture, mediante l'analisi delle segnalazioni spontanee presenti nel database FDA_AERS (Adverse Event Reporting System). Metodi. Sono state raccolte tutte le segnalazioni spontanee di reazioni avverse (Adverse Drug Reaction - ADR) da farmaci antidiabetici presenti nel database FDA_AERS da gennaio 2005 a dicembre 2008. I dati sono stati sottoposti a procedure di data cleaning semiautomatiche, per eliminare i duplicati e i record multipli. L'associazione farmaco-reazione è stata analizzata mediante il metodo del caso/non-caso. I casi sono rappresentati dalle segnalazioni in cui i glitazoni sono associati alla specifica reazione, classificata secondo la terminologia MedDRA, mentre i non-casi sono costituiti dalle segnalazioni della stessa reazione associata a farmaci antidiabetici diversi dai glitazoni. L'associazione farmaco-razione è stata analizzata calcolando il Reporting Odds Ratio (ROR) che identifica una disproporzionalità tra il farmaco oggetto dell'analisi e gli altri farmaci antidiabetici. L'analisi è stata eseguita sia per classi di farmaci antidiabetici, sia per singolo principio attivo. Infine, allo scopo di valutare il possibile pubblication bias sull'incidenza di segnalazione l'analisi è stata effettuata anche per singolo trimestre. Risultati. Sono state raccolte 77.669 segnalazioni di ADR da antidiabetici, corrispondenti a 301.950 coppie farmaco-reazione. Queste riguardavano principalmente biguanidi (26%), seguite da sulfaniluree (22%), exenatide (18%) e glitazoni (16%). I glitazoni hanno mostrato una disproporzionalità significativa per l'infarto miocardico (ROR 4,71 IC95% 4,40-5,05), per l'edema maculare (3,88; 2,79-5,39) e per le fratture (1,73; 1,53-1,96). Considerando i due glitazoni separatamente, il solo rosiglitazone è risultato associato all'infarto del miocardio (7,86; 7,34-8,34) e all'edema maculare (5,55; 3,94-7,79), mentre il pioglitazone al rischio di fratture (2,00; 1,70-2,35) in particolare al livello degli arti e del bacino. L'analisi del trend temporale per l'ROR dell'infarto miocardico evidenzia che già nel periodo gennaio-marzo2005 il valore di ROR era statisticamente significativo (3,13; 2,38-4,10), per poi raggiungere un picco nel periodo ottobre-dicembre 2007 (8,71; 6,02-12,90). Conclusioni. Lo studio ha confermato, tramite l'analisi delle segnalazioni spontanee, il rischio di infarto miocardico, di edema maculare e di fratture per il glitazoni rispetto agli altri farmaci antidiabetici. Inoltre, è stata evidenziata un'ampia differenza tra rosiglitazone e pioglitazone, il primo associato a infarto miocardico ed edema maculare, mentre il secondo al rischio di fratture. L'analisi del trend temporale mostra come l'impiego dei dati di segnalazioni spontanee può generare segnali di farmacovigilanza precoci, in quanto l'infarto miocardico presentava un segnale di disproporzionalità ben prima della pubblicazione della metanalisi di Nissen del 2007. I risultati del presente studio contribuiscono a delineare il profilo di rischio dei glitazoni e a sottolineare le differenze esistenti tra i due principi attivi; informazioni fondamentali per consentire alle agenzie regolatorie di rivalutare il rapporto rischio/beneficio di questi farmaci.

Background: Thiazolidinediones (TZDs) are used for the therapy of type II diabetes. Several warning on their cardiovascular (CV) and fracture risks have been raised. Their benefit/risk profile is therefore still uncertain. Objectives: To evaluate the safety profile of TZDs, in particular on the risk of CV events and bone fractures, on the basis of FDA Adverse Event Reporting System (AERS). Methods: Association between drugs and ADRs was analysed by case/non case method. Cases were ADR reports with TZDs as suspected drug and non-cases were all same reactions induced by other drugs. Association between TZDs and ADRs were calculated by the ADR reporting odds ratio (ROR). Safety data for TZDs, and for individual drugs, were compared against other anti-diabetic drugs. Results: Evidence of disproportionality were observed for CV ADRs compared to other anti-diabetics, in particular for cardiac failure congestive (ROR 6.11, CI 95%5.68–6.56 vs 0.66, 0.60–0.73) and myocardial infarction (2.46, 2.33–2.59 vs 0.32, 0.30–0.34). Rosiglitazone showed the highest ROR for cardiac ADRs, whereas pioglitazone only for cardiac failure. Concerning fractures, TZDs showed significant RORs compared to other anti-diabetic drugs, e.g. radius (3.64, 2.15–6.06 vs 0.47, 0.24–0.91), foot (2.16, 1.55–2.99 vs 0.98, 77–1.24), and humerus (2.76, 1.82– 4.15 vs 0.28, 0.15–0.51). Among TZDs, pioglitazone achieved significant RORs for ulna, radius, fibula, humerus, tibia and ankle fractures, whereas rosiglitazone was significantly associated to foot, humerus and radius fractures. Conclusions: The frequency of CV reactions and fractures occurrences were significantly higher for TZDs in comparison to other anti-diabetic drugs. Rosiglitazone showed a significant disproportionality for CV ADRs whereas pioglitazone for multiple site fractures. These differences should be considered when rosiglitazone or pioglitazone are prescribed.

Pediatric early T-cell precursor leukemia with NF1 deletion and high-sensitivity in vitro to tipifarnib

The hepatitis B virus (HBV) genotypes distribution and the core promoter (CP)/precore (PC) variability were evaluated by a line probe assay in 272 patients infected chronically enrolled consecutively in an area of the North-Eastern Italy. Seven out of the eight genotypes were detected. Italian subjects (83% of the sample) were infected mainly by genotype D (73%) and A (26%); genotype F, and genotype H, were detected only in one subject. In foreigners, the genotype distribution reflected the distribution described for the areas of origin, that is, in Asia genotypes B, C, and D; in Africa genotypes A and E. CP and PC variants prevalence rates were 51% and 60%, respectively, and were significantly higher in Italian patients, probably in relation to their older age. In the analysis restricted to genotypes A and D, PC wild type was linked strongly to genotype A (OR = 4.08, 95% CI = 3.07-5.43, P < 0.0001). In genotype A-infected patients, only e seroconversion was associated significantly with CP variants. In genotype D-infected subjects, CP variants were linked significantly to older age and to a higher e seroconversion rate, while PC variants also showed a strong relationship with an ALT lower activity and a lower viral load. In multivariate analysis, HBeAg positivity was associated strongly and independently with younger age, genotype A and CP wild type. Independent determinants of higher viral loads were recognized by increasing age, in male gender and concomitant presence of HBeAg and the CP wild type virus.