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Contemporary practices for hemodynamically supported high-risk percutaneous coronary intervention have evolved over the last decade. This study sought to compare outcomes of the prospective, multicenter, PROTECT III study to historic patients treated with Impella in the PROTECT II randomized controlled trial.Of 1,134 patients enrolled in PROTECT III from March 2017 to March 2020, 504 were "PROTECT II-like" (met eligibility for PROTECT II randomized controlled trial) and are referred to as PROTECT III for comparative analysis. Major adverse cardiac and cerebrovascular events (MACCE), comprising all-cause mortality, stroke/transient ischemic attack, myocardial infarction, and repeat revascularization, were compared at hospital discharge and 90 days.Compared with PROTECT II (N = 216), PROTECT III patients were less often Caucasian (77.1% vs 83.8%, P = .045), with less prior CABG (13.7% vs 39.4%; P.001) and prior myocardial infarction (40.7% vs 69.3%; P.001). More PROTECT III patients underwent rotational atherectomy (37.1% vs 14.8%, P.001) and duration of support was longer (median 1.6 vs 1.3 hours; p0.001), with greater improvement achieved in myocardial ischemia jeopardy scores (7.0±2.4 vs 4.4±2.9; P.001) and SYNTAX scores (21.4±10.8 vs 15.7±9.5; P.001). In-hospital bleeding requiring transfusion was significantly lower in PROTECT III (1.8% vs 9.3%; P.001), as was procedural hypotension (2.2% vs 10.1%; P.001) and cardiopulmonary resuscitation or ventricular arrhythmia (1.6% vs 6.9%; P.001). At 90 days, MACCE was 15.1% and 21.9% in PROTECT III and PROTECT II, respectively (p=0.037). Following propensity score matching, Kaplan-Meier analysis showed improved 90-day MACCE rates in PROTECT III (10.4% vs 16.9%, P = .048).The PROTECT III study demonstrates improved completeness of revascularization, less bleeding, and improved 90-day clinical outcomes compared to PROTECT II for Impella-supported high-risk percutaneous coronary intervention among patients with severely depressed LVEF.

The primary study objective is to compare the outcomes of patients taking oral anticoagulant medications in two distinct populations treated according to different management models (comprehensive vs. usual care). (Design: regional prospective cohort study; setting: hospital admission data from two regions). Eligible partecipants were patients taking oral anticoagulant drugs (vitamin K antagonist or direct oral anticoagulants), residents in the Vicenza and Cremona districts from February 1st, 2016 to June 30th, 2017. Patients were identified by accessing the administrative databases of patient drug prescriptions. The primary study outcome was admission to the Emergency Department for stroke, systemic arterial embolism, recurrence of venous thromboembolism or major bleeding. The study evaluated outcomes in 14,226 patients taking oral anticoagulants, of whom 6725 being followed in Cremona with a comprehensive management model. There were 19 and 45 thromboembolic events over 6205 and 6530 patient-years in the Cremona and Vicenza cohort, respectively (IRR 0.44, 95% CI 0.24-0.77). The reduction of events in the Cremona cohort was almost entirely explained by a decrease of events in patients taking VKA (IRR 0.41, 95% CI 0.20-0.78) but not DOACs (IRR 1.08, 95% CI 0.25-5.24). The rate of major bleeding was non-significantly higher in Cremona than in Vicenza (IRI 1.32; 95% CI 0.74-2.40). Across the two cohorts, the risk of bleeding was lower in patients being treated with DOACs rather than warfarin (10/4574 vs. 42/8161 event/person-years, respectively, IRR 0.42 95% CI 0.19-0.86). We conclude that a comprehensive management model providing centralized dose prescription and follow-up may significantly reduce the rate of thromboembolic complications, without substantially increasing the number of bleeding complications. Patients treated with direct oral anticoagulants appear to have a rate of thromboembolic complications comparable to VKA patients under the best management model, with a reduction of major bleeding.

The cell division cycle 25 (Cdc25) protein family plays a crucial role in controlling cell proliferation, making it an excellent target for cancer therapy. In this work, a set of small molecules were identified as Cdc25 modulators by applying a mixed ligand-structure-based approach and taking advantage of the correlation between the chemosensitivity of selected structures and the protein expression pattern of the proposed target. In the first step of the in silico protocol, a set of molecules acting as Cdc25 inhibitors were identified through a new ligand-based protocol and the evaluation of a large database of molecular structures. Subsequently, induced-fit docking (IFD) studies allowed us to further reduce the number of compounds biologically screened. In vitro antiproliferative and enzymatic inhibition assays on the selected compounds led to the identification of new structurally heterogeneous inhibitors of Cdc25 proteins. Among them, J3955, the most active inhibitor, showed concentration-dependent antiproliferative activity against HepG2 cells, with GI50 in the low micromolar range. When J3955 was tested in cell-cycle perturbation experiments, it caused mitotic failure by G2/M-phase cell-cycle arrest. Finally, Western blotting analysis showed an increment of phosphorylated Cdk1 levels in cells exposed to J3955, indicating its specific influence in cellular pathways involving Cdc25 proteins.

Motivation New in silico tools to predict biological affinities for input structures are presented. The tools are implemented in the DRUDIT (DRUgs DIscovery Tools) web service. The DRUDIT biological finder module is based on molecular descriptors that are calculated by the MOLDESTO (MOLecular DEScriptors TOol) software module developed by the same authors, which is able to calculate more than one thousand molecular descriptors. At this stage, DRUDIT includes 250 biological targets, but new external targets can be added. This feature extends the application scope of DRUDIT to several fields. Moreover, two more functions are implemented: the multi- and on/off-target tasks. These tools applied to input structures allow for predicting the polypharmacology and evaluating the collateral effects. Results The applications described in the article show that DRUDIT is able to predict a single biological target, to identify similarities among biological targets, and to discriminate different target isoforms. The main advantages of DRUDIT for the scientific community lie in its ease of use by worldwide scientists and the possibility to be used also without specific, and often expensive, hardware and software. In fact, it is fully accessible through the WWW from any device to perform calculations. Just a click or a tap can start tasks to predict biological properties for new compounds or repurpose drugs, lead compounds, or unsuccessful compounds. To date, DRUDIT is supported by four servers each able to execute 8 jobs simultaneously. Availability and implementation The web service is accessible at the www.drudit.com URL and its use is free of charge. Supplementary information Supplementary data are available at Bioinformatics online.

The aim of this study was to compare clinical and radiographical results for treatment of lower limb multiaxial deformities +/- limb length discrepancy (LLD) of at least 2 cm with the Truelok hexapod fixator system (TL-HEX). All consecutive cases of lower limb multiaxial deformities were included. Patients were divided in two groups: group 1, lower limb angular deformity+LLD less than 2 cm, and group 2, lower limb angular deformity+LLD of at least 2 cm. Only patients with age younger than or equal to 20 years and follow-up of 6 months after removal of the external fixator were included. A total of 27 (six femur and 39 tibia treated) and 20 patients (12 femur and 19 tibia) were enrolled in groups 1 and 2, respectively. Complete correction of the deformity was achieved in 90 and 96% of the patients in groups 1 and 2, respectively. There were no differences in terms of external fixator, maturation, and distraction indexes between the two groups and between different anatomical sites. Good to excellent functional results (ASAMI score) were obtained in 93% of patients in group 1 and 75% in group 2 (P=0.01). Complication rate was similar between the two groups (7.4 vs. 10%, respectively). Average follow-up after removal of the external fixator was 25.6 (range: 7.0-54.0) months. The TL-HEX external fixator system allows a predictable correction of complex lower limb deformities regardless of the presence of LLD. Although complication rate is similar between the two groups, lower functional outcomes can be expected in patients with significant preoperative LLD.

Electrospun veils from copolyethersulfones (coPES) with a number-average molar mass (Mn) of 9000 g/mol (coPES9k) and 20,000 g/mol (coPES20k) were prepared as soluble interlaminar veils for carbon fiber/epoxy composites. Dry carbon fabrics were covered with electrospun veils and then infused with an unmodified epoxy resin to prepare reinforced laminates. CoPES powder was predissolved in the unmodified epoxy to obtain an epoxy/coPES blend used for preimpregnation of laminates which were compared to the laminates obtained with resin infusion. The thermoplastic content varied from 10wt% to 20wt% for coPES9k and from 5wt% to 10wt% for coPES20k. Unreinforced samples with no carbon fabrics were also studied. The coPES9k veils showed full solubility and homogeneous morphology when added to the epoxy resin. Unreinforced samples, modified by coPES9k veils, showed only minor morphological differences compared to epoxy/coPES blends obtained from coPES9k powder predissolution. The glass transition temperatures for these samples displayed differences less than 10°C. Carbon-reinforced samples obtained using the same route showed larger differences. The coPES20k veils showed undissolved fibers and inhomogeneous morphologies when blended with an epoxy in the unreinforced samples.

Electrospun veils from copolyethersulfones (coPES) were prepared as soluble interlaminar veils for carbon fiber/epoxy composites. Neat, resin samples were impregnated into coPES veils with unmodified resin, while dry carbon fabrics were covered with electrospun veils and then infused with the unmodified epoxy resin to prepare reinforced laminates. The thermoplastic content varied from 10 wt% to 20 wt%. TGAP epoxy monomer showed improved and fast dissolution for all the temperatures tested. The unreinforced samples were cured first at 180 °C for 2 h and then were post-cured at 220 °C for 3 h. These sample showed a high dependence on the curing cycle. Carbon reinforced samples showed significant differences compared to the neat resin samples in terms of both viscoelastic and morphological properties.

Two different epoxy monomers, based on the diglycidylether of bisphenol A (DGEBA) and triglycidyl-p-aminophenol (TGAP), which are di- and tri-functional, respectively, were mixed in varying proportions and cured with bis(2,6-diethylaniline) (MDEA). Toughened epoxy resins were prepared by adding a coPolyethersulfone (coPES) to the resin mixture. The dynamic mechanical and morphological properties of the cured materials were measured. It was found that the blends based on TGAP presented different viscoelastic and morphological behavior compared to DGEBA-based formulations. Mixing TGAP with DGEBA resulted in increased glass transition temperature and homogeneous phase morphology distribution.

MF59-adjuvanted trivalent influenza vaccine (Novartis Vaccines and Diagnostics, Siena, Italy) has been shown to be more effective than nonadjuvanted vaccine in the elderly population. Here we present results from a large-scale, observational, noninterventional, prospective postlicensure study that evaluated the safety of MF59-adjuvanted vaccine in elderly subjects aged 65 years or more. The study was performed in 5 northern Italian health districts during the 2006–2007, 2007–2008, and 2008–2009 influenza seasons. The choice of vaccine—either adjuvanted vaccine or a nonadjuvanted influenza vaccine—was determined by individual providers on the basis of local influenza vaccination policy. Hospitalizations for potential adverse events of special interest (AESIs) were identified from hospital databases and then reviewed against recognized case definitions to identify confirmed cases of AESI. Cumulative incidences were calculated for AESIs in predefined biologically plausible time windows, as well as in a 6-month window following vaccination. During the 3-year study period, 170,988 vaccine doses were administered to a total of 107,661 persons. Despite the large study size, cases of AESI resulting in hospitalization were rare, and risks of AESI were similar in both the MF59-adjuvanted and nonadjuvanted vaccination groups. In conclusion, similar safety profiles were observed for both nonadjuvanted and MF59-adjuvanted seasonal influenza vaccines in elderly recipients. adjuvants; elderly; influenza; influenza vaccine; MF59; vaccines; vaccine safety

This collaborative study, based on data collected by the network of Italian Cancer Registries (AIRTUM), describes the burden of rare cancers in Italy. Estimated number of new rare cancer cases yearly diagnosed (incidence), proportion of patients alive after diagnosis (survival), and estimated number of people still alive after a new cancer diagnosis (prevalence) are provided for about 200 different cancer entities.Data herein presented were provided by AIRTUM population- based cancer registries (CRs), covering nowadays 52% of the Italian population. This monograph uses the AIRTUM database (January 2015), which includes all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to the International Classification of Diseases for Oncology (ICD-O-3). Data underwent standard quality checks (described in the AIRTUM data management protocol) and were checked against rare-cancer specific quality indicators proposed and published by RARECARE and HAEMACARE (www.rarecarenet.eu; www.haemacare.eu). The definition and list of rare cancers proposed by the RARECAREnet "Information Network on Rare Cancers" project were adopted: rare cancers are entities (defined as a combination of topographical and morphological codes of the ICD-O-3) having an incidence rate of less than 6 per 100,000 per year in the European population. This monograph presents 198 rare cancers grouped in 14 major groups. Crude incidence rates were estimated as the number of all new cancers occurring in 2000-2010 divided by the overall population at risk, for males and females (also for gender-specific tumours).The proportion of rare cancers out of the total cancers (rare and common) by site was also calculated. Incidence rates by sex and age are reported. The expected number of new cases in 2015 in Italy was estimated assuming the incidence in Italy to be the same as in the AIRTUM area. One- and 5-year relative survival estimates of cases aged 0-99 years diagnosed between 2000 and 2008 in the AIRTUM database, and followed up to 31 December 2009, were calculated using complete cohort survival analysis. To estimate the observed prevalence in Italy, incidence and follow-up data from 11 CRs for the period 1992-2006 were used, with a prevalence index date of 1 January 2007. Observed prevalence in the general population was disentangled by time prior to the reference date (≤2 years, 2-5 years, ≤15 years). To calculate the complete prevalence proportion at 1 January 2007 in Italy, the 15-year observed prevalence was corrected by the completeness index, in order to account for those cancer survivors diagnosed before the cancer registry activity started. The completeness index by cancer and age was obtained by means of statistical regression models, using incidence and survival data available in the European RARECAREnet data.In total, 339,403 tumours were included in the incidence analysis. The annual incidence rate (IR) of all 198 rare cancers in the period 2000-2010 was 147 per 100,000 per year, corresponding to about 89,000 new diagnoses in Italy each year, accounting for 25% of all cancer. Five cancers, rare at European level, were not rare in Italy because their IR was higher than 6 per 100,000; these tumours were: diffuse large B-cell lymphoma and squamous cell carcinoma of larynx (whose IRs in Italy were 7 per 100,000), multiple myeloma (IR: 8 per 100,000), hepatocellular carcinoma (IR: 9 per 100,000) and carcinoma of thyroid gland (IR: 14 per 100,000). Among the remaining 193 rare cancers, more than two thirds (No. 139) had an annual IR0.5 per 100,000, accounting for about 7,100 new cancers cases; for 25 cancer types, the IR ranged between 0.5 and 1 per 100,000, accounting for about 10,000 new diagnoses; while for 29 cancer types the IR was between 1 and 6 per 100,000, accounting for about 41,000 new cancer cases. Among all rare cancers diagnosed in Italy, 7% were rare haematological diseases (IR: 41 per 100,000), 18% were solid rare cancers. Among the latter, the rare epithelial tumours of the digestive system were the most common (23%, IR: 26 per 100,000), followed by epithelial tumours of head and neck (17%, IR: 19) and rare cancers of the female genital system (17%, IR: 17), endocrine tumours (13% including thyroid carcinomas and less than 1% with an IR of 0.4 excluding thyroid carcinomas), sarcomas (8%, IR: 9 per 100,000), central nervous system tumours and rare epithelial tumours of the thoracic cavity (5%with an IR equal to 6 and 5 per 100,000, respectively). The remaining (rare male genital tumours, IR: 4 per 100,000; tumours of eye, IR: 0.7 per 100,000; neuroendocrine tumours, IR: 4 per 100,000; embryonal tumours, IR: 0.4 per 100,000; rare skin tumours and malignant melanoma of mucosae, IR: 0.8 per 100,000) each constituted4% of all solid rare cancers. Patients with rare cancers were on average younger than those with common cancers. Essentially, all childhood cancers were rare, while after age 40 years, the common cancers (breast, prostate, colon, rectum, and lung) became increasingly more frequent. For 254,821 rare cancers diagnosed in 2000-2008, 5-year RS was on average 55%, lower than the corresponding figures for patients with common cancers (68%). RS was lower for rare cancers than for common cancers at 1 year and continued to diverge up to 3 years, while the gap remained constant from 3 to 5 years after diagnosis. For rare and common cancers, survival decreased with increasing age. Five-year RS was similar and high for both rare and common cancers up to 54 years; it decreased with age, especially after 54 years, with the elderly (75+ years) having a 37% and 20% lower survival than those aged 55-64 years for rare and common cancers, respectively. We estimated that about 900,000 people were alive in Italy with a previous diagnosis of a rare cancer in 2010 (prevalence). The highest prevalence was observed for rare haematological diseases (278 per 100,000) and rare tumours of the female genital system (265 per 100,000). Very low prevalence (10 prt 100,000) was observed for rare epithelial skin cancers, for rare epithelial tumours of the digestive system and rare epithelial tumours of the thoracic cavity.One in four cancers cases diagnosed in Italy is a rare cancer, in agreement with estimates of 24% calculated in Europe overall. In Italy, the group of all rare cancers combined, include 5 cancer types with an IR6 per 100,000 in Italy, in particular thyroid cancer (IR: 14 per 100,000).The exclusion of thyroid carcinoma from rare cancers reduces the proportion of them in Italy in 2010 to 22%. Differences in incidence across population can be due to the different distribution of risk factors (whether environmental, lifestyle, occupational, or genetic), heterogeneous diagnostic intensity activity, as well as different diagnostic capacity; moreover heterogeneity in accuracy of registration may determine some minor differences in the account of rare cancers. Rare cancers had worse prognosis than common cancers at 1, 3, and 5 years from diagnosis. Differences between rare and common cancers were small 1 year after diagnosis, but survival for rare cancers declined more markedly thereafter, consistent with the idea that treatments for rare cancers are less effective than those for common cancers. However, differences in stage at diagnosis could not be excluded, as 1- and 3-year RS for rare cancers was lower than the corresponding figures for common cancers. Moreover, rare cancers include many cancer entities with a bad prognosis (5-year RS50%): cancer of head and neck, oesophagus, small intestine, ovary, brain, biliary tract, liver, pleura, multiple myeloma, acute myeloid and lymphatic leukaemia; in contrast, most common cancer cases are breast, prostate, and colorectal cancers, which have a good prognosis. The high prevalence observed for rare haematological diseases and rare tumours of the female genital system is due to their high incidence (the majority of haematological diseases are rare and gynaecological cancers added up to fairly high incidence rates) and relatively good prognosis. The low prevalence of rare epithelial tumours of the digestive system was due to the low survival rates of the majority of tumours included in this group (oesophagus, stomach, small intestine, pancreas, and liver), regardless of the high incidence rate of rare epithelial cancers of these sites. This AIRTUM study confirms that rare cancers are a major public health problem in Italy and provides quantitative estimations, for the first time in Italy, to a problem long known to exist. This monograph provides detailed epidemiologic indicators for almost 200 rare cancers, the majority of which (72%) are very rare (IR0.5 per 100,000). These data are of major interest for different stakeholders. Health care planners can find useful information herein to properly plan and think of how to reorganise health care services. Researchers now have numbers to design clinical trials considering alternative study designs and statistical approaches. Population-based cancer registries with good quality data are the best source of information to describe the rare cancer burden in a population.

OBJECTIVE Some obese individuals have normal insulin sensitivity. It is controversial whether this phenotype is associated with increased all-cause mortality risk. RESEARCH DESIGN AND METHODS Fifteen-year all-cause mortality data were obtained through the Regional Health Registry for 2,011 of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes in Italy. Individuals were divided in four categories according to BMI (nonobese: RESULTS Obese insulin-sensitive subjects represented 11% (95% CI 8.1–14.5) of the obese population. This phenotype had similar BMI but lower waist circumference, blood pressure, fasting glucose, triglycerides, and fibrinogen and higher HDL cholesterol than obese insulin-resistant subjects. In the 15-year follow-up, 495 deaths (cardiovascular disease [CVD]: n = 221; cancer: n = 180) occurred. All-cause mortality adjusted for age and sex was higher in the obese insulin-resistant subjects (hazard ratio 1.40 [95% CI 1.08–1.81], P = 0.01) but not in the obese insulin-sensitive subjects (0.99 [0.46–2.11], P = 0.97) when compared with nonobese insulin-sensitive subjects. Also, mortality for CVD and cancer was higher in the obese insulin-resistant subjects but not in the obese insulin-sensitive subjects when compared with nonobese insulin-sensitive subjects. CONCLUSIONS In contrast to obese insulin-resistant subjects, metabolically healthy obese individuals are less common than previously thought and do not show increased all-cause, cancer, and CVD mortality risks in a 15-year follow-up study.

Rationale, aims and objectives Assuring the best standards of care – in a sustainable way – in chronic diseases as breast cancer is nowadays an important challenge for any health system. The aim of this study was to present the methodology used to define a set of quality indicators, computable from administrative data for the pathway of care of breast cancer, and its application at a population level. Method The cohort of 2007–2009 incident cases of breast cancer was identified through a network of six cancer registers in Northern Italy. Cases of sarcoma and lymphoma, patients with multiple primary cancers and those metastatic at diagnosis were excluded; 9614 women were retained for the analysis. For each indicator, the sub-cohort of women eligible for the diagnostic/therapeutic procedures was identified and calculations were performed through record linkage between the cohort and sources of health information. Data on potential available confounders or prognostic factors were also collected. Results For a few indicators, such as cyto-histological assessment before surgery (62%) and intensive follow-up (79%), deviation from recommendations was evident. Younger patients (≤50 years) more frequently needed a short term re-intervention, while older patients less frequently underwent reconstructive surgery and received palliative care. Several indicators had a great variability across hospitals. In some cases, this heterogeneity appeared to be related to the hospital size, with high-volume hospitals being more compliant to guidelines. Conclusion It is possible to evaluate the quality of cancer care delivered in clinical practice in recent years, in order to implement interventions aimed to improve adherence to international standards of care.

to present a set of indicators developed from six Local Health Authorities of the Lombardy Region to monitor the diagnostic and therapeutic pathway of breast cancer patients, applied to 2007-2009 incident cases.retrospective cohort study.all subjects with primary breast cancer, incident in the period 2007-2009, and collected by cancer registries of Milano 1, Bergamo, Cremona, Milano, Milano 2 and Monza-Brianza (5,320,272 inhabitants) were included.through the use of combined current health databases (health registry, hospitalizations, outpatient, pharmaceutical prescription and specific database for anticancer drugs), for each incident case 34 different indicators have been developed to measure the appropriateness of the procedures provided for diagnosis, treatment (surgical and medical) and follow-up. For each indicator, we analyzed the relationship with age, stage, deprivation index, type of treatment, volume of the specific procedure of the hospital where primary surgery was performed. Estimates were adjusted using multilevel regression models.12,988 incident cases, without metastatic diseases and other cancers, were included in the cohort: 62% were localized to the breast, 33% to the axillary lymph-nodes, 3% metastatic ab initio, and 2% with unknown stage. Deviations from the expected value of different magnitude depending on the type of indicator were observed: the most important differences were detected for the follow-up indicators. There was, in fact, an excess of several procedures in the first year of follow-up: 75% of the cases performed a dosage of a tumor marker, 67% an ecography or a CT scan or an MR, and 37% a bone scan. On the other hand, the access to neoadjuvant and adjuvant treatments in older women was far below the expected values.the study presents data derived from a large cohort of population cases; the set of indicators was validated by a board of oncologists. The use of indicators calculated by linking the cancer registries (that provide staging) and administrative databases allows the assessment of compliance to the guidelines for diagnosis and treatment of tumours. This experience shows that it is possible to develop a methodology, shared with clinicians, to define indicators that measure the distance between guidelines and current clinical practice in order to decrease variability, to limit inappropriateness, and to reduce unnecessary diagnostic tests for patients (and, consequently, hospitals organizational overload). In order to be sustainable and equitable, a health care system must be able to ensure implementation of protocols/procedures based exclusively on the best available scientific evidences.

Dislocations of a total knee arthroplasty (TKA) are an uncommon injury and only few cases of anterior dislocations have been reported. We report a rare case of anterior dislocation of a 10-year-old posterior stabilized total knee arthroplasty in a 74-year-old woman. The patient was successfully treated by close reduction of the dislocation followed by immobilization in full extension with a long leg cast. Because of a high risk of neurovascular complications, a high index of suspicion for vascular injury must be maintained. For this reason, a proper diagnosis is required and immediate reduction is recommended.

Diabetes type 2, caused mainly by insulin resistance, is growing in incidence worldwide. In addition to being a major public health concern, type 2 diabetes is also a risk factor for dementia, including Alzheimer’s disease type dementia. Coffee consumption is reported to have protective effects in both diabetes and Alzheimer’s disease. We review here the reported beneficial effects of coffee in both disease conditions and the previously identified active ingredients of coffee. Furthermore, we revisit our recent findings of improved glucose utilization in the periphery and in the brain in a mouse model of high-fat diet induced type 2 diabetes after treatment with a decaffeinated green coffee preparation. Overall, consumption of coffee appears to improve diabetes and reduce the risk of dementia, although future studies are required to further identify the active components and the type of coffee that is most effective in addressing these conditions.

The present paper is focused on the development of a novel technique to obtain multifunctional fiber reinforced composites. The technique is based on the use of thermoplastic veils composed of nano and micro thermoplastic fibers which preferentially dissolve upon curing in the epoxy matrix. The technique allows to control the phase morphology in the inter- and intra-laminar region of the laminates. Moreover, the selective dissolution of the fibers allow to achieve tailored dispersion of different types of nanofillers in the composites to obtain a functional graded material.

We performed this study with the aims of describing the trend of asthma-related mortality in Italy between 1980 and 1994, and to evaluate the relationship between sale estimates of beta2-agonists drugs and mortality from asthma. For asthma mortality we used data provided by National Institute of Statistics, for sale estimates of beta2-agonists we used data provided by IMS HEALTH. We calculated the gender specific age-standardized incidence rates of asthma-related deaths for all ages and for age classes. We found that estimates for asthma-related mortality steadily increased between 1980 and 1987 in both sexes, and thereafter decreased. In people, aged between 34 and 64 and over 64, death rates in males were significantly higher than in females while the rates in those aged less than 34, were mostly similar in both gender. The overall exposure to beta2-agonists (alone and in combination) increased from 1980 to 1990, remained stable between 1990 and 1993, and increased steeply in 1994. We conclude that asthma-related death rates have declined since the mid-1980's. This decline has been more pronounced in males and in the older ages, while the rates in younger patients of both genders have remained nearly unchanged. Our data do not substantiate the hypothesis of an increased risk of asthma-related mortality associated to the use of inhaled beta2-agonists in general nor fenoterol or salbutamol in particular.

We have conducted a cohort study of users of omeprazole and H2 antagonists in Italy to investigate whether the peroral use of these drugs may be associated with an increased incidence of ocular disorders leading to loss of vision. We have used the Sistema Informativo Sanitario Regionale (SISR database) in Friuli-Venezia-Giulia to identify all subjects who received at least one prescription for cimetidine, famotidine, niperotidine, nizatidine, omeprazole, ranitidine or roxatidine between 1 January 1991 and 31 December 1994. We have identified all hospital admissions for serious vascular or inflammatory ocular disorders following any such prescription, reviewed and validated all medical records. There were 71,108 users of any of the study drugs, contributing a total of 101,827 person years of observation. Seven cases of serious eye disorders were identified, giving an annual incidence rate of 7/100,000 persons. By comparison to non-users, the incidence rate ratio for current users of all of the study drugs together was 0, with a 95% confidence interval of 0 to 2·1. By comparison to non-users, the incidence rate ratio for past users was 0·47 (95% CI: 0·06–2·4). Our data are consistent with previous studies and add weight to the general impression of the ocular safety of these drugs. © 1998 John Wiley & Sons, Ltd.

Informatics information organizing techniques have been applied to the causality assessment of adverse drug reactions since the 1970s. There has not appeared an easily applied and accurate method. The problem has to do with low quality and poorly organized input information or the attempted application of methods that are too rigid for some problems and inapplicable for others. Potentially the best current method, based on Bayesian probability, is difficult to use because of low quality or quantity of information. This handicap requires extrapolations which tend to result in a form of numerical global introspection. We suggest that the problem might be approached by using a generalized decision support algorithm which can be used with many different decision methods and proper informatics support for the immediate environment of the assessor in drug safety. The decision support algorithm we apply is based on an analytical hierarchical process algorithm implemented in the software CRITERIUM©. We give as an example the application of the algorithm to a suspected adverse drug reaction, cholestatic jaundice, as a result of treatment by chloropromazine. However, to support any decision-making method, the information and informatics environment around the decision-maker must be planned and developed. A set of requirements that best reflect adverse drug reaction causality assessment needs is discussed.

Washington State reports one of the highest rates of sudden infant death syndrome (SIDS) in the United States; within the state, Native Americans have the highest rate of any racial group. To explore this apparent genetic predisposition, we conducted a population-based retrospective cohort study. Using the state's linked birth and death certificate file for 1984 to 1988, we compared infants whose mothers were coded as "American Indian" with infants whose mothers were coded as "white." Native American infants were more than three times more likely than white infants to die of SIDS (crude relative risk = 3.25; 95% confidence interval = 2.41 to 4.38). However, this elevated risk diminished after adjustment for differences between Native American and white mothers in age, marital status, parity, and smoking status during pregnancy (adjusted relative risk = 1.82; 95% confidence interval = 1.28 to 2.58). The high SIDS rate of Washington's Native Americans appears to be due to the high prevalence of SIDS risk factors among Native American mothers, rather than to a genetic predisposition in the infants. Because many of these maternal factors are related to socioeconomic status, it is likely that programs to improve the overall health of Native Americans might lessen both the impact of SIDS and that of other causes of infant morbidity and death.

Pain afflicts most cancer patients, mainly in the advanced and metastatic phases of the disease. Despite the existence of several guidelines for cancer pain management that are based on the recommendations by the World Health Organization and the availability of effective treatments for 70% to 90% of cases, undertreatment is well documented and can involve up to 40% of patients. Undertreatment is usually attributed to an incorrect use of opioids for reasons often conceptualized in terms of barriers related to healthcare provider, patient, family, institution, and society. In Italy, opioid consumption rates are among the lowest in Europe despite some of recent efforts to improve the analgesic prescription and utilization. In the context of a wide project coordinated by the Mario Negri Institute, a non-for-profit private foundation located in Milan, Italy, 4 activities were launched: (1) a critical appraisal of information available on the Web, with the preparation and publication of a meta-site to facilitate the use of selected resources; (2) an evaluation of prescriptions of analgesic drugs in a cohort of cancer patients using a large administrative database; (3) a nationwide outcome research study to assess the epidemiology, quality, and effectiveness of different analgesic strategies; and (4) a multimodal, community-based intervention based on information, education, and training programs to change the knowledge, opinions, and attitude toward cancer pain treatment. Activities started in 2005. Some results and outputs are already available; others will be ready by the end of 2007.

Background and Objective. Results from a relatively small case-control study recently showed that niflumic acid increases the risk of serious mucocutaneous reactions in children. As a consequence, the Italian Ministry of Health sent a “Dear Doctor” letter in June 2001 to warn pediatricians about the alleged adverse effects. The objective of this study was to estimate and compare the incidence of mild and severe mucocutaneous reactions among children using niflumic acid, other nonsteroidal antiinflammatory drugs (NSAIDs), or nonopioid analgesics. Design. Retrospective cohort study. Setting. Italy is one of the few countries in which a specific primary care system is devoted to children up to 14 years of age: every child is registered at birth and receives free medical care from 1 of the ∼6000 family pediatricians working for the National Health Service. This study was conducted with the Pedianet network of Italian family pediatricians who use computerized electronic patient records for routine care; 185 pediatricians participated in the study. The patient records comprise information on demographics, diagnoses, symptoms, prescriptions, referrals, laboratory examinations, and hospitalizations. Participants. Children aged 0 to 14 years and registered with 1 of the collaborating pediatricians between January 1, 1998, and May 31, 2001. Main Outcome Measures. The incidence rate of severe (hospitalized or referred) and mild mucocutaneous reactions (exanthema, disseminated or localized pruritus, urticaria, angioedema, fixed eruption, dermatitis, erythema multiforme, vesicles, bullae, pustules, toxic epidermal necrolysis, purpura, and vasculitis) was estimated during use of niflumic acid, other NSAIDs, or nonopioid analgesics. For each episode of drug use, the following covariates were assessed: age, gender, region, year, indication for study drug, use of antibiotics, antimycotic agents, glucocorticoids, and other NSAIDs. Multivariate Poisson regression analysis was used to estimate the adjusted relative risk of mucocutaneous disorders during use of niflumic acid compared with use of other NSAIDs or use of acetaminophen alone. Results. The population included 193727 children, 45351 of whom received at least 1 of the study drugs. The most frequently prescribed drugs were niflumic acid, acetaminophen, and propionic acid derivatives (ketoprofen and flurbiprofen). Users of niflumic acid (n = 32150) were younger and slightly more often had otitis media or upper respiratory tract infections as an indication compared with the other NSAIDs. During use of the various study drugs we identified 1451 mild mucocutaneous events and 42 severe reactions. The incidence rates of severe and mild mucocutaneous reactions after the administration of any study drug were 10.3 per 100000 exposure person-days and 3.7 per 1000 exposure person-days, respectively. Both incidence rates decreased strongly with increasing age. In comparison with other NSAIDs, the adjusted relative risks of niflumic acid were 0.5 (95% confidence interval: 0.23–1.27) for severe and 0.9 (95% confidence interval: 0.79–1.11) for mild mucocutaneous reactions. The use of acetaminophen as a reference category instead of other NSAIDs, restriction of the children to those who received NSAIDs for respiratory tract infections, or restriction to those who did not use antibiotics never revealed an increased risk of serious or mild mucocutaneous reactions during use of niflumic acid. Conclusions. In comparison with other NSAIDs or acetaminophen, niflumic acid is not associated with an increased risk of severe or mild mucocutaneous reactions in children. This was true for the different age groups and various types of mucocutaneous reactions, was independent of the concomitant use of antibiotics, and was not sensitive to changes in our assumptions regarding exposure and outcomes.

BACKGROUND: Interest in the incidence of varicella (chickenpox) has increased since the discovery of an effective vaccine, but calculations to date have incorrectedly ignored the question of susceptibility. METHODS: We studied the occurrence of varicella in Italy on the basis of 33,343 children (age 0-14 years) cared for by 35 pediatricians between 1 October 1997 and 30 September 1998. The life-table technique was used to calculate the number of susceptible children. On this basis, we estimated the corrected age-specific and cumulative incidence. RESULTS: We identified 1749 cases among the estimated 21,783 susceptible children, for a crude incidence of 8.0% (95% confidence interval [CI] = 7.7-8.4). The rate age-standardized to the Italian population 0-14 years old was 6.8 (CI = 6.5-7.2). The incidence was more than 16% among children age 3-4 years and more than 4% for those age 1-10 years. Comparison of the usual method and our corrected method showed that the uncorrected method underestimates the crude annual incidence (5.2% 8.0%), shifts the peak incidence to earlier ages, and underestimates cumulative incidence (at age 14, 49% 67%). CONCLUSIONS: The use of our corrected method provides more valid estimates of the incidence of varicella than the ones that are currently available. Corrected estimates should be preferred to uncorrected ones in models to study the cost-effectiveness of universal vaccination against varicella.

Objective To estimate the iatrogenic costs of nonsteroidal antiinflammatory drug (NSAID) treatment from the perspective of the Italian National Health Service. Methods We conducted a retrospective cohort study using the primary and secondary care claims data registered in the regional health service database in the Friuli-Venezia Giulia (Italy). The study cohort comprised all persons(265,114) who received at least one prescription for any NSAID between August 1996 and July 1998. The outcomes of interest were the costs of medical interventions for upper gastrointestinal disorders following NSAID treatment (i.e., prescriptions for gastroprotective drugs, hospitalizations, and outpatient diagnostic procedures). Results The study population received a total of 660,311 NSAID prescriptions for a cost of 6,587,533 Euros (€) (€0.53 per treatment day). The cost of medical interventions for gastrointestinal events added 58% to the cost of NSAID therapy (€0.31 per NSAID treatment day, up to 64% directly attributable to NSAID use). The iatrogenic costs were generated by 12.4% of the patients, 77% of whom had a positive history of gastrointestinal disorders and 82% of whom were older than 50 years. Co-prescriptions for gastroprotective drugs accounted for 78.6% of the overall iatrogenic costs. The iatrogenic costs did not differ between cyclooxygenase (COX) nonselective and COX-2 preferential drugs within strata of age and prior history of gastrointestinal disorders, but were significantly higher for the parenteral NSAIDs than the oral or rectal formulations. Conclusions In Italy, the iatrogenic costs of NSAID therapy add 58% to the cost of NSAID treatment; most of the cost is generated by co-prescriptions of gastroprotective drugs to elderly NSAID users or patients with a history of gastrointestinal disorders.

ARTICLE In Reply .— We recently published our population-based cohort study on the incidence of mucocutaneous reactions in children treated with niflumic acid, other nonsteroidal antiinflammatory drugs (NSAIDs), or nonopioid analgesics.1 This study followed an ad hoc, hospital-based, case-control study by Menniti-Ippolito et al,2 which raised a safety issue for pediatric use of niflumic acid. The 2 studies have contrasting findings, as occurs frequently in pharmacoepidemiology. Whereas Menniti-Ippolito et al found a 4.9-fold increased risk of mucocutaneous disorders with niflumic-acid use, we found no association. In light of these contrasting findings, we speculated in our discussion about potential reasons for the discrepancies. The Naples study was initiated to study various adverse drug reactions in children, and all children who presented to the emergency unit with conditions that are often drug-related (ie, gastroduodenal ulcers, neurologic disorders, noninfectious mucocutaneous disorders, and thrombocytopenia) were included in the study.1 The association between use of niflumic acid and mucocutaneous disorders was assessed with reference to …

1. Recently, some cases have been reported where intravenous use of omeprazole was followed by loss of vision. We followed up a cohort of close to 140,000 persons during periods of treatment and non-treatment with five anti-ulcer drugs. 2. The relative risk of vascular disorders of the eye during use of omeprazole compared with non-use was 1.8 (95% CI 0.5-6.0). Use of other anti-ulcer drugs was associated with a similar risk of vascular disorders. The relative risk associated with current use of any anti-ulcer drug was 1.9 (95% CI 1.1-3.4). We did not find a single case of optic inflammatory disorder during treatment with any of the five anti-ulcer drugs. 3. These results do not suggest a major increased risk for vascular or inflammatory disorders of the eye associated with use of omeprazole or other anti-ulcer drugs.

Although vaccination against influenza is recommended for elderly and high-risk patients in many countries, efficacy in the elderly has been suboptimal. The MF59 adjuvanted trivalent inactivated vaccine (ATIV) was developed to increase the immune response of elderly subjects to influenza vaccination, but its effectiveness has not yet been well documented. This prospective, observational study evaluated the relative effectiveness of ATIV versus nonadjuvanted trivalent inactivated vaccine (TIV) in individuals at least 65 years of age in Lombardy, northern Italy. Hospitalizations for influenza or pneumonia (International Classification of Diseases, Ninth Revision, Clinical Modification, codes 480-487) during the 2006-2007, 2007-2008, and 2008-2009 influenza seasons were identified from administrative databases. Stratified and regression analyses, including the propensity score to adjust for confounding, as well as generalized estimating equations to account for repeated vaccination, were used. Overall, 107,661 records were evaluated, contributing 170,988 person-seasons of observation. Since ATIV is preferentially recommended for more frail individuals, subjects vaccinated with ATIV were older and had more functional impairment and comorbidities. In the primary analysis, risk of hospitalization for influenza or pneumonia was 25% lower for ATIV relative to TIV (relative risk = 0.75, 95% confidence interval: 0.57, 0.98). To the extent that there is residual bias, ATIV is likely to be even more protective than this result suggests.