Beyond "Cirrhosis" A Proposal From the International Liver Pathology Study Group

Cirrhosis is a moiphologic term that has been used for almost 200 years to denote the end stage of a variety of chronic liver diseases. The term implies a condition with adverse prognosis due to the well-known complications of portal hypertension, hepatocellular carcinoma, and liver failure. However, recent advances in the diagnosis and treatment of chronic liver diseases have changed the natural history of cirrhosis significantly. This consensus document by the International Liver Pathology Study Group challenges the usefulness of the word cirrhosis in modern medicine and suggests that this is an appropriate time to consider discontinuing the use of this term. The role of pathologists should evolve to the diagnosis of advanced stage of chronic liver disease, with emphasis on etiology, grade of activity, features suggestive of progression or regression, presence of other diseases, and risk factors for malignancy, within the perspective of an integrated clinicopathologic assessment.

RHYTHM-AF: design of an international registry on cardioversion of atrial fibrillation and characteristics of participating centers

Background: Atrial fibrillation is a serious public health problem posing a considerable burden to not only patients, but the healthcare environment due to high rates of morbidity, mortality, and medical resource utilization. There are limited data on the variation in treatment practice patterns across different countries, healthcare settings and the associated health outcomes. Methods/design: RHYTHM-AF was a prospective observational multinational study of management of recent onset atrial fibrillation patients considered for cardioversion designed to collect data on international treatment patterns and short term outcomes related to cardioversion. We present data collected in 10 countries between May 2010 and June 2011. Enrollment was ongoing in Italy and Brazil at the time of data analysis. Data were collected at the time of atrial fibrillation episode in all countries (Australia, Brazil, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom), and cumulative follow-up data were collected at day 60 (+/- 10) in all but Spain. Information on center characteristics, enrollment data, patient demographics, detail of atrial fibrillation episode, medical history, diagnostic procedures, acute treatment of atrial fibrillation, discharge information and the follow-up data on major events and rehospitalizations up to day 60 were collected. Discussion: A total of 3940 patients were enrolled from 175 acute care centers. 70.5% of the centers were either academic (44%) or teaching (26%) hospitals with an overall median capacity of 510 beds. The sites were mostly specialized with anticoagulation clinics (65.9%), heart failure (75.1%) and hypertension clinics (60.1%) available. The RHYTHM-AF registry will provide insight into regional variability of antiarrhythmic and antithrombotic treatment of atrial fibrillation, the appropriateness of such treatments with respect to outcomes, and their cost-efficacy. Observations will help inform strategies to improve cardiovascular outcomes in patients with atrial fibrillation.

Why Are Women With Cervical Cancer Not Being Diagnosed in Preinvasive Phase? An Analysis of Risk Factors Using a Hierarchical Model

Objective: To assess the risk factors for delayed diagnosis of uterine cervical lesions. Materials and Methods: This is a case-control study that recruited 178 women at 2 Brazilian hospitals. The cases (n = 74) were composed of women with a late diagnosis of a lesion in the uterine cervix (invasive carcinoma in any stage). The controls (n = 104) were composed of women with cervical lesions diagnosed early on (low-or high-grade intraepithelial lesions). The analysis was performed by means of logistic regression model using a hierarchical model. The socioeconomic and demographic variables were included at level I (distal). Level II (intermediate) included the personal and family antecedents and knowledge about the Papanicolaou test and human papillomavirus. Level III (proximal) encompassed the variables relating to individuals' care for their own health, gynecologic symptoms, and variables relating to access to the health care system. Results: The risk factors for late diagnosis of uterine cervical lesions were age older than 40 years (odds ratio [OR] = 10.4; 95% confidence interval [CI], 2.3-48.4), not knowing the difference between the Papanicolaou test and gynecological pelvic examinations (OR, = 2.5; 95% CI, 1.3-4.9), not thinking that the Papanicolaou test was important (odds ratio [OR], 4.2; 95% CI, 1.3-13.4), and abnormal vaginal bleeding (OR, 15.0; 95% CI, 6.5-35.0). Previous treatment for sexually transmissible disease was a protective factor (OR, 0.3; 95% CI, 0.1-0.8) for delayed diagnosis. Conclusions: Deficiencies in cervical cancer prevention programs in developing countries are not simply a matter of better provision and coverage of Papanicolaou tests. The misconception about the Papanicolaou test is a serious educational problem, as demonstrated by the present study.

Cardiometabolic risk reduction through lifestyle intervention programs in the Brazilian public health system

Public health strategies to reduce cardiovascular morbidity and mortality should focus on global cardiometabolic risk reduction. The efficacy of lifestyle changes to prevent type 2 diabetes have been demonstrated, but low-cost interventions to reduce cardiometabolic risk in Latin-America have been rarely reported. Our group developed 2 programs to promote health of high-risk individuals attending a primary care center in Brazil. This study compared the effects of two 9-month lifestyle interventions, one based on medical consultations (traditional) and another with 13 multi-professional group sessions in addition to the medical consultations (intensive) on cardiometabolic parameters. Adults were eligible if they had pre-diabetes (according to the American Diabetes Association) and/or metabolic syndrome (International Diabetes Federation criteria for Latin-America). Data were expressed as means and standard deviations or percentages and compared between groups or testing visits. A p-value < 0.05 was considered significant. Results: 180 individuals agreed to participate (35.0% men, mean age 54.7 ± 12.3 years, 86.1% overweight or obese). 83 were allocated to the traditional and 97 to the intensive program. Both interventions reduced body mass index, waist circumference and tumor necrosis factor-α. Only intensive program reduced 2-hour plasma glucose and blood pressure and increased adiponectin values, but HDL-cholesterol increased only in the traditional. Also, responses to programs were better in intensive compared to traditional program in terms of blood pressure and adiponectin improvements. No new case of diabetes in intensive but 3 cases and one myocardial infarction in traditional program were detected. Both programs induced metabolic improvement in the short-term, but if better results in the intensive are due to higher awareness about risk and self-motivation deserves further investigation. In conclusion, these low-cost interventions are able to minimize cardiometabolic risk factors involved in the progression to type 2 diabetes and/or cardiovascular disease.

Management of diabetes mellitus and associated cardiovascular risk factors in Brazil – the Brazilian study on the practice of diabetes care

Abstract Background The Brazilian Study on the Practice of Diabetes Care main objective was to provide an epidemiological profile of individuals with type 1 and 2 diabetes mellitus (DM) in Brazil, concerning therapy and adherence to international guidelines in the medical practice. Methods This observational, cross-sectional, multicenter study collected and analyzed data from individuals with type 1 and 2 DM attending public or private clinics in Brazil. Each investigator included the first 10 patients with type 2 DM who visited his/her office, and the first 5 patients with type 1 DM. Results A total of 1,358 patients were analyzed; 375 (27.6%) had type 1 and 983 (72.4%) had type 2 DM. Most individuals were women, Caucasian, and private health care users. High prevalence rates of hypertension, dyslipidemia and central obesity were observed, particularly in type 2 DM. Only 7.3% and 5.1% of the individuals with types 1 and 2 DM, respectively, had optimal control of blood pressure, plasma glucose and lipids. The absence of hypertension and female sex were associated with better control of type 1 DM and other cardiovascular risk factors. In type 2 DM, older age was also associated with better control. Conclusions Female sex, older age, and absence of hypertension were associated with better metabolic control. An optimal control of plasma glucose and other cardiovascular risk factors are obtained only in a minority of individuals with diabetes. Local numbers, compared to those from other countries are worse.

Genetica molecolare dell'autismo: studi di associazione ed analisi di geni candidati

Autism is a neurodevelpmental disorder characterized by impaired verbal communication, limited reciprocal social interaction, restricted interests and repetitive behaviours. Twin and family studies indicate a large genetic contribution to ASDs (Autism Spectrum Disorders). During my Ph.D. I have been involved in several projects in which I used different genetic approaches in order to identify susceptibility genes in autism on chromosomes 2, 7 and X: 1)High-density SNP association and CNV analysis of two Autism Susceptibility Loci. The International Molecular Genetic Study of Autism Consortium (IMGSAC) previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we evaluated the patterns of linkage disequilibrium (LD) and the distribution of haplotype blocks, utilising data from the HapMap project, across the two strongest peaks of linkage on chromosome 2 and 7. More than 3000 SNPs have been selected in each locus in all known genes, as well as SNPs in non-genic highly conserved sequences. All markers have been genotyped to perform a high-density association analysis and to explore copy number variation within these regions. The study sample consisted of 127 and 126 multiplex families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Association and CNV analysis implicated several new genes, including IMMP2L and DOCK4 on chromosome 7 and ZNF533 and NOSTRIN on the chromosome 2. Particularly, my contribution to this project focused on the characterization of the best candidate gene in each locus: On the AUTS5 locus I carried out a transcript study of ZNF533 in different human tissues to verify which isoforms and start exons were expressed. High transcript variability and a new exon, never described before, has been identified in this analysis. Furthermore, I selected 31 probands for the risk haplotype and performed a mutation screen of all known exons in order to identify novel coding variants associated to autism. On the AUTS1 locus a duplication was detected in one multiplex family that was transmitted from father to an affected son. This duplication interrupts two genes: IMMP2L and DOCK4 and warranted further analysis. Thus, I performed a screening of the cohort of IMGSAC collection (285 multiplex families), using a QMPSF assay (Quantitative Multiplex PCR of Short fluorescent Fragments) to analyse if CNVs in this genic region segregate with autism phenotype and compare their frequency with a sample of 475 UK controls. Evidence for a role of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family. 2)Analysis of X chromosome inactivation. Skewed X chromosome inactivation (XCI) is observed in females carrying gene mutations involved in several X-linked syndromes. We aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 164 affected girls. The study sample included families from different european consortia. I analysed the XCI inactivation pattern in a sample of italian mothers from singletons families with ASD and also a control groups (144 adult females and 40 young females). We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (≥80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z score of 1.75 close to rs719489. In this region FMR1 and MECP2 have been associated in some cases with austim and therefore represent candidates for the disorder. I performed a mutation screen of MECP2 in 33 unrelated probands from IMGSAC and italian families, showing XCI skewness. Recently, Xq28 duplications including MECP2, have been identified in families with MR, with asymptomatic carrier females showing extreme (>85%) skewing of XCI. For these reason I used the sample of probands from X-skewed families to perform CNV analysis by Real-time quantitative PCR. No duplications have been found in our sample. I have also confirmed all data using as alternative method the MLPA assay (Multiplex Ligation dependent Probe Amplification). 3)ASMT as functional candidate gene for autism. Recently, a possible involvement of the acetylserotonin O-methyltransferase (ASMT) gene in susceptibility to ASDs has been reported: mutation screening of the ASMT gene in 250 individuals from the PARIS collection revealed several rare variants with a likely functional role; Moreover, significant association was reported for two SNPs (rs4446909 and rs5989681) located in one of the two alternative promoters of the gene. To further investigate these findings, I carried out a replication study using a sample of 263 affected individuals from the IMGSAC collection and 390 control individuals. Several rare mutations were identified, including the splice site mutation IVS5+2T>C and the L326F substitution previously reported by Melke et al (2007), but the same rare variants have been found also in control individuals in our study. Interestingly, a new R319X stop mutation was found in a single autism proband of Italian origin and is absent from the entire control sample. Furthermore, no replication has been found in our case-control study typing the SNPs on the ASMT promoter B.

International cooperation in endourology: percutaneous and flexible ureteroscopic treatment of lower pole kidney stones

Introduction Lower pole kidney stones represent at time a challenge for the urologist. The gold standard treatment for intrarenal stones <2 cm is Extracorporeal Shock Wave Lithotripsy (ESWL) while for those >2 cm is Percutaneous Nephrolithotomy (PCNL). The success rate of ESWL, however, decreases when it is employed for lower pole stones, and this is particularly true in the presence of narrow calices or acute infundibular angles. Studies have proved that ureteroscopy (URS) is an efficacious alternative to ESWL for lower pole stones <2 cm, but this is not reflected by either the European or the American guidelines. The aim of this study is to present the results of a large series of flexible ureteroscopies and PCNLs for lower pole kidney stones from high-volume centers, in order to provide more evidences on the potential indications of the flexible ureteroscopy for the treatment of kidney stones. Materials and Methods A database was created and the participating centres retrospectively entered their data relating to the percutaneous and flexible ureteroscopic management of lower pole kidney stones. Patients included were treated between January 2005 and January 2010. Variables analyzed included case load number, preoperative and postoperative imaging, stone burden, anaesthesia (general vs. spinal), type of lithotripter, access location and size, access dilation type, ureteral access sheath use, visual clarity, operative time, stone-free rate, complication rate, hospital stay, analgesic requirement and follow-up time. Stone-free rate was defined as absence of residual fragments or presence of a single fragment <2 mm in size at follow-up imaging. Primary end-point was to test the efficacy and safety of flexible URS for the treatment of lower pole stones; the same descriptive analysis was conducted for the PCNL approach, as considered the gold standard for the treatment of lower pole kidney stones. In this setting, no statistical analysis was conducted owing to the different selection criteria of the patients. Secondary end-point consisted in matching the results of stone-free rates, operative time and complications rate of flexible URS and PCNL in the subgroup of patients harbouring lower pole kidney stones between 1 and 2 cm in the higher diameter. Results A total 246 patients met the criteria for inclusion. There were 117 PCNLs (group 1) and 129 flexible URS (group 2). Ninety-six percent of cases were diagnosed by CT KUB scan. Mean stone burden was 175±160 and 50±62 mm2 for groups 1 and 2, respectively. General anaesthesia was induced in 100 % and 80% of groups 1 and 2, respectively. Pneumo-ultrasonic energy was used in 84% of cases in the PCNL group, and holmium laser in 95% of the cases in the flexible URS group. The mean operative time was 76.9±44 and 63±37 minutes for groups 1 and 2 respectively. There were 12 major complications (11%) in group 1 (mainly Grade II complications according to Clavidien classification) and no major complications in group 2. Mean hospital stay was 5.7 and 2.6 days for groups 1 and 2, respectively. Ninety-five percent of group 1 and 52% of group 2 required analgesia for a period longer than 24 hours. Intraoperative stone-free rate after a single treatment was 88.9% for group 1 and 79.1% for group 2. Overall, 6% of group 1 and 14.7% of group 2 required a second look procedure. At 3 months, stone-free rates were 90.6% and 92.2% for groups 1 and 2, respectively, as documented by follow-up CT KUB (22%) or combination of intra-venous pyelogram, regular KUB and/or kidney ultrasound (78%). In the subanalysis conducted comparing 82 vs 65 patients who underwent PCNL and flexible URS for lower pole stones between 1 and 2 cm, intreoperative stone-free rates were 88% vs 68% (p= 0.03), respectively; anyway, after an auxiliary procedure which was necessary in 6% of the cases in group 1 and 23% in group 2 (p=0.03), stone-free rates at 3 months were not statistically significant (91.5% vs 89.2%; p=0.6). Conversely, the patients undergoing PCNL maintained a higher risk of complications during the procedure, with 9 cases observed in this group versus 0 in the group of patients treated with URS (p=0.01) Conclusions These data highlight the value of flexible URS as a very effective and safe option for the treatment of kidney stones; thanks to the latest generation of flexible devices, this new technical approach seems to be a valid alternative in particular for the treatment of lower pole kidney stones less than 2 cm. In high-volume centres and in the hands of skilled surgeons, this technique can approach the stone-free rates achievable through PCNL in lower pole stones between 1 and 2 cm, with a very low risk of complications. Furthermore, the results confirm the high success rate and relatively low morbidity of modern PCNL for lower pole stones, with no difference detectable between the prone and supine position.

International Agricultural Trade under Regulatory Asymmetry: An Economic Analysis of SME Export Behavior

Over the last three decades, international agricultural trade has grown significantly. Technological advances in transportation logistics and storage have created opportunities to ship anything almost anywhere. Bilateral and multilateral trade agreements have also opened new pathways to an increasingly global market place. Yet, international agricultural trade is often constrained by differences in regulatory regimes. The impact of “regulatory asymmetry” is particularly acute for small and medium sized enterprises (SMEs) that lack resources and expertise to successfully operate in markets that have substantially different regulatory structures. As governments seek to encourage the development of SMEs, policy makers often confront the critical question of what ultimately motivates SME export behavior. Specifically, there is considerable interest in understanding how SMEs confront the challenges of regulatory asymmetry. Neoclassical models of the firm generally emphasize expected profit maximization under uncertainty, however these approaches do not adequately explain the entrepreneurial decision under regulatory asymmetry. Behavioral theories of the firm offer a far richer understanding of decision making by taking into account aspirations and adaptive performance in risky environments. This paper develops an analytical framework for decision making of a single agent. Considering risk, uncertainty and opportunity cost, the analysis focuses on the export behavior response of an SME in a situation of regulatory asymmetry. Drawing on the experience of fruit processor in Muzaffarpur, India, who must consider different regulatory environments when shipping fruit treated with sulfur dioxide, the study dissects the firm-level decision using @Risk, a Monte Carlo computational tool.

Risk appetite e risk tolerance: strumenti di supporto agli istituti di credito per l'assunzione di rischi in tempi di crisi

Negli ultimi anni l’attenzione di legislatori e degli Organi di Vigilanza, in base alle riforme regolamentari attivate in risposta alla crisi economica, si sono focalizzate sulle pratiche di risk management delle Banche, sottolineando l’importanza dei sistemi di controllo e gestione dei rischi. Il presente lavoro nasce con l’intento di analizzare e valutare le caratteristiche salienti del processo di assunzione e gestione dei rischi nel sistema economico finanziario attuale. Numerosi e autorevoli esperti, come gli operatori del Financial Stability Board , Institute of International Finance e Senior Supervisory Group, si sono espressi sulle cause della crisi finanziaria ed hanno sollevato dubbi circa la qualità delle azioni intraprese da alcuni manager, sulle loro politiche gestionali e sulla comprensione delle reali condizioni in cui versavano le loro Banche (in termini di esposizione ai rischi, report da aggregazione dati su performance aziendali e qualità dei dati aggregati) , si è ritenuto giusto dal punto di vista teorico approfondire in particolare i temi del Risk Appetite e Risk Tolerance, novità introdotte nelle diverse direttive e normative in risposta alle citate ed ambigue politiche di gestione ed assunzione rischi. I concetti, qui introdotti, di appetito e tolleranza al rischio conducono ad una ampia sfera di riferimento che guarda alla necessità di fissare degli obiettivi di rischio e loro limiti per poter meglio controllare e valutare la stabilità economica/finanziaria e stimare gli effetti di condizioni peggiorative (reali o soltanto teoriche, come gli stress test) sulla solvibilità e profittabilità delle Banche nazionali ed internazionali. Inoltre, ad integrazione di quanto precedentemente esposto sarà illustrata una survey sulla disclosure delle principali Banche europee in relazione alle informazioni sul Risk Appetite e sul Risk Tolerance.

Plasma homocysteine and cardiovascular risk in heart failure with and without cardiorenal syndrome

Plasma homocysteine (Hcy) has been associated with an increased cardiovascular (CV) risk in patients with chronic heart failure (CHF). Thus, we investigated whether Hcy has a prognostic impact on CV events in CHF-patients with and without cardiorenal syndrome (CRS).

Risk factors contributing to symptomatic miniplate removal: a retrospective study of 153 bilateral sagittal split osteotomy patients

Removal of miniplates is a controversial topic in oral and maxillofacial surgery. Originally, miniplates were designed to be removed on completion of bone healing. The introduction of low profile titanium miniplates has led to the routine removal of miniplates becoming comparatively rare in many parts of the world. Few studies have investigated the reasons for non-routine removal of miniplates and the factors that affect osteosynthesis after osteotomy in large numbers of patients. The aim of the present study was to investigate complications related to osteosynthesis after bilateral sagittal split osteotomy (BSSO) in a large number (n=153) of patients. In addition to the rates of removal, emphasis was placed on investigating the reasons and risk factors associated with symptomatic miniplate removal. The rate of plate removal per patient was 18.6%, the corresponding rate per plate being 18.2%. Reasons for plate removal included plate-related complications in 16 patients and subjective discomfort in 13 patients. Half of the plates were removed during the first postoperative year. Smoking was the only significant predictor for plate removal. Patients undergoing orthognathic surgery should be screened with regard to smoking and encouraged and assisted to cease smoking, at least perioperatively.

Randomized trial of a computerized coronary heart disease risk assessment tool in HIV-infected patients receiving combination antiretroviral therapy

Exposure to combination antiretroviral therapy (cART) can lead to important metabolic changes and increased risk of coronary heart disease (CHD). Computerized clinical decision support systems have been advocated to improve the management of patients at risk for CHD but it is unclear whether such systems reduce patients' risk for CHD.

Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609?620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.

Impact of non-steroidal anti-inflammatory drugs (NSAIDs) on cardiovascular outcomes in patients with stable atherothrombosis or multiple risk factors

We aimed to assess whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of cardiovascular (CV) events in stable patients with established atherothrombosis or multiple risk factors.

Period prevalence and risk factors for postoperative short-term wound complications in vulvar cancer: a cross-sectional study

Although clinicians recognize that postoperative wound management in patients with vulvar cancer (VC) is challenging, the prevalence and risk factors for different types of short-term wound complications (WCs) remain unclear. The aims of this study were: (1) to determine the period prevalence of postoperative short-term WCs and (2) to identify risk factors associated with short-term WCs in patients with VC.