The Cost-effectiveness of Genetic Screening for Familial Hypercholesterolemia: a Systematic Review.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder that leads to elevated plasma LDL-cholesterol levels and premature coronary heart disease (CHD). An understanding of the mutations responsible for FH and the effectiveness of statins in lowering the risk of CHD in FH patients has increased interest in genetic screening strategies to improve FH diagnosis. In this study, we aimed to evaluate the cost-effectiveness of such strategies. METHODS: We performed a systematic review of full economic evaluations that assessed the cost-effectiveness of FH genetic screening strategies. We used relevant search terms to investigate Medline, Scopus, Web of Science, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment Database, and the National Health Service Economic Evaluation Database. Data extraction and assessment of the quality of the studies were performed independently by two reviewers. The key features of the included studies are summarized in a narrative synthesis. RESULTS: We included seven economic evaluations that assessed the cost-effectiveness of genetic screening for FH, published mainly in Europe between 2002 and 2015. Most studies had a no-screening strategy as a comparator, focused on relatives of index cases with genetic or clinical diagnosis of FH (cascade screening), considered a lifetime horizon and adopted a health care payer viewpoint. Cascade screening, based on genetic testing of relatives of an index case with confirmed clinical or genetic diagnosis of FH, was shown to be cost-effective in most settings. CONCLUSIONS: Our review confirms the cost-effectiveness of cascade genetic screening for the diagnosis of FH. Further research may be needed to assess the cost-effectiveness of cascade screening following the introduction of newly recommended therapeutic regimes and next-generation sequencing.

The end of measles and congenital rubella: an achievable dream?

BACKGROUND: Despite substantial progress towards measles and rubella control, outbreaks continue to threaten elimination goals worldwide. STUDY DESIGN: This paper aims to document progress towards the global eradication of measles and rubella. In particular, it investigates the major challenges faced by Italy in reaching the elimination goals. METHODS: A review of the most important literature was carried out. Furthermore, a systematic review of the scientific literature on measles and rubella in the Italian setting was performed for the period 2000-2016. RESULTS: In the National Plan 2010-2015, Italy renewed its commitment to eliminate measles and rubella by 2015. However, Italy recently experienced a high measles burden (2,205 cases in 2013, 1,694 in 2014). Between June 2015 and May 2016, 515 cases were reported, accounting for 28% all cases in Europe. Immunization coverage decreased in recent years, with no Region reaching the 95% target. The systematic review included a total of 175 papers, with an upward trend in the number of published articles, which demonstrates an increasing interest in the field of measles and rubella. The review highlights the need to improve the commitment of the Italian Regions to the elimination goals; to promote Supplementary Immunization Activities (SIAs); to improve the communication skills of health care workers; to improve the health literacy of citizens; and to enhance integrated measles and rubella surveillance. CONCLUSION: Elimination of measles and rubella in Italy will require a substantial improvement in both commitment of the 21 Regions and activity of the whole country towards the WHO goals.

Current state of genomic policies in healthcare among EU member states: results of a survey of chief medical officers.

Background: A need for a governance of genomics in healthcare among European Union (EU) countries arose during an international meeting of experts on public health genomics (PHG). We have conducted a survey on existing national genomic policies in healthcare among Chief Medical Officers (CMOs) of the 28 EU member states, plus Norway. Methods: A questionnaire was sent to CMOs after a meeting on the policy implications of PHG held during the Italian presidency of the Council of EU in 2014. The survey was closed in November 2015. Results: CMOs response rate was 65.5% (19/29). Twelve (63.2%) reported that their countries had a policy for genomics in healthcare in place, and 15 (78.9%) reported that public funding existed. Public research facilities for the development of such policies were documented in 13 (68.4%) countries, and 15 (83.3%) had working groups devoted to policy development. National agencies carrying out Health Technology Assessment of genomic-based technologies were present in nine countries (50%). Sixteen (88.9%) countries reported having agencies dealing with ethical issues related to genomic technologies. About 55% of countries disclosed the lack of information campaigns aimed at citizens, and 44.4% reported they had a legal framework for direct-to-consumer genetic tests. Conclusion: Belgium, France, Italy, Spain and UK documented the presence of a policy on genomics in healthcare. While many caveats are necessary because of the methodology, results suggest a need for a co-ordinated effort to foster development and harmonization of dedicated policies across EU to responsibly integrate genomics policies into existing health systems.

The need to improve implementation and use of lifestyle surveillance systems for planning prevention activities: an analysis of the Italian Regions.

OBJECTIVES: To describe the level of use of lifestyle surveillance systems in Italy and to identify predictors of their use by the Italian Regions for planning and monitoring purposes. STUDY DESIGN: Data were extracted from the 19 Regional Prevention Plans (RPPs) and the health promotion and prevention projects included in them developed by the Italian Regions within the National Prevention Plan 2010-2013. METHODS: The 19 RPPs and the 702 projects were appraised using a tool specifically developed for the purpose. Multiple logistic regression was performed to identify predictors of use of surveillance systems in the 359 projects that could use them. RESULTS: The analysis of regional epidemiological contexts does not always rely upon surveillance system data and there were too few projects aimed at the maintenance and the development of these systems. Moreover, fewer than half of projects that could have used surveillance systems for planning and evaluation procedures actually did so, despite the potential value of these data. There was a statistically significant association between Regional Health Care Expenditure (RHCE) and the use of surveillance system data for planning and/or evaluation of the projects (OR 7.81, 95% CI 2.86-21.29). CONCLUSIONS: Use of surveillance systems for regional prevention planning in Italy is not optimal due to late implementation, presence of different data collecting systems and RGDP inequalities. There is a pressing need for full implementation of surveillance systems to allow better definition of the priorities and objectives of public health interventions.

Education and training among Italian postgraduate medical schools in public health: a comparative analysis.

BACKGROUND: The postgraduate medical Schools in Public Health (locally known as School of Hygiene and Preventive Medicine) should ensure adequate scientific and technical knowledge and professional skills in preventive medicine, health promotion and healthcare planning as provided by Ministerial Decree 285/2005. The Italian Committee of Medical Residents in Hygiene, Preventive Medicine and Public Health of the Italian Society of Hygiene, Public Health and Preventive Medicine - S.It.I. (Consulta Nazionale dei medici in formazione specialistica S.It.I.) has always been engaged in monitoring activities on public health teaching, guaranteeing the homogeneity of educational proposals among all national Schools in Public Health. The purpose of this study is to provide a 'snapshot' of public health education and training in Italy and to identify the improvement actions needed for implementing an innovative and homogeneous public health training. METHODS: A cross-sectional study was carried out over a period of three months (March to May 2013). A self-administered questionnaire was e-mailed to local Committee's delegates of all 32 postgraduate medical Schools in Public Health in Italy. The questionnaire was structured in four sections: general information, University education and training, extra-University training, interdisciplinary activities. The majority of local Committee's delegates have agreed to be enrolled in the survey. RESULTS: A total of 28 questionnaires were returned (88% response rate). The number of residents in each Italian School in Public Health ranged from 7 to 31. The distribution of professors in relation to residents is not similar for each University Schools. The ratio professors/residents spanning from 0.2 to 2. About teaching, only 4 University Schools offered all courses requested by Ministerial Decree 285/2005. Most of them offered at least 75% of the requested courses, but there were Schools in which the courses were less than 50%. The vast majority of schools held more than 60% of the qualifying activities considered essential according to the Decree, while 2 Schools were below 50%. All Schools required an internship of 6-12 months in local health authority offices (ASL), mainly concerning the Department of Prevention activities. In all Schools a period of stay in a Hospital Medical Direction was scheduled, while professional activities at Residential care homes were very rarely included in training programmes. Many Schools allowed residents to attend companies with biological hazard or to follow similar activities in dedicated services of ASL. Finally, in the majority of Schools, a training period in various local (Service for Water Control), regional (Departments) or national (Ministry, National Institute of Health) health facilities was contemplated and, in some cases, also in other Universities or Research Institutes. CONCLUSIONS: Although the Ministerial Decree indicates the essential milestones of the public health education, flexibility is seen as an important element in order to optimize resources and contextualize the adequate education of residents. In any case, at least regarding public health courses, the majority of University education and extra-University training activities should be carried out by all Schools. In order to obtain shared knowledge and skills, the Ministerial Decree should be revised taking into account flexibility and changing as intrinsic characteristics of public health profession and learners should be involved in the reform to strengthening the role of public health teaching.

Predictive genetic testing for complex diseases: a public health perspective.

From a public health perspective, systematic, evidence-based technology assessments and economic evaluations are needed to guide the incorporation of genomics into clinical and public health practice. However, scientific evidence on the effectiveness of predictive genetic tests is difficult to obtain. This review first highlights the similarities and differences between traditional screening tests and predictive genetic testing for complex diseases and goes on to describe frameworks for the evaluation of genetic testing that have been developed in recent years providing some evidence that currently genetic tests are not used in an appropriate way. Nevertheless, evidence-based recommendations are already available for some genomic applications that can reduce morbidity and mortality and many more are expected to emerge over the next decade. The time is now ripe for the introduction of a range of genetic tests into healthcare practice, but this will require the development of specific health policies, proper public health evaluations, organizational changes within the healthcare systems, capacity building among the healthcare workforce and the education of the public.

Reconstructing the genealogy of a BRCA1 founder mutation by phylogenetic analysis.

Estimating the age of founder mutations may contribute to improve our knowledge of population genetics and evolutionary history of diseases. Previous haplotype analysis suggested that the BRCA1*1499insA mutation was a founder allele, probably originated in Tuscany (Italy). Here, we collected additional pedigrees carrying this mutation, and applied a phylogenetic method for estimating mutation age. A chromosome segment of about 25 cM, including 37 short tandem repeats (STRs) on both sides of the BRCA1 gene (DeCode map), was typed in 50 subjects (28 mutation carriers) from 14 unrelated families. The time to the most recent common ancestor (MRCA) of the mutation carriers was estimated by the length of the shared haplotype between all possible pairs of individuals. A function relating the length of the shared haplotype to the time to the MRCA was obtained by a computer simulation. This approach gives results comparable with those of other existing mutation-dating methods, but does not depend explicitly on population-specific parameters such as allele frequencies, provides narrower confidence intervals (CI), and allows one to build an extended genealogical tree of all mutation carriers. The 1499insA mutation shared by the investigated subjects was estimated to be present in an individual living about 30 generations ago (95% CL 22-56), or 750 years (95% CL 550-1,400).

Skeletal muscle subsarcolemmal mitochondrial dysfunction in high-fat fed rats exhibiting impaired glucose homeostasis.

OBJECTIVE: To investigate whether changes in body energy balance induced by long-term high-fat feeding in adult rats could be associated with modifications in energetic behaviour and oxidative stress of skeletal muscle subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial populations. DESIGN: Adult rats were fed low-fat or high-fat diet for 7 weeks. MEASUREMENTS: Body energy balance and composition analysis together with plasma insulin and glucose level determination in the whole animal. Oxidative capacity, basal and induced proton leaks as well as aconitase and superoxide dismutase activities in SS and IMF mitochondria from skeletal muscle. RESULTS: High-fat fed rats exhibit increased body lipid content, as well as hyperinsulinemia, hyperglycaemia and higher plasma non-esterified fatty acids. In addition, SS mitochondria display lower respiratory capacity and a different behaviour of SS and IMF mitochondria is found in the prevention from oxidative damage. CONCLUSIONS: A deleterious consequence of decreased oxidative capacity in SS mitochondria from rats fed high-fat diet would be a reduced utilization of energy substrates, especially fatty acids, which may lead to intracellular triglyceride accumulation, lipotoxicity and insulin resistance development. Our results thus reveal a possible role for SS mitochondria in the impairment of glucose homeostasis induced by high-fat diet.

Methyl group metabolism gene polymorphisms as modifier of breast cancer risk in Italian BRCA1/2 carriers.

BRCA1 and 2 are major cancer susceptibility genes but their penetrance is highly variable. The folate metabolism plays an important role in DNA methylation and its alterated metabolism is associated with cancer risk. The role of allele variants 677T and 1298C (MTHFR gene) and 2756G (MS gene) has been investigated as potentially modifying factors of BRCA gene penetrance, evaluated as age at first diagnosis of cancer, in 484 BRCA1/BRCA2 carriers and in 108 sporadic breast cancer cases as a control group. The genotype analysis has been performed by means of PCR/RFLP's. The analysis of association between a particular genotype and disease risk was performed using Cox Regression with time to breast or ovarian cancer onset as the end-point. The presence of 677T allele confers an increased risk of breast cancer in BRCA1 carriers (P = 0.007) and the presence of 1298C allele confers an increased risk of breast cancer in sporadic cases (P = 0.015).

Heterogeneous bioenergetic behaviour of subsarcolemmal and intermyofibrillar mitochondria in fed and fasted rats.

This study was designed to examine energetic behaviour of skeletal muscle subsarcolemmal and intermyofibrillar mitochondrial populations. The data show that subsarcolemmal mitochondria exhibited a lower degree of coupling and efficiency than intermyofibrillar ones, and can therefore be considered less efficient at producing ATP. In addition, subsarcolemmal mitochondria showed an increased sensitivity to palmitate-induced uncoupling, in line with high adenine nucleotide translocator content and decreased oxidative damage. We then determined the effect of 24 h fasting on energetic characteristics of skeletal muscle mitochondrial populations. We found that fasting enhanced proton leak and decreased the degree of coupling and efficiency, both in the absence and in the presence of palmitate only in subsarcolemmal mitochondria. Moreover, this mitochondrial population showed lower oxidative damage, probably due to a counter-regulatory mechanism mediated by uncoupling protein 3. Subsarcolemmal and intermyofibrillar mitochondria appear to exhibit different energetic characteristics and can be differently affected by physiological stimuli.

Large genomic deletions inactivate the BRCA2 gene in breast cancer families.

BACKGROUND: BRCA1 and BRCA2 are the two major genes responsible for the breast and ovarian cancers that cluster in families with a genetically determined predisposition. However, regardless of the mutation detection method employed, the percentage of families without identifiable alterations of these genes exceeds 50%, even when applying stringent criteria for family selection. A small but significant increase in mutation detection rate has resulted from the discovery of large genomic alterations in BRCA1. A few studies have addressed the question of whether BRCA2 might be inactivated by the same kinds of alteration, but most were either done on a relatively small number of samples or employed cumbersome mutation detection methods of variable sensitivity. OBJECTIVE: To analyse 121 highly selected families using the recently available BRCA2 multiplex ligation dependent probe amplification (MLPA) technique. RESULTS: Three different large genomic deletions were identified and confirmed by analysis of the mutant transcript and genomic characterisation of the breakpoints. CONCLUSIONS: Contrary to initial suggestions, the presence of BRCA2 genomic rearrangements is worth investigating in high risk breast or ovarian cancer families.

Efeitos agudos dos extratos hidroalcoólicos do alho (Allium sativum L.) e do capim-limão (Cymbopogon citratus (DC) Stapf) sobre a pressão arterial média de ratos anestesiados / Acute effects of Allium sativum L. and Cympobongon citratus (DC) Stapf hydroalcoholic extracts on arterial blood pressure of anesthetized rats

Este trabalho objetivou verificar os efeitos da aplicação aguda endovenosa dos extratos hidroalcoólicos de Allium sativum e de Cymbopogon citratus sobre a pressão arterial de ratos. Foram usados Rattus novergicus albinus, n=7, anestesiados, traqueostomizados e canulados através da veia jugular e da artéria carótida. Foram injetadas doses de 1 mg dos extratos separadamente e em associação (1mg + 1mg), em volumes de 0,2mL. A pressão arterial média (PAM) foi registrada com um sistema Biopac, modelo MP100. O Allium sativum diminuiu a PAM de 124±2 mmHg, no controle, para 108±2 mmHg aos 15s. Da mesma forma, o Cymbopogon citratus diminuiu a PAM de 122±2 mmHg, no controle, para 106± 2 mmHg aos 15s. A associação de ambos também diminuiu a PAM de 126±3 mmHg, no controle, para 113±3 mmHg aos 15s. Os efeitos das duas plantas foram iguais e não foram incrementados quando associadas.

This work aimed to verify the effects of acute intravenous applications of Allium sativum and Cymbopogon citratus hydroalcoholic extracts on arterial blood pressure of anesthetized rats. Adult male rats (Rattus novergicus albinus), n=7, were used. The rats were anesthetized, tracheotomy and cannulation of both jugular and carotid were carried out. The injected doses were 1 mg separately as well as the association of both extracts, in volumes of 0,2 mL. The mean arterial blood pressure (MAP) was recorded with a Biopac System, model MP100. The Allium sativum decreased the MAP only from 124±2 mmHg (control) to 108±2 mmHg at 15s. The Cymbopogon citratus also decreased the MAP from 122±2 mmHg (control) to 106±2 mmHg after 15s. The 1mg of Allium sativum + 1mg of Cymbopogon citratus also decreased the MAP from 126±3 mmHg (control) to 113±3 mmHg after 15s. The effects of the two plants were the same and were not increased when in association.

Operative files of legal medical emergency in Calabria: study team.

In Calabria, a study team form legal medicine emergency (LME) formed to initiate a Crisis Unit (CU) able to manage and deal LME with complicated operations and roles, people and technical aspects involvement. First steps are planning, scene study and organization. Everything connecting the first and second emergency to have practicable application.

Lack of association between androgen receptor CAG polymorphism and familial breast/ovarian cancer.

The human androgen receptor (AR) gene contains a highly polymorphic CAG repeat in exon 1 that is inversely correlated with AR transcriptional activity in vitro. Several studies have shown that fewer CAG repeats are associated with an increased risk as well as more aggressive forms of prostate cancer. More recently, AR allele length was also inversely correlated with the histological grade of breast cancer, but no association was found between the AR-CAG polymorphism and the risk of either breast or ovary cancer. On the contrary, it was proposed that a longer CAG repeat sequence might be associated with an increased risk of breast cancer in BRCA1 mutation carriers, thus suggesting a different role of the AR-CAG polymorphism in sporadic and inherited breast cancers. With the intent of better understanding the role of the AR-CAG polymorphism as a cancer risk modifier, we defined the AR genotype of 151 patients (101 with breast and 50 with ovary cancer) belonging to high-risk breast/ovary cancer families. No difference in CAG repeat length was found between either breast and ovary cancer patients or age at diagnosis of both tumors. These results were also confirmed in a sub-group of 47 breast cancer cases, that either carried a BRCA gene mutation (11 cases) or were identified by very stringent operational criteria as hereditary breast cancers. Even though a substantially larger sample size would be required to reach conclusive evidence, our findings suggest that the AR-CAG polymorphism does not act as a modifier of tumor onset or tumor phenotype in breast/ovarian cancer families.

The feasibility of high-dose chemotherapy in breast cancer patients with impaired left ventricular function.

Breast cancer patients with cardiac disease are usually excluded from clinical trials of high-dose chemotherapy. We treated 52 patients with inflammatory and/or metastatic disease with sequential high-dose melphalan and stem cell rescue followed by high-dose thiotepa and stem cell rescue. Stem cells were mobilized with cyclophosphamide and/or paclitaxel and filgrastim. Left ventricular ejection fraction (LVEF) was measured by equilibrium radionuclide angiocardiography (ERNA) at baseline, after each course of chemotherapy and 4 weeks after completing both transplants. The mean absolute decrease in LVEF after the two transplants was 3.6% (P = 0. 008 for the comparison with baseline LVEF), and most of this drop (-2.5%, P = 0.007) occurred after mobilization. Unexpectedly, paclitaxel was associated with a mean absolute decrease in LVEF of 3. 4% (P = 0.032, n = 19), cyclophosphamide alone was not associated with a significant change in LVEF (-1.3%, P = 0.23), but mobilization with sequential paclitaxel and cyclophosphamide resulted in a mean absolute drop of 4.9% in LVEF (P = 0.009). Twelve patients were found to have a reduced LVEF (<50%) at least once during treatment and had a mean absolute decrease in LVEF of 10% (P = 0.008) from baseline, compared with a drop of only 1.8% (P = 0. 176) in the patients without impaired LV function. Although two of these 12 patients developed symptomatic heart failure, their cardiac symptoms were easily treated and there were no cardiac deaths. We conclude that our protocol has acceptable cardiac toxicity and breast cancer patients with impaired LV function should not be denied high-dose chemotherapy if otherwise indicated.

Co-existence of cutaneous T-cell lymphoma and B hairy cell leukemia.

A primary cutaneous form of peripheral T-cell lymphoma (PTCL) and a low grade B-cell non-Hodgkin's lymphoma that was classified as a variant of hairy cell leukemia (HCL) were simultaneously diagnosed in a 79-year-old woman by both phenotypic and genotypic analyses. The coexistence of a T- and B-cell lymphoma in the same patient is rare, and, to our knowledge, this particular association has not been previously described. The patient was referred to our Department for evaluation of multiple cutaneous itchy, reddish plaques; laboratory analyses disclosed a lymphocytosis, that presented 6 years earlier. A bone marrow aspirate showed a 50% B-cell interstitial infiltrate, while a skin biopsy surprisingly revealed a PTCL. Clonality of both neoplastic processes was assessed by Southern blot analysis. The indolent clinical course of the cutaneous disease, and the low and stable number of circulating neoplastic T cells supported the diagnosis of a mycosis fungoides (MF)-like PTCL. Possible oncogenic events and/or putative underlying viral infections which could have played a role in the occurrence of B- and T-cell non-Hodgkin's lymphomas in the same patient are discussed.

Anomalous transcripts and allelic deletions of the FHIT gene in human esophageal cancer.

The fragile histidine triad (FHIT) gene is localized on chromosome 3p14 and spans the common fragile site FRA3B. Even though its role in carcinogenesis is still unclear, this gene is frequently inactivated by carcinogen-induced intragenic deletions in many types of cancers, and FHIT abnormal transcripts are found in many primary tumors and tumor-derived cell lines. We evaluated FHIT gene involvement in 39 esophageal carcinomas (18 adenocarcinomas [AC¿, 21 squamous cell carcinomas [SCC]) by both reverse transcriptase-polymerase chain reaction (RT-PCR) amplification and loss of heterozygosity analysis (LOH). Thirty cases (77%) displayed either aberrant FHIT transcripts (12 cases) and/or LOH (24 cases); among these, only 6 samples displayed both aberrant transcripts and LOH, thus suggesting that the two events are probably independent. Moreover, LOH was significantly higher in SCC (80%) than in AC (44%), and because most of our patients are heavy smokers and/or alcohol consumers, these results suggest that the FHIT gene might be a common target for carcinogens also in the esophagus.

Identification of a 3 kb Alu-mediated BRCA1 gene rearrangement in two breast/ovarian cancer families.

Most of the hereditary breast cancers are attributed to constitutive alterations of either BRCA1 or BRCA2 genes; nonetheless, germline mutations of these genes in 'high risk' families are found less frequently than expected from linkage data. Recent findings suggest that major genomic rearrangements of the BRCA1 gene might account for at least some of the apparently mutation negative cases. We studied 60 affected probands belonging to families with a strong history of breast and/or ovarian cancer who scored negative for BRCA1 gene mutations by PTT and SSCP analysis. DNA was analysed by the Southern blotting procedure using three different restriction enzymes, and two probes obtained by RT-PCR of the 5' and 3' BRCA1 coding sequence. A 3 kb deletion encompassing exon 17 and causing a frameshift mutation was identified in two independently ascertained families. RT-PCR and long-range DNA PCR were employed to characterize the rearrangement that was finally shown to be the result of a recombination between two very similar Alu repeats. This type of mutation is not identified by the conventional methods of mutation detection which are based on PCR amplification of single exons. Therefore, further search for gene rearrangements is needed to better define the proportion of 'high risk' families that might be explained by gross genomic alterations of the BRCA1 gene.