The cost of severe haemophilia in Europe: the CHESS study

Background Severe haemophilia is associated with major psychological and economic burden for patients, caregivers, and the wider health care system. This burden has been quantified and documented for a number of European countries in recent years. However, few studies have taken a standardised methodology across multiple countries simultaneously, and sought to amalgamate all three levels of burden for severe disease. The overall aim of the ‘Cost of Haemophilia in Europe: a Socioeconomic Survey’ (CHESS) study was to capture the annualised economic and psychosocial burden of severe haemophilia in five European countries. A cross-section of haemophilia specialists (surveyed between January and April 2015) provided demographic and clinical information and 12-month ambulatory and secondary care activity for patients via an online survey. In turn, patients provided corresponding direct and indirect non-medical cost information, including work loss and out-of-pocket expenses, as well as information on quality of life and adherence. The direct and indirect costs for the patient sample were calculated and extrapolated to population level. Results Clinical reports for a total of 1,285 patients were received. Five hundred and fifty-two patients (43% of the sample) provided information on indirect costs and health-related quality of life via the PSC. The total annual cost of severe haemophilia across the five countries for 2014 was estimated at EUR 1.4 billion, or just under EUR 200,000 per patient. The highest per-patient costs were in Germany (mean EUR 319,024) and the lowest were in the United Kingdom (mean EUR 129,365), with a study average of EUR 199,541. As expected, consumption of clotting factor replacement therapy represented the vast majority of costs (up to 99%). Indirect costs are driven by patient and caregiver work loss. Conclusions The results of the CHESS study reflect previous research findings suggesting that costs of factor replacement therapy account for the vast majority of the cost burden in severe haemophilia. However, the importance of the indirect impact of haemophilia on the patient and family should not be overlooked. The CHESS study highlights the benefits of observational study methodologies in capturing a ‘snapshot’ of information for patients with rare diseases

Correction: Exome Sequencing in an Admixed Isolated Population IndicatesNFXL1 Variants Confer a Risk for Specific Language Impairment

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model

Sucrose in the concentrated solution or the supercooled “state” : a review of caramelisation reactions and physical behaviour

Sucrose is probably one of the most studied molecules by food scientists, since it plays an important role as an ingredient or preserving agent in many formulations and technological processes. When sucrose is present in a product with a concentration near or greater than the saturation point—i.e. in the supercooled state—it possesses high potentialities for the food industry in areas as different as pastry industry, dairy and frozen desserts or films and coatings production. This paper presents a review on critical issues and research on highly concentrated sucrose solutions—mainly, on sucrose thermal degradation and relaxation behaviour in such solutions. The reviewed works allow identifying several issues with great potential for contributing to significant advances in Food Science and Technology.Authors are grateful for the valuable discussions with Teresa S. Brandao and Rosiane Lopes da Cunha during this research. Author M. A. C. Quintas acknowledges the financial support of her research by FCT grant SFRH/BPD/41715/2007

Effectiveness of proactive telephone counselling for smoking cessation in parents: Study protocol of a randomized controlled trial

Contains fulltext : 99284.pdf (publisher's version ) (Open Access)Background Smoking is the world's fourth most common risk factor for disease, the leading preventable cause of death, and it is associated with tremendous social costs. In the Netherlands, the smoking prevalence rate is high. A total of 27.7% of the population over age 15 years smokes. In addition to the direct advantages of smoking cessation for the smoker, parents who quit smoking may also decrease their children's risk of smoking initiation. Methods/Design A randomized controlled trial will be conducted to evaluate the effectiveness of proactive telephone counselling to increase smoking cessation rates among smoking parents. A total of 512 smoking parents will be proactively recruited through their children's primary schools and randomly assigned to either proactive telephone counselling or a control condition. Proactive telephone counselling will consist of up to seven counsellor-initiated telephone calls (based on cognitive-behavioural skill building and Motivational Interviewing), distributed over a period of three months. Three supplementary brochures will also be provided. In the control condition, parents will receive a standard brochure to aid smoking cessation. Assessments will take place at baseline, three months after start of the intervention (post-measurement), and twelve months after start of the intervention (follow-up measurement). Primary outcome measures will include sustained abstinence between post-measurement and follow-up measurement and 7-day point prevalence abstinence and 24-hours point prevalence abstinence at both post- and follow-up measurement. Several secondary outcome measures will also be included (e.g., smoking intensity, smoking policies at home). In addition, we will evaluate smoking-related cognitions (e.g., attitudes towards smoking, social norms, self-efficacy, intention to smoke) in 9-12 year old children of smoking parents. Discussion This study protocol describes the design of a randomized controlled trial to evaluate the effectiveness of proactive telephone counselling in smoking cessation. It is expected that, in the telephone counseling condition, parental smoking cessation rates will be higher and children's cognitions will be less favorable about smoking compared to the control condition. Trial registration The protocol for this study is registered with the Netherlands Trial Register NTR2707.6 p

Genomic Resources for Sea Lice: Analysis of ESTs and Mitochondrial Genomes

Sea lice are common parasites of both farmed and wild salmon. Salmon farming constitutes an important economic market in North America, South America, and Northern Europe. Infections with sea lice can result in significant production losses. A compilation of genomic information on different genera of sea lice is an important resource for understanding their biology as well as for the study of population genetics and control strategies. We report on over 150,000 expressed sequence tags (ESTs) from five different species (Pacific Lepeophtheirus salmonis (49,672 new ESTs in addition to 14,994 previously reported ESTs), Atlantic L. salmonis (57,349 ESTs), Caligus clemensi (14,821 ESTs), Caligus rogercresseyi (32,135 ESTs), and Lernaeocera branchialis (16,441 ESTs)). For each species, ESTs were assembled into complete or partial genes and annotated by comparisons to known proteins in public databases. In addition, whole mitochondrial (mt) genome sequences of C. clemensi (13,440 bp) and C. rogercresseyi (13,468 bp) were determined and compared to L. salmonis. Both nuclear and mtDNA genes show very high levels of sequence divergence between these ectoparastic copepods suggesting that the different species of sea lice have been in existence for 37–113 million years and that parasitic association with salmonids is also quite ancient. Our ESTs and mtDNA data provide a novel resource for the study of sea louse biology, population genetics, and control strategies. This genomic information provides the material basis for the development of a 38K sea louse microarray that can be used in conjunction with our existing 44K salmon microarray to study host–parasite interactions at the molecular level. This report represents the largest genomic resource for any copepod species to date

Cyclin-Dependent Kinase 9 Activity Regulates Neutrophil Spontaneous Apoptosis

Neutrophils are the most abundant leukocyte and play a central role in the immune defense against rapidly dividing bacteria. However, they are also the shortest lived cell in the blood with a lifespan in the circulation of 5.4 days. The mechanisms underlying their short lifespan and spontaneous entry into apoptosis are poorly understood. Recently, the broad range cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to increase neutrophil apoptosis, implicating CDKs in the regulation of neutrophil lifespan. To determine which CDKs were involved in regulating neutrophil lifespan we first examined CDK expression in human neutrophils and found that only three CDKs: CDK5, CDK7 and CDK9 were expressed in these cells. The use of CDK inhibitors with differing selectivity towards the various CDKs suggested that CDK9 activity regulates neutrophil lifespan. Furthermore CDK9 activity and the expression of its activating partner cyclin T1 both declined as neutrophils aged and entered apoptosis spontaneously. CDK9 is a component of the P-TEFb complex involved in transcriptional regulation and its inhibition will preferentially affect proteins with short half-lives. Treatment of neutrophils with flavopiridol, a potent CDK9 inhibitor, increased apoptosis and caused a rapid decline in the level of the anti-apoptotic protein Mcl-1, whilst Bcl2A was unaffected. We propose that CDK9 activity is a key regulator of neutrophil lifespan, preventing apoptosis by maintaining levels of short lived anti-apoptotic proteins such as Mcl-1. Furthermore, as inappropriate inhibition of neutrophil apoptosis contributes to chronic inflammatory diseases such as Rheumatoid Arthritis, CDK9 represents a novel therapeutic target in such diseases

Fish as Reservoirs and Vectors of Vibrio cholerae

Vibrio cholerae, the etiologic agent of cholera, is autochthonous to various aquatic environments, but despite intensive efforts its ecology remains an enigma. Recently, it was suggested that copepods and chironomids, both considered as natural reservoirs of V. cholerae, are dispersed by migratory waterbirds, thus possibly distributing the bacteria between water bodies within and between continents. Although fish have been implicated in the scientific literature with cholera cases, as far as we know, no study actually surveyed the presence of the bacteria in the fish. Here we show for the first time that fish of various species and habitats contain V. cholerae in their digestive tract. Fish (n = 110) were randomly sampled from freshwater and marine habitats in Israel. Ten different fish species sampled from freshwater habitats (lake, rivers and fish ponds), and one marine species, were found to carry V. cholerae. The fish intestine of Sarotherodon galilaeus harboured ca. 5×103 V. cholerae cfu per 1 gr intestine content—high rates compared with known V. cholerae cfu numbers in the bacteria's natural reservoirs. Our results, combined with evidence from the literature, suggest that fish are reservoirs of V. cholerae. As fish carrying the bacteria swim from one location to another (some fish species move from rivers to lakes or sea and vice versa), they serve as vectors on a small scale. Nevertheless, fish are consumed by waterbirds, which disseminate the bacteria on a global scale. Moreover, V. cholerae isolates had the ability to degrade chitin, indicating a commensal relationship between V. cholerae and fish. Better understanding of V. cholerae ecology can help reduce the times that human beings come into contact with this pathogen and thus minimize the health risk this poses

Sociocultural Determinants of Teenage Childbearing Among Latinas in California

Objectives U.S. Latinas have a persistently high rate of teenage childbearing, which is associated with adverse outcomes for both mother and child. This study was designed to investigate the roles of socioeconomic factors and acculturation in teenage childbearing in this population. Methods Logistic regression was used to analyze the association of measures of acculturation (language spoken at home, nativity, and age at immigration) and respondents’ parents’ education with age at first birth in a stratified sample of post-partum women in California. Results The unadjusted odds ratio for teenage birth for Latinas versus non-Latina Whites was 5.2 (95% CI 4.1–6.6). Nativity was not significantly associated with teen birth, but speaking Spanish at home was positively associated and immigrating at a later age was negatively associated with teen birth. Overall, these measures of acculturation accounted for 17% (95% CI 8–28%) of the difference in odds of teen birth between Latinas and non-Latina Whites. Higher levels of education among respondents’ parents had differentially protective effects across the racial/ethnic groups. Controlling for disparities in respondents’ parents’ education without changing its differential effects across racial/ethnic groups reduced the odds ratio for Latinas compared to non-Latina Whites by 30% (95% CI 14–60%). Conclusion These findings call into question common assumptions about the protective effect of acculturation on teen fertility and suggest that improving childhood socioeconomic factors among Latinas may decrease teen childbearing

The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency

Background: Fumarate hydratase (HGNC approved gene symbol – FH), also known as fumarase, is an enzyme of the tricarboxylic acid (TCA) cycle, involved in fundamental cellular energy production. First described by Zinn et al in 1986, deficiency of FH results in early onset, severe encephalopathy. In 2002, the Multiple Leiomyoma Consortium identified heterozygous germline mutations of FH in patients with multiple cutaneous and uterine leiomyomas, (MCUL: OMIM 150800). In some families renal cell cancer also forms a component of the complex and as such has been described as hereditary leiomyomatosis and renal cell cancer (HLRCC: OMIM 605839). The identification of FH as a tumor suppressor was an unexpected finding and following the identification of subunits of succinate dehydrogenase in 2000 and 2001, was only the second description of the involvement of an enzyme of intermediary metabolism in tumorigenesis. Description: The FH mutation database is a part of the TCA cycle gene mutation database (formerly the succinate dehydrogenase gene mutation database) and is based on the Leiden Open (source) Variation Database (LOVD) system. The variants included in the database were derived from the published literature and annotated to conform to current mutation nomenclature. The FH database applies HGVS nomenclature guidelines, and will assist researchers in applying these guidelines when directly submitting new sequence variants online. Since the first molecular characterization of an FH mutation by Bourgeron et al in 1994, a series of reports of both FH deficiency patients and patients with MCUL/HLRRC have described 107 variants, of which 93 are thought to be pathogenic. The most common type of mutation is missense (57%), followed by frameshifts and nonsense (27%), and diverse deletions, insertions and duplications. Here we introduce an online database detailing all reported FH sequence variants. Conclusion: The FH mutation database strives to systematically unify all current genetic knowledge of FH variants. We believe that this knowledge will assist clinical geneticists and treating physicians when advising patients and their families, will provide a rapid and convenient resource for research scientists, and may eventually assist in gaining novel insights into FH and its related clinical syndromes. </p