Endoscopic colorectal cancer screening: a cost-saving analysis

BACKGROUND: Comprehensive analyses have shown that screening for cancer usually induces net costs. In this study, the possible costs and savings of endoscopic colorectal cancer screening are explored to investigate whether the induced savings may compensate for the costs of screening. METHODS: A simulation model for evaluation of colorectal cancer screening, MISCAN-COLON, is used to predict costs and savings for the U.S. population, assuming that screening is performed during a period of 30 years. Plausible baseline parameter values of epidemiology, natural history, screening test characteristics, and unit costs are based on available data and expert opinion. Important parameters are varied to extreme but plausible values. RESULTS: Given the expert opinion-based assumptions, a program based on every 5-year sigmoidoscopy screenings could result in a net savings of direct health care costs due to prevention of cancer treatment costs that compensate for the costs of screening, diagnostic follow-up, and surveillance. This result persists when costs and health effects are discounted at 3%. The "break-even" point, the time required before savings exceed costs, is 35 years for a screening program that terminates after 30 years and 44 years for a screening program that continues on indefinitely. However, net savings increase or turn into net costs when alternative assumptions about natural history of colorectal cancer, costs of screening, surveillance, and diagnostics are considered. CONCLUSIONS: Given the present, limited knowledge of the disease process of colorectal cancer, test characteristics, and costs, it may well be that the induced savings by endoscopic colorectal cancer screening completely compensate for the costs

A novel heterozygous mutation in the STAT1 SH2 domain causes chronic mucocutaneous candidiasis, atypically diverse infections, autoimmunity, and impaired cytokine regulation

Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency characterized by persistent or recurrent skin and mucosal surface infections with Candida species. Different gene mutations leading to CMC have been identified. These include various heterozygous gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) that are not only associated with infections but also with autoimmune manifestations. Recently, two STAT1 GOF mutations involving the Src homology 2 (SH2) domain have been reported, while so far, over 50 mutations have been described mainly in the coiled coil and the DNA-binding domains. Here, we present two members of a Dutch family with a novel STAT1 mutation located in the SH2 domain. T lymphocytes of these patients revealed STAT1 hyperphosphorylation and higher expression of STAT1 target genes. The clinical picture of CMC in our patients could be explained by diminished production of interleukin (IL)-17 and IL-22, cytokines important in the protection against fungal infections

Alinhamento interpessoal, representacional e morfossintático na Gramática Discursivo-Funcional

Este artigo se debruça sobre o mapeamento entre os Níveis Interpessoal, Representacional e Morfossintático da gramática, o chamado alinhamento, segundo o arcabouço da Gramática Discursivo-Funcional (GDF). Propõe uma tipologia das línguas baseada no que a sua organização morfossintática codifica: distinções pragmáticas (p.ex. em Tagalo), distinções semânticas (p.ex. em Achém), ou distinções inerentes à morfossintaxe (p.ex. em Inglês, Basco ou a língua Kham). A inclusão tanto do Sujeito como do Objeto e de línguas tanto acusativas como ergativas no tratamento do alinhamento morfossintático permitiu-nos abranger tipos tipologicamente mais variáveis e demonstrar o potencial da GDF para a análise contrastiva das línguas.<br>Within the framework of Functional Discourse Grammar (FDG), alignment concerns the relations between the Interpersonal, Representational and Morphosyntactic Levels of grammar. This article proposes a typology of languages based upon what we find to be encoded in their morphosyntactic organization: pragmatic distinctions (as in Tagalog), semantic distinctions (as in Acheh), or distinctions inherent to the morphosyntax (as in English, Basque and Kham). By including both subject and object, and both accusative and ergative languages in our treatment of morphosyntactic alignment, we provide a better coverage of typological variation and show the potential of FDG for cross-linguistic analysis

Gene expression profiling of early intervertebral disc degeneration reveals a down-regulation of canonical Wnt signaling and caveolin-1 expression: implications for development of regenerative strategies

INTRODUCTION: Early degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs). The purpose of this study was to investigate the gene expression profiles involved in this process using NP tissue from non-chondrodystrophic and chondrodystrophic dogs, a species with naturally occurring IVD degeneration. METHODS: Dual channel DNA microarrays were used to compare 1) healthy NP tissue containing only NCs (NC-rich), 2) NP tissue with a mixed population of NCs and CLCs (Mixed), and 3) NP tissue containing solely CLCs (CLC-rich) in both non-chondrodystrophic and chondrodystrophic dogs. Based on previous reports and the findings of the microarray analyses, canonical Wnt signaling was further evaluated using qPCR of relevant Wnt target genes. We hypothesized that caveolin-1, a regulator of Wnt signaling that showed significant changes in gene expression in the microarray analyses, played a significant role in early IVD degeneration. Caveolin-1 expression was investigated in IVD tissue sections and in cultured NCs. To investigate the significance of Caveolin-1 in IVD health and degeneration, the NP of 3-month-old Caveolin-1 knock-out mice was histopathologically evaluated and compared with the NP of wild-type mice of the same age. RESULTS: Early IVD degeneration involved significant changes in numerous pathways, including Wnt/β-catenin signaling. With regard to Wnt/β-catenin signaling, axin2 gene expression was significantly higher in chondrodystrophic dogs compared with non-chondrodystrophic dogs. IVD degeneration involved significant down-regulation of axin2 gene expression. IVD degeneration involved significant down-regulation in Caveolin-1 gene and protein expression. NCs showed abundant caveolin-1 expression in vivo and in vitro, whereas CLCs did not. The NP of wild-type mice was rich in viable NCs, whereas the NP of Caveolin-1 knock-out mice contained chondroid-like matrix with mainly apoptotic, small, rounded cells. CONCLUSIONS: Early IVD degeneration involves down-regulation of canonical Wnt signaling and Caveolin-1 expression, which appears to be essential to the physiology and preservation of NCs. Therefore, Caveolin-1 may be regarded an exciting target for developing strategies for IVD regeneration

Age-Related Attenuation of Dominant Hand Superiority

The decline of motor performance of the human hand-arm system with age is well-documented. While dominant hand performance is superior to that of the non-dominant hand in young individuals, little is known of possible age-related changes in hand dominance. We investigated age-related alterations of hand dominance in 20 to 90 year old subjects. All subjects were unambiguously right-handed according to the Edinburgh Handedness Inventory. In Experiment 1, motor performance for aiming, postural tremor, precision of arm-hand movement, speed of arm-hand movement, and wrist-finger speed tasks were tested. In Experiment 2, accelerometer-sensors were used to obtain objective records of hand use in everyday activities

Comparative Analysis of ESBL-Positive Escherichia coli isolates from Animals and Humans from the UK, the Netherlands and Germany

The putative virulence and antimicrobial resistance gene contents of extended spectrum β-lactamase (ESBL)-positive E. coli (n=629) isolated between 2005 and 2009 from humans, animals and animal food products in Germany, The Netherlands and the UK were compared using a microarray approach to test the suitability of this approach with regard to determining their similarities. A selection of isolates (n=313) were also analysed by multilocus sequence typing (MLST). Isolates harbouring blaCTX-M-group-1 dominated (66%, n=418) and originated from both animals and cases of human infections in all three countries; 23% (n=144) of all isolates contained both blaCTX-M-group-1 and blaOXA-1-like genes, predominantly from humans (n=127) and UK cattle (n=15). The antimicrobial resistance and virulence gene profiles of this collection of isolates were highly diverse. A substantial number of human isolates (32%, n=87) did not share more than 40% similarity (based on the Jaccard coefficient) with animal isolates. A further 43% of human isolates from the three countries (n=117) were at least 40% similar to each other and to five isolates from UK cattle and one each from Dutch chicken meat and a German dog; the members of this group usually harboured genes such as mph(A), mrx, aac(6’)-Ib, catB3, blaOXA-1-like and blaCTX-M-group-1. forty-four per cent of the MLST-typed isolates in this group belonged to ST131 (n=18) and 22% to ST405 (n=9), all from humans. Among animal isolates subjected to MLST (n=258), only 1.2% (n=3) were more than 70% similar to human isolates in gene profiles and shared the same MLST clonal complex with the corresponding human isolates. The results suggest that minimising human-to-human transmission is essential to control the spread of ESBL-positive E. coli in humans

The impact of pre-exposure prophylaxis (PrEP) on HIV epidemics in Africa and India: A simulation study

Background: Pre-exposure prophylaxis (PrEP) is a promising new HIV prevention method, especially for women. An urgent demand for implementation of PrEP is expected at the moment efficacy has been demonstrated in clinical trials. We explored the long-term impact of PrEP on HIV transmission in different HIV epidemics. Methodology/Principal Findings: We used a mathematical model that distinguishes the general population, sex workers and their clients. PrEP scenarios varying in effectiveness, coverage and target group were modeled in the epidemiological settings of Botswana, Nyanza Province in Kenya, and Southern India. We also studied the effect of condom addition or condom substitution during PrEP use. Main outcome was number of HIV infections averted over ten years of PrEP use. PrEP strategies with high effectiveness and high coverage can have a substantial impact in African settings. In Southern India, by contrast, the number of averted HIV infections in different PrEP scenarios would be much lower. The impact of PrEP may be strongly diminished or even reversed by behavioral disinhibition, especially in scenarios with low coverage and low effectiveness. However, additional condom use during low coverage and low effective PrEP doubled the amount of averted HIV infections. Conclusions/Significance: The public health impact of PrEP can be substantial. However, this impact may be diminished, or even reversed, by changes in risk behavior. Implementation of PrEP strategies should therefore come on top of current condom campaigns, not as a substitution

Adjectival and Adverbial Modification:The View from Modern Type Theories

In this paper we present a study of adjectival/adverbial modification using modern type theories (MTTs), i.e. type theories within the tradition of Martin-Lof. We present an account of various issues concerning adjectival/adverbial modification and argue that MTTs can be used as an adequate language for interpreting NL semantics. MTTs are not only expressive enough to deal with a range of modification phenomena, but are furthermore well-suited to perform reasoning tasks that can be easily implemented (e.g. in proof-assistants) given their proof-theoretic nature. In MTT-semantics, common nouns are interpreted as types rather than predicates. Therefore, in order to capture the semantics of adjectives adequately, one needs to meet the challenge of modeling CNs modified by adjectives as types. To explicate that this can be done successfully, we first look at the mainstream classification of adjectives, i.e. intersective, subsective and non-subsective adjectives. There, we show that the rich type structure available in MTTs, along with a suitable subtyping framework, offers an adequate mechanism to model these cases. In particular, this modelling naturally takes care of the characterising inferences associated with each class of adjectives. Then, more advanced issues on adjectival modification are discussed: (a) degree adjectives, (b) comparatives and (c) multidimensional adjectives. There, it is shown that the use of indexed types can be usefully applied in order to deal with these cases. In the same vein, the issue of adverbial modification is discussed. We study two general typings for sentence and VP adverbs respectively. It is shown that the rich type structure in MTTs further provides useful organisational mechanisms in giving formal semantics for adverbs. In particular, we discuss the use of -types to capture the veridicality/non-veridicality distinction and further discuss cases of intensional adverbs using the type theoretic notion of context (i.e. without resorting to intensional typing). We also look at manner, subject and speech act adverbials and propose solutions using MTTs. Finally, we show that the current proof technology can help mechanically check the associated inferences. A number of our proposals concerning adjectival and adverbial modification have been formalised in the proof assistant Coq and many of the associated inference patterns are checked to be correctly captured

Unraveling the Immunogenetics of STAT Proteins:Clinical Perspectives on Gain-of-Function and Loss-of-Function Variants

Signal Transducer and Activator of Transcription (STAT) proteins play pivotal roles in immune regulation. The dysregulation of these proteins, attributed to both gain-of-function (GOF) and loss-of-function (LOF) variants, has emerged as a substantial and intricate area of research. This comprehensive review delves into the intricate details of the diverse clinical spectrum associated with STAT variants and the immunological findings linked to these genetic alterations. Although this review does not encompass the treatment of each individual disease, we discuss investigative approaches ranging from immunophenotyping assessment to evaluation of STAT protein activity. These investigations play a crucial role in identifying affected patients and understanding the complexities of STAT.</p