Latent cluster analysis of ALS phenotypes identifies prognostically differing groups

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes. METHODS Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method. RESULTS The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001). CONCLUSION The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research

Child abuse inventory at emergency rooms: CHAIN-ER rationale and design

<p>Abstract</p> <p>Background</p> <p>Child abuse and neglect is an important international health problem with unacceptable levels of morbidity and mortality. Although maltreatment as a cause of injury is estimated to be only 1% or less of the injured children attending the emergency room, the consequences of both missed child abuse cases and wrong suspicions are substantial. Therefore, the accuracy of ongoing detection at emergency rooms by health care professionals is highly important. Internationally, several diagnostic instruments or strategies for child abuse detection are used at emergency rooms, but their diagnostic value is still unknown. The aim of the study 'Child Abuse Inventory at Emergency Rooms' (CHAIN-ER) is to assess if active structured inquiry by emergency room staff can accurately detect physical maltreatment in children presenting at emergency rooms with physical injury.</p> <p>Methods/design</p> <p>CHAIN-ER is a multi-centre, cross-sectional study with 6 months diagnostic follow-up. Five thousand children aged 0-7 presenting with injury at an emergency room will be included. The index test - the SPUTOVAMO-R questionnaire- is to be tested for its diagnostic value against the decision of an expert panel. All SPUTOVAMO-R positives and a 15% random sample of the SPUTOVAMO-R negatives will undergo the same systematic diagnostic work up, which consists of an adequate history being taken by a pediatrician, inquiry with other health care providers by structured questionnaires in order to obtain child abuse predictors, and by additional follow-up information. Eventually, an expert panel (reference test) determines the <it>true </it>presence or absence of child abuse.</p> <p>Discussion</p> <p>CHAIN-ER will determine both positive and negative predictive value of a child abuse detection instrument used in the emergency room. We mention a benefit of the use of an expert panel and of the use of complete data. Conducting a diagnostic accuracy study on a child abuse detection instrument is also accompanied by scientific hurdles, such as the lack of an accepted reference standard and potential (non-) response. Notwithstanding these scientific challenges, CHAIN-ER will provide accurate data on the predictive value of SPUTOVAMO-R.</p

A fast algorithm for estimating transmission probabilities in QTL detection designs with dense maps

<p>Abstract</p> <p>Background</p> <p>In the case of an autosomal locus, four transmission events from the parents to progeny are possible, specified by the grand parental origin of the alleles inherited by this individual. Computing the probabilities of these transmission events is essential to perform QTL detection methods.</p> <p>Results</p> <p>A fast algorithm for the estimation of these probabilities conditional to parental phases has been developed. It is adapted to classical QTL detection designs applied to outbred populations, in particular to designs composed of half and/or full sib families. It assumes the absence of interference.</p> <p>Conclusion</p> <p>The theory is fully developed and an example is given.</p

An Agenda for Best Practice Research on Group Singing, Health, and Well-Being

Research on choirs and other forms of group singing has been conducted for several decades and there has been a recent focus on the potential health and well-being benefits, particularly in amateur singers. Experimental, quantitative, and qualitative studies show evidence of a range of biopsychosocial and well-being benefits to singers; however, there are many challenges to rigor and replicability. To support the advances of research into group singing, the authors met and discussed theoretical and methodological issues to be addressed in future studies. The authors are from five countries and represent the following disciplinary perspectives: music psychology, music therapy, community music, clinical psychology, educational and developmental psychology, evolutionary psychology, health psychology, social psychology, and public health. This article summarizes our collective thoughts in relation to the priority questions for future group singing research, theoretical frameworks, potential solutions for design and ethical challenges, quantitative measures, qualitative methods, and whether there is scope for a benchmarking set of measures across singing projects. With eight key recommendations, the article sets an agenda for best practice research on group singing

Hierarchy Theory of Evolution and the Extended Evolutionary Synthesis: Some Epistemic Bridges, Some Conceptual Rifts

Contemporary evolutionary biology comprises a plural landscape of multiple co-existent conceptual frameworks and strenuous voices that disagree on the nature and scope of evolutionary theory. Since the mid-eighties, some of these conceptual frameworks have denounced the ontologies of the Modern Synthesis and of the updated Standard Theory of Evolution as unfinished or even flawed. In this paper, we analyze and compare two of those conceptual frameworks, namely Niles Eldredge’s Hierarchy Theory of Evolution (with its extended ontology of evolutionary entities) and the Extended Evolutionary Synthesis (with its proposal of an extended ontology of evolutionary processes), in an attempt to map some epistemic bridges (e.g. compatible views of causation; niche construction) and some conceptual rifts (e.g. extra-genetic inheritance; different perspectives on macroevolution; contrasting standpoints held in the “externalism–internalism” debate) that exist between them. This paper seeks to encourage theoretical, philosophical and historiographical discussions about pluralism or the possible unification of contemporary evolutionary biology

Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.

Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification

Diagnostic utility of snail in metaplastic breast carcinoma

Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer characterized by coexistence of carcinomatous and sarcomatous components. Snail is a nuclear transcription factor incriminated in the transition of epithelial to mesenchymal differentiation of breast cancer. Aberrant Snail expression results in lost expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. We aimed to identify the utility of Snail, and of traditional immunohistochemical markers, in accurate MBC classification and to evaluate clinicopathologic characteristics and outcome

Cancer mortality and morbidity among plutonium workers at the Sellafield plant of British Nuclear Fuels

The mortality of all 14 319 workers employed at the Sellafield plant of British Nuclear Fuels between 1947 and 1975 was studied up to the end of 1992, and cancer incidence was examined from 1971 to 1986, in relation to their exposures to plutonium and to external radiation. The cancer mortality rate was 5% lower than that of England and Wales and 3% less than that of Cumbria. The significant excesses of deaths from cancer of the pleura and thyroid found in an earlier study persist with further follow-up (14 observed, 4.0 expected for pleura; 6 observed, 2.2 expected for thyroid). All of the deaths from pleural cancer were among radiation workers. For neither site was there a significant association between the risk of the cancer and accumulated radiation dose. There were significant deficits of deaths from cancers of mouth and pharynx, liver and gall bladder, and larynx and leukaemia when compared with the national rates. Among all radiation workers, there was a significant positive association between accumulated external radiation dose and mortality from cancers of ill-defined and secondary sites (10-year lag, P = 0.04), leukaemia (no lag, P = 0.03; 2-year lag, P = 0.05), multiple myeloma (20-year lag, P = 0.02), all lymphatic and haematopoietic cancers (20-year lag, P = 0.03) and all causes of death combined (20-year lag, P = 0.008). Among plutonium workers, there were significant excesses of deaths from cancer of the breast (6 observed, 2.6 expected) and ill-defined and secondary cancers (29 observed, 20.1 expected). No significant positive trends were observed between the risk of deaths from cancers of any specific site, or all cancers combined, and cumulative plutonium and external radiation doses. For no cancer site was there a significant excess of cancer registrations compared with rates for England and Wales. Analysis of trends in cancer incidence showed significant increases in risk with cumulative plutonium plus external radiation doses for all lymphatic and haematopoietic neoplasms for 0-, 10- and 20-year lag periods. Taken as a whole, our findings do not suggest that workers at Sellafield who have been exposed to plutonium are at an overall significantly increased risk of cancer compared with other radiation workers. © 1999 Cancer Research Campaig