Accurate reconstruction of insertion-deletion histories by statistical phylogenetics

The Multiple Sequence Alignment (MSA) is a computational abstraction that represents a partial summary either of indel history, or of structural similarity. Taking the former view (indel history), it is possible to use formal automata theory to generalize the phylogenetic likelihood framework for finite substitution models (Dayhoff's probability matrices and Felsenstein's pruning algorithm) to arbitrary-length sequences. In this paper, we report results of a simulation-based benchmark of several methods for reconstruction of indel history. The methods tested include a relatively new algorithm for statistical marginalization of MSAs that sums over a stochastically-sampled ensemble of the most probable evolutionary histories. For mammalian evolutionary parameters on several different trees, the single most likely history sampled by our algorithm appears less biased than histories reconstructed by other MSA methods. The algorithm can also be used for alignment-free inference, where the MSA is explicitly summed out of the analysis. As an illustration of our method, we discuss reconstruction of the evolutionary histories of human protein-coding genes.Comment: 28 pages, 15 figures. arXiv admin note: text overlap with arXiv:1103.434

Effects of Screening and Brief Intervention Training on Resident and Faculty Alcohol Intervention Behaviours: A Pre- Post-Intervention Assessment

Background: Many hazardous and harmful drinkers do not receive clinician advice to reduce their drinking. Previous studies suggest under-detection and clinician reluctance to intervene despite awareness of problem drinking (PD). The Healthy Habits Project previously reported chart review data documenting increased screening and intervention with hazardous and harmful drinkers after training clinicians and implementing routine screening. This report describes the impact of the Healthy Habits training program on clinicians\u27 rates of identification of PD, level of certainty in identifying PD and the proportion of patients given advice to reduce alcohol use, based on self-report data using clinician exit questionnaires. Methods: 28 residents and 10 faculty in a family medicine residency clinic completed four cycles of clinician exit interview questionnaires before and after screening and intervention training. Rates of identifying PD, level of diagnostic certainty, and frequency of advice to reduce drinking were compared across intervention status (pre vs. post). Findings were compared with rates of PD and advice to reduce drinking documented on chart review. Results: 1,052 clinician exit questionnaires were collected. There were no significant differences in rates of PD identified before and after intervention (9.8% vs. 7.4%, p = .308). Faculty demonstrated greater certainty in PD diagnoses than residents (p = .028) and gave more advice to reduce drinking (p = .042) throughout the program. Faculty and residents reported higher levels of diagnostic certainty after training (p = .039 and .030, respectively). After training, residents showed greater increases than faculty in the percentage of patients given advice to reduce drinking (p = .038), and patients felt to be problem drinkers were significantly more likely to receive advice to reduce drinking by all clinicians (50% vs. 75%, p = .047). The number of patients receiving advice to reduce drinking after program implementation exceeded the number of patients felt to be problem drinkers. Recognition rates of PD were four to eight times higher than rates documented on chart review (p = .028). Conclusion: This program resulted in greater clinician certainty in diagnosing PD and increases in the number of patients with PD who received advice to reduce drinking. Future programs should include booster training sessions and emphasize documentation of PD and brief intervention

Using visual methods to understand physical activity maintenance following cardiac rehabilitation

© 2015 Hardcastle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Few studies have explored the factors associated with long-term maintenance of exercise following cardiac rehabilitation. The present study used auto-photography and interviews to explore the factors that influence motivation and continued participation in physical activity among post cardiac rehabilitation patients. Twenty-three semi-structured interviews were conducted alongside participant-selected photographs or drawings with participants that had continued participation in physical activity for at least two years following the cardiac rehabilitation programme. Participants were recruited from circuit training classes in East Sussex in the UK. Thematic content analysis revealed seven main themes: fear of death and ill health avoidance, critical incidents, overcoming aging, social influences, being able to enjoy life, provision of routine and structure, enjoyment and psychological well-being. Fear of death, illness avoidance, overcoming aging, and being able to enjoy life were powerful motives for continued participation in exercise. The social nature of the exercise class was also identified as a key facilitator of continued participation. Group-based exercise suited those that continued exercise participation post cardiac rehabilitation and fostered adherence

Illusory Memories of Emotionally Charged Words in Autism Spectrum Disorder: Further Evidence for Atypical Emotion Processing Outside the Social Domain

Recent evidence suggests that individuals with ASD may not accumulate distinct representations of emotional information throughout development. On the basis of this observation we predicted that such individuals would not be any less likely to falsely remember emotionally significant as compared to neutral words when such illusory memories are induced by asking participants to study lists of words that are orthographically associated to these words. Our findings showed that typical participants are far less likely to experience illusory memories of emotionally charged as compared to neutral words. Individuals with ASD, on the other hand, did not exhibit this emotional modulation of false memories. We discuss this finding in relation to the role of emotional processing atypicalities in ASD

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Malaria Infections Do Not Compromise Vaccine-Induced Immunity against Tuberculosis in Mice

BACKGROUND: Given the considerable geographic overlap in the endemic regions for malaria and tuberculosis, it is probable that co-infections with Mycobacterium tuberculosis and Plasmodium species are prevalent. Thus, it is quite likely that both malaria and TB vaccines may be used in the same populations in endemic areas. While novel vaccines are currently being developed and tested individually against each of these pathogens, the efficacy of these vaccines has not been evaluated in co-infection models. To further assess the effectiveness of these new immunization strategies, we investigated whether co-infection with malaria would impact the anti-tuberculosis protection induced by four different types of TB vaccines in a mouse model of pulmonary tuberculosis. PRINCIPAL FINDINGS: Here we show that the anti-tuberculosis protective immunity induced by four different tuberculosis vaccines was not impacted by a concurrent infection with Plasmodium yoelii NL, a nonlethal form of murine malaria. After an aerogenic challenge with virulent M. tuberculosis, the lung bacterial burdens of vaccinated animals were not statistically different in malaria infected and malaria naïve mice. Multi-parameter flow cytometric analysis showed that the frequency and the median fluorescence intensities (MFI) for specific multifunctional T (MFT) cells expressing IFN-γ, TNF-α, and/or IL-2 were suppressed by the presence of malaria parasites at 2 weeks following the malaria infection but was not affected after parasite clearance at 7 and 10 weeks post-challenge with P. yoelii NL. CONCLUSIONS: Our data indicate that the effectiveness of novel TB vaccines in protecting against tuberculosis was unaffected by a primary malaria co-infection in a mouse model of pulmonary tuberculosis. While the activities of specific MFT cell subsets were reduced at elevated levels of malaria parasitemia, the T cell suppression was short-lived. Our findings have important relevance in developing strategies for the deployment of new TB vaccines in malaria endemic areas

The association between malnutrition and the incidence of malaria among young HIV-infected and -uninfected Ugandan children: a prospective study

BACKGROUND: In sub-Saharan Africa, malnutrition and malaria remain major causes of morbidity and mortality in young children. There are conflicting data as to whether malnutrition is associated with an increased or decreased risk of malaria. In addition, data are limited on the potential interaction between HIV infection and the association between malnutrition and the risk of malaria. METHODS: A cohort of 100 HIV-unexposed, 203 HIV-exposed (HIV negative children born to HIV-infected mothers) and 48 HIV-infected children aged 6 weeks to 1 year were recruited from an area of high malaria transmission intensity in rural Uganda and followed until the age of 2.5 years. All children were provided with insecticide-treated bed nets at enrolment and daily trimethoprim-sulphamethoxazole prophylaxis (TS) was prescribed for HIV-exposed breastfeeding and HIV-infected children. Monthly routine assessments, including measurement of height and weight, were conducted at the study clinic. Nutritional outcomes including stunting (low height-for-age) and underweight (low weight-for-age), classified as mild (mean z-scores between -1 and -2 during follow-up) and moderate-severe (mean z-scores < -2 during follow-up) were considered. Malaria was diagnosed when a child presented with fever and a positive blood smear. The incidence of malaria was compared using negative binomial regression controlling for potential confounders with measures of association expressed as an incidence rate ratio (IRR). RESULTS: The overall incidence of malaria was 3.64 cases per person year. Mild stunting (IRR = 1.24, 95% CI 1.06-1.46, p = 0.008) and moderate-severe stunting (IRR = 1.24, 95% CI 1.03-1.48, p = 0.02) were associated with a similarly increased incidence of malaria compared to non-stunted children. Being mildly underweight (IRR = 1.09, 95% CI 0.95-1.25, p = 0.24) and moderate-severe underweight (IRR = 1.12, 95% CI 0.86-1.46, p = 0.39) were not associated with a significant difference in the incidence of malaria compared to children who were not underweight. There were no significant interactions between HIV-infected, HIV-exposed children taking TS and the associations between malnutrition and the incidence of malaria. CONCLUSIONS: Stunting, indicative of chronic malnutrition, was associated with an increased incidence of malaria among a cohort of HIV-infected and -uninfected young children living in an area of high malaria transmission intensity. However, caution should be made when making causal inferences given the observational study design and inability to disentangle the temporal relationship between malnutrition and the incidence of malaria. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00527800

Cluster Lenses

Clusters of galaxies are the most recently assembled, massive, bound structures in the Universe. As predicted by General Relativity, given their masses, clusters strongly deform space-time in their vicinity. Clusters act as some of the most powerful gravitational lenses in the Universe. Light rays traversing through clusters from distant sources are hence deflected, and the resulting images of these distant objects therefore appear distorted and magnified. Lensing by clusters occurs in two regimes, each with unique observational signatures. The strong lensing regime is characterized by effects readily seen by eye, namely, the production of giant arcs, multiple-images, and arclets. The weak lensing regime is characterized by small deformations in the shapes of background galaxies only detectable statistically. Cluster lenses have been exploited successfully to address several important current questions in cosmology: (i) the study of the lens(es) - understanding cluster mass distributions and issues pertaining to cluster formation and evolution, as well as constraining the nature of dark matter; (ii) the study of the lensed objects - probing the properties of the background lensed galaxy population - which is statistically at higher redshifts and of lower intrinsic luminosity thus enabling the probing of galaxy formation at the earliest times right up to the Dark Ages; and (iii) the study of the geometry of the Universe - as the strength of lensing depends on the ratios of angular diameter distances between the lens, source and observer, lens deflections are sensitive to the value of cosmological parameters and offer a powerful geometric tool to probe Dark Energy. In this review, we present the basics of cluster lensing and provide a current status report of the field.Comment: About 120 pages - Published in Open Access at: http://www.springerlink.com/content/j183018170485723/ . arXiv admin note: text overlap with arXiv:astro-ph/0504478 and arXiv:1003.3674 by other author

TOIB Study. Are topical or oral ibuprofen equally effective for the treatment of chronic knee pain presenting in primary care: a randomised controlled trial with patient preference study. [ISRCTN79353052]

BACKGROUND: Many older people have chronic knee pain. Both topical and oral non- steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat this. Oral NSAIDS are effective, at least in the short term, but can have severe adverse effects. Topical NSAIDs also appear to be effective, at least in the short term. One might expect topical NSAIDs both to be less effective and to have fewer adverse effects than oral NSAIDs. If topical NSAIDs have fewer adverse effects this may outweigh both the reduction in effectiveness and the higher cost of topical compared to oral treatment. Patient preferences may influence the comparative effectiveness of drugs delivered via different routes. METHODS: TOIB is a randomised trial comparing topical and oral ibuprofen, with a parallel patient preference study. We are recruiting people aged 50 or over with chronic knee pain, from 27 MRC General Practice Research Framework practices across the UK. We are seeking to recruit 283 participants to the RCT and 379 to the PPS. Participants will be followed up for up to two years (with the majority reaching one year). Outcomes will be assessed by postal questionnaire, nurse examination, laboratory tests and medical record searches at one and two years or the end of the study. DISCUSSION: This study will provide new evidence on the overall costs and benefits of treating chronic knee pain with either oral or topical ibuprofen. The use of a patient preference design is unusual, but will allow us to explore how preference influences response to a medication. In addition, it will provide more information on adverse events. This study will provide evidence to inform primary care practitioners, and possibly influence practice

Two Strategies for the Delivery of IPTc in an Area of Seasonal Malaria Transmission in The Gambia: A Randomised Controlled Trial

Bojang and colleagues report a randomized trial showing that delivery of intermittent preventive treatment for malaria in children by village health workers is more effective than delivery by reproductive and child health trekking clinics