Fine time scaling of purifying selection on human nonsynonymous mtDNA mutations based on the worldwide population tree and mother-child pairs

A high-resolution mtDNA phylogenetic tree allowed us to look backward in time to investigate purifying selection. Purifying selection was very strong in the last 2,500 years, continuously eliminating pathogenic mutations back until the end of the Younger Dryas (∼11,000 years ago), when a large population expansion likely relaxed selection pressure. This was preceded by a phase of stable selection until another relaxation occurred in the out-of-Africa migration. Demography and selection are closely related: expansions led to relaxation of selection and higher pathogenicity mutations significantly decreased the growth of descendants. The only detectible positive selection was the recurrence of highly pathogenic nonsynonymous mutations (m.3394T>C-m.3397A>G-m.3398T>C) at interior branches of the tree, preventing the formation of a dinucleotide STR (TATATA) in the MT-ND1 gene. At the most recent time scale in 124 mother-children transmissions, purifying selection was detectable through the loss of mtDNA variants with high predicted pathogenicity. A few haplogroup-defining sites were also heteroplasmic, agreeing with a significant propensity in 349 positions in the phylogenetic tree to revert back to the ancestral variant. This nonrandom mutation property explains the observation of heteroplasmic mutations at some haplogroup-defining sites in sequencing datasets, which may not indicate poor quality as has been claimed.

Approved Drug Products with Theurapeutic Equivalence Evaluation - 34th edition

The publication, Approved Drug Products with Therapeutic Equivalence Evaluations (the List, commonly known as the Orange Book), identifies drug products approved on the basis of safety and effectiveness by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (the Act). Drugs on the market approved only on the basis of safety (covered by the ongoing Drug Efficacy Study Implementation [DESI] review [e.g., Donnatal® Tablets and Librax® Capsules] or pre-1938 drugs [e.g., Phenobarbital Tablets]) are not included in this publication. The main criterion for the inclusion of any product is that the product is the subject of an application with an effective approval that has not been withdrawn for safety or efficacy reasons. Inclusion of products on the List is independent of any current regulatory action through administrative or judicial means against a drug product. In addition, the List contains therapeutic equivalence evaluations for approved multisource prescription drug products. These evaluations have been prepared to serve as public information and advice to state health agencies, prescribers, and pharmacists to promote public education in the area of drug product selection and to foster containment of health care costs. Therapeutic equivalence evaluations in this publication are not official FDA actions affecting the legal status of products under the Act.

Effects of selection and drift on G matrix evolution in a heterogeneous environment: a multivariate Qst-Fst Test with the freshwater snail Galba truncatula.

Unraveling the effect of selection vs. drift on the evolution of quantitative traits is commonly achieved by one of two methods. Either one contrasts population differentiation estimates for genetic markers and quantitative traits (the Q(st)-F(st) contrast) or multivariate methods are used to study the covariance between sets of traits. In particular, many studies have focused on the genetic variance-covariance matrix (the G matrix). However, both drift and selection can cause changes in G. To understand their joint effects, we recently combined the two methods into a single test (accompanying article by Martin et al.), which we apply here to a network of 16 natural populations of the freshwater snail Galba truncatula. Using this new neutrality test, extended to hierarchical population structures, we studied the multivariate equivalent of the Q(st)-F(st) contrast for several life-history traits of G. truncatula. We found strong evidence of selection acting on multivariate phenotypes. Selection was homogeneous among populations within each habitat and heterogeneous between habitats. We found that the G matrices were relatively stable within each habitat, with proportionality between the among-populations (D) and the within-populations (G) covariance matrices. The effect of habitat heterogeneity is to break this proportionality because of selection for habitat-dependent optima. Individual-based simulations mimicking our empirical system confirmed that these patterns are expected under the selective regime inferred. We show that homogenizing selection can mimic some effect of drift on the G matrix (G and D almost proportional), but that incorporating information from molecular markers (multivariate Q(st)-F(st)) allows disentangling the two effects.

Cost evaluation of cardiovascular magnetic resonance versus coronary angiography for the diagnostic work-up of coronary artery disease: Application of the European Cardiovascular Magnetic Resonance registry data to the German, United Kingdom, Swiss, and United States health care systems.

ABSTRACT: BACKGROUND: Cardiovascular magnetic resonance (CMR) has favorable characteristics for diagnostic evaluation and risk stratification of patients with known or suspected CAD. CMR utilization in CAD detection is growing fast. However, data on its cost-effectiveness are scarce. The goal of this study is to compare the costs of two strategies for detection of significant coronary artery stenoses in patients with suspected coronary artery disease (CAD): 1) Performing CMR first to assess myocardial ischemia and/or infarct scar before referring positive patients (defined as presence of ischemia and/or infarct scar to coronary angiography (CXA) versus 2) a hypothetical CXA performed in all patients as a single test to detect CAD. METHODS: A subgroup of the European CMR pilot registry was used including 2,717 consecutive patients who underwent stress-CMR. From these patients, 21% were positive for CAD (ischemia and/or infarct scar), 73% negative, and 6% uncertain and underwent additional testing. The diagnostic costs were evaluated using invoicing costs of each test performed. Costs analysis was performed from a health care payer perspective in German, United Kingdom, Swiss, and United States health care settings. RESULTS: In the public sectors of the German, United Kingdom, and Swiss health care systems, cost savings from the CMR-driven strategy were 50%, 25% and 23%, respectively, versus outpatient CXA. If CXA was carried out as an inpatient procedure, cost savings were 46%, 50% and 48%, respectively. In the United States context, cost savings were 51% when compared with inpatient CXA, but higher for CMR by 8% versus outpatient CXA. CONCLUSION: This analysis suggests that from an economic perspective, the use of CMR should be encouraged as a management option for patients with suspected CAD.

Selection on age at first and at last reproduction in the long-lived Alpine Swift Apus melba

The way an organism spreads its reproduction over time is defined as a life-history trait, and selection is expected to favour life-history traits associated with the highest fitness return. We use a long-term dataset of 277 life histories to investigate the shape and strength of selection acting on the age at first reproduction and at last reproduction in the long-lived Alpine Swift. Both traits were under strong directional selection, but in opposite directions, with selection favouring birds starting their reproductive career early and being able to reproduce for longer. There was also evidence for stabilising selection acting on both traits, suggesting that individuals should nonetheless refrain from reproducing in their first 2 years of life (i.e. when inexperienced), and that reproducing after 7 years of age had little effect on lifetime fitness, probably due to senescence.

Acute acquired toxoplasmosis: clinical-laboratorial aspects and ophthalmologic evaluation in a cohort of immunocompetent patients

Most cases of acute acquired toxoplasmosis (AAT) are oligosymptomatic and self-limited. Therefore, these infections rarely indicate treatment. Prospective studies of AAT patients are rare in the medical literature. The frequency of systemic manifestations has not been sufficiently studied. In order to search for risks factors for systemic and ocular involvement, 37 patients were submitted to a diagnostic investigative protocol. The most frequent findings were lymph node enlargement (94.6%), asthenia (86.5%), headache (70.3%), fever (67.6%) and weight loss (62.2%). Hepatomegaly and/or splenomegaly were present in 21.6% of cases (8/37). Liver transaminases were elevated in 11 patients (29.7%) and lactic dehydrogenase in 17 patients (45.9%). Anaemia was found in four patients (10.8%), leucopoenia in six patients (16.2%), lymphocytosis in 14 patients (37.8%) and thrombocytopenia in one patient (2.7%). Fundoscopic examination revealed retinochoroiditis in four patients (10.8%). No statistical association was found between any one morbidity and retinochoroiditis. Nevertheless, a significant association was found between the presence of more than eight morbidity features at evaluation and long-lasting disease. An ideal diagnostic protocol for AAT would include evidence of systemic involvement. Such a protocol could be used when planning treatment.

Acupuncture and rehabilitation of the painful shoulder: study protocol of an ongoing multicentre randomised controlled clinical trial [ISRCTN28687220]

BACKGROUND Although the painful shoulder is one of the most common dysfunctions of the locomotor apparatus, and is frequently treated both at primary healthcare centres and by specialists, little evidence has been reported to support or refute the effectiveness of the treatments most commonly applied. According to the bibliography reviewed, physiotherapy, which is the most common action taken to alleviate this problem, has not yet been proven to be effective, because of the small size of sample groups and the lack of methodological rigor in the papers published on the subject. No reviews have been made to assess the effectiveness of acupuncture in treating this complaint, but in recent years controlled randomised studies have been made and these demonstrate an increasing use of acupuncture to treat pathologies of the soft tissues of the shoulder. In this study, we seek to evaluate the effectiveness of physiotherapy applied jointly with acupuncture, compared with physiotherapy applied with a TENS-placebo, in the treatment of painful shoulder caused by subacromial syndrome (rotator cuff tendinitis and subacromial bursitis). METHODS/DESIGN Randomised controlled multicentre study with blind evaluation by an independent observer and blind, independent analysis. A study will be made of 465 patients referred to the rehabilitation services at participating healthcare centres, belonging to the regional public health systems of Andalusia and Murcia, these patients presenting symptoms of painful shoulder and a diagnosis of subacromial syndrome (rotator cuff tendinitis and subacromial bursitis). The patients will be randomised into two groups: 1) experimental (acupuncture + physiotherapy); 2) control (TENS-placebo + physiotherapy); the administration of rescue medication will also be allowed. The treatment period will have a duration of three weeks. The main result variable will be the change produced on Constant's Shoulder Function Assessment (SFA) Scale; as secondary variables, we will record the changes in diurnal pain intensity on a visual analogue scale (VAS), nocturnal pain intensity on the VAS, doses of non-steroid anti-inflammatory drugs (NSAIDs) taken during the study period, credibility scale for the treatment, degree of improvement perceived by the patient and degree of improvement perceived by the evaluator. A follow up examination will be made at 3, 6 and 12 months after the study period has ended. Two types of population will be considered for analysis: per protocol and per intention to treat. DISCUSSION The discussion will take into account the limitations of the study, together with considerations such as the choice of a simple, safe method to treat this shoulder complaint, the choice of the control group, and the blinding of the patients, evaluators and those responsible for carrying out the final analysis.

The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates

The CD209 gene family that encodes C-type lectins in primates includes CD209 (DC-SIGN), CD209L (L-SIGN) and CD209L2. Understanding the evolution of these genes can help understand the duplication events generating this family, the process leading to the repeated neck region and identify protein domains under selective pressure. We compiled sequences from 14 primates representing 40 million years of evolution and from three non-primate mammal species. Phylogenetic analyses used Bayesian inference, and nucleotide substitutional patterns were assessed by codon-based maximum likelihood. Analyses suggest that CD209 genes emerged from a first duplication event in the common ancestor of anthropoids, yielding CD209L2 and an ancestral CD209 gene, which, in turn, duplicated in the common Old World primate ancestor, giving rise to CD209L and CD209. K(A)/K(S) values averaged over the entire tree were 0.43 (CD209), 0.52 (CD209L) and 0.35 (CD209L2), consistent with overall signatures of purifying selection. We also assessed the Toll-like receptor (TLR) gene family, which shares with CD209 genes a common profile of evolutionary constraint. The general feature of purifying selection of CD209 genes, despite an apparent redundancy (gene absence and gene loss), may reflect the need to faithfully recognize a multiplicity of pathogen motifs, commensals and a number of self-antigens

Offer and use of complementary and alternative medicine in hospitals of the French-speaking part of Switzerland.

BACKGROUND: In 2004, complementary and alternative medicine (CAM) was offered by physicians in one-third of Swiss hospitals. Since then, CAM health policy has changed considerably. This study aimed to describe the present supply and use of CAM in hospitals in the French-speaking part of Switzerland, and to explore qualitatively the characteristics of this offer. METHODS: Between June 2011 and March 2012, a short questionnaire was sent to the medical directors of hospitals (n = 46), asking them whether CAM was offered, where and by whom. Then, a semi-directive interview was conducted with ten CAM therapists. RESULTS: Among 37 responses (return rate 80%), 19 medical directors indicated that their hospital offered at least one CAM and 18 reported that they did not. Acupuncture was the most frequently available CAM, followed by manual therapies, osteopathy and aromatherapy. The disciplines that offered CAM most frequently were rehabilitation, gynaecology and obstetrics, palliative care, psychiatry, and anaesthetics. In eight out of ten interviews, it appeared that the procedures for introducing a CAM in the hospital were not tightly supervised by the hospital and were mainly based on the goodwill of the therapists, rather than clinical/scientific evidence. CONCLUSION: The number of hospitals offering CAM in the French-speaking part of Switzerland seemed to have risen since 2004. The selection of a CAM to be offered in a hospital should be based on the same procedure of evaluation and validation as conventional therapy, and if the safety and efficiency of the CAM is evidence-based, it should receive the same resources as a conventional therapy.

Evaluation of the RapidAir 457 Air Void Analyzer, March 2012

An adequate air void system is imperative to produce concrete with freeze-thaw durability in a wet freeze environment such as found in Iowa. Specifications rely on a percentage of air obtained in the plastic state by the pressure meter. Actual, in place air contents, of some concrete pavements in Iowa, have been found with reduced air content due to a number of factors such as excessive vibration and inadequate mixing. Determining hardened air void parameters is a time consuming process involving potential for human error. The RapidAir 457 air void analyzer is an automated device used to determine hardened air void parameters. The device is used in Europe and has been shown to quickly produce accurate and repeatable hardened air results. This research investigates how well the RapidAir 457 results correlate to plastic air content and the image analysis air technique. The repeatability and operator variation were also investigated, as well as, the impact of aggregate porosity and selection of threshold value on hardened air results.

Manual for Evaluation, Rehabilitation and Strengthening of Low Volume Bridges, HR-323, 1993

This report contains an evaluation and design manual for strengthening and replacing low volume steel stringer and timber stringer bridges. An advisory panel consisting of county and municipal engineers provided direction for the development of the manual. NBI bridge data, along with results from questionnaires sent to county and municipal engineers were used to formulate the manual. Types of structures shown to have the greatest need for cost-effective strengthening methods are steel stringer and timber stringer bridges. Procedures for strengthening these two types of structures have been developed. Various types of replacement bridges have also been included so that the most cost effective solution for a deficient bridge may be obtained. The key results of this study is an extensive compilation, which can be used by county engineers, of the most effective techniques for strengthening deficient existing bridges. The replacement bridge types included have been used in numerous low volume applications in surrounding states, as well as in Iowa. An economic analysis for determining the cost-effectiveness of the various strengthening methods and replacement bridges is also an important part of the manual. Microcomputer spreadsheet software for several of the strengthening methods, types of replacement bridges and for the economic analysis has been developed, documented and presented in the manual. So the manual, Chp. 3 of the final report, can be easily located, blue divider pages have been inserted to delineate the manual from the rest of the report.

Positional bias of general and tissue-specific regulatory motifs in mouse gene promoters

Background: The arrangement of regulatory motifs in gene promoters, or promoterarchitecture, is the result of mutation and selection processes that have operated over manymillions of years. In mammals, tissue-specific transcriptional regulation is related to the presence ofspecific protein-interacting DNA motifs in gene promoters. However, little is known about therelative location and spacing of these motifs. To fill this gap, we have performed a systematic searchfor motifs that show significant bias at specific promoter locations in a large collection ofhousekeeping and tissue-specific genes.Results: We observe that promoters driving housekeeping gene expression are enriched inparticular motifs with strong positional bias, such as YY1, which are of little relevance in promotersdriving tissue-specific expression. We also identify a large number of motifs that show positionalbias in genes expressed in a highly tissue-specific manner. They include well-known tissue-specificmotifs, such as HNF1 and HNF4 motifs in liver, kidney and small intestine, or RFX motifs in testis,as well as many potentially novel regulatory motifs. Based on this analysis, we provide predictionsfor 559 tissue-specific motifs in mouse gene promoters.Conclusion: The study shows that motif positional bias is an important feature of mammalianproximal promoters and that it affects both general and tissue-specific motifs. Motif positionalconstraints define very distinct promoter architectures depending on breadth of expression andtype of tissue.

Validation of microsatellite markers for assisted selection of soybean resistance to cyst nematode races 3 and 14

The objective of this work was to validate microsatellite markers associated with resistance to soybean cyst nematode (Heterodera glycines Ichinohe) races 3 and 14, in soybean (Glycine max L.) genotypes, for use in marker-assisted selection (MAS) programs. Microsatellites of soybean linkage groups A2, D2 and G were tested in two populations, and their selection efficiencies were determined. The populations were 65 F2:3 families from Msoy8001 (resistant) x Conquista (susceptible) cross, and 66 F2:3 families of S5995 (resistant) x Renascença (susceptible) cross, evaluated for resistance to races 3 and 14, respectively. Families with female index up to 30% were considered moderately resistant. Markers of A2 and G linkage groups were associated with resistance to race 3. Markers Satt309 and GMENOD2B explained the greatest proportion of phenotypic variance in the different groups. The combinations Satt309+GMENOD2B and Satt309+Satt187 presented 100% selection efficiency. Resistance to race 14 was associated with markers of G linkage group, and selection efficiency in the Satt309+Satt356 combination was 100%. The selection differential obtained by phenotypic and marker assisted selection showed that both can result in similar gains.

Heritability and quantitative genetic divergence of serotiny, a fire-persistence plant trait.

BACKGROUND AND AIMS: Although it is well known that fire acts as a selective pressure shaping plant phenotypes, there are no quantitative estimates of the heritability of any trait related to plant persistence under recurrent fires, such as serotiny. In this study, the heritability of serotiny in Pinus halepensis is calculated, and an evaluation is made as to whether fire has left a selection signature on the level of serotiny among populations by comparing the genetic divergence of serotiny with the expected divergence of neutral molecular markers (QST-FST comparison). METHODS: A common garden of P. halepensis was used, located in inland Spain and composed of 145 open-pollinated families from 29 provenances covering the entire natural range of P. halepensis in the Iberian Peninsula and Balearic Islands. Narrow-sense heritability (h(2)) and quantitative genetic differentiation among populations for serotiny (QST) were estimated by means of an 'animal model' fitted by Bayesian inference. In order to determine whether genetic differentiation for serotiny is the result of differential natural selection, QST estimates for serotiny were compared with FST estimates obtained from allozyme data. Finally, a test was made of whether levels of serotiny in the different provenances were related to different fire regimes, using summer rainfall as a proxy for fire regime in each provenance. KEY RESULTS: Serotiny showed a significant narrow-sense heritability (h(2)) of 0·20 (credible interval 0·09-0·40). Quantitative genetic differentiation among provenances for serotiny (QST = 0·44) was significantly higher than expected under a neutral process (FST = 0·12), suggesting adaptive differentiation. A significant negative relationship was found between the serotiny level of trees in the common garden and summer rainfall of their provenance sites. CONCLUSIONS: Serotiny is a heritable trait in P. halepensis, and selection acts on it, giving rise to contrasting serotiny levels among populations depending on the fire regime, and supporting the role of fire in generating genetic divergence for adaptive traits.

Offer and use of complementary and alternative medicine in hospitals of the French-speaking part of Switzerland.

Background: In 2004, complementary and alternative medicine (CAM) was offered by physicians in one third of Swiss hospitals. Since then, CAM health policy has considerably changed. This study aims at describing the present supply and use of CAM in hospitals of the French-speaking part of Switzerland, and qualitatively explores the characteristics of this supply. Methods: Between June 2011 and March 2012, a short questionnaire was sent to the medical directors of hospitals (N=46), asking them whether a CAM was offered, where and by whom. Then, a semi-directive interview was conducted with 10 CAM therapists. Results: Among 37 responses (return rate 80%), 19 medical directors indicated that their hospital offered at least one CAM and 18 reported that they did not. Acupuncture was the most frequently proposed CAM, followed by manual therapies, osteopathy and aromatherapy. The disciplines that offered CAM most frequently were rehabilitation, gynaecology- obstetrics, palliative care, psychiatry and anaesthesiology. In eight out of ten interviews, it appeared that the procedures for introducing a CAM in the hospital were not tightly supervised by the hospital but were mainly based on the goodwill of the therapists, rather than clinical/scientific evidence. Conclusion: Hospitals offering CAM in the French-speaking part of Switzerland seems to have risen since 2004. The selection of CAM to be offered in a hospital should be based on the same procedure of evaluation and validation as conventional care, and if their safety and efficiency is evidence-based, they should receive the same structural resources.