Using EMRALD to assess baseline body mass index among children living within and outside communities participating in the Ontario, Canada Healthy Kids Community Challenge.
The Healthy Kids Community Challenge is a large-scale, centrally-coordinated, community-based intervention in Ontario, Canada that promotes healthy behaviours towards improving healthy weights among children. With the goal of exploring tools available to evaluators, we leveraged electronic medical records from primary care physicians to assess child weights prior to launch of the Healthy Kids Community Challenge. This study compares the baseline (i.e. pre-intervention) prevalence of overweight and obesity in children 1-12 years of age living within and outside Healthy Kids Community Challenge communities. Cross-sectional analysis of a primary care patient cohort. Electronic Medical Record Administrative data Linked Database (EMRALD) in Ontario, Canada. A cohort of 19 920 Ontario children who are rostered to an EMRALD physician. Children were 1-12 years of age at a primary care visit with recorded measured height and weight, between January 1, 2014 and December 31, 2015. Overweight and obesity as determined by age- and sex-standardized body mass index using World Health Organization's Growth Standards. In Healthy Kids Community Challenge communities, 25.6% (95% CI 24.6-26.6%) of children had zBMI above normal (i.e. >1) compared to 26.7% (95% CI 25.9-27.5%) for children living outside of Healthy Kids Community Challenge communities. Despite some differences in sociodemographic characteristics, zBMI of children aged 1-12 years were similar inside and outside of Healthy Kids Community Challenge community boundaries prior to program launch.


A Prospective Study of Axillary Hair Reduction in Patients Treated With Microwave Technology.
Removing unwanted body hair is a growing trend in society today, and there are many laser-based devices for hair reduction. There are some limitations to those methods, including the lack of efficacy for lighter color hair. The objective was to quantify hair reduction in the axillae after treatment with a noninvasive microwave energy device. A prospective, multicenter study was performed at 3 private dermatology clinics. Fifty-six adult subjects seeking axillary hair reduction were enrolled and treated with the device in 1 or 2 treatment sessions 3 months apart at various energy levels, and followed for 12 months. The primary analysis was monitoring reduction of hair counts from baseline to follow-up visits. A subject assessment of overall satisfaction, odor ratings, and sweat reduction ratings was provided at follow-up visits. Fifty-six subjects received treatment, with an average total underarm hair reduction of approximately 70% for both light and dark hair. Percentage of patients with hair reduction of 30% or more was significantly higher than 50% at all follow-up visits. Half of treated subjects reported expected mild transient post-treatment effects such as localized edema, discomfort, and bruising. Other reported events were mild. This clinical study provides evidence for safe and permanent axillary hair reduction, showing stable average reduction that lasted through the year of follow-up. Most notably, the study has shown the treatment's efficacy for reduction of light-colored axillary hair.


Mutations in the non-helical linker segment L1-2 of keratin 5 in patients with Weber-Cockayne epidermolysis bullosa simplex.
Keratins are the major structural proteins of the epidermis. Analyzing keratin gene sequences, appreciating the switch in keratin gene expression that takes place as epidermal cells commit to terminally differentiate, and elucidating how keratins assemble into 10 nm filaments, have provided the foundation that has led to the discoveries of the genetic bases of two major classes of human skin diseases, epidermolysis bullosa simplex (EBS) and epidermolytic hyperkeratosis (EH). These diseases involve point mutations in either the basal epidermal keratin pair, K5 and K14 (EBS), or the suprabasal pair, K1 and K10 (EH). In severe cases of EBS and EH, mutations are found in the highly conserved ends of the alpha-helical rod domain, regions that, by random mutagenesis, had already been found to be important for 10 nm filament assembly. In order to identify regions of the keratin polypeptides that might be more subtly involved in 10 nm filament assembly and to explore the diversity in mutations within milder cases of these diseases, we have focused on Weber-Cockayne EBS, where mild blistering occurs primarily on the hands and feet in response to mechanical stress. In this report, we show that affected members of two different W-C EBS families have point mutations within 1 residue of each other in the non-helical linker segment of the K5 polypeptide. Genetic linkage analyses, the absence of this mutation in > 150 wild-type alleles and filament assembly studies suggest that these mutations are responsible for the W-C EBS phenotype. These findings provide the best evidence to date that the non-helical linker region in the middle of the keratin polypeptides plays a subtle but significant role in intermediate filament structure and/or intermediate filament cytoskeletal architecture.


Association of the X-chromosomal genes TIMP1 and IL9R with rheumatoid arthritis.
Rheumatoid arthritis (RA) is an inflammatory joint disease with features of an autoimmune disease with female predominance. Candidate genes located on the X-chromosome were selected for a family trio-based association study. A total of 1452 individuals belonging to 3 different sample sets were genotyped for 16 single-nucleotide polymorphisms (SNP) in 7 genes. The first 2 sets consisted of 100 family trios, each of French Caucasian origin, and the third of 284 additional family trios of European Caucasian origin. Subgroups were analyzed according to sex of patient and presence of anti-cyclic citrullinated peptide (anti-CCP) autoantibodies. Four SNP were associated with RA in the first sample set and were genotyped in the second set. In combined analysis of sets 1 and 2, evidence remained for association of 3 SNP in the genes UBA1, TIMP1, and IL9R. These were again genotyped in the third sample set. Two SNP were associated with RA in the joint analysis of all samples: rs6520278 (TIMP1) was associated with RA in general (p = 0.035) and rs3093457 (IL9R) with anti-CCP-positive RA patients (p = 0.037) and male RA patients (p = 0.010). A comparison of the results with data from whole-genome association studies further supports an association of RA with TIMPL The sex-specific association of rs3093457 (IL9R) was supported by the observation that men homozygous for rs3093457-CC are at a significantly higher risk to develop RA than women (risk ratio male/female = 2.98; p = 0.048). We provide evidence for an association of at least 2 X-chromosomal genes with RA: TIMP1 (rs6520278) and IL9R (rs3093457).


Mutations causing childhood ataxia with central nervous system hypomyelination reduce eukaryotic initiation factor 2B complex formation and activity.
Childhood ataxia with central nervous system hypomyelination (CACH), or vanishing white matter leukoencephalopathy (VWM), is a fatal brain disorder caused by mutations in eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for protein synthesis and regulates translation in response to cellular stresses. We performed mutagenesis to introduce changes equivalent to 12 human CACH/VWM mutations in three subunits of the equivalent factor from yeast (Saccharomyces cerevisiae) and analyzed effects on cell growth, translation, and gene expression in response to stresses. None of the mutations is lethal or temperature sensitive, but almost all confer some defect in eIF2B function significant enough to alter growth or gene expression under normal or stress conditions. Biochemical analyses indicate that mutations analyzed in eIF2Balpha and -epsilon reduce the steady-state level of the affected subunit, while the most severe mutant tested, eIF2Bbeta(V341D) (human eIF2B(betaV316D)), forms complexes with reduced stability and lower eIF2B activity. eIF2Bdelta is excluded from eIF2Bbeta(V341D) complexes. eIF2B(betav341D) function can be rescued by overexpression of eIF2Bdelta alone. Our findings imply CACH/VWM mutations do not specifically impair responses to eIF2 phosphorylation, but instead cause protein structure defects that impair eIF2B activity. Altered protein folding is characteristic of other diseases, including cystic fibrosis and neurodegenerative disorders such as Huntington, Alzheimer's, and prion diseases.


Investigation of neuro-inflammatory parameters in a cuprizone induced mouse model of multiple sclerosis.
Cuprizone, copper chelator, treatment of mouse is a toxic model of multiple sclerosis (MS) in which oligodendrocyte death, demyelination and remyelination can be observed. Understanding T and B cell subset as well as their cytokines involved in MS pathogenesis still requires further scrutiny to better understand immune component of MS. The study presented here, aimed to evaluate relevant cytokines, lymphocytes, and gene expressions profiles during demyelination and remyelination in the cuprizone mouse model of MS. Eighty male C57BL/6J mice fed with 0.2% cuprizone for eight weeks. Cuprizone has been removed from the diet in the following eight weeks. Cuprizone treated and control mice sacrificed biweekly, and corpus callosum of the brain was investigated by staining. Lymphocyte cells of mice analyzed by flow cytometry with CD3e, CD11b, CD19, CD80, CD86, CD4, CD25 and FOXP3 antibodies. IFN-gamma, IL-1alpha, IL-2, IL-5, IL-6, IL-10, IL-17, TNF-alpha cytokines were analyzed in plasma samples. Neuregulin 1 (Nrg1), ciliary neurotrophic factor (Cntf) and C-X-C chemokine receptor type 4 (Cxcr4) gene expressions in corpus callosum sections of the mice brain were quantified. Histochemistry analysis showed that demyelination began at the fourth week of cuprizone administration and total demyelination occurred at the twelfth week in chronic model. Remyelination occurred at the fourth week of following withdrawal of cuprizone from diet. The level of mature and activated T cells, regulatory T cells, T helper cells and mature B cells increased during demyelination and decreased when cuprizone removed from diet. Further, both type 1 and type 2 cytokines together with the proinflammatory cytokines increased. The level of oligodendrocyte maturation and survival genes showed differential gene expression in parallel to that of demyelination and remyelination. In conclusion, for the first-time, involvement of both cellular immune response and antibody response as well as oligodendrocyte maturation and survival factors having role in demyelination and remyelination of cuprizone mouse model of MS have been shown.


How did the 'state of emergency' declaration in Japan due to the COVID-19 pandemic affect the acoustic environment in a rather quiet residential area?
The COVID-19 pandemic caused lockdowns in many countries worldwide. Acousticians have made surveys to monitor how cities became quieter under the lockdown, mainly in central areas in cities. However, there have been few studies on the changes in the acoustic environment due to the pandemic in the usually quieter residential areas. It may be expected to be different from the effect in 'originally noisy' areas. Also, the effect could be different in Japan, because the 'state of emergency' declaration there was different to lockdowns elsewhere. Considering these circumstances, this article reports the results of noise monitoring and makes some observations on the acoustic environment in residential areas far from city centres, to provide an example of how the acoustic environment was affected by the state of emergency declaration due to the COVID-19 pandemic in Japan. The results showed that the reduction of noise levels was somewhat less than that reported in large cities. Also, comparing the results after the cancellation of the state of emergency, the noise level increased again. However, observations of noise sources imply that a possible change in human behaviour may have also affected the acoustic environment.


Convergent functional genomics of genome-wide association data for bipolar disorder: comprehensive identification of candidate genes, pathways and mechanisms.
Given the mounting convergent evidence implicating many more genes in complex disorders such as bipolar disorder than the small number identified unambiguously by the first-generation Genome-Wide Association studies (GWAS) to date, there is a strong need for improvements in methodology. One strategy is to include in the next generation GWAS larger numbers of subjects, and/or to pool independent studies into meta-analyses. We propose and provide proof of principle for the use of a complementary approach, convergent functional genomics (CFG), as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach. With the CFG approach, the integration of genetics with genomics, of human and animal model data, and of multiple independent lines of evidence converging on the same genes offers a way of extracting signal from noise and prioritizing candidates. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder, yielding a series of novel (such as Klf12, Aldh1a1, A2bp1, Ak3l1, Rorb, Rora) and previously known (such as Bdnf, Arntl, Gsk3b, Disc1, Nrg1, Htr2a) candidate genes, blood biomarkers, as well as a comprehensive identification of pathways and mechanisms. These become prime targets for hypothesis driven follow-up studies, new drug development and personalized medicine approaches.


Heritability of the function and structure of the arterial wall: findings of the Erasmus Rucphen Family (ERF) study.
Using 930 individuals connected in a single pedigree from an isolated population, participants of the Erasmus Rucphen Family (ERF) study, we investigated the heritability of carotid-femoral pulse wave velocity (PWV), carotid intima media thickness (IMT), and carotid plaque score. PWV was measured between the carotid and femoral arteries as an indicator of aortic stiffness. Common carotid IMT and plaque score, quantifying alterations in arterial wall structure, were measured by ultrasonography. All 3 traits were significantly associated with classic cardiovascular risk factors. Age- and gender-adjusted heritability estimates were 0.36 for PWV, 0.41 for carotid IMT, and 0.28 for plaque score. After adjustment for appropriate risk factors, the heritabilities were 0.26, 0.35, and 0.21 for PWV, IMT, and plaque score, respectively. All heritability estimates were statistically significant (P<0.001). Taking into account different proportions of variance associated with covariates for each trait, genetic factors explained &12% of the total variability for each of the phenotypes. To our knowledge, this is the first report on the heritability of PWV. The heritability estimates of IMT and plaque score were similar to those in previous reports. We conclude that genetic factors significantly contribute to arterial structure and function in this isolated population, presenting the opportunity to locate susceptibility genes related to cardiovascular disorders.


Synthesis and Cyclic Voltammetry Studies of Copper Complexes of Bromo- and Alkoxyphenyl-Substituted Derivatives of Tris(2-pyridylmethyl)amine: Influence of Cation-Alkoxy Interactions on Copper Redox Potentials.
A combination of host-guest chemistry and coordination chemistry in the design of electrochemical sensors for alkali metal and ammonium ions is described. The sensor molecules are coordination complexes between a copper ion and a functionalized tripodal ligand. Upon presentation of the ion to the sensor molecule, a shift in the redox potential of the copper ion occurs. In the course of the study, three new alkoxyphenyl-substituted derivatives of the ligand tris(2-pyridylmethyl)amine (TPA) were prepared and characterized. The synthesis of the new ligands involved the preparation of bromopyridyl-TPA derivatives followed by Suzuki coupling with substituted phenylboronic acids. Cyclic voltammetry studies of copper complexes of the ligands indicated that steric effects played a dominant role in the overall determination of the copper redox couple. Studies of the alkoxyphenyl ligands indicated that small but reproducible changes in the copper redox couple occurred upon presentation of a guest cation that would be expected to form a complex with the copper-ligand complex.


Number of natural teeth, denture use and mortality in Chinese elderly: a population-based prospective cohort study.
The associations between the number of natural teeth/denture use and all-cause mortality remain unclear due to lake of investigation for the potential interaction between tooth loss and denture use and for the potential changes in these exposures over time in older adults. We undertake this study to evaluate the associations of the number of natural teeth and/or denture use with mortality in Chinese elderly. This is a prospective cohort study of 36,283 older adults (median age: 90). The number of natural teeth and denture use were collected with structured questionnaire. We evaluated hazard ratios (HRs) and confidence intervals (CIs) using a Cox proportional hazards model adjusting for demographic factors, education, income, lifestyle factors, and comorbidities. We documented 25,857 deaths during 145,947 person-years of observation. Compared to those with 20+ teeth, tooth loss was associated with a gradual increase in mortality, with an adjusted HR of 1.14 (95% CI, 1.06 to 1.23) for those with 10-19 teeth, 1.23 (95% CI, 1.15 to 1.31) for those with 1-9 teeth, and 1.35 (95% CI, 1.26 to 1.44) for those without natural teeth. Denture use was associated with lower risk of mortality (adjusted HR 0.81; 95% CI, 0.77 to 0.84). Subgroup analyses indicated that the benefit of denture use was greater in men than in women (P = 0.02) and tended to decrease with age (P < 0.001). The effects of denture use did not differ among various degrees of tooth loss (P = 0.17). Tooth loss was associated with an increased risk of mortality in older adults. Denture use provided a protective effect against death for all degrees of tooth loss however, this effect appeared to be modified by sex and age.


Passive avoidance training enhances cell proliferation in 1-day-old chicks.
One-day-old domestic chicks were injected i.p. with bromodeoxyuridine (BrdU) before training on a one-trial passive avoidance task where the aversive experience was a bead coated with a bitter tasting substance, methyl anthranilate (MeA). Animals were tested 24 h later; those avoiding (if MeA-trained) or pecking if water (W)-trained (which they peck appetitively), along with a group of untrained naïve chicks, were used to determine cell proliferation either 24 h or 9 days post BrdU injection. In all three groups, BrdU positive cells were identified sparsely throughout the forebrain but labelling was pronounced around ventricular zone (VZ) surfaces at both 24 h and 9 days post-BrdU-injection. Double immunolabelling with neuronal specific antibodies, to either NeuN, or beta-tubulin III, confirmed that most BrdU labelled cells appeared to be neurons. Unbiased stereological analysis of labelled cells in selected forebrain areas 24 h post BrdU injection showed a significant MeA-training induced increase in labelled cells in both the dorsal VZ surface bordering the intermediate and medial hyperstriatum ventrale (IMHV) and the tuberculum olfactorium (TO). By 9 days post-BrdU-injection, there was a significantly greater number of BrdU labelled cells in MeA-trained birds within the IMHV, lobus parolfactorius (LPO) and TO. These results demonstrate that avoidance training in 1-day-old chicks has a marked effect on cell proliferation, in the LPO and IMHV, regions of the chick previously identified as a key loci of memory formation, and in a second region (TO), which has olfactory functions, but has not been previously investigated in relation to avoidance learning.


Empirical evaluation of the association between daily living skills of adults with autism and parental caregiver burden.
Despite the joy of parenting, the burden of daily caregiving for children with autism spectrum disorders (ASD) can be overwhelming and constant. Parents can expect to provide enduring care for their children with ASD. Given that the majority of individuals with autism spectrum disorders (ASD) remain in their family homes well into adulthood, often the need for assistance with activities of daily living (ADLs) is placed on parents. Providing ongoing support to adult children who have difficulty with completing ADLs can increase parental caregiving demands. Therefore, the purpose of this study was to examine the relationship between the ability of adults with ASD to perform ADLs with parental perceptions of caregiver burden. Quantitative analysis of cross-sectional multi-state data gathered electronically using Qualtrics from 320 aging parents of adults with ASD was conducted. Regression models were fit to examine the association of ADL challenges with total caregiver burden and its four domains (emotional, financial, time dependence, and developmental). Parental perceptions of caregiver burden decreased, particularly time dependence and developmental burden, when adult children were less dependent in ADLs, even after adjusting for parental health and behavioral challenges. Findings support the need for family-centered interventions to improve the capacity of adults with ASD to perform ADLs independently.


The knirps and knirps-related genes organize development of the second wing vein in Drosophila.
The neighboring homologous knirps (kni) and knirps-related (knrl) genes in Drosophila encode transcription factors in the steroid hormone receptor superfamily. During early embryogenesis, kni functions as a gap gene to control expression of segmentation genes within the abdominal region of the embryo. In this study, we present evidence that kni and knrl link A/P positional information in larval wing imaginal discs to morphogenesis of the second longitudinal wing vein (L2). We show that kni and knrl are expressed in similar narrow stripes corresponding to the position of the L2 primordium. The kni and knrl L2 stripes abut the anterior border of the broad central expression domain of the Dpp target gene spalt major (salm). We provide evidence that radius incompletus (ri), a well-known viable mutant lacking the L2 vein, is a regulatory mutant of the kni/knrl locus. In ri mutant wing discs, kni and knrl fail to be expressed in the L2 primordium. In addition, the positions of molecular breakpoints in the kni/knrl locus indicate that the ri function is provided by cis-acting sequences upstream of the kni transcription unit. Epistasis tests reveal that the kni/knrl locus functions downstream of spalt major (salm) and upstream of genes required to initiate vein-versus-intervein differentiation. Mis-expression experiments suggest that kni and knrl expressing cells inhibit neighboring cells from becoming vein cells. Finally, kni and knrl are likely to refine the L2 position by positively auto-regulating their own expression and by providing negative feedback to repress salm expression. We propose a model in which the combined activities of kni and knrl organize development of the L2 vein in the appropriate position.


A highly bioactive bone extracellular matrix-biomimetic nanofibrous system with rapid angiogenesis promotes diabetic wound healing.
Treatment of diabetic wounds with a rapid healing performance remains a critical clinical challenge. An extracellular matrix (ECM)-biomimetic structure has shown promise in promoting tissue regeneration through a mediating cellular microenvironment. Herein, we report bone ECM-biomimetic cell-free nanofibrous scaffolds for enhancing healing in diabetic full-thickness wounds. This bioactive nanofibrous matrix was composed of ECM-componential collagen (Col, mimicking protein), polycaprolactone (PCL), and bioactive glass nanoparticles (BGNs, mimicking biological apatite) (CPB). The influence and mechanism of CPB on endothelial cell behaviors, angiogenic and healing abilities were investigated in a diabetic wound rat model. CPB significantly improved attachment and proliferation of endothelial cells, and upregulated the expression of the angiogenesis marker (CD31). In vivo, CPB also significantly enhanced the angiogenesis, through greatly upregulating the mRNA and protein expressions of Hif-1α, VEGF, Col1 and α-SMA. Furthermore, due to rapid angiogenesis, granulation tissue formation, collagen matrix remodeling and epidermis differentiation were accelerated in the CPB group, and as a result efficient diabetic wound healing was observed. Our results demonstrated that the cell-free bone-ECM-biomimetic BGN-based nanofibrous matrix could efficiently enhance blood tissue regeneration and diabetic wound healing without additional growth factors. Our biomimetic materials system may also be suitable for other blood vessel-related tissue repair and regeneration processes.


Assessment of skeletal muscle mass in critically ill patients: considerations for the utility of computed tomography imaging and ultrasonography.
Low muscularity and skeletal muscle atrophy are commonly exhibited in critically ill patients and have major implications on patient outcomes. Typically, in the ICU, body composition is assessed through anthropometrics or bioelectrical impedance analysis, but these modalities cannot specifically quantify skeletal muscle; thus, we evaluate the merits and challenges of using computed tomography (CT) and ultrasonography to specifically measure skeletal muscle in the ICU. CT-based cut points have been used to identify critically ill patients with low muscle mass, and low muscularity associates with poor clinical outcomes and function. Ultrasonography is emerging as a useful tool to quantify skeletal muscle loss and degradation in architecture, as well as prospectively track changes in these parameters over time. Rates of muscle atrophy and changes in muscle architecture has been quantified by ultrasonography and associated with poor clinical outcomes, but identification of critically ill patients with low muscularity is still in its infancy. CT imaging and ultrasonography require additional comprehensive validations against accurate measures of whole body muscle mass. As these validations begin to emerge, there will be a need to translate this knowledge into a simple tool that clinicians can apply as part of routine care.


Arthroaspis n. gen., a common element of the Sirius Passet Lagerstätte (Cambrian, North Greenland), sheds light on trilobite ancestry.
Exceptionally preserved Palaeozoic faunas have yielded a plethora of trilobite-like arthropods, often referred to as lamellipedians. Among these, Artiopoda is supposed to contain taxa united by a distinctive appendage structure. This includes several well supported groups, Helmetiida, Nektaspida, and Trilobita, as well as a number of problematic taxa. Interrelationships remain unclear, and the position of the lamellipedian arthropods as a whole also remains the subject of debate. Arthroaspis bergstroemi n. gen. n. sp., a new arthropod from the early Cambrian Sirius Passet Lagerstätte of North Greenland shows a striking combination of both dorsal and ventral characters of Helmetiida, Nektaspida, and Trilobita. Cladistic analysis with a broad taxon sampling of predominantly early Palaeozoic arthropods yields a monophyletic Lamellipedia as sister taxon to the Crustacea or Tetraconata. Artiopoda is resolved as paraphyletic, giving rise to the Marrellomorpha. Within Lamellipedia, a clade of pygidium bearing taxa is resolved that can be shown to have a broadly helmetiid-like tergite morphology in its ground pattern. This morphology is plesiomorphically retained in Helmetiida and in Arthroaspis, which falls basally into a clade containing Trilobita. The trilobite appendages, though similar to those of other lamellipedians in gross morphology, have a unique outward rotation of the anterior trunk appendages, resulting in a 'hard wired' lateral splay, different to that observed in other Lamellipedia. The combination of helmetiid, trilobite, and nektaspid characters in Arthroaspis gives important hints concerning character polarisation within the trilobite-like arthropods. The distinctive tergite morphology of trilobites, with its sophisticated articulating devices, is derived from flanged edge-to-edge articulating tergites forming a shield similar to the helmetiids, previously considered autapomorphic for that group. The stereotypical lateral splay of the appendages of lamellipedians is a homoplastic character shown to be achieved by several groups independently.


Frequency shift and cavity length in photorefractive resonators.
Photorefractive resonators exhibit an extremely small frequency difference (Deltaomega/omega~10(-15)) between the oscillating and pumping beams. The observed frequency difference is proportional to cavity-length detuning. This dependence is explained by a photorefractive phase shift that is due to slightly nondegenerate two-wave mixing that compensates for cavity detuning and satisfies the round-trip phase condition for steady-state oscillation. The measured onset or threshold of oscillation as a function of photorefractive gain and intensity agrees with theory.


The Shigella Vaccines Pipeline.
Shigella is the leading cause of global diarrheal deaths that currently lacks a licensed vaccine. Shigellosis drives antimicrobial resistance and leads to economic impact through linear growth faltering. Today, there is a robust pipeline of vaccines in clinical development which are broadly divided into parenteral glycoconjugate vaccines, consisting of O-antigen conjugated to carrier proteins, and oral live attenuated vaccines, which incorporate targeted genetic mutations seeking to optimize the balance between reactogenicity, immunogenicity and ultimately protection. Proof of efficacy has previously been shown with both approaches but for various reasons no vaccine has been licensed to date. In this report, we outline the requirements for a Shigella vaccine and describe the current pipeline in the context of the many candidates that have previously failed or been abandoned. The report refers to papers from individual vaccine developers in this special supplement of Vaccines which is focused on Shigella vaccines. Once readouts of safety and immunogenicity from current trials of lead candidate vaccines among the target population of young children in low- and middle-income countries are available, the likely time to licensure of a first Shigella vaccine will become clearer.


Reduced mortality risk in alcoholics who achieve long-term abstinence.
To determine if alcoholic men who achieved stable abstinence experienced fewer deaths than those who relapsed and to develop a model predictive of premature mortality. A cohort of alcoholic men recruited into a prospective study of neurocognitive effects of alcoholism was followed up from 1 through 11 years. A demographically equated group of nonalcoholic men was also followed up. Alcoholics were classified as stable abstainers or relapsers. Alcoholics were patients or ex-patients from a Department of Veterans Affairs Alcoholism Treatment Program and/or members of local chapters of Alcoholics Anonymous. There were 234 alcoholic men who met the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, criteria for alcohol dependence. Follow-up status regarding relapse and mortality was obtained for 199 alcoholic subjects (85%). Of these, 101 had relapsed and 98 had abstained. Ninety-eight nonalcoholic controls equated for age, education, and sex also participated. Mortality status was obtained for 92 subjects in this group (94%). Major medical and psychiatric illness and history of nonalcoholic drug abuse. Death during a follow-up period of 1 through 11 years. Death was ascertained through the National Death Index, the California State Department of Health and Vital Statistics, the State Department of Motor Vehicles, and through personal contact with informants, relatives, and significant others of the subjects. There were 19 deaths among relapsed alcoholics compared with the expected number of 3.83 (99% confidence interval (CI), 9.64 to 33.38). Among abstinent alcoholics there were four deaths (expected = 3.21; 99% CI, 0.67 to 12.59). The standardized mortality ratio for relapsed alcoholics was 4.96, which significantly exceeded the expected ratio (P less than .001), whereas the standardized mortality ratio for abstinent alcoholics (1.25) was indistinguishable from the expected. Cox proportional hazards analysis was used to determine if any of several demographic, medical, cognitive, or drinking history variables (in addition to relapse) helped predict mortality among alcoholics. Only relapse was significantly related to increased mortality (chi 2 = 9.15, P = .003). Alcoholic men who achieve stable abstinence do not differ from nonalcoholic men in mortality experience; however, alcoholics who relapse die at a rate 4.96 times that of an age-, sex-, and race-matched representative sample from the US Bureau of the Census.


High Rate of Acquisition but Short Duration of Carriage of Multidrug-Resistant Enterobacteriaceae After Travel to the Tropics.
Multidrug-resistant Enterobacteriaceae (MRE) are widespread in the community, especially in tropical regions. Travelers are at risk of acquiring MRE in these regions, but the precise extent of the problem is not known. From February 2012 to April 2013, travelers attending 6 international vaccination centers in the Paris area prior to traveling to tropical regions were asked to provide a fecal sample before and after their trip. Those found to have acquired MRE were asked to send fecal samples 1, 2, 3, 6, and 12 months after their return, or until MRE was no longer detected. The fecal relative abundance of MRE among all Enterobacteriaceae was determined in each carrier. Among 824 participating travelers, 574 provided fecal samples before and after travel and were not MRE carriers before departure. Of these, 292 (50.9%) acquired an average of 1.8 MRE. Three travelers (0.5%) acquired carbapenemase-producing Enterobacteriaceae. The acquisition rate was higher in Asia (142/196 [72.4%]) than in sub-Saharan Africa (93/195 [47.7%]) or Latin America (57/183 [31.1%]). MRE acquisition was associated with the type of travel, diarrhea, and exposure to β-lactams during the travel. Three months after return, 4.7% of the travelers carried MRE. Carriage lasted longer in travelers returning from Asia and in travelers with a high relative abundance of MRE at return. MRE acquisition is very frequent among travelers to tropical regions. Travel to these regions should be considered a risk factor of MRE carriage during the first 3 months after return, but not beyond. NCT01526187.


Principles of transverse flow fractionation of microparticles in superhydrophobic channels.
We propose a concept of fractionation of micron-sized particles in a microfluidic device with a bottom wall decorated by superhydrophobic stripes. The stripes are oriented at an angle α to the direction of a driving force, G, which generally includes an applied pressure gradient and gravity. Separation relies on the initial sedimentation of particles under gravity in the main forward flow, and their subsequent lateral deflection near a superhydrophobic wall due to generation of a secondary flow transverse to G. We provide some theoretical arguments allowing us to quantify the transverse displacement of particles in the microfluidic channel, and confirm the validity of theoretical predictions in test experiments with monodisperse fractions of microparticles. Our results can guide the design of superhydrophobic microfluidic devices for efficient sorting of microparticles with a relatively small difference in size and density.


Methods of the International Tobacco Control (ITC) Four Country Survey.
This paper outlines the design features, data collection methods and analytic strategies of the International Tobacco Control (ITC) Four Country Survey, a prospective study of more than 2000 longitudinal respondents per country with yearly replenishments. This survey possesses unique features that sets it apart among surveys on tobacco use and cessation. One of these features is the use of theory-driven conceptual models. In this paper, however, the focus is on the two key statistical features of the survey: longitudinal and "quasi-experimental" designs. Although it is often possible to address the same scientific questions with a cross-sectional or a longitudinal study, the latter has the major advantage of being able to distinguish changes over time within individuals from differences among people at baseline (that is, differences between age and cohort effects). Furthermore, quasi-experiments, where countries not implementing a given new tobacco control policy act as the control group to which the country implementing such a policy will be compared, provide much stronger evidence than observational studies on the effects of national-level tobacco control policies. In summary, application of rigorous research methods enables this survey to be a rich data resource, not only to evaluate policies, but also to gain new insights into the natural history of smoking cessation, through longitudinal analyses of smoker behaviour.


Mechanistic insight into the ruthenium-catalysed anti-Markovnikov hydration of alkynes using a self-assembled complex: a crucial role for ligand-assisted proton shuttle processes.
A combined computational and experimental study is presented that investigates the mechanism of the anti-Markovnikov hydration of phenylacetylene by [Ru(η(5)-C5H5)(6-DPPAP)(3-DPICon)](+) (where 6-DPPAP = 6-(diphenylphosphino)-N-pivaloyl-2-aminopyridine) and 3-DPICon = 3-diphenylphosphinoisoquinolone). The proposed mechanism, modelled using density functional calculations, involves an initial alkyne-vinylidene tautomerism, which occurs via a ligand-assisted proton shuttle (LAPS) mechanism. Intramolecular ligand assistance from the 6-DPPAP and 3-DPICon ligands, particularly the basic nitrogen of 6-DPPAP, is also involved in subsequent stages of the mechanism and three LAPS processes in total are observed. The self-assembled ligand backbone helps to create a water-binding pocket close to the metal centre, which facilitates nucleophilic attack of water at the vinylidene α-carbon and mediates protonation and deprotonation of subsequent acyl and vinyl intermediates. Experimental evidence is also presented for a novel non-productive catalyst deactivation pathway, which appears to arise from an initial lactam-lactim tautomerism of the 3-DPICon ligand followed by coupling with a vinylidene.


A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment.
Erroneous replication of lesions in DNA by DNA polymerases leads to elevated mutagenesis. To understand the molecular basis of DNA damage-induced mutagenesis, we have determined the x-ray structures of the Y-family polymerase, Dpo4, in complex with a DNA substrate containing a bulky DNA lesion and incoming nucleotides. The DNA lesion is derived from an environmentally widespread carcinogenic polycyclic aromatic hydrocarbon, benzo[a]pyrene (BP). The potent carcinogen BP is metabolized to diol epoxides that form covalent adducts with cellular DNA. In the present study, the major BP diol epoxide adduct in DNA, BP-N(2)-deoxyguanosine (BP-dG), was placed at a template-primer junction. Three ternary complexes reveal replication blockage, extension past a mismatched lesion, and a -1 frameshift mutation. In the productive structures, the bulky adduct is flipped/looped out of the DNA helix into a structural gap between the little finger and core domains. Sequestering of the hydrophobic BP adduct in this new substrate-binding site permits the DNA to exhibit normal geometry for primer extension. Extrusion of the lesion by template misalignment allows the base 5' to the adduct to serve as the template, resulting in a -1 frameshift. Subsequent strand realignment produces a mismatched base opposite the lesion. These structural observations, in combination with replication and mutagenesis data, suggest a model in which the additional substrate-binding site stabilizes the extrahelical nucleotide for lesion bypass and generation of base substitutions and -1 frameshift mutations.


Cellular pathophysiology of Friedreich's ataxia cardiomyopathy.
Friedreich's ataxia (FRDA) is a hereditary neuromuscular disorder. Cardiomyopathy is the leading cause of premature death in FRDA. FRDA cardiomyopathy is a complex and progressive disease with no cure or treatment to slow its progression. At the cellular level, cardiomyocyte hypertrophy, apoptosis and fibrosis contribute to the cardiac pathology. However, the heart is composed of multiple cell types and several clinical studies have reported the involvement of cardiac non-myocytes such as vascular cells, autonomic neurons, and inflammatory cells in the pathogenesis of FRDA cardiomyopathy. In fact, several of the cardiac pathologies associated with FRDA including cardiomyocyte necrosis, fibrosis, and arrhythmia, could be contributed to by a diseased vasculature and autonomic dysfunction. Here, we review available evidence regarding the current understanding of cellular mechanisms for, and the involvement of, cardiac non-myocytes in the pathogenesis of FRDA cardiomyopathy.


Determinants of in vivo activity of neutral endopeptidase 184.108.40.206 and angiotensin converting enzyme inhibitors.
Simultaneous inhibition of neutral endopeptidase EC 22.214.171.124 (NEP) and angiotensin converting enzyme (ACE) by equimolar doses (100 mumol/kg i.v.) of SQ 28603 (N-[2-(mercaptomethyl)-1-oxo-3- phenylpropyl]-beta-alanine) and captopril increased sodium excretion by 888 +/- 377 microEq/3 hr and significantly lowered blood pressure by -6 +/- 2 mm Hg in conscious cynomolgus monkeys. This rate of sodium excretion was not significantly different from that elicited by 100 mumol/kg i.v. of SQ 28603 alone (1453 +/- 315 microEq/3 hr). In addition, the natriuretic response to captopril plus SQ 28603 was potentiated by infusion of 10 pmol/kg/min of human atrial natriuretic peptide (hANP 99-126) despite a reduction in renal perfusion pressure from 100 +/- 2 to 86 +/- 2 mm Hg. Lower doses (0.3 to 3 mumol/kg i.v.) of SQ 28603 that had no effect on blood pressure or renal function potentiated the natriuretic, urinary cyclic guanosine monophosphate and atrial natriuretic peptide responses without affecting the depressor activity of 0.3 nmol/kg i.v. of hANP 99-126. The potentiation of the natriuretic activity of 0.3 nmol/kg of hANP 99-126 by 1 or 3 mumol/kg of SQ 28603 was not significantly affected by the addition of equimolar doses of captopril. These results confirmed that the renal responses to the combined inhibitors resulted from NEP inhibition. In contrast, the depressor activity of the combined inhibitors was dependent on the level of ACE inhibition and was not significantly affected by either infusion of hANP 99-126 or prior sodium loading. Therefore, the vascular responses to combined NEP and ACE inhibitors did not necessarily depend upon increases in circulating atrial natriuretic peptide or reductions in angiotensin II levels. The unique profile of renal and vascular responses to combined NEP and ACE inhibition suggested that dual NEP/ACE inhibitors may be useful for the treatment of cardiovascular disorders.


Predicting postoperative hydrocephalus in 227 patients with skull base meningioma.
Some patients develop communicating hydrocephalus after meningioma surgery, and this can develop into a serious clinical condition. However, this has rarely been addressed in the literature. Therefore, the authors sought to determine predictive patient variables for the occurrence of postoperative hydrocephalus following skull base meningioma surgery. For this purpose, the authors retrospectively analyzed all patients who underwent resection of intracranial meningiomas between 1998 and 2009 at the Department of Neurosurgery, University Hospital Zurich, Switzerland. Of 594 patients with meningioma, 227 (38%) had a lesion located at the skull base, and thus were included for analysis. The following patient variables were examined: demographic data (age and sex); tumor number (solitary vs multiple); tumor side and localization within the skull base region (anterior, medial, posterior); infiltration of the cavernous sinus; compression of the optic channel/optic nerve; tumor volume; preoperative embolization (yes/no); duration of surgery; Simpson grade of resection; histopathological features (WHO grade); number of surgeries (single vs multiple); preoperative embolization; duration of hospital stay; tumor recurrence; use of an artificial dural substitute; postoperative infection rate; and clinical outcome (Glasgow Outcome Scale score at discharge and at 3 months, and vital status at last follow-up). Hierarchical clustering, factor analysis, and stepwise regression models revealed a ranking list for the top predictive variables for the occurrence of postoperative hydrocephalus. A total of 35 patients (5.9%) of the cohort of 594 developed communicating postoperative hydrocephalus, with no patient manifesting obstructive hydrocephalus. Of these 35 patients, 18 had a meningioma located at the skull base (18 [7.9%] of 227), in contrast to 17 patients with meningiomas in other locations (17 [4.6%] of 367). The following patient variables correlated with the occurrence of hydrocephalus, as defined by factor analysis: age, duration of surgery, duration of hospital stay, tumor volume, postoperative infection, and preoperative embolization. A stepwise regression analysis of the latter variables identified 2 variables as significantly predictive: age (p = 0.0012) and duration of surgery (p = 0.0013). In this study, the incidence of communicating postoperative hydrocephalus was almost twice as high in patients with skull base lesions as in patients with meningiomas in other locations. Patient age, duration of surgery, duration of hospital stay, tumor volume, postoperative infection, and preoperative embolization were associated with the occurrence of hydrocephalus. In the statistical prediction model, patient age and duration of surgery were the most significant predictors of postoperative hydrocephalus after skull base meningioma surgery.


The Epstein-Barr virus Zta transactivator: a member of the bZIP family with unique DNA-binding specificity and a dimerization domain that lacks the characteristic heptad leucine zipper motif.
Introduction of the zta gene of Epstein-Barr virus into latently infected B cells leads to induction of the entire lytic cycle program of the virus. The Zta gene product is a sequence-specific DNA-binding protein of 35 kilodaltons that behaves as a specific transcriptional transactivator in transient cotransfection assays. All known Zta-responsive target promoters contain one or more members of a family of consensus-binding sites known as ZREs. On the basis of the presence of limited amino acid similarity within a basic carboxy-terminal domain, Zta has been proposed to be a highly divergent member of the c-Jun/c-Fos/GCN4 family of AP-1-binding proteins. We show here that in vitro-translated Zta and the Jun:Fos proteins have overlapping but distinct target DNA-binding specificies; both recognize canonical AP-1 sites, but only Zta recognizes ZRE sites and only Jun:Fos recognizes CRE sites. The relative binding affinity of Zta for oligonucleotides containing the 7-base-pair c-Fos AP-1 site TGAGTCA was twofold greater than that for the ZRE core motifs TGAGCAA, TG TGCAA, and TGAGTAA, but 10-fold greater than that for TGTGTCA, as measured by gel mobility retardation and competition DNA-binding assays. Cross-linking and cotranslational heterodimerization assays showed that like GCN4, Zta forms a stable homodimer in both its DNA-bound and unbound forms. Furthermore, we show that a potential coiled-coil helical domain adjacent to the basic domain of Zta can substitute for the leucine zipper of c-Fos to produce a DNA-binding protein that has a very stringent target DNA specificity and can only recognize symmetric 9-base-pair AP-1 sites (ATGAGTCAT). Therefore, despite the absence of the repeated heptad leucine zipper motifs, the Zta protein retains the characteristic features of a juxtaposed basic region and an exactly aligned coiled-coil alpha-helical dimerization domain of the bZIP class of transcriptional regulatory factors.


Trajectories of pain predict disabilities affecting daily living in arthritis.
To examine the interplay between pain and disability in arthritis when adjusting for patient heterogeneity in pain progression. There is consistent evidence to suggest that people experience osteoarthritis heterogeneously, with subgroups of people having different trajectories of pain. However, at present it is unclear how these pain trajectories are related to functional disability. We ask the question: Do levels of disability track changes in pain across different pain trajectories? Secondary analysis of a subset (n = 889) from a cohort of older English adults, representative of the general population (the English Longitudinal Study of Ageing). The relationship between pain and functional disability was compared in three domains of disability: mobility, activities of daily living (ADL) and instrumental ADL. These represent increasingly complex forms of self-care required for independent living. Data analysis compared the heterogeneous analysis of pain (different trajectories) and disability compared to treating pain as a simpler homogenous construct. On a population level, pain was significantly positively correlated with increased disability in all three domains, and the relationship remained stable over time. However, when heterogeneity was examined respondents whose pain improved did not show a corresponding improvement in disability in two domains (ADL and mobility). These findings highlight how, for some people, alleviating pain, the main symptom of arthritis, might not prevent the persistence or progression of disability. Even when pain improves, further interventions that improve disability are likely to be required. Statement of contribution What is already known on this subject? Pain and functional limitation in daily living are common symptoms of arthritis. Arthritis pain is heterogeneous - there are trajectories of people whose pain gets better or worse. However, to date no study has looked at the relationship between trajectories of arthritis pain and functional disability outside of the minority of people with rheumatoid arthritis. What does this study add? Treating pain as heterogeneous explained disability better than treating pain as a single entity. Respondents in a trajectory of worsening pain reported functional disability in two domains (mobility and activities of daily living) also got worse over time. People in a trajectory of decreasing pain over time did not experience a reduction in disability, despite pain being the most common reason for why people limit their daily functioning. This suggests further intervention is required for people with arthritis, even when the most visible symptoms have been alleviated.


A Longitudinal Study of the Presence of Dental Anomalies in the Primary and Permanent Dentitions of Cleft Lip and/or Palate Patients.
The aim is to survey primary and permanent dental anomalies: hypodontia, microdontia, a supernumerary tooth, and fused teeth in patients with cleft lip and/or palate. Retrospective longitudinal study Subjects : The subjects were selected from all 1724 patients with cleft lip and/or palate who were registered at the orthodontic clinic of Kyushu University Hospital, Fukuoka, Japan, from 1970 to 2009. Finally, 994 subjects were evaluated for primary dentition, 1352 for permanent dentition, and 871 for the longitudinal changes from primary to permanent dentition. The prevalence of dental anomalies was compared for each tooth type, among various cleft types, between males and females, and between the alveolar cleft area and the noncleft area. The prevalence of hypodontia was 16.2% for primary dentition and 52.7% for permanent dentition in the subjects with cleft lip and/or palate. Hypodontia increased with the severity of the cleft type. Multiple hypodontia was found more frequently in the subjects with bilateral cleft lip and palate and the subjects with unilateral cleft lip and palate. Microformed lateral incisors were found in 22.7% of permanent lateral incisors but not in primary dentition. Supernumerary teeth were found in 17.7% of the subjects with cleft lip and/or palate for primary maxillary dentition and in 5.7% for permanent maxillary dentition. The prevalence of hypodontia was greater in permanent dentition than in primary dentition; although, it was not much different between males and females or between the right and left sides. The prevalence of dental anomalies was significantly different among four groups by cleft type: cleft lip, cleft lip and alveolus, cleft lip and palate, and cleft palate.


Who should have carotid surgery or angioplasty?
Carotid endarterectomy reduces the overall risk of stroke in patients with ECST70-99% recently symptomatic stenosis, and to a lesser extent, at least in the short-term, in patients with severe asymptomatic stenosis. Whether angioplasty and stenting is a reasonable alternative will be decided by the results of ongoing RCTs of angioplasty versus endarterectomy. The current policy of operating on all patients with a recently symptomatic severe carotid stenosis will, on average, do more good than harm. However, the number of patients needed to treat to prevent one stroke is still relatively high. The effectiveness of endarterectomy could be improved by selecting patients more rigorously. Subgroup analysis and risk factor modelling are likely to be of some value, but further testing is required before final models can be recommended for routine use in clinical practice. However, it is also likely that predictive models will eventually also take into account information on cerebral microemboli, cerebral perfusion, and genetic characteristics. The development and validation of integrated predictive models, combining these different modalities, will require large prospective clinical studies.


Rate of caffeine metabolism and risk of spontaneous abortion.
In a case-control study of 73 women with and 141 women without spontaneous abortion, the authors determined the activity of the three principal caffeine-metabolizing enzymes--cytochrome P-4501A2 (CYP1A2), xanthine oxidase, and N-acetyltransferase 2--by measuring levels of caffeine metabolites in urine. After examining the effect of enzyme activity and different levels of caffeine intake, they concluded that there was no evidence that an interaction between enzyme activity and caffeine intake during pregnancy resulted in risk of spontaneous abortion. In a subsample comparing 24 cases with recurrent (two or more) spontaneous abortions and 21 controls with two or more livebirths and no previous spontaneous abortions, the unadjusted odds ratio for low CYP1A2 enzyme activity (below the median) was 0.92 (95% confidence interval (CI) 0.28-3.04) compared with higher CYP1A2 activity. The odds ratio for risk of recurrent spontaneous abortion and low xanthine oxidase activity (below the median) versus higher activity was 0.37 (95% CI 0.10-1.29). Phenotypically slow acetylators (N-acetyltransferase 2 index <0.37) had an odds ratio of 1.58 (95% CI 0.48-5.13) for recurrent loss compared with rapid acetylators. Thus, some association of the latter two caffeine-metabolizing enzymes with recurrent spontaneous abortion is suggested but may also be due to chance.


Validation of a novel stand-alone software tool for image guided cardiac catheter therapy.
Comparison of the targeting accuracy of a new software method for MRI-fluoroscopy guided endomyocardial interventions with a clinically available 3D endocardial electromechanical mapping system. The new CARTBox2 software enables therapy target selection based on infarction transmurality and local myocardial wall thickness deduced from preoperative MRI scans. The selected targets are stored in standard DICOM datasets. Fusion of these datasets with live fluoroscopy enables real-time visualization of MRI defined targets during fluoroscopy guided interventions without the need for external hardware. In ten pigs (60-75 kg), late gadolinium enhanced (LGE) MRI scans were performed 4 weeks after a 90-min LAD occlusion. Subsequently, 10-16 targeted fluorescent biomaterial injections were delivered in the infarct border zone (IBZ) using either the NOGA 3D-mapping system or CARTBox2. The primary endpoint was the distance of the injections to the IBZ on histology. Secondary endpoints were total procedure time, fluoroscopy time and dose, and the number of ventricular arrhythmias. The average distance of the injections to the IBZ was similar for CARTBox2 (0.5 ± 3.2 mm) and NOGA (- 0.7 ± 2.2 mm; p = 0.52). Injection procedures with CARTBox2 and NOGA required 69 ± 12 and 60 ± 17 min, respectively (p = 0.36). The required endocardial mapping procedure with NOGA prior to injections, leads to a significantly longer total procedure time (p < 0.001) with NOGA. Fluoroscopy time with NOGA (18.7 ± 11.0 min) was significantly lower than with CARTBox2 (43.4 ± 6.5 min; p = 0.0003). Procedures with CARTBox2 show a trend towards less ventricular arrhythmias compared to NOGA. CARTBox2 is an accurate and fast software-only system to facilitate cardiac catheter therapy based on gold standard MRI imaging and live fluoroscopy.


A framework for multiple imputation in cluster analysis.
Multiple imputation is a common technique for dealing with missing values and is mostly applied in regression settings. Its application in cluster analysis problems, where the main objective is to classify individuals into homogenous groups, involves several difficulties which are not well characterized in the current literature. In this paper, we propose a framework for applying multiple imputation to cluster analysis when the original data contain missing values. The proposed framework incorporates the selection of the final number of clusters and a variable reduction procedure, which may be needed in data sets where the ratio of the number of persons to the number of variables is small. We suggest some ways to report how the uncertainty due to multiple imputation of missing data affects the cluster analysis outcomes-namely the final number of clusters, the results of a variable selection procedure (if applied), and the assignment of individuals to clusters. The proposed framework is illustrated with data from the Phenotype and Course of Chronic Obstructive Pulmonary Disease (PAC-COPD) Study (Spain, 2004-2008), which aimed to classify patients with chronic obstructive pulmonary disease into different disease subtypes.


Exposure to environmental radionuclides is associated with altered metabolic and immunity pathways in a wild rodent.
Wildlife inhabiting environments contaminated by radionuclides face putative detrimental effects of exposure to ionizing radiation, with biomarkers such as an increase in DNA damage and/or oxidative stress commonly associated with radiation exposure. To examine the effects of exposure to radiation on gene expression in wildlife, we conducted a de novo RNA sequencing study of liver and spleen tissues from a rodent, the bank vole Myodes glareolus. Bank voles were collected from the Chernobyl Exclusion Zone (CEZ), where animals were exposed to elevated levels of radionuclides, and from uncontaminated areas near Kyiv, Ukraine. Counter to expectations, we did not observe a strong DNA damage response in animals exposed to radionuclides, although some signs of oxidative stress were identified. Rather, exposure to environmental radionuclides was associated with upregulation of genes involved in lipid metabolism and fatty acid oxidation in the livers - an apparent shift in energy metabolism. Moreover, using stable isotope analysis, we identified that fur from bank voles inhabiting the CEZ had enriched isotope values of nitrogen: such an increase is consistent with increased fatty acid metabolism, but also could arise from a difference in diet or habitat between the CEZ and elsewhere. In livers and spleens, voles inhabiting the CEZ were characterized by immunosuppression, such as impaired antigen processing, and activation of leucocytes involved in inflammatory responses. In conclusion, exposure to low dose environmental radiation impacts pathways associated with immunity and lipid metabolism, potentially as a stress-induced coping mechanism.


Induction of fenarimol-efflux activity in Aspergillus nidulans by fungicides inhibiting sterol biosynthesis.
Fungicides inhibiting sterol biosynthesis belong to chemically distinct classes such as imidazole, morpholine, pyridine, pyrimidine and triazole derivatives. Incubation of mycelium of Aspergillus nidulans for 90 min with representatives of these fungicides induced an efflux activity which prevented accumulation of fenarimol, a pyrimidine derivative, into the mycelium. Induction of this efflux activity reduced the fungitoxicity of fenarimol. Addition of oligomycin to mycelium in which fenarimol-efflux activity was induced immediately increased the uptake of fenarimol, indicating that the efflux activity is energy-dependent. Subsequent disruption of membrane permeability with sodium lauryl sulphate instantaneously caused leakage of fenarimol from the mycelium into the medium. The ability to induce fenarimol efflux is rather specific for inhibitors of sterol biosynthesis: except for pimaricin, fungicides with unrelated mechanisms of action did not have this ability.


Glucose uptake patterns in exercised skeletal muscles of elite male long-distance and short-distance runners.
The aim of this study was to determine glucose uptake patterns in exercised skeletal muscles of elite male long-distance and short-distance runners. Positron emission tomography (PET) using 18F-fluoro-2-deoxyglucose (FDG) was performed to determine the patterns of glucose uptake in lower limbs of short-distance (SD group, n=8) and long-distance (LD group, n=8) male runners after a modified 20 min Bruce treadmill test. Magnetic resonance imaging (MRI) was used to delineate the muscle groups in lower limbs. Muscle groups from hip, knee, and ankle movers were measured. The total FDG uptake and the standard uptake value (SUV) for each muscle group were compared between the 2 groups. For the SD and LD runners, the 2 major muscle groups utilizing glucose during running were knee extensors and ankle plantarflexors, which accounted for 49.3 +/- 8.1% (25.1 +/- 4.7% and 24.2 +/- 6.0%) of overall lower extremity glucose uptake for SD group, and 51.3 +/- 8.0% (27.2 +/- 2.7% and 24.0 +/- 8.1%) for LD group. No difference in muscle glucose uptake was noted for other muscle groups. For SD runners, the SUVs for the muscle groups varied from 0.49 +/- 0.27 for the ankle plantarflexors, to 0.20 +/- 0.08 for the hip flexor. For the LD runners, the highest and lowest SUVs were 0.43 +/- 0.15 for the ankle dorsiflexors and 0.21 +/- 0.19 for the hip. For SD and LD groups, no difference in muscle SUV was noted for the muscle groups. However, the SUV ratio between the ankle dorsiflexors and plantarflexors in the LD group was significantly greater than that in the SD group. We thus conclude that the major propelling muscle groups account for approximately 50% of lower limb glucose utilization during running. Thus, the other muscle groups involving maintenance of balance, limb deceleration, and shock absorption utilize an equal amount. This result provides a new insight into glucose distribution in skeletal muscle, suggesting that propellers and supporters are both energetically important during running. Furthermore, for each unit muscle volume, movers of ankle are more glucose-demanding than those of hip.


Role of Trientine in Hypertrophic Cardiomyopathy: A Review of Mechanistic Aspects.
Abnormality in myocardial copper homeostasis is believed to contribute to the development of cardiomyopathy. Trientine, a copper-chelating drug used in the management of patients with Wilson's disease, demonstrates beneficial effects in patients with hypertrophic cardiomyopathy. This review aims to present the updated development of the roles of trientine in hypertrophic cardiomyopathy. The drug has been demonstrated in animal studies to restore myocardial intracellular copper content. However, its mechanisms for improving the medical condition remain unclear. Thus, comprehending its mechanistic aspects in cardiomyopathy is crucial and could help to expedite future research.


Hypochlorous acid-mediated oxidation of lipid components and antioxidants present in low-density lipoproteins: absolute rate constants, product analysis, and computational modeling.
Oxidation of low-density lipoproteins (LDL) is believed to contribute to the increased uptake of LDL by macrophages, which is an early event in atherosclerosis. Hypochlorous acid (HOCl) has been implicated as one of the major oxidants involved in these processes. In a previous study, the rates of reaction of HOCl with the reactive sites in proteins were investigated (Pattison, D. I., and Davies, M. J. (2001) Chem. Res. Toxicol. 14, 1453-1464). The work presented here expands on those studies to determine absolute second-order rate constants for the reactions of HOCl with various lipid components and antioxidants in aqueous solution (pH 7.4). The reactions of HOCl with phosphoryl-serine and phosphoryl-ethanolamine are rapid (k approximately 10(5) M(-)(1) s(-)(1)) and of comparable reactivity to many of the protein sites. The major products formed in these reactions are chloramines, which decay to give both nitrogen- and carbon-centered radicals. Subsequent reactions of these species may induce oxidation of the LDL lipid component. In contrast, phosphoryl-choline reacted much more slowly (k < 10(-)(2) M(-)(1) s(-)(1)). Reaction of HOCl with 3-pentenoic acid was used as a model of lipid double bonds and yielded k = 9 M(-)(1) s(-)(1). The reactions of the lipid-soluble antioxidants, alpha-tocopherol and ubiquinol-10, with HOCl were investigated with model compounds. For the reactions of HOCl with both Trolox and ubiquinol-0, k = 1.3 x 10(3) M(-)(1) s(-)(1); thus, these lipid soluble antioxidants are relatively ineffective as direct scavengers for HOCl as compared to water soluble antioxidants (e.g., ascorbate, k ca. 10(6) M(-)(1) s(-)(1)). The reaction of HOCl with hydroquinone (a simple model for ubiquinol-10) was also investigated both in aqueous solution (k = 45 M(-)(1) s(-)(1)) and in a less polar environment (k approximately 0.5 M(-)(1) s(-)(1) in THF). A computational model was developed using these kinetic parameters to predict which LDL targets are oxidized with varying molar excesses of HOCl, in both the absence and the presence of added ascorbate. The results from these models compare well with experimental data and can be used to predict the effects of HOCl-mediated oxidation on LDL composition.


Concentration dependent structural ordering of poloxamine 908 on polystyrene nanoparticles and their modulatory role on complement consumption.
Adsorption of poloxamine 908, a tetrafunctional polyethylene oxide (PEO)-polypropylene oxide ethylenediamine block copolymer, onto the surface of monodispersed polystyrene nanoparticles (232 +/- 0.33 nm) follows a bimodal pattern. Initially, the isotherm follows a Langmuir profile with a plateau observable over a very narrow equilibrium poloxamine concentration (0.0018-0.0031 mM). The isotherm then begins to rise again, reaching a final plateau at equilibrium poloxamine concentrations above 0.0089 mM. Similarly, the profile of the adsorbed layer thickness of poloxamine on the surface of nanoparticles is bimodal. The first plateau corresponds to a thickness of 4.6 +/- 0.07 nm, which occurs over the same range of poloxamine concentrations as in the initial plateau of the adsorption isotherm. The second plateau corresponds to a thickness of 9.53 +/- 0.32 nm, observable at a minimum poloxamine concentration of 0.0067 mM. By using a calculated radius of gyration of a PEO chain in poloxamine as 3.1 nm, these observations reflect dynamic changes in the arrangement of surface projected PEO chains; a mushroom-like conformation at the first plateau region of the adsorption isotherm, followed by a transition into a brush-like conformation. These conformational changes are also reflected in rheological studies; the apparent viscosity of nanoparticles in which the PEO chains are in mushroom conformation is considerably higher than particles displaying the brush conformation. Further, atomic force microscopy studies (height profile and phase lag measurements) corroborated that the proposed poloxamine concentration dependent transition of surface associated PEO chains from mushroom to brush appearance is conserved when nanoparticles are dried under ambient conditions. Finally, we compared the influence of the surface PEO characteristics on complement consumption in human serum. Our results show complement-activating nature of all poloxamine-coated nanoparticles. However, complement consumption is reduced substantially with particles bearing a minimum of 11448 poloxamine molecules on their surface, thus demonstrating the importance of PEO surface density as well as brush conformation in suppressing complement consumption. This relationship between surface characteristics of poloxamine nanoparticles and their in vivo performance is discussed.


Telescoper: de novo assembly of highly repetitive regions.
With advances in sequencing technology, it has become faster and cheaper to obtain short-read data from which to assemble genomes. Although there has been considerable progress in the field of genome assembly, producing high-quality de novo assemblies from short-reads remains challenging, primarily because of the complex repeat structures found in the genomes of most higher organisms. The telomeric regions of many genomes are particularly difficult to assemble, though much could be gained from the study of these regions, as their evolution has not been fully characterized and they have been linked to aging. In this article, we tackle the problem of assembling highly repetitive regions by developing a novel algorithm that iteratively extends long paths through a series of read-overlap graphs and evaluates them based on a statistical framework. Our algorithm, Telescoper, uses short- and long-insert libraries in an integrated way throughout the assembly process. Results on real and simulated data demonstrate that our approach can effectively resolve much of the complex repeat structures found in the telomeres of yeast genomes, especially when longer long-insert libraries are used. Telescoper is publicly available for download at sourceforge.net/p/telescoper. email@example.com Supplementary data are available at Bioinformatics online.


Quality of life during clinical trials: conceptual model for the Lung Cancer Symptom Scale (LCSS).
To appreciate the full benefits of treatment for lung cancer, especially in trials that fail to show improvements in survival, data recording the quality of life must be captured and refined to produce meaningful information. A conceptual model for quality of life for lung cancer patients was tested to obtain information about the dimensions of the quality-of-life construct for ongoing development and testing of a subjective measure for clinical trials. Using a longitudinal study design, the stability of predictive factors of the physical and functional dimensions of quality of life were examined using regression analysis. A patient-rated quality-of-life measure, the Lung Cancer Symptom Scale (LCSS), was administered to 144 non-small-cell lung cancer patients at baseline, day 29, and day 71 of a chemotherapy trial. The range of explained variance for all three components of the lung cancer model over three assessment points was as follows: symptomatic distress 41%-53%, activity status 48%-52%, and overall quality of life 35%-53%. The three dimensions fluctuated slightly during intervention, but were relatively stable factors across all three times of evaluation. The LCSS model explained nearly half of the variance for quality of life experienced by lung cancer patients during therapy with a new chemotherapeutic agent. These findings provide support that the physical and functional dimensions are important predictors of quality of life for individuals with lung cancer. Meaningful subjective quality-of-life data can be obtained to evaluate an intervention by using a disease- and site-specific quality-of-life measure for individuals with lung cancer, based on a reproducible conceptual model such as the LCSS, which is suitable for serial measurement for the progressive disease of lung cancer.


Cost-benefit analysis.
Cost-benefit analysis is probably the most comprehensive method of economic evaluation available and it can be applied in two ways. The human capital approach means that the value of people's contributions is linked to what they are paid. The approach based on individuals' observed or stated preference means that their personal valuations are placed on an activity by assessing how much money they are prepared to accept for an increased risk or to pay for a particular service. Each method has its disadvantages and the most successful that has been devised so far is the "willingness to pay" (stated preference) approach, though the response to this is to a large extent dependent on the income of the person being questioned. There are still problems with its application, however, so its usefulness is limited.


HIV risk and behaviour among part-time versus professional FSW: baseline report of an interventional cohort in Burkina Faso.
To readjust HIV control programmes in Africa, we assessed the factors associated with high-risk behaviours and HIV infection among young female sex workers (FSW) in Burkina Faso. We carried out a cross-sectional study from September 2009 to September 2010 in Ouagadougou, the capital city. FSW were categorised as professionals and part-time sex workers (PTSW). After a face-to-face questionnaire, blood and urine samples were collected for HIV, HSV-2, genital infections and pregnancy. High-risk behaviour was defined as a recent unprotected sex with either casual clients, regular clients or regular partners. We recruited 609 FSW including 188 (30.9%) professionals. Their median age was 21 years (IQR 19-23), and the prevalence of HIV was 10.3% among professionals and 6.5% among PTSW. Only 3 of 46 HIV-infected women were aware of their status. Overall, 277 (45.6%) women reported high-risk behaviours (41.2% among professionals and 47.5% among PTSW), which were driven mainly by non-systematic condom use with regular partners. In multivariable analysis, PTSW (adjusted OR (AOR)=1.89; 95% CI 1.27 to 2.82) and having a primary (AOR=1.75; 95% CI 1.15 to 2.67) or higher education level (AOR=1.80; 95% CI 1.13 to 2.89) remained associated with high-risk behaviours. HIV infection was associated with older age (AOR=1.44; 95% CI 1.22 to 1.71), with being married/cohabiting (AOR=2.70; 95% CI 1.21 to 6.04) and with Trichomonas vaginalis infection (AOR=9.63; 95% CI 2.93 to 31.59), while history of HIV testing was associated with a decreased risk (AOR=0.18; 95% CI 0.08 to 0.40). This study highlights the need for targeted interventions among young FSW focusing particularly on PTSW, sexual behaviours with regular partners and regular HIV testing.


Nonlocal and spontaneous material responses: Reply to comment on "Rigorous solution for transient propagation of electromagnetic waves through a medium: causality plus diffraction in time".
I reply to the Comment by Weiglhofer and Lakhtakia on Opt. Lett. 25, 995 (2000). I agree with the comment to such an extent that it is generally known that nonlocal effects and material response time have to be considered in using collective macroscopic material response parameters. However, I believe that the Comment is incomplete and bears no special connection with the study that I reported in the original Letter.


A Context-Sensing Mobile Phone App (Q Sense) for Smoking Cessation: A Mixed-Methods Study.
A major cause of lapse and relapse to smoking during a quit attempt is craving triggered by cues from a smoker's immediate environment. To help smokers address these cue-induced cravings when attempting to quit, we have developed a context-aware smoking cessation app, Q Sense, which uses a smoking episode-reporting system combined with location sensing and geofencing to tailor support content and trigger support delivery in real time. We sought to (1) assess smokers' compliance with reporting their smoking in real time and identify reasons for noncompliance, (2) assess the app's accuracy in identifying user-specific high-risk locations for smoking, (3) explore the feasibility and user perspective of geofence-triggered support, and (4) identify any technological issues or privacy concerns. An explanatory sequential mixed-methods design was used, where data collected by the app informed semistructured interviews. Participants were smokers who owned an Android mobile phone and were willing to set a quit date within one month (N=15). App data included smoking reports with context information and geolocation, end-of-day (EoD) surveys of smoking beliefs and behavior, support message ratings, and app interaction data. Interviews were undertaken and analyzed thematically (N=13). Quantitative and qualitative data were analyzed separately and findings presented sequentially. Out of 15 participants, 3 (20%) discontinued use of the app prematurely. Pre-quit date, the mean number of smoking reports received was 37.8 (SD 21.2) per participant, or 2.0 (SD 2.2) per day per participant. EoD surveys indicated that participants underreported smoking on at least 56.2% of days. Geolocation was collected in 97.0% of smoking reports with a mean accuracy of 31.6 (SD 16.8) meters. A total of 5 out of 9 (56%) eligible participants received geofence-triggered support. Interaction data indicated that 50.0% (137/274) of geofence-triggered message notifications were tapped within 30 minutes of being generated, resulting in delivery of a support message, and 78.2% (158/202) of delivered messages were rated by participants. Qualitative findings identified multiple reasons for noncompliance in reporting smoking, most notably due to environmental constraints and forgetting. Participants verified the app's identification of their smoking locations, were largely positive about the value of geofence-triggered support, and had no privacy concerns about the data collected by the app. User-initiated self-report is feasible for training a cessation app about an individual's smoking behavior, although underreporting is likely. Geofencing was a reliable and accurate method of identifying smoking locations, and geofence-triggered support was regarded positively by participants.


Experience-Based Probabilities Modulate Expectations in a Gender-Coded Artificial Language.
The current study combines artificial language learning with visual world eyetracking to investigate acquisition of representations associating spoken words and visual referents using morphologically complex pseudowords. Pseudowords were constructed to consistently encode referential gender by means of suffixation for a set of imaginary figures that could be either male or female. During training, the frequency of exposure to pseudowords and their imaginary figure referents were manipulated such that a given word and its referent would be more likely to occur in either the masculine form or the feminine form, or both forms would be equally likely. Results show that these experience-based probabilities affect the formation of new representations to the extent that participants were faster at recognizing a referent whose gender was consistent with the induced expectation than a referent whose gender was inconsistent with this expectation. Disambiguating gender information available from the suffix did not mask the induced expectations. Eyetracking data provide additional evidence that such expectations surface during online lexical processing. Taken together, these findings indicate that experience-based information is accessible during the earliest stages of processing, and are consistent with the view that language comprehension depends on the activation of perceptual memory traces.


An ecosystem framework for understanding and treating disease.
Pathogens and cancers are pervasive health risks in the human population. I argue that if we are to better understand disease and its treatment, then we need to take an ecological perspective of disease itself. I generalize and extend an emerging framework that views disease as an ecosystem and many of its components as interacting in a community. I develop the framework for biological etiological agents (BEAs) that multiply within humans-focusing on bacterial pathogens and cancers-but the framework could be extended to include other host and parasite species. I begin by describing why we need an ecosystem framework to understand disease, and the main components and interactions in bacterial and cancer disease ecosystems. Focus is then given to the BEA and how it may proceed through characteristic states, including emergence, growth, spread and regression. The framework is then applied to therapeutic interventions. Central to success is preventing BEA evasion, the best known being antibiotic resistance and chemotherapeutic resistance in cancers. With risks of evasion in mind, I propose six measures that either introduce new components into the disease ecosystem or manipulate existing ones. An ecosystem framework promises to enhance our understanding of disease, BEA and host (co)evolution, and how we can improve therapeutic outcomes.


Risk of peptic ulcer hospitalizations in users of NSAIDs with gastroprotective cotherapy versus coxibs.
The primary strategies to reduce the risk of serious gastropathy caused by traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are use of a coxib or concurrent use of a proton pump inhibitor or double-dose histamine-2 receptor antagonist. However, the relative clinical effectiveness of these therapeutic alternatives is understudied. We studied peptic ulcer hospitalizations in a cohort of Tennessee Medicaid enrollees between 1996 and 2004. To decrease potential "channeling" bias, the study included only new episodes of prescribed NSAID or coxib use and controlled for multiple baseline risk factors for upper gastrointestinal disease. There were 234,010 and 48,710 new episodes of NSAID and coxib use, respectively, with 363,037 person-years of follow-up and 1223 peptic ulcer hospitalizations. Current users of NSAIDs with no gastroprotective cotherapy had an adjusted incidence of peptic ulcer hospitalizations of 5.65 per 1000 person-years, 2.76 (95% confidence interval, 2.35-3.23) times greater than that for persons not currently using either NSAIDs or coxibs. This risk was reduced by 39% (16%-56%, 95% CI) for current users of NSAIDs with gastroprotective cotherapy and 40% (23%-54%) for current users of coxibs without such cotherapy. Concurrent users of NSAIDs and proton pump inhibitors had a 54% (27%-72%) risk reduction, very similar to the 50% (27%-66%) reduction for concurrent users of proton pump inhibitors and coxibs. These findings suggest that coprescribing a proton pump inhibitor with an NSAID is as effective as use of a coxib for reducing the risk of NSAID-induced gastropathy.


The effect of surgeon specialization on outcomes after ruptured abdominal aortic aneurysm repair.
Although mortality after elective abdominal aortic aneurysm (AAA) repair has steadily declined, operative mortality for a ruptured AAA (rAAA) remains high. Repair of rAAA at hospitals with a higher elective aneurysm workload has been associated with lower mortality rates irrespective of the mode of treatment. This study sought to determine the association between surgeon specialization and outcomes after rAAA repair. The American College of Surgeons National Surgical Quality Improvement Project database from 2005 to 2010 was used to examine the 30-day mortality and morbidity outcomes of patients undergoing rAAA repair by vascular and general surgeons. Multivariable logistic regression analysis was performed for each death and morbidity, adjusting for all independently predictive preoperative risk factors. Survival curves were compared using the log-rank test. We identified 1893 repairs of rAAAs, of which 1767 (96.1%) were performed by vascular surgeons and 72 (3.9%) were performed by general surgeons. There were no significant differences between patients operated on by general vs vascular surgeons in preoperative risk factors or method of repair. Overall 30-day mortality was 34.3% (649 of 1893). After risk adjustment, mortality was significantly lower in the vascular surgery group compared with the general surgery group (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.30-0.86; P = .011). The risk of returning to the operating room (OR, 0.58; 95% CI, 0.35-0.97; P = .038), renal failure (OR, 0.54; 95% CI, 0.31-0.95; P = .034), and a cardiac complication (OR, 0.53; 95% CI, 0.28-0.99; P = .047) were all significantly less in the vascular surgery group. Despite similar preoperative risk factors profiles, patients who were operated on by vascular surgeons had lower mortality, less frequent returns to the operating room, and decreased incidences of postoperative renal failure and cardiac events. These data add weight to the case for further centralization of vascular services.


RNAi-Based Biocontrol of Wheat Nematodes Using Natural Poly-Component Biostimulants.
With the growing global demands on sustainable food production, one of the biggest challenges to agriculture is associated with crop losses due to parasitic nematodes. While chemical pesticides have been quite successful in crop protection and mitigation of damage from parasites, their potential harm to humans and environment, as well as the emergence of nematode resistance, have necessitated the development of viable alternatives to chemical pesticides. One of the most promising and targeted approaches to biocontrol of parasitic nematodes in crops is that of RNA interference (RNAi). In this study we explore the possibility of using biostimulants obtained from metabolites of soil streptomycetes to protect wheat (Triticum aestivum L.) against the cereal cyst nematode Heterodera avenae by means of inducing RNAi in wheat plants. Theoretical models of uptake of organic compounds by plants, and within-plant RNAi dynamics, have provided us with useful insights regarding the choice of routes for delivery of RNAi-inducing biostimulants into plants. We then conducted in planta experiments with several streptomycete-derived biostimulants, which have demonstrated the efficiency of these biostimulants at improving plant growth and development, as well as in providing resistance against the cereal cyst nematode. Using dot blot hybridization we demonstrate that biostimulants trigger a significant increase of the production in plant cells of si/miRNA complementary with plant and nematode mRNA. Wheat germ cell-free experiments show that these si/miRNAs are indeed very effective at silencing the translation of nematode mRNA having complementary sequences, thus reducing the level of nematode infestation and improving plant resistance to nematodes. Thus, we conclude that natural biostimulants produced from metabolites of soil streptomycetes provide an effective tool for biocontrol of wheat nematode.


Source specific exposure and risk assessment for indoor aerosols.
Poor air quality is a leading contributor to the global disease burden and total number of deaths worldwide. Humans spend most of their time in built environments where the majority of the inhalation exposure occurs. Indoor Air Quality (IAQ) is challenged by outdoor air pollution entering indoors through ventilation and infiltration and by indoor emission sources. The aim of this study was to understand the current knowledge level and gaps regarding effective approaches to improve IAQ. Emission regulations currently focus on outdoor emissions, whereas quantitative understanding of emissions from indoor sources is generally lacking. Therefore, specific indoor sources need to be identified, characterized, and quantified according to their environmental and human health impact. The emission sources should be stored in terms of relevant metrics and statistics in an easily accessible format that is applicable for source specific exposure assessment by using mathematical mass balance modelings. This forms a foundation for comprehensive risk assessment and efficient interventions. For such a general exposure assessment model we need 1) systematic methods for indoor aerosol emission source assessment, 2) source emission documentation in terms of relevant a) aerosol metrics and b) biological metrics, 3) default model parameterization for predictive exposure modeling, 4) other needs related to aerosol characterization techniques and modeling methods. Such a general exposure assessment model can be applicable for private, public, and occupational indoor exposure assessment, making it a valuable tool for public health professionals, product safety designers, industrial hygienists, building scientists, and environmental consultants working in the field of IAQ and health.


A budget impact analysis of telemedicine-based collaborative care for depression.
Patients with depression use more health services than patients without depression. However, when depression symptoms respond to treatment, use of health services declines. Most depression quality improvement studies increase total cost in the short run, which if unevenly distributed across stakeholders, could compromise buy-in and sustainability. The objective of this budget impact analysis was to examine patterns of utilization and cost associated with telemedicine-based collaborative care, an intervention that targets patients treated in small rural primary care clinics. Patients with depression were recruited from VA Community-based Outpatient Clinics, and 395 patients were enrolled and randomized to telemedicine-based collaborative care or usual care. Dependent variables representing utilization and cost were collected from administrative data. Independent variables representing clinical casemix were collected from self-report at baseline. There were no significant group differences in the total number or cost of primary care encounters. However, as intended, patients in the intervention group had significantly greater depression-related primary care encounters (marginal effect=0.34, P=0.004) and cost (marginal effect=$61.4, P=0.013) to adjust antidepressant therapy for nonresponders. There were no significant group differences in total mental health encounters or cost. However, as intended, the intervention group had significantly higher depression-related mental health costs (marginal effect=$107.55, P=0.03) due to referrals of treatment-resistant patients. Unexpectedly, patients in the intervention group had significantly greater specialty physical health encounters (marginal effect =0.42, P=0.001) and cost (marginal effect =$490.6, P=0.003), but not depression-related encounters or cost. Overall, intervention patients had a significantly greater total outpatient cost compared with usual care (marginal effect=$599.28, P=0.012). Results suggest that telemedicine-based collaborative care does not increase total workload for primary care or mental health providers. Thus, there is no disincentive for mental health providers to offer telemedicine-based collaborative care or for primary care providers to refer patients to telemedicine-based collaborative care.


Synthesis of D- and L-myo-inositol 2,4,5-trisphosphate and trisphosphorothioate: structural analogues of D-myo-inositol 1,4,5-trisphosphate.
The preparation of D- and L-myo-inositol 2,4,5-trisphosphate is described, together with the phosphorothioate counterparts. The known chiral diols D- and L-1,4-di-O-benzyl-5,6-bis-O-p-methoxybenzyl-myo-inositol were regioselectively protected at the 3-position using a benzyl group via a 2,3-O-stannylene acetal. Removal of the p-methoxybenzyl groups of each enantiomer gave D- and L-1,3,6-tri-O-benzyl-myo-inositol. Phosphitylation with bis(benzyloxy)diisoproplyaminophosphine and 1H-tetrazole gave the trisphosphite intermediate for each enantiomer. Oxidation with 3-chloroperoxybenzoic acid gave the fully protected D- and L-myo-inositol 2,4,5-trisphosphates. Sulphoxidation of the D- and L-2,4,5-trisphosphite intermediates gave the fully protected D- and L-myo-inositol 2,4,5-trisphosphorothioate compounds. The fully protected trisphosphates were deblocked using hydrogenolysis and the phosphorothioates were deprotected using sodium in liquid ammonia. The individual compounds were then purified using ion exchange chromatography to afford pure D- and L-myo-inositol 2,4,5-trisphosphates together with the corresponding phosphorothioates.


An integrated practice approach to mobility care for older people.
Mobility is important to older people in nursing homes and residential facilities since it contributes to their health and quality of life. Many residents in such facilities require some form of assistance to move and accomplish activities of daily living. Therefore, nurses and healthcare assistants should have the knowledge and skills to provide effective mobility care. This article discusses three important aspects of mobility care: safety, mobility optimisation and person-centred approaches to care. Safety is important as residents and staff are at risk of injury during mobility care. Mobility optimisation is essential to ensure residents maintain their independence. Person-centred approaches to care are central to providing an integrated approach to mobility care.


Effects of image reconstruction on fiber orientation mapping from multichannel diffusion MRI: reducing the noise floor using SENSE.
To examine the effects of the reconstruction algorithm of magnitude images from multichannel diffusion MRI on fiber orientation estimation. It is well established that the method used to combine signals from different coil elements in multichannel MRI can have an impact on the properties of the reconstructed magnitude image. Using a root-sum-of-squares approach results in a magnitude signal that follows an effective noncentral-χ distribution. As a result, the noise floor, the minimum measurable in the absence of any true signal, is elevated. This is particularly relevant for diffusion-weighted MRI, where the signal attenuation is of interest. In this study, we illustrate problems that such image reconstruction characteristics may cause in the estimation of fiber orientations, both for model-based and model-free approaches, when modern 32-channel coils are used. We further propose an alternative image reconstruction method that is based on sensitivity encoding (SENSE) and preserves the Rician nature of the single-channel, magnitude MR signal. We show that for the same k-space data, root-sum-of-squares can cause excessive overfitting and reduced precision in orientation estimation compared with the SENSE-based approach. These results highlight the importance of choosing the appropriate image reconstruction method for tractography studies that use multichannel receiver coils for diffusion MRI acquisition.


Global diversity of sponges (Porifera).
With the completion of a single unified classification, the Systema Porifera (SP) and subsequent development of an online species database, the World Porifera Database (WPD), we are now equipped to provide a first comprehensive picture of the global biodiversity of the Porifera. An introductory overview of the four classes of the Porifera is followed by a description of the structure of our main source of data for this paper, the WPD. From this we extracted numbers of all 'known' sponges to date: the number of valid Recent sponges is established at 8,553, with the vast majority, 83%, belonging to the class Demospongiae. We also mapped for the first time the species richness of a comprehensive set of marine ecoregions of the world, data also extracted from the WPD. Perhaps not surprisingly, these distributions appear to show a strong bias towards collection and taxonomy efforts. Only when species richness is accumulated into large marine realms does a pattern emerge that is also recognized in many other marine animal groups: high numbers in tropical regions, lesser numbers in the colder parts of the world oceans. Preliminary similarity analysis of a matrix of species and marine ecoregions extracted from the WPD failed to yield a consistent hierarchical pattern of ecoregions into marine provinces. Global sponge diversity information is mostly generated in regional projects and resources: results obtained demonstrate that regional approaches to analytical biogeography are at present more likely to achieve insights into the biogeographic history of sponges than a global perspective, which appears currently too ambitious. We also review information on invasive sponges that might well have some influence on distribution patterns of the future.