Molecular evolution, diversity and adaptation of H7N9 viruses in China during 2013-2017

The substantial increase in prevalence and emergence of antigenically divergent or highly pathogenic influenza A(H7N9) viruses during 2016–17 raises concerns about the epizootic potential of these viruses. We investigated the evolution and adaptation of H7N9 viruses by analyzing available data and newly generated virus sequences isolated in Guangdong Province, China, during 2015–2017. Phylogenetic analyses showed that circulating H7N9 viruses belong to distinct lineages with differing spatial distributions. Hemagglutination inhibition assays performed on serum samples from patients infected with these viruses identified 3 antigenic clusters for 16 strains of different virus lineages. We used ancestral sequence reconstruction to identify parallel amino acid changes on multiple separate lineages. We inferred that mutations in hemagglutinin occur primarily at sites involved in receptor recognition or antigenicity. Our results indicate that highly pathogenic strains likely emerged from viruses circulating in eastern Guangdong Province during March 2016 and are associated with a high rate of adaptive molecular evolution

A methodology for identifying high-need, high-cost patient personas for international comparisons.

ObjectiveTo establish a methodological approach to compare two high-need, high-cost (HNHC) patient personas internationally.Data sourcesLinked individual-level administrative data from the inpatient and outpatient sectors compiled by the International Collaborative on Costs, Outcomes, and Needs in Care (ICCONIC) across 11 countries: Australia, Canada, England, France, Germany, the Netherlands, New Zealand, Spain, Sweden, Switzerland, and the United States.Study designWe outline a methodological approach to identify HNHC patient types for international comparisons that reflect complex, priority populations defined by the National Academy of Medicine. We define two patient profiles using accessible patient-level datasets linked across different domains of care-hospital care, primary care, outpatient specialty care, post-acute rehabilitative care, long-term care, home-health care, and outpatient drugs. The personas include a frail older adult with a hip fracture with subsequent hip replacement and an older person with complex multimorbidity, including heart failure and diabetes. We demonstrate their comparability by examining the characteristics and clinical diagnoses captured across countries.Data collection/extraction methodsData collected by ICCONIC partners.Principal findingsAcross 11 countries, the identification of HNHC patient personas was feasible to examine variations in healthcare utilization, spending, and patient outcomes. The ability of countries to examine linked, individual-level data varied, with the Netherlands, Canada, and Germany able to comprehensively examine care across all seven domains, whereas other countries such as England, Switzerland, and New Zealand were more limited. All countries were able to identify a hip fracture persona and a heart failure persona. Patient characteristics were reassuringly similar across countries.ConclusionAlthough there are cross-country differences in the availability and structure of data sources, countries had the ability to effectively identify comparable HNHC personas for international study. This work serves as the methodological paper for six accompanying papers examining differences in spending, utilization, and outcomes for these personas across countries

Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study

Background Diagnosing drug-resistance remains an obstacle to the elimination of tuberculosis. Phenotypic drug-susceptibility testing is slow and expensive, and commercial genotypic assays screen only common resistance-determining mutations. We used whole-genome sequencing to characterise common and rare mutations predicting drug resistance, or consistency with susceptibility, for all first-line and second-line drugs for tuberculosis. Methods Between Sept 1, 2010, and Dec 1, 2013, we sequenced a training set of 2099 Mycobacterium tuberculosis genomes. For 23 candidate genes identified from the drug-resistance scientific literature, we algorithmically characterised genetic mutations as not conferring resistance (benign), resistance determinants, or uncharacterised. We then assessed the ability of these characterisations to predict phenotypic drug-susceptibility testing for an independent validation set of 1552 genomes. We sought mutations under similar selection pressure to those characterised as resistance determinants outside candidate genes to account for residual phenotypic resistance. Findings We characterised 120 training-set mutations as resistance determining, and 772 as benign. With these mutations, we could predict 89·2% of the validation-set phenotypes with a mean 92·3% sensitivity (95% CI 90·7–93·7) and 98·4% specificity (98·1–98·7). 10·8% of validation-set phenotypes could not be predicted because uncharacterised mutations were present. With an in-silico comparison, characterised resistance determinants had higher sensitivity than the mutations from three line-probe assays (85·1% vs 81·6%). No additional resistance determinants were identified among mutations under selection pressure in non-candidate genes. Interpretation A broad catalogue of genetic mutations enable data from whole-genome sequencing to be used clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically predicted. This approach could be integrated into routine diagnostic workflows, phasing out phenotypic drug-susceptibility testing while reporting drug resistance early

Tracing Water Sources of Terrestrial Animal Populations with Stable Isotopes: Laboratory Tests with Crickets and Spiders

Fluxes of carbon, nitrogen, and water between ecosystem components and organisms have great impacts across levels of biological organization. Although much progress has been made in tracing carbon and nitrogen, difficulty remains in tracing water sources from the ecosystem to animals and among animals (the “water web”). Naturally occurring, non-radioactive isotopes of hydrogen and oxygen in water provide a potential method for tracing water sources. However, using this approach for terrestrial animals is complicated by a change in water isotopes within the body due to differences in activity of heavy and light isotopes during cuticular and transpiratory water losses. Here we present a technique to use stable water isotopes to estimate the mean mix of water sources in a population by sampling a group of sympatric animals over time. Strong correlations between H and O isotopes in the body water of animals collected over time provide linear patterns of enrichment that can be used to predict a mean mix of water sources useful in standard mixing models to determine relative source contribution. Multiple temperature and humidity treatment levels do not greatly alter these relationships, thus having little effect on our ability to estimate this population-level mix of water sources. We show evidence for the validity of using multiple samples of animal body water, collected across time, to estimate the isotopic mix of water sources in a population and more accurately trace water sources. The ability to use isotopes to document patterns of animal water use should be a great asset to biologists globally, especially those studying drylands, droughts, streamside areas, irrigated landscapes, and the effects of climate change

Adjunctive long-acting risperidone in patients with bipolar disorder who relapse frequently and have active mood symptoms

<p>Abstract</p> <p>Background</p> <p>The objective of this exploratory analysis was to characterize efficacy and onset of action of a 3-month treatment period with risperidone long-acting injection (RLAI), adjunctive to an individual's treatment regimen, in subjects with symptomatic bipolar disorder who relapsed frequently and had significant symptoms of mania and/or depression.</p> <p>Methods</p> <p>Subjects with bipolar disorder with ≥4 mood episodes in the past 12 months entered the open-label stabilization phase preceding a placebo-controlled, double-blind study. Subjects with significant depressive or manic/mixed symptoms at baseline were analyzed. Significant depressive symptoms were defined as Montgomery-Åsberg Depression Rating Scale (MADRS) ≥16 and Young Mania Rating Scale (YMRS) < 16; manic/mixed symptoms were YMRS ≥16 with any MADRS score. Subjects received open-label RLAI (25-50 mg every 2 weeks) for 16 weeks, adjunctive to a subject's individualized treatment for bipolar disorder (mood stabilizers, antidepressants, and/or anxiolytics). Clinical status was evaluated with the Clinical Global Impressions of Bipolar Disorder-Severity (CGI-BP-S) scale and changes on the MADRS and YMRS scales. Within-group changes were evaluated using paired <it>t </it>tests; categorical differences were assessed using Fisher exact test. No adjustment was made for multiplicity.</p> <p>Results</p> <p>162 subjects who relapsed frequently met criteria for significant mood symptoms at open-label baseline; 59/162 (36.4%) had depressive symptoms, 103/162 (63.6%) had manic/mixed symptoms. Most subjects (89.5%) were receiving ≥1 medication for bipolar disorder before enrollment. Significant improvements were observed for the total population on the CGI-BP-S, MADRS, and YMRS scales (p < .001 vs. baseline, all variables). Eighty-two (53.3%) subjects achieved remission at the week 16 LOCF end point. The subpopulation with depressive symptoms at open-label baseline experienced significant improvement on the CGI-BP-S and MADRS scales (p < .001 vs. baseline, all variables). Subjects with manic/mixed symptoms at baseline had significant improvements on the CGI-BP-S and YMRS scales (p < .001 vs. baseline, all variables). No unexpected tolerability findings were observed.</p> <p>Conclusions</p> <p>Exploratory analysis of changes in overall clinical status and depression/mania symptoms in subjects with symptomatic bipolar disorder who relapse frequently showed improvements in each of these areas after treatment with RLAI, adjunctive to a subject's individualized treatment. Prospective controlled studies are needed to confirm these findings.</p

The basal ganglia and thalamus of the long-tailed macaque in stereotaxic coordinates. A template atlas based on coronal, sagittal and horizontal brain sections

A stereotaxic brain atlas of the basal ganglia and thalamus of Macaca fascicularis presented here is designed with a surgical perspective. In this regard, all coordinates have been referenced to a line linking the anterior and posterior commissures (ac–pc line) and considering the center of the ac at the midline as the origin of the bicommissural space. The atlas comprises of 43 different plates (19 coronal levels, 10 sagittal levels and 14 horizontal levels). In addition to ‘classical’ cyto- and chemoarchitectural techniques such as the Nissl method and the acetylcholinesterase stain, several immunohistochemical stains have been performed in adjacent sections, including the detection of tyrosine hydroxylase, enkephalin, neurofilaments, parvalbumin and calbindin. In comparison to other existing stereotaxic atlases for M. fasicularis, this atlas has two main advantages: firstly, brain cartography is based on a wide variety of cyto- and chemoarchitectural stains carried out on adjacent sections, therefore enabling accurate segmentation. Secondly and most importantly, sagittal and horizontal planes are included. Sagittal planes are very useful for calculating oblique trajectories, whereas, clinical researchers engaged in neuroimaging studies will be more familiar with horizontal sections, as they use horizontal (also called “axial”) brain images in their daily routine of their clinical practices

An Incomplete TCA Cycle Increases Survival of Salmonella Typhimurium during Infection of Resting and Activated Murine Macrophages

In comparison to the comprehensive analyses performed on virulence gene expression, regulation and action, the intracellular metabolism of Salmonella during infection is a relatively under-studied area. We investigated the role of the tricarboxylic acid (TCA) cycle in the intracellular replication of Salmonella Typhimurium in resting and activated macrophages, epithelial cells, and during infection of mice.We constructed deletion mutations of 5 TCA cycle genes in S. Typhimurium including gltA, mdh, sdhCDAB, sucAB, and sucCD. We found that the mutants exhibited increased net intracellular replication in resting and activated murine macrophages compared to the wild-type. In contrast, an epithelial cell infection model showed that the S. Typhimurium ΔsucCD and ΔgltA strains had reduced net intracellular replication compared to the wild-type. The glyoxylate shunt was not responsible for the net increased replication of the TCA cycle mutants within resting macrophages. We also confirmed that, in a murine infection model, the S. Typhimurium ΔsucAB and ΔsucCD strains are attenuated for virulence.Our results suggest that disruption of the TCA cycle increases the ability of S. Typhimurium to survive within resting and activated murine macrophages. In contrast, epithelial cells are non-phagocytic cells and unlike macrophages cannot mount an oxidative and nitrosative defence response against pathogens; our results show that in HeLa cells the S. Typhimurium TCA cycle mutant strains show reduced or no change in intracellular levels compared to the wild-type. The attenuation of the S. Typhimurium ΔsucAB and ΔsucCD mutants in mice, compared to their increased net intracellular replication in resting and activated macrophages suggest that Salmonella may encounter environments within the host where a complete TCA cycle is advantageous

No relationship between 2',3'-cyclic nucleotide 3'-phosphodiesterase and schizophrenia in the Chinese Han population: an expression study and meta-analysis

<p>Abstract</p> <p>Background</p> <p>2',3'-Cyclic nucleotide 3'-phosphodiesterase (<it>CNP</it>), one of the promising candidate genes for schizophrenia, plays a key part in the oligodendrocyte function and in myelination. The present study aims to investigate the relationship between <it>CNP </it>and schizophrenia in the Chinese population and the effect of different factors on the expression level of <it>CNP </it>in schizophrenia.</p> <p>Methods</p> <p>Five <it>CNP </it>single nucleotide polymorphisms (SNPs) were investigated in a Chinese Han schizophrenia case-control sample set (n = 180) using direct sequencing. The results were included in the following meta-analysis. Quantitative real-time polymerase chain reaction (PCR) was conducted to examine <it>CNP </it>expression levels in peripheral blood lymphocytes.</p> <p>Results</p> <p>Factors including gender, genotype, sub-diagnosis and antipsychotics-treatment were found not to contribute to the expression regulation of the <it>CNP </it>gene in schizophrenia. Our meta-analysis produced similar negative results.</p> <p>Conclusion</p> <p>The results suggest that the <it>CNP </it>gene may not be involved in the etiology and pathology of schizophrenia in the Chinese population.</p

The Brain Atlas Concordance Problem: Quantitative Comparison of Anatomical Parcellations

Many neuroscientific reports reference discrete macro-anatomical regions of the brain which were delineated according to a brain atlas or parcellation protocol. Currently, however, no widely accepted standards exist for partitioning the cortex and subcortical structures, or for assigning labels to the resulting regions, and many procedures are being actively used. Previous attempts to reconcile neuroanatomical nomenclatures have been largely qualitative, focusing on the development of thesauri or simple semantic mappings between terms. Here we take a fundamentally different approach, discounting the names of regions and instead comparing their definitions as spatial entities in an effort to provide more precise quantitative mappings between anatomical entities as defined by different atlases. We develop an analytical framework for studying this brain atlas concordance problem, and apply these methods in a comparison of eight diverse labeling methods used by the neuroimaging community. These analyses result in conditional probabilities that enable mapping between regions across atlases, which also form the input to graph-based methods for extracting higher-order relationships between sets of regions and to procedures for assessing the global similarity between different parcellations of the same brain. At a global scale, the overall results demonstrate a considerable lack of concordance between available parcellation schemes, falling within chance levels for some atlas pairs. At a finer level, this study reveals spatial relationships between sets of defined regions that are not obviously apparent; these are of high potential interest to researchers faced with the challenge of comparing results that were based on these different anatomical models, particularly when coordinate-based data are not available. The complexity of the spatial overlap patterns revealed points to problems for attempts to reconcile anatomical parcellations and nomenclatures using strictly qualitative and/or categorical methods. Detailed results from this study are made available via an interactive web site at http://obart.info