Antibiotic resistance among clinical isolates of Haemophilus influenzae in the United States in 1994 and 1995 and detection of beta-lactamase-positive strains resistant to amoxicillin-clavulanate: results of a national multicenter surveillance study.
A total of 1,537 clinical isolates of Haemophilus influenzae were recovered in 30 U.S. medical center laboratories between 1 November 1994 and 30 April 1995 and were characterized in a central laboratory with respect to serotype and beta-lactamase production and the in vitro activities of 15 oral antimicrobial agents. Overall, 36.4% of the isolates were found to produce beta-lactamase. The rank order of activity of six cephalosporins on the basis of MICs was cefixime > cefpodoxime > cefuroxime > loracarbef > or = cefaclor > cefprozil. On the basis of current National Committee for Clinical Laboratory Standards (NCCLS) breakpoints ages of isolates found to be resistant or intermediate to these agents were as follows: 0.1, 0.3, 6.4, 16.3, 18.3, and 29.8, respectively (National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed. M7-A4, 1995). Azithromycin was, on a weight basis, the most potent of the macrolides tested in this study, followed by erythromycin and then clarithromycin. Azithromycin was typically fourfold more active than erythromycin, which was, in turn, slightly more active than clarithromycin. However, when compared on the basis of the frequency of resistance determined by using current NCCLS breakpoints, there was essentially no difference between azithromycin and clarithromycin, i.e., 0.5 and 1.9%, respectively (P = 0.086). Interpretive breakpoints for erythromycin MIC tests versus H. influenzae have not been developed. Resistance to other non- beta-lactam agents was variable, as follows: trimethoprim-sulfamethoxazole, 9.0%; chloramphenicol, 0.2%; tetracycline, 1.3%; and rifampin, 0.3%. Two conspicuous findings in this study were the identification of 39 strains H. influenzae that were beta-lactamase negative but ampicillin intermediate or resistant (BLNAR) and, even more surprisingly, 17 beta-lactamase-positive isolates that were resistant to amoxicillin-clavulanate (BLPACR). Strains of H. influenzae in the first group have heretofore been very uncommon; organisms in the second group have not previously been described in the literature. The percentages of all study isolates comprised of BLNAR and BLPACR organisms were 2.5 and 1.1, respectively. Overall resistance to ampicillin was thus 38.9%, and that to amoxicillin-clavulanate was 4.5%.


Growth and asymmetry of soil microfungal colonies from "Evolution Canyon," Lower Nahal Oren, Mount Carmel, Israel.
Fluctuating asymmetry is a contentious indicator of stress in populations of animals and plants. Nevertheless, it is a measure of developmental noise, typically obtained by measuring asymmetry across an individual organism's left-right axis of symmetry. These individual, signed asymmetries are symmetrically distributed around a mean of zero. Fluctuating asymmetry, however, has rarely been studied in microorganisms, and never in fungi. We examined colony growth and random phenotypic variation of five soil microfungal species isolated from the opposing slopes of "Evolution Canyon," Mount Carmel, Israel. This canyon provides an opportunity to study diverse taxa inhabiting a single microsite, under different kinds and intensities of abiotic and biotic stress. The south-facing "African" slope of "Evolution Canyon" is xeric, warm, and tropical. It is only 200 m, on average, from the north-facing "European" slope, which is mesic, cool, and temperate. Five fungal species inhabiting both the south-facing "African" slope, and the north-facing "European" slope of the canyon were grown under controlled laboratory conditions, where we measured the fluctuating radial asymmetry and sizes of their colonies. Different species displayed different amounts of radial asymmetry (and colony size). Moreover, there were highly significant slope by species interactions for size, and marginally significant ones for fluctuating asymmetry. There were no universal differences (i.e., across all species) in radial asymmetry and colony size between strains from "African" and "European" slopes, but colonies of Clonostachys rosea from the "African" slope were more asymmetric than those from the "European" slope. Our study suggests that fluctuating radial asymmetry has potential as an indicator of random phenotypic variation and stress in soil microfungi. Interaction of slope and species for both growth rate and asymmetry of microfungi in a common environment is evidence of genetic differences between the "African" and "European" slopes of "Evolution Canyon."


Arthropod Distribution in a Tropical Rainforest: Tackling a Four Dimensional Puzzle.
Quantifying the spatio-temporal distribution of arthropods in tropical rainforests represents a first step towards scrutinizing the global distribution of biodiversity on Earth. To date most studies have focused on narrow taxonomic groups or lack a design that allows partitioning of the components of diversity. Here, we consider an exceptionally large dataset (113,952 individuals representing 5,858 species), obtained from the San Lorenzo forest in Panama, where the phylogenetic breadth of arthropod taxa was surveyed using 14 protocols targeting the soil, litter, understory, lower and upper canopy habitats, replicated across seasons in 2003 and 2004. This dataset is used to explore the relative influence of horizontal, vertical and seasonal drivers of arthropod distribution in this forest. We considered arthropod abundance, observed and estimated species richness, additive decomposition of species richness, multiplicative partitioning of species diversity, variation in species composition, species turnover and guild structure as components of diversity. At the scale of our study (2 km of distance, 40 m in height and 400 days), the effects related to the vertical and seasonal dimensions were most important. Most adult arthropods were collected from the soil/litter or the upper canopy and species richness was highest in the canopy. We compared the distribution of arthropods and trees within our study system. Effects related to the seasonal dimension were stronger for arthropods than for trees. We conclude that: (1) models of beta diversity developed for tropical trees are unlikely to be applicable to tropical arthropods; (2) it is imperative that estimates of global biodiversity derived from mass collecting of arthropods in tropical rainforests embrace the strong vertical and seasonal partitioning observed here; and (3) given the high species turnover observed between seasons, global climate change may have severe consequences for rainforest arthropods.


Live imaging using adaptive optics with fluorescent protein guide-stars.
Spatially and temporally dependent optical aberrations induced by the inhomogeneous refractive index of live samples limit the resolution of live dynamic imaging. We introduce an adaptive optical microscope with a direct wavefront sensing method using a Shack-Hartmann wavefront sensor and fluorescent protein guide-stars for live imaging. The results of imaging Drosophila embryos demonstrate its ability to correct aberrations and achieve near diffraction limited images of medial sections of large Drosophila embryos. GFP-polo labeled centrosomes can be observed clearly after correction but cannot be observed before correction. Four dimensional time lapse images are achieved with the correction of dynamic aberrations. These studies also demonstrate that the GFP-tagged centrosome proteins, Polo and Cnn, serve as excellent biological guide-stars for adaptive optics based microscopy.


Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans.
Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.


Who is predisposed to insomnia: a review of familial aggregation, stress-reactivity, personality and coping style.
Insomnia is a common health complaint world-wide. Insomnia is a risk factor in the development of other psychological and physiological disorders. Therefore understanding the mechanisms which predispose an individual to developing insomnia has great transdiagnostic value. However, whilst it is largely accepted that a vulnerable phenotype exists there is a lack of research which aims to systematically assess the make-up of this phenotype. This review outlines the research to-date, considering familial aggregation and the genetics and psychology of stress-reactivity. A model will be presented in which negative affect (neuroticism) and genetics (5HTTLPR) are argued to lead to disrupted sleep via an increase in stress-reactivity, and further that the interaction of these variables leads to an increase in learned negative associations, which further increase the likelihood of poor sleep and the development of insomnia.


Association between Urinary Sodium Excretion and Bone Health in Male and Female Adults.
High salt intake is a well-known risk factor for osteoporosis, but the association between bone mass and urinary sodium excretion has not been studied as yet. This study investigates the hypothesis that urinary sodium excretion is negatively associated with bone mass and the risk of osteoporosis. This cross-sectional study was performed using data from the Korea National Health and Nutrition Examination Survey, 2008-2011. Participants (n = 16,279) were divided into age groups; men were categorized as younger than 50 years of age or 50 years or greater, women were categorized as pre- or post-menopausal. Multivariate linear regression analysis showed that urinary sodium excretion was negatively associated with bone mineral content (BMC) and bone mineral density (BMD) in premenopausal and postmenopausal women. Sodium excretion was negatively associated with BMC and BMD of the lumbar spine in women with normal bone health, osteopenia and osteoporosis, but there was no association in men. Increased sodium excretion was significantly associated with risk for osteoporosis/osteopenia in premenopausal women. This study demonstrates that urinary sodium excretion is negatively associated with bone health, suggesting that high salt intake could be a possible risk factor for osteoporosis in Korean women, but not in men.


Guiding functional connectivity estimation by structural connectivity in MEG: an application to discrimination of conditions of mild cognitive impairment.
Whole brain resting state connectivity is a promising biomarker that might help to obtain an early diagnosis in many neurological diseases, such as dementia. Inferring resting-state connectivity is often based on correlations, which are sensitive to indirect connections, leading to an inaccurate representation of the real backbone of the network. The precision matrix is a better representation for whole brain connectivity, as it considers only direct connections. The network structure can be estimated using the graphical lasso (GL), which achieves sparsity through l1-regularization on the precision matrix. In this paper, we propose a structural connectivity adaptive version of the GL, where weaker anatomical connections are represented as stronger penalties on the corresponding functional connections. We applied beamformer source reconstruction to the resting state MEG recordings of 81 subjects, where 29 were healthy controls, 22 were single-domain amnestic Mild Cognitive Impaired (MCI), and 30 were multiple-domain amnestic MCI. An atlas-based anatomical parcellation of 66 regions was obtained for each subject, and time series were assigned to each of the regions. The fiber densities between the regions, obtained with deterministic tractography from diffusion-weighted MRI, were used to define the anatomical connectivity. Precision matrices were obtained with the region specific time series in five different frequency bands. We compared our method with the traditional GL and a functional adaptive version of the GL, in terms of log-likelihood and classification accuracies between the three groups. We conclude that introducing an anatomical prior improves the expressivity of the model and, in most cases, leads to a better classification between groups.


Alternative control: what's WASp doing in the nucleus?
Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency disorder of childhood that is caused by mutations in the WAS gene. WAS encodes WASp, a protein that is known to function in the cytoplasm of hematopoietic cells and is required for the induced differentiation of CD4+ T helper type 1 (TH1) lymphocytes. Now, a paper in Science Translational Medicine describes another mechanism for impaired immunity in WAS by showing that WASp localizes in the nucleus and regulates histone modifications and chromatin structure, thereby modulating expression of the TH1 master gene TBX21 (TBET).


Black carbon aerosol size in snow.
The effect of anthropogenic black carbon (BC) aerosol on snow is of enduring interest due to its consequences for climate forcing. Until now, too little attention has been focused on BC's size in snow, an important parameter affecting BC light absorption in snow. Here we present first observations of this parameter, revealing that BC can be shifted to larger sizes in snow than are typically seen in the atmosphere, in part due to the processes associated with BC removal from the atmosphere. Mie theory analysis indicates a corresponding reduction in BC absorption in snow of 40%, making BC size in snow the dominant source of uncertainty in BC's absorption properties for calculations of BC's snow albedo climate forcing. The shift reduces estimated BC global mean snow forcing by 30%, and has scientific implications for our understanding of snow albedo and the processing of atmospheric BC aerosol in snowfall.


Assessing impact and sustainability of health, water, and sanitation interventions in Bolivia six years post-project.
To assess the impact and sustainability of health, water, and sanitation interventions in Bolivia six years post-project. A mixed-method (qualitative-quantitative) study was conducted in 14 rural intervention and control communities in Bolivia in November 2008, six years after the completion of interventions designed to improve knowledge and practices related to maternal and child health and nutrition, community water systems, and household water and sanitation facilities. The degree to which participants had sustained the community and household practices promoted by the interventions was a particular focus. Community site visits were made to evaluate the status (functional condition) and sustainability (state of maintenance and repair) of community and household water and sanitation infrastructure. Key informant interviews and focus group discussions were conducted to assess knowledge and practices, and perceptions about the value of the interventions to the community. Six years post-project, participants remained committed to sustaining the practices promoted in the interventions. The average rating for the functional condition of community water systems was 42% higher than the average rating in control communities. In addition, more than two-thirds of households continued to practice selected maternal and child health behaviors promoted by the interventions (compared to less than half of the households in the control communities). Communities that received integrated investments (development and health) seemed to sustain the practices promoted in the interventions better than communities that received assistance in only one of the two sectors. Infrastructure for community water systems and household water and sanitation facilities was better built and maintained, and selected maternal and child health behaviors practiced more frequently, in intervention communities versus control communities.


Fast, robust, and accurate monocular peer-to-peer tracking for surgical navigation.
This work presents a new monocular peer-to-peer tracking concept overcoming the distinction between tracking tools and tracked tools for optical navigation systems. A marker model concept based on marker triplets combined with a fast and robust algorithm for assigning image feature points to the corresponding markers of the tracker is introduced. Also included is a new and fast algorithm for pose estimation. A peer-to-peer tracker consists of seven markers, which can be tracked by other peers, and one camera which is used to track the position and orientation of other peers. The special marker layout enables a fast and robust algorithm for assigning image feature points to the correct markers. The iterative pose estimation algorithm is based on point-to-line matching with Lagrange-Newton optimization and does not rely on initial guesses. Uniformly distributed quaternions in 4D (the vertices of a hexacosichora) are used as starting points and always provide the global minimum. Experiments have shown that the marker assignment algorithm robustly assigns image feature points to the correct markers even under challenging conditions. The pose estimation algorithm works fast, robustly and always finds the correct pose of the trackers. Image processing, marker assignment, and pose estimation for two trackers are handled in less than 18 ms on an Intel i7-6700 desktop computer at 3.4 GHz. The new peer-to-peer tracking concept is a valuable approach to a decentralized navigation system that offers more freedom in the operating room while providing accurate, fast, and robust results.


Coherency matrix formulation for partially coherent imaging to evaluate the degree of coherence for image.
This paper defines a matrix from which coherence property of imaging by partially coherent Koehler illumination is determined. The matrix termed coherency matrix in imaging system is derived by the space average of a product of a column vector and its transpose conjugate where each row of the column vector represents mutually incoherent light. The coherency matrix in imaging system has similar properties to the polarization matrix that is utilized for calculating the light intensity and degree of polarization of polarized light. The coherency matrix in imaging system enables us to calculate not only image intensity but also degree of coherence for image. Simulation results of the degree of coherence for image given by the coherency matrix in imaging system correspond to the complex degree of coherence obtained by the van Cittert-Zernike theorem.


Medication-induced mitochondrial damage and disease.
Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health and disease. Damage to mitochondria is now understood to play a role in the pathogenesis of a wide range of seemingly unrelated disorders such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis. Medications have now emerged as a major cause of mitochondrial damage, which may explain many adverse effects. All classes of psychotropic drugs have been documented to damage mitochondria, as have stain medications, analgesics such as acetaminophen, and many others. While targeted nutrient therapies using antioxidants or their precursors (e. g., N-acetylcysteine) hold promise for improving mitochondrial function, there are large gaps in our knowledge. The most rational approach is to understand the mechanisms underlying mitochondrial damage for specific medications and attempt to counteract their deleterious effects with nutritional therapies. This article reviews our basic understanding of how mitochondria function and how medications damage mitochondria to create their occasionally fatal adverse effects.


Voluntary step execution in patients with knee osteoarthritis: Symptomatic vs. non-symptomatic legs.
Individuals with osteoarthritis fall at a greater rate than the general population, likely as a result of weakness, pain, movement limitations, and a decline in balance. Due to the high prevalence of osteoarthritis in the population, understanding the mechanisms leading to greater fall risk is an important issue to better understand. What is the influence of unilateral knee osteoarthritis on the characteristics of performing a voluntary step (i.e., similar to that performed to avoid a fall after a perturbation), compared to healthy age-matched controls? Case-control study performed in a Health maintenance organization physical therapy clinic. The research group consisted of a referred sample of 21 patients with unilateral knee osteoarthritis. The control group consisted of 22 age-matched healthy individuals. All participants were over 65 years of age. Participants were excluded if they had a surgical procedure to back or lower limb within one year before testing, oncological or neurological disease or a deficit in tactile sense. Movements were performed with and without dual tasking. Duration of the initiation phase (cue to step initiation), preparatory phase (step initiation to foot off) and swing phase (foot off to foot contact). In the preparatory phase and swing phase, the osteoarthritis group moved more slowly than the control group, and these differences were larger for forward compared to backward movements. Dual-tasking slowed responses in the pre-movement initiation stage across groups. The differences in basic parameters, and the slower movements in the osteoarthritis group, are consistent with known features of osteoarthritis, being a disease commonly regarded as primarily "mechanical", and are likely to increase fall risk. These response deficits suggest we should take advantage of advanced rehabilitation techniques, including cognitive loading, to help prevent falls in older adults with osteoarthritis.


Genome sequence of the pea aphid Acyrthosiphon pisum.
Aphids are important agricultural pests and also biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and the developmental causes of extreme phenotypic plasticity. Here we present the 464 Mb draft genome assembly of the pea aphid Acyrthosiphon pisum. This first published whole genome sequence of a basal hemimetabolous insect provides an outgroup to the multiple published genomes of holometabolous insects. Pea aphids are host-plant specialists, they can reproduce both sexually and asexually, and they have coevolved with an obligate bacterial symbiont. Here we highlight findings from whole genome analysis that may be related to these unusual biological features. These findings include discovery of extensive gene duplication in more than 2000 gene families as well as loss of evolutionarily conserved genes. Gene family expansions relative to other published genomes include genes involved in chromatin modification, miRNA synthesis, and sugar transport. Gene losses include genes central to the IMD immune pathway, selenoprotein utilization, purine salvage, and the entire urea cycle. The pea aphid genome reveals that only a limited number of genes have been acquired from bacteria; thus the reduced gene count of Buchnera does not reflect gene transfer to the host genome. The inventory of metabolic genes in the pea aphid genome suggests that there is extensive metabolite exchange between the aphid and Buchnera, including sharing of amino acid biosynthesis between the aphid and Buchnera. The pea aphid genome provides a foundation for post-genomic studies of fundamental biological questions and applied agricultural problems.


Fate mapping using Cited1-CreERT2 mice demonstrates that the cap mesenchyme contains self-renewing progenitor cells and gives rise exclusively to nephronic epithelia.
Classic tissue recombination and in vitro lineage tracing studies suggest that condensed metanephric mesenchyme (MM) gives rise to nephronic epithelium of the adult kidney. However, these studies do not distinguish between cap mesenchyme and pre-tubular aggregates comprising the condensed MM, nor do they establish whether these cells have self-renewing capacity. To address these questions, we generated Cited1-CreER(T2) BAC transgenic mice, which express tamoxifen-regulated Cre recombinase exclusively in the cap mesenchyme. Fate mapping was performed by crossing these mice with the Rosa26R(LacZ) reporter line and evaluating the location and cellular characteristics of LacZ positive cells at different time points following tamoxifen injection. These studies confirmed expected results from previous in vitro analysis of MM cell fate, and provide in vivo evidence that the cap mesenchyme does not contribute to collecting duct epithelium in the adult. Furthermore, by exploiting the temporally regulated Cre recombinase, these studies show that nephronic epithelium arising at different stages of nephrogenesis has distinct spatial distribution in the adult kidney, and demonstrate for the first time that the cap mesenchyme includes a population of self-renewing epithelial progenitor cells.


House-dust mite species in Bloemfontein, South Africa.
House-dust mites (HDMs) are an important source of allergens that are reputed to act as a trigger for atopic disease. Climatic conditions in parts of South Africa are not suitable for their proliferation, and there is doubt whether they occur on the Highveld. We studied whether HDMs occur in homes in Bloemfontein, Free State. Ten houses were sampled over a 1-year period. Dust was collected monthly or quarterly from a mattress, a bedroom floor and the living room floor of each house and examined for the presence of HDMs. Climate data were collected during the same period and a questionnaire was completed by home-owners to gather data on indoor factors that could influence mite proliferation. HDMs were regularly found in 3 houses (30%). Dermatophagoides farinae was the dominant species (97.5%). The highest numbers were found in winter, when climatic conditions were the least favourable. Climatic conditions never met the requirements for active proliferation of the mites. Indoor factors that may have promoted mite proliferation in some houses were artificial heating (especially under-floor heating), en-suite bathrooms and lack of adequate ventilation during the winter months. HDMs do occur in central South Africa, owing to a microclimate created indoors. Adequate ventilation, to reduce indoor humidity, should suffice to reduce mite numbers and prevent atopic symptoms induced by them.


Batracobdella leeches, environmental features and Hydromantes salamanders.
Leeches can parasitize many vertebrate taxa. In amphibians, leech parasitism often has potential detrimental effects including population decline. Most of studies on the host-parasite interactions involving leeches and amphibians focus on freshwater environments, while they are very scarce for terrestrial amphibians. In this work, we studied the relationship between the leech Batracobdella algira and the European terrestrial salamanders of the genus Hydromantes, identifying environmental features related to the presence of the leeches and their possible effects on the hosts. We performed observation throughout Sardinia (Italy), covering the distribution area of all Hydromantes species endemic to this island. From September 2015 to May 2017, we conducted >150 surveys in 26 underground environments, collecting data on 2629 salamanders and 131 leeches. Water hardness was the only environmental feature correlated with the presence of B. algira, linking this leech to active karstic systems. Leeches were more frequently parasitizing salamanders with large body size. Body Condition Index was not significantly different between parasitized and non-parasitized salamanders. Our study shows the importance of abiotic environmental features for host-parasite interactions, and poses new questions on complex interspecific interactions between this ectoparasite and amphibians.


Relative abuse liability of GHB in humans: A comparison of psychomotor, subjective, and cognitive effects of supratherapeutic doses of triazolam, pentobarbital, and GHB.
Although preclinical studies suggest that GHB has low likelihood for abuse, case reports indicate that GHB is abused. This study evaluated the relative abuse liability of GHB in 14 volunteers with histories of drug abuse. Psychomotor, subjective, and cognitive effects of a broad range of GHB doses (2-18 g/70 kg), up to a dose that produced severe behavioral impairment in each participant, were compared to placebo and two abused sedative/hypnotic drugs, triazolam (0.5 and 1 mg/70 kg) and pentobarbital (200 and 400 mg/70 kg), under double-blind, double-dummy conditions at a residential research facility. In general, GHB produced effects similar to triazolam and pentobarbital, although GHB was not identified as a benzodiazepine or barbiturate by participants that correctly identified triazolam and pentobarbital as such. On most measures of likelihood of abuse (eg ratings of liking, reinforcing effects), effects of pentobarbital were significantly greater than those of triazolam, with GHB being intermediate. GHB produced significantly greater negative subjective effects, including nausea, than the other drugs. Memory impairment after GHB was less than that after triazolam and pentobarbital. Within participants, the dose-effect function for sedation was steeper for GHB than for triazolam and pentobarbital. Also, at higher doses, GHB was associated with greater sedation and more variability across participants in sedation. Taken together, these data suggest that the profile of effects of GHB only partially overlaps with that of triazolam and pentobarbital. Although the likelihood for GHB to be abused is intermediate to triazolam and pentobarbital, the possibility of accidental overdose (ie greater sedation than intended) with GHB appears to be greater.


Results of National Colorectal Cancer Screening Program in Croatia (2007-2011).
To study the epidemiologic indicators of uptake and characteristic colonoscopic findings in the Croatian National Colorectal Cancer Screening Program. Colorectal cancer (CRC) was the second leading cause of cancer mortality in men (n = 1063, 49.77/100,000), as well as women (n = 803, 34.89/100,000) in Croatia in 2009. The Croatian National CRC Screening Program was established by the Ministry of Health and Social Welfare, and its implementation started in September, 2007. The coordinators were recruited in each county institute of public health with an obligation to provide fecal occult blood testing (FOBT) to the participants, followed by colonoscopy in all positive cases. The FOBT was performed by hypersensitive guaiac-based Hemognost card test (Biognost, Zagreb). The test and short questionnaire were delivered to the home addresses of all citizens aged 50-74 years consecutively during a 3-year period. Each participant was required to complete the questionnaire and send it together with the stool specimen on three test cards back to the institute for further analysis. About 4% FOBT positive cases are expected in normal risk populations. A descriptive analysis was performed. A total of 1,056,694 individuals (born between 1933-1945 and 1952-1957) were invited to screening by the end of September 2011. In total, 210,239 (19.9%) persons returned the envelope with a completed questionnaire, and 181,102 of them returned it with a correctly placed stool specimen on FOBT cards. Until now, 12,477 (6.9%), FOBT-positive patients have been found, which is at the upper limit of the expected values in European Guidelines for Quality Assurance in CRC Screening and Diagnosis [European Union (EU) Guidelines]. Colonoscopy was performed in 8541 cases (uptake 66%). Screening has identified CRC in 472 patients (5.5% of colonoscopied, 3.8% of FOBT-positive, and 0.26% of all screened individuals). This is also in the expected range according to EU Guidelines. Polyps were found and removed in 3329 (39% of colonoscopied) patients. The largest number of polyps were found in the left half of the colon: 64% (19%, 37% and 8% in the rectum, sigma, and descendens, respectively). The other 36% were detected in the proximal part (17% in the transverse colon and 19% in ceco-ascending colon). Small polyps in the rectum (5-10 mm in diameter), sigmoid and descending colon were histologically found to be tubular adenomas in 60% of cases, with a low degree of dysplasia, and 40% were classified as hyperplastic. Polyps of this size in the transverse or ceco-ascending colon in almost 20% had a histologically villous component, but still had a low degree of dysplasia. Polyps sized 10-20 mm in diameter were in 43% cases tubulovillous, and among them, 32% had areas with a high degree of dysplasia, especially those polyps in the ceco-ascending or transverse part. The characteristics of the Croatian CRC Screening National Program in the first 3 years were as follows: relatively low percentage of returned FOBT, higher number of FOBT-positive persons but still in the range for population-based programs, and higher number of pathologic findings (polyps and cancers). These results suggest a need for intervention strategies that include organizational changes and educational activities to improve awareness of CRC screening usefulness and increase participation rates.


Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase.
Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.


Gender differences in smiling: An evolutionary neuroandrogenic theory.
Studies have found that, under a wide variety of social circumstances, females are more likely than males to smile. The present article offers a theoretical explanation for this difference based on the premise that testosterone (along with other sex hormones) has evolved the tendency to alter brain functioning in ways that inhibit male smiling, especially during their most reproductively active years. Underlying the theory are the assumptions that (a) females have been naturally selected for preferring to mate with males who have the ability to assist in long-term child rearing primarily by provisioning resources, that (b) males partially accommodate this female preference by competing with rival males who are also vying for resources with which to attract mates, and that (c) male smiling interferes with their ability to most effectively intimidate rivals. If this reasoning is correct, genes must be involved in promoting the tendency to compete for resources, the most likely location for which would be on the Y-chromosome. According to the present theory, these genes operate in part by inhibiting social signals of fear and submissiveness. An additional element of the theory asserts that testosterone alters brain functioning in ways that shift the neocortex away from the left (more "prosocial and friendly") hemisphere toward the right (less "prosocial and friendly") hemisphere. Current evidence bearing on the theory is reviewed and a number of largely untested hypotheses are derived from the theory for future assessment of its predictive power.


Urinary peptide profiling identifies a panel of putative biomarkers for diagnosing and staging endometriosis.
To identify a potential diagnostic endometriosis marker using matrix-enhanced laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS)-based urinary proteomics. Prospective randomized pilot study. University hospital, tertiary referral center for endometriosis. 53 women undergoing laparoscopic surgery for pain and/or infertility comprising 30 women without endometriosis and 23 with endometriosis. Laparoscopy and urine specimens. Urinary peptide profiles. We observed distinct patterns of peptide profiles in the urine samples of women presenting with typical clinical symptoms of endometriosis. Six statistically significant putative peptide markers were identified (four during the periovulatory phase and two during the luteal phase) by comparing controls with moderate/severe endometriosis patients. The periovulatory peptide mass of 1,767.1 Da and the luteal peptide mass of 1,824.3 Da both showed a sensitivity of 75% and a specificity of 85% and 71%, respectively. Also detected were seven peptide markers (two during the periovulatory phase and five during the luteal phase) by comparing the urinary peptide profiles of patients with minimal/mild to moderate/severe endometriosis. The periovulatory peptide mass of 3,280.9 Da and the luteal peptide mass of 1,933.8 Da showed a sensitivity of 82% and 75% and a specificity of 88% and 75%, respectively. Urinary proteomic analysis may provide a novel method of diagnosing and staging endometriosis.


A safe lithium mimetic for bipolar disorder.
Lithium is the most effective mood stabilizer for the treatment of bipolar disorder, but it is toxic at only twice the therapeutic dosage and has many undesirable side effects. It is likely that a small molecule could be found with lithium-like efficacy but without toxicity through target-based drug discovery; however, therapeutic target of lithium remains equivocal. Inositol monophosphatase is a possible target but no bioavailable inhibitors exist. Here we report that the antioxidant ebselen inhibits inositol monophosphatase and induces lithium-like effects on mouse behaviour, which are reversed with inositol, consistent with a mechanism involving inhibition of inositol recycling. Ebselen is part of the National Institutes of Health Clinical Collection, a chemical library of bioavailable drugs considered clinically safe but without proven use. Therefore, ebselen represents a lithium mimetic with the potential both to validate inositol monophosphatase inhibition as a treatment for bipolar disorder and to serve as a treatment itself.


Association between endogenous plasma hormone concentrations and fracture risk in men and women: the EPIC-Oxford prospective cohort study.
Sex steroids have an important role in bone health, however previous studies on fracture risk have been carried out in older populations. The EPIC-Oxford study is a prospective cohort of men and women living in the UK. Five years after recruitment, participants self-reported previous fractures. Sex steroid concentrations (plasma estradiol, testosterone and sex hormone binding globulin) were measured in 436 cases (155 men, 46 premenopausal women and 235 postmenopausal women) with an incident fracture and 868 matched controls. Fracture risk was inversely related to concentrations of estradiol among men (RR for a doubling of estradiol 0.35, 95% CI 0.44-0.96) but there was no association between fracture risk and testosterone levels. There were no clear associations between fracture risk and hormone levels among postmenopausal women, however there was suggestion of an inverse association for both estradiol and testosterone as the RR in the highest compared with the lowest tertile for estradiol was 0.74 (95% CI 0.46, 1.18) and testosterone was 0.75 (95% CI 0.49, 1.16). Among premenopausal women fracture risk was inversely associated with levels of testosterone (RR for doubling of testosterone 0.46, 95% CI 0.26-0.81), with no association between estradiol and fracture risk. SHBG was not associated with risk of fracture among either men or women. In summary, this study finds evidence of an inverse association between endogenous estradiol and risk of fracture in men, and between endogenous testosterone and risk of fracture in premenopausal women but no clear associations among postmenopausal women.


Collaboration Across Worldviews: Managers and Scientists on Hawai'i Island Utilize Knowledge Coproduction to Facilitate Climate Change Adaptation.
Complex socio-ecological issues, such as climate change have historically been addressed through technical problem solving methods. Yet today, climate science approaches are increasingly accounting for the roles of diverse social perceptions, experiences, cultural norms, and worldviews. In support of this shift, we developed a research program on Hawai'i Island that utilizes knowledge coproduction to integrate the diverse worldviews of natural and cultural resource managers, policy professionals, and researchers within actionable science products. Through their work, local field managers regularly experience discrete land and waterscapes. Additionally, in highly interconnected rural communities, such as Hawai'i Island, managers often participate in the social norms and values of communities that utilize these ecosystems. Such local manager networks offer powerful frameworks within which to co-develop and implement actionable science. We interviewed a diverse set of local managers with the aim of incorporating their perspectives into the development of a collaborative climate change research agenda that builds upon existing professional networks utilized by managers and scientists while developing new research products. We report our manager needs assessment, the development process of our climate change program, our interactive forums, and our ongoing research products. Our needs assessment showed that the managers' primary source of information were other professional colleagues, and our in-person forums informed us that local managers are very interested in interacting with a wider range of networks to build upon their management capacities. Our initial programmatic progress suggests that co-created research products and in-person forums strengthen the capacities of local managers to adapt to change.


Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators.
A growing body of research shows that mindfulness meditation can alter neural, behavioral and biochemical processes. However, the mechanisms responsible for such clinically relevant effects remain elusive. Here we explored the impact of a day of intensive practice of mindfulness meditation in experienced subjects (n=19) on the expression of circadian, chromatin modulatory and inflammatory genes in peripheral blood mononuclear cells (PBMC). In parallel, we analyzed a control group of subjects with no meditation experience who engaged in leisure activities in the same environment (n=21). PBMC from all participants were obtained before (t1) and after (t2) the intervention (t2-t1=8h) and gene expression was analyzed using custom pathway focused quantitative-real time PCR assays. Both groups were also presented with the Trier Social Stress Test (TSST). Core clock gene expression at baseline (t1) was similar between groups and their rhythmicity was not influenced in meditators by the intensive day of practice. Similarly, we found that all the epigenetic regulatory enzymes and inflammatory genes analyzed exhibited similar basal expression levels in the two groups. In contrast, after the brief intervention we detected reduced expression of histone deacetylase genes (HDAC 2, 3 and 9), alterations in global modification of histones (H4ac; H3K4me3) and decreased expression of pro-inflammatory genes (RIPK2 and COX2) in meditators compared with controls. We found that the expression of RIPK2 and HDAC2 genes was associated with a faster cortisol recovery to the TSST in both groups. The regulation of HDACs and inflammatory pathways may represent some of the mechanisms underlying the therapeutic potential of mindfulness-based interventions. Our findings set the foundation for future studies to further assess meditation strategies for the treatment of chronic inflammatory conditions.


Retinal Tissue Bioengineering, Materials and Methods for the Treatment of Glaucoma.
Glaucoma, a characteristic type of optic nerve degeneration in the posterior pole of the eye, is a common cause of irreversible vision loss and the second leading cause of blindness worldwide. As an optic neuropathy, glaucoma is identified by increasing degeneration of retinal ganglion cells (RGCs), with consequential vision loss. Current treatments only postpone the development of retinal degeneration, and there are as yet no treatments available for this disability. Recent studies have shown that replacing lost or damaged RGCs with healthy RGCs or RGC precursors, supported by appropriately designed bio-material scaffolds, could facilitate the development and enhancement of connections to ganglion cells and optic nerve axons. The consequence may be an improved retinal regeneration. This technique could also offer the possibility for retinal regeneration in treating other forms of optic nerve ailments through RGC replacement. In this brief review, we describe the innovations and recent developments in retinal regenerative medicine such as retinal organoids and gene therapy which are specific to glaucoma treatment and focus on the selection of appropriate bio-engineering principles, biomaterials and cell therapies that are presently employed in this growing research area. Identification of optimal sources of cells, improving cell survival, functional integration upon transplantation, and developing techniques to deliver cells into the retinal space without provoking immune responses are the main challenges in retinal cell replacement therapies. The restoration of visual function in glaucoma patients by the RGC replacement therapies requires appropriate protocols and biotechnology methods. Tissue-engineered scaffolds, the generation of retinal organoids, and gene therapy may help to overcome some of the challenges in the generation of clinically safe RGCs.


Prevalence of active convulsive epilepsy in sub-Saharan Africa and associated risk factors: cross-sectional and case-control studies.
The prevalence of epilepsy in sub-Saharan Africa seems to be higher than in other parts of the world, but estimates vary substantially for unknown reasons. We assessed the prevalence and risk factors of active convulsive epilepsy across five centres in this region. We did large population-based cross-sectional and case-control studies in five Health and Demographic Surveillance System centres: Kilifi, Kenya (Dec 3, 2007-July 31, 2008); Agincourt, South Africa (Aug 4, 2008-Feb 27, 2009); Iganga-Mayuge, Uganda (Feb 2, 2009-Oct 30, 2009); Ifakara, Tanzania (May 4, 2009-Dec 31, 2009); and Kintampo, Ghana (Aug 2, 2010-April 29, 2011). We used a three-stage screening process to identify people with active convulsive epilepsy. Prevalence was estimated as the ratio of confirmed cases to the population screened and was adjusted for sensitivity and attrition between stages. For each case, an age-matched control individual was randomly selected from the relevant centre's census database. Fieldworkers masked to the status of the person they were interviewing administered questionnaires to individuals with active convulsive epilepsy and control individuals to assess sociodemographic variables and historical risk factors (perinatal events, head injuries, and diet). Blood samples were taken from a randomly selected subgroup of 300 participants with epilepsy and 300 control individuals from each centre and were screened for antibodies to Toxocara canis, Toxoplasma gondii, Onchocerca volvulus, Plasmodium falciparum, Taenia solium, and HIV. We estimated odds ratios (ORs) with logistic regression, adjusted for age, sex, education, employment, and marital status. 586,607 residents in the study areas were screened in stage one, of whom 1711 were diagnosed as having active convulsive epilepsy. Prevalence adjusted for attrition and sensitivity varied between sites: 7·8 per 1000 people (95% CI 7·5-8·2) in Kilifi, 7·0 (6·2-7·4) in Agincourt, 10·3 (9·5-11·1) in Iganga-Mayuge, 14·8 (13·8-15·4) in Ifakara, and 10·1 (9·5-10·7) in Kintampo. The 1711 individuals with the disorder and 2032 control individuals were given questionnaires. In children (aged <18 years), the greatest relative increases in prevalence were associated with difficulties feeding, crying, or breathing after birth (OR 10·23, 95% CI 5·85-17·88; p<0·0001); abnormal antenatal periods (2·15, 1·53-3·02; p<0·0001); and head injury (1·97, 1·28-3·03; p=0·002). In adults (aged ≥18 years), the disorder was significantly associated with admission to hospital with malaria or fever (2·28, 1·06-4·92; p=0·036), exposure to T canis (1·74, 1·27-2·40; p=0·0006), exposure to T gondii (1·39, 1·05-1·84; p=0·021), and exposure to O volvulus (2·23, 1·56-3·19; p<0·0001). Hypertension (2·13, 1·08-4·20; p=0·029) and exposure to T solium (7·03, 2·06-24·00; p=0·002) were risk factors for adult-onset disease. The prevalence of active convulsive epilepsy varies in sub-Saharan Africa and that the variation is probably a result of differences in risk factors. Programmes to control parasitic diseases and interventions to improve antenatal and perinatal care could substantially reduce the prevalence of epilepsy in this region.


Trends in purchases and intake of foods and beverages containing caloric and low-calorie sweeteners over the last decade in the United States.
Current food databases might not capture rapidly occurring changes in the food supply, such as the increased use of caloric (CS) and low-calorie sweeteners (LCS) in products. We explored trends in purchases and intake of foods and beverages containing LCS, CS or both sweeteners over the last decade in the United States, as well as household and socioeconomic status (SES) predictors of these trends. We analyzed household purchases from Homescan 2000-2010 (n = 140 352 households; 408 458 individuals) and dietary intake from National Health And Nutrition Examination Survey (NHANES) 2003-2010 (n = 34 391 individuals). We estimated per capita purchases and intake (g or mL d(-1)) and percent of consumers of foods and beverages containing LCS, CS or both LCS + CS. We estimated change in purchases associated with SES and household composition using random-effects longitudinal models. From 2000 to 2010, percent of households purchasing CS products decreased, whereas that for LCS and LCS + CS products increased among all types of households and particularly among those with children. African-American, Hispanic and households with children had a higher % CS beverage purchases (+9, +4 and +3%, respectively, P < 0.001) and lower % LCS beverage purchases (-12, -5 and -2%, respectively, P < 0.001). During a period of declining purchases and consumption of CS products, we have documented an increasing trend in products that contain LCS and a previously unexplored trend in products with both LCS and CS, especially important among households with children.


Virtual reality in the treatment of persecutory delusions: randomised controlled experimental study testing how to reduce delusional conviction.
Persecutory delusions may be unfounded threat beliefs maintained by safety-seeking behaviours that prevent disconfirmatory evidence being successfully processed. Use of virtual reality could facilitate new learning. To test the hypothesis that enabling patients to test the threat predictions of persecutory delusions in virtual reality social environments with the dropping of safety-seeking behaviours (virtual reality cognitive therapy) would lead to greater delusion reduction than exposure alone (virtual reality exposure). Conviction in delusions and distress in a real-world situation were assessed in 30 patients with persecutory delusions. Patients were then randomised to virtual reality cognitive therapy or virtual reality exposure, both with 30 min in graded virtual reality social environments. Delusion conviction and real-world distress were then reassessed. In comparison with exposure, virtual reality cognitive therapy led to large reductions in delusional conviction (reduction 22.0%, P = 0.024, Cohen's d = 1.3) and real-world distress (reduction 19.6%, P = 0.020, Cohen's d = 0.8). Cognitive therapy using virtual reality could prove highly effective in treating delusions.


Alternatives to inpatient mental health care for children and young people.
Current policy in the UK and elsewhere places emphasis on the provision of mental health services in the least restrictive setting, whilst also recognising that some children will require inpatient care. As a result, there are a range of mental health services to manage young people with serious mental health problems who are at risk of being admitted to an inpatient unit in community or outpatient settings. 1. To assess the effectiveness, acceptability and cost of mental health services that provide an alternative to inpatient care for children and young people. 2. To identify the range and prevalence of different models of service that seek to avoid inpatient care for children and young people. Our search included the Cochrane Effective Practice and Organisation of Care Group Specialised Register (2007), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, issue 4), MEDLINE (1966 to 2007), EMBASE (1982 to 2006), the British Nursing Index (1994 to 2006), RCN database (1985 to 1996), CINAHL (1982 to 2006) and PsycInfo (1972 to 2007). Randomised controlled trials of mental health services providing specialist care, beyond the scope of generic outpatient provision, as an alternative to inpatient mental health care, for children or adolescents aged from five to 18 years who have a serious mental health condition requiring specialist services beyond the capacity of generic outpatient provision. The control group received mental health services in an inpatient or equivalent setting. Two authors independently extracted data and assessed study quality. We grouped studies according to the intervention type but did not pool data because of differences in the interventions and measures of outcome. Where data were available we calculated confidence intervals (CIs) for differences between groups at follow up. We also calculated standardised mean differences (SMDs) and 95% CIs for each outcome in terms of mean change from baseline to follow up using the follow-up SDs. We calculated SMDs (taking into account the direction of change and the scoring of each instrument) so that negative SMDs indicate results that favour treatment and positive SMDs favour the control group. We included seven randomised controlled trials (recruiting a total of 799 participants) evaluating four distinct models of care: multi-systemic therapy (MST) at home, specialist outpatient service, intensive home treatment and intensive home-based crisis intervention ('Homebuilders' model for crisis intervention). Young people receiving home-based MST experienced some improved functioning in terms of externalising symptoms and they spent fewer days out of school and out-of-home placement. At short term follow up the control group had a greater improvement in terms of adaptability and cohesion; this was not sustained at four months follow up. There were small, significant patient improvements reported in both groups in the trial evaluating the intensive home-based crisis intervention using the 'Homebuilders' model. No differences at follow up were reported in the two trials evaluating intensive home treatment, or in the trials evaluating specialist outpatient services. The quality of the evidence base currently provides very little guidance for the development of services. If randomised controlled trials are not feasible then consideration should be given to alternative study designs, such as prospective systems of audit conducted across several centres, as this has the potential to improve the current level of evidence. These studies should include baseline measurement at admission along with demographic data, and outcomes measured using a few standardised robust instruments.


On the nature and sociology of bioethics.
Much has been written in the last decade about how we should understand the value of the sociology of bioethics. Increasingly the value of the sociology of bioethics is interpreted by its advocates directly in terms of its relationship to bioethics. It is claimed that the sociology of bioethics (and related disciplinary approaches) should be seen as an important component of work in bioethics. In this paper we wish to examine whether, and how, the sociology of bioethics can be defended as a valid and justified research activity, in the context of debates about the nature of bioethics. We begin by presenting and arguing for an account of bioethics that does justice to the content of the field, the range of questions that belong within this field, and the justificatory standards (and methodological orientations) that can provide convincing answers to these questions. We then consider the role of sociology in bioethics and show how and under what conditions it can contribute to answering questions within bioethics. In the final section, we return to the sociology of bioethics to show that it can make only a limited contribution to the field.


A Semi-automated and Scalable 3D Spheroid Assay to Study Neuroblast Migration.
The subventricular zone of the mammalian brain is the major source of adult born neurons. These neuroblasts normally migrate long distances to the olfactory bulbs but can be re-routed to locations of injury and promote neuroregeneration. Mechanistic understanding and pharmacological targets regulating neuroblast migration is sparse. Furthermore, lack of migration assays limits development of pharmaceutical interventions targeting neuroblast recruitment. We therefore developed a physiologically relevant 3D neuroblast spheroid migration assay that permits the investigation of large numbers of interventions. To verify the assay, 1,012 kinase inhibitors were screened for their effects on migration. Several induced significant increases or decreases in migration. MuSK and PIK3CB were selected as putative targets and their knockdown validated increased neuroblast migration. Thus, compounds identified through this assay system could be explored for their potential in augmenting neuroblast recruitment to sites of injury for neuroregeneration, or for decreasing malignant invasion.


A model of cellular cardiac-neural coupling that captures the sympathetic control of sinoatrial node excitability in normotensive and hypertensive rats.
Hypertension is associated with sympathetic hyperactivity. To represent this neural-myocyte coupling, and to elucidate the mechanisms underlying sympathetic control of the cardiac pacemaker, we developed a new (to our knowledge) cellular mathematical model that incorporates signaling information from cell-to-cell communications between the sympathetic varicosity and sinoatrial node (SAN) in both normotensive (WKY) and hypertensive (SHR) rats. Features of the model include 1), a description of pacemaker activity with specific ion-channel functions and Ca(2+) handling elements; 2), dynamic β-adrenergic modulation of the excitation of the SAN; 3), representation of ionic activity of sympathetic varicosity with NE release dynamics; and 4), coupling of the varicosity model to the SAN model to simulate presynaptic transmitter release driving postsynaptic excitability. This framework captures neural-myocyte coupling and the modulation of pacemaking by nitric oxide and cyclic GMP. It also reproduces the chronotropic response to brief sympathetic stimulations. Finally, the SHR model quantitatively suggests that the impairment of cyclic GMP regulation at both sides of the sympathetic cleft is crucial for development of the autonomic phenotype observed in hypertension.


Genetic susceptibility according to three metabolic pathways in cancers of the lung and bladder and in myeloid leukemias in nonsmokers.
We chose a set of candidate single nucleotide polymorphisms (SNPs) to investigate gene-environment interactions in three types of cancer that have been related to air pollution (lung, bladder and myeloid leukemia). The study has been conducted as a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (409 cancer cases and 757 matched controls). We included never and ex-smokers. SNPs were in genes involved in oxidative stress, phase I metabolizing genes, phase II metabolizing genes and methylenetetrahydrofolate reductase (MTHFR). The most notable findings are: GSTM1 deletion and bladder cancer risk [odds ratio (OR) = 1.60; 95% confidence interval 1.00-2.56]; CYP1A1 and leukemia (2.22, 1.33-3.70; heterozygotes); CYP1B1 and leukemia (0.47, 0.27-0.84; homozygotes); MnSOD and leukemia (1.91, 1.08-3.38; homozygotes) and NQO1 and lung cancer (8.03, 1.73-37.3; homozygotes). Other statistically significant associations were found in subgroups defined by smoking habits (never or ex-smokers), environmental tobacco smoke or gender, with no obvious pattern. When gene variants were organized according to the three main pathways, the emerging picture was of a strong involvement of combined phase I enzymes in leukemia, with an OR of 5 (1.63-15.4) for those having three or more variant alleles. The association was considerably stronger for leukemias arising before the age of 55.


An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer.
Urinary biomarkers are needed to improve the care and reduce the cost of managing bladder cancer. Current biomarkers struggle to identify both high and low-grade cancers due to differing molecular pathways. Changes in microRNA (miR) expression are seen in urothelial carcinogenesis in a phenotype-specific manner. We hypothesised that urinary miRs reflecting low- and high-grade pathways could detect bladder cancers and overcome differences in genetic events seen within the disease. We investigated urinary samples (n=121) from patients with bladder cancer (n=68) and age-matched controls (n=53). Fifteen miRs were quantified using real-time PCR. We found that miR is stable within urinary cells despite adverse handling and detected differential expression of 10 miRs from patients with cancer and controls (miRs-15a/15b/24-1/27b/100/135b/203/212/328/1224, ANOVA P<0.05). Individually, miR-1224-3p had the best individual performance with specificity, positive and negative predictive values and concordance of 83%, 83%, 75% and 77%, respectively. The combination of miRs-135b/15b/1224-3p detected bladder cancer with a high sensitivity (94.1%), sufficient specificity (51%) and was correct in 86% of patients (concordance). The use of this panel in patients with haematuria would have found 94% of urothelial cell carcinoma, while reducing cystoscopy rates by 26%. However, two invasive cancers (3%) would have been missed.


A model invalidation-based approach for elucidating biological signalling pathways, applied to the chemotaxis pathway in R. sphaeroides.
Developing methods for understanding the connectivity of signalling pathways is a major challenge in biological research. For this purpose, mathematical models are routinely developed based on experimental observations, which also allow the prediction of the system behaviour under different experimental conditions. Often, however, the same experimental data can be represented by several competing network models. In this paper, we developed a novel mathematical model/experiment design cycle to help determine the probable network connectivity by iteratively invalidating models corresponding to competing signalling pathways. To do this, we systematically design experiments in silico that discriminate best between models of the competing signalling pathways. The method determines the inputs and parameter perturbations that will differentiate best between model outputs, corresponding to what can be measured/observed experimentally. We applied our method to the unknown connectivities in the chemotaxis pathway of the bacterium Rhodobacter sphaeroides. We first developed several models of R. sphaeroides chemotaxis corresponding to different signalling networks, all of which are biologically plausible. Parameters in these models were fitted so that they all represented wild type data equally well. The models were then compared to current mutant data and some were invalidated. To discriminate between the remaining models we used ideas from control systems theory to determine efficiently in silico an input profile that would result in the biggest difference in model outputs. However, when we applied this input to the models, we found it to be insufficient for discrimination in silico. Thus, to achieve better discrimination, we determined the best change in initial conditions (total protein concentrations) as well as the best change in the input profile. The designed experiments were then performed on live cells and the resulting data used to invalidate all but one of the remaining candidate models. We successfully applied our method to chemotaxis in R. sphaeroides and the results from the experiments designed using this methodology allowed us to invalidate all but one of the proposed network models. The methodology we present is general and can be applied to a range of other biological networks.


The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts.
Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - http://www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.


Fluorescent fatty acid transfer from bovine serum albumin to phospholipid vesicles: collision or diffusion mediated uptake.
The extent of palmitate uptake by hepatocytes is dependent upon the surface charge of the extracellular binding protein. Specifically, hepatocyte uptake is greater when palmitate is bound to cationic binding proteins than when it is bound to anionic proteins. To further understand the role of protein surface charge on the uptake process of protein-bound ligands, we examined the rate of transfer of fluorescent anthroyloxy palmitic acid (AOPA) in the presence of anionic and cationic extracellular proteins to model membranes containing different surface charged groups. AOPA transfer rate in the presence of bovine serum albumin (ALB; isoelectric point pI = 4.8-5.0) or modified ALB (ALBe; pI = 7.0-7.5) to negative, positive and neutral lipid vesicles was investigated using a fluorescence resonance energy transfer assay. The rate of AOPA transfer from both proteins was decreased when ionic strength was increased; directly dependent on the concentration of acceptor lipid vesicles; and was affected by both the lipid membrane surface charge and protein-bound concentration. The data support the notion that AOPA transfer from binding proteins to lipid membranes occurred through two concomitant processes, aqueous diffusion of the unbound ligand (diffusion-mediated process) and a collisional interaction between the protein-ligand complex and acceptor membrane. The contribution of diffusional mediated transfer to the overall uptake process was determined to be 3 to 4 times less than the contribution of a collisional interaction. This study strengthened the hypothesis that charged amino acid residues on proteins are important for effective collisional interaction between protein-ligand complexes and cell membranes through which more free ligand could be supplied for the uptake process.


Gyrification of Broca's region is anomalously lateralized at onset of schizophrenia in adolescence and regresses at 2 year follow-up.
Gyrification of the human cerebral cortex starts in the foetus and progresses in early infancy; the pattern of folding in later life provides a lead to early developmental aberration. By studying gyrification at illness onset in adolescence we hoped to clarify the pathophysiology of schizophrenia. Here we find 1) an area of hypergyria includes Broca's area and extends into the Sylvian fissure to encroach on the anterior insula in the left hemisphere, and 2) an area of hypogyria in the superior temporal lobe approximates to Wernicke's area but is located in the right hemisphere and encroaches on the posterior insula. In Broca's/anterior insula area, right lateralization was present in healthy controls but patients were left lateralized: at two year follow-up gyrification had decreased in patients while it increased in controls, and the reduction predicted impaired category fluency. Progressive change was unaccompanied by cortical thinning (investigated only in the brain regions showing baseline changes in gyrification) indicating that the disease process affecting these brain regions (insula, inferior frontal and superior temporal) is not primarily degenerative. A deviation in the lateralized development of peri-Sylvian areas for language production and comprehension appears critical to the pathophysiology of schizophrenia and may point to its species-specific origin.


Effects of yoga on the quality of life in cancer patients.
This study sought to investigate the effects of yoga on the quality of life in patients with breast cancer. Twenty patients between 30 and 50 years of age presently under treatment for breast cancer were included in the study. The physical characteristics of the patients were recorded and general physiotherapy assessments performed. Eight sessions of a yoga program including warming and breathing exercises, asanas, relaxation in supine position, and meditation were applied to participants. The pre- and post-yoga quality of life assessments for the patients were conducted using the Nottingham Health Profile (NHP). Patients' stress levels were assessed using the STAI-I and STAI-II anxiety inventory. Their satisfaction levels about the yoga program was evaluated using the visual analog scale (VAS). It was found that patients' quality of life scores after the yoga program were better than scores obtained before the yoga program (p < 0.05). After sessions, there was a statistically significant decrease in their STAI-I (measuring the reactions of anxiety) scores and STAI-II (measuring the permanence of anxiety) scores (p < 0.05). It was found out that the satisfaction score concerning the yoga program was considerably increased after the yoga program (p < 0.05). It can be concluded that yoga is valuable in helping to achieve relaxation and diminish stress, helps cancer patients perform daily and routine activities, and increases the quality of life in cancer patients. This result was positively reflected in patients satisfaction with the yoga program.


Base-specific spin-labeling of RNA for structure determination.
To facilitate the measurement of intramolecular distances in solvated RNA systems, a combination of spin-labeling, electron paramagnetic resonance (EPR), and molecular dynamics (MD) simulation is presented. The fairly rigid spin label 2,2,5,5-tetramethyl-pyrrolin-1-yloxyl-3-acetylene (TPA) was base and site specifically introduced into RNA through a Sonogashira palladium catalyzed cross-coupling on column. For this purpose 5-iodo-uridine, 5-iodo-cytidine and 2-iodo-adenosine phosphoramidites were synthesized and incorporated into RNA-sequences. Application of the recently developed ACE chemistry presented the main advantage to limit the reduction of the nitroxide to an amine during the oligonucleotide automated synthesis and thus to increase substantially the reliability of the synthesis and the yield of labeled oligonucleotides. 4-Pulse Electron Double Resonance (PELDOR) was then successfully used to measure the intramolecular spin-spin distances in six doubly labeled RNA-duplexes. Comparison of these results with our previous work on DNA showed that A- and B-Form can be differentiated. Using an all-atom force field with explicit solvent, MD simulations gave results in good agreement with the measured distances and indicated that the RNA A-Form was conserved despite a local destabilization effect of the nitroxide label. The applicability of the method to more complex biological systems is discussed.


Dynamic forcing of end-tidal carbon dioxide and oxygen applied to functional magnetic resonance imaging.
Investigations into the blood oxygenation level-dependent (BOLD) functional MRI signal have used respiratory challenges with the aim of probing cerebrovascular physiology. Such challenges have altered the inspired partial pressures of either carbon dioxide or oxygen, typically to a fixed and constant level (fixed inspired challenge (FIC)). The resulting end-tidal gas partial pressures then depend on the subject's metabolism and ventilatory responses. In contrast, dynamic end-tidal forcing (DEF) rapidly and independently sets end-tidal oxygen and carbon dioxide to desired levels by altering the inspired gas partial pressures on a breath-by-breath basis using computer-controlled feedback. This study implements DEF in the MRI environment to map BOLD signal reactivity to CO(2). We performed BOLD (T2(*)) contrast FMRI in four healthy male volunteers, while using DEF to provide a cyclic normocapnic-hypercapnic challenge, with each cycle lasting 4 mins (PET(CO(2)) mean+/-s.d., from 40.9+/-1.8 to 46.4+/-1.6 mm Hg). This was compared with a traditional fixed-inspired (FI(CO(2))=5%) hypercapnic challenge (PET(CO(2)) mean+/-s.d., from 38.2+/-2.1 to 45.6+/-1.4 mm Hg). Dynamic end-tidal forcing achieved the desired target PET(CO(2)) for each subject while maintaining PET(O(2)) constant. As a result of CO(2)-induced increases in ventilation, the FIC showed a greater cyclic fluctuation in PET(O(2)). These were associated with spatially widespread fluctuations in BOLD signal that were eliminated largely by the control of PET(O(2)) during DEF. The DEF system can provide flexible, convenient, and physiologically well-controlled respiratory challenges in the MRI environment for mapping dynamic responses of the cerebrovasculature.


The effect of diet on risk of cancer.
Diet-related factors are thought to account for about 30% of cancers in developed countries. Obesity increases the risk of cancers in the oesophagus, colorectum, breast, endometrium, and kidney. Alcohol causes cancers of the oral cavity, pharynx, larynx, oesophagus, and liver, and causes a small increase in the risk of breast cancer. Adequate intakes of fruit and vegetables probably lower the risk for several types of cancer, especially cancers of the gastrointestinal tract. The importance of other factors, including meat, fibre, and vitamins, is not yet clear. Prudent advice is to eat a varied diet including plenty of fruit, vegetables, and cereals to maintain a healthy bodyweight with the help of regular physical activity and to restrict consumption of alcohol.


Estimated 10-year cardiovascular risk in a British population: results of a national screening project.
To estimate 10-year cardiovascular disease (CVD) risk using the risk equation and risk categories of the Joint British Societies' Guidelines on Prevention of Cardiovascular Disease in Clinical Practice (2005). A cross-sectional CVD screening programme was conducted in 35 towns in Great Britain. In total, 27,776 men and 43,261 women aged at least 18 years were screened. The estimated 10-year risk of CVD was calculated and directly standardised to the population of Great Britain. The age standardised combined prevalence of known CVD, diabetes, lipid-lowering or antihypertensive drug therapy, which preclude multifactorial risk assessment, was 18.0% for men and 18.1% for women. CVD risk was calculated for 56,863 individuals, and the age-standardised prevalence of an estimated 10-year CVD risk < 10% was 42.7% (95% CI: 42.2-43.1) for men and 60.4% (95% CI: 60.1-60.7) for women; 10% to < 20% was 19.6% (19.1-20.6) and 15.6% (15.2-15.9); and > or = 20% was 19.6% (19.1-20.0) and 6.0% (5.8-6.2) respectively. After aggregating known CVD, diabetes, antihypertensive or lipid-lowering drug therapy, or an estimated CVD risk of > or = 20%, the combined standardised prevalence of high CVD risk for individuals aged 50 years or more was 74.1% (73.5-74.8) for men (n = 14,787) and 45.5% (44.8-46.2) for women (n = 24,400). Using current risk thresholds, there is a substantial unmet need for primary prevention of CVD, particularly among middle-aged men. The results emphasise the scale of intervention that a strategy of individual risk assessment and pharmacological intervention requires.


The current state-of-the-art of spinal cord imaging: methods.
A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small cross-sectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research.


The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: design, results and future prospects.
The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.


Drug excretion mediated by a new prototype of polyspecific transporter.
Cationic drugs of different types and structures (antihistaminics, antiarrhythmics, sedatives, opiates, cytostatics and antibiotics, for example) are excreted in mammals by epithelial cells of the renal proximal tubules and by hepatocytes in the liver. In the proximal tubules, two functionally disparate transport systems are involved which are localized in the basolateral and luminal plasma membrane and are different from the previously identified neuronal monoamine transporters and ATP-dependent multidrug exporting proteins. Here we report the isolation of a complementary DNA from rat kidney that encodes a 556-amino-acid membrane protein, OCT1, which has the functional characteristics of organic cation uptake over the basolateral membrane of renal proximal tubules and of organic cation uptake into hepatocytes. OCT1 is not homologous to any other known protein and is found in kidney, liver and intestine. As OCT1 translocates hydrophobic and hydrophilic organic cations of different structures, it is considered to be a new prototype of polyspecific transporters that are important for drug elimination.


Economic costs of diabetes in the U.S. in 2012.
This study updates previous estimates of the economic burden of diagnosed diabetes and quantifies the increased health resource use and lost productivity associated with diabetes in 2012. The study uses a prevalence-based approach that combines the demographics of the U.S. population in 2012 with diabetes prevalence, epidemiological data, health care cost, and economic data into a Cost of Diabetes Model. Health resource use and associated medical costs are analyzed by age, sex, race/ethnicity, insurance coverage, medical condition, and health service category. Data sources include national surveys, Medicare standard analytical files, and one of the largest claims databases for the commercially insured population in the U.S. The total estimated cost of diagnosed diabetes in 2012 is $245 billion, including $176 billion in direct medical costs and $69 billion in reduced productivity. The largest components of medical expenditures are hospital inpatient care (43% of the total medical cost), prescription medications to treat the complications of diabetes (18%), antidiabetic agents and diabetes supplies (12%), physician office visits (9%), and nursing/residential facility stays (8%). People with diagnosed diabetes incur average medical expenditures of about $13,700 per year, of which about $7,900 is attributed to diabetes. People with diagnosed diabetes, on average, have medical expenditures approximately 2.3 times higher than what expenditures would be in the absence of diabetes. For the cost categories analyzed, care for people with diagnosed diabetes accounts for more than 1 in 5 health care dollars in the U.S., and more than half of that expenditure is directly attributable to diabetes. Indirect costs include increased absenteeism ($5 billion) and reduced productivity while at work ($20.8 billion) for the employed population, reduced productivity for those not in the labor force ($2.7 billion), inability to work as a result of disease-related disability ($21.6 billion), and lost productive capacity due to early mortality ($18.5 billion). The estimated total economic cost of diagnosed diabetes in 2012 is $245 billion, a 41% increase from our previous estimate of $174 billion (in 2007 dollars). This estimate highlights the substantial burden that diabetes imposes on society. Additional components of societal burden omitted from our study include intangibles from pain and suffering, resources from care provided by nonpaid caregivers, and the burden associated with undiagnosed diabetes.


Calculation of carcinogenic potency from long-term animal carcinogenesis experiments.
An index of carcinogenic potency for chemicals tested in chronic animal experiments is described. By analogy with the well-known 'lethal dose 50' (LD50) of quantal bioassay, a 'tumorigenic dose 50' (TD50) may be defined (in the absence both of tumors in the control group and of intercurrent deaths) as that (daily) dose of chemical which gives 50% of the test animals tumors by some fixed age. Tumors in the control (zero-dose) group are handled exactly as for the LD50, and intercurrent deaths are handled by life-table methods. Nonparametric procedures are developed for estimating the TD50 and for constructing confidence intervals. These are based on likelihoods which assume that the tumor hazard is linear in dose.


Synchronization dynamics in response to plaid stimuli in monkey V1.
Gamma synchronization has generally been associated with grouping processes in the visual system. Here, we examine in monkey V1 whether gamma oscillations play a functional role in segmenting surfaces of plaid stimuli. Local field potentials (LFPs) and spiking activity were recorded simultaneously from multiple sites in the opercular and calcarine regions while the monkeys were presented with sequences of single and superimposed components of plaid stimuli. In accord with the previous studies, responses to the single components (gratings) exhibited strong and sustained gamma-band oscillations (30-65 Hz). The superposition of the second component, however, led to profound changes in the temporal structure of the responses, characterized by a drastic reduction of gamma oscillations in the spiking activity and systematic shifts to higher frequencies in the LFP ( approximately 10% increase). Comparisons between cerebral hemispheres and across monkeys revealed robust subject-specific spectral signatures. A possible interpretation of our results may be that single gratings induce strong cooperative interactions among populations of cells that share similar response properties, whereas plaids lead to competition. Overall, our results suggest that the functional architecture of the cortex is a major determinant of the neuronal synchronization dynamics in V1.


Acoustic telemetry validates a citizen science approach for monitoring sharks on coral reefs.
Citizen science is promoted as a simple and cost-effective alternative to traditional approaches for the monitoring of populations of marine megafauna. However, the reliability of datasets collected by these initiatives often remains poorly quantified. We compared datasets of shark counts collected by professional dive guides with acoustic telemetry data from tagged sharks collected at the same coral reef sites over a period of five years. There was a strong correlation between the number of grey reef sharks (Carcharhinus amblyrhynchos) observed by dive guides and the telemetry data at both daily and monthly intervals, suggesting that variation in relative abundance of sharks was detectable in datasets collected by dive guides in a similar manner to data derived from telemetry at these time scales. There was no correlation between the number or mean depth of sharks recorded by telemetry and the presence of tourist divers, suggesting that the behaviour of sharks was not affected by the presence of divers during our study. Data recorded by dive guides showed that current strength and temperature were important drivers of the relative abundance of sharks at monitored sites. Our study validates the use of datasets of shark abundance collected by professional dive guides in frequently-visited dive sites in Palau, and supports the participation of experienced recreational divers as contributors to long-term monitoring programs of shark populations.


Total or Partial Knee Arthroplasty Trial - TOPKAT: study protocol for a randomised controlled trial.
In the majority of patients with osteoarthritis of the knee the disease originates in the medial compartment. There are two fundamentally different approaches to knee replacement for patients with unicompartmental disease: some surgeons feel that it is always best to replace both the knee compartments with a total knee replacement (TKR); whereas others feel it is best to replace just the damaged component of the knee using a partial or unicompartment replacement (UKR). Both interventions are established and well-documented procedures. Little evidence exists to prove the clinical and cost-effectiveness of either management option. This provides an explanation for the high variation in treatment of choice by individual surgeons for the same knee pathology.The aim of the TOPKAT study will be to assess the clinical and cost effectiveness of TKRs compared to UKRs in patients with medial compartment osteoarthritis. The design of the study is a single layer multicentre superiority type randomised controlled trial of unilateral knee replacement patients. Blinding will not be possible as the surgical scars for each procedure differ.We aim to recruit 500 patients from approximately 28 secondary care orthopaedic units from across the UK including district general and teaching hospitals. Participants will be randomised to either UKR or TKR. Randomisation will occur using a web-based randomisation system. The study is pragmatic in terms of implant selection for the knee replacement operation. Participants will be followed up for 5 years. The primary outcome is the Oxford Knee Score, which will be collected via questionnaires at 2 months, 1 year and then annually to 5 years. Secondary outcomes will include cost-effectiveness, patient satisfaction and complications data. Current Controlled Trials ISRCTN03013488; ClinicalTrials.gov Identifier: NCT01352247.


Population and fertility by age and sex for 195 countries and territories, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017.
Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardised estimates of mortality. We present single-calendar year and single-year of age estimates of fertility and population by sex with standardised and replicable methods. We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10-54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10-14 years and 50-54 years was estimated from data on fertility in women aged 15-19 years and 45-49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories. From 1950 to 2017, TFRs decreased by 49·4% (95% uncertainty interval [UI] 46·4-52·0). The TFR decreased from 4·7 livebirths (4·5-4·9) to 2·4 livebirths (2·2-2·5), and the ASFR of mothers aged 10-19 years decreased from 37 livebirths (34-40) to 22 livebirths (19-24) per 1000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83·8 million people per year since 1985. The global population increased by 197·2% (193·3-200·8) since 1950, from 2·6 billion (2·5-2·6) to 7·6 billion (7·4-7·9) people in 2017; much of this increase was in the proportion of the global population in south Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2·0%; this rate then remained nearly constant until 1970 and then decreased to 1·1% in 2017. Population growth rates in the southeast Asia, east Asia, and Oceania GBD super-region decreased from 2·5% in 1963 to 0·7% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2·7%. The global average age increased from 26·6 years in 1950 to 32·1 years in 2017, and the proportion of the population that is of working age (age 15-64 years) increased from 59·9% to 65·3%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1·0 livebirths (95% UI 0·9-1·2) in Cyprus to a high of 7·1 livebirths (6·8-7·4) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0·08 livebirths (0·07-0·09) in South Korea to 2·4 livebirths (2·2-2·6) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0·3 livebirths (0·3-0·4) in Puerto Rico to a high of 3·1 livebirths (3·0-3·2) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in central, eastern, and western Europe, whereas population growth rates of more than 2·0% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger. Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress. Bill & Melinda Gates Foundation.