How does pollen chemistry impact development and feeding behaviour of polylectic bees?
Larvae and imagos of bees rely exclusively on floral rewards as a food source but host-plant range can vary greatly among bee species. While oligolectic species forage on pollen from a single family of host plants, polylectic bees, such as bumblebees, collect pollen from many families of plants. These polylectic species contend with interspecific variability in essential nutrients of their host-plants but we have only a limited understanding of the way in which chemicals and chemical combinations influence bee development and feeding behaviour. In this paper, we investigated five different pollen diets (Calluna vulgaris, Cistus sp., Cytisus scoparius, Salix caprea and Sorbus aucuparia) to determine how their chemical content affected bumblebee colony development and pollen/syrup collection. Three compounds were used to characterise pollen content: polypeptides, amino acids and sterols. Several parameters were used to determine the impact of diet on micro-colonies: (i) Number and weight of larvae (total and mean weight of larvae), (ii) weight of pollen collected, (iii) pollen efficacy (total weight of larvae divided by weight of the pollen collected) and (iv) syrup collection. Our results show that pollen collection is similar regardless of chemical variation in pollen diet while syrup collection is variable. Micro-colonies fed on S. aucuparia and C. scoparius pollen produced larger larvae (i.e. better mates and winter survivors) and fed less on nectar compared to the other diets. Pollen from both of these species contains 24-methylenecholesterol and high concentrations of polypeptides/total amino acids. This pollen nutritional "theme" seems therefore to promote worker reproduction in B. terrestris micro-colonies and could be linked to high fitness for queenright colonies. As workers are able to selectively forage on pollen of high chemical quality, plants may be evolutionarily selected for their pollen content, which might attract and increase the degree of fidelity of generalist pollinators, such as bumblebees.


Toward knowledge-based liver surgery: holistic information processing for surgical decision support.
Malignant neoplasms of the liver are among the most frequent cancers worldwide. Given the diversity of options for liver cancer therapy, the choice of treatment depends on various parameters including patient condition, tumor size and location, liver function, and previous interventions. To address this issue, we present the first approach to treatment strategy planning based on holistic processing of patient-individual data, practical knowledge (i.e., case knowledge), and factual knowledge (e.g., clinical guidelines and studies). The contributions of this paper are as follows: (1) a formalized dynamic patient model that incorporates all the heterogeneous data acquired for a specific patient in the whole course of disease treatment; (2) a concept for formalizing factual knowledge; and (3) a technical infrastructure that enables storing, accessing, and processing of heterogeneous data to support clinical decision making. Our patient model, which currently covers 602 patient-individual parameters, was successfully instantiated for 184 patients. It was sufficiently comprehensive to serve as the basis for the formalization of a total of 72 rules extracted from studies on patients with colorectal liver metastases or hepatocellular carcinoma. For a subset of 70 patients with these diagnoses, the system derived an average of [Formula: see text] assertions per patient. The proposed concept paves the way for holistic treatment strategy planning by enabling joint storing and processing of heterogeneous data from various information sources.


National audit of the use of surgery and radiological embolization after failed endoscopic haemostasis for non-variceal upper gastrointestinal bleeding.
Following non-variceal upper gastrointestinal bleeding (NVUGIB), 10-15 per cent of patients experience further bleeding. Although surgery has been the traditional salvage therapy, there is renewed interest in transcatheter arterial embolization (TAE). This study examined the use, clinical characteristics and outcomes of patients receiving salvage surgery or TAE after failed endoscopic haemostasis for NVUGIB. A UK national audit of upper gastrointestinal bleeding was undertaken in May and June 2007. A logistic regression model was used to identify clinical predictors of endoscopic failure. Data were analysed from 4478 patients involving 212 UK centres. Some 533 (11·9 per cent) experienced further bleeding, of whom 163 (30·6 per cent) proceeded to salvage therapy with surgery (97), TAE (60) or both (6). Among surgical patients (mean age 71 years), 66·0 per cent (68 of 103) had a Rockall score of at least 3 and emergency surgery was carried out between midnight and 08.00 hours in 21 per cent, with a consultant surgeon present in 89 per cent of operations. Some 9 per cent of patients had further bleeding after TAE, resulting in later surgery. The mortality rate was 29 per cent after surgery, 10 per cent after TAE and 23·2 per cent among those with further bleeding after the index endoscopy that was managed by endoscopy alone. The strongest predictors of endoscopic failure were coagulopathy (odds ratio 3·27, 95 per cent confidence interval 2·37 to 4·53) and a haemoglobin level of 10 g/dl or less (odds ratio 2·22, 1·71 to 2·87, for haemoglobin 8-10 g/dl). Salvage surgery and embolization are required in fewer than 4 per cent of patients with NVUGIB. The high postoperative mortality rate, reflecting age, co-morbidity and severity of bleeding, warrants a prospective study to establish the effectiveness and safety of TAE as an alternative to surgery in the management of bleeding after failure of endoscopic therapy.


Serum microRNA-21 as marker for necroinflammation in hepatitis C patients with and without hepatocellular carcinoma.
MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC. 62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = -0.494, P = 0.00002), alanine aminotransferase (ALT) (r = -0.309, P = 0.007), aspartate aminotransferase (r = -0.495, P = 0.000007), bilirubin (r = -0.362, P = 0.002), international normalized ratio (r = -0.338, P = 0.034) and γ-glutamyltransferase (r = -0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dC(T) of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%. The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC.


Origin and evolution of the unique hepatitis C virus circulating recombinant form 2k/1b.
Since its initial identification in St. Petersburg, Russia, the recombinant hepatitis C virus (HCV) 2k/1b has been isolated from several countries throughout Eurasia. The 2k/1b strain is the only recombinant HCV to have spread widely, raising questions about the epidemiological background in which it first appeared. In order to further understand the circumstances by which HCV recombinants might be formed and spread, we estimated the date of the recombination event that generated the 2k/1b strain using a Bayesian phylogenetic approach. Our study incorporates newly isolated 2k/1b strains from Amsterdam, The Netherlands, and has employed a hierarchical Bayesian framework to combine information from different genomic regions. We estimate that 2k/1b originated sometime between 1923 and 1956, substantially before the first detection of the strain in 1999. The timescale and the geographic spread of 2k/1b suggest that it originated in the former Soviet Union at about the time that the world's first centralized national blood transfusion and storage service was being established. We also reconstructed the epidemic history of 2k/1b using coalescent theory-based methods, matching patterns previously reported for other epidemic HCV subtypes. This study demonstrates the practicality of jointly estimating dates of recombination from flanking regions of the breakpoint and further illustrates that rare genetic-exchange events can be particularly informative about the underlying epidemiological processes.


Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout mice.
Group II metabotropic glutamate receptors (mGlu2 and mGlu3, encoded by Grm2 and Grm3) have been the focus of attention as treatment targets for a number of psychiatric conditions. Double knockout mice lacking mGlu2 and mGlu3 (mGlu2/3-/-) show a subtle behavioural phenotype, being hypoactive under basal conditions and in response to amphetamine, and with a spatial memory deficit that depends on the arousal properties of the task. The neurochemical correlates of this profile are unknown. Here, we measured tissue levels of dopamine, 5-HT, noradrenaline and their metabolites in the striatum and frontal cortex of mGlu2/3-/- double knockout mice, using high performance liquid chromatography. We also measured the same parameters in mGlu2-/- and mGlu3-/- single knockout mice. mGlu2/3-/-mice had reduced dopamine levels in the striatum but not in frontal cortex, compared to wild-types. In a separate cohort we replicated this deficit and, using tissue punches, found it was more prominent in the nucleus accumbens than in dorsolateral striatum. Noradrenaline, 5-HT and their metabolites were not altered in the striatum of mGlu2/3-/- mice, although the noradrenaline metabolite MHPG was increased in the cortex. In mGlu2-/- and mGlu3-/- single knockout mice we found no difference in any monoamine or metabolite, in either brain region, compared to their wild-type littermates. Group II metabotropic glutamate receptors impact upon striatal dopamine. The effect may contribute to the behavioural phenotype of mGlu2/3-/- mice. The lack of dopaminergic alterations in mGlu2-/- and mGlu3-/- single knockout mice reveals a degree of redundancy between the two receptors. The findings support the possibility that interactions between mGlu2/3 and dopamine may be relevant to the pathophysiology and therapy of schizophrenia and other disorders.


The SysteMHC Atlas project.
Mass spectrometry (MS)-based immunopeptidomics investigates the repertoire of peptides presented at the cell surface by major histocompatibility complex (MHC) molecules. The broad clinical relevance of MHC-associated peptides, e.g. in precision medicine, provides a strong rationale for the large-scale generation of immunopeptidomic datasets and recent developments in MS-based peptide analysis technologies now support the generation of the required data. Importantly, the availability of diverse immunopeptidomic datasets has resulted in an increasing need to standardize, store and exchange this type of data to enable better collaborations among researchers, to advance the field more efficiently and to establish quality measures required for the meaningful comparison of datasets. Here we present the SysteMHC Atlas (https://systemhcatlas.org), a public database that aims at collecting, organizing, sharing, visualizing and exploring immunopeptidomic data generated by MS. The Atlas includes raw mass spectrometer output files collected from several laboratories around the globe, a catalog of context-specific datasets of MHC class I and class II peptides, standardized MHC allele-specific peptide spectral libraries consisting of consensus spectra calculated from repeat measurements of the same peptide sequence, and links to other proteomics and immunology databases. The SysteMHC Atlas project was created and will be further expanded using a uniform and open computational pipeline that controls the quality of peptide identifications and peptide annotations. Thus, the SysteMHC Atlas disseminates quality controlled immunopeptidomic information to the public domain and serves as a community resource toward the generation of a high-quality comprehensive map of the human immunopeptidome and the support of consistent measurement of immunopeptidomic sample cohorts.


PPAR-gamma: adipogenic regulator and thiazolidinedione receptor.
The past several years have seen an explosive increase in our understanding of the transcriptional basis of adipose cell differentiation. In particular, a key role has been illustrated for PPAR-gamma, a member of the nuclear hormone receptor superfamily. PPAR-gamma has also been recently identified as the major functional receptor for the thiazolidinedione class of insulin-sensitizing drugs. This review examines the evidence that has implicated this transcription factor in the processes of adipogenesis and systemic insulin action. In addition, several models are discussed that may explain how a single protein can be involved in these related but distinct physiological actions. I also point out several important areas where our knowledge is incomplete and more research is needed. Finally, I discuss how advances in our understanding of nuclear receptor function, particularly the docking of cofactors in a ligand-dependent fashion, should lead to improved drugs that utilize the PPAR-gamma system for the treatment of insulin resistance.


Natural and synthetic regulators of embryonic stem cell cardiogenesis.
Debilitating cardiomyocyte loss underlies the progression to heart failure. Although there have been significant advances in treatment, current therapies are intended to improve or preserve heart function rather than regenerate lost myocardium. A major hurdle in implementing a cell-based regenerative therapy is the inefficient differentiation of cardiomyocytes from either endogenous or exogenous stem cell sources. Moreover, cardiomyocytes that develop in human embryonic stem cell (hESC) or human-induced pluripotent stem cell (hIPSC) cultures are comparatively immature, even after prolonged culture, and differences in their calcium handling, ion channel, and force generation properties relative to adult cardiomyocytes raise concerns of improper integration and function after transplantation. Thus, the discovery of natural and novel small molecule synthetic regulators of differentiation and maturation would accelerate the development of stem-cell-based myocardial therapies. Here, we document recent advances in defining natural signaling pathways that direct the multistep cardiomyogenic differentiation program and the development of small molecules that might be used to enhance differentiation as well as the potential characteristics of lead candidates for pharmaceutical stimulation of endogenous myocardial replacement.


Psychological, nutritional, and energy expenditure differences in college females with anorexia nervosa vs. comparable-mass controls.
This is the first study to examine psychological and behavioral variables in nonhospitalized college females with subclinical anorexia nervosa (AN) as compared to healthy college females of comparable body mass (i.e., body mass index (BMI)<19). Participants who met all DSM-IV [Diagnostic and statistical manual of mental disorders, 4th ed. (1994). Washington, DC: APA.] criteria for AN-restrictive type (except for BMI<17.5; n=11) and control participants (n=15) with comparable body mass completed psychological, nutritional, and exercise assessments. Results suggested that those with AN evidenced more general psychopathology, more eating disorder symptoms, more dieting, more compulsive exercise, and less consumption of calories compared to participants in the control group. There was no difference in macronutrient consumption. There was no significant difference in expenditure of energy, despite differences in reports of compulsive exercise. Given similar body mass, this suggests that the women with AN were experiencing an energy deficit consistent with the disorder's defining features of "fear of gaining weight or becoming fat" and provides us with more understanding of individuals with AN in their natural environment.


Risk structure compensation in Germany's statutory health insurance.
In 1996 insurees in Germany's statutory health insurance system were given a right to choose their sickness fund. To ensure that all funds had an equal starting position, a risk structure compensation scheme based on income and average expenditure by age and sex was introduced. From an analysis of expenditure and transfers, data on sickness fund membership and a published survey, the following effects can be identified: sickness funds merged, with a reduction in number from 1,221 to 420 between 1993 and 2000; the risk compensation scheme narrowed differences in contribution rates; insurees left the more expensive funds for cheaper ones; and increasing transfer sums indicate further risk segregation. Thus, the compensation mechanism will have to be retained permanently, although modifications are likely.


Antimicrobial and P450 inhibitory properties of common functional foods.
To study the effect of functional foods on human cytochrome P450 (CYP) and the gut bacterial microflora that may potentially affect drug metabolism and ultimately affect human health and wellness. This study examined a variety of food plants from the Apiaceae, Fabaceae, and Lamiaceae families for their inhibitory potential on cytochrome 2D6-, 3A4-, 3A5-, and 3A7-mediated metabolism. The antimicrobial effects of these samples were also investigated with 7 selected bacterial surrogate species to determine potential effects on the gut microflora. The highest CYP inhibitory activities, based upon visual examination, were observed from extracts of celery seed, cumin, fennel seed, basil, oregano, and rosemary belonging to the Apiaceae and Lamiaceae families, respectively. Likewise, the strongest antimicrobial activities were also observed in the Apiaceae and Lamiaceae. No significant antimicrobial and CYP inhibition was observed in the Fabaceae extracts. Results demonstrated the possible risk of food-drug interactions from spice and herb plants may affect drug disposition and safety.


Bactericidal antibody persistence 2 years after immunization with 2 investigational serogroup B meningococcal vaccines at 6, 8 and 12 months and immunogenicity of preschool booster doses: a follow-on study to a randomized clinical trial.
In a previous study, 60 infants receiving an investigational serogroup B meningococcal vaccine containing recombinant meningococcal proteins alone (rMenB) or combined with an outer membrane vesicle from Neisseria meningitidis (4CMenB) at 6, 8 and 12 months of age produced serum bactericidal antibodies (SBAs) against meningococcal strains expressing vaccine antigens. We studied persistence of this response and the response to a booster dose of vaccine. In this extension study, SBA titers were evaluated before and after a booster dose of rMenB or 4CMenB at 40 months of age. MenB vaccine naïve age-matched children served as a control group. Before the booster doses, the proportions of 4CMenB recipients with SBA titers ≥1:4 were 36% (n = 14, 95% confidence interval: 13-65%) for strain 44/76-SL, 100% (77-100%) for 5/99, 14% (2-43%) for NZ98/254 and 79% (49-95%) for M10713. These percentages were 14% to 29% for rMenB recipients (n = 14), except for 5/99 (93%, 66-100%). For controls (n = 40), these proportions were ≤3% for all strains except M10713 (53%, 36-68%). One month after the boosters, ≥93% of 4CMenB recipients had SBA titers ≥1:4 for all 4 strains. For controls receiving their first dose of 4CMenB, 23% (11-39%) had SBA titers ≥1:4 for NZ98/254, compared with 62% to 87% for the remaining strains. Bactericidal antibodies wane after infant immunization with rMenB or 4CMenB, but there is an anamnestic response to a booster dose. Booster doses of 4CMenB may be required to maintain immune protection through childhood and adolescence.


Gene-environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study.
Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study. We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption). After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm [162.9-163.2]; p=0.01 after allowance for multiple testing). Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors. Cancer Research UK and the UK Medical Research Council.


Suggestive linkage of the parathyroid receptor type 1 to osteoporosis.
We have investigated the role of 23 candidate genes in the control of bone mineral density (BMD) by linkage studies in families of probands with osteoporosis (lumbar spine [LS] or femoral neck [FN] BMD T score < -2.5) and low BMD relative to an age- and gender-matched cohort (Z score < -2.0). One hundred and fifteen probands (35 male, 80 female) and 499 of their first- or second-degree relatives (223 males and 276 females) were recruited for the study. BMD was measured at the LS and FN using dual-energy X-ray absorptiometry and expressed as age- and gender-matched Z scores corrected for body mass index. The candidate genes studied were the androgen receptor, type I collagen A1 (COLIA1), COLIA2, COLIIA1, vitamin D receptor (VDR), colony-stimulating factor 1, calcium-sensing receptor, epidermal growth factor (EGF), estrogen receptor 1 (ESR1), fibrillin type 1, insulin-like growth factor 1, interleukin-1 alpha (IL-1alpha), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-11 (IL-11), osteopontin, parathyroid hormone (PTH), PTH-related peptide, PTH receptor type 1 (PTHR1), transforming growth factor-beta 1, and tumor necrosis factors alpha and beta. Sixty-four microsatellites lying close to or within these genes were investigated for linkage with BMD. Using the program MapMaker/Sibs there was suggestive evidence of linkage between BMD and PTHR1 (maximum LOD score obtained [MLS] 2.7-3.5). Moderate evidence of linkage was also observed with EGF (MLS 1.8), COLIA1 (MLS 1.7), COLIIA1/VDR (MLS 1.7), ESR1 (MLS 1.4), IL-1alpha (MLS 1.4), IL-4 (MLS 1.2), and IL-6 (MLS 1.2). Variance components analysis using the program ACT, correcting for proband-wise ascertainment, also showed evidence of linkage (p </= 0.05) at markers close to or within the candidate genes IL-1alpha, PTHR1, IL-6, and COLIIA1/VDR. Further studies will be required to confirm these findings, to refine the location of gene responsible for the observed linkage, and to screen the candidate genes targeted at these loci for mutations.


16S ribosomal DNA amplification for phylogenetic study.
A set of oligonucleotide primers capable of initiating enzymatic amplification (polymerase chain reaction) on a phylogenetically and taxonomically wide range of bacteria is described along with methods for their use and examples. One pair of primers is capable of amplifying nearly full-length 16S ribosomal DNA (rDNA) from many bacterial genera; the additional primers are useful for various exceptional sequences. Methods for purification of amplified material, direct sequencing, cloning, sequencing, and transcription are outlined. An obligate intracellular parasite of bovine erythrocytes, Anaplasma marginale, is used as an example; its 16S rDNA was amplified, cloned, sequenced, and phylogenetically placed. Anaplasmas are related to the genera Rickettsia and Ehrlichia. In addition, 16S rDNAs from several species were readily amplified from material found in lyophilized ampoules from the American Type Culture Collection. By use of this method, the phylogenetic study of extremely fastidious or highly pathogenic bacterial species can be carried out without the need to culture them. In theory, any gene segment for which polymerase chain reaction primer design is possible can be derived from a readily obtainable lyophilized bacterial culture.


Exploitation of De Novo helper-lipids for effective gene delivery.
In gene delivery, a fusogenic lipid such as dioleyl phosphatidylethanolamine (DOPE) which is a component of cationic liposomal vector is important factor for effective transfection efficiency. We investigated the effect of penetration enhancers as alternative helper-lipids to DOPE. Transdermal penetraion enhancers such as N-lauroylsarcosine (LS), (R)-(+)-limonene (LM), vitamin E (VE), and phosphatidyl choline from eggs (EggPC) were used in this experiments as helper-lipids with N-[1-(2, 3-dioleyloxy) propyl]-N, N, N-trimethlylammonium chloride (DOTMA) and cholesterol (CHOL). We examined in vitro transfection efficiency, cytotoxicity, hematotoxicity, and in vivo transfection efficiency of plasmid DNA/cationic liposomes complexes. In transfection experiments in vitro, the cationic lipoplexes containing LS had highest transfection efficiency among the other lipoplexes independently of FBS. Furthermore, the lipoplexes containing LS had lowest cell toxicity among the other lipoplexes in the presence of FBS. As the results of erythrocytes interaction experiment, DOTMA/LS/CHOL, DOTMA/VE/CHOL, and DOTMA/EggPC/CHOL lipoplexes showed extremely lower hematotoxicity. On the basis of these results, the in vivo transfection efficiencies of the lipoplexes were examined. The lipoplexes containing LS had the highest transfection activity among the other lipoplexes. In conclusion, several transdermal penetration enhancers are available for alternative helper-lipids to DOPE in cationic liposomal vectors. Among them, DOTMA/LS/CHOL lipoplexes showed superior characteristics in in vitro transfection efficiency, cell toxicity, hematotoxicity, and in vivo transfection efficiency.


Evaluation of specialists' outreach clinics in general practice in England: process and acceptability to patients, specialists, and general practitioners.
The wider study aimed to evaluate specialists' outreach clinics in relation to their costs, processes, and effectiveness, including patients' and professionals' attitudes. The data on processes and attitudes are presented here. Self administered questionnaires were drawn up for patients, their general practitioners (GPs) and specialists, and managers in the practice. Information was sought from hospital trusts. The study formed a pilot phase prior to a wider evaluation. Nine outreach clinics in general practices in England, each with a hospital outpatient department as a control clinic were studied. The specialties included were ear, nose, and throat surgery; rheumatology; and gynaecology. The subjects were the patients who attended either the outreach clinics or hospital outpatients clinics during the study period, the outreach patients' GPs, the outreach patients' and outpatients' specialists, the managers in the practices, and the NHS trusts which employed the specialists. Process items included waiting lists, waiting times in clinics, number of follow up visits, investigations and procedures performed, treatment, health status, patients' and specialists' travelling times, and patients' and doctors' attitudes to, and satisfaction with, the clinic. There was no difference in the health status of patients in relation to the clinic site (ie, outreach and hospital outpatients' clinics) at baseline, and all but one of the specialists said there were no differences in casemix between their outreach and outpatients' clinics. Patients preferred, and were more satisfied with, care in specialists' outreach clinics in general practice, in comparison with outpatients' clinics. The outreach clinics were rated as more convenient than outpatients' clinics in relation to journey times; those outreach patients in work lost less time away from work than outpatients' clinic patients due to the clinic attendance. Length of time on the waiting list was significantly reduced for gynaecology patients; waiting times in clinics were lower for outreach patients than outpatients across all specialties. In addition, outreach patients were more likely to be first rather than follow up attenders; rheumatology outreach patients were more likely than hospital outpatients to receive therapy. GPs' referrals to hospital outpatients' clinics were greatly reduced by the availability of outreach clinics. Both specialists and GPs saw the main advantages of outreach clinics in relation to the greater convenience and better access to care for patients. Few of the specialists and GPs in the outreach practices held formal training and education sessions in the outreach clinic, although over half of the GPs felt that their skills/expertise had broadened as a result of the outreach clinic. The processes of care (waiting times, patient satisfaction, convenience to patients, follow up attendances) were better in outreach than in outpatients' clinics. However, waiting lists were only significantly reduced for gynaecology patients, despite both GPs and consultants reporting reduced waiting lists for patients as one of the main advantages of outreach. Whether these improvements merit the increased cost to the specialists (in terms of their increased travelling times and time spent away from their hospital base) and whether the development of what is, in effect, two standards of care between practices with and without outreach can be stemmed and the standard of care raised in all practices (eg, by sharing outreach clinics between GPs in an area) remain the subject of debate. As the data were based on the pilot study, the results should be viewed with some caution, although statistical power was adequate for comparisons of sites if not specialties.


Vascular disease in women: comparison of diagnoses in hospital episode statistics and general practice records in England.
Electronic linkage to routine administrative datasets, such as the Hospital Episode Statistics (HES) in England, is increasingly used in medical research. Relatively little is known about the reliability of HES diagnostic information for epidemiological studies. In the United Kingdom (UK), general practitioners hold comprehensive records for individuals relating to their primary, secondary and tertiary care. For a random sample of participants in a large UK cohort, we compared vascular disease diagnoses in HES and general practice records to assess agreement between the two sources. Million Women Study participants with a HES record of hospital admission with vascular disease (ischaemic heart disease [ICD-10 codes I20-I25], cerebrovascular disease [G45, I60-I69] or venous thromboembolism [I26, I80-I82]) between April 1st 1997 and March 31st 2005 were identified. In each broad diagnostic group and in women with no such HES diagnoses, a random sample of about a thousand women was selected for study. We asked each woman's general practitioner to provide information on her history of vascular disease and this information was compared with the HES diagnosis record. Over 90% of study forms sent to general practitioners were returned and 88% of these contained analysable data. For the vast majority of study participants for whom information was available, diagnostic information from general practice and HES records was consistent. Overall, for 93% of women with a HES diagnosis of vascular disease, general practice records agreed with the HES diagnosis; and for 97% of women with no HES diagnosis of vascular disease, the general practitioner had no record of a diagnosis of vascular disease. For severe vascular disease, including myocardial infarction (I21-22), stroke, both overall (I60-64) and by subtype, and pulmonary embolism (I26), HES records appeared to be both reliable and complete. Hospital admission data in England provide diagnostic information for vascular disease of sufficient reliability for epidemiological analyses.


Resting-state FMRI single subject cortical parcellation based on region growing.
We propose a new method to parcellate the cerebral cortex based on spatial dependancy in the fluctuations observed with functional Magnetic Resonance Imaging (fMRI) during rest. Our surface-based approach uses a region growing method. In contrast to previous methods, locally stable seed points are identified on the cortical surface and these are grown into a (relatively large 1000 to 5000) number of spatially contiguous regions on both hemispheres. Spatially constrained hierarchical clustering is then used to further combine these regions in a hierarchical tree. Using short-TR resting state fMRI data, this approach allows a subject specific parcellation of the cortex into anatomically plausible subregions, identified with high scan-to-scan reproducibility and with borders that delineate clear changes in functional connectivity.


Aqueous-phase mechanism for secondary organic aerosol formation from isoprene: application to the Southeast United States and co-benefit of SO2 emission controls.
Isoprene emitted by vegetation is an important precursor of secondary organic aerosol (SOA), but the mechanism and yields are uncertain. Aerosol is prevailingly aqueous under the humid conditions typical of isoprene-emitting regions. Here we develop an aqueous-phase mechanism for isoprene SOA formation coupled to a detailed gas-phase isoprene oxidation scheme. The mechanism is based on aerosol reactive uptake coefficients (γ) for water-soluble isoprene oxidation products, including sensitivity to aerosol acidity and nucleophile concentrations. We apply this mechanism to simulation of aircraft (SEAC4RS) and ground-based (SOAS) observations over the Southeast US in summer 2013 using the GEOS-Chem chemical transport model. Emissions of nitrogen oxides (NOx ≡ NO + NO2) over the Southeast US are such that the peroxy radicals produced from isoprene oxidation (ISOPO2) react significantly with both NO (high-NOx pathway) and HO2 (low-NOx pathway), leading to different suites of isoprene SOA precursors. We find a mean SOA mass yield of 3.3 % from isoprene oxidation, consistent with the observed relationship of total fine organic aerosol (OA) and formaldehyde (a product of isoprene oxidation). Isoprene SOA production is mainly contributed by two immediate gas-phase precursors, isoprene epoxydiols (IEPOX, 58% of isoprene SOA) from the low-NOx pathway and glyoxal (28%) from both low- and high-NOx pathways. This speciation is consistent with observations of IEPOX SOA from SOAS and SEAC4RS. Observations show a strong relationship between IEPOX SOA and sulfate aerosol that we explain as due to the effect of sulfate on aerosol acidity and volume. Isoprene SOA concentrations increase as NOx emissions decrease (favoring the low-NOx pathway for isoprene oxidation), but decrease more strongly as SO2 emissions decrease (due to the effect of sulfate on aerosol acidity and volume). The US EPA projects 2013-2025 decreases in anthropogenic emissions of 34% for NOx (leading to 7% increase in isoprene SOA) and 48% for SO2 (35% decrease in isoprene SOA). Reducing SO2 emissions decreases sulfate and isoprene SOA by a similar magnitude, representing a factor of 2 co-benefit for PM2.5 from SO2 emission controls.


The investigation and analysis of critical incidents and adverse events in healthcare.
To carry out a review of published and unpublished work on the analysis on methods of accident investigation in high-risk industries, and of critical incidents in healthcare. To develop and pilot guidelines for the analysis of critical incidents in healthcare for the hospital sector, mental health and primary care. Literature already available in the Clinical Risk Unit, University College London. Work by known experts in the field of accident investigation and analysis. Electronic databases including PsycINFO and MEDLINE. Websites for accident investigation reports. Twelve techniques from other high-risk industries were reviewed in detail using criteria developed for the purpose. This review provided a conceptual framework for the healthcare review and appraisal process, as well as providing a critical assessment of the industry techniques. Rigorous searching and screening identified 138 papers for formal appraisal and a further 114 were designated as providing potentially useful background information. A formal appraisal instrument was designed, piloted and modified until acceptable reliability was achieved. From the 138 papers, six techniques were identified as representing clearly definable approaches to incident investigation and analysis. All relevant papers were reviewed for each of the six techniques: Australian Incident Monitoring System, the Critical Incident Technique, Significant Event Auditing, Root Cause Analysis, Organisational Accident Causation Model and Comparison with Standards approach. All healthcare techniques had the potential of being applied in any specialty or discipline related to healthcare. While a few studies looked solely at death as an outcome, most used a variety of outcomes including near misses. Most techniques used interviewing and primary document review to investigate incidents. All techniques included papers that identified clinical issues and some attempt to assess underlying errors, causes and contributory factors. However the extent and sophistication of the various attempts varied widely. Only a third of papers referred to an established model of accident causation. In most studies examined there was little or no information on the training of investigators, how the data was extracted or any information on quality assurance for data collection and analysis. There was some variation in the level of expertise and training required but to undertake the investigation to an acceptable depth all required some expertise. In most papers there was little or no discussion of implementation of any changes as a result of the investigations. A quarter of publications gave some description of the implementation of changes, though few addressed evaluation of changes. The reviews demonstrate that, while much valuable work has been accomplished, there is considerable potential for further development of techniques, the utilisation of a wider range of techniques and a need for validation and evaluation of existing methods which would make incident investigation more versatile and use limited resources more effectively. Further exploration of techniques used in high-risk industries, with interviews and observation of actual investigations should prove valuable. Existing healthcare techniques would benefit from formal evaluation of their outcomes and effectiveness. Studies should examine depth of investigation and analysis, adequacy and feasibility of recommendations and cost effectiveness. Examining implementation of recommendations is a key issue.


Distinct migratory and non-migratory ecotypes of an endemic New Zealand eleotrid (Gobiomorphus cotidianus) - implications for incipient speciation in island freshwater fish species.
Many postglacial lakes contain fish species with distinct ecomorphs. Similar evolutionary scenarios might be acting on evolutionarily young fish communities in lakes of remote islands. One process that drives diversification in island freshwater fish species is the colonization of depauperate freshwater environments by diadromous (migratory) taxa, which secondarily lose their migratory behaviour. The loss of migration limits dispersal and gene flow between distant populations, and, therefore, is expected to facilitate local morphological and genetic differentiation. To date, most studies have focused on interspecific relationships among migratory species and their non-migratory sister taxa. We hypothesize that the loss of migration facilitates intraspecific morphological, behavioural, and genetic differentiation between migratory and non-migratory populations of facultatively diadromous taxa, and, hence, incipient speciation of island freshwater fish species. Microchemical analyses of otolith isotopes (88Sr, 137Ba and 43Ca) differentiated migratory and non-migratory stocks of the New Zealand endemic Gobiomorphus cotidianus McDowall (Eleotridae). Samples were taken from two rivers, one lake and two geographically-separated outgroup locations. Meristic analyses of oculoscapular lateral line canals documented a gradual reduction of these structures in the non-migratory populations. Amplified fragment length polymorphism (AFLP) fingerprints revealed considerable genetic isolation between migratory and non-migratory populations. Temporal differences in reproductive timing (migratory = winter spawners, non-migratory = summer spawners; as inferred from gonadosomatic indices) provide a prezygotic reproductive isolation mechanism between the two ecotypes. This study provides a holistic look at the role of diadromy in incipient speciation of island freshwater fish species. All four analytical approaches (otolith microchemistry, morphology, spawning timing, population genetics) yield congruent results, and provide clear and independent evidence for the existence of distinct migratory and non-migratory ecotypes within a river in a geographically confined range. The morphological changes within the non-migratory populations parallel interspecific patterns observed in all non-migratory New Zealand endemic Gobiomorphus species and other derived gobiid taxa, a pattern suggesting parallel evolution. This study indicates, for the first time, that distinct ecotypes of island freshwater fish species may be formed as a consequence of loss of migration and subsequent diversification. Therefore, if reproductive isolation persists, these processes may provide a mechanism to facilitate speciation.


INCIDENTAL AND NONINCIDENTAL CANINE THYROID TUMORS ASSESSED BY MULTIDETECTOR ROW COMPUTED TOMOGRAPHY: A SINGLE-CENTRE CROSS SECTIONAL STUDY IN 4520 DOGS.
Thyroid nodules are common in dogs and are increasingly likely to be detected with the increased use of advanced imaging modalities. An unsuspected, nonpalpable, asymptomatic lesion, defined as a thyroid incidentaloma, may be discovered on an imaging study unrelated to the thyroid gland. The objective of this single-center cross-sectional study was to assess the prevalence and computed tomography (CT) characteristics of incidental and nonincidental thyroid tumors in a large population of dogs, using prospective recruitment of patients undergoing CT examination for various reasons during the period of 2005-2015. Unilateral or bilateral thyroid masses were detected in 96/4520 dogs (prevalence, 2.12%; 95% confidence interval [CI], 1.70-2.54%). Seventy-nine (82.3%) lesions were malignant and 17 (17.7%) were benign. Masses were discovered incidentally in 34/96 dogs (overall prevalence of incidentaloma, 0.76%; 95% CI, 0.51-1.02), and 24 (70.6%) of these 34 masses were thyroid carcinomas. Among the CT variables assessed, mineralization, vascular invasion, and tissue invasion were detected only in malignant tumors. Intratumoral vascularization was significantly associated with the presence of thyroid malignancy (P < 0.001). Although incidental thyroid nodules in dogs are relatively rare, they are often malignant. Findings indicated that the neck should be thoroughly assessed in middle-aged and old patients undergoing body CT for various reasons. Thyroid nodules detected incidentally on CT should be sampled to avoid missing thyroid cancer.


Sex-biased migration in humans: what should we expect from genetic data?
Different patterns of mitochondrial and Y-chromosome diversity have been cited as evidence of long-term patrilocality in human populations. However, what patterns are expected depends on the nature of the sampling scheme. Samples from a local region reveal only the recent demographic history of that region, whereas sampling over larger geographic scales accesses older demographic processes. A historical change in migration becomes evident first at local geographic scales, and alters global patterns of genetic diversity only after sufficient time has passed. Analysis of forager populations in the ethnographic record suggests that patrilocality may not have predominated among pre-agricultural humans. The higher female migration rate inferred by some genetic studies may reflect a shift to patrilocality in association with the emergence of agriculture. A recent global survey does not show the expected effects of higher female migration, possibly because the sampling scheme used for this study is accessing pre-agricultural human migration patterns. In this paper, we show how the demographic shift associated with agriculture might affect genetic diversity over different spatial scales. We also consider the prospects for studying sex-biased migration using the X-linked and autosomal markers. These multi-locus comparisons have the potential of providing more robust estimates of sex differences than Y-linked and mitochondrial data, but only if a very large number of loci are included in the analysis.


Parent Mindfulness and Child Outcome: The Roles of Parent Depressive Symptoms and Parenting.
The purpose of this study was to examine pathways in a model which proposed associations among parent mindfulness, parent depressive symptoms, two types of parenting, and child problem behavior. Participants' data were from the baseline assessment of a NIMH-sponsored Family-Group Cognitive-Behavioral intervention program (FGCB) for the prevention of child and adolescent depression (Compas et al., 2009). Participants consisted of 145 mothers and 17 fathers (mean age = 41.89 yrs, SD = 7.73) with a history of depression and 211 children (106 males) (mean age = 11.49 yrs, SD = 2.00). Analyses showed that (a) positive parenting appears to play a significant role in helping explain how parent depressive symptoms relate to child externalizing problems and (b) mindfulness is related to child internalizing and externalizing problems; however, the intervening constructs examined did not appear to help explain the mindfulness-child problem behavior associations. Suggestions for future research on parent mindfulness and child problem outcome are described.


Moderate inhibition of mitochondrial function augments carotid body hypoxic sensitivity.
A functional role for the mitochondria in acute O2 sensing in the carotid body (CB) remains undetermined. Whilst total inhibition of mitochondrial activity causes intense CB stimulation, it is unclear whether this response can be moderated such that graded impairment of oxidative phosphorylation might be a mechanism that sets and modifies the O2 sensitivity of the whole organ. We assessed NADH autofluorescence and [Ca2+]i in freshly dissociated CB type I cells and sensory chemoafferent discharge frequency in an intact CB preparation, in the presence of varying concentrations of nitrite (NO2 −), a mitochondrial nitric oxide (NO) donor and a competitive inhibitor of mitochondrial complex IV. NO2 − increased CB type I cell NADH in a manner that was dose-dependent and rapidly reversible. Similar concentrations of NO2 − raised type I cell [Ca2+]i via L-type channels in a PO2-dependent manner and increased chemoafferent discharge frequency. Moderate inhibition of the CB mitochondria by NO2 − augmented chemoafferent discharge frequency during graded hypoxia, consistent with a heightened CB O2 sensitivity. Furthermore, NO2 − also exaggerated chemoafferent excitation during hypercapnia signifying an increase in CB CO2 sensitivity. These data show that NO2 − can moderate the hypoxia sensitivity of the CB and thus suggest that O2 sensitivity could be set and modified in this organ by interactions between NO and mitochondrial complex IV.


Increased CO2 stimulates reproduction in a coral reef fish.
Ocean acidification is predicted to negatively impact the reproduction of many marine species, either by reducing fertilization success or diverting energy from reproductive effort. While recent studies have demonstrated how ocean acidification will affect larval and juvenile fishes, little is known about how increasing partial pressure of carbon dioxide (pCO(2)) and decreasing pH might affect reproduction in adult fishes. We investigated the effects of near-future levels of pCO(2) on the reproductive performance of the cinnamon anemonefish, Amphiprion melanopus, from the Great Barrier Reef, Australia. Breeding pairs were held under three CO(2) treatments [Current-day Control (430 μatm), Moderate (584 μatm) and High (1032 μatm)] for a 9-month period that included the summer breeding season. Unexpectedly, increased CO(2) dramatically stimulated breeding activity in this species of fish. Over twice as many pairs bred in the Moderate (67% of pairs) and High (55%) compared to the Control (27%) CO(2) treatment. Pairs in the High CO(2) group produced double the number of clutches per pair and 67% more eggs per clutch compared to the Moderate and Control groups. As a result, reproductive output in the High group was 82% higher than that in the Control group and 50% higher than that in the Moderate group. Despite the increase in reproductive activity, there was no difference in adult body condition among the three treatment groups. There was no significant difference in hatchling length between the treatment groups, but larvae from the High CO(2) group had smaller yolks than Controls. This study provides the first evidence of the potential effects of ocean acidification on key reproductive attributes of marine fishes and, contrary to expectations, demonstrates an initially stimulatory (hormetic) effect in response to increased pCO(2). However, any long-term consequences of increased reproductive effort on individuals or populations remain to be determined.


Analysis of transcriptome and metabolome profiles alterations in fatty liver induced by high-fat diet in rat.
Excessive energy intake greatly contributes to the development of nonalcoholic fatty liver disease (NAFLD) in modern society. To better understand the comprehensive mechanisms of NAFLD development, we investigated the metabolic alterations of rats with NAFLD induced by high-fat diet (HFD). Male Wistar rats were fed a HFD or standard chow for control. After 16 weeks, rat serum was collected for biochemical measurement. The rats' livers were resected and subjected to histology inspection and gene expression analysis with complementary DNA microarray and metabolic analysis with gas chromatography-mass spectroscopy. In HFD rats, the serum cholesterol, triglycerides, glucose, and insulin contents were increased; and the total cholesterol and triglycerides in the livers were also significantly increased. Complementary DNA microarray analysis revealed that 130 genes were regulated by HFD. Together with real-time reverse transcriptase polymerase chain reaction, lipid metabolism regulatory members like sterol regulatory element binding factor 1 and stearoyl-coenzyme A desaturase 1 had up-regulation, whereas others like peroxisome proliferator-activated receptor, carnitine palmitoyltransferase 1, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase had repressed expression, in HFD rat livers. Metabolomic analysis showed that tetradecanoic acid, hexadecanoic acid, and oleic acid had elevation and arachidonic acid and eicosapentaenoic acid had decreased content in HFD rat livers. Amino acids including glycine, alanine, aspartic acid, glutamic acid, and proline contents were decreased. The integrative results from transcriptomic and metabolomic studies revealed that, in HFD rat livers, fatty acid utilization through beta-oxidation was inhibited and lipogenesis was enhanced. These observations facilitated our understanding of the pathways involved in the development of NAFLD induced by HFD.


Effects of in vivo hepatic ischemia-reperfusion injury on the hepatobiliary disposition of rhodamine 123 and its metabolites in isolated perfused rat livers.
A few studies have shown that normothermic hepatic ischemia-reperfusion (IR) injury may affect the mRNA and/or protein levels of canalicular transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2). However, the effects of the injury on the functions of these canalicular transporters with respect to the biliary excretion of drugs remain largely unknown. Therefore, the purpose of this study was to investigate the effects of warm hepatic IR on the hepatobiliary disposition of rhodamine 123 (RH-123), a P-gp substrate, and its glucuronidated metabolite (RH-Glu), an Mrp2 substrate, in rats. Twenty four or 72 h following a 60-min partial ischemia or sham operation in rats, livers were isolated and perfused ex vivo with a constant concentration (~100 ng/mL) of RH-123. The concentration of RH-123 and its glucuronidated (RH-Glu) and deacylated (RH-110) metabolites were determined in the outlet perfusate, bile, and the liver tissue using HPLC, and relevant pharmacokinetic parameters were estimated. Twenty-four-h IR caused a significant reduction in the hepatic extraction ratio of RH-123 (IR: 0.857 ± 0.078; Sham: 0.980 ± 0.017) and the biliary recovery of the parent drug and RH-Glu by 43% and 44%, respectively. The reductions in the biliary recovery were associated with significant reductions in the apparent biliary clearance of RH-123 and RH-Glu. Mass balance data showed that the formation of the glucuronidated or deacylated metabolite was not significantly affected by the 24-h IR injury. In contrast to the 24-h IR, the injury did not have any effect on the hepatobiliary disposition of RH-123 or its metabolites following 72 h of reperfusion. It is concluded that the pharmacokinetics of drugs that are subject to biliary excretion by the canalicular P-gp and Mrp2 transporters may be altered shortly after hepatic IR injury.


Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.
Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4-61·9) in 1980 to 71·8 years (71·5-72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7-17·4), to 62·6 years (56·5-70·2). Total deaths increased by 4·1% (2·6-5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8-18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6-16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9-14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1-44·6), malaria (43·1%, 34·7-51·8), neonatal preterm birth complications (29·8%, 24·8-34·9), and maternal disorders (29·1%, 19·3-37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Bill & Melinda Gates Foundation.


Consulting communities on feedback of genetic findings in international health research: sharing sickle cell disease and carrier information in coastal Kenya.
International health research in malaria-endemic settings may include screening for sickle cell disease, given the relationship between this important genetic condition and resistance to malaria, generating questions about whether and how findings should be disclosed. The literature on disclosing genetic findings in the context of research highlights the role of community consultation in understanding and balancing ethically important issues from participants' perspectives, including social forms of benefit and harm, and the influence of access to care. To inform research practice locally, and contribute to policy more widely, this study aimed to explore the views of local residents in Kilifi County in coastal Kenya on how researchers should manage study-generated information on sickle cell disease and carrier status. Between June 2010 and July 2011, we consulted 62 purposively selected Kilifi residents on how researchers should manage study-generated sickle cell disease findings. Methods drew on a series of deliberative informed small group discussions. Data were analysed thematically, using charts, to describe participants' perceptions of the importance of disclosing findings, including reasoning, difference and underlying values. Themes were derived from the underlying research questions and from issues emerging from discussions. Data interpretation drew on relevant areas of social science and bioethics literature. Perceived health and social benefits generated strong support for disclosing findings on sickle cell disease, but the balance of social benefits and harms was less clear for sickle cell trait. Many forms of health and social benefits and harms of information-sharing were identified, with important underlying values related to family interests and the importance of openness. The influence of micro and macro level contextual features and prioritization of values led to marked diversity of opinion. The approach demonstrates a high ethical importance in many malaria endemic low-to-middle income country settings of disclosing sickle cell disease findings generated during research, alongside provision of effective care and locally-informed counselling. Since these services are central to the benefits of disclosure, health researchers whose studies include screening for sickle cell disease should actively promote the development of health policy and services for this condition in situations of unmet need, including through the prior development of collaborative partnerships with government health managers and providers. Community consultation can importantly enrich ethical debate on research practice where in-depth exploration of informed views and the potential for difference are taken into account.


Cause-specific mortality rates in sub-Saharan Africa and Bangladesh.
To provide internationally comparable data on the frequencies of different causes of death. We analysed verbal autopsies obtained during 1999 -2002 from 12 demographic surveillance sites in sub-Saharan Africa and Bangladesh to find cause-specific and age-specific mortality rates. The cause-of-death codes used by the sites were harmonized to conform to the ICD-10 system, and summarized with the classification system of the Global Burden of Disease 2000 (Version 2). Causes of death in the African sites differ strongly from those in Bangladesh, where there is some evidence of a health transition from communicable to noncommunicable diseases, and little malaria. HIV dominates in causes of mortality in the South African sites, which contrast with those in highly malaria endemic sites elsewhere in sub-Saharan Africa (even in neighbouring Mozambique). The contributions of measles and diarrhoeal diseases to mortality in sub-Saharan Africa are lower than has been previously suggested, while malaria is of relatively greater importance. The different patterns of mortality we identified may be a result of recent changes in the availability and effectiveness of health interventions against childhood cluster diseases.


Counter-stimulatory effects on pain perception and processing are significantly altered by attention: an fMRI study.
Counter-stimulation reduces pain perception; however, the role of attention during this process is rarely discussed despite attention itself being a well known modulator of pain perception. This study investigated the effect of attentional modulation on pain perception during counter-stimulation using fMRI. Subjects received a noxious thermal stimulus together with an innocuous vibratory counter-stimulus. Subjects directed their attention towards either pain, vibration, or a neutral visual stimulus. During painful and counter-stimulation all subjects reported a reduction in pain perception when attending to counter-stimulation compared with attending to pain. Imaging data supported this behavioural finding showing reduced activity in pain processing areas (anterior cingulate, insula, thalamus). These results suggest attention plays an important part in the pain relief experienced from counter-stimulation.


Climate change and influenza: the likelihood of early and severe influenza seasons following warmer than average winters.
The 2012-13 influenza season had an unusually early and severe start in the US, succeeding the record mild 2011-12 influenza season, which occurred during the fourth warmest winter on record. Our analysis of climate and past US influenza epidemic seasons between 1997-98 to present indicates that warm winters tend to be followed by severe epidemics with early onset, and that these patterns are seen for both influenza A and B. We posit that fewer people are infected with influenza during warm winters, thereby leaving an unnaturally large fraction of susceptible individuals in the population going into the next season, which can lead to early and severe epidemics. In the event of continued global warming, warm winters such as that of 2011-12 are expected to occur more frequently. Our results thus suggest that expedited manufacture and distribution of influenza vaccines after mild winters has the potential to mitigate the severity of future influenza epidemics.


A molecular assay for sensitive detection of pathogen-specific T-cells.
Here we describe the development and validation of a highly sensitive assay of antigen-specific IFN-γ production using real time quantitative PCR (qPCR) for two reporters--monokine-induced by IFN-γ (MIG) and the IFN-γ inducible protein-10 (IP10). We developed and validated the assay and applied it to the detection of CMV, HIV and Mycobacterium tuberculosis (MTB) specific responses, in a cohort of HIV co-infected patients. We compared the sensitivity of this assay to that of the ex vivo RD1 (ESAT-6 and CFP-10)-specific IFN-γ Elispot assay. We observed a clear quantitative correlation between the two assays (P<0.001). Our assay proved to be a sensitive assay for the detection of MTB-specific T cells, could be performed on whole blood samples of fingerprick (50 uL) volumes, and was not affected by HIV-mediated immunosuppression. This assay platform is potentially of utility in diagnosis of infection in this and other clinical settings.


Adaptive algorithms for two-channel polarization sensing under various polarization statistics with nonuniform distributions.
The polarization of light carries much useful information about the environment. Biological studies have shown that some animal species use polarization information for navigation and other purposes. It has been previously shown that a bioinspired polarization-difference imaging (PDI) technique can facilitate detection and feature extraction of targets in scattering media. It has also been established [J. Opt. Soc. Am. A 15, 359 (1998)] that polarization sum and polarization difference are the optimum pair of linear combinations of images taken through two orthogonally oriented linear polarizers of a scene having a uniform distribution of polarization directions. However, in many real environments the scene has a nonuniform distribution of polarization directions. Using principal component analysis of the polarization statistics of the scene, we develop a method to determine the two optimum information channels with unequal weighting coefficients that can be formed as linear combinations of the images of a scene taken through a pair of linear polarizers not constrained to the horizontal and vertical directions of the scene. We determine the optimal orientations of linear polarization filters that enhance separation of a target from the background, where the target is defined as an area with distinct polarization characteristics as compared to the background. Experimental results confirm that in most situations adaptive PDI outperforms conventional PDI with fixed channels.


Relative incidence of common cancers in people with severe mental illness. Cohort study in the United Kingdom THIN primary care database.
A recent United Kingdom (UK) report found that breast and colorectal cancers were more common in people with severe mental illness (SMI) and recommended targeted screening. Epidemiological evidence is however inconsistent. To estimate relative incidence rates for colorectal, breast and lung cancer, and the overall incidence of the commonest other UK cancers, in people with SMI compared with people without SMI. Cohort study in the UK using The Health Improvement Network (THIN) primary care database between 1990 and June 2008. Poisson regression was used to obtain adjusted incidence rate ratios (IRRs) for cancer, comparing two cohorts of people over 18; with and without a diagnosis of SMI. We identified 20,632 people with SMI and 116,152 people without, with median follow up of over 6years. No significant associations were observed between SMI and cancers of the breast (adjusted IRR 1.17; 95% confidence interval 0.95-1.45), colon (0.70; 0.46-1.05), rectum (1.05; 0.65-1.69) or lung (0.84; 0.65-1.10). The adjusted IRR for an aggregate cancer outcome in SMI was 0.95; 0.85-1.06. Results were similar for schizophrenia and bipolar disorder. In a cohort analysis within a large UK primary care database, the incidence of colo-rectal, breast and lung cancer, and of all common cancers, did not differ significantly in people with SMI, including schizophrenia, compared with people without SMI. Our results do not support enhanced screening procedures for cancer in people with SMI.


Working memory recall precision is a more sensitive index than span.
Delayed adjustment tasks have recently been developed to examine working memory (WM) precision, that is, the resolution with which items maintained in memory are recalled. However, despite their emerging use in experimental studies of healthy people, evaluation of patient populations is sparse. We first investigated the validity of adjustment tasks, comparing precision with classical span measures of memory across the lifespan in 114 people. Second, we asked whether precision measures can potentially provide a more sensitive measure of WM than traditional span measures. Specifically, we tested this hypothesis examining WM in a group with early, untreated Parkinson's disease (PD) and its modulation by subsequent treatment on dopaminergic medication. Span measures correlated with precision across the lifespan: in children, young, and elderly participants. However, they failed to detect changes in WM in PD patients, either pre- or post-treatment initiation. By contrast, recall precision was sensitive enough to pick up such changes. PD patients pre-medication were significantly impaired compared to controls, but improved significantly after 3 months of being established on dopaminergic medication. These findings suggest that precision methods might provide a sensitive means to investigate WM and its modulation by interventions in clinical populations.


Diverse hepatitis C virus glycoproteins mediate viral infection in a CD81-dependent manner.
We recently reported that retroviral pseudotypes bearing the hepatitis C virus (HCV) strain H and Con1 glycoproteins, genotype 1a and 1b, respectively, require CD81 as a coreceptor for virus-cell entry and infection. Soluble truncated E2 cloned from a number of diverse HCV genotypes fail to interact with CD81, suggesting that viruses of diverse origin may utilize different receptors and display altered cell tropism. We have used the pseudotyping system to study the tropism of viruses bearing diverse HCV glycoproteins. Viruses bearing these glycoproteins showed a 150-fold range in infectivity for hepatoma cells and failed to infect lymphoid cells. The level of glycoprotein incorporation into particles varied considerably between strains, generally reflecting the E2 expression level within transfected cells. However, differences in glycoprotein incorporation were not associated with virus infectivity, suggesting that infectivity is not limited by the absolute level of glycoprotein. All HCV pseudotypes failed to infect HepG2 cells and yet infected the same cells after transduction to express human CD81, confirming the critical role of CD81 in HCV infection. Interestingly, these HCV pseudotypes differed in their ability to infect HepG2 cells expressing a panel of CD81 variants, suggesting subtle differences in the interaction of CD81 residues with diverse viral glycoproteins. Our current model of HCV infection suggests that CD81, together with additional unknown liver specific receptor(s), mediate the virus-cell entry process.


Acute fluoxetine modulates emotional processing in young adult volunteers.
Fluoxetine is generally regarded as the first-line pharmacological treatment for young people, as it is believed to show a more favourable benefit:risk ratio than other antidepressants. However, the mechanisms through which fluoxetine influences symptoms in youth have been little investigated. This study examined whether acute administration of fluoxetine in a sample of young healthy adults altered the processing of affective information, including positive, sad and anger cues. A total of 35 male and female volunteers aged between 18 and 21 years old were randomized to receive a single 20 mg dose of fluoxetine or placebo. At 6 h after administration, participants completed a facial expression recognition task, an emotion-potentiated startle task, an attentional dot-probe task and the Rapid Serial Visual Presentation. Subjective ratings of mood, anxiety and side effects were also taken pre- and post-fluoxetine/placebo administration. Relative to placebo-treated participants, participants receiving fluoxetine were less accurate at identifying anger and sadness and did not show the emotion-potentiated startle effect. There were no overall significant effects of fluoxetine on subjective ratings of mood. Fluoxetine can modulate emotional processing after a single dose in young adults. This pattern of effects suggests a potential cognitive mechanism for the greater benefit:risk ratio of fluoxetine in adolescent patients.


Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies.
Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase-inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further, we observed that 6-ETI induces ATP depletion and cell death accompanied by S phase arrest and DNA damage only in ADK-expressing cells. Immunohistochemistry for ADK served as a biomarker approach to identify 6-ETI-sensitive tumors, which we documented for other lymphoid malignancies with plasmacytic features. Notably, multiple myeloma (MM) expresses high levels of ADK, and 6-ETI was toxic to MM cell lines and primary specimens and had a robust antitumor effect in a disseminated MM mouse model. Several nucleoside analogs are effective in treating leukemias and T cell lymphomas, and 6-ETI may fill this niche for the treatment of PEL, plasmablastic lymphoma, MM, and other ADK-expressing cancers.


"Nine Dimensions": A multidisciplinary approach for community engagement in a complex postwar border region as part of the targeted malaria elimination in Karen/Kayin State, Myanmar.
Background: In light of growing antimalarial drug resistance in Southeast Asia, control programmes have become increasingly focused on malaria elimination, composed of mass drug administration coupled with prompt diagnosis and treatment of symptomatic cases. The key to a successful elimination programme centres on high participation rates in targeted communities, often enhanced by community engagement (CE) efforts. Social science research was conducted to develop a conceptual framework used for CE activities in the Targeted Malaria Elimination programme, as a cross-border operation in Karen/Kayin State, Myanmar. Methods: Data was collected from three main sources: (1) participant observation and semi-structured interviews of CE team members; (2) participant observation and semi-structured interviews with villagers; and (3) records of CE workshops with CE workers conducted as part of the TME programme. Results: Interviews were conducted with 17 CE team members, with 10 participant observations and interviews conducted with villagers and a total of 3 workshops conducted over the course of this pilot programme in 4 villages (November 2013 to October 2014). Thematic analysis was used to construct the nine dimensions for CE in this complex, post-war region: i) history of the people; ii) space; iii) work; iv) knowledge about the world; v) intriguing obstacle (rumour); vi) relationship with the health care system; vii) migration; viii) logic of capitalism influencing openness; and ix) power relations. Conclusions: Conducting CE for the Targeted Malaria Elimination programme was immensely complicated in Karen/Kayin State because of three key realities: heterogeneous terrains, a post-war atmosphere and cross-border operations. These three key realities constituted the nine dimensions, which proved integral to health worker success in conducting CE. Summary of this approach can aid in infectious disease control programmes, such as those using mass drug administration, to engender high rates of community participation.


Postmenopausal endometrial cancer risk and body size in early life and middle age: prospective cohort study.
Greater adiposity in early life has been linked to increased endometrial cancer risk in later life, but the extent to which this association is mediated through adiposity in later life is unclear. Among postmenopausal women who had never used menopausal hormone therapies and reported not having had a hysterectomy, adjusted relative risks (RRs) of endometrial cancer were estimated using Cox regression. Among 249 791 postmenopausal women with 7.3 years of follow-up on average (1.8 million person-years), endometrial cancer risk (n=1410 cases) was strongly associated with current body mass index (BMI) at baseline (RR=1.87 per 5 kg m(-2) increase in BMI, 95% confidence interval (CI): 1.77-1.96). Compared with women thinner than average at age 10, the increased risk among women plumper at age 10 (RR=1.27, 95% CI: 1.09-1.49) disappeared after adjustment for current BMI (RR=0.90, 95% CI: 0.77-1.06). Similarly, compared with women with clothes size 12 or less at age 20, the increased risk among women with clothes size 16 or larger (RR=1.87, 95% CI: 1.61-2.18) was not significant after adjustment for current BMI (RR=1.03, 95% CI: 0.88-1.22). Among women who have never used hormone therapy for menopause, the association between body size in early life and endometrial cancer risk in postmenopausal women can be largely explained by women's current BMI.


Draft genome of the Arabidopsis thaliana phyllosphere bacterium, Williamsia sp. ARP1.
The Gram-positive actinomycete Williamsia sp. ARP1 was originally isolated from the Arabidopsis thaliana phyllosphere. Here we describe the general physiological features of this microorganism together with the draft genome sequence and annotation. The 4,745,080 bp long genome contains 4434 protein-coding genes and 70 RNA genes. To our knowledge, this is only the second reported genome from the genus Williamsia and the first sequenced strain from the phyllosphere. The presented genomic information is interpreted in the context of an adaptation to the phyllosphere habitat.


Gramene 2013: comparative plant genomics resources.
Gramene (http://www.gramene.org) is a curated online resource for comparative functional genomics in crops and model plant species, currently hosting 27 fully and 10 partially sequenced reference genomes in its build number 38. Its strength derives from the application of a phylogenetic framework for genome comparison and the use of ontologies to integrate structural and functional annotation data. Whole-genome alignments complemented by phylogenetic gene family trees help infer syntenic and orthologous relationships. Genetic variation data, sequences and genome mappings available for 10 species, including Arabidopsis, rice and maize, help infer putative variant effects on genes and transcripts. The pathways section also hosts 10 species-specific metabolic pathways databases developed in-house or by our collaborators using Pathway Tools software, which facilitates searches for pathway, reaction and metabolite annotations, and allows analyses of user-defined expression datasets. Recently, we released a Plant Reactome portal featuring 133 curated rice pathways. This portal will be expanded for Arabidopsis, maize and other plant species. We continue to provide genetic and QTL maps and marker datasets developed by crop researchers. The project provides a unique community platform to support scientific research in plant genomics including studies in evolution, genetics, plant breeding, molecular biology, biochemistry and systems biology.


How the best of the best get better and better.
What is the real key to elite performance? According to sports psychologist turned executive coach Graham Jones, star athletes and businesspeople share one defining trait: mental toughness. People who become champions aren't necessarily more gifted than others; they're just masters at managing pressure, meticulously tackling goals, and driving themselves to stay ahead of the competition. Jones, who has advised Olympic medalists and Fortune 500 executives, sees many parallels between the arenas of business and sports, especially in the behavior of people who rise to the very top. These stars have learned to love pressure because it spurs them to achieve. Inner-focused and self-directed, they concentrate on their own excellence and forget the rest. They don't get distracted by others' victories or failures--or even by a personal tragedy off the field of competition. Like Darren Clarke, the golfer who inspired his team to a Ryder Cup victory shortly after the death of his beloved wife, elite performers are masters of compartmentalization. Superstars rebound from defeats more easily, Jones observes, because they don't engage in self-flagellation. One of the keys to their success is a relentless focus on the long-term and the careful planning of short-term goals that will help them attain major milestones. Competition doesn't daunt elite performers; they just use it to challenge themselves--and they never stop striving. Even after becoming benchmarks in their fields, stars keep their edge by reinventing themselves. Star business people and athletes also recognize the importance of celebrating their wins. It's not just the emotional reward that's important, however: The very best performers also analyze the factors underpinning their success. That helps them build their expertise and their confidence.


Quantitative Proteomics Uncovers Novel Factors Involved in Developmental Differentiation of Trypanosoma brucei.
Developmental differentiation is a universal biological process that allows cells to adapt to different environments to perform specific functions. African trypanosomes progress through a tightly regulated life cycle in order to survive in different host environments when they shuttle between an insect vector and a vertebrate host. Transcriptomics has been useful to gain insight into RNA changes during stage transitions; however, RNA levels are only a moderate proxy for protein abundance in trypanosomes. We quantified 4270 protein groups during stage differentiation from the mammalian-infective to the insect form and provide classification for their expression profiles during development. Our label-free quantitative proteomics study revealed previously unknown components of the differentiation machinery that are involved in essential biological processes such as signaling, posttranslational protein modifications, trafficking and nuclear transport. Furthermore, guided by our proteomic survey, we identified the cause of the previously observed differentiation impairment in the histone methyltransferase DOT1B knock-out strain as it is required for accurate karyokinesis in the first cell division during differentiation. This epigenetic regulator is likely involved in essential chromatin restructuring during developmental differentiation, which might also be important for differentiation in higher eukaryotic cells. Our proteome dataset will serve as a resource for detailed investigations of cell differentiation to shed more light on the molecular mechanisms of this process in trypanosomes and other eukaryotes.


VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia.
Vascular endothelial growth factor (VEGF) is an angiogenic protein with therapeutic potential in ischemic disorders, including stroke. VEGF confers neuroprotection and promotes neurogenesis and cerebral angiogenesis, but the manner in which these effects may interact in the ischemic brain is poorly understood. We produced focal cerebral ischemia by middle cerebral artery occlusion for 90 minutes in the adult rat brain and measured infarct size, neurological function, BrdU labeling of neuroproliferative zones, and vWF-immunoreactive vascular profiles, without and with intracerebroventricular administration of VEGF on days 1-3 of reperfusion. VEGF reduced infarct size, improved neurological performance, enhanced the delayed survival of newborn neurons in the dentate gyrus and subventricular zone, and stimulated angiogenesis in the striatal ischemic penumbra, but not the dentate gyrus. We conclude that in the ischemic brain VEGF exerts an acute neuroprotective effect, as well as longer latency effects on survival of new neurons and on angiogenesis, and that these effects appear to operate independently. VEGF may, therefore, improve histological and functional outcome from stroke through multiple mechanisms.


Imaging DNA damage allows detection of preneoplasia in the BALB-neuT model of breast cancer.
A prominent feature of many human cancers is oncogene-driven activation of the DNA damage response (DDR) during early tumorigenesis. It has been shown previously that noninvasive imaging of the phosphorylated histone H2A variant H2AX, γH2AX, a DNA damage signaling protein, is possible using (111)In-labeled anti-γH2AX antibody conjugated to the cell-penetrating peptide transactivator of transcription (TAT). The purpose of this study was to investigate whether (111)In-anti-γH2AX-TAT detects the DDR during mammary oncogenesis in BALB-neuT mice. Mammary fat pads from BALB-neuT and wild-type mice (age, 40-106 d) were immunostained for γH2AX. (111)In-anti-γH2AX-TAT or a control probe was administered intravenously to BALB-neuT mice. SPECT was performed weekly and compared with tumor detection using palpation and dynamic contrast-enhanced MR imaging. γH2AX expression was elevated in hyperplastic lesions in the mammary fat pads of BALB-neuT mice aged 76-106 d, compared with normal fat pads from younger mice and carcinomas from older mice (13.5 ± 1.2 γH2AX foci/cell vs. 5.2 ± 1.5 [P < 0.05] and 3.4 ± 1.1 [P < 0.001], respectively). Serial SPECT imaging revealed a 2.5-fold increase in (111)In-anti-γH2AX-TAT accumulation in the mammary fat pads of mice aged 76-106 d, compared with control probe (P = 0.01). The median time to detection of neoplastic lesions by (111)In-anti-γH2AX-TAT (defined as >5% injected dose per gram of tissue) was 96 d, compared with 120 and 131 d for dynamic contrast-enhanced MR imaging and palpation, respectively (P < 0.001). DDR imaging using (111)In-anti-γH2AX-TAT identified mammary tumors significantly earlier than MR imaging. Imaging the DDR holds promise for the detection of preneoplasia and as a technique for screening cancer-prone individuals.


Bullying victimisation and risk of psychotic phenomena: analyses of British national survey data.
Being bullied is an aversive experience with short-term and long-term consequences, and is incorporated in biopsychosocial models of psychosis. We used the 2000 and the 2007 British Adult Psychiatric Morbidity Surveys to test the hypothesis that bullying is associated with individual psychotic phenomena and with psychosis, and predicts the later emergence of persecutory ideation and hallucinations. We analysed two nationally representative surveys of individuals aged 16 years or older in Great Britain (2000) and England (2007). Respondents were presented with a card listing stressful events to identify experiences of bullying over the entire lifespan. We assessed associations with the dependent variables persecutory ideation, auditory and visual hallucinations, and diagnosis of probable psychosis. All analyses were controlled for sociodemographic confounders, intelligence quotient (IQ), and other traumas. We used data for 8580 respondents from 2000 and 7403 from 2007. Bullying was associated with presence of persecutory ideation and hallucinations, remaining so after adjustment for sociodemographic factors, IQ, other traumas, and childhood sexual abuse. Bullying was associated with a diagnosis of probable psychosis. If reported at baseline, bullying predicted emergence and maintenance of persecutory ideation and hallucinations during 18 months of follow-up in the 2000 survey. Controlling for other traumas and childhood sexual abuse did not affect the association between bullying and psychotic symptoms, but reduced the significance of the association with diagnosis of probable psychosis. Bullying was most strongly associated with the presence of concurrent persecutory ideation and hallucinations. Bullying victimisation increases the risk of individual psychotic symptoms and of a diagnosis of probable psychosis. Early detection of bullying and use of treatments oriented towards its psychological consequences might ameliorate the course of psychosis. None.


Neutrophil gelatinase-associated lipocalin (NGAL) predicts response to neoadjuvant chemotherapy and clinical outcome in primary human breast cancer.
In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.


Social health insurance in a developing country: the case of the Philippines.
Very little is known about the Philippine health care system, and in particular its experience with social health insurance (SHI). Having initiated an SHI programme 35 years ago, the Philippines hold many lessons for the development of such schemes in other low and middle-income countries. We analyse the challenges currently facing PhilHealth, the national health insurer. PhilHealth was formed in 1995 as a successor to the Medicare programme and was given a mandate to achieve universal coverage by 2010. To date, PhilHealth has been quite successful in some areas (e.g. enrollment), but lags behind in others (e.g. quality and price control). We conclude that SHI in the Philippines has been a success story so far and provides lessons for countries in a similar situation. For example: (i) SHI is based on value decisions and the clear statement of societal goals can give guidance in the technical execution, (ii) SHI is a financing institution and needs to be treated accordingly, (iii) SHI can be implemented independently of the current economic situation and might actually contribute to economic development, (iv) community-based health care financing schemes should be merged with the national SHI in the long run, and (v) there is a strong need to push for high quality care and improved physical access. No clear suggestions can be given with respect to the benefit catalogue and the balance between economies of scale and decentralisation. Although riddled with many inadequacies, PhilHealth was set up as a strong and largely politically independent institution for the development of SHI. SHI can act as a stabilizing institution in a politically and economically volatile environment.


Instrumented arthrometry for diagnosing partial versus complete anterior cruciate ligament tears.
Nineteen patients with the clinical diagnosis of anterior cruciate ligament injury were examined by KT-1000 arthrometry before arthroscopy in an effort to differentiate partial from complete tears. To this end, the KT-1000 arthrometer was equipped with a strain gauge and processor that permitted the required force to increase the anterior displacement by 1-mm increments, to be read on a light-emitting diode. The measured force has been plotted against anterior displacement expressed in non-linear increments along the x-axis to allow for the viscoelastic nature of the ligament. The results show that stress-strain diagrams of partially torn and completely torn ligaments are similar to those obtained by graded stress radiography. Using arthroscopy as the standard of measurement, partial tears can be differentiated from complete tears with a sensitivity of 80% and a specificity of 100%. The figures for complete tears versus partial tears are 100% and 80%, respectively. Graded arthrometry with x-y recording of the force-displacement relationship that allows for the viscoelastic qualities of ligament further extends the capabilities of instrumented arthrometry.