Mass of the B_c Meson in Three-Flavor Lattice QCD

We use lattice QCD to predict the mass of the $B_c$ meson. We use the MILC Collaboration's ensembles of lattice gauge fields, which have a quark sea with two flavors much lighter than a third. Our final result is $m_{B_c}=6304\pm12^{+18}_{- 0} MeV$. The first error bar is a sum in quadrature of statistical and systematic uncertainties, and the second is an estimate of heavy-quark discretization effects.Comment: 4 pages, 3 figures; shorten to fit in PRL; published versio

Variation in prescribing for anxiety and depression: a reflection of health inequalities, cultural differences or variations in access to care?

BACKGROUND: There are large variations in mental health prescribing in UK populations. However the underlying reasons for these differences, which may be related to differences in prevalence, cultural expectations or practical difficulties in access to treatment, remain uncertain. METHODS: Linear modelling was used to investigate whether population characteristics or access to primary care account for variations in mental health prescribing across 39 deprived neighbourhoods. RESULTS: The proportion of sampled respondents whose first language was not English and the ratio of general practitioners to population explained 61% of variation. Deprivation and mental health status were not significant predictors of prescribing in these relatively deprived communities. CONCLUSION: These findings suggest that mental health prescribing, within deprived areas, as well as reflecting cultural and social differences in prescribing, may also be a proxy measure of access to care

Food safety in hospital: knowledge, attitudes and practices of nursing staff of two hospitals in Sicily, Italy

BACKGROUND: Food hygiene in hospital poses peculiar problems, particularly given the presence of patients who could be more vulnerable than healthy subjects to microbiological and nutritional risks. Moreover, in nosocomial outbreaks of infectious intestinal disease, the mortality risk has been proved to be significantly higher than the community outbreaks and highest for foodborne outbreaks. On the other hand, the common involvement in the role of food handlers of nurses or domestic staff, not specifically trained about food hygiene and HACCP, may represent a further cause of concern. The purpose of this study was to evaluate knowledge, attitudes, and practices concerning food safety of the nursing staff of two hospitals in Palermo, Italy. Association with some demographic and work-related determinants was also investigated. METHODS: The survey was conducted, by using a semi-structured questionnaire, in March-November 2005 in an acute general hospital and a paediatric hospital, where nursing staff is routinely involved in food service functions. RESULTS: Overall, 401 nurses (279, 37.1%, of the General Hospital and 122, 53.5%, of the Paediatric Hospital, respectively) answered. Among the respondents there was a generalized lack of knowledge about etiologic agents and food vehicles associated to foodborne diseases and proper temperatures of storage of hot and cold ready to eat foods. A general positive attitude towards temperature control and using clothing and gloves, when handling food, was shared by the respondents nurses, but questions about cross-contamination, refreezing and handling unwrapped food with cuts or abrasions on hands were frequently answered incorrectly. The practice section performed better, though sharing of utensils for raw and uncooked foods and thawing of frozen foods at room temperatures proved to be widely frequent among the respondents. Age, gender, educational level and length of service were inconsistently associated with the answer pattern. More than 80% of the respondent nurses did not attend any educational course on food hygiene. Those who attended at least one training course fared significantly better about some knowledge issues, but no difference was detected in both the attitude and practice sections. CONCLUSION: Results strongly emphasize the need for a safer management of catering in the hospitals, where non professional food handlers, like nursing or domestic staff, are involved in food service functions

Predictions from Lattice QCD

In the past year, we calculated with lattice QCD three quantities that were unknown or poorly known. They are the $q^2$ dependence of the form factor in semileptonic $D\to Kl\nu$ decay, the decay constant of the $D$ meson, and the mass of the $B_c$ meson. In this talk, we summarize these calculations, with emphasis on their (subsequent) confirmation by experiments.Comment: v1: talk given at the International Conference on QCD and Hadronic Physics, Beijing, June 16-20, 2005; v2: poster presented at the XXIIIrd International Symposium on Lattice Field Theory, Dublin, July 25-3

Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a clinically, genetically and pathologically heterogeneous disorder. Within FTLD with ubiquitin-positive inclusions (FTLD-U), a new pathological subtype named FTLD-FUS was recently found with fused in sarcoma (FUS) positive, TDP-43-negative inclusions, and striking atrophy of the caudate nucleus. The aim of this study was to determine the frequency of FTLD-FUS in our pathological FTLD series, and to describe the clinical, neuroimaging and neuropathological features of FTLD-FUS, especially caudate atrophy. Demographic and clinical data collected prospectively from 387 patients with frontotemporal dementia (FTD) yielded 74 brain specimens. Immunostaining was carried out using a panel of antibodies, including AT-8, ubiquitin, p62, FUS, and TDP-43. Cortical and caudate atrophy on MRI (n = 136) was rated as normal, mild-moderate or severe. Of the 37 FTLD-U cases, 33 were reclassified as FTLD-TDP and four (0.11, 95%: 0.00–0.21) as FTLD-FUS, with ubiquitin and FUS-positive, p62 and TDP-43-negative neuronal intranuclear inclusions (NII). All four FTLD-FUS cases had a negative family history, behavioural variant FTD (bvFTD), and three had an age at onset ≤40 years. MRI revealed mild-moderate or severe caudate atrophy in all, with a mean duration from onset till MRI of 63 months (range 16–119 months). In our total clinical FTD cohort, we found 11 patients (0.03; 95% CI: 0.01–0.05) with bvFTD, negative family history, and age at onset ≤40 years. Caudate atrophy was present in 10 out of 136 MRIs, and included all four FUS-cases. The newly identified FTLD-FUS has a frequency of 11% in FTLD-U, and an estimated frequency of three percent in our clinical FTD cohort. The existence of this pathological subtype can be predicted with reasonable certainty by age at onset ≤40 years, negative family history, bvFTD and caudate atrophy on MRI

Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction

Inequalities in colorectal cancer screening participation in the first round of the national screening programme in England

BACKGROUND: Introduction of organised, population-based, colorectal cancer screening in the United Kingdom using the faecal occult blood test (FOBT) has the potential to reduce overall colorectal cancer mortality. However, socio-economic variation in screening participation could exacerbate existing inequalities in mortality.METHODS: This study examined FOBT uptake rates in London, England in relation to area-level socio-economic deprivation over the first 30 months of the programme during which 401 197 individuals were sent an FOBT kit. Uptake was defined as return of a completed test kit within 3 months. Area-level deprivation in each postcode sector was indexed with the Townsend Material Deprivation Index. Analyses controlled for area-level household mobility, ethnic diversity and poor health, each of which was associated with lower return rates.RESULTS: The results showed a strong socio-economic gradient in FOBT uptake, which declined from 49% in the least deprived quintile of postcodes to 38% in the middle quintile and 32% in the most deprived quintile. Variation in socio-economic deprivation between sectors accounted for 62% of the variance in return rates, with little attenuation as a result of controlling for ethnic diversity, household mobility or health status.CONCLUSION: These results highlight the need to understand the causes of socio-economic gradients in screening participation and address barriers that could otherwise increase disparities in colorectal cancer survival

Coaggregation of RNA-Binding Proteins in a Model of TDP-43 Proteinopathy with Selective RGG Motif Methylation and a Role for RRM1 Ubiquitination

TAR DNA-binding protein 43 (TDP-43) is a major component within ubiquitin-positive inclusions of a number of neurodegenerative diseases that increasingly are considered as TDP-43 proteinopathies. Identities of other inclusion proteins associated with TDP-43 aggregation remain poorly defined. In this study, we identify and quantitate 35 co-aggregating proteins in the detergent-resistant fraction of HEK-293 cells in which TDP-43 or a particularly aggregate prone variant, TDP-S6, were enriched following overexpression, using stable isotope-labeled (SILAC) internal standards and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). We also searched for differential post-translational modification (PTM) sites of ubiquitination. Four sites of ubiquitin conjugation to TDP-43 or TDP-S6 were confirmed by dialkylated GST-TDP-43 external reference peptides, occurring on or near RNA binding motif (RRM) 1. RRM-containing proteins co-enriched in cytoplasmic granular structures in HEK-293 cells and primary motor neurons with insoluble TDP-S6, including cytoplasmic stress granule associated proteins G3BP, PABPC1, and eIF4A1. Proteomic evidence for TDP-43 co-aggregation with paraspeckle markers RBM14, PSF and NonO was also validated by western blot and by immunocytochemistry in HEK-293 cells. An increase in peptides from methylated arginine-glycine-glycine (RGG) RNA-binding motifs of FUS/TLS and hnRNPs was found in the detergent-insoluble fraction of TDP-overexpressing cells. Finally, TDP-43 and TDP-S6 detergent-insoluble species were reduced by mutagenesis of the identified ubiquitination sites, even following oxidative or proteolytic stress. Together, these findings define some of the aggregation partners of TDP-43, and suggest that TDP-43 ubiquitination influences TDP-43 oligomerization

Hyperphosphorylation as a Defense Mechanism to Reduce TDP-43 Aggregation

Several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are characterized by inclusion bodies formed by TDP-43 (TDP). We established cell and transgenic Drosophila models expressing TDP carboxyl terminal fragment (ND251 and ND207), which developed aggregates recapitulating important features of TDP inclusions in ALS/FTLD-U, including hyperphosphorylation at previously reported serine403,404,409,410 residues, polyubiquitination and colocalization with optineurin. These models were used to address the pathogenic role of hyperphosphorylation in ALS/FTLD-U. We demonstrated that hyperphosphorylation and ubiquitination occurred temporally later than aggregation in cells. Expression of CK2α which phosphorylated TDP decreased the aggregation propensity of ND251 or ND207; this effect could be blocked by CK2 inhibitor DMAT. Mutation of serines379,403,404,409,410 to alanines (S5A) to eliminate phosphorylation increased the aggregation propensity and number of aggregates of TDP, but mutation to aspartic acids (S5D) or glutamic acids (S5E) to simulate hyperphosphorylation had the opposite effect. Functionally, ND251 or ND207 aggregates decreased the number of neurites of Neuro2a cells induced by retinoic acid or number of cells by MTT assay. S5A mutation aggravated, but S5E mutation alleviated these cytotoxic effects of aggregates. Finally, ND251 or ND251S5A developed aggregates in neurons, and salivary gland of transgenic Drosophila, but ND251S5E did not. Taken together, our data indicate that hyperphosphorylation may represent a compensatory defense mechanism to stop or prevent pathogenic TDP from aggregation. Therefore, enhancement of phosphorylation may serve as an effective therapeutic strategy against ALS/FTLD-U

Prescriptive variability of drugs by general practitioners

<div><p>Prescription drug spending is growing faster than any other sector of healthcare. However, very little is known about patterns of prescribing and cost of prescribing between general practices. In this study, we examined variation in prescription rates and prescription costs through time for 55 GP surgeries in Northern Ireland Western Health and Social Care Trust. Temporal changes in variability of prescribing rates and costs were assessed using the Mann–Kendall test. Outlier practices contributing to between practice variation in prescribing rates were identified with the interquartile range outlier detection method. The relationship between rates and cost of prescribing was explored with Spearman's statistics. The differences in variability and mean number of prescribing rates associated with the practice setting and socioeconomic deprivation were tested using t-test and <i>F</i>-test respectively. The largest between-practice difference in prescribing rates was observed for Apr-Jun 2015, with the number of prescriptions ranging from 3.34 to 8.36 per patient. We showed that practices with outlier prescribing rates greatly contributed to between-practice variability. The largest difference in prescribing costs was reported for Apr-Jun 2014, with the prescription cost per patient ranging from £26.4 to £64.5. In addition, the temporal changes in variability of prescribing rates and costs were shown to undergo an upward trend. We demonstrated that practice setting and socio-economic deprivation accounted for some of the between-practice variation in prescribing. Rural practices had higher between practice variability than urban practices at all time points. Practices situated in more deprived areas had higher prescribing rates but lower variability than those located in less deprived areas. Further analysis is recommended to assess if variation in prescribing can be explained by demographic characteristics of patient population and practice features. Identification of other factors contributing to prescribing variability can help us better address potential inappropriateness of prescribing.</p></div