Mirels’ Score for upper limb metastatic lesions: Do we need a different cut-off for recommending prophylactic fixation?

The aim of this study was to investigate the reproducibility, reliability and accuracy of Mirels’s score in upper limb bony metastatic disease and validate its use in predicting pathological fractures. Methods 45 patients with upper limb bony metastases met the inclusion criteria (62% male 28/45). Mean age was 69 years (SD 9.5) and commonest primaries were lung (29% 13/45), followed by prostate and hematological (each 20% 9/45). The most commonly affected bone was the humerus (76% 35/45), followed by the ulna (6.5% 3/45). Mirels’s score was calculated in 32 patients; with plain radiographs at index presentation scored using Mirels’s system by 6 raters. The radiological aspects (lesion size and appearance) were scored twice by each rater (2-weeks apart). Intra- and interobserver reliability were calculated using Fleiss’ kappa test. Bland-Altman plots compared the variances of both individual components and total Mirels’s score. Results The overall fracture rate of upper limb metastatic lesions was 76% (35/46) with a mean follow-up of 3.6 years (range 11 months-6.8 years). Where time from diagnosis to fracture was known (n=20), fractures occurred at a median 19 days (IQR 60-10) and 80% (16/20) occurred within 3-months of diagnosis. Mirels’s score of ≥9 did not accurately predict lesions that fractured (fracture rate 11% 5/46 for Mirels’s ≥9 versus 65% 30/46 for Mirels’s ≤8, p<0.001). Sensitivity was 14% and specificity was 73%. When Mirels’s cut-off was lowered to ≥7, patients were more likely to fracture than not (48% 22/46 versus 28% 13/46, p=0.045), sensitivity rose to 63% but specificity fell to 55%. Kappa values for interobserver variability were k=0.358 (fair, 95% confidence interval CI 0.288-0.429) for lesion size, k=0.107 (poor, 95% CI 0.02-0.193) for radiological appearance and k=0.274 (fair, 95% CI 0.229-0.318) for total Mirels’s score. Values for intraobserver variability were k=0.716 (good, 95% CI 0.432-0.999) for lesion size, k=0.427 (moderate, 95% CI 0.195-0.768) for radiological appearance and 0.580 (moderate, 95% CI 0.395-0.765) for total Mirels’s score. Conclusions This study demonstrates moderate to substantial agreement between and within raters using Mirels’s score on upper limb radiographs. However, Mirels’s score had a poor sensitivity and specificity in predicting upper extremity fractures. Until a more valid scoring system has been developed, based on our study, we recommend a Mirels’s threshold of ≥7/12 for considering prophylactic fixation of impending upper limb pathological fractures. This contrasts with the current ≥9/12 cut-off, which is recommended for lower limb pathological fractures

First reported outbreak of locally acquired hepatitis E virus infection in Australia

Objective: To determine the source and extent of a locally acquired hepatitis E virus (HEV) infection outbreak. Design, setting and participants: A cluster of notified cases of HEV infection linked to a single restaurant (X) was identified in May 2014. People with laboratory-confirmed HEV infection in New South Wales between January 2013 and December 2014 were interviewed about potential risk factors for HEV infection. Co-diners at restaurant X and patients with suspected but unexplained viral hepatitis were retrospectively tested. Foods eaten by the infected persons were compared with those of seronegative co-diners. HEV RNA detected in sera from infected persons was sequenced and genotyped. Implicated foods were traced back to their sources. Main outcome measures: Potential sources of infection, including overseas travel and foods eaten, and origin of implicated food products. Results: In 55 serologically confirmed cases of HEV infection, 24 people had not travelled overseas during their incubation periods. Of the 24, 17 reported having eaten at restaurant X, 15 of whom could be interviewed. All reported consuming pork liver pâté, compared with only four of seven uninfected co-diners (P < 0.05). The other seven people with locally acquired infections each reported consuming a pork product during their incubation periods. HEV RNA was detected in 16 of the 24 cases; all were of genotype 3. Sequencing indicated greater than 99% homology among restaurant X isolates. HEV RNA was isolated from pork sausages from a batch implicated in one of the locally acquired infections not linked with restaurant X. The pork livers used for pâté preparation by restaurant X were traced to a single Australian farm. Conclusions: This is the first reported HEV outbreak in Australia. HEV should be considered in patients presenting with a compatible illness, even without a history of overseas travel. Pork products should be thoroughly cooked before consumption

RAD51C Germline Mutations in Breast and Ovarian Cancer Cases from High-Risk Families

BRCA1 and BRCA2 are the most well-known breast cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. One such gene, RAD51C, is essential for homologous recombination repair. Several likely pathogenic RAD51C mutations have been identified in BRCA1- and BRCA2-negative breast and ovarian cancer families. We performed complete sequencing of RAD51C in germline DNA of 286 female breast and/or ovarian cancer cases with a family history of breast and ovarian cancers, who had previously tested negative for mutations in BRCA1 and BRCA2. We screened 133 breast cancer cases, 119 ovarian cancer cases, and 34 with both breast and ovarian cancers. Fifteen DNA sequence variants were identified; including four intronic, one 5′ UTR, one promoter, three synonymous, and six non-synonymous variants. None were truncating. The in-silico SIFT and Polyphen programs were used to predict possible pathogenicity of the six non-synonomous variants based on sequence conservation. G153D and T287A were predicted to be likely pathogenic. Two additional variants, A126T and R214C alter amino acids in important domains of the protein such that they could be pathogenic. Two-hybrid screening and immunoblot analyses were performed to assess the functionality of these four non-synonomous variants in yeast. The RAD51C-G153D protein displayed no detectable interaction with either XRCC3 or RAD51B, and RAD51C-R214C displayed significantly decreased interaction with both XRCC3 and RAD51B (p<0.001). Immunoblots of RAD51C-Gal4 activation domain fusion peptides showed protein levels of RAD51C-G153D and RAD51C-R214C that were 50% and 60% of the wild-type, respectively. Based on these data, the RAD51C-G153D variant is likely to be pathogenic, while the RAD51C- R214C variant is hypomorphic of uncertain pathogenicity. These results provide further support that RAD51C is a rare breast and ovarian cancer susceptibility gene

Home care utilization and outcomes among Asian and other Canadian patients with heart failure

Article deposited according to publisher policy posted on SHERPA/RoMEO, 16/08/2010.YesFunding provided by the Open Access Authors Fund

Transferability of PCR-based diagnostic protocols: An international collaborative case study assessing protocols targeting the quarantine pine pathogen Fusarium circinatum

[EN] Fusarium circinatum is a harmful pathogenic fungus mostly attacking Pinus species and also Pseudotsuga menziesii, causing cankers in trees of all ages, damping-off in seedlings, and mortality in cuttings and mother plants for clonal production. This fungus is listed as a quarantine pest in several parts of the world and the trade of potentially contaminated pine material such as cuttings, seedlings or seeds is restricted in order to prevent its spread to disease-free areas. Inspection of plant material often relies on DNA testing and several conventional or real-time PCR based tests targeting F. circinatum are available in the literature. In this work, an international collaborative study joined 23 partners to assess the transferability and the performance of nine molecular protocols, using a wide panel of DNA from 71 representative strains of F. circinatum and related Fusarium species. Diagnostic sensitivity, specificity and accuracy of the nine protocols all reached values >80%, and the diagnostic specificity was the only parameter differing significantly between protocols. The rates of false positives and of false negatives were computed and only the false positive rates differed significantly, ranging from 3.0% to 17.3%. The difference between protocols for some of the performance values were mainly due to cross-reactions with DNA from non-target species, which were either not tested or documented in the original articles. Considering that participating laboratories were free to use their own reagents and equipment, this study demonstrated that the diagnostic protocols for F. circinatum were not easily transferable to end-users. More generally, our results suggest that the use of protocols using conventional or real-time PCR outside their initial development and validation conditions should require careful characterization of the performance data prior to use under modified conditions (i.e. reagents and equipment). Suggestions to improve the transfer are proposed.This work was supported by COST action FP1406 Pinestrength . The work of the Estonian team was supported by the Estonian Science Foundation grants PSG136 and IUT21-04. The work of Portuguese team from INIAV was financed by INIAV I.P. Institute. The work at U. Aveiro (Portugal) was financed by European Funds through COMPETE and National Funds through the Portuguese Foundation for Science and Technology (FCT) to CESAM (UID/AMB/50017/2013 POCI-01- 0145-FEDER-007638). The work of Slovenian team was financed through Slovenian Research Agency (P4-0107) and by the Slovenian Ministry of Agriculture, Forestry and Food (Public Forestry Service). The British work was financially supported by the Forestry Commission, UK. The French work was financially supported by the French Agency for Food, environmental and occupational health safety (ANSES). The work in New Zealand was funded by Operational Research Programmes, Ministry for Primary Industries, New Zealand.Ioos, R.; Aloi, F.; Piskur, B.; Guinet, C.; Mullett, M.; Berbegal Martinez, M.; Bragança, H.... (2019). Transferability of PCR-based diagnostic protocols: An international collaborative case study assessing protocols targeting the quarantine pine pathogen Fusarium circinatum. Scientific Reports. 9:1-17. https://doi.org/10.1038/s41598-019-44672-8S1179Schmale, D. G. III & Gordon, T. R. Variation in susceptibility to pitch canker disease, caused by Fusarium circinatum, in native stands of Pinus muricata. Plant Pathol. 52, 720–725 (2003).Gordon, T. R., Kirkpatrick, S. C., Aegerter, B. J., Wood, D. L. & Storer, A. J. 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Polymerase chain reaction-based detection of Fusarium circinatum, the causal agent of pitch canker disease. Molecular Ecology Resources 8, 1270–1273 (2008).Ioos, R., Fourrier, C., Iancu, G. & Gordon, T. R. Sensitive Detection of Fusarium circinatum in Pine Seed by Combining an Enrichment Procedure with a Real-Time Polymerase Chain Reaction Using Dual-Labeled Probe Chemistry. Phytopathology 99, 582–590, https://doi.org/10.1094/PHYTO-99-5-0582 (2009).Dreaden, T. J., Smith, J. A., Barnard, E. L. & Blakeslee, G. Development and evaluation of a real-time PCR seed lot screening method for Fusarium circinatum, causal agent of pitch canker disease. For. Path. 42, 405–411, https://doi.org/10.1111/j.1439-0329.2012.00774.x (2012).Fourie, G. et al. Culture-independent detection and quantification of Fusarium circinatum in a pine-producing seedling nursery. Southern Forests: a Journal of Forest Science 76, 137–143, https://doi.org/10.2989/20702620.2014.899058 (2014).Lamarche, J. et al. 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Clinical chemistry 47, 47–55 (2001).Boutigny, A.-L. et al. Optimization of a real-time PCR assay for the detection of the quarantine pathogen Melampsora medusae f. sp. deltoidae. Fungal Biology 117, 389–398, https://doi.org/10.1016/j.funbio.2013.04.001 (2013).Guinet, C., Fourrier-Jeandel, C., Cerf-Wendling, I. & Ioos, R. One-step detection of Monilinia fructicola, M. fructigena, and M. laxa on Prunus and Malus by a multiplex real-time PCR assay. Plant Dis. 100, 2465–2474, https://doi.org/10.1094/PDIS-05-16-0655-RE (2016).Aguayo, J. et al. Development of a hydrolysis probe-based real-time assay for the detection of tropical strains of Fusarium oxysporum f. sp. cubense race 4. PLoS ONE 12, e0171767, https://doi.org/10.1371/journal.pone.0171767 (2017).Broeders, S. et al. Guidelines for validation of qualitative real-time PCR methods. Trends in Food Science & Technology 37, 115–126, https://doi.org/10.1016/j.tifs.2014.03.008 (2014).Pelloux, H. et al. 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Impact on and use of an inner-city London Infectious Diseases Department by international migrants: a questionnaire survey

<p>Abstract</p> <p>Background</p> <p>The UK has witnessed a considerable increase in immigration in the past decade. Migrant may face barriers to accessing appropriate health care on arrival and the current focus on screening certain migrants for tuberculosis on arrival is considered inadequate. We assessed the implications for an inner-city London Infectious Diseases Department in a high migrant area.</p> <p>Methods</p> <p>We administered an anonymous 20-point questionnaire survey to all admitted patients during a 6 week period. Questions related to sociodemographic characteristics and clinical presentation. Analysis was by migration status (UK born <it>vs </it>overseas born).</p> <p>Results</p> <p>111 of 133 patients completed the survey (response rate 83.4%). 58 (52.2%) were born in the UK; 53 (47.7%) of the cohort were overseas born. Overseas-born were over-represented in comparison to Census data for this survey site (47.7% <it>vs </it>33.6%; proportional difference 0.142 [95% CI 0.049–0.235]; p = 0.002): overseas born reported 33 different countries of birth, most (73.6%) of whom arrived in the UK pre-1975 and self-reported their nationality as British. A smaller number (26.4%) were new migrants to the UK (≤10 years), mostly refugees/asylum seekers. Overseas-born patients presented with a broad range and more severe spectrum of infections, differing from the UK-born population, resulting in two deaths in this group only. Presentation with a primary infection was associated with refugee/asylum status (n = 8; OR 6.35 [95% CI 1.28–31.50]; p = 0.023), being a new migrant (12; 10.62 [2.24–50.23]; p = 0.003), and being overseas born (31; 3.69 [1.67–8.18]; p = 0.001). Not having registered with a primary-care physician was associated with being overseas born, being a refugee/asylum seeker, being a new migrant, not having English as a first language, and being in the UK for ≤5 years. No significant differences were found between groups in terms of duration of illness prior to presentation or duration of hospitalisation (mean 11.74 days [SD 12.69]).</p> <p>Conclusion</p> <p>Migrants presented with a range of more severe infections, which suggests they face barriers to accessing appropriate health care and screening both on arrival and once settled through primary care services. A more organised and holistic approach to migrant health care is required.</p

Increased deep sleep in a medication-free, detoxified female offender with schizophrenia, alcoholism and a history of attempted homicide: Case report

BACKGROUND: Psychiatric sleep research has attempted to identify diagnostically sensitive and specific sleep patterns associated with particular disorders. Both schizophrenia and alcoholism are typically characterized by a severe sleep disturbance associated with decreased amounts of slow wave sleep, the physiologically significant, refreshing part of the sleep. Antisocial behaviour with severe aggression, on the contrary, has been reported to associate with increased deep sleep reflecting either specific brain pathology or a delay in the normal development of sleep patterns. The authors are not aware of previous sleep studies in patients with both schizophrenia and antisocial personality disorder. CASE PRESENTATION: The aim of the present case-study was to characterize the sleep architecture of a violent, medication-free and detoxified female offender with schizophrenia, alcoholism and features of antisocial personality disorder using polysomnography. The controls consisted of three healthy, age-matched women with no history of physical violence. The offender's sleep architecture was otherwise very typical for patients with schizophrenia and/or alcoholism, but an extremely high amount of deep sleep was observed in her sleep recording. CONCLUSIONS: The finding strengthens the view that severe aggression is related to an abnormal sleep pattern with increased deep sleep. The authors were able to observe this phenomenon in an antisocially behaving, violent female offender with schizophrenia and alcohol dependence, the latter disorders previously reported to be associated with low levels of slow wave sleep. New studies are, however, needed to confirm and explain this preliminary finding

The B-Cell Specific Transcription Factor, Oct-2, Promotes Epstein-Barr Virus Latency by Inhibiting the Viral Immediate-Early Protein, BZLF1

The Epstein-Barr virus (EBV) latent-lytic switch is mediated by the BZLF1 immediate-early protein. EBV is normally latent in memory B cells, but cellular factors which promote viral latency specifically in B cells have not been identified. In this report, we demonstrate that the B-cell specific transcription factor, Oct-2, inhibits the function of the viral immediate-early protein, BZLF1, and prevents lytic viral reactivation. Co-transfected Oct-2 reduces the ability of BZLF1 to activate lytic gene expression in two different latently infected nasopharyngeal carcinoma cell lines. Furthermore, Oct-2 inhibits BZLF1 activation of lytic EBV promoters in reporter gene assays, and attenuates BZLF1 binding to lytic viral promoters in vivo. Oct-2 interacts directly with BZLF1, and this interaction requires the DNA-binding/dimerization domain of BZLF1 and the POU domain of Oct-2. An Oct-2 mutant (Δ262–302) deficient for interaction with BZLF1 is unable to inhibit BZLF1-mediated lytic reactivation. However, an Oct-2 mutant defective for DNA-binding (Q221A) retains the ability to inhibit BZLF1 transcriptional effects and DNA-binding. Importantly, shRNA-mediated knockdown of endogenous Oct-2 expression in several EBV-positive Burkitt lymphoma and lymphoblastoid cell lines increases the level of lytic EBV gene expression, while decreasing EBNA1 expression. Moreover, treatments which induce EBV lytic reactivation, such as anti-IgG cross-linking and chemical inducers, also decrease the level of Oct-2 protein expression at the transcriptional level. We conclude that Oct-2 potentiates establishment of EBV latency in B cells

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives