Highly polarized light from stable ordered magnetic fields in GRB 120308A.

After the initial burst of γ-rays that defines a γ-ray burst (GRB), expanding ejecta collide with the circumburst medium and begin to decelerate at the onset of the afterglow, during which a forward shock travels outwards and a reverse shock propagates backwards into the oncoming collimated flow, or 'jet'. Light from the reverse shock should be highly polarized if the jet's magnetic field is globally ordered and advected from the central engine, with a position angle that is predicted to remain stable in magnetized baryonic jet models or vary randomly with time if the field is produced locally by plasma or magnetohydrodynamic instabilities. Degrees of linear polarization of P ≈ 10 per cent in the optical band have previously been detected in the early afterglow, but the lack of temporal measurements prevented definitive tests of competing jet models. Hours to days after the γ-ray burst, polarization levels are low (P < 4 per cent), when emission from the shocked ambient medium dominates. Here we report the detection of P =28(+4)(-4) per cent in the immediate afterglow of Swift γ-ray burst GRB 120308A, four minutes after its discovery in the γ-ray band, decreasing to P = 16(+5)(-4) per cent over the subsequent ten minutes. The polarization position angle remains stable, changing by no more than 15 degrees over this time, with a possible trend suggesting gradual rotation and ruling out plasma or magnetohydrodynamic instabilities. Instead, the polarization properties show that GRBs contain magnetized baryonic jets with large-scale uniform fields that can survive long after the initial explosion.

Variants in CIB2 cause DFNB48 and not USH1J.

The genetic, mutational and phenotypic spectrum of deafness-causing genes shows great diversity and pleiotropy. The best examples are the group of genes, which when mutated can either cause non-syndromic hearing loss (NSHL) or the most common dual sensory impairment, Usher syndrome (USH). Variants in the CIB2 gene have been previously reported to cause hearing loss at the DFNB48 locus and deaf-blindness at the USH1J locus. In this study, we characterize the phenotypic spectrum in a multiethnic cohort with autosomal recessive non-syndromic hearing loss (ARNSHL) due to variants in the CIB2 gene. Of the 6 families we ascertained, 3 segregated novel loss-of-function (LOF) variants, 2 families segregated missense variants (1 novel) and 1 family segregated a previously reported pathogenic variant in trans with a frameshift variant. This report is the first to show that biallelic LOF variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here, we provide evidence disqualifying CIB2 as an USH-causing gene.

Risk factors for acquisition of multidrug-resistant Escherichia coli and development of community-acquired urinary tract infections.

We examined risk factors associated with the intestinal acquisition of antimicrobial-resistant extraintestinal pathogenic Escherichia coli (ExPEC) and development of community-acquired urinary tract infection (UTI) in a case-control study of young women across Canada. A total of 399 women were recruited; 164 women had a UTI caused by E. coli resistant to ⩾1 antimicrobial classes and 98 had a UTI caused by E. coli resistant to ⩾3 antimicrobial classes. After adjustment for age, student health service (region of Canada) and either prior antibiotic use or UTI history, consumption of processed or ground chicken, cooked or raw shellfish, street foods and any organic fruit; as well as, contact with chickens, dogs and pet treats; and travel to Asia, were associated with an increased risk of UTI caused by antimicrobial resistant E. coli. A decreased risk of antimicrobial resistant UTI was associated with consumption of apples, nectarines, peppers, fresh herbs, peanuts and cooked beef. Drug-resistant UTI linked to foodborne and environmental exposures may be a significant public health concern and understanding the risk factors for intestinal acquisition of existing or newly emerging lineages of drug-resistant ExPEC is important for epidemiology, antimicrobial stewardship and prevention efforts.

Post-operative paediatric cerebellar mutism syndrome: time to move beyond structural MRI.

PURPOSE: To determine the value of structural magnetic resonance imaging (MRI) in predicting post-operative paediatric cerebellar mutism syndrome (pCMS) in children undergoing surgical treatment for medulloblastoma. METHODS: Retrospective cohort study design. Electronic/paper case note review of all children with medulloblastoma presenting to Great Ormond Street Hospital between 2003 and 2013. The diagnosis of pCMS was established through a scoring system incorporating mutism, ataxia, behavioural disturbance and cranial nerve deficits. MRI scans performed at three time points were assessed by neuroradiologists blinded to the diagnosis of pCMS. RESULTS: Of 56 children included, 12 (21.4%) developed pCMS as judged by a core symptom of mutism. pCMS was more common in those aged 5 or younger. There was no statistically significant difference in pre-operative distortion or signal change of the dentate or red nuclei or superior cerebellar peduncles (SCPs) between those who did and did not develop pCMS. In both early (median 5 days) and late (median 31 months) post-operative scans, T2-weighted signal change in SCPs was more common in the pCMS group (p = 0.040 and 0.046 respectively). Late scans also showed statistically significant signal change in the dentate nuclei (p = 0.024). CONCLUSIONS: The development of pCMS could not be linked to any observable changes on pre-operative structural MRI scans. Post-operative T2-weighted signal change in the SCPs and dentate nuclei underlines the role of cerebellar efferent injury in pCMS. Further research using advanced quantitative MRI sequences is warranted given the inability of conventional pre-surgical MRI to predict pCMS.

Screening of Living Kidney Donors for Genetic Diseases Using a Comprehensive Genetic Testing Strategy.

Related living kidney donors (LKDs) are at higher risk of end-stage renal disease (ESRD) compared with unrelated LKDs. A genetic panel was developed to screen 115 genes associated with renal diseases. We used this panel to screen six negative controls, four transplant candidates with presumed genetic renal disease and six related LKDs. After removing common variants, pathogenicity was predicted using six algorithms to score genetic variants based on conservation and function. All variants were evaluated in the context of patient phenotype and clinical data. We identified causal variants in three of the four transplant candidates. Two patients with a family history of autosomal dominant polycystic kidney disease segregated variants in PKD1. These findings excluded genetic risk in three of four relatives accepted as potential LKDs. A third patient with an atypical history for Alport syndrome had a splice site mutation in COL4A5. This pathogenic variant was excluded in a sibling accepted as an LKD. In another patient with a strong family history of ESRD, a negative genetic screen combined with negative comparative genomic hybridization in the recipient facilitated counseling of the related donor. This genetic renal disease panel will allow rapid, efficient and cost-effective evaluation of related LKDs.

FLAIR* to visualize veins in white matter lesions: A new tool for the diagnosis of multiple sclerosis?

OBJECTIVE: To explore the potential of a post-processing technique combining FLAIR and T2* (FLAIR*) to distinguish between lesions caused by multiple sclerosis (MS) from cerebral small vessel disease (SVD) in a clinical setting. METHODS: FLAIR and T2* head datasets acquired at 3T of 25 people with relapsing MS (pwRMS) and ten with pwSVD were used. After post-processing, FLAIR* maps were used to determine the proportion of white matter lesions (WML) showing the 'vein in lesion' sign (VIL), a characteristic histopathological feature of MS plaques. Sensitivity and specificity of MS diagnosis were examined on the basis of >45% VIL+ and >60% VIL+ WML, and compared with current dissemination in space (DIS) MRI criteria. RESULTS: All pwRMS had >45% VIL+ WML (range 58-100%) whilst in pwSVD the proportion of VIL+ WML was significantly lower (0-64%; mean 32±20%). Sensitivity based on >45% VIL+ was 100% and specificity 80% whilst with >60% VIL+ as the criterion, sensitivity was 96% and specificity 90%. DIS criteria had 96% sensitivity and 40% specificity. CONCLUSION: FLAIR* enables VIL+ WML detection in a clinical setting, facilitating differentiation of MS from SVD based on brain MRI. KEY POINTS: • FLAIR* in a clinical setting allows visualization of veins in white matter lesions. • Significant proportions of MS lesions demonstrate a vein in lesion on MRI. • Microangiopathic lesions demonstrate a lower proportion of intralesional veins than MS lesions. • Intralesional vein-based criteria may complement current MRI criteria for MS diagnosis.

Comprehensive genetic testing with ethnic-specific filtering by allele frequency in a Japanese hearing-loss population.

Recent advances in targeted genomic enrichment with massively parallel sequencing (TGE+MPS) have made comprehensive genetic testing for non-syndromic hearing loss (NSHL) possible. After excluding NSHL subjects with causative mutations in GJB2 and the MT-RNR1 (1555A>G) variant by Sanger sequencing, we completed TGE+MPS on 194 probands with presumed NSHL identified across Japan. We used both publicly available minor allele frequency (MAF) datasets and ethnic-specific MAF filtering against an in-house database of 200 normal-hearing Japanese controls. Ethnic-specific MAF filtering allowed us to re-categorize as common 203 variants otherwise annotated as rare or novel in non-Japanese ethnicities. This step minimizes false-positive results and improves the annotation of identified variants. Causative variants were identified in 27% of probands with solve rates of 35%, 35% and 19% for dominant, recessive and sporadic NSHL, respectively. Mutations in MYO15A and CDH23 follow GJB2 as the frequent causes of recessive NSHL; copy number variations in STRC are a major cause of mild-to-moderate NSHL. Ethnic-specific filtering by allele frequency is essential to optimize the interpretation of genetic data.

Targeted genomic enrichment and massively parallel sequencing identifies novel nonsyndromic hearing impairment pathogenic variants in Cameroonian families.

In sub-Saharan Africa GJB2-related nonsyndromic hearing impairment (NSHI) is rare. Ten Cameroonian families was studied using a platform (OtoSCOPE®) with 116 genes. In seven of 10 families (70%), 12 pathogenic variants were identified in six genes. Five of the 12 (41.6%) variants are novel. These results confirm the efficiency of comprehensive genetic testing in defining the causes of NSHI in sub-Saharan Africa.

Modelling considerations in the analysis of associations between antimicrobial use and resistance in beef feedlot cattle.

A number of sophisticated modelling approaches are available to investigate potential associations between antimicrobial use (AMU) and resistance (AMR) in animal health settings. All have their advantages and disadvantages, making it unclear as to which model is most appropriate. We used advanced regression modelling to investigate AMU-AMR associations in faecal non-type-specific Escherichia coli (NTSEC) isolates recovered from 275 pens of feedlot cattle. Ten modelling strategies were employed to investigate AMU associations with resistance to chloramphenicol, ampicillin, sulfisoxazole, tetracycline and streptomycin. Goodness-of-fit statistics did not show a consistent advantage for any one model type. Three AMU-AMR associations were significant in all models. Recent parenteral tetracycline use increased the odds of finding tetracycline-resistant NTSEC [odds ratios (OR) 1·1-3·2]; recent parenteral sulfonamide use increased the odds of finding sulfisoxazole-resistant NTSEC (OR 1·4-2·5); and recent parenteral macrolide use decreased the odds of recovering ampicillin-resistant NTSEC (OR 0·03-0·2). Other results varied markedly depending on the modelling approach, emphasizing the importance of exploring and reporting multiple modelling methods based on a balanced consideration of important factors such as study design, mathematical appropriateness, research question and target audience.

Applications of mathematical modeling in managing the spread of chronic wasting disease (CWD) in wild deer under alternative harvesting scenarios.

The application of a recently developed mathematical model for predicting the spread of chronic wasting disease (CWD) in wild deer was assessed under different scenarios where harvesting is employed in disease management. A process-based mathematical model for CWD transmission in wild deer populations was recently developed and parameterized by Al-arydah et al. (2011) to provide a scientific basis for understanding the factors that affect spread of CWD and evaluate concomitant disease-control strategies. The impact of gender on CWD transmission was shown to have a significant influence on the spread of the disease in the wild. Our model demonstrates a range of harvesting rates in which CWD is controlled and deer populations survive. However, if harvesting rates are too low, the disease remains endemic for decades. Conversely, the Canadian deer population is eradicated if harvesting rates are excessive. Future investigation includes building the model to assess the spread of CWD under different disease-management scenarios.

Ten per cent polarized optical emission from GRB 090102.

The nature of the jets and the role of magnetic fields in gamma-ray bursts (GRBs) remains unclear. In a baryon-dominated jet only weak, tangled fields generated in situ through shocks would be present. In an alternative model, jets are threaded with large-scale magnetic fields that originate at the central engine and that accelerate and collimate the material. To distinguish between the models the degree of polarization in early-time emission must be measured; however, previous claims of gamma-ray polarization have been controversial. Here we report that the early optical emission from GRB 090102 was polarized at 10 +/- 1 per cent, indicating the presence of large-scale fields originating in the expanding fireball. If the degree of polarization and its position angle were variable on timescales shorter than our 60-second exposure, then the peak polarization may have been larger than ten per cent.

Purinergic signaling mediated by P2X7 receptors controls myelination in sciatic nerves.

Adenosine-5'-triphosphate, the physiological ligand of P2X receptors, is an important factor in peripheral nerve development. P2X7 receptor is expressed in Schwann cells (SCs), but the specific effects of P2X7 purinergic signaling on peripheral nerve development, myelination, and function are largely unknown. In this study, sciatic nerves from P2X7 knockout mice were analyzed for altered expression of myelin-associated proteins and for alterations in nerve morphology. Immunohistochemical analyses revealed that, in the wild-type peripheral nerves, the P2X7 receptor was localized mainly in myelinating SCs, with only a few immunopositive nonmyelinating SCs. Complete absence of P2X7 receptor protein was confirmed in the sciatic nerves of the knockout mice by Western blot and immunohistochemistry. Western blot analysis revealed that expression levels of the myelin proteins protein zero and myelin-associated glycoprotein are reduced in P2X7 knockout nerves. In accordance with the molecular results, transmission electron microscopy analyses revealed that P2X7 knockout nerves possess significantly more unmyelinated axons, contained in a higher number of Remak bundles. The myelinating/nonmyelinating SC ratio was also decreased in knockout mice, and we found a significantly increased number of irregular fibers compared with control nerves. Nevertheless, the myelin thickness in the knockout was unaltered, suggesting a stronger role for P2X7 in determining SC maturation than in myelin formation. In conclusion, we present morphological and molecular evidence of the importance of P2X7 signaling in peripheral nerve maturation and in determining SC commitment to a myelinating phenotype.

Latent class comparison of test accuracy when evaluating antimicrobial susceptibility using disk diffusion and broth microdilution to test Escherichia coli and Mannheimia haemolytica isolates recovered from beef feedlot cattle.

The study objective was to use Bayesian latent class analysis to evaluate the accuracy of susceptibility test results obtained from disk diffusion and broth microdilution using bacteria recovered from beef feedlot cattle. Isolates of Escherichia coli and Mannheimia haemolytica were tested for susceptibility to ampicillin, ceftiofur, streptomycin, sulfisoxazole, tetracycline, and trimethoprim-sulfamethoxazole. Results showed that neither testing method was always or even generally superior to the other. Specificity (ability to correctly classify non-resistant isolates) was extremely high for both testing methods, but sensitivity (ability to correctly classify resistant isolates) was lower, variable in the drugs evaluated, and variable between the two bacterial species. Predictive values estimated using Bayesian Markov chain Monte Carlo models showed that the ability to predict true susceptibility status was equivalent for test results obtained with the two testing methods for some drugs, but for others there were marked differences between results obtained from disk diffusion and broth microdilution tests.

Broadband observations of the naked-eye gamma-ray burst GRB 080319B.

Long-duration gamma-ray bursts (GRBs) release copious amounts of energy across the entire electromagnetic spectrum, and so provide a window into the process of black hole formation from the collapse of massive stars. Previous early optical observations of even the most exceptional GRBs (990123 and 030329) lacked both the temporal resolution to probe the optical flash in detail and the accuracy needed to trace the transition from the prompt emission within the outflow to external shocks caused by interaction with the progenitor environment. Here we report observations of the extraordinarily bright prompt optical and gamma-ray emission of GRB 080319B that provide diagnostics within seconds of its formation, followed by broadband observations of the afterglow decay that continued for weeks. We show that the prompt emission stems from a single physical region, implying an extremely relativistic outflow that propagates within the narrow inner core of a two-component jet.

Systematic review and meta-analysis of liver resection for metastatic melanoma.

BACKGROUND: The multidisciplinary management of metastatic melanoma now occasionally includes major hepatic resection. The objective of this work was to conduct a systematic review of the literature on liver resection for metastatic melanoma. METHODS: MEDLINE, Embase, the Cochrane Library and Scopus were searched (1990 to December 2012). Studies with at least ten patients undergoing liver resection for metastatic melanoma were included. Data on the outcomes of overall survival (OS) and/or disease-free survival (DFS) were abstracted and synthesized. Hazard ratios (HRs) were derived from survival curves and subjected to meta-analysis using random-effects models. RESULTS: Twenty-two studies involving 579 patients (13 per cent weighted resection rate) who underwent liver resection were included. Study quality was poor to moderate. Median follow-up ranged from 9 to 59 months. Median DFS ranged from 8 to 23 months, and median OS ranged from 14 to 41 months (R0, 22-66 months, R2, 10-16 months; R0 versus R1/R2: HR 0.52, 95 per cent confidence interval (c.i.) 0.37 to 0.73). The OS rate was 56-100 per cent at 1 year, 34-53 per cent at 3 years and 11-36 per cent at 5 years. Median OS with non-operative management ranged from 4 to 12 months. Comparison of OS with resection and non-operative management favoured resection (HR 0.32, 95 per cent c.i. 0.22 to 0.46). CONCLUSION: Radical resection of liver metastases from melanoma appears to improve overall survival compared with non-operative management or incomplete resection, but this observation requires future confirmation as selection bias may have confounded the results.

Burden of illness and factors associated with duration of illness in clinical campylobacteriosis.

A population-based study investigated the burden of illness, including the duration of illness associated with laboratory-confirmed cases of campylobacteriosis in two health unit areas. Questionnaire data were collected for 250 cases. The median duration of illness was 8 days and 66% of cases reported symptoms of moderate severity or greater. A Cox proportional hazards model identified antimicrobial use factors associated with a significantly increased rate of symptom resolution (shorter duration of illness): macrolides for less than the recommended number of days, ciprofloxacin for at least 3 days, and antimicrobials not recommended for campylobacteriosis. The impact of antimicrobial use was consistent regardless of when, during the course of illness, the antimicrobial use began. The effectiveness of ciprofloxacin in these results may be due to the low prevalence of resistance to ciprofloxacin in isolates from this study. The effect of antimicrobials not recommended for campylobacteriosis should be further investigated.

Phomopsis Dieback: A Grapevine Trunk Disease Caused by Phomopsis viticola in California.

Field surveys recently conducted in California and in other grape-growing regions in the United States showed Phomopsis viticola to be one of the most prevalent fungi isolated from grapevine perennial cankers in declining vines. The current study has not only confirmed the presence of P. viticola from grapevine cankers in California but also has for the first time revealed the occurrence of Diaporthe ambigua, D. eres, and D. neotheicola in symptomatic grapevine wood in California by means of morphological studies and multi-gene sequence analysis. Pathogenicity trials conducted on mature cordons of Vitis vinifera 'Syrah' and 'Red Globe', as well as on lignified Syrah dormant canes, showed P. viticola isolates from California to be capable of causing perennial cankers. Lengths of vascular discoloration caused by P. viticola were similar to those caused by Eutypa lata and several Botryosphaeriaceae spp., which are well-known grapevine trunk disease pathogens. Additionally, a lack of spring growth was commonly observed in dormant canes inoculated with P. viticola spore suspensions in two pathogenicity trials. As part of this study, V. vinifera 'Cabernet Sauvignon' and 'Zinfandel' wood was shown to be more susceptible to infection by P. viticola than 'Barbera', 'Chardonnay', 'Merlot', and 'Thompson Seedless' wood. After more than 40 years overlooking P. viticola as a grapevine wood pathogen, this study provides strong evidence of the role of P. viticola as a canker-causing organism, and suggests its addition to the fungi involved in the grapevine trunk disease complex. Results from this study suggest D. ambigua and D. neotheicola to be saprophytes or weak pathogens on grapevine wood.

Normal hearing in Splotch (Sp/+), the mouse homologue of Waardenburg syndrome type 1.

Splotch is considered a model of Waardenburg syndrome type I (WSI) because the abnormalities are caused by mutations in homologous genes, Pax-3 in mice and PAX3 (HuP2) in humans. We examined inner ear structure and function in Splotch mutants (Sp/+) and found no sign of auditory defects, in contrast to the deafness in many WSI individuals. The difference in expression of the genes in the two species may be due to different parts of the gene being mutated, or may result from variations in modifying influences as yet undefined.

Nonsyndromic hearing impairment is associated with a mutation in DFNA5.

Nonsyndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 loci mapped on the human genome, however, only a limited number of genes implicated in hearing loss have been identified. We previously reported linkage to chromosome 7p15 for autosomal dominant hearing impairment segregating in an extended Dutch family (DFNA5). Here, we report a further refinement of the DFNA5 candidate region and the isolation of a gene from this region that is expressed in the cochlea. In intron 7 of this gene, we identified an insertion/deletion mutation that does not affect intron-exon boundaries, but deletes five G-triplets at the 3' end of the intron. The mutation co-segregated with deafness in the family and causes skipping of exon 8, resulting in premature termination of the open reading frame. As no physiological function could be assigned, the gene was designated DFNA5.

Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment.

The tectorial membrane is an extracellular matrix of the inner ear that contacts the stereocilia bundles of specialized sensory hair cells. Sound induces movement of these hair cells relative to the tectorial membrane, deflects the stereocilia, and leads to fluctuations in hair-cell membrane potential, transducing sound into electrical signals. Alpha-tectorin is one of the major non-collagenous components of the tectorial membrane. Recently, the gene encoding mouse alpha-tectorin (Tecta) was mapped to a region of mouse chromosome 9, which shows evolutionary conservation with human chromosome 11q (ref. 3), where linkage was found in two families, one Belgian (DFNA12; ref. 4) and the other, Austrian (DFNA8; unpublished data), with autosomal dominant non-syndromic hearing impairment. We determined the complete sequence and the intron-exon structure of the human TECTA gene. In both families, mutation analysis revealed missense mutations which replace conserved amino-acid residues within the zona pellucida domain of TECTA. These findings indicate that mutations in TECTA are responsible for hearing impairment in these families, and implicate a new type of protein in the pathogenesis of hearing impairment.