Measurements of neutrino oscillation parameters from the T2K experiment using 3.6×1021 protons on target.

The T2K experiment presents new measurements of neutrino oscillation parameters using 19.7(16.3)×1020 protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional 4.7×1020 POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on sin2θ13 and the impact of priors on the δCP measurement. Both analyses prefer the normal mass ordering and upper octant of sin2θ23 with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on sin2θ13 from reactors, sin2θ23=0.561-0.032+0.021 using Feldman-Cousins corrected intervals, and Δm322=2.494-0.058+0.041×10-3eV2 using constant Δχ2 intervals. The CP-violating phase is constrained to δCP=-1.97-0.70+0.97 using Feldman-Cousins corrected intervals, and δCP=0,π is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than 2σ credible level using a flat prior in δCP, and just below 2σ using a flat prior in sinδCP. When the external constraint on sin2θ13 is removed, sin2θ13=28.0-6.5+2.8×10-3, in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses.

Matrix Matters: Assessment of Commutability among BK Virus Assays and Standards.

Quantitative testing of BK virus (BKPyV) nucleic acid has become the standard of care in transplant patients. While the relationship between interassay harmonization and commutability has been well characterized for other transplant-related viruses, it has been less well studied for BKPyV, particularly regarding differences in commutability between matrices. Here, interassay agreement was evaluated among six real-time nucleic acid amplification tests (NAATs) and one digital PCR (dPCR) BKPyV assay. Differences in the commutability of three quantitative standards was examined across all assays using a variety of statistical approaches. Panels, including 40 samples each of plasma and urine samples previously positive for BKPyV, together with one previously negative plasma sample and four previously negative urine samples, were tested using all assays, with each real-time NAAT utilizing its usual quantitative calibrators. Serial dilutions of WHO, National Institute for Standards and Technology (NIST), and commercially produced (Exact/Bio-Rad) reference materials were also run by each assay as unknowns. The agreement of the clinical sample values was assessed as a group and in a pairwise manner. The commutability was estimated using both relativistic and quantitative means. The quantitative agreement across assays in the urine samples was within a single log10 unit across all assays, while the results from the plasma samples varied by 2 to 3 log10 IU/mL. The commutability showed a similar disparity between the matrices. Recalibration using international standards diminished the resulting discrepancies in some but not all cases. Differences in the sample matrix can affect the commutability and interassay agreement of quantitative BKPyV assays. Differences in commutability between matrices may largely be due to factors other than those such as amplicon size, previously described as important in the case of cytomegalovirus. Continued efforts to standardize viral load measurements must address multiple sources of variability and account for differences in assay systems, quantitative standards, and sample matrices.

Impact of Fragmentation on Commutability of Epstein-Barr Virus and Cytomegalovirus Quantitative Standards.

Despite the adaptation of international standards, quantitative viral load testing of transplant-associated viruses continues to be limited by interlaboratory disagreement. Studies have suggested that this disagreement and the poor commutability of standards may, in some cases, be linked to amplicon size and the fragmentation of circulating viral DNA. We evaluated target fragmentation as a cause of noncommutability and pretest fragmentation of quantitative standards as a potential means of increasing commutability and interassay agreement. Forty-two cytomegalovirus (CMV)-positive and 41 Epstein-Barr virus (EBV)-positive plasma samples, together with two different quantitative standards for each virus, were tested as unknowns using 10 different quantitative PCR assays at 5 different laboratories. Standards were tested both intact and after intentional fragmentation by ultrasonication. Quantitative agreement between methods was assessed, together with commutability, using multiple statistical approaches. Most assays yielded results within 0.5 log10 IU/ml of the mean for CMV, while for EBV a greater variability of up to 1.5 log10 IU/ml of the mean was shown. Commutability showed marked improvement following fragmentation of both CMV standards but not after fragmentation of the EBV standards. These findings confirm the impact of amplicon size and target fragmentation on commutability for CMV and suggest that for some (but not all) viruses, interlaboratory harmonization can be improved through the use of fragmented quantitative standards.

Interobserver agreement of an electronic von Frey device for measuring mechanical sensory thresholds in normal dogs.

Electronic von Frey Aesthesiometry (VFA) has been previously reported as a useful method of mechanical quantitative sensory testing (QST) for evaluating neuropathic pain in dogs. Intraobserver agreement has been shown to be good to excellent; however, interobserver agreement has not been evaluated and is vital to the use of this technique in multicenter veterinary clinical trials in neuropathic pain. The goal of this study was to evaluate the interobserver agreement of sensory thresholds obtained using electronic VFA in a group of normal small breed dogs. Twenty healthy dogs (<20 kg) were recruited from the general practice population at the Ohio State University Veterinary Medical Center. Three clinically experienced yet QST novice evaluators used an electronic von Frey device to measure mechanical sensory threshold (ST) after a standardised training session conducted by an expert evaluator. Each dog was assessed by all three evaluators on the same day with both evaluator and limb test order randomised and testing sessions separated by 5 min. Mean ST values were averaged for all four limbs to produce a single value per dog for comparison between evaluators. Agreement between evaluators was determined using the intra-class correlation coefficient (ICC; two-way model for consistency, single measures). ICC across all three evaluators was 0.48, indicating moderate agreement. Moderate interobserver agreement is not sufficient to support the use of this technique in multi-center clinical trials, and our results underscore the importance of using a single evaluator for this QST technique until better agreement can be demonstrated.

Maternal and child health after injuries: a two-year follow-up of a nationally representative sample.

OBJECTIVE: The objective of this study was to examine the association between childhood injury and health outcomes among survivors and their mothers using a national survey in the United States (US). STUDY DESIGN: This was a longitudinal analysis of a nationally representative sample. METHODS: Secondary analysis of the 1997-2013 Medical Expenditure Panel Survey (MEPS) was performed. Children (aged 2-18 years) with or without injuries were followed up for two years. Injuries captured in the study were those associated with at least one hospitalization, emergency department visit, or office-based visit. Outcome measures were child and maternal general and mental health status. Multiple mixed-logistic regressions were used with suboptimal health defined as the response of poor or fair health versus good, very good, or excellent health. RESULTS: Of the 63,422 children analyzed, 3251 (4.9%) were injured, representing 3.6 million US children. Injured children were more likely to be male, white, and older than those without injuries (P < 0.01). About a fifth of injured children suffered head injuries. Injuries were strongly associated with suboptimal general and mental health status in children (adjusted odds ratios [AORs], 1.35 and 1.36, respectively, P < 0.05). Mothers of children with injuries were also more likely to report suboptimal mental health (AOR, 1.30, P < 0.05). CONCLUSION: Injuries among children are associated with lasting adverse effects in general and mental health. To improve health outcomes of pediatric injuries, further follow-up care may be needed to ensure that they return to pre-injury health levels. These results highlight the importance of primary prevention and the long-term impact of injuries on the health of children and their mothers.

Investigation of Feshbach resonances in ultracold 40K spin mixtures.

Magnetically tunable Feshbach resonances are an indispensable tool for experiments with atomic quantum gases. We report on 37 thus far unpublished Feshbach resonances and four further probable Feshbach resonances in spin mixtures of ultracold fermionic 40K with temperatures well below 100 nK. In particular, we locate a broad resonance at B = 389.7G with a magnetic width of 26.7 G. Here 1 G = 10-4 T. Furthermore, by exciting low-energy spin waves, we demonstrate a means to precisely determine the zero crossing of the scattering length for this broad Feshbach resonance. Our findings allow for further tunability in experiments with ultracold 40K quantum gases.

No difference found in time to publication by statistical significance of trial results: a methodological review.

OBJECTIVE: Time-lag from study completion to publication is a potential source of publication bias in randomised controlled trials. This study sought to update the evidence base by identifying the effect of the statistical significance of research findings on time to publication of trial results. DESIGN: Literature searches were carried out in four general medical journals from June 2013 to June 2014 inclusive (BMJ, JAMA, the Lancet and the New England Journal of Medicine). SETTING: Methodological review of four general medical journals. PARTICIPANTS: Original research articles presenting the primary analyses from phase 2, 3 and 4 parallel-group randomised controlled trials were included. MAIN OUTCOME MEASURES: Time from trial completion to publication. RESULTS: The median time from trial completion to publication was 431 days (n = 208, interquartile range 278-618). A multivariable adjusted Cox model found no statistically significant difference in time to publication for trials reporting positive or negative results (hazard ratio: 0.86, 95% CI 0.64 to 1.16, p = 0.32). CONCLUSION: In contrast to previous studies, this review did not demonstrate the presence of time-lag bias in time to publication. This may be a result of these articles being published in four high-impact general medical journals that may be more inclined to publish rapidly, whatever the findings. Further research is needed to explore the presence of time-lag bias in lower quality studies and lower impact journals.

A review of the genus Capulinia Signoret (Hemiptera: Coccoidea: Eriococcidae) with description of two new species.

The eriococcid genus Capulinia Signoret currently comprises four Neotropical species (the type species C. sallei Signoret, C. crateraformis Hempel, C. jaboticabae Ihering and an undescribed species recognised in the literature) and one species from New Zealand (C. orbiculata Hoy). All species feed on plants in the family Myrtaceae and the undescribed species is a pest of guava, Psidium guajava, in Venezuela and Colombia. Here we describe the pest species based on the adult female and first-instar nymph and name it Capulinia linarosae Kondo & Gullan sp. n. We provide a summary of published information on the biology and pest status of C. linarosae by translating the Spanish literature. We also describe the adult female and first-instar nymph of a new Argentine species that we name as C. luma Kondo & Gullan sp. n. after its host Luma apiculata. In addition, we redescribe the adult female of C. jaboticabae and include notes on C. crateraformis, C. orbiculata and C. sallei. We provide a revised generic diagnosis and keys to all Capulinia species based on adult females and, where available, first-instar nymphs, as well as a revised key to South American eriococcid genera. Phylogenetic analyses of 18S rDNA place Capulinia within the "Gondwanan" clade of eriococcids, mostly likely within the Myrtaceae-feeding group.

How antigen specificity directs regulatory T-cell function: self, foreign and engineered specificity.

Regulatory T cells (Tregs) are a suppressive subset of T cells that have important roles in maintaining self-tolerance and preventing immunopathology. The T-cell receptor (TCR) and its antigen specificity play a dominant role in the differentiation of cells to a Treg fate, either in the thymus or in the periphery. This review focuses on the effects of the TCR and its antigen specificity on Treg biology. The role of Tregs with specificity for self-antigen has primarily been studied in the context of autoimmune disease, although recent studies have focused on their role in steady-state conditions. The role of Tregs that are specific for pathogens, dietary antigens and allergens is much less studied, although recent data suggest a significant and previously underappreciated role for Tregs during memory responses to a wide range of foreign antigens. The development of TCR- or chimeric antigen receptor (CAR)-transduced T cells means we are now able to engineer Tregs with disease-relevant antigen specificities, paving the way for ensuring specificity with Treg-based therapies. Understanding the role that antigens play in driving the generation and function of Tregs is critical for defining the pathophysiology of many immune-mediated diseases, and developing new therapeutic interventions.

Kinematic Magnetic Resonance Imaging for Evaluation of Disc-Associated Cervical Spondylomyelopathy in Doberman Pinschers.

BACKGROUND: The dynamic component of disc-associated cervical spondylomyelopathy (DA-CSM) currently is evaluated using traction magnetic resonance imaging (MRI), which does not assess changes in flexion and extension of the cervical vertebral column. In humans with cervical spondylotic myelopathy, kinematic MRI is used to identify dynamic compressions. HYPOTHESIS/OBJECTIVES: To evaluate the feasibility and utility of kMRI in Doberman Pinschers with DA-CSM using a novel positioning device. We hypothesized that kMRI would identify compressive lesions not observed with neutral positioning and change the dimensions of the spinal cord and cervical vertebral canal. ANIMALS: Nine client-owned Doberman Pinschers with DA-CSM. METHODS: Prospective study. After standard MR imaging of the cervical spine confirmed DA-CSM, dogs were placed on a positioning device to allow imaging in flexion and extension. Morphologic and morphometric assessments were compared between neutral, flexion, and extension images. RESULTS: Flexion was associated with improvement or resolution of spinal cord compression in 4/9 patients, whereas extension caused worsening of compressions in 6/9 patients. Extension identified 6 new compressive lesions and was significantly associated with dorsal and ventral compression at C5-C6 (P = .021) and C6-C7 (P = .031). A significant decrease in spinal cord height occurred at C6-C7 from neutral to extension (P = .003) and in vertebral canal height at C5-C6 and C6-C7 from neutral to extension (P = .011 and .017, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Our results suggest that kMRI is feasible and provides additional information beyond what is observed with neutral imaging, primarily when using extension views, in dogs with DA-CSM.

Dietary fibre linked to decreased inflammation in overweight minority youth.

OBJECTIVE: The objective of this study was to examine the relationship between diet and inflammation, and adiposity in minority youth. DESIGN AND METHODS: The study was designed as a cross-sectional analysis of 142 overweight (≥85th body mass index percentile) Hispanic and African-American adolescents (14-18 years) with the following measures: anthropometrics, adiposity via magnetic resonance imaging, dietary intake via 24-h dietary recalls, and inflammation markers from fasting blood draws utilizing a multiplex panel. Partial correlations were estimated and analysis of covariance (ancova) models fit to examine the relationship among dietary variables, inflammation markers and adiposity measures with the following a priori covariates: Tanner stage, ethnicity, sex, total energy intake, total body fat and total lean mass. RESULTS: Inference based on ancova models showed that the highest tertile of fibre intake (mean intake of 21.3 ± 6.1 g d(-1) ) vs. the lowest tertile of fibre intake (mean intake of 7.4 ± 1.8 g d(-1) ) was associated with 36% lower plasminogen activator inhibitor-1 (P = 0.02) and 43% lower resistin (P = 0.02), independent of covariates. Similar results were seen for insoluble fibre. No other dietary variables included in this study were associated with inflammation markers. CONCLUSIONS: These results suggest that increases in dietary fibre could play an important role in lowering inflammation and therefore metabolic disease risk in high-risk minority youth.

Immune Compromise in HIV-1/HTLV-1 Coinfection With Paradoxical Resolution of CD4 Lymphocytosis During Antiretroviral Therapy: A Case Report.

Human immunodeficiency virus type-1 (HIV-1) and human T lymphotropic virus type-1 (HTLV-1) infections have complex effects on adaptive immunity, with specific tropism for, but contrasting effects on, CD4 T lymphocytes: depletion with HIV-1, proliferation with HTLV-1. Impaired T lymphocyte function occurs early in HIV-1 infection but opportunistic infections (OIs) rarely occur in the absence of CD4 lymphopenia. In the unusual case where a HIV-1 infected individual with a high CD4 count presents with recurrent OIs, a clinician is faced with the possibility of a second underlying comorbidity. We present a case of pseudo-adult T cell leukemia/lymphoma (ATLL) in HIV-1/HTLV-1 coinfection where the individual fulfilled Shimoyama criteria for chronic ATLL and had pulmonary Mycobacterium kansasii, despite a high CD4 lymphocyte count. However, there was no evidence of clonal T-cell proliferation by T-cell receptor gene rearrangement studies nor of monoclonal HTLV-1 integration by high-throughput sequencing. Mutually beneficial interplay between HIV-1 and HTLV-1, maintaining high level HIV-1 and HTLV-1 viremia and proliferation of poorly functional CD4 cells despite chronicity of infection is a postulated mechanism. Despite good microbiological response to antimycobacterial therapy, the patient remained systemically unwell with refractory anemia. Subsequent initiation of combined antiretroviral therapy led to paradoxical resolution of CD4 T lymphocytosis as well as HIV-1 viral suppression and decreased HTLV-1 proviral load. This is proposed to be the result of attenuation of immune activation post-HIV virological control. This case illustrates the importance of screening for HTLV-1 in HIV-1 patients with appropriate clinical presentation and epidemiological risk factors and explores mechanisms for the complex interactions on HIV-1/HTLV-1 adaptive immunity.

Commutability of the First World Health Organization International Standard for Human Cytomegalovirus.

Quantitative detection of cytomegalovirus (CMV) DNA has become a standard part of care for many groups of immunocompromised patients; recent development of the first WHO international standard for human CMV DNA has raised hopes of reducing interlaboratory variability of results. Commutability of reference material has been shown to be necessary if such material is to reduce variability among laboratories. Here we evaluated the commutability of the WHO standard using 10 different real-time quantitative CMV PCR assays run by eight different laboratories. Test panels, including aliquots of 50 patient samples (40 positive samples and 10 negative samples) and lyophilized CMV standard, were run, with each testing center using its own quantitative calibrators, reagents, and nucleic acid extraction methods. Commutability was assessed both on a pairwise basis and over the entire group of assays, using linear regression and correspondence analyses. Commutability of the WHO material differed among the tests that were evaluated, and these differences appeared to vary depending on the method of statistical analysis used and the cohort of assays included in the analysis. Depending on the methodology used, the WHO material showed poor or absent commutability with up to 50% of assays. Determination of commutability may require a multifaceted approach; the lack of commutability seen when using the WHO standard with several of the assays here suggests that further work is needed to bring us toward true consensus.

Key innovation or adaptive change? A test of leaf traits using Triodiinae in Australia.

The evolution of novel traits ("key innovations") allows some lineages to move into new environments or adapt to changing climates, whereas other lineages may track suitable habitat or go extinct. We test whether, and how, trait shifts are linked to environmental change using Triodiinae, C4 grasses that form the dominant understory over about 30% of Australia. Using phylogenetic and relaxed molecular clock estimates, we assess the Australian biogeographic origins of Triodiinae and reconstruct the evolution of stomatal and vascular bundle positioning. Triodiinae diversified from the mid-Miocene, coincident with the aridification of Australia. Subsequent niche shifts have been mostly from the Eremaean biome to the savannah, coincident with the expansion of the latter. Biome shifts are correlated with changes in leaf anatomy and radiations within Triodiinae are largely regional. Symplectrodia and Monodia are nested within Triodia. Rather than enabling biome shifts, convergent changes in leaf anatomy have probably occurred after taxa moved into the savannah biome-they are likely to have been subsequent adaptions rather than key innovations. Our study highlights the importance of testing the timing and origin of traits assumed to be phenotypic innovations that enabled ecological shifts.

Assessing the Performance of Clostridium perfringens Cooling Models for Cooked, Uncured Meat and Poultry Products.

Heat-resistant spores of Clostridium perfringens may germinate and multiply in cooked meat and poultry products when the rate and extent of cooling does not occur in a timely manner. Therefore, six cooling models (PMP 7.0 broth model; PMIP uncured beef, chicken, and pork models; Smith-Schaffner version 3; and UK IFR ComBase Perfringens Predictor) were evaluated for relative performance in predicting growth of C. perfringens under dynamic temperature conditions encountered during cooling of cooked, uncured meat and poultry products. The predicted growth responses from the models were extensively compared with those observed in food. Data from 188 time-temperature cooling profiles (176 for single-rate exponential cooling and 12 for dual-rate exponential cooling) were collected from 17 independent sources (16 peer-reviewed publications and one report) for model evaluation. Data were obtained for a variety of cooked products, including meat and poultry slurries, ground meat and poultry products with and without added ingredients (e.g., potato starch, sodium triphosphate, and potassium tetrapyrophosphate), and processed products such as ham and roast beef. Performance of the models was evaluated using three sets of criteria, and accuracy was defined within a 1- to 2-log range. The percentages of accurate, fail-safe, or fail-dangerous predictions for each cooling model differed depending on which criterion was used to evaluate the data set. Nevertheless, the combined percentages of accurate and fail-safe predictions based on the three performance criteria were 34.66 to 42.61% for the PMP 7.0 beef broth model, 100% for the PMIP cooling models for uncured beef, uncured pork and uncured chicken, 80.11 to 93.18% for the Smith-Schaffner cooling model, and 74.43 to 85.23% for the UK IFR ComBase Perfringens Predictor model during single-rate exponential chilling. Except for the PMP 7.0 broth model, the other five cooling models (PMIP, Smith-Schaffner, and UK IFR ComBase) are useful and reliable tools that food processors and regulatory agencies can use to evaluate the safety of cooked or heat-treated uncured meat and poultry products exposed to cooling deviations or to develop customized cooling schedules.

Conditioning with rabbit versus horse ATG dramatically alters clinical outcomes in identical twins with severe aplastic anemia transplanted with the same allogeneic donor.

Severe aplastic anemia (SAA) is a rare disorder leading to bone marrow failure, which if left untreated, is invariably fatal. Conventional therapies with immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation (HSCT) are highly effective. HSCT can offer a greater outcome in younger patients who have an available HLA match-related donor. Recent studies showing the addition of antithymocyte globulin (ATG) to the conditioning regimen improves engraftment and reduces the risk of graft-versus-host disease (GVHD).There are currently two ATG preparations in the USA, equine (or horse) and rabbit ATG. These agents are pharmacologically distinct, having significant differences in their pharmacokinetics and in vivo immunosuppressive effects [N Engl J Med 365(5):430-438, 2011]. Here, we report a case of two monozygotic twins with constitutional SAA that evolved to myelodysplastic syndrome (MDS) who both underwent allogeneic peripheral blood stem cell transplantation (PBSC) from the same single HLA antigen mismatched sibling donor with the only difference in the transplant regimen being the type of ATG used in the preparative regimen; one twin received horse ATG and the other received rabbit ATG during conditioning. This report emphasizes that dramatic differences in donor T cell chimerism and clinical outcomes including GVHD can occur as a consequence of the type of ATG that is utilized in the transplant conditioning regimen. These differences highlight that these agents should not be considered interchangeable drugs when used in this setting.

Linked Records of Children with Traumatic Brain Injury. Probabilistic Linkage without Use of Protected Health Information.

OBJECTIVE: Record linkage may create powerful datasets with which investigators can conduct comparative effectiveness studies evaluating the impact of tests or interventions on health. All linkages of health care data files to date have used protected health information (PHI) in their linkage variables. A technique to link datasets without using PHI would be advantageous both to preserve privacy and to increase the number of potential linkages. METHODS: We applied probabilistic linkage to records of injured children in the National Trauma Data Bank (NTDB, N = 156,357) and the Pediatric Health Information Systems (PHIS, N = 104,049) databases from 2007 to 2010. 49 match variables without PHI were used, many of them administrative variables and indicators for procedures recorded as International Classification of Diseases, 9th revision, Clinical Modification codes. We validated the accuracy of the linkage using identified data from a single center that submits to both databases. RESULTS: We accurately linked the PHIS and NTDB records for 69% of children with any injury, and 88% of those with severe traumatic brain injury eligible for a study of intervention effectiveness (positive predictive value of 98%, specificity of 99.99%). Accurate linkage was associated with longer lengths of stay, more severe injuries, and multiple injuries. CONCLUSION: In populations with substantial illness or injury severity, accurate record linkage may be possible in the absence of PHI. This methodology may enable linkages and, in turn, comparative effectiveness studies that would be unlikely or impossible otherwise.