Precision, Reliability, and Responsiveness of a Novel Automated Quantification Tool for Cartilage Thickness: Data from the Osteoarthritis Initiative

Objective; Accurate automated segmentation of cartilage should provide rapid reliable outcomes for both epidemiological studies and clinical trials. We aimed to assess the precision and responsiveness of cartilage thickness measured with careful manual segmentation or a novel automated technique. Methods; Agreement of automated segmentation was assessed against two manual segmentation datasets: 379 MR images manually segmented in-house (Training set), and 582 from the OAI with data available at 0, 1, and 2 years (Biomarkers set). Agreement of mean thickness was assessed using Bland-Altman plots, change with pairwise Students t-test, in the central medial femur and tibia regions (cMF, cMT). Repeatability was assessed on a set of 19 knees imaged twice on the same day. Responsiveness was assessed using standardised response means (SRMs). Results; Agreement of manual vs automated methods was excellent with no meaningful systematic bias (Training set cMF bias 0.1mm 95%CI ±0.35, Biomarkers set bias 0.1mm ±0.4). The smallest detectable difference (SDD) for cMF was 0.13mm, coefficient of variation (CoV) 3.1%; cMT 0.16 mm, 2.65%. Reported change using manual segmentations in the cMF region at 1 year was -0.031mm, confidence limit (-0.022, -0.039), p<10-4, SRM -0.31 (-0.23,-0.38); at 2 years was -0.071 (-0.058,-0.085), p<10-4, SRM -0.43(-0.36,-0.49). Reported change using automated segmentations in the cMF at 1 year was - 0.059 (-0.047, -0.071), p<10-4, SRM -0.41(-0.34,-0.48) ; 2 years: -0.14 (-0.123,-0.157), p<10-4, SRM -0.67 (-0.6,-0.72). Conclusion; A novel cartilage segmentation method provides highly accurate and repeatable measures with comparable cartilage thickness measurements to careful manual segmentation, but with improved responsiveness

Dopamine restores reward prediction errors in old age.

Senescence affects the ability to utilize information about the likelihood of rewards for optimal decision-making. Using functional magnetic resonance imaging in humans, we found that healthy older adults had an abnormal signature of expected value, resulting in an incomplete reward prediction error (RPE) signal in the nucleus accumbens, a brain region that receives rich input projections from substantia nigra/ventral tegmental area (SN/VTA) dopaminergic neurons. Structural connectivity between SN/VTA and striatum, measured by diffusion tensor imaging, was tightly coupled to inter-individual differences in the expression of this expected reward value signal. The dopamine precursor levodopa (L-DOPA) increased the task-based learning rate and task performance in some older adults to the level of young adults. This drug effect was linked to restoration of a canonical neural RPE. Our results identify a neurochemical signature underlying abnormal reward processing in older adults and indicate that this can be modulated by L-DOPA

A new hammer to crack an old nut : interspecific competitive resource capture by plants is regulated by nutrient supply, not climate

Peer reviewedPublisher PD

Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy.

OBJECTIVE: To explore the diagnostic utility and cost effectiveness of whole exome sequencing (WES) in a cohort of individuals with peripheral neuropathy. METHODS: Singleton WES was performed in individuals recruited though one pediatric and one adult tertiary center between February 2014 and December 2015. Initial analysis was restricted to a virtual panel of 55 genes associated with peripheral neuropathies. Patients with uninformative results underwent expanded analysis of the WES data. Data on the cost of prior investigations and assessments performed for diagnostic purposes in each patient was collected. RESULTS: Fifty patients with a peripheral neuropathy were recruited (median age 18 years; range 2-68 years). The median time from initial presentation to study enrollment was 6 years 9 months (range 2 months-62 years), and the average cost of prior investigations and assessments for diagnostic purposes AU$4013 per patient. Eleven individuals received a diagnosis from the virtual panel. Eight individuals received a diagnosis following expanded analysis of the WES data, increasing the overall diagnostic yield to 38%. Two additional individuals were diagnosed with pathogenic copy number variants through SNP microarray. CONCLUSIONS: This study provides evidence that WES has a high diagnostic utility and is cost effective in patients with a peripheral neuropathy. Expanded analysis of WES data significantly improves the diagnostic yield in patients in whom a diagnosis is not found on the initial targeted analysis. This is primarily due to diagnosis of conditions caused by newly discovered genes and the resolution of complex and atypical phenotypes

The DREEM, part 1: measurement of the educational environment in an osteopathy teaching program

Background Measurement of the educational environment has become more common in health professional education programs. Information gained from these investigations can be used to implement and measure changes to the curricula, educational delivery and the physical environment. A number of questionnaires exist to measure the educational environment, and the most commonly utilised of these is the Dundee Ready Educational Environment Measure (DREEM). Methods The DREEM was administered to students in all year levels of the osteopathy program at Victoria University (VU), Melbourne, Australia. Students also completed a demographic survey. Inferential and correlational statistics were employed to investigate the educational environment based on the scores obtained from the DREEM. Results A response rate of 90% was achieved. The mean total DREEM score was 135.37 (+/- 19.33) with the scores ranging from 72 to 179. Some subscales and items demonstrated differences for gender, clinical phase, age and whether the student was in receipt of a government allowance. Conclusions There are a number of areas in the program that are performing well, and some aspects that could be improved. Overall students rated the VU osteopathy program as more positive than negative. The information obtained in the present study has identified areas for improvement and will enable the program leaders to facilitate changes. It will also provide other educational institutions with data on which they can make comparisons with their own programs

Focal Distribution of Hepatitis C Virus RNA in Infected Livers

Background: Hepatitis C virus (HCV) is a plus-strand RNA virus that replicates by amplification of genomic RNA from minus strands leading to accumulation of almost one thousand copies per cell under in vitro cell culture conditions. In contrast, HCV RNA copy numbers in livers of infected patients appear to be much lower, estimated at a few copies per cell. Methodology/Principal Findings: To gain insights into mechanisms that control HCV replication in vivo, we analyzed HCV RNA levels as well as expression of interferon beta (IFNb) and several interferon stimulated genes (ISGs) from whole liver sections and micro-dissected subpopulations of hepatocytes in biopsy samples from 21 HCV-infected patients. The results showed that intrahepatic HCV RNA levels range form less than one copy per hepatocyte to a maximum of about eight. A correlation existed between viral RNA levels and IFNb expression, but not between viral RNA and ISG levels. Also, IFNb expression did not correlate with ISGs levels. Replication of HCV RNA occurred in focal areas in the liver in the presence of a general induction of ISGs. Conclusion/Significance: The low average levels of HCV RNA in biopsy samples can be explained by focal distribution of infected hepatocytes. HCV replication directly induces IFNb, which then activates ISGs. The apparent lack of a correlation between levels of IFNb and ISG expression indicates that control of the innate immune response during HCV infection

Quantum numbers of the X(3872)X(3872) state and orbital angular momentum in its ρ0Jψ\rho^0 J\psi decay

Angular correlations in $B^+\to X(3872) K^+$ decays, with $X(3872)\to \rho^0 J/\psi$, $\rho^0\to\pi^+\pi^-$ and $J/\psi \to\mu^+\mu^-$, are used to measure orbital angular momentum contributions and to determine the $J^{PC}$ value of the $X(3872)$ meson. The data correspond to an integrated luminosity of 3.0 fb$^{-1}$ of proton-proton collisions collected with the LHCb detector. This determination, for the first time performed without assuming a value for the orbital angular momentum, confirms the quantum numbers to be $J^{PC}=1^{++}$. The $X(3872)$ is found to decay predominantly through S wave and an upper limit of $4\%$ at $95\%$ C.L. is set on the fraction of D wave.Comment: 16 pages, 4 figure

FAM5C Contributes to Aggressive Periodontitis

Aggressive periodontitis is characterized by a rapid and severe periodontal destruction in young systemically healthy subjects. A greater prevalence is reported in Africans and African descendent groups than in Caucasians and Hispanics. We first fine mapped the interval 1q24.2 to 1q31.3 suggested as containing an aggressive periodontitis locus. Three hundred and eighty-nine subjects from 55 pedigrees were studied. Saliva samples were collected from all subjects, and DNA was extracted. Twenty-one single nucleotide polymorphisms were selected and analyzed by standard polymerase chain reaction using TaqMan chemistry. Non-parametric linkage and transmission distortion analyses were performed. Although linkage results were negative, statistically significant association between two markers, rs1935881 and rs1342913, in the FAM5C gene and aggressive periodontitis (p = 0.03) was found. Haplotype analysis showed an association between aggressive periodontitis and the haplotype A-G (rs1935881-rs1342913; p = 0.009). Sequence analysis of FAM5C coding regions did not disclose any mutations, but two variants in conserved intronic regions of FAM5C, rs57694932 and rs10494634, were found. However, these two variants are not associated with aggressive periodontitis. Secondly, we investigated the pattern of FAM5C expression in aggressive periodontitis lesions and its possible correlations with inflammatory/immunological factors and pathogens commonly associated with periodontal diseases. FAM5C mRNA expression was significantly higher in diseased versus healthy sites, and was found to be correlated to the IL-1β, IL-17A, IL-4 and RANKL mRNA levels. No correlations were found between FAM5C levels and the presence and load of red complex periodontopathogens or Aggregatibacter actinomycetemcomitans. This study provides evidence that FAM5C contributes to aggressive periodontitis

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

High CO2 and Silicate Limitation Synergistically Increase the Toxicity of Pseudo-nitzschia fraudulenta

Anthropogenic CO2 is progressively acidifying the ocean, but the responses of harmful algal bloom species that produce toxins that can bioaccumulate remain virtually unknown. The neurotoxin domoic acid is produced by the globally-distributed diatom genus Pseudo-nitzschia. This toxin is responsible for amnesic shellfish poisoning, which can result in illness or death in humans and regularly causes mass mortalities of marine mammals and birds. Domoic acid production by Pseudo-nitzschia cells is known to be regulated by nutrient availability, but potential interactions with increasing seawater CO2 concentrations are poorly understood. Here we present experiments measuring domoic acid production by acclimatized cultures of Pseudo-nitzschia fraudulenta that demonstrate a strong synergism between projected future CO2 levels (765 ppm) and silicate-limited growth, which greatly increases cellular toxicity relative to growth under modern atmospheric (360 ppm) or pre-industrial (200 ppm) CO2 conditions. Cellular Si∶C ratios decrease with increasing CO2, in a trend opposite to that seen for domoic acid production. The coastal California upwelling system where this species was isolated currently exhibits rapidly increasing levels of anthropogenic acidification, as well as widespread episodic silicate limitation of diatom growth. Our results suggest that the current ecosystem and human health impacts of toxic Pseudo-nitzschia blooms could be greatly exacerbated by future ocean acidification and ‘carbon fertilization’ of the coastal ocean