Comparison of polychlorinated biphenyl levels across studies of human neurodevelopment.

Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain, and detectable amounts are in the blood of almost every person in most populations that have been examined. Extensive evidence from animal studies shows that PCBs are neurotoxins, even at low doses. Interpretation of human data regarding low-level, early-life PCB exposure and subsequent neurodevelopment is problematic because levels of exposure were not similarly quantified across studies. We expressed the exposure levels from 10 studies of PCB and neurodevelopment in a uniform manner using a combination of data from original investigators, laboratory reanalyses, calculations based on published data, and expert opinion. The mainstay of our comparison was the median level of PCB 153 in maternal pregnancy serum. The median concentration of PCB 153 in the 10 studies ranged from 30 to 450 ng/g serum lipid, and the median of the 10 medians was 110 ng/g. We found that (a)) the distribution of PCB 153 exposure in most studies overlapped substantially, (b)) exposure levels in the Faroe Islands study were about 3-4-fold higher than in most other studies, and (c)) the exposure levels in the two recent U.S. studies were about one-third of those in the four earlier U.S. studies or recent Dutch, German, and northern Québec studies. Our results will facilitate a direct comparison of the findings on PCBs and neurodevelopment when they are published for all 10 studies

Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression

A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense suppression and has been thought to mediate the insertion of near-cognate tRNAs at PTCs. However, direct evidence for this activity has been lacking. Here, we expressed multiple nonsense mutation reporters in human cells and yeast and identified the amino acids inserted when a PTC occupies the ribosomal A site in control, ataluren-treated, and aminoglycoside-treated cells. We find that ataluren\u27s likely target is the ribosome and that it produces full-length protein by promoting insertion of near-cognate tRNAs at the site of the nonsense codon without apparent effects on transcription, mRNA processing, mRNA stability, or protein stability. The resulting readthrough proteins retain function and contain amino acid replacements similar to those derived from endogenous readthrough, namely Gln, Lys, or Tyr at UAA or UAG PTCs and Trp, Arg, or Cys at UGA PTCs. These insertion biases arise primarily from mRNA:tRNA mispairing at codon positions 1 and 3 and reflect, in part, the preferred use of certain nonstandard base pairs, e.g., U-G. Ataluren\u27s retention of similar specificity of near-cognate tRNA insertion as occurs endogenously has important implications for its general use in therapeutic nonsense suppression

Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy – ACTG A5286

Background. Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART)

Development and assessment of a new framework for disease surveillance, prediction, and risk adjustment: the diagnostic items classification system

IMPORTANCE: Current disease risk-adjustment formulas in the US rely on diagnostic classification frameworks that predate the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). OBJECTIVE: To develop an ICD-10-CM-based classification framework for predicting diverse health care payment, quality, and performance outcomes. DESIGN SETTING AND PARTICIPANTS: Physician teams mapped all ICD-10-CM diagnoses into 3 types of diagnostic items (DXIs): main effect DXIs that specify diseases; modifiers, such as laterality, timing, and acuity; and scaled variables, such as body mass index, gestational age, and birth weight. Every diagnosis was mapped to at least 1 DXI. Stepwise and weighted least-squares estimation predicted cost and utilization outcomes, and their performance was compared with models built on (1) the Agency for Healthcare Research and Quality Clinical Classifications Software Refined (CCSR) categories, and (2) the Health and Human Services Hierarchical Condition Categories (HHS-HCC) used in the Affordable Care Act Marketplace. Each model's performance was validated using R 2, mean absolute error, the Cumming prediction measure, and comparisons of actual to predicted outcomes by spending percentiles and by diagnostic frequency. The IBM MarketScan Commercial Claims and Encounters Database, 2016 to 2018, was used, which included privately insured, full- or partial-year eligible enrollees aged 0 to 64 years in plans with medical, drug, and mental health/substance use coverage. MAIN OUTCOMES AND MEASURES: Fourteen concurrent outcomes were predicted: overall and plan-paid health care spending (top-coded and not top-coded); enrollee out-of-pocket spending; hospital days and admissions; emergency department visits; and spending for 6 types of services. The primary outcome was annual health care spending top-coded at $250 000. RESULTS: A total of 65 901 460 person-years were split into 90$5821 [$17 653]) selected 76% of the main effect DXIs with no evidence of overfitting. Validated R 2 was 0.589 in the DXI model, 0.539 for CCSR, and 0.428 for HHS-HCC. Use of DXIs reduced underpayment for enrollees with rare (1-in-a-million) diagnoses by 83% relative to HHS-HCCs. CONCLUSIONS: In this diagnostic modeling study, the new DXI classification system showed improved predictions over existing diagnostic classification systems for all spending and utilization outcomes considered.Published versio

Comparison of Polychlorinated Biphenyl Levels across Studies of Human Neurodevelopment

Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain, and detectable amounts are in the blood of almost every person in most populations that have been examined. Extensive evidence from animal studies shows that PCBs are neurotoxins, even at low doses. Interpretation of human data regarding low-level, early-life PCB exposure and subsequent neurodevelopment is problematic because levels of exposure were not similarly quantified across studies. We expressed the exposure levels from 10 studies of PCB and neurodevelopment in a uniform manner using a combination of data from original investigators, laboratory reanalyses, calculations based on published data, and expert opinion. The mainstay of our comparison was the median level of PCB 153 in maternal pregnancy serum. The median concentration of PCB 153 in the 10 studies ranged from 30 to 450 ng/g serum lipid, and the median of the 10 medians was 110 ng/g. We found that (a)) the distribution of PCB 153 exposure in most studies overlapped substantially, (b)) exposure levels in the Faroe Islands study were about 3-4-fold higher than in most other studies, and (c)) the exposure levels in the two recent U.S. studies were about one-third of those in the four earlier U.S. studies or recent Dutch, German, and northern Québec studies. Our results will facilitate a direct comparison of the findings on PCBs and neurodevelopment when they are published for all 10 studies

Degradation of YRA1 Pre-mRNA in the Cytoplasm Requires Translational Repression, Multiple Modular Intronic Elements, Edc3p, and Mex67p

The yeast YRA1 pre-mRNA contains multiple intronic elements that regulate transcript decay and translatability via the Edc3p decapping activator and the Mex67p/Mtr2p export receptor

Mutagenesis and Functional Studies with Succinate Dehydrogenase Inhibitors in the Wheat Pathogen Mycosphaerella graminicola

A range of novel carboxamide fungicides, inhibitors of the succinate dehydrogenase enzyme (SDH, EC 1.3.5.1) is currently being introduced to the crop protection market. The aim of this study was to explore the impact of structurally distinct carboxamides on target site resistance development and to assess possible impact on fitness

Black-carbon absorption enhancement in the atmosphere determined by particle mixing state

Atmospheric black carbon makes an important but poorly quantified contribution to the warming of the global atmosphere. Laboratory and modelling studies have shown that the addition of non-black-carbon materials to black-carbon particles may enhance the particles’ light absorption by 50 to 60% by refracting and reflecting light. Real-world experimental evidence for this ‘lensing’ effect is scant and conflicting, showing that absorption enhancements can be less than 5% or as large as 140%. Here we present simultaneous quantifications of the composition and optical properties of individual atmospheric black-carbon particles. We show that particles with a mass ratio of non-black carbon to black carbon of less than 1.5, which is typical of fresh traffic sources, are best represented as having no absorption enhancement. In contrast, black-carbon particles with a ratio greater than 3, which is typical of biomass-burning emissions, are best described assuming optical lensing leading to an absorption enhancement. We introduce a generalized hybrid model approach for estimating scattering and absorption enhancements based on laboratory and atmospheric observations. We conclude that the occurrence of the absorption enhancement of black-carbon particles is determined by the particles’ mass ratio of non-black carbon to black carbon

The Antarctic Impulsive Transient Antenna Ultra-high Energy Neutrino Detector Design, Performance, and Sensitivity for 2006-2007 Balloon Flight

We present a detailed report on the experimental details of the Antarctic Impulsive Transient Antenna (ANITA) long duration balloon payload, including the design philosophy and realization, physics simulations, performance of the instrument during its first Antarctic flight completed in January of 2007, and expectations for the limiting neutrino detection sensitivity. Neutrino physics results will be reported separately.Comment: 50 pages, 49 figures, in preparation for PR