LANGUAGE OUTCOMES IN SCHOOL-AGED CHILDREN ADOPTED FROM EASTERN EUROPEAN ORPHANAGES

Developmental studies by pediatricians and surveys of adoptive parents of children that have been adopted to the United States from foreign countries indicate that many of these children are experiencing substantial difficulties with the acquisition of their new language. Language difficulties may compromise the adopted child's abilities to understand, negotiate, and adjust to a new family and environment (Jenista, 1993). Reports range from 100% of the children having difficulties (Willig, 1995) to 34% (Groza,1995), with the majority of researchers reporting incidences in the 30-50% range (Johnson et al. 1996; Hough, 1996). These figures are in-line with research from countries such as Norway (Dalen, 2001a; Saetersdal & Dalen, 1987), Denmark (Rorbech, 1997) and Holland (Hoksbergen, 1997). To date, no studies directly assessing the language skills, long-term outcomes, or the types of language difficulties experienced by these children after experiencing an abrupt language switch have been completed. This study evaluated the language skills of a group of 44 school-aged, post-institutionalized Eastern European adoptees (EEA-PI) to determine the extent, and the types, of problems present in the areas of semantics, morphology, syntax, pragmatics, and reading, and explored the factors of institutionalization that might predict language development. Results showed that as a group, EEA-PI children, in comparison to the normative data on the standardized and spontaneous speech measures, performed lower than age expectations on all of the measures, with the exception of measures of listening (receptive language). The disparity within the group's performance was notable. Though institutional factors of time in institution, age of adoption, and time in U.S. did not correlate with measures of receptive and expressive language, they were significant for reading and nonword repetition scores. This research furthers our professional knowledge regarding long-term language outcomes and the selection of appropriate diagnostic measures for these children and other children experiencing early neglect in our country

Why are the 2-oxoacid dehydrogenase complexes so large? Generation of an active trimeric complex

The four-component polypeptides of the 2-oxoacid dehydrogenase complex from the thermophilic archaeon Thermoplasma acidophilum assemble to give an active multienzyme complex possessing activity with the branched-chain 2-oxoacids derived from leucine, isoleucine and valine, and with pyruvate. The dihydrolipoyl acyl-transferase (E2) core of the complex is composed of identical trimer-forming units that assemble into a novel 42-mer structure comprising octahedral and icosahedral geometric aspects. From our previously determined structure of this catalytic core, the inter-trimer interactions involve a tyrosine residue near the C-terminus secured in a hydrophobic pocket of an adjacent trimer like a ball-and-socket joint. In the present study, we have deleted the five C-terminal amino acids of the E2 polypeptide (IIYEI) and shown by equilibrium centrifugation that it now only assembles into a trimeric enzyme. This was confirmed by SAXS analysis, although this technique showed the presence of approximately 20% hexamers. The crystal structure of the trimeric truncated E2 core has been determined and shown to be virtually identical with the ones observed in the 42-mer, demonstrating that removal of the C-terminal anchor does not significantly affect the individual monomer or trimer structures. The truncated E2 is still able to bind both 2-oxoacid decarboxylase (E1) and dihydrolipoamide dehydrogenase (E3) components to give an active complex with catalytic activity similar to the native multienzyme complex. This is the first report of an active mini-complex for this enzyme, and raises the question of why all 2-oxoacid dehydrogenase complexes assemble into such large structures.</jats:p

A Multisite Study of Nurse-Reported Perceptions and Practice of ABCDEF Bundle Components

Objectives: ABCDEF bundle implementation in the Intensive Care Unit (ICU) is associated with dose dependent improvements in patient outcomes. The objective was to compare nurse attitudes about the ABCDEF bundle to self-reported adherence to bundle components. Research methodology/design: Cross-sectional study. Setting: Nurses providing direct patient care in 28 ICUs within 18 hospitals across the United States. Main outcome measures: 53-item survey of attitudes and practice of the ABCDEF bundle components was administered between November 2011 and August 2015 (n = 1661). Results: We did not find clinically significant correlations between nurse attitudes and adherence to Awakening trials, Breathing trials, and sedation protocol adherence (rs = 0.05-0.28) or sedation plan discussion during rounds and Awakening and Breathing trial Coordination (rs = 0.19). Delirium is more likely to be discussed during rounds when ICU physicians and nurse managers facilitate delirium reduction (rs = 0.27-0.36). Early mobilization is more likely to occur when ICU physicians, nurse managers, staffing, equipment, and the ICU environment facilitate early mobility (rs = 0.36-0.47). Physician leadership had the strongest correlation with reporting an ICU environment that facilitates ABCDEF bundle implementation (rs = 0.63-0.74). Conclusions: Nurse attitudes about bundle implementation did not predict bundle adherence. Nurse manager and physician leadership played a large role in creating a supportive ICU environment

Population exposure to trace elements in the Kilembe copper mine area, Western Uganda: a pilot study

The mining and processing of copper in Kilembe, Western Uganda, from 1956 to 1982 left over 15 Mt. of tailings containing cupriferous and cobaltiferous pyrite dumped within a mountain river valley. This pilot study was conducted to assess the nature and extent of risk to local populations from metal contamination arising from those mining activities. We determined trace element concentrations in mine tailings, soils, locally cultivated foods,house dust, drinking water and human biomarkers (toenails) using ICP-MS analysis of acid digested samples. The results showed that tailings, containing higher concentrations of Co, Cu, Ni and As compared with world average crust values had eroded and contaminated local soils. Pollution load indices revealed that 51% of agricultural soils sampled were contaminated with trace elements. Local water supplies were contaminated, with Co concentrations that exceeded Wisconsin (US) thresholds in 25% of domestic water supplies and 40% of Nyamwamba river water samples. Zinc exceeded WHO/FAO thresholds of 99.4 mg kg−1 in 36% of Amaranthus vegetable samples, Cu exceeded EC thresholds of 20 mg kg−1 in 19% of Amaranthus while Pb exceeded WHO thresholds of 0.3 mg kg−1 in 47% of Amaranthus vegetables. In bananas, 20% of samples contained Pb concentrations that exceeded the WHO/FAO recommended threshold of 0.3 mg kg−1. However, risk assessment of local foods and water, based on hazard quotients (HQ values) revealed no potential health effects. The high external contamination of volunteers' toenails with some elements (even after a washing process) calls into question their use as a biomarker for metal exposure in human populations where feet are frequently exposed to soil

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects