Chemical Abundances of the Leo II Dwarf Galaxy

We use previously-published moderate-resolution spectra in combination with stellar atmosphere models to derive the first measured chemical abundance ratios in the Leo II dSph galaxy. We find that for spectra with SNR > 24, we are able to measure abundances from weak Ti, Fe and Mg lines located near the calcium infrared triplet (CaT). We also quantify and discuss discrepancies between the metallicities measured from Fe I lines and those estimated from the CaT features. We find that while the most metal-poor ([Fe/H] <-2.0]) Leo II stars have Ca and Ti abundance ratios similar to those of Galactic globular clusters, the more metal-rich stars show a gradual decline of Ti, Mg and Ca abundance ratio with increasing metallicity. Finding these trends in this distant and apparently dynamically stable dSph galaxy supports the hypothesis that the slow chemical enrichment histories of the dSph galaxies is universal, independent of any interaction with the Milky Way. Combining our spectroscopic abundances with published broadband photometry and updated isochrones, we are able to approximate stellar ages for our bright RGB stars to a relative precision of 2-3 Gyr. While the derived age-metallicity relationship of Leo II hints at some amount of slow enrichment, the data are still statistically consistent with no enrichment over the history of Leo II.Comment: Accepted to A

High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington\u27s disease CAG knock-in mice across multiple genetic backgrounds.

Huntington\u27s disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+  mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis

Regional Systems of Care Demonstration Project: American Heart Association Mission: Lifeline STEMI Systems Accelerator.

BACKGROUND: Up to 50% of patients fail to meet ST-segment-elevation myocardial infarction (STEMI) guideline goals recommending a first medical contact-to-device time of <90 minutes for patients directly presenting to percutaneous coronary intervention-capable hospitals and <120 minutes for transferred patients. We sought to increase the proportion of patients treated within guideline goals by organizing coordinated regional reperfusion plans. METHODS: We established leadership teams, coordinated protocols, and provided regular feedback for 484 hospitals and 1253 emergency medical services (EMS) agencies in 16 regions across the United States. RESULTS: Between July 2012 and December 2013, 23 809 patients presented with acute STEMI (direct to percutaneous coronary intervention hospital: 11 765 EMS transported and 6502 self-transported; 5542 transferred). EMS-transported patients differed from self-transported patients in symptom onset to first medical contact time (median, 47 versus 114 minutes), incidence of cardiac arrest (10% versus 3%), shock on admission (11% versus 3%), and in-hospital mortality (8% versus 3%; P<0.001 for all comparisons). There was a significant increase in the proportion of patients meeting guideline goals of first medical contact-to-device time, including those directly presenting via EMS (50% to 55%; P<0.001) and transferred patients (44%-48%; P=0.002). Despite regional variability, the greatest gains occurred among patients in the 5 most improved regions, increasing from 45% to 57% (direct EMS; P<0.001) and 38% to 50% (transfers; P<0.001). CONCLUSIONS: This Mission: Lifeline STEMI Systems Accelerator demonstration project represents the largest national effort to organize regional STEMI care. By focusing on first medical contact-to-device time, coordinated treatment protocols, and regional data collection and reporting, we were able to increase significantly the proportion of patients treated within guideline goals

Antiretroviral Therapy Outcomes in HIV-Infected Children after Adjusting Protease Inhibitor Dosing during Tuberculosis Treatment

Modification of ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy is required for HIV-infected children co-treated for tuberculosis (TB). We aimed to determine virologic and toxicity outcomes among TB/HIV co-treated children with the following modifications to their antiretroviral therapy (ART): (1) super-boosted LPV/r, (2) double-dose LPV/r or (3) ritonavir.A medical record review was conducted at two clinical sites in Johannesburg, South Africa. The records of children 6-24 months of age initiating LPV/r-based therapy were reviewed. Children co-treated for TB were categorized based on the modifications made to their ART regimen and were compared to children of the same age at each site not treated for TB. Included are 526 children, 294 (56%) co-treated for TB. All co-treated children had more severe HIV disease, including lower CD4 percents and worse growth indicators, than comparisons. Children in the super-boosted group (n = 156) were as likely to be virally suppressed (<400 copies/ml) at 6 months as comparisons (69.2% vs. 74.8%, p = 0.36). Children in the double-dose (n = 47) and ritonavir groups (n = 91) were significantly less likely to be virally suppressed at 6 months (53.1% and 49.3%) than comparisons (74.8% and 82.1%; p = 0.02 and p<0.0001, respectively). At 12 months only children in the ritonavir group still had lower rates of virological suppression relative to comparisons (63.9% vs 83.3% p<0.05). Grade 1 or greater ALT elevations were more common in the super-boosted (75%) than double-dose (54.6%) or ritonavir (33.9%) groups (p = 0.09 and p<0.0001) but grade 3/4 elevations were observed in 3 (13.6%) of the super-boosted, 7 (15.9%) of the double-dose and 5 (8.9%) of the ritonavir group (p = 0.81 and p = 0.29).Good short-term virologic outcomes were achieved in children co-treated for TB and HIV who received super-boosted LPV/r. Treatment limiting toxicity was rare. Strategies for increased dosing of LPV/r with TB treatment warrant further investigation

The Relationship between Telomere Length and Mortality in Chronic Obstructive Pulmonary Disease (COPD)

Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV1 and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy “mid-life” volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy “mid-life” volunteers (p<.001). Compared to individuals in the 4th quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD

Funding source, trial outcome and reporting quality: are they related? Results of a pilot study

BACKGROUND: There has been increasing concern regarding the potential effects of the commercialization of research. METHODS: In order to examine the relationships between funding source, trial outcome and reporting quality, recent issues of five peer-reviewed, high impact factor, general medical journals were hand-searched to identify a sample of 100 randomized controlled trials (20 trials/journal). Relevant data, including funding source (industry/not-for-profit/mixed/not reported) and statistical significance of primary outcome (favouring new treatment/favouring conventional treatment/neutral/unclear), were abstracted. Quality scores were assigned using the Jadad scale and the adequacy of allocation concealment. RESULTS: Sixty-six percent of trials received some industry funding. Trial outcome was not associated with funding source (p= .461). There was a preponderance of favourable statistical conclusions among published trials with 67% reporting results that favored a new treatment whereas 6% favoured the conventional treatment. Quality scores were not associated with funding source or trial outcome. CONCLUSIONS: It is not known whether the absence of significant associations between funding source, trial outcome and reporting quality reflects a true absence of an association or is an artefact of inadequate statistical power, reliance on voluntary disclosure of funding information, a focus on trials recently published in the top medical journals, or some combination thereof. Continued and expanded monitoring of potential conflicts is recommended, particularly in light of new guidelines for disclosure that have been endorsed by the ICMJE

Genetic and functional analyses point to FAN1 as the source of multiple Huntington Disease modifier effects

A recent genome-wide association study of Huntington’s disease (HD) implicated genes involved in DNA maintenance processes as modifiers of onset, including multiple genome-wide significant signals in a chr15 region containing the DNA repair gene FAN1. Here, we have carried out detailed genetic, molecular and cellular investigation of the modifiers at this locus. We find that missense changes within or near the DNA binding domain (p.Arg507His and p.Arg377Trp) reduce FAN1's DNA binding activity and its capacity to rescue mitomycin C-induced cytotoxicity, accounting for two infrequent onset-hastening modifier signals. We also identified a third onset-hastening modifier signal whose mechanism of action remains uncertain but does not involve an amino acid change in FAN1. We present additional evidence that a frequent onset-delaying modifier signal does not alter FAN1 coding sequence but is associated with increased FAN1 mRNA expression in the cerebral cortex. Consistent with these findings and other cellular overexpression/suppression studies, knock out of FAN1 increased CAG repeat expansion in HD induced pluripotent stem cells. Together, these studies support the process of somatic CAG repeat expansion as a therapeutic target in HD, and clearly indicate that multiple genetic variations act by different means through FAN1 to influence HD onset in a manner that is largely additive, except in the rare circumstance that two onset-hastening alleles are present. Thus, an individual’s particular combination of FAN1 haplotypes may influence their suitability for HD clinical trials, particularly if the therapeutic agent aims to reduce CAG repeat instability

The Metallicity Distribution Function of Red Giants in the LMC

We report new metallicity determinations for 39 red giants in a 220 square arcminute region, 1.8 degrees southwest of the bar of the Large Magellanic Cloud. These abundance measurements are based on spectroscopy of the Ca II infrared triplet. The metallicity distribution function (MDF) shows a strong peak at [Fe/H] = -0.57 +/- 0.04. Half the red giants in our field fall within the range -0.83 < [Fe/H] < -0.41. We find a striking contrast in the shape of the MDF below [Fe/H] < -1 between our inner disk field and the distant outer field studied by Olszewski (1993). Our field-star MDF seems similar to that of the intermediate-age (1-3 Gyr) star clusters. We have also obtained abundance estimates using Stromgren photometry for ~1000 red giants in the same field. The Stromgren measurements, which are sensitive to a combination of cyanogen and iron lines, correlate well with the Ca II measurements, but a metallicity-dependent offset is found (abridged).Comment: 55 pages, 16 figures, AASTeX v5.0, extended data table not included, to appear in the October, 2000 issue of The Astronomical Journa

Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington’s disease motor onset

Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations

Genomewide association study of acute anterior uveitis identifies new susceptibility loci

Acknowledgments The authors thank all participating subjects with AS and healthy individuals who provided the DNA and clinical information necessary for this study. We would like to acknowledge the contributions of Anna Deminger, Sahlgrenska Academy at University of Gothenburg, and Urban Hellman, Umeå University, for their assistance in case recruitment and assessment and handling biological samples Funding Information: The survey was conducted by NatCen and the genomewide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https: www. understandingsociety.ac.uk/ . We acknowledge and thank the TCRA AS Group for their support in recruiting patients for the study. M.A.B. is funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship, and support for this study was received from a National Health and Medical Research Council (Australia) program Grant (566938) and project Grant (569829), and from the Australian Cancer Research Foundation and Rebecca Cooper Medical Research Foundation. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and Spondyloarthritis Association of America in case recruitment. Additional financial and technical support for patient recruitment was provided by the National Institute for Health Research Oxford Musculoskeletal Biomedical Research Unit and NIHR Thames Valley Comprehensive Local Research and an unrestricted educational grant from Abbott Laboratories. The authors acknowledge the sharing of data and samples by the BSRBR-AS Register in Aberdeen. Chief Investigator, Prof Gary Macfarlane and Dr Gareth Jones, Deputy Chief Investigator, created the BSRBR-AS study, which was commissioned by the British Society for Rheumatology, funded in part by Abbvie, Pfizer, and UCB. We are grateful to every patient, past and present staff of the BSRBR-AS register team, and to all clinical staff who recruited patients, followed them up and entered data – details here: https://www.abdn.ac.uk/iahs/research/ epidemiology/spondyloarthritis.php#panel1011. Funding was also received from the Swedish Research Council and The Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement. The Irish data was derived from participants in ASRI – The Ankylosing Spondylitis Registry of Ireland, which is funded by unrestricted grants from Abbvie and Pfizer. Funding bodies involved played no role in the study design, performance, or preparation of this manuscript. Funding Information: X.F.H. was funded by the National Natural Science Foundation of China (31771390). The TASC study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants P01-052915, R01-AR046208. Funding was also received from the University of Texas Health Science Center at Houston CTSA grant UL1RR02418, Cedars-Sinai GCRC grant MO1-RR00425, Intramural Research Program, NIAMS/NIH, and Rebecca Cooper Foundation (Australia). This study was funded, in part, by Arthritis Research UK (Grants 19536 and 18797), by the Wellcome Trust (Grant number 076113), and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (Theme Code: A91202). The New Zealand data was derived from participants in the Spondyloarthritis Genetics and the Environment Study (SAGE) and was funded by The Health Research Council, New Zealand. H.X. was funded by the National Natural Science Foundation of China Grant 81020108029 and 30872339. French sample collection was performed by the Groupe Française d’Etude Génétique des Spondylarthrites, coordinated by Professor Maxime Breban, and funded by the Agence Nationale de Recherche GEMISA grant reference ANR-10-MIDI-0002. We acknowledge the Understanding Society: The UK Household Longitudinal Study. This is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. Publisher Copyright: © 2020 Association for Research in Vision and Ophthalmology Inc.. All rights reserved.Peer reviewedPublisher PD