Air mass factor formulation for spectroscopic measurements from satellites: Application to formaldehyde retrievals from the Global Ozone Monitoring Experiment

Abstract. We present a new formulation for the air mass factor (AMF) to convert slant column measurements of optically thin atmospheric species from space into total vertical columns. Because of atmospheric scattering, the AMF depends on the vertical distribution of the species. We formulate the AMF as the integral of the relative vertical distribution (shape factor) of the species over the depth of the atmosphere, weighted by altitudedependent coefficients (scattering weights) computed independently from a radiative transfer model. The scattering weights are readily tabulated, and one can then obtain the AMF for any observation scene by using shape factors from a three dimensional (3-D) atmospheric chemistry model for the period of observation. This approach subsequently allows objective evaluation of the 3-D model with the observed vertical columns, since the shape factor and the vertical column in the model represent two independent pieces of information. We demonstrate the AMF method by using slant column measurements of formaldehyde at 346 nm from the Global Ozone Monitoring Experiment satellite instrument over North America during July 1996. Shape factors are computed with the Global Earth Observing System CHEMistry (GEOS-CHEM) global 3-D model and are checked for consistency with the few available aircraft measurements. Scattering weights increase by an order of magnitude from the surface to the upper troposphere. The AMFs are typically 20-40 % less over continents than over the oceans and are approximately half the values calculated in the absence of scattering. Model-induced errors in the AMF are estimated to be • 10%. The GEOS-CHEM model captures 50 % and 60 % of the variances in the observed slant and vertical columns, respectively. Comparison of the simulated and observed vertical columns allows assessment of model bias. 1

Mapping isoprene emissions over North America using formaldehyde column observations from space

[1] We present a methodology for deriving emissions of volatile organic compounds (VOC) using space-based column observations of formaldehyde (HCHO) and apply it to data from the Global Ozone Monitoring Experiment (GOME) satellite instrument over North America during July 1996. The HCHO column is related to local VOC emissions, with a spatial smearing that increases with the VOC lifetime. Isoprene is the dominant HCHO precursor over North America in summer, and its lifetime ('1 hour) is sufficiently short that the smearing can be neglected. We use the Goddard Earth Observing System global 3-D model of tropospheric chemistry (GEOS-CHEM) to derive the relationship between isoprene emissions and HCHO columns over North America and use these relationships to convert the GOME HCHO columns to isoprene emissions. We also use the GEOS-CHEM model as an intermediary to validate the GOME HCHO column measurements by comparison with in situ observations. The GEOS-CHEM model including the Global Emissions Inventory Activity (GEIA) isoprene emission inventory provides a good simulation of both the GOME data (r 2 = 0.69, n = 756, bias = +11%) and the in situ summertime HCHO measurements over North America (r 2 = 0.47, n = 10, bias = À3%). The GOME observations show high values over regions of known high isoprene emissions and a day-to-day variability that is consistent with the temperature dependence of isoprene emission. Isoprene emissions inferred from the GOME data are 20% less than GEIA on average over North America and twice those from the U.S. EPA Biogenic Emissions Inventory System (BEIS2) inventory. The GOME isoprene inventory when implemented in the GEOS-CHEM model provides a better simulation of the HCHO in situ measurements than either GEIA or BEIS2 (r 2 = 0.71, n = 10, bias = À10%)

Harnessing person-generated health data to accelerate patient-centered outcomes research: the Crohn’s and Colitis Foundation of America PCORnet Patient Powered Research Network (CCFA Partners)

The Crohn’s and Colitis Foundation of America Partners Patient-Powered Research Network (PPRN) seeks to advance and accelerate comparative effectiveness and translational research in inflammatory bowel diseases (IBDs). Our IBD-focused PCORnet PPRN has been designed to overcome the major obstacles that have limited patient-centered outcomes research in IBD by providing the technical infrastructure, patient governance, and patient-driven functionality needed to: 1) identify, prioritize, and undertake a patient-centered research agenda through sharing person-generated health data; 2) develop and test patient and provider-focused tools that utilize individual patient data to improve health behaviors and inform health care decisions and, ultimately, outcomes; and 3) rapidly disseminate new knowledge to patients, enabling them to improve their health. The Crohn’s and Colitis Foundation of America Partners PPRN has fostered the development of a community of citizen scientists in IBD; created a portal that will recruit, retain, and engage members and encourage partnerships with external scientists; and produced an efficient infrastructure for identifying, screening, and contacting network members for participation in research

Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Phase 1 Safety and Immunogenicity Evaluation of ADVAX, a Multigenic, DNA-Based Clade C/B' HIV-1 Candidate Vaccine

BACKGROUND: We conducted a Phase I dose escalation trial of ADVAX, a DNA-based candidate HIV-1 vaccine expressing Clade C/B' env, gag, pol, nef, and tat genes. Sequences were derived from a prevalent circulating recombinant form in Yunnan, China, an area of high HIV-1 incidence. The objective was to evaluate the safety and immunogenicity of ADVAX in human volunteers. METHODOLOGY/PRINCIPAL FINDINGS: ADVAX or placebo was administered intramuscularly at months 0, 1 and 3 to 45 healthy volunteers not at high risk for HIV-1. Three dosage levels [0.2 mg (low), 1.0 mg (mid), and 4.0 mg (high)] were tested. Twelve volunteers in each dosage group were assigned to receive ADVAX and three to receive placebo in a double-blind design. Subjects were followed for local and systemic reactogenicity, adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA. Cellular immunogenicity was assessed by a validated IFNgamma ELISpot assay and intracellular cytokine staining. ADVAX was safe and well-tolerated, with no vaccine-related serious adverse events. Local and systemic reactogenicity events were reported by 64% and 42% of vaccine recipients, respectively. The majority of events were mild. The IFNgamma ELISpot response rates to any HIV antigen were 0/9 (0%) in the placebo group, 3/12 (25%) in the low-dosage group, 4/12 (33%) in the mid-dosage group, and 2/12 (17%) in the high-dosage group. Overall, responses were generally transient and occurred to each gene product, although volunteers responded to single antigens only. Binding antibodies to gp120 were not detected in any volunteers, and HIV seroconversion did not occur. CONCLUSIONS/SIGNIFICANCE: ADVAX delivered intramuscularly is safe, well-tolerated, and elicits modest but transient cellular immune responses. TRIAL REGISTRATION: Clinicaltrials.gov NCT00249106.published_or_final_versio

Standardised Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD): study protocol for establishing a core outcome set in polycystic kidney disease

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life threatening inherited kidney disease and is responsible for 5-10% of cases of end-stage kidney disease (ESKD). Cystic kidneys may enlarge up to 20 times the weight of a normal kidney due to the growth of renal cysts, and patients with ADPKD have an increased risk of morbidity, premature mortality, and other life-time complications including renal and hepatic cyst and urinary tract infection, intracranial aneurysm, diverticulosis, and kidney pain which impair quality of life. Despite some therapeutic advances and the growing number of clinical trials in ADPKD, the outcomes that are relevant to patients and clinicians, such as symptoms and quality of life, are infrequently and inconsistently reported. This potentially limits the contribution of trials to inform evidence-based decision-making. The Standardised Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) project aims to establish a consensus-based set of core outcomes for trials in PKD (with an initial focus on ADPKD but inclusive of all stages) that patients and health professionals identify as critically important. METHODS: The five phases of SONG-PKD are: a systematic review to identify outcomes that have been reported in existing PKD trials; focus groups with nominal group technique with patients and caregivers to identify, rank, and describe reasons for their choices; qualitative stakeholder interviews with health professionals to elicit individual values and perspectives on outcomes for trials involving patients with PKD; an international three-round Delphi survey with all stakeholder groups (including patients, caregivers, healthcare providers, policy makers, researchers, and industry) to gain consensus on critically important core outcome domains; and a consensus workshop to review and establish a set of core outcome domains and measures for trials in PKD. DISCUSSION: The SONG-PKD core outcome set is aimed at improving the consistency and completeness of outcome reporting across ADPKD trials, leading to improvements in the reliability and relevance of trial-based evidence to inform decisions about treatment and ultimately improve the care and outcomes for people with ADPKD

Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol

Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r2 > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10−12). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT– haplotype] versus 16-fold [CC+ haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus