Seismic Risk Analysis for a Site Along the Gorda Segment of the Cascadia Subduction Zone

A seismic risk evaluation was conducted on a site near Eureka, California. The site was subject to potential earthquake loading from a number of sources. These sources were: (1) Mendocino Fracture Zone, (2) Gorda Segment of the Cascadia Subduction Zone, (3) Little Salmon thrust fault under the site, (4) Mad River Fault Zone, and (5) Intra plate west - Gorda Plate. The geology of thrust faults in Northern California is examined along with that of the Mendocino Fracture Zone, and the southern section (Gorda Segment) of the Cascadia subduction zone. A trench log showing a splay of the Little Salmon Fault is presented. A seismic risk analysis of the site was performed using recurrence curves for the various seismic sources estimated from both trench studies and historic seismicity. Using this information the acceleration at the site due to the Maximum Credible Earthquake is estimated to be 0.85g. The corresponding acceleration due to the Maximum Probable Earthquake and assuming that the various fault zones act independently or co-seismically is estimated to be 0.5g

Compressional and Shear Waves Tests Through Upper Sheet of Low Angle Thrust Fault

Compressional and shear wave tests were conducted on the upper thrust sheet of the low angle Little Salmon thrust fault. The study was conducted on the campus of the College of the Redwoods. The campus is located approximately 8 miles south of Eureka and 24 miles north-northeast of Cape Mendocino and the Mendocino Triple Junction (MTJ) in Northern California. The MTJ is the point of transition from strike-slip faulting of the San Andreas transform system to low-angle reverse (thrust) faulting and folding associated with the convergent margin of the Cascadia Subduction Zone. The campus is located on the southwest limb of the Humboldt Hill anticline, one of the folds in the fold and thrust belt. The Little Salmon fault zone is a low angle thrust fault that day lights on the south side of the campus and then projects underneath striking northwest and dipping northeast. A boring was drilled down to the fault plane located at a depth of 200 ft. in the upper thrust block to develop a mode1 of the stratification as well as the material properties. The boring also revealed the trunk of a redwood tree located at a depth of 180 feet. Results of compressional and shear wave velocities as a function of depth that were determined using an downhole geophysical technique. Results indicated two shear wave velocity units. Unit 1 was from 0 to 120 ft. with a shear wave velocity ranging from 950- 1400 fps. Unit 2 ranged from 120 to 190 ft. with a shear wave velocity ranging from 2300 to 2600 fps. Compression wave velocity measurements obtained from the same test boring also depict a change in velocity in the 100 to 120 foot range. A response spectra was generated based on this in-situ mode1 using SHARE91 and compared against one developed using the Boore, Joyner and Fumal empirical model

GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity.

Abnormal activation of the epidermal growth factor receptor (EGFR) due to a deletion of exons 2-7 of EGFR (EGFRvIII) is a common alteration in glioblastoma (GBM). While this alteration can drive gliomagenesis, tumors harboring EGFRvIII are heterogeneous. To investigate the role for EGFRvIII activation in tumor phenotype we used a neural progenitor cell-based murine model of GBM driven by EGFR signaling and generated tumor progenitor cells with high and low EGFRvIII activation, pEGFRHi and pEGFRLo. In vivo, ex vivo, and in vitro studies suggested a direct association between EGFRvIII activity and increased tumor cell proliferation, decreased tumor cell adhesion to the extracellular matrix, and altered progenitor cell phenotype. Time-lapse confocal imaging of tumor cells in brain slice cultures demonstrated blood vessel co-option by tumor cells and highlighted differences in invasive pattern. Inhibition of EGFR signaling in pEGFRHi promoted cell differentiation and increased cell-matrix adhesion. Conversely, increased EGFRvIII activation in pEGFRLo reduced cell-matrix adhesion. Our study using a murine model for GBM driven by a single genetic driver, suggests differences in EGFR activation contribute to tumor heterogeneity and aggressiveness

Use of Microzonation to Site Facility on Low Angle Thrust and Associated Fault Bend Folding

The campus of the College of the Redwoods is located completely within the Little Salmon Fault Zone, designated by the State of California as an active fault. The College has been extensively investigated for fault rupture and other seismic hazards in 1989, 1993, 1997, 1998, and 1999. The Little Salmon Fault Zone bounds the College and consists of two main northwest-striking, northeastdipping, low-angle thrusts. The west splay daylights along the southwest edge of the campus and projects beneath it. A recurrence interval of 268 years and slip rate of 5+/-3 mm/yr is estimated by CDMG. Individual dip-slip displacements along the west trace are reported to be 12 to 15 feet (3.6 to 4.5 m). Movement on the Little Salmon fault (LSF) is accompanied by growth of broad asymmetric folds in the upper thrust sheet resulting in surface rupture, localized uplift and discreet fault-bend fold axial surfaces. College of the Redwoods is located approximately 8 miles (13 km) south of Eureka and 25 miles (40 km) north-northeast of Cape Mendocino and the Mendocino Triple Junction (MTJ) in northern California. The \u27MTJ is the point of transition fi-om strike-slip faulting of the San Andreas transform system to low-angle thrust faulting and folding associated with the convergent margin of the Cascadia Subduction Zone. Campus infrastructure is located along the base of the Humboldt Hill Anticline (HHA), a major faultbend fold of the Cascadia fold and thrust belt. A new learning resource center (LRC) is proposed for a location 400 feet (120 m) northeast of where the west trace of the LSF daylights and 200 feet (60 m) above the low-angle fault plane. Building setback and design recommendations to mitigate for both fault rupture hazards and fault-generated folding hazards are presented

Data Package of Samples Collected for Hydrogeologic and Geochemical Characterization: 300 Area RI/FS Sediment Cores

This is a data package for sediment samples received from the 300 FF 5 OU. This report was prepared for CHPRC. Between August 16, 2010 and April 25, 2011 sediment samples were received from 300-FF-5 for geochemical studies. The analyses for this project were performed at the 331 building located in the 300 Area of the Hanford Site. The analyses were performed according to Pacific Northwest National Laboratory (PNNL) approved procedures and/or nationally recognized test procedures. The data sets include the sample identification numbers, analytical results, estimated quantification limits (EQL), and quality control data. The preparatory and analytical quality control requirements, calibration requirements, acceptance criteria, and failure actions are defined in the on-line QA plan 'Conducting Analytical Work in Support of Regulatory Programs' (CAW). This QA plan implements the Hanford Analytical Services Quality Assurance Requirements Documents (HASQARD) for PNNL

Short Children with CHARGE Syndrome: Do They Benefit from Growth Hormone Therapy?

AIM: The aim of this study was to evaluate the response to recombinant growth hormone (GH) treatment in short children with CHARGE syndrome. PATIENTS: We identified 51 children (28 boys and 23 girls) in KIGS (Pfizer International Growth Database). The median chronological age was 7.6 years at the start of GH therapy and 13.2 years at the latest visit. Evaluation for GH deficiency (n = 33) was based on the following: peak GH level 7.3 μg/l and IGF-I level -2.01 standard deviation score (SDS). Sixteen subjects (9 boys) were followed longitudinally for 2 years. RESULTS: Birth length (median SDS, -0.47) and weight (-0.97) were slightly reduced. At the start of GH therapy, height was -3.6 SDS, BMI -0.7 SDS, and the GH dose was 0.26 mg/kg/week. At the latest visit after 2.7 years of GH therapy, height had increased to -2.2 SDS and BMI to -0.5 SDS. In the longitudinal group, height increased from -3.72 SDS at the start of GH therapy to -2.92 SDS after 1 year to -2.37 SDS after 2 years of therapy (start - 2 years: p < 0.05), height velocity increased from -1.69 to 2.98 to 0.95 SDS, and BMI and GH dose (mg/kg/week) remained almost unchanged. CONCLUSIONS: Our data show a positive effect of conventional doses of GH on short-term growth velocity for the longitudinal as well as for the total group, without any safety issues.This study was sponsored by Pfizer Inc.This is the author accepted manuscript. The final version is available from Karger via http://dx.doi.org/10.1159/00038201

Dapagliflozin in patients with chronic kidney disease

Background: Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known. Methods: We randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Results: The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed. Conclusions: Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo

Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial.

BACKGROUND: Recent cardiovascular outcome trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes. METHODS: DAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2-4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin-angiotensin system inhibitor at enrolment. RESULTS: After a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05). CONCLUSION: DAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes

The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics

Background: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium–glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials. Methods: In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol). Results: Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n = 2510) were ischaemic/hypertensive nephropathy (n = 687) and chronic glomerulonephritis (n = 695), of which immunoglobulin A nephropathy (n = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR). Conclusions: Participants with a wide range of underlying kidney diseases receiving renin–angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2–4 and increased albuminuria, with and without T2D