Academic literature on the topic 'Liberia International Foundation for Elevation'

Union democracy was a preoccupation of the federal legislature from the 1920s to the 1970s. It was quiescent as a public policy issue for two decades until revived by the Howard government in 1996. Examination of the statutory provisions for union democracy reveals deficiencies in terms of the benchmarks provided by both liberal pluralist and Marxist models. The traditional rationale for state intervention in union government is found to have been significantly weakened. At the same time, union democracy has been reinstated as a principal object of the statute. A new rationale for intervention is needed, as is a review of current regulation to assess its capacity to facilitate the achievement of tbe statutory objects. In analysing the relationship between regulation for union democracy and for participation in collective bargaining we can identify otber anomalies. These include: different standards for participation in the arbitration spbere (consent awards) from the bargaining sphere ( certified agreements); variation in the degree of regulation of different decisions—high-level regulation for elections and for merger decisions, and low-level regulation of decisions relating to the primary union function of improving wages and conditions; and extension of participa tion rights to non-unionists in the negotiation of union agreements, that is, elevation of an 'employee constituency' at the expense of a 'union-member constituency'. The industrial citizenship paradigm serves to highlight the anomalies and also resonates with the currently espoused value of employee choice. This model could provide a theoretical foundation for a more comistent and principled approach to public policy concerning participation in collective bargaining.

The article is devoted to the socio-economic policy pursued by Barak Obama who had won elections and entered the presidential office in the midst of the strongest economic crisis. The author considers in depth each of the new administration's strategy directions in taking simultaneously both short-term measures necessary for the fastest crisis recovery and actions aimed at laying the foundation for the future long-term prosperity of the country. The feature of the current stage is the elevation of social policy to the rank of national priorities, and the crisis does not abolish it.

Abstract Objectives Anemia is defined by hemoglobin (Hb) lower than normal based on cutoffs specific to age and sex. Hb increases with elevation as a response to lower blood oxygen, thus adjusting Hb for elevation is necessary before applying cutoffs. Recent evidence among preschool-aged children (PSC) and reproductive-aged women (WRA) suggests current World Health Organization (WHO) recommended Hb elevation adjustments need updating. We examined the Hb and elevation association among school-age children (SAC) to confirm these findings. Methods Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project data include SAC aged 5–14 years (n = 23,454; 53.5% female) with data on Hb and elevation (−6 to 3,834 meters, m) from 6 population-based surveys from 5 countries (Columbia, Ecuador, Malawi, Mexico, United Kingdom). Anemia was defined as Hb < 115 g/L for SAC < 12 years and < 120 g/L for SAC 12–14 years after elevation adjustments. Generalized linear models were used to assess the association between Hb and elevation, including controlling for inflammation-corrected iron and vitamin A deficiency. Hb adjustments for each 500 m increase in elevation from sea level are proposed and compared to current WHO recommendations and new proposed PSC and WRA adjustments. Results Hb was positively associated with elevation. There was no sex interaction, and the association was robust to model specification. The association among SAC and the resulting Hb adjustments were consistent with PSC and WRA findings, suggesting current WHO recommendations may under-adjust Hb at lower elevation (500–2500 m) and over-adjust Hb at higher elevation (>3000 m). Anemia prevalence in SAC using new elevation adjustments increased by 0.7 (UK) to 14.1 (Malawi) percentage points relative to current WHO elevation adjustments. Conclusions Results confirm current WHO recommended Hb elevation adjustments may need updating, and anemia prevalence in SAC may be higher than currently estimated. Findings will inform global guidelines on use of elevation-adjusted Hb for anemia assessment and possible need for intervention among SAC. Funding Sources Bill & Melinda Gates Foundation, Centers for Disease Control and Prevention, Eunice Kennedy Shriver National Institute of Child Health and Human Development, HarvestPlus, and United States Agency for International Development.

Aims: Social reintegration and rehabilitation of obstetric fistula patients before and after repair enhance their overall status, which may be unattainable even with a successful repair. Nonetheless, there is little traceable documentation about it even with supportive programs and projects, the thrust of this study.
 Methods: This is a systematic review involving a search of relevant literature from PubMed, Google scholar, PsychINFO, African Journals Online, Australian Journals Online, and open access journals of international organizations such as WHO, UNFPA, USAID, Engender Health, Fistula Foundation and Fistula Care Plus published between 1978 to date. Of the 46 articles identified, 25 were suitable for achievement of this study’s purpose.
 Results:Sub-Saharan African countries have recognized the overall burden of obstetric fistula and have devised strategies for its holistic management. Most countries have National Obstetric Fistula Strategic Frameworks which emphasize multi-sectoral and multidisciplinary approaches other than medical paradigms. Social reintegration and rehabilitation have been done through the identification of individual patient’s need/s. Projects and programs aiming to combat obstetric fistula and restore patients’ self-worth and dignity are: Lamaneh Suisse, and Delta Survie in Mali, Dimol in Niger, Medecins Sans Frontieres (MSF) in Burundi, FORWARD in Nigeria and Sierra Leone, Handicap International in Benin Republic, Women For Africa in Ghana and Liberia, TERREWODE and CoRSU both in Uganda, Hamlin Fistula Ethiopia in Ethiopia, and others which cut across the region.
 Conclusions: Effective social reintegration and rehabilitation strategies are still inadequate in Sub-Saharan Africa due to lack of political commitment and inadequate outreach programs.
 Keywords: obstetric fistula, recto-vaginal fistula, rehabilitation, social reintegration, vesico-vaginal fistula.

The Antarctic digital topographic database is the outcome of a truly international collaborative project between 11 nations. Data capture was co-ordinated in the UK, under the auspices of the Scientific Committee on Antarctic Research (SCAR), during a two-year period. Over 200 maps, at scales ranging from 1:200 000 to 1:5 000 000, were digitized for the project and reference was made to a similar number of satellite images (mostly Landsat photographic products). Editing and harmonization of the data derived from the different sources has produced a seamless map of Antarctica which has the most up-to-date coastline now available. The topographic database created, to be published on one CD-ROM, will form the foundation for future GIS needs in Antarctic research. Products already derived from the database include digital elevation models and customized maps; the latter can be reproduced by research groups to meet their own mapping needs.

Context: The recent Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism (PHPT) set 60 ml/min as the precise level of glomerular filtration rate (GFR) below which surgery is recommended because it is considered a threshold of concern in patients with PHPT. Objective: The aim of the study was to investigate the relationship between different stages of renal insufficiency and PTH levels in PHPT patients. Design: We conducted a cross-sectional study. Patients and Methods: We studied 294 consecutive PHPT patients. Biochemical evaluation included total and ionized serum calcium, phosphate, creatinine, immunoreactive intact PTH, and 25-hydroxyvitamin D3 levels in the fasting state. GFR was assessed with the Modification of Diet in Renal Disease Study formula. Results: The mean GFR of the whole group of PHPT patients was 92.3 ± 31.6 ml/min · 1.73 m2. The patients were divided into four groups according to National Kidney Foundation Disease Outcomes Quality Initiative (K/DOQI) guidelines: group 1 with normal or increased GRF (>90 ml/min · 1.73 m2; n = 153); group 2 with mild decreased GFR (60–89 ml/min · 1.73 m2; n = 90); group 3 with moderately decreased GFR (30–59 ml/min · 1.73 m2; n = 45); and group 4 with severely decreased GFR (<30 ml/min · 1.73 m2; n = 6). PTH levels were comparable across groups 1–3, whereas group 4 showed significantly higher PTH levels (P < 0.0001). Conclusion: In our series of PHPT patients, only a severe impairment of GFR was characterized by a further PTH increase. These findings challenge the concept of a PTH elevation below the threshold of 60 ml/min of GFR. In a large series of contemporary PHPT patients, only a severe impairment of glomerular filtration rate (i.e., <30 ml/min/1.73 m2) is characterized by a further PTH elevation.

The main objective of this research was to model the zonation of wrap faced embankment on soft clay foundation, by applying a shake table test. Also, to investigate the dynamic behaviors of clay soil, such as acceleration amplification, displacement and pore water pressure of wrap faced embankment. This was done with respect to changes in frequencies of 1 Hz, 3 Hz, 5 Hz, 10 Hz, 12 Hz and 15 Hz respectively. Constant acceleration (0.1 g) and surcharge (19 Kg) were applied by using a laminar box, placed on a shake table testing machine. The main elements of this research were the laboratory test, which was used for preparing reconstitute soil samples, and wrap faced embankment with frequency arrangement. After applying all test parameters, dynamic parameters were increased by rise in elevation with respect to frequency. The result shows that the maximum dynamic parameters were found at the frequency of 10 Hz. It is beneficial to the relative performances of the wrap faced embankment, which is the updated design parameter.
 Keywords: Seismic; Clay Soil; Frequency; Shake Table Test; Wrap Faced; Soil Zonation
 
 Copyright (c) 2020 Geosfera Indonesia Journal and Department of Geography Education, University of Jember
 This work is licensed under a Creative Commons Attribution-Share A like 4.0 International License

Abstract Background: Ponatinib is a third generation tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in patients (pts) with CML who have failed multiple therapies and those with a T315I mutation or other BCR-ABL mutations. In this study, we have assessed the efficacy and safety of ponatinib as a frontline therapy in pts with CML-CP. Methods: Fifty one pts with CML-CP were treated with ponatinib as initial therapy for CML in a single-arm, single-institution clinical trial. The starting dose of ponatinib was 45 mg orally daily in 43 pts and, after an amendment, 30 mg in 8 pts. Other eligibility criteria included age ≥18 yrs, ECOG PS 0-2, normal organ function, and absence of significant cardiac history or prior pancreatitis. Pts with clonal evolution at time of diagnosis were eligible without other evidence of accelerated phase. Dose reductions to 30mg/d, 15 mg/d, or 15 mg every other day were indicated for adverse events. Pts were followed with cytogenetic analysis and PCR every 3 months for the first 12 months, then every 6 months. Cytogenetic and molecular (by International Scale) response criteria were standard. Results: From May 2012 to June 2014, 51 pts were treated. The median age was 48 yrs (range, 21-75), 1 patient had clonal evolution, and 3 started therapy while in CHR. Sokal risk score was low in 69%, intermediate in 22% and high in 10%. The median follow-up was 15.6 months (range 5.6-23.7 months). Complete hematologic response (CHR) was achieved in 95% of pts, complete cytogenetic response (CCyR) in 95%, major molecular response (MMR) in 80%, molecular response 4.5-log (MR4.5) in 55% and undetectable BCR-ABL in 38%. At 3 months, 90% of 50 evaluable pts achieved CCyR, and at 6 months 93% of 45 evaluable pts had CCyR. The median transcript levels at 3 months was 0.096 and at 6 months 0.005. Rates of MMR at 3 and 6 months were 50% and 80%, and rates of undetectable BCR-ABL1 were 0% and 22%, respectively. None of the pts progressed, including no transformations to accelerated or blast phase and all pts were alive. Forty three (85%) pts required treatment interruptions. The median duration of treatment interruptions was 9 days (range, 1-48). The median dose for all pts was 30 mg/d. As of June 2014, all pts were taken off study – 38 per FDA recommendation for concerns of risk of thrombotic events and 13 due to adverse events. Of these 13 pts – 3 had vasoocclusive disease grade 3 (peripheral arterial disease, femoral artery thrombosis, gastrointestinal ischemia), 2 with acute coronary syndrome (grade 3), 2 had cerebrovascular events grade 3 (1 transient ischemic attack and 1 Moya Moya disease), 2 multiple toxicities, 1 grade 3 hypertension, 1 with resistance and grade 2 arthralgia, 1 grade 3 skin xerosis, 1 grade 4 myelosuppression. Cardiovascular events were observed in 24 (47%) pts, of which 11 had >1 cardiovascular event. Hypertension in 14 pts (7 were grade 3), chest pain in 8 (one pericarditis grade 2), acute coronary syndrome in 2 (grade 3), vasoocclusive disease in 3 (one suspected gastrointestinal ischemia; all grade 3), stroke in 3 (one TIA and one carotid arterial disease both grade 3), Raynaud’s phenomenon in 2 (grade 1-2), one each had toe cramps with tingling, palpitations, prolonged QTc. Non-cardiovascular adverse events included - skin rash in 35 (2 pts with grade 3/4), dry skin in 22 (all grade 1/2), lipase elevation in 32 (23 with grade 3/4), symptomatic grade 3 pancreatitis in 10 pts, constipation in 26 pts (all grade 1/2), and memory loss in 6 pts (all grade 1/2). Grade 3-4 myelosuppression occurred in 14 pts. Conclusion: Ponatinib therapy leads to fast and deep cytogenetic and molecular responses in pts with CML-CP. Cardiovascular toxicities, skin toxicity and lipase elevation were observed in several patients. Dose adjustment, regular monitoring and counselling of the pts for thromboembolic events can be used to manage pts on ponatinib. However, considering the risk of vascular thrombotic events and the availability of alternative options for these patients, the study has been terminated at the recommendation of the FDA. Disclosures Borthakur: Tetralogic Pharmaceuticals: Research Funding. Ravandi:Cellerant Therapeutics: Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach for relapsed refractory hematologic malignancies. The Indiana strain of Vesicular Stomatitis Virus (VSV) has been engineered to encode interferon beta (IFNβ) and sodium iodine symporter (NIS) to produce VSV-IFNβ-NIS. The virally encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. The NIS is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. Here we present results of Arm A (patients with low tumor burden) of the Phase I clinical trial (NCT03017820) of intravenous administration of VSV-IFNβ-NIS for patients (pts) with relapsed refractory hematological malignancies: MM, AML, and TCL. Methods: This was a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (50% tissue culture infectious dose) level 1 through 1.7x10^11 TCID50 dose level 4 given as a single IV dose. The primary objective was determining the maximum tolerated dose of VSV-IFNβ-NIS alone; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding and changes in the immune profile of peripheral blood leukocytes. Adverse events (AEs) are reported based on CTCAE v4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014; 124(2):188-195) criteria. Results: From April 2017, 12 pts have received IV VSV-IFNβ-NIS in Arm A: MM (7), TCL(4) and AML(1); 3 pts were treated at each dose level (DL) 1 to 4. At DL1, there were five grade 3 hematologic AEs (leukopenia [1], neutropenia [1], lymphopenia [3]) and no grade 3+ non-hematologic AEs. At DL2, three grade 3 hematologic AEs (anemia [2], lymphopenia [1]), four grade 4 hematologic AEs (neutropenia [1], leukopenia [1], lymphopenia [1] and thrombocytopenia [1]). There was 1 event of grade 2 CRS at DL2, two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). At DL3, there was one grade 4 hematologic AE (neutropenia [1]), three grade 3 hematologic AEs (lymphopenia [2], leukopenia [1]), and one grade 3 non-hematologic AE (vasovagal reaction [1]). One grade 2 and grade 1 CRS by Lee criteria were observed. At DL4, there were three grade 3 hematologic AEs (lymphopenia [1], neutropenia [1], thrombocytopenia [1]), and three grade 3 non-hematologic AEs (AST increase [1], skin infection [1], soft tissue infection [1])and two grade 2 CRS. There were no dose limiting toxicities. There was one partial response (DL2) and one complete response (DL4); 3 pts had stable disease, 7 pts progressed. The MM pts receiving VSV-IFNβ-NIS at DL4 had stable disease. Six of the 7 MM pts demonstrated transient reduction in serum level of involved free light chain (LC) after VSV-IFNβ-NIS infusion, with median 20.4% reduction of the involved LC within 48 hrs. Viremia was detectable in all pts at the end of infusion, to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hrs post infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. The IFN levels were detectable within 30 minutes of infusion and peaked between 4 and 48 hrs. The pts with a diagnosis of TCL mounted higher hIFNβ levels within 48 hrs. Remarkably, the TCL pt with CR (DL4) mounted a peak hIFNβ response of 18213.3pg/ml at 48 hrs post infusion, approximately 15-fold higher than any other pt enrolled in the study; and highest neutralizing antibody titer (1:40960). Conclusion: VSV-IFNβ-NIS can be safely administered by intravenous infusion in pts with hematological malignancies, up to a dose level of 1.7 x 1011 TCID50, without dose limiting toxicities and no CRS higher than grade 2. In this small phase 1 study, pts with T-cell lymphoma demonstrated the strongest signal of response, with one confirmed partial response at DL2 and one complete response at DL4. IFNβ is an early biomarker of tumor susceptibility; the magnitude of IFNβ elevation appears to correlate with treatment response. There were no confirmed responses in pts with MM, but the 20.4% transient reduction in LC suggests that combination strategies with VSV-IFNβ-NIS may result in deeper and sustained responses in MM. Future trials investigating combination strategies with immune modulatory drugs are being planned. Disclosures Peng: Imanis: Other: Equity Ownership. Witzig:Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Incyte: Consultancy; Acerta: Research Funding; MorphSys: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Research Funding. Dispenzieri:Intellia: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Alnylam: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Gertz:Celgene: Consultancy; Annexon: Consultancy; Sanofi: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; NCI SPORE MM: Research Funding; Johnson and Johnson: Speakers Bureau; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy; Ionis/Akcea: Consultancy; Spectrum: Consultancy, Research Funding; Prothena: Consultancy; DAVA oncology: Speakers Bureau; i3Health: Consultancy; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; International Waldenstrom Foundation: Research Funding. Dingli:Rigel: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy; Karyopharm Therapeutics: Research Funding; Millenium: Consultancy; Sanofi-Genzyme: Consultancy. Kapoor:Cellectar: Consultancy; Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy. Kumar:Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Carsgen: Other, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Sanofi: Research Funding; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; MedImmune: Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Karyopharm: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Genecentrix: Consultancy; Tenebio: Other, Research Funding. Russell:Imanis: Other: Equity Ownership. OffLabel Disclosure: This describes of administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and human interferon, in Patients with Relapsed or Refractory Hematologic malignacies

Abstract Background: Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, has been approved for the treatment of disease-related splenomegaly or symptoms in adults with primary myelofibrosis (MF), post-polycythemia vera (PPV) MF, and post-essential thrombocythemia (PET) MF. In a murine model of MF, ruxolitinib in combination with the hedgehog pathway inhibitor (HPI) sonidegib, improved splenomegaly and bone marrow (BM) fibrosis more than ruxolitinib monotherapy (Bhagwat, ASH 2013). Building on these data, ruxolitinib and sonidegib combination therapy is being assessed in a phase 1b/2 study in patients (pts) with MF (NCT01787552). Findings from the phase 1b portion of this study determined the recommended phase 2 dose (RP2D) to be sonidegib 400 mg once daily and ruxolitinib 20 mg twice daily (Gupta, ASH 2014). Combination treatment was generally well tolerated; the maximum tolerated dose was not reached, and the only observed dose-limiting toxicity was creatine kinase (CK) elevation. In this report, safety and efficacy data from the analysis performed 24 weeks after the last pt enrollment (data cutoff, 08 May 2015) are presented for pts treated at the RP2D. Methods: Eligible pts includedadults with primary or secondary (PPV or PET) intermediate (Int)- or high-risk MF with palpable splenomegaly who were not previously treated with a JAK inhibitor or HPI. The primary objective was to assess the efficacy of co-administration of ruxolitinib and sonidegib determined by reduction in spleen volume per MRI/CT by central review at the end of weeks 24 and 48. Results: Overall, 27 pts with primary MF (n = 16; 59.3%), PET-MF (n = 7; 25.9%), and PPV-MF (n = 4; 14.8%) were treated at the RP2D (median exposure, 28.6 weeks). The median age was 69 years (range, 44 to 83 years), 70.4% of pts were male, and 85.2% were JAK2 V617F positive. According to the International Prognosis Scoring System, 1 pt (3.7%) was low risk, 4 pts (14.8%) were Int-1, 4 pts (14.8%) were Int-2, and 18 pts (66.7%) were high risk. At data cutoff, 20 pts (74.1%) remained on treatment; 5 pts discontinued treatment due to an adverse event (AE), and 1 pt each due to pt decision and death (multi-organ failure unrelated to study treatment occurring 2 days after discontinuation). Overall, the most common AEs regardless of causality (all grade; grade 3/4; Table) were anemia (52%; 33%) and muscle spasms (48%; 4%). AEs requiring dose adjustment or interruption were experienced by 17 pts (63%), with the most common being increased CK (19% [n = 5]) and myalgia (19% [n = 5]). The mean hemoglobin level at baseline (BL) was ≈ 100 g/L and it remained relatively stable throughout treatment. Mean platelet count decreased from BL levels of ≈ 300 × 109/L to ≈ 150 × 109/L by week 4, and then remained relatively stable at ≈ 200 × 109/L. At the end of week 24, 12 pts (44.4%) had a ≥ 35% reduction in spleen volume as measured by MRI/CT and 15 pts (55.6%) achieved a ≥ 35% reduction in spleen volume at any time on treatment (Figure 1). A ≥ 50% reduction in palpable spleen length was achieved by 15 pts (55.6%) at the end of week 24; a best response of ≥ 50% reduction in spleen length at any time on treatment was achieved by 25 pts (92.6%), with 15 pts (55.6%) having a non-palpable spleen (Figure 2). The mean change in JAK2 V617F allele burden was -9.0% (range, -56.5% to 7.0%) from BL to the end of week 24. Investigator-assessed changes in BM fibrosis in pts with BL and post-BL values indicated that 2 pts had an improvement (from grade 3 to grade 2), 8 pts remained stable, and 3 pts had a worsening from BL by the end of week 24. Pharmacokinetics of the combination will be presented. Conclusions: The combination of ruxolitinib and sonidegib has activity in pts with MF and may provide improved benefit over ruxolitinib monotherapy. Combination treatment was generally well tolerated, with ≈ 74% of pts remaining on treatment at data cutoff. Table. Most Common Adverse Events Sonidegib 400 mg Once Daily + Ruxolitinib 20 mg Twice Daily(n = 27) AEs of any cause in ≥ 10% of pts, n (%) All Grade 3/4 Anemia 14 (52) 9 (33) Muscle spasms 13 (48) 1 (4) Increased CK 10 (37) 5 (19) Myalgia 8 (30) 2 (7) Dysgeusia 8 (30) - Thrombocytopenia 7 (26) 3 (11) Diarrhea 7 (26) 1 (4) Fatigue 7 (26) 0 Pyrexia 6 (22) 1 (4) Alopecia 6 (22) - Constipation 5 (19) 0 Nausea 5 (19) 0 Abdominal pain 4 (15) 0 Dizziness 4 (15) 0 Headache 4 (15) 0 Decreased platelet count 3 (11) 1 (4) Asthenia 3 (11) 0 Cough 3 (11) 0 Decreased weight 3 (11) 0 Dry mouth 3 (11) 0 Dyspnea 3 (11) 0 Extremity pain 3 (11) 0 Increased creatinine 3 (11) 0 Disclosures Gupta: Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Ruxolitinib is a kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Sonidegib is approved for the treatment of locally advanced basal cell carcinoma. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria; Shire: Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Hasselbalch:Novartis: Research Funding. Koschmieder:Novartis Foundation: Research Funding; Baxalta/CTI: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences ; Janssen Cilag: Other: Travel reimbursement for scientific conferences ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences , Research Funding. Cervantes:Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy. Bao:Novartis Pharmaceuticals Corporation: Employment. Kalambakas:Novartis: Employment, Equity Ownership. Atienza:Novartis Pharmaceuticals Corporation: Employment. Gopalakrishna:Novartis Pharma AG: Employment. Heidel:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Two-dimensional irregular waves on a sloping bed and their impact on a bottom mounted circular cylinder is modeled by three different numerical methods and the results are validated against laboratory experiments. We here consider the performance of a linear-, a fully nonlinear potential flow solver and a fully nonlinear Navier-Stokes/VOF solver. The validation is carried out in terms of both the free surface elevation and the inline force. Special attention is paid to the ultimate load in case of a single wave event and the general ability of the numerical models to capture the higher harmonic forcing. The test case is representative for monopile foundations at intermediate water depths. The potential flow computations are carried out in a two-dimensional vertical plane and the inline force on the cylinder is evaluated by the Morison equation. The Navier-Stokes/VOF computations are carried out in three-dimensions and the force is obtained by spatial pressure integration over the wettet area of the cylinder. In terms of both the free surface elevation and the inline force, the linear potential flow model is shown to be of limited accuracy and large deviations are generally seen when compared to the experimental measurements. The fully nonlinear Navier-Stokes/VOF computations are accurately predicting both the free surface elevation and the inline force. However, the computational cost is high relative to the potential flow solvers. Despite the fact that the nonlinear potential flow model is carried out in two-dimensions it is shown to perform just as good as the three-dimensional Navier-Stokes/VOF solver. This is observed for both the free surface elevation and the inline force, where both the ultimate load and the higher harmonic forces are accurately predicted. This shows that for moderately steep irregular waves a Morison equation combined with a fully nonlinear two-dimensional potential flow solver can be a good approximation.

Abstract Bucket foundation has broad application prospects in marine engineering as a competitive foundation. By providing internal cylindrical and cruciform skirts inside the bucket foundation,. the performance of the bucket foundation can be improved . But penetration resistance will also increase. However, few large deformation numerical analysis is carried out to simulate the penetration process of the bucket foundation with internal skirts. In this paper, three-dimensional large deformation finite element (LDFE) models for bucket foundations with and without internal cylindrical and cruciform skirts considering strain softening effect of soft soil were established using the coupled Eulerian-Lagrangian (CEL) approach. It was found that the elevation of the soil surface inside the bucket is higher than that of initial soil surface when the penetration depth ratio is relatively small for the bucket foundation with internal cylindrical and cruciform skirts. However, with increase of the penetration depth ratio, the increased frictions on the cylindrical and cruciform skirts drive the soil inside the inner cylinder downward, and the elevation of the soil surface inside the inner cylinder is lower than that of initial soil surface. It is also lower than that of soil surface between outer and inner cylinders. The average lateral friction per unit area on each skirt decreases from outer to inner skirt. The soil flow can explain well for the evolution of the penetration resistance.

Abstract The present paper is concerned with the accurate prediction of nonlinear wave kinematics underneath measured time histories of surface elevation. It is desired to develop a method which is useful in analysis of offshore measurements close to wind turbine foundations. The method should therefore be robust in relatively shallow water and should be able to account for the presence of the foundation and the shortcrestedness of offshore seastates. The present method employs measurements of surface elevation time histories at one or a small number of locations and solves the associated velocity potential by minimizing the error in the free surface boundary conditions. The velocity potential satisfies exactly Laplace’s equation, the bed boundary condition and (optionally) the boundary condition on the wall of a uniform surface piercing column. This is achieved by associating one wavenumber with every wave frequency thereby sacrificing the possibility of following the nonlinear wave evolution but ensuring a good description of the wave properties locally. For shortcrested waves, the direction of wave component propagation is drawn from a known or assumed directional spectrum. No attempt is made to calculate the directional distribution of the wave field from the surface elevation measurements since this is usually not realistically possible with the available data. The method is set up for analysis with or without a uniform current, for shortcrested or longcrested waves and with or without a surface piercing column in the wave field. It has been compared with laboratory data for steep longcrested and shortcrested waves. The method is shown to be in good agreement with measurements. Since the method is based on a Fourier series of surface elevation, however, it cannot model overtopping breaking waves and associated wave impact loading. For problems where wave breaking is important, the method may serve as a screening analysis used to select wave events for detailed analysis using Computational Fluid Dynamics (CFD).

The horizontal axis tidal stream turbine with a mono-pile foundation is one of the most used devices for the exploitation of tidal stream energy, because of its convenience and low expense in construction and high efficiency in extracting energy. A 3D hydrodynamic model is developed to investigate flow field around the tidal stream turbine subjected to a steady current. After verified with the previous experimental works, the numerical model is used to study the complex flow motion around the horizontal axis tidal stream turbine with a mono-pile foundation. The numerical results show that the existence of tidal stream turbine may largely change the flow dynamics. A wake region with low velocity is formed behind the device. Water surface in front of the turbine fluctuates periodically. It is also found that the installing elevation of the turbine and the incoming flow speed have significant impacts on the mean kinetic energy and the resulting fluid force of the rotating turbine.

The WindFloat is a semi-submersible floating foundation supporting multi-megawatt wind turbines. A full-scale 2MW WindFloat demonstration unit was installed off the coast of Portugal in October 2011. Many instruments are installed on this prototype to measure the environmental conditions and the response of the platform at the site. The first section of the paper focuses on the validation of the wave measurements obtained from two radar-based wave probes onboard the platform. The wave elevation at the site is reconstructed and typical wave statistics are computed. The results are compared and validated with independent buoy measurements close to site. The second section of the paper presents estimates of prevailing wave direction and directional wave spectra based on platform motions. These results are also benchmarked with onsite buoy measurements.

Touqui et al (1986) have suggested that phosphorylation by protein kinase C of a 1ipomodulin-1 ike polypeptide extracted from platelets renders it inactive as an inhibitor of phospholipase A2. We have examined this suggestion by measuring thromboxane (Tx) B2 generation and cytosolic free calcium concentration ([Ca++]i) in stimulated, washed human platelets loaded with or without quin-2. Addition of thrombin (0.077, 0.23, 0.77, 2.3 and 7.7 nM) to control platelets produces a dose-related elevation of [Ca++]i (10±5, 50±7, 260±30, 550±25 and 1500±100 nM respectively) and generation of TxB2 (0, 9±4, 45±6, 194±10 and 375±30 pmoles/108 platelets respectively). Preincubation of platelets for 1 min with 1-oleoyl-2-acetyl-rac-glycerol (OAG, 22-198 μM), phorbol myristate acetate (PMA, 1.616 nM) or EGTA (2 mM) produces a marked inhibition of high and low dose thrombin (7.7 nM and 0.77 nM) or NaF (18 mM) induced elevation of [Ca++]i and TxB2 generation. Pretreatment of platelets with the protein kinase C inhibitor, H-7 (60 uM), prevented the inhibition of TxB2 formation induced by PMA (4.816 nM) or OAG (66-198 μM) in either thrombin (0.77 nM) or NaF (18 mM) stimulated platelets. When arachidonic acid (AA, 10 μM) is used as the stimulus, the Δ[Ca++]i is 190±15 nM and TxB2 generation is 35.9±2 pmoles/108 platelets. While pretreatment with 4.8 nM PMA obliterates the AA-induced Δ[Ca++]i and partially reduces (p< 0.05) the TxB2 generation to 27.8+3 pmoles/108 platelets. PMA and OAG pretreatment also inhibits TxB2 generation in thrombin-stimulated, non-quin-2-1oaded platelets. Thus, at least with intact, agonist- and NaF-stimulated platelets, activation of protein kinase C inhibits eicosanoid production.We thank the British Heart Foundation and Ciba-Geigy USA for financial support.

To estimate soil stiffness parameters under spudcan foundations and assess the performance of a jack-up rig, a strategy for identifying spudcan fixity of a jack-up rig based on the measured acceleration responses is developed. The finite element model of a jack-up rig is set up, in which the interaction of soil and a spudcan foundation is modeled as a system of horizontal, vertical, and rotational elastic springs. The ‘measured’ acceleration responses along each leg is archived by simulating the jack-up under a selected storm loading in the North sea, including random wave, current and wind loadings. The random wave loading is calculated using JONSWAP water surface elevation spectrum in conjunction with Morison’s equation. The spudcan fixity of a jack-up rig is effectively identified using an improved genetic algorithm (GA) method. The identification strategy proposed works by matching the time histories of the measured accelerations up with those of the numerical simulated accelerations through an objective function in GA. The results indicate that the soil stiffness parameters under spudcan foundations are exactly identified in noise free case. Error less than 1.2% in identified rotational and vertical spring stiffnesses of interest is archived with the worst case of 10% noise and only two acceleration measurements at hull. In addition, it is observed that the vertical and rotational stiffness parameters are more accurately identified than the horizontal one. The identified stiffness values of spudcan fixity help to enhance the understanding of jack-up foundation behavior and improve the operational envelop for a specific jack-up design. With full-scale measurements of environmental conditions and dynamic responses of a jack-up rig, this strategy can be employed to verify recent findings on the conservatism of predicting soil stiffness parameters.

Over the past two decades a number of advances have been made in the use of radar systems for the measurement of ocean waves, building on early work at universities and the Naval Research Lab (NRL) to investigate the potential for extracting wave field measurements from the sea clutter seen in shipboard radar images. This early work was the foundation for modern wave radar systems, with hardware systems ranging from commercial off the shelf (COTS) incoherent navigation radar to specially developed, calibrated, coherent instrumentation radar and phased-array systems. Software algorithms and image analysis techniques have also been in constant development, which have evolved from 2D analysis of digitized images into modern techniques performing real-time 3D transformation of high resolution images. Most of these systems are being utilized to measure the directional wave spectra, with some systems also providing wave height estimates and sea surface elevation maps. More recently, the Naval Surface Warfare Center, Carderock Division (NSWCCD) and others have begun to utilize these techniques for shipboard measurement of open ocean waves. All these efforts have led to higher fidelity data, as well as data that were previously unobtainable. In this paper we provide an overview and history of the development of COTS incoherent wave radar systems, analysis techniques, and capabilities, from early characterization of sea clutter return to the latest developments in image inversion and sea surface topography. This review and summary provides a foundation on which to develop analysis techniques for the higher fidelity data, using lessons learned to improve future analysis. While not intending to be exhaustive, this paper seeks to highlight the insights gained from both historical and recent applications of these techniques, as well as the difficulties and issues associated with shipboard measurements such as ship motion, logistical constraints, and environmental factors.

Fura 2 is one of a recently-introduced family of Ca++ indicators with improved fluorescent properties compared to quin 2 (Grynkiewicz et al 1985). This study has examined the role of [Ca++]i in thrombin-induced dense granule release using prostacyclin-washed human platelets loaded with either thedense granule marker 14C-5HT (5HT) alone or with 5HT together with quin 2 ([quin2]i = 0.8mM) or fura 2 ([fura 2]i 20-30µM). In the presence of ImM extracellular calcium concentration ([Ca++]i) the [Ca++]e in quin 2 and fura 2 loaded platelets was 93±2 (n=10 experiments) and 133±0.3nM (n=12 experiments) respectively. In either quin 2 or fura 2 loaded platelets suspended in the presence of ImM [Ca++]e, thrombin (0.23-23.InM) promoted a rapid (in secs)concentration-dependent elevation of [Ca++]i from basal values to levels l-2µM, together with a parallel release of dense granules almost identical to that obtained with thrombin in non dye loaded platelets. In fura 2 loaded cells, removal of [Ca++]e inhibited the elevation of [Ca++]i induced by a sub-maximal concentration of thrombin (0.77nM) by 43+5% (n=4) but interestingly had no significant effect (p<0.05) on the rise in [Ca++]i elicited by low thrombin doses (0.231nM). Neither did lowering [Ca++]e inhibit the release of 5HT evoked by thrombin ( 0.231-23.InM) from either fura 2 loaded or non dye loaded platelets. In contrast, in quin 2 loaded platelets, removal of [Ca++]e inhibited the thrombin (0.231-23.InM) stimulated rise in [Ca++]i-by 90% and the 5HT release response to either low (0.231nM), sub-maximal (0.77nM) or maximal (23.InM) thrombin by 100% (n=4), 87+2°/o (n=6)and 2+l°/o (n=4) respectively. Fura 2 but not quin 2 loaded cells suspended in ImM [Ca++]e exhibited a Ca++ response to thrombin concentrations >2.31nM which could be separated into a rapid phasic component and a more sustained 'tonic' like component inhibitable by removal of [Ca++]e or by addition of ImM Ni++ . These data suggest the use of fura 2 rather than quin 2 for investigating stimulus response coupling in platelets, particularly when [Ca++]e is less than physiological. We thank the British Heart Foundation and Ciba-Geigy USA for financial support.

This paper studies how the hydrodynamics coefficients of added mass and damping varies when an oscillating disk approaches a seabed. Analysis was performed by OpenFOAM code using the ‘PIMPLE’ algorithm. The simulations considered the flow as laminar and hence no turbulence model was used. Simulations were conducted for a solid disk of 200 mm diameter, 2 mm thick, oscillating at amplitudes varying from 1–48 mm and elevation ‘h’ of the disk from the seabed varying from 0.2–2 times the disk radius. The geometry and parameters used here were the same as that of Wadhwa et al. (2010) [1] and Vu et al. (2008) [2]. The forces on the disk were calculated using a Tool for post-processing force/lift/drag data with function tool available in OpenFOAM. The motions of the disk were restricted to axial (heave) direction. The calculated forces and displacement were analyzed using a Fourier projection to separate the added mass and damping effects. Numerical results were compared with the experiments conducted by Wadhwa et al. (2010) [1] with a sandy bottom. Results show that the added mass and damping increase monotonically with the Keulegan-Carpenter number (KC) up to a critical value, beyond which the behavior becomes random. The critical KC increases linearly with increasing distance from the seabed. The hydrodynamic problem has important applications in structures such as foundation templates and subsea structures oscillating in proximity to the seabed. The computations show vortex lines of the flow, and the influence of the seabed on the flow around the structure.