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2022 ◽  
Vol 164 ◽  
pp. 29-41
Nan Wang ◽  
Eef Dries ◽  
Ewan D. Fowler ◽  
Stephen C. Harmer ◽  
Jules C. Hancox ◽  

2022 ◽  
Vol 11 (1) ◽  
pp. 51-68
Nuanphan Chaiyama ◽  
Nimnoul Kaewpila

<p style="text-align: justify;">The purposes of this study were to explore factors and indicators of life and career skills and to develop a life and career skills in the 21st century test for undergraduate students. This research employed a mixed-method study adopting an exploratory design: instrument development model to generate research tools. This study was divided into two phases; Phase 1 was to explore factors and indicators of life and career skills in 21st century, by using a qualitative method to analyze relevant documents; Phase 2 was the development of a life and career skills in 21st century test by adopting a quantitative method to collect data from students studying in 12 universities of the north-eastern region of Thailand via the test. In the second phase, the data were analyzed by descriptive statistics and Confirmatory Factor Analysis (CFA) Results revealed that the skills consisted of 6 factors and 35 indicators, and the test comprised 105 items. The quality of the test has been examined by five expertise, the reliability of all test items is acceptable, and all 6 factors demonstrated good construct validity. Factor loadings of six factors were 0.7940 -1.7816. This study can be implemented to measure the life and career skills of undergraduate students in any university to obtain data for establishing a policy and plans for maximizing students’ potential to achieve their careers and a happy living in 21st century after their graduation.</p>

2022 ◽  
Michael J. Koren ◽  
Patrick Maurice Moriarty ◽  
Seth J. Baum ◽  
Joel Neutel ◽  
Martha Hernandez-Illas ◽  

L. A. Godoi ◽  
B. C. Silva ◽  
G. A. P. Souza ◽  
B. C. Lage ◽  
D. Zanetti ◽  

Abstract This study aims to determine the effects of dietary crude protein (CP) content of early-weaned calves; and the influence of flint maize processing methods on intake, total tract nutrient digestibilities and performance of Nellore heifer calves. Fifteen early-weaned Nellore female calves (4 ± 0.5 months; 108 ± 13.1 kg) were used. In phase 1, animals were fed one of the following diets for 112 days: 130, 145 or 160 g CP/kg dry matter (DM). In phase 2, animals received one of the two diets for 84 days: 0.60 dry ground maize grain, 0.30 whole-plant maize silage plus 0.10 mineral-protein supplement or 0.90 snaplage plus 0.10 mineral-protein supplement. In phase 1, intake and digestibility of dietary components were not affected (P > 0.05) by increasing dietary CP content. Daily total urinary nitrogen (N) and urinary urea N increased (P < 0.05) in response to increasing dietary CP content. Animal performance was not affected (P > 0.05) by dietary CP content. In phase 2, maize processing methods did not affect (P > 0.05) intake and digestibility of dietary components as well as animal performance, carcase characteristics and carcase composition. Therefore, based on the current experimental condition, we conclude that dietary CP concentrations of 130 g/kg DM can be indicated for early-weaned Nellore calves. However, more studies are recommended to validate this result and to evaluate concentrations below 130 g CP/kg DM for early-weaned Nellore calves. Moreover, snaplage could be used as an exclusive fibre and energy source for finishing cattle in feedlot.

2022 ◽  
Vol 11 ◽  
Justin Watts ◽  
Tara L. Lin ◽  
Alice Mims ◽  
Prapti Patel ◽  
Cynthia Lee ◽  

APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels &gt;0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients’ T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.

2022 ◽  
Deyun Qiu ◽  
Jinxin V. Pei ◽  
James E. O. Rosling ◽  
Dongdi Li ◽  
Yi Xue ◽  

Small-molecule inhibitors of PfATP4, a Plasmodium falciparum protein that is believed to pump Na+ out of the parasite while importing H+, are on track to become much-needed new antimalarial drugs. The spiroindolone cipargamin is poised to become the first PfATP4 inhibitor to reach the field, having performed strongly in Phase 1 and 2 clinical trials. Previous attempts to generate cipargamin-resistant parasites in the laboratory have yielded parasites with reduced susceptibility to the drug; however, the highest 50% inhibitory concentration reported to date is 24 nM. Here, we show that P. falciparum parasites can acquire a clinically-significant level of resistance to cipargamin that enables them to withstand micromolar concentrations of the drug. Independent experiments to generate high-level cipargamin resistance using different protocols and strains led to the same change each time - a G358S mutation in PfATP4. Parasites with this mutation showed high-level resistance not only to cipargamin, but also to the dihydroisoquinolone (+)-SJ733. However, for certain other (less clinically advanced) PfATP4-associated compounds the G358S mutation in PfATP4 conferred only moderate resistance or no resistance. The G358S mutation in PfATP4 did not affect parasite susceptibility to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation in the Toxoplasma gondii ATP4 homologue (G419S), decreased the sensitivity of the Na+-ATPase activity of ATP4 to inhibition by cipargamin and (+)-SJ733, and decreased the sensitivity of parasites expressing these ATP4 mutations to disruption of parasite Na+ regulation by cipargamin- and (+)-SJ733. The G358S mutation in PfATP4 reduced the affinity of the protein for Na+ and was associated with an increase in the parasite's resting cytosolic Na+ concentration; however, no significant defect in parasite growth rate was observed. Our findings suggest that codon 358 in pfatp4 should be monitored closely in the field as a molecular marker for cipargamin resistance, and that PfATP4 inhibitors in clinical development should be tested for their activity against PfATP4G358S parasites.

2022 ◽  
Alistair Malcolm Roy ◽  
Graeme Henry Allan ◽  
Corrado Giuliani ◽  
Shakeel Ahmad ◽  
Charlotte Giraud ◽  

Abstract The Greater Clair area, Europe's largest oilfield, has two existing platforms, Clair Phase 1 and Clair Ridge, on production with future potential for a third platform targeting undeveloped Lower Clair Group to the South of Ph1. Clair Phase 1 was the initial development of Clair, targeting Lower Clair Group (LCG) reservoir consisting of a complex Devonian sandstone in six units. Most Phase 1 wells penetrated relatively good quality reservoir enhanced by natural fractures, while more recently Clair Ridge wells took a similar approach targeting natural fractures, however that strategy is continually being evaluated. In some areas however low matrix quality and lack of natural fractures were the dominant characteristics resulting in lower production rates. A brief comparison of the range of production outcomes will be presented, including potential downsides of reliance on natural fractures. Given the large oil volumes in areas of known poorer rock quality, alongside variable production results, a hydraulic fracturing trial was initiated in 2017. Well 206/08-A23 (A23) targeted previously under-developed, poor-quality Unit VI within the Phase 1 Graben area where natural fractures are absent. A pre-frac production test established baseline production of 900BOPD in December 2018. The A23 objectives included subsequent hydraulically fracturing the well to test this techniques ability to unlock production from tight, matrix dominated formation. Detailed analysis of core, log and limited vertical well fracturing data (from initial fracturing trials of 1980's vintage), yielded robust designs. Key challenges included overcoming very low KV/KH ratios with fracture heights exceeding 300ft. The resulting detailed designs provided consistent and predictable hydraulic fracturing execution in A23 in 2019, including placement of four planned 500klbs treatments combined with coil clean-outs after each stage to unload solids and fluids from the well. Initial fracture designs were conservative in terms of pad and proppant scheduling which, alongside learnings around operational logistics offshore West of Shetlands and completion design, offer significant optimisations for future hydraulic fractures. Post frac A23 became the highest non-natural fractured producer across Clair. Initially a six-fold production increase was observed with monitoring of transient production ongoing. Tracer analysis confirmed production contribution from all zones. Proving fracturing technology brings opportunities to unlock poorer Phase 1 and Ridge reservoir areas. Additionally, significant portions of the undeveloped Lower Clair Group to the South of Ph1 comprises lower permeability reservoir with higher viscosity oil and reduced natural fracture presence. Hydraulic fracturing is therefore a crucial completion technique for developing this lower quality reservoir and brings significant value enhancement to the project. Efficient delivery of numerous large fractures in a harsh offshore environment West of Shetlands presents significant challenges. The influence of how the A23 fracturing results and learnings are guiding future hydraulic fracturing concept are detailed, including optimising platform engineering design to facilitate efficient fracturing operations while maintaining the required productivity in this challenging scenario.

Daniel Tobias Michaeli ◽  
Hasan Basri Yagmur ◽  
Timur Achmadeev ◽  
Thomas Michaeli

Abstract Objectives This study evaluates the association of Biopharma company valuation with the lead drug’s development stage, orphan status, number of indications, and disease area. We also estimated annual returns Bioentrepreneurs and investors can expect from founding and investing in drug development ventures. Methods SDC Thomson Reuter and S&P Capital IQ were screened for majority acquisitions of US and EU Biopharma companies developing new molecular entities for prescription use (SIC code: 2834). Acquisition data were complemented with drug characteristics extracted from, the US Food and Drug Administration (FDA), and deal announcements. Thereafter, company valuations were combined with previously published clinical development periods alongside orphan-, indication-, and disease-specific success rates to estimate annual returns for investments in drug developing companies. Results Based on a sample of 311 Biopharma acquisitions from 2005 to 2020, companies developing orphan, multi-indication, and oncology drugs were valued significantly higher than their peers during later development stages (p < 0.05). We also estimated significantly higher returns for shareholders of companies with orphan relative to non-orphan-designated lead drugs from Phase 1 to FDA approval (46% vs. 12%, p < 0.001). Drugs developed across multiple indications also provided higher returns than single-indication agents from Pre-Clinic to FDA approval (21% vs. 11%, p < 0.001). Returns for oncology drugs exceeded other disease areas (26% vs. 8%, p < 0.001). Conclusions Clinical and economic conditions surrounding orphan-designated drugs translate to a favorable financial risk-return profile for Bioentrepreneurs and investors. Bioentrepreneurs must be aware of the upside real option value their multi-indication drug could offer when negotiating acquisition or licensing agreements.

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