Letteratura scientifica selezionata sul tema "Schroeder Company"

Recent years have witnessed the rapid development of Human Resources Management. Nowadays HR issues are significant not only in domestic market but also, because of globalisation process, they are becoming more important in international companies relation. In such circumstances companies have to face new challenges and create appropriate conditions for multicultural working. Studies of Hofstede (1980) show the importance of place and culture in which people have grown up to their feelings and behaviours. Recently, researches have examined the effects of culture in International Human Resource Management. Cultural differences determinate HRM activities in most of the company subsidiaries areas of action (Schneider and Barsoux, 1997). This practise begins from staffing policy, then it is going through knowledge sharing to talent management. Thanks to effective HRM practices in these areas companies creates future competitive position (Ahmad and Schroeder, 2003). That process is strengthened by building socialization mechanism, described by Hong and Vai (2008).

Abstract Introduction The term ICUS has been used to describe patients with persistent unexplained cytopenia(s) who do not meet the minimal diagnostic criteria for MDS. While studies on ICUS have been few and small to date, it is clear that a subset of patients do progress to overt MDS or acute myeloid leukemia (AML), supporting the concept of an early or pre-phase of MDS (Wimazal, Leuk Res 2007; Hanson, Leuk Res 2009; Schroeder, Ann Oncol 2010). Through the use of NGS-based profiling, the majority of patients with MDS are now known to harbor one or more somatic mutations in driver genes, with RNA splicing and epigenetic pathways most commonly altered (Haferlach, Leukemia 2014). The aim of this study is to elucidate the genomic landscape of ICUS and to evaluate its potential relationship to lower-risk MDS. Methods DNA exon sequences in SF3B1, SRSF2, U2AF1, ZRSR2, TET2, IDH1, IDH2, DNMT3A, EZH2, ASXL1, SETBP1, TP53, PHF6, RUNX1, ETV6, CBL1, NRAS, KIT, JAK2, MPL, and NPM1 were determined from the bone marrow aspirates of 250 patients with ICUS and 90 patients with lower-risk MDS (7 MDS with isolated del(5q), 7 MDS-unclassified, 12 refractory cytopenia with unilineage dysplasia, 27 refractory cytopenia with multilineage dysplasia, and 37 refractory anemia with ring sideroblasts) using a clinically validated and sensitive NGS assay on the Illumina MiSeq platform. The lower limit of detection of the assay was 5% with a minimum depth of coverage of 500x. Mutations were compared for concordance between duplicate samples and annotated using software that queried databases and published literature containing somatic mutations and germline variants. Results One or more somatic mutations were detected in 33% (82/250) of patients with ICUS. Among this mutated subgroup (ICUS-MUT), the mean number of mutations was 1.8 per patient. TET2 mutation, postulated to be an early genetic event in the pathogenesis of myeloid neoplasms, was the most common mutation detected (38%). DNMT3A (20%), ASXL1 (18%), SRSF2 (15%), and ZRSR2 (11%) mutations were the next most common, with the remaining mutations each detected in <10% of patients. The two most common pathways involved were epigenetic (65%) and RNA splicing (18%). The mean allele frequency for mutations was 33% (range 6-99%), with 14% of mutations having an allele frequency of <10%. The most common type of mutation was missense (60%), followed by frameshift (17%), nonsense (16%), splicing (4%), and other (3%). While no significant difference was observed in the median hemoglobin, absolute neutrophil count, and platelet count between the ICUS-MUT and wild-type (ICUS-WT) subgroups, the ICUS-MUT subgroup was significantly older (78 vs. 69 years, P < 0.0001) and more commonly male (male:female ratio of 1.3:1 vs. 0.8:1, P= 0.0139). In lower-risk MDS, one or more somatic mutations were detected in 83% (75/90) of patients. The mean number of mutations was 1.8 per patient, identical to that observed in ICUS-MUT. SF3B1 mutation, which is highly associated with ring sideroblasts, was the most common mutation detected (47%). ASXL1 (16%), TET2 (14%), and DNMT3A (10%) mutations were the next most common, with the remaining mutations each detected in <10% of patients. The two most common pathways involved were RNA splicing (58%) and epigenetic (49%). The mean allele frequency for mutations was 32% (range 5-89%), with 6% of mutations having an allele frequency of <10%. The most common type of mutation was missense (66%), followed by frameshift (14%), nonsense (12%), splicing (7%), and other (1%). While no significant difference was observed in the median absolute neutrophil count, platelet count, age, and male:female ratio between lower-risk MDS and ICUS-MUT, lower-risk MDS patients were significantly more anemic (hemoglobin 9.7 vs. 10.5 g/dL, P= 0.0058). Conclusions Through the use of NGS-based profiling, one or more somatic mutations were detected in 33% of patients with ICUS. The ICUS-MUT subgroup displayed clinical parameters that were more similar to lower-risk MDS than the ICUS-WT subgroup. The ICUS-MUT subgroup was also similar to lower-risk MDS at the genomic level, with similar pathways involved, mean number of mutations, mean allele frequency, and type of mutations observed. Prior studies have shown that a subset of patients with ICUS do progress to overt MDS or AML. NGS-based profiling may be helpful in identifying those patients with potential early or pre-phase of MDS. Disclosures Kwok: Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Reddy:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Lin:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Flamholz:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Yung:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Dabbas:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. McGinniss:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Nahas:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Kines:Genoptix, Inc., a Novartis company: Employment. Xu:Genoptix, Inc., a Novartis company: Employment, Equity Ownership.

LiquidPower Specialty Products Inc. (LSPI) said it can increase the flow capacity of subsea flowlines from wells to platforms by up to 35%. Based on the company’s long history in that business, that sounds doable. The hard part is convincing users that it can dependably deliver the chemical to the offshore wells where it is needed. The delivery barrier has made subsea production lines one of the few oil pipeline markets not served by LSPI, whose history dates to 1979 when it began selling an additive, a drag-reducing agent (DRA), that dramatically increased pipeline flows. The polymer was invented by scientists at what was then Conoco, in the early 1970s. Among the inventors was Yung Lee, who is still with the company which is now owned by Berkshire Hathaway. The chemical able to increase oil flows by 80% proved popular, and its use spread around the world. Now, the maker of a product used in 80% of US oil pipelines is looking for new markets. Lines running from offshore wells to platforms look like an attractive growth market, as oil companies focus on finding oil near existing platforms where the risks and costs are low. “It is going to be substantial. It is not huge like pipelines. Still, more and more people are going to discover oil-bearing formations away from platforms,” said Lee, engineering and technical services director for LSPI. The short explanation for how LSPI’s DRA works is that the long molecular chains of the ultrahigh-weight polymer in a pipeline reduce turbulence. That allows more oil to flow through a pipe and reduces the pressure needed to do so. There are offshore markets for DRA, where it is used in large lines delivering oil to shore and in multiphase lines connecting platforms. Pipelines from subsea wells to platforms are not on the list because LSPI has been unable to find a way to deliver DRA to those remote locations. The obvious way to do so would seem to be to pump the relatively small amount of chemical needed each day through an umbilical. For more than 15 years, LSPI tried to develop a DRA molecule that would flow dependably through the narrow tube in an umbilical. The problem was “DRAs contain solid particles [polymer] that will coat the internal wall and eventually plug the umbilical,” according to a recent Offshore Technology Conference (OTC) paper describing the prolonged search (OTC 31054). That problem created an opportunity for Safe Marine Transfer, which was looking for customers needing an alternative delivery method, said Art Schroeder, CEO of the Houston company. Inside the Box Three years ago, at the OTC, LSPI met the founders of Safe Marine, who convinced them to consider delivering DRA in a box. The box intentionally looks like a cargo container. Its dimensions— 40×8×8.5 ft—make it possible to load the box on a truck and move it to a dock on its way offshore. Inside is a large, tough bladder designed to hold 200 bbl of fluid. The container allows water to enter, equalizing the pressure so the frame can stand up to extreme deepwater pressure.

Abstract The hallmark of sickle cell disease (SCD) is polymerization of deoxygenated hemoglobin S (HbS), resulting in red blood cell (RBC) sickling, oxidative and membrane damage, hemolysis, vaso-occlusion, and end-organ damage. Exacerbating the pathogenesis of SCD, the sickle RBC (sRBC) has increased 2,3-DPG levels with decreased oxygen (O 2) affinity (increased P 50) and decreased ATP. Etavopivat, a small molecule activator of erythrocyte pyruvate kinase (PKR), increases PKR activity, resulting in decreased 2,3-DPG levels and increased ATP levels in RBCs. In a Phase 1 study in patients with SCD [NCT03815695], etavopivat significantly improved anemia and hemolysis after 2 weeks of treatment (Brown et al. Blood 2020). To evaluate the potential of etavopivat to reduce vaso-occlusive crises, exploratory studies were conducted to characterize the sRBC specific (intrinsic) and systemic effects of PKR activation. Patients with SCD received once daily etavopivat 300 or 600 mg for 2 weeks or 400 mg for up to 12 weeks. Peripheral blood was collected prior to treatment (ie, baseline), on treatment and 7-28 days post treatment. Studies to assess the sRBC intrinsic effects of PKR activation included evaluation of RBC parameters and reticulocyte counts (ADVIA ®), membrane deformability (Lorrca ®), enzyme function studies, and membrane markers by flow cytometry. Studies to assess the systemic effects of PKR activation included markers of coagulation, inflammation, and hypoxia in the 12-week cohort only. As of May 24, 2021, 15 patients who completed the 2-week dose cohorts and 7 patients treated in the 12-week dose cohort were evaluable for this analysis. The intrinsic effects of etavopivat on the sRBCs of patients receiving 2 weeks of treatment are summarized in Table 1. Etavopivat significantly increased Hb and reduced reticulocytes, including immature reticulocytes (CD71 +), suggesting that an etavopivat-mediated increase in sRBC lifespan is accompanied by a decrease in erythropoietic stress. In addition, etavopivat reduced 2,3-DPG levels thereby increasing HbS O 2 affinity (decreased P 50) resulting in a significant shift in the point of sickling (PoS) to a lower partial O 2 pressure. The deformability (EI max) of the sRBCs as measured by oxygenscan and osmoscan was significantly improved with etavopivat treatment, consistent with reduced membrane damage due to decreased HbS polymerization and improved membrane repair enabled by increased ATP production, collectively improving the health of the sRBC membrane. This improvement in membrane health was further supported by a significant reduction in the external expression of phosphatidylserine (PS) following etavopivat treatment. Finally, etavopivat significantly improved enzymatic activity not only of PKR but also superoxide dismutase and glutathione reductase, enzymes involved in reducing oxidative stress in sRBCs. This suggests that etavopivat-treated sRBCs may have an improved ability to inhibit and repair damage caused by reactive O 2 species, thereby improving overall sRBC health and function. Initial results on the effect of etavopivat on systemic biomarkers that are commonly elevated in SCD are shown in Table 2. In patients receiving etavopivat 400 mg once daily for up to 12 weeks, tumor necrosis factor-a and prothrombin 1.2, as systemic markers of inflammation and hypercoagulability, respectively, showed a significant decrease compared with baseline. Furthermore, a trend towards reduced erythropoietin levels suggests that etavopivat treatment may reduce tissue hypoxia. Patients with SCD treated with etavopivat for at least 2 weeks demonstrated a significant increase in RBC membrane deformability and improved antioxidant capacity that resulted in increased sRBC survival and decreased anemia. The reduced reticulocyte count and lowered PS surface membrane expression suggest that etavopivat-treated sRBC may have reduced adhesive properties and may thus be less likely to promote vaso-occlusion. Initial studies evaluating the downstream effects of up to 12 weeks of etavopivat treatment once daily provided evidence for a reduction in markers of inflammation and hypercoagulability, with improved O 2 delivery capacity. These initial results suggest that the multimodal effects of decreased 2,3-DPG and increased ATP by PKR activation with etavopivat may have an impact on both the anemia and vaso-occlusive events that characterize SCD. Figure 1 Figure 1. Disclosures Kalfa: Agios Pharmaceuticals, Inc.: Other: Steering Committee, Research Funding; FORMA Therapeutics, Inc: Research Funding. Telen: GlycoMimetics, Inc.: Consultancy; Novartis, Inc.: Other: Data Safety Monitoring Board; Forma Therapeutics, Inc.: Consultancy, Research Funding; CSL Behring, Inc.: Research Funding; Doris Duke Charitable Foundation: Research Funding; National Institutes of Health: Research Funding. Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Brown: Novo Nordisk: Consultancy; Imara: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Forma Therapeutics: Research Funding. Larkin: Forma Therapeutics, Inc.: Research Funding. Ribadeneira: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Schroeder: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Wu: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Kelly: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Kuypers: Forma Therapeutics, Inc.: Research Funding.

Abstract Etavopivat is a small molecule activator of erythrocyte pyruvate kinase (PKR), that increases PKR activity, resulting in decreased 2,3-DPG and increased ATP in red blood cells (RBCs) of healthy volunteers (HV) and patients (pts) with sickle cell disease (SCD) (Kalfa 2019, Brown 2020). Based on initial safety, pharmacokinetic (PK) and pharmacodynamic (PD) data for HVs and pts with SCD, we performed multiple-dose studies in pts with SCD (NCT03815695): 2-wk multiple ascending dose (MD) cohorts to identify the once daily etavopivat dose that provides maximum PD activity with an acceptable safety profile and a 12-wk open label (OL) study to further characterize the safety and clinical activity at the maximum PD dose. These data are presented here. In the completed MD cohorts, 20 pts with SCD were randomized 8:2 to receive etavopivat (300 mg, then 600 mg) or placebo (PBO) once daily for 2 wks. In the ongoing OL cohort, up to 20 pts will receive etavopivat 400 mg once daily for 12 wks. Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and peripheral blood laboratory parameters. PK/PD blood sampling was performed for up to 72 h after last dose and at end of study visit. RBC function studies were performed to assess membrane deformability (Lorrca ®). Enrollment in the MD cohorts (n=17 HbSS, n=2 HbSβ+thalassemia, n=1 HbSC) is complete and data unblinded (n=8: 300 mg etavopivat; n=8: 600 mg etavopivat; n=4: PBO). As of July 13, 2021, 11 pts (n=10 HbSS, 1 HbSC) have been treated in the OL cohort: median treatment duration was 12 (range 1-12) wks, 6 pts completed 12 wks of treatment. In MD pts, etavopivat demonstrated dose-proportional PK with overlapping PD responses (decreased 2,3-DPG and increased ATP), confirming prior results in HVs that etavopivat 400 mg once daily provides near maximal PD activity. Etavopivat was well tolerated in both MD and OL cohorts. AEs were reported in 1 of 4 (25%) MD PBO pts, most were grade (gr) ≤3, with 1 gr 4 blood creatine phosphokinase (CPK) increase. 13 of 16 (81%) etavopivat-treated MD pts reported AEs, most were gr 1/2 and commonly (&gt;2 pts) included sickle cell pain (n=6 [38%]), headache (n=5 [31%]), and nausea (n=3 [19%]). One pt had a serious AE (SAE) of gr 3 vaso-occlusive crisis (VOC) after completion of etavopivat (considered unrelated). In the OL cohort, AEs were reported in 7 of 11 (64%) pts who received at least 1 wk of etavopivat. AEs reported in &gt;1 pt were headache and VOC (n=2 [18%] each). Most AEs were gr 1/2; one pt had SAEs of gr 3 acute chest syndrome and VOC (unrelated), one pt had an SAE of gr 3 deep vein thrombosis (possibly related), and one pt had an AE of gr 4 transient blood CPK increase (unrelated). Hematologic and hemolytic parameters were significantly improved at end of treatment in both MD and OL cohorts (Table 1); 11 of 15 (73%) evaluable MD pts achieved a Hb increase ≥1g/dL over baseline (mean 1.1 g/dL, P&lt;0.004). Decreases in absolute reticulocyte count (ARC), indirect bilirubin and lactate dehydrogenase (LDH) were observed (Table 1). These initial observations were sustained in pts receiving up to 12 wks of etavopivat in the OL cohort (Table 1, Fig. 1). Of 6 pts who completed 12 wks of etavopivat treatment, 5 (83%) achieved &gt;1g/dL Hb increase over baseline (mean 1.39 g/dL). Reductions in ARC, indirect bilirubin and LDH were also observed. Of 9 pts on etavopivat for at least 4 wks, 8 (89%) reported an increase in Hb &gt;1g/dL, and the highest mean Hb increase was 1.81 g/dL during active treatment. Etavopivat-treated RBCs from MD pts (n=14) demonstrated improved functional health, including point of sickling and deformability. The improved deformability persisted up to 1 wk after etavopivat treatment in 36% of pts. Similar results were observed in the initial OL pts. Data on additional treated pts will be presented. Etavopivat 400 mg once daily for up to 12 wks was well-tolerated, with a safety profile consistent with underlying SCD. Increases in Hb &gt;1 g/dL were observed in 89% of pts and maintained throughout 12 wks of treatment in the majority (83%) of pts. Increased Hb and a significant reduction in ARC indicated that etavopivat enhanced survival of sickle RBCs and significantly improved the severe anemia associated with SCD. These longer-living sickle RBCs have improved membrane health that may further reduce the risk of VOCs and end-organ damage. These results support further evaluation of etavopivat in the ongoing Phase 2/3 Hibiscus Study in pts with SCD (NCT04624659). Figure 1 Figure 1. Disclosures Brown: Imara: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Novo Nordisk: Consultancy; Forma Therapeutics: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Idowu: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics, Inc.: Research Funding; Ironwood: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kalfa: Agios Pharmaceuticals, Inc.: Other: Steering Committee, Research Funding; FORMA Therapeutics, Inc: Research Funding. Geib: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Forsyth: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Schroeder: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Wu: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Kelly: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Telen: GlycoMimetics, Inc.: Consultancy; Novartis, Inc.: Other: Data Safety Monitoring Board; Forma Therapeutics, Inc.: Consultancy, Research Funding; CSL Behring, Inc.: Research Funding; Doris Duke Charitable Foundation: Research Funding; National Institutes of Health: Research Funding.

Abstract Background Long-term survival and late mortality risk compared to general population for patients (pts) who underwent an allogeneic hematopoietic cell transplant (HCT) is unknown. We analyzed long-term outcomes of 2-year (yr) HCT survivors with acute lymphoblastic leukemia (ALL). Methods Adult pts with ALL who were alive and relapse-free at 2 yrs after first HCT from 2005-2012 were included. We excluded patients who had a cord blood transplant and ex vivo T cell depletion (TCD). Relative survival analysis was used to estimate HCT-related crude mortality taking into account for background population mortality rates of the general population, matched for age, sex, and country in the year of HCT (www.mortality.org). Results A total of 2701 pts were included with a median follow up interval of 99 months and median age of 34 (range 18 - 73.5) yrs. The majority (78.6%) of pts were in 1 st complete remission (CR1) with undetectable MRD (68.3%). There were similar numbers of matched sibling donor (MSD) (43.7%) and unrelated donor transplants (MUD) (53.2%). Most pts received myeloablative conditioning (MAC) (86.5%) and peripheral blood (PB) grafts (75.7%) without in vivo TCD (55.7%). The 10-yr probability for overall survival (OS) and leukemia-free survival (LFS) was 81.3% and 78.2%, respectively. Cumulative incidence of disease relapse and non-relapse mortality (NRM) at 10 years was 9.9% and 11.9%, respectively. The probability of chronic GVHD-relapse-free survival (cGRFS) at 10-yrs was 73.3% (Figure 1). Relapsed ALL and chronic GVHD were common causes of late mortality accounting for 33.9% and 29% of reported deaths, respectively, followed by infection and secondary malignancy. For patients transplanted in countries with available mortality data (92% of patients in our cohort), the probability of dying from another cause is negligible at 1.5% compared to the probability of dying from HCT (16.8%) 10 years after HCT (Figure 1F). Conclusions In a large registry-based study, we showed excellent long-term survival of 81.3% at 10-yr among the 2-yr survivors of HCT for ALL. There was no difference in long term outcomes with respect to conditioning intensity, but utilization of BM graft and in vivo TCD resulted in lower NRM, and better OS. Long-term mortality risk among HCT survivors remains significantly higher than expected for the general age-matched population. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Schroeder: Celgene: Honoraria, Other: Travel support, Research Funding. Bethge: Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Nicholson: Pfizer: Consultancy; BMS/Celgene: Consultancy; Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; Novartis: Consultancy, Other: Conference fees. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Peric: Therakos, Servier, MSD, Astellas, Novartis, Abbvie, Pfizer: Honoraria. Dholaria: Janssen: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Theoretical basis Brands are socially constructed (Askegaard, 2006) and are culturally dependent on the “cultural codes of branding” by taking into consideration the history, images and myths that can influence brand meaning (Schroeder, 2009). Brands can be of great value when they hold a favorable image in the consumer’s mind (Anholt, 2010). Regional differences and demographics can impact what has a favorable image in the consumer’s mind and can bias the expectancy set for consumers. When selecting a brand name, the SMILE and SCRATCH test should be used (Neck et al., 2018; Watkins, 2014). This name evaluation test can be used to assess the strength of a brand name. If the name has these five qualities, it should be kept, or you should “smile”: suggestive – it evokes positivity; meaningful – customers can understand it; imagery – it is visually memorable; legs – it lends itself well to a theme to run with; and emotional – it resonates with your market. On the contrary, if the name has any of these traits, it should be “scratched”: spelling-challenged – it is hard to spell; copycat – it is too similar to competitors’ names; restrictive – it would be hard to grow or evolve with; annoying – it is annoying; tame – it is lame or uninspired; curse of knowledge – only insiders or some people will understand it; and hard-to-pronounce – it is hard to say (Neck et al., 2018; Watkins, 2014). The marketing mix or 4P’s of marketing – product, price, promotion and place – is a set of tools business owners can use to achieve their marketing goals and is based on McCarthy’s (1960) work. The S.A.V.E. framework – solution, access, value and education (Ettenson et al., 2013) – has more recently been cited as a more modern replacement to the long used 4P’s model (Ettenson et al., 2013). Through this framework, business owners can work to align their brand to provide a solution to customers’ problems, give them access to the solution, provide value for customers and educate them about the product or service. The S.A.V.E. framework focuses on solutions, access, value and education rather than product, place, price and promotion. In this framework, the business should focus on meeting their customers’ needs and being accessible to customers along their entire journey from hearing about the company to making a purchase. Additionally, companies should provide value for their customers rather than solely worrying about price, and instead educate customers by providing information they care about (Ettenson et al., 2013; Neck et al., 2018). Research methodology Teaching case. Case overview/synopsis This case presents the story of Big Momma’s, a coffee shop in a deteriorated historic district in Springfield, Missouri. Big Momma’s owner Lyle, a black man in a predominantly white region, was new to the area and launched the business quickly, without much market testing of the concept or brand. Soon after launching, Lyle wondered if he was set up for doom as customers constantly ask for Momma or barbeque. It seemed necessary to take a critical look at the marketing and branding plans. Complexity academic level This case could have multiple uses, primarily for early stage undergraduate students studying entrepreneurship or integrated marketing communications. The case lines up nicely with the following textbook lessons. Entrepreneurship: the case can be used with Entrepreneurship: The Practice and Mindset (Neck et al., 2018), chapter 16, lesson on branding with a specific tie to the SMILE and SCRATCH test described in Table 16.1 and the S.A.V.E. framework described on pages 453–454. It can also be used with Entrepreneurship (Zacharakis et al., 2018), chapter 6, lesson on marketing strategy for entrepreneurs with a specific tie to the sections on marketing mix and value proposition described on pages 183–198. Integrated marketing communications: this case can be used with Advertising, Promotion, and Other Aspects of Integrated Marketing Communications (Shrimp and Andrews, 2013), chapter 3, lesson on brand naming. Supplementary materials Teaching notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes.

Abstract Introduction: Haploidentical peripheral blood allogeneic hematopoietic cell transplantation (PB haplo-HCT) can be complicated by graft-versus-host disease (GVHD) and cytokine release syndrome (CRS). Acute GVHD rates are higher with PB grafts compared with bone marrow, affecting 35-45% of patients and outcomes are poor in steroid refractory cases. Severe CRS occurs in 10-15% of patients receiving PB haplo-HCT and is associated with high non-relapse mortality and dismal one year overall survival between 25-30%. As interferon-γ and IL-6 are important mediators in both acute GVHD and CRS, we hypothesized that JAK1 inhibition with itacitinib could prevent these toxicities without impairing engraftment. Here we report the clinical outcomes from our pilot study of itacitinib with haplo-HCT (NCT03755414). Methods: Patients with AML, ALL, or NHL in remission undergoing PB haplo-HCT were treated with itacitinib 200 mg/day on days -3 through +100, followed by a taper. Myeloablative and reduced intensity conditioning were allowed. GVHD prophylaxis was tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide. Primary outcomes were incidence of primary graft failure and incidence of grade III-IV acute GVHD. Secondary outcomes included incidence and severity of CRS (graded by Lee criteria). Peripheral blood and serum samples were banked prior to conditioning and on days -1, 1, 3, 7, 14, 28, 60, 100, end of treatment, and time of diagnosis of acute GVHD. Matched control samples were collected from patients undergoing haplo-HCT off clinical trials. Correlative studies include flow cytometry (FACS) with five 28-color panels for cellular subsets, mass cytometry (CyTOF) with 40-colors for intracellular signaling events, single cell RNA sequencing, and serum cytokine and chemokine measurements. Results: Twenty of a planned 20 patients completed enrollment and underwent haplo-HCT between 11/2019 and 3/2021. Median age at transplant was 49 (21-74). Diagnoses were AML (13), ALL (5) and NHL (2). Median follow up is 319 days, with 18/20 beyond 180 days. There were no cases of engraftment failure with short median times to neutrophil (14 days, range 12-20) and platelet (14 days, range 7-54) engraftment (historical 16 and 25 days, respectively). There were no cases of grade III-IV acute GVHD. The incidence of grade II acute GVHD on day 100 was 15%. Two patients developed grade I-II skin acute GVHD during itacitinib taper and responded to resumption of a higher dose. There were no cases of extensive chronic GVHD. There were no cases of severe CRS (historical rate 17%), with 90% of patients having grade 1 CRS and 10% having no CRS. Furthermore, no anti-IL6R or steroid therapy was used. Overall survival at day 180 was 90% (95% CI 75-100%) by Kaplan-Meier estimate. Incidence of relapse at 180 days was 5.5% (95% CI 0-15.6%). Refined GVHD and relapse-free survival at 180 days was 83% (95% CI 68-100%). All patients had full donor engraftment and &gt;95% chimerism at day 100. FACS and CyTOF have been performed and analyzed for the day 28 time point from 14 patients and four controls. Flow cytometry revealed no difference in cell subset numbers between controls and patient samples. CyTOF revealed differences in intracellular signaling molecules between itacitinib and control patients - including higher Ki-67, pNF-κB, and Caspase3 in controls. Phospho-Stat1 and pStat3 were lower CD4 T subsets. FACS and CyTOF at remaining time points, single cell RNA sequencing, and serum cytokine and chemokine measurements are underway and will be presented at the ASH 2021 meeting. Conclusions: Itacitinib with PB haplo-HCT was safe with no engraftment failure and prompt engraftment. Rates of acute and chronic GVHD were low, without increased risk of relapse or transplant related mortality. Severe CRS was not seen in this trial, and no anti-IL6 or steroid therapy was used. Flow cytometry demonstrated comparable immune reconstitution in terms of cell lineage and number between treated patients and controls. Mass cytometry revealed lower Ki-67, pNF-κB, and caspase3 levels, among other markers, which suggest lower immune cell activity, proliferation, and apoptosis. An extension cohort of 20 additional patients is enrolling. Multi-platform correlative studies are underway, comparing samples from haplo-HCT patients treated with and without itacitinib. Figure 1 Figure 1. Disclosures Uy: Astellas: Honoraria, Speakers Bureau; Novartis: Consultancy; Agios: Consultancy; Jazz: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Macrogenics: Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Pusic: Syndax: Other: Advisory Board. Schroeder: Equillium Inc: Honoraria; Janssen: Honoraria; Sanofi Genzyme: Honoraria.

T2D in youth remains challenging to manage and there is need for an expanded treatment armamentarium. The DINAMO study was designed to overcome recruitment difficulties that plagued previous T2D studies in youth. Within 3 years, DINAMO enrolled 158 patients aged to &lt;18 years at 64 sites in 12 countries with HbA1c 6.5-10.5% on metformin and/or insulin. Unique to this study, participants with a modifiable exclusion initially could be re-screened up to 5 times. Patients were randomized to linagliptin (5 mg) , empagliflozin (mg) , or placebo (1:1:1) . At week 12, 50% of empagliflozin patients who could not attain HbA1c &lt;7.0% were re-randomized to either remain on mg or increase to 25 mg. HbA1c change from baseline to week 26 was the primary efficacy endpoint and safety was evaluated over 52 weeks. The main reason for screen failure was HbA1c out of range (57%) . Baseline characteristics of participants are shown below. The study will be completed in fall 2022. Innovative approaches (e.g., testing multiple agents against a single placebo, re-screening patients with modifiable exclusion criteria, using a consortium model to consolidate efforts of several centers, and creating a Steering Committee to adjust study design) can successfully overcome the challenges of conducting clinical trials in youth with T2D. Disclosure L.M. Laffel: Advisory Panel; Medtronic, Roche Diabetes Care. Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. T. Danne: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Lilly, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Sanofi, Ypsomed AG. Research Support; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Lilly, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Sanofi, Ypsomed AG. Stock/Shareholder; DreaMed Diabetes, Ltd. W.V. Tamborlane: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Medtronic, Novo Nordisk, Sanofi, Takeda Pharmaceutical Company Limited. G.J. Klingensmith: Research Support; AstraZeneca, Novo Nordisk, Takeda Pharmaceutical Company Limited. Stock/Shareholder; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. C. Schroeder: Employee; Boehringer Ingelheim Inc. D. Neubacher: Employee; Boehringer Ingelheim International GmbH. N. Soleymanlou: Employee; Boehringer Ingelheim Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals Inc. J. Marquard: Employee; Boehringer Ingelheim Inc. P. Zeitler: Consultant; Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Takeda Pharmaceutical Company Limited. S.M. Willi: Advisory Panel; Boehringer Ingelheim International GmbH, Medtronic. Research Support; Jaeb Center for Health Research, Provention Bio, Inc. Other Relationship; National Institute of Diabetes and Digestive and Kidney Diseases. Funding Boehringer Ingelheim

The bulk of this chapter addresses the question: what is the proper semantics for deontic modal expressions in English? We consider a representative sample of recent challenges to a Kratzer-style formal semantics for modal expressions, as well as the rival views—Fabrizio Cariani’s contrastivism, John MacFarlane’s relativism, and Mark Schroeder’s ambiguity theory—those challenges are thought to motivate. We argue that the challenges can be met and that the rival views face challenges of their own. Our overall conclusion is that a Kratzer-style semantics remains the one to beat. With this assumption in place, we turn to the question: what is the connection between true deontic modal statements and normative reasons? We argue that acceptance of Kratzer’s semantics for deontic modals can, in many cases, leave open for substantive normative theorizing the question of whether an agent has a normative reason to comply with what she ought to do.

Abstract The Japanese electronics companies that opened production facilities in the United States during the 1980s faced the same kinds of intercultural challenges in managing a foreign workforce that are common to all multinational corporations (MNCs). As several chapters in the present volume indicate, many MNCs have found these intercultural challenges to be an integral part of transferring advanced manufacturing practices. For example, Nakamura, Sakakibara, and Schroeder (chapter 11, this volume) effectively argue that the fluidity of the U.S. labor market may jeopardize the returns on investment in human capital in the United States that Japanese companies have come to expect at home. We describe here the complementary risks of investing in expatriate supervisors. In the present chapter, we illustrate these risks by analyzing the role that expatriate supervisors played in one such Japanese company.

This chapter explores three musicals for which Young co-wrote the libretto and/or lyrics: The Red Petticoat (music by Jerome Kern, text co-written with Paul West), When Love Is Young (music by William Schroeder, text co-written with William Cary Duncan), and His Little Widows (also with Schroeder and Duncan). The Red Petticoat and When Love Is Young were adaptations of earlier plays by Young. For both, the chapter compares Young’s original script with its musical libretto to try to distinguish Young’s writing style and voice from those of her collaborators. This task was more challenging for His Little Widows, as there was no previous material with which to compare it. Again, for each show, the chapter provides a synopsis and analysis of the libretto and lyrics.

Abstract Objectives/Scope Single well deconvolution (von Schroeter et al., 2001) has been added to the well test interpretation toolbox nearly twenty years ago. In recent years, the single well deconvolution algorithm has been extended to multiple interfering wells (Cumming et al., 2013), and further improved with the additions of constraints to account for existing a-priory knowledge on the reservoir (constrained multiwell deconvolution, Cumming et al., 2019). The main objective of multiwell deconvolution is to identify the signatures of all wells involved and the interference signals between wells, from which information can be extracted about the reservoir that may not be obtainable otherwise, e.g. heterogeneities, boundaries and compartmentalization. The single well deconvolution algorithm has also been shown to be capable of restoring erroneous or missing rates (Gringarten, 2010). As shown in this paper, the same is true with multiwell deconvolution, which is able to restore erroneous or missing rates in all the wells involved. Methods, Procedures, Process Starting with arbitrary initial guesses for the missing rates in the various wells involved, we use multiwell deconvolution to estimate these missing flow rates or correct for erroneous ones. Two methods are presented: (1) we use unconstrained multiwell deconvolution as a first step to estimate the missing/erroneous rates, then use constrained multiwell deconvolution with these rates to estimate deconvolved derivatives; and (2) we restore/correct the flow rates and derive deconvolved derivatives simultaneously using constrained multiwell deconvolution. We show that the first approach is more accurate than the second one. In both approaches, we only obtain rates that are proportional to the true flow rates. To obtain the true flow rates, we need to know either one of the actual flow rates in each well, or the corresponding permeabilities. Results, Observations, Conclusions We prove the ability of multiwell deconvolution to estimate rates on synthetic oil reservoirs and gas reservoirs with moderate average reservoir pressure depletion, that include non-interfering wells. We then apply to oil and gas field examples and compare restored vs. actually measured rates. In all cases, the agreement is very good. Novel/Additive Information Using only measured pressure data, constrained multiwell deconvolution can be used to restore unknown flow rates and/or correct for erroneous rates, in addition to estimating deconvolved derivatives of all wells. This is particularly useful in the case of allocated rates or when rates are missing in some of the interfering wells.