Impact of Obesity on Voriconazole Pharmacokinetics among Pediatric Hematopoietic Cell Transplant Recipients

ABSTRACT Voriconazole (VCZ) is an antifungal agent with wide inter- and intrapatient pharmacokinetic (PK) variability and narrow therapeutic index. Although obesity was associated with higher VCZ trough concentrations in adults, the impact of obesity had yet to be studied in children. We characterized the PK of VCZ in obese patients by accounting for age and CYP2C19 phenotype. We conducted intensive PK studies of VCZ and VCZ N-oxide metabolite in 44 hematopoietic stem cell transplantation (HSCT) recipients aged 2 to 21 years who received prophylactic intravenous VCZ every 12 hours (q12h). Blood samples were collected at 5 and 30 minutes; at 1, 3, 6, and 9 hours after infusion completion; and immediately before the next infusion start. We estimated PK parameters with noncompartmental analysis and evaluated for an association with obesity by multiple linear regression analysis. The 44 participants included 9 (20%) with obesity. CYP2C19 metabolism phenotypes were identified as normal in 22 (50%), poor/intermediate in 13 (30%), and rapid/ultrarapid in 9 patients (21%). Obesity status significantly affects the VCZ minimum concentration of drug in serum (Cmin) (higher by 1.4 mg/liter; 95% confidence interval [CI], 0.0 to 2.8; P = 0.047) and VCZ metabolism ratio (VCZRATIO) (higher by 0.4; 95% CI, 0.0 to 0.7; P = 0.03), while no association was observed with VCZ area under the curve (AUC) (P = 0.09) after adjusting for clinical factors. A younger age and a CYP2C19 phenotype were associated with lower VCZ AUC. Obesity was associated with decreased metabolism of VCZ to its inactive N-oxide metabolite and, concurrently, increased VCZ Cmin, which is deemed clinically meaningful. Future research should aim to further characterize its effects and determine a proper dosing regimen for the obese.

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Donor T Cells from B Cell Deficient Mice Inhibit B Cell Development in Normal Recipients after Hematopoietic Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.3265.3265 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3265-3265

Author(s):

Antonia M.S. Mueller ◽

Jessica A. Allen ◽

David Miklos ◽

Judith A. Shizuru

Keyword(s):

T Cells ◽

B Cell ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Cell Transplant ◽

Hematopoietic Cell Transplant ◽

Hematopoietic Stem ◽

Donor Chimerism ◽

Donor T Cells ◽

The Impact

Abstract Allogeneic hematopoietic cell transplant (HCT) recipients often exhibit B cell (BC) lymphopenia due, in part, to graft-versus-host-disease (GVHD). Here, we studied the impact of donor T cells (TC) on BC deficiency post minor antigen-mismatched HCT. Following lethal irradiation, BALB.B mice were given FACS purified hematopoietic stem cells (HSC: cKIT+Thy1.1loLin-Sca-1+) alone, with whole splenocytes (SP), CD4 or CD8 TC from minor antigen-mismatched C57BL/6 (B6) mice. Chimerism analyses were performed on day (d) 30, 60, and 90. When pure HSC were transplanted, BCs reconstituted promptly (median 33% of lymphocytes [d30]; 61% [d60]; 74% [d90]), whereas TC engraftment was retarded and did not achieve full donor chimerism. Addition of SP or CD4 TCs, or to a lesser degree CD8 TCs, delayed BC reconstitution, with extremely low percentages of BCs beyond d60. This BC suppression correlated with the degree of acute GVHD, and BC numbers increased with recovery from GVHD. Additionally, this BC suppression was in stark contrast to TC development, with TC transfer resulting in early conversion to full donor chimerism. To test if previous events in the donor sensitize TCs against BC features (e.g. minor antigens), thereby promoting anti-BC cytotoxicity post-HCT, TCs from B6 muMT mice were co-transplanted with HSC. muMT mice are devoid of mature BCs because they lack the mu chain; consequently, their TCs were not exposed to BCs prior to transfer. Remarkably, BC engraftment was completely prevented through d90. TCs regenerated faster, but the vast majority originated from spleen and not HSC. To differentiate this lack of BC engraftment from GVHD-associated, alloreactive BC lymphopenia, syngenic B6 recipients were used. Again, initially complete blockade of BC engraftment was observed, although this suppression was overcome earlier post-HCT as compared to the minor-mismatched pair (median % BC d60: ’HSC only’ recipients 52%; +CD4 17%; +CD8 48%). To clarify if this phenomenon was a purely cytotoxic reaction of muMT TC against BCs, we used WT B6 HSC +/− SP as donors and lethally or sublethally irradiated muMT mice as recipients. All groups, including sublethally irradiated animals, where host muMT TC were still present, engrafted BCs making a direct anti-BC cytotoxicity unlikely as the sole cause of the BC inhibition. FACS analysis of bone marrow was used to assess the developmental stages of BCs (Hardy fractions (Fr.) A-F) and revealed GVHD recipients with peripheral B lymphopenia have a shift of B220+ cells from more mature Fr. D-F to immature Fr. A-C stages and a lower proportion of IgM expressing BC. Recipients of the muMT TCs showed, in addition to a shift to more immature stages, a clear block in BC development with an absent switch to the expression of IgM (stage D to E)(Fig. 1). In conclusion, muMT TCs are capable of blocking BC maturation when transferred into WT mice, suggesting defective TC activity in muMT animals necessary for the co-development of both BCs and TCs. Furthermore, this study provides evidence that mature TCs are capable of interfering with BC regeneration post-HCT. Hence, our HCT combinations using WT and muMT B6 mice provide a powerful tool to study the role of TC function in the process of donor BC development post-HCT.

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Race as a Factor in Donor Selection and Survival of Children with Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplant in Florida

10.22541/au.161800122.22940406/v1 ◽

2021 ◽

Author(s):

Biljana Horn ◽

Deepak Chellapandian ◽

Nikhil Lamba ◽

Gauri Sunkersett ◽

Jorge GalvezSilva ◽

...

Keyword(s):

Hematologic Malignancies ◽

Unrelated Donor ◽

Cell Transplant ◽

Hla Matching ◽

Hematopoietic Cell Transplant ◽

Hematopoietic Stem ◽

Significant Difference ◽

Related Donor ◽

The Impact ◽

To Receive

Background Previous studies have explored post-hematopoietic cell transplant (HCT) outcomes by race in adults; however, pediatric data addressing this topic are scarce. Procedure This retrospective registry study included 238 White (W) and 57 Black (B) children with hematologic malignancies (HM) receiving first allogeneic HCT between 2010 and 2019 in one of five Florida pediatric HCT centers. Results We found no differences between W and B children by transplant characteristics, other than donor type. There was a significant difference in use of HLA-mismatched donors (HLA-MMD) (53% W, 71% B, p=0.01). When comparing HLA-MMD use to fully HLA-matched donors, B had RR of 1.47 [95% CI 0.7-3] of receiving a mismatched unrelated donor (MMUD), RR of 2.34 [95% CI 1.2-4.4] of receiving a mismatched related donor (MMRD), and a RR of 1.9 [95% CI 0.99-3.6] of receiving a mismatched cord blood donor (MMCBD) HCT, respectively. There was no significant difference in the incidence of aGVHD (48% W, 35% B), p=0.1 or cGVHD (19% W 28% B, p=0.1), or primary cause of death. Overall 24-month survival was 61% [95% CI 54-68%] for W, and 60% [95% CI 38-68] for B children, log-rank p=0.72. While HLA matching improved survival in W children, the number of B children receiving HLA-matched HCT was too small to identify the impact of HLA matching on survival. Conclusions In this contemporary cohort of children with HM we found that B children were more likely to receive HLA-MMD transplants, but this did not adversely affect survival or GVHD rates.

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1762. Genotype Prevalence and Molecular Characteristics of Human Adenovirus in Pediatric Hematopoietic Stem Cell Transplant Recipients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1625 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S648-S649

Author(s):

Jesse Blumenstock ◽

Despoina M Galetaki ◽

Craig L K Boge ◽

Sydney G Shuster ◽

Alix Seif ◽

...

Keyword(s):

Molecular Typing ◽

Human Adenovirus ◽

Common Species ◽

Molecular Characteristics ◽

Cell Transplant ◽

Hematopoietic Cell Transplant ◽

Convenience Sample ◽

Hematopoietic Stem ◽

Clinical Specimens ◽

The Impact

Abstract Background Human adenovirus (HAdV) is a documented source of morbidity and mortality after hematopoietic cell transplant (HCT); however, there are limited data documenting HAdV species and type in this population. Understanding the molecular characteristics of HAdV could inform the development and assessment of interventions. The species and type of HAdV-positive specimens are detailed using an archived convenience sample of specimens obtained in pediatric HCT recipients. Methods The cohort included autologous and allogeneic HCT recipients between January 2000 and December 2013. An archived clinical repository of frozen specimens was interrogated to identify residual HAdV-positive specimens, which were sent to Lovelace Respiratory Research Institute (LRRI) to determine species and type. Medical chart review was performed to determine whether an isolate was related to HAdV disease or HAdV-attributable death. Results There were 547 HAdV PCR-positive clinical specimens from 87 HCT recipients. Of the 547 specimens, 289 were identified from an archived repository and sent to LRRI to determine species and type, and HAdV was successfully isolated and typed from 61 (Figure 1). Species C was the most common species (59.0%) with C2 being the most frequent type (34.4%). Of the 15 recipients with type C2, plasma was the most common specimen source (57.1%). Three recipients with C2 had this species and type detected from multiple sources (Tables 1 and 2). Among those with a typing result, type C2 also was responsible for 33.3% of all HAdV-attributed disease and 38.1% of all HAdV-attributed death. Conclusion Species C was the most common species to be isolated in a convenience sample of HAdV-positive clinical specimens from a single-center cohort of pediatric HCT recipients. Type C2 was most commonly associated with HAdV disease and attributable death. These results suggest HAdV species and type influence the impact of HAdV in this patient population. The findings need to be confirmed in prospective cohorts but suggest real-time molecular typing may be relevant and provide possible targets for the development of future interventions. These results must be interpreted with caution; not all clinical specimens were available for molecular typing, and it is possible C2 is easier to isolate from archived specimens. Disclosures All authors: No reported disclosures.

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The impact of the intellectual capital components on firm’s performance in emerging markets

Risk Governance and Control Financial Markets & Institutions ◽

10.22495/rgcv11i2p1 ◽

2021 ◽

Vol 11 (2) ◽

pp. 8-17

Author(s):

Noomen Chaabane

Keyword(s):

Human Capital ◽

Intellectual Capital ◽

Stock Exchange ◽

Linear Regression Analysis ◽

Value Added ◽

Multiple Linear Regression Analysis ◽

Future Research ◽

Structural Capital ◽

Stock Market Performance ◽

The Impact

The objective of this research is to review, analyse, and provide empirical evidence about the impact of the intellectual capital (IC) characteristics on the firm performance on listed 26 companies in Tunisian Stock Exchange for the years 2010–2019. 260 companies were taken as a sample of this research using the purposive sampling method. The efficiency of intellectual capital was measured using the value added intellectual coefficient (VAIC) method developed by Pulic (2000). The research method used was multiple linear regression analysis. Our empirical analysis substantiates the fundamental role of IC components in improving the financial and stock market performance of listed Tunisian companies. The results obtained on the human capital efficiency variable contribute to improving the market of Tunisian listed companies and confirm the role attributed to human capital in the knowledge economy and even the basic hypothesis of the VAIC method. Investors do not place any importance on the following variables: structural capital, human capital and the efficiency of structural capital during market valuation. Future research is suggested to use cross-country companies as the sample.

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The strong influence of sound corporate governance on economic Growth: evidence from Zimbabwe

Problems and Perspectives in Management ◽

10.21511/ppm.15(2-2).2017.13 ◽

2017 ◽

Vol 15 (2) ◽

pp. 445-455 ◽

Cited By ~ 1

Author(s):

Alexander Maune

Keyword(s):

Economic Growth ◽

Corporate Governance ◽

Linear Regression Analysis ◽

Secondary Data ◽

Political Stability ◽

Multiple Linear Regression Analysis ◽

Policy Formulation ◽

Future Research ◽

P Value ◽

The Impact

The study examined the impact of sound corporate governance on economic growth in Zimbabwe using an econometric model. A multiple linear regression analysis was employed to examine the relationship. Secondary data for the period 1968 to 2015 was collected from World Bank’s Worldwide Governance and World Development Indicators databases. It was found that sound corporate governance is significantly correlated to economic growth in Zimbabwe in a positive and negative manner with a p-value of 0.000023235 at 5% level of confidence. On one hand, control of corruption is negatively significantly related to economic growth and, on the other hand, political stability and absence of violence/terrorism positively significantly related to economic growth. Government effectiveness, regulatory quality, rule of law and voice and accountability are insignificant in influencing economic growth in Zimbabwe at 5% level of significance. The findings from this article will assist policy formulation, policy implementation and future research. This article, however, is of great importance to government, private sector and the academia.

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The Impact of Supplier Selection Criteria and Supplier Involvement Towards Supplier Performance at CV Teguh Jaya

KnE Social Sciences ◽

10.18502/kss.v4i3.6369 ◽

2020 ◽

Author(s):

Yashinta Kartikasari ◽

Tina Melinda

Keyword(s):

Supplier Selection ◽

Selection Criteria ◽

Business Processes ◽

Linear Regression Analysis ◽

Sampling Technique ◽

Multiple Linear Regression Analysis ◽

Future Research ◽

Supplier Performance ◽

Supplier Involvement ◽

The Impact

The aim of this study is to determine the impact of supplier selection criteria and supplier involvement on supplier performance in CV Teguh Jaya. The variables studied were supplier selection criteria (X1) and supplier involvement (X2). There are five indicators in supplier selection criteria, namely cost, quality, delivery, flexibility, and reliability. Whereas Supplier Involvement can be inferred from indicators such as how active the supplier is in updating goods and data, providing responses to customers, and minimizing problems in business processes. The analytical tool used in this study was multiple linear regression analysis. The population in this study was resellers who have become regular customers in CV Teguh Jaya with a sample size of 98 respondents, determined through purposive sampling technique with the criterion of being a fixed customer for at least 2 years. From the data analysis results we can infer that both supplier selection criteria and supplier involvement have impact on supplier performance. Based on the analysis results, CV Teguh Jaya needs to maintain the elements that were deemed satisfactory by the customers and need to improve on elements deemed lacking. Future research can consider adding other variables used in the previous studies. Keywords: Supplier selection criteria; Supplier involvement; and Supplier performance

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The impact of store flyers on store performance: a format and customer related approach

International Journal of Retail & Distribution Management ◽

10.1108/ijrdm-11-2012-0101 ◽

2014 ◽

Vol 42 (3) ◽

pp. 219-234 ◽

Cited By ~ 11

Author(s):

Beatrice Luceri ◽

Sabrina Latusi ◽

Donata Tania Vergura ◽

Gianpiero Lugli

Keyword(s):

Design Methodology ◽

Linear Regression Analysis ◽

Multiple Linear Regression Analysis ◽

Future Research ◽

Store Loyalty ◽

Content Type ◽

Store Performance ◽

Related Approach ◽

Promotional Strategies ◽

The Impact

Purpose – The study aims to investigate the impact of store flyer characteristics on store performance for different formats (hypermarket and supermarket) and customer segments (additional and regular shoppers). Specifically, the paper tests propositions on how flyer duration, variety of featured purchasing options, the category and brand mix on feature and the method used to communicate the deal price affect store traffic and sales. Design/methodology/approach – Data were made available for analysis by a grocery chain that utilizes a hi-lo pricing strategy. To test the hypothesis a multiple linear regression analysis was used. Findings – Results indicate that optimal store flyer configuration is related to the store format. Moreover, the response to flyer promotion programs varies across customer segments in relation to their degree of store loyalty. Research limitations/implications – Findings can assist marketers to develop more effective promotional strategies with regards to the bundle of promotions to be offered and the way they should be communicated. Future research should extend the analysis to other retailers and trading areas. Furthermore, it would be useful to replicate the analysis by separating the impact of in-store activities and store flyer effects. Originality/value – This is the first attempt to analyse flyer impact on store performance for different formats and customer segments. Prior research is confined to supermarkets, although the enhancement of store traffic is related to format size. Moreover, the traffic and sales implications of store flyer composition have so far been analysed in an aggregate manner, disregarding customers' shopping patterns.

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Physical activity does not attenuate the relationship between daily cortisol and metabolic syndrome in obese youth

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2015-0185 ◽

2016 ◽

Vol 29 (1) ◽

Cited By ~ 2

Author(s):

Emily Hill Guseman ◽

Karin A. Pfeiffer ◽

Joseph J. Carlson ◽

Kathy Stansbury ◽

Joey C. Eisenmann

Keyword(s):

Physical Activity ◽

Metabolic Syndrome ◽

Linear Regression Analysis ◽

Area Under The Curve ◽

Multiple Linear Regression Analysis ◽

Future Research ◽

Obese Youth ◽

Continuous Metabolic Syndrome Score ◽

Metabolic Syndrome Score

Abstract: We examined the associations among daily cortisol, physical activity (MVPA) and continuous metabolic syndrome score (cMetS) in obese youth.: Fifty adolescents (mean age 14.8±1.9 years) were recruited from medical clinics. Daily MVPA (min/day) was assessed by accelerometry. Saliva was sampled at prescribed times: immediately upon waking; 30 min after waking; and 3, 6 and 9 h after waking. Fasting lipids, glucose, waist circumference and blood pressure were used to calculate a continuous metabolic syndrome score (cMetS). Multiple linear regression analysis was used to examine associations among variables.: The mean cMetS score was 4.16±4.30 and did not differ by clinic or sex. No significant relationship was found between cortisol area under the curve (cAUC) and cMetS, nor did the interaction of MVPA with cAUC significantly predict cMetS.: Physical activity, cortisol, and metabolic risk were not associated in this sample of obese adolescents. Future research should examine the role of insulin sensitivity in these relationships.

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Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Cancers ◽

10.3390/cancers13040613 ◽

2021 ◽

Vol 13 (4) ◽

pp. 613

Author(s):

Nidhi Sharma ◽

Qiuhong Zhao ◽

Bin Ni ◽

Patrick Elder ◽

Marcin Puto ◽

...

Keyword(s):

Stem Cell ◽

Graft Versus Host Disease ◽

Tacrolimus Concentration ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

The Impact ◽

Risk Of Relapse ◽

Acute Graft

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

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THU0433 TREATMENT WITH PEGLOTICASE IMPROVES HEPATIC FIBROSIS ESTIMATED BY FIBROSIS-4 INDEX IN SUBJECTS WITH CHRONIC REFRACTORY GOUT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2360 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 454.1-454

Author(s):

N. Schlesinger ◽

A. Yeo ◽

P. Lipsky

Keyword(s):

Liver Disease ◽

Linear Regression ◽

Rank Order ◽

Linear Regression Analysis ◽

Area Under The Curve ◽

Serum Urate ◽

Complete Analysis ◽

Alcoholic Fatty Liver ◽

Significant Difference ◽

The Impact

Background:Hyperuricemia is associated with non-alcoholic fatty liver disease (NAFLD)1,2, but the relationship to fibrosis remains uncertain3. Moreover, it is not known whether lowering serum urate will affect the course of NAFLD. The availability of data from two randomized trials of pegloticase, a pegylated recombinant mammalian uricase, that profoundly decreases serum urate afforded the opportunity to test the hypothesis that lowering urate might improve NAFLD.Objectives:To determine whether treatment of chronic refractory gout patients with pegloticase was associated with improvement in NAFLD determined by Fibrosis 4 index (Fib4).Methods:Databases from patients with chronic refractory gout who participated in two randomized 6 month clinical trials (RCTs) of pegloticase were analyzed4. Sub-sets who had persistent urate lowering to levels <1 mg/dL in response to biweekly pegloticase (Responders, n=36) were compared to those who received placebo (n=43). Since liver biopsy information was not available on these subjects, we relied on Fib4, a validated non-invasive estimate of liver fibrosis in a variety of liver diseases5,6calculated from measurements of AST, ALT, platelet count and age (Age x AST/platelets x √ALT). A Fib4 value of 1.3 is an indication that further evaluation of liver disease is warranted.Results:At baseline, the mean Fib4 values were 1.40 ± 0.86 in pegloticase responders and 1.04 ± 0.53 in subjects receiving placebo. As shown in figure 1, subjects receiving placebo exhibited a change of 0.26 ± 0.41 in the Fib4 score over the six months of the RCTs compared with 0.13 ± 0.62 in the pegloticase responders (p=0.048; by linear regression). When only the subjects with a Fib4 value > 1.3 were considered, a significant difference in the change in the Fib4 values over the 6 months of the trial between pegloticase responders and those receiving placebo was also observed (-0.15 ± 0.67 vs 0.37 ± 0.42, p=0.004, by linear regression). The correlations between serum urate area under the curve (AUC) over the 6 months of the trial and the change in Fib4 value was rs=0.33, p=0.0.0004 (Spearman rank-order correlation coefficient). Finally, multiple linear regression analysis indicated serum urate AUC (as a surrogate measure for group) is the main contributor to the change in Fib4 (p=0.018 by linear regression).Conclusion:The data are consistent with the conclusion that persistent lowering of serum urate had a significant impact on Fib4 levels, implying a possible effect on the course of NAFLD. The results support a more complete analysis involving biopsy examination of the impact of urate on liver inflammation and fibrosis.References:[1]Yang C et al. PlosOne2017; 12:e0177249[2]Jaruvongvanich V et al. Eur J Gastroenterol Hepatol 2017; 29:1031[3]Jaruvongvanich V et al. Eur J Gastroenterol Hepatol 2017; 29:694[4]Sundy JS, et al. JAMA. 2011; 306 (7):711-20[5]Sterling RK et al. Hepatol 2006; 43:1317[6]Shah AG et al. Clin Gastroenterol Hepatol 2009;7:1104Disclosure of Interests: :Naomi Schlesinger Grant/research support from: Pfizer, Amgen, Consultant of: Novartis, Horizon Therapeutics, Selecta Biosciences, Olatec, IFM Therapeutics, Mallinckrodt Pharmaceuticals, Anthony Yeo Employee of: Horizon Therapeutics, Peter Lipsky Consultant of: Horizon Therapeutics

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