Evaluation of real-world versus clinical trial outcomes of tyrosine kinase inhibitor therapy for chronic myeloid leukemia

Tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for chronic myeloid leukemia (CML). Patients enrolled in clinical trials investigating the safety and efficacy of TKIs in CML are generally younger, have fewer comorbidities, and are monitored differently than patients treated in the real world. This narrative literature review summarizes efficacy outcomes (complete cytogenetic response, major molecular response, and disease progression) and safety outcomes (duration of TKI therapy, TKI discontinuation rates, dosage changes, and frequently reported adverse events) from landmark clinical trials as well as real-world studies. Patients with CML treated with TKIs in a real-world setting may achieve different rates of specific response milestones than those treated on clinical trials. While real-world studies reported similar overall incidences of adverse events as clinical trials, real-world patients with CML were more likely to discontinue TKIs due to adverse events

Investigating the Moderating Impact of National Culture in Information Systems Security Policy Violation: The Case of Italy and Ethiopia

Information systems security (ISS) has become one of the top agendas of companies located in the developed world. Despite this fact, there is an increasing trend in the types and frequency of ISS breaches. Most of the time researchers and practitioners focus on threat that are caused by external agents while most of the threats are originated from insiders. In addition to this, the majority of the investments and researches around ISS are limited to technically oriented solutions. It is now realized that the technical approach alone couldn’t bring the required level of ISS, and this led ISS researchers to embark on socio-technical approaches. One of the critical social factors that has been given little emphasis is culture. Thus, this research investigates the impact of national culture on employees’ ISS behaviour. Specifically, it answers the question “what is the moderating impact of national culture on the influence of ISS countermeasures on employees’ intention to violate ISS policies?” We will develop and test an empirical ISS compliance model, using rational choice theory and national culture constructs. Survey will be used to collect data from Italy and Ethiopia

Modeling the impact of climate change on the hydrology of Andasa watershed

This paper was aimed to study the impact of climate change on the hydrology of Andasa watershed for the period 2013–2099. The soil and water assessment tool (SWAT) was calibrated and validated, and thereby used to study the impact of climate change on the water balance. The future climate change scenarios were developed using future climate outputs from the Hadley Center Climate Model version 3 (HadCM3) A2 (high) and B2 (low) emission scenarios and Canadian Earth System Model version 2 (CanESM2) Representative concentration pathways (RCP) 4.5 and 8.5 scenarios. The large-scale maximum/minimum temperature and rainfall data were downscaled to fine-scale resolution using the Statistical Downscaling Model (SDSM). The mean monthly temperature projection of the four scenarios indicated an increase by a range of 0.4–8.5 °C while the mean monthly rainfall showed both a decrease of up to 97% and an increase of up to 109%. The long-term mean of all the scenarios indicated an increasing temperature and decreasing rainfall trends. Simulations showed that climate change may cause substantial impacts in the hydrology of the watershed by increasing the potential evapotranspiration (PET) by 4.4–17.3% and decreasing streamflow and soil water by 48.8–95.6% and 12.7–76.8%, respectively. The findings suggested that climate change may cause moisture-constrained environments in the watershed, which may impact agricultural activities in the watershed. Appropriate agricultural water management interventions should be implemented to mitigate and adapt to the plausible impacts of climate change by conserving soil moisture and reducing evapotranspiration

Determinants of birth asphyxia among preterm newborns in Ethiopia : a systematic review and meta-analysis of observational studies protocol

Background: Birth asphyxia accounted for nearly 50% of neonatal mortality in Sub-Saharan African countries. This scenario has been worst in Ethiopia where every two out of three deaths attributed to birth asphyxia. Moreover, studies conducted in Ethiopia were highly variable and inconclusive to estimate the pooled prevalence and determinants of perinatal birth asphyxia among preterm babies. Objective: This study aimed to estimate the pooled prevalence of birth asphyxia and its determinants among preterm newborns in Ethiopia. Methods: The protocol for this review is registered at PROSPERO with registration number CRD42020158224. A comprehensive online databases (PubMed, HINARI, Scopus, EMBASE, Science direct, and Cochrane library database), Google Scholar, African Journals online, other gray and online repository accessed studies will be searched using different search engines. In addition, maternity and infant care databases uploaded at Ethiopian Health Development Journal and Ethiopian Journal of Health Sciences will be searched until 30 June 2020. Newcastle-Ottawa Quality Assessment Scale (NOS) will be used for critical appraisal of studies. Three reviewers will screen all retrieved articles, conduct data extraction, and then critically appraise all identified studies. All identified observational studies reporting the prevalence of birth asphyxia and associated factors among neonates in Ethiopia will be considered. The analysis of data will be done using STATA 11.0. We will demonstrate pooled estimates and determinants of birth asphyxia with effect size and 95% confidence interval. Heterogeneity among the included studies will be assessed through the Cochrane Q test statistics and I2 test. Publication bias will be checked using funnel plot and Egger’s test. Finally, statistical significance level will be declared at a p value of less than 0.05. Discussion: The result from this systematic review will inform and guide health policy planners to invest limited resources on maternal and neonatal health. Furthermore, it will be a stimulus for future cumulative meta-analysis researchers in developing nations

Pharmaceutical assistance programs for cancer patients in the era of orally administered chemotherapeutics

Introduction: The rising cost of cancer drugs may make treatment unaffordable for some patients. Patients often rely on drug manufacturer-administered Pharmaceutical Assistance Programs (PAPs) to obtain drugs and reduced or no cost. The overall usage of PAPs within cancer care delivery is unknown. Methods: We included all cancer patients across an academically affiliated, integrated health system in North Carolina during 2014 (N = 8591). We identified the subset of patients receiving PAP assistance to afford one or more cancer drugs, in order to calculate the proportion of patients receiving PAP assistance, and the retail value of the assistance. Results: Among 8591 cancer patients, 215 unique patients submitted a total of 478 successful PAP requests for cancer drugs. 40% of PAP-utilizing patients were uninsured, 23% had Medicaid coverage, 20% had Medicare coverage, 2% were dual Medicare/Medicaid eligible, and 14% were commercially insured. Among all cancer patients who received medical treatment, 6.0% required PAP assistance, whereas 10.6% receiving an oral agent required PAP assistance. The proportion receiving PAP assistance varied substantially by drug, ranging from <1% of patients (e.g. carboplatin, methotrexate) to 50% of patients (e.g. ponatinib, temsirolimus). The majority of the retail value obtained was for oral agents, including $1,556,575 of imatinib and$1,449,633 of dasatinib, which were the two drugs with the highest aggregate retail value. Conclusions: A substantial proportion of cancer patients receive private charitable assistance to obtain standard-of-care treatments. This includes patients with federal and private insurance, suggesting an inability of patients to meet cost-sharing requirements

Comparative safety and health care expenditures among patients with chronic myeloid leukemia initiating first-line imatinib, dasatinib, or nilotinib

PURPOSE Tyrosine kinase inhibitors (TKIs) have dramatically improved survival for patients with chronic myeloid leukemia (CML). No overall survival differences were observed between patients initiating first- and second-generation TKIs in trials; however, real-world safety and cost outcomes are unclear. We evaluated comparative safety and health care expenditures between first-line imatinib, dasatinib, and nilotinib among patients with CML. PATIENTS AND METHODS Eligible patients had one or more fills for imatinib, dasatinib, or nilotinib in the MarketScan Commercial and Medicare Supplemental databases between January 1, 2011, and December 31, 2016 (earliest fill is the index date), 6 months pre-index continuous enrollment, CML diagnosis, and no TKI use in the pre-index period. Hospitalizations or emergency department visits (safety events) were compared across treatment groups using propensity-score-weighted 1-year relative risks (RRs) and subdistribution hazard ratios (HRs). Inflation-adjusted annual health care expenditures were compared using quantile regression. RESULTS Eligible patients included 1,417 receiving imatinib, 1,067 receiving dasatinib, and 647 receiving nilotinib. The 1-year risk of safety events was high: imatinib, 37%; dasatinib, 44%; and nilotinib, 40%, with higher risks among patients receiving dasatinib (RR, 1.17; 95% CI, 1.06 to 1.30) and nilotinib (RR, 1.07; 95% CI, 0.93 to 1.23) compared with those receiving imatinib. Over a median of 1.7 years, the cumulative incidence of safety events was higher among patients receiving dasatinib (HR, 1.23; 95% CI, 1.10 to 1.38) and nilotinib (HR, 1.08; 95% CI, 0.95 to 1.24) than among those receiving imatinib. One-year health care expenditures were high (median, $125,987) and were significantly higher among patients initiating second-generation TKIs compared with those receiving imatinib (difference in medians: dasatinib v imatinib,$22,393; 95% CI, $17,068 to$27,718; nilotinib v imatinib, $19,463; 95$14,689 to $24,236). CONCLUSION Patients receiving imatinib had the lowest risk of hospitalization or emergency department visits and 1-year health care expenditures. Given a lack of significant differences in overall survival, imatinib may represent the ideal first-line therapy for patients, on average

A human endothelial cell-based recycling assay for screening of FcRn targeted molecules.

Albumin and IgG have remarkably long serum half-lives due to pH-dependent FcRn-mediated cellular recycling that rescues both ligands from intracellular degradation. Furthermore, increase in half-lives of IgG and albumin-based therapeutics has the potential to improve their efficacies, but there is a great need for robust methods for screening of relative FcRn-dependent recycling ability. Here, we report on a novel human endothelial cell-based recycling assay (HERA) that can be used for such pre-clinical screening. In HERA, rescue from degradation depends on FcRn, and engineered ligands are recycled in a manner that correlates with their half-lives in human FcRn transgenic mice. Thus, HERA is a novel cellular assay that can be used to predict how FcRn-binding proteins are rescued from intracellular degradation. Nat Commun 2018 Feb 12; 9(1):621

Impact of pregnancy related hormones on drug metabolizing enzyme and transport protein concentrations in human hepatocytes

Pregnancy alters the disposition and exposure to multiple drugs indicated for pregnancy-related complications. Previous in vitro studies have shown that pregnancy-related hormones (PRHs) alter the expression and function of certain cytochrome P450s (CYPs) in human hepatocytes. However, the impact of PRHs on hepatic concentrations of non-CYP drug-metabolizing enzymes (DMEs) and transport proteins remain largely unknown. In this study, sandwich-cultured human hepatocytes (SCHH) from five female donors were exposed to vehicle or PRHs (estrone, estradiol, estriol, progesterone, cortisol, and placental growth hormone), administered individually or in combination, across a range of physiologically relevant PRH concentrations for 72 h. Absolute concentrations of 33 hepatic non-CYP DMEs and transport proteins were quantified in SCHH membrane fractions using a quantitative targeted absolute proteomics (QTAP) isotope dilution nanoLC-MS/MS method. The data revealed that PRHs altered the absolute protein concentration of various DMEs and transporters in a concentration-, isoform-, and hepatocyte donor-dependent manner. Overall, eight of 33 (24%) proteins exhibited a significant PRH-evoked net change in absolute protein concentration relative to vehicle control (ANOVA p < 0.05) across hepatocyte donors: 1/11 UGTs (9%; UGT1A4), 4/6 other DMEs (67%; CES1, CES2, FMO5, POR), and 3/16 transport proteins (19%; OAT2, OCT3, P-GP). An additional 8 (24%) proteins (UGT1A1, UGT2B4, UGT2B10, FMO3, OCT1, MRP2, MRP3, ENT1) exhibited significant PRH alterations in absolute protein concentration within at least two individual hepatocyte donors. In contrast, 17 (52%) proteins exhibited no discernable impact by PRHs either within or across hepatocyte donors. Collectively, these results provide the first comprehensive quantitative proteomic evaluation of PRH effects on non-CYP DMEs and transport proteins in SCHH and offer mechanistic insight into the altered disposition of drug substrates cleared by these pathways during pregnancy

Structural Analysis of the Western Afar Margin, East Africa: Evidence for Multiphase Rotational Rifting

The Afar region in East Africa represents a key location to study continental breakup. We present an integrated structural analysis of the Western Afar Margin (WAM) aiming to better understand rifted margin development and the role of plate rotation during rifting. New structural information from remote sensing, fieldwork, and earthquake data sets reveals that the N-S striking WAM is still actively deforming and is characterized by NNW-SSE normal faulting as well as a series of marginal grabens. Seismicity distribution analysis and the first-ever borehole-calibrated sections of this developing passive margin show recent slip concentrated along antithetic faults. Tectonic stress parameters derived from earthquake focal mechanisms reveal different extension directions along the WAM (82°N), in Afar (66°N) and in the Main Ethiopian Rift (108°N). Fault slip analysis along the WAM yields the same extension direction. Combined with GPS data, this shows that current tectonics in Afar is dominated by the local rotation of the Danakil Block, considered to have occurred since 11 Ma. Earlier stages of Afar development (since 31–25 Ma) were most likely related to the large-scale rotation of the Arabian plate. Various authors have proposed scenarios for the evolution of the WAM. Any complete model should consider, among other factors, the multiphase tectonic history and antithetic fault activity of the margin. The findings of this study are not only relevant for a better understanding of the WAM but also provide insights into the role of multiphase rotational extension during rifting and passive margin formation in general.</p

Response to Tyrosine Kinase Inhibitors in Real-World Patients With Chronic Myeloid Leukemia

Background: Tyrosine kinase inhibitors (TKIs) are the front-line therapy for chronic myeloid leukemia (CML), where phase 3 clinical trials have demonstrated their safety and efficacy. However, trial patients may not be representative of real-world patients (RWPs). Objective: To evaluate RWP clinical factors associated with effectiveness and safety in CML patients treated with TKIs. Methods: Patients with CML treated with at least 30 days of imatinib, dasatinib, nilotinib, or bosutinib between 2014 and 2018 were included. Patients were stratified into categories based on the number of factors that would have precluded enrollment into pivotal TKI phase 3 trials (0, 1, ≥2). End points included complete hematologic response (CHR), early molecular response (EMR), major molecular response (MMR), adverse event (AE)-induced dose decreases, treatment interruptions, and treatment discontinuations. Results: Final analyses included 174 patients. Patients with ≥2 factors had a higher risk of dose decreases (relative risk = 1.54; 95% CI = 1.02-2.34; P = 0.02) and a shorter time to dose decrease (hazard ratio = 2.43; 95% CI = 1.23-4.97; P = 0.006) compared with patients with 0 factors. Significant differences were observed in CHR at 1 month and MMR at 3 months between patients with 0 and ≥2 factors (P = 0.03 and P = 0.04, respectively). Conclusion and Relevance: Approximately 60% of our RWPs would have been excluded from the pivotal phase 3 TKI trials. These data suggest that RWPs require more precise dosing to achieve CML clinical milestones and to mitigate AEs, but findings should be validated prospectively