bluuebunny/crossref_metadata_2025_split huggingface dataset:
Value‐based pricing: Toward achieving a balance between individual and population gains in health benefits
Authors: Parmar Ambica , Jiao Tina , Saluja Ronak , Chan Kelvin K. W. 
Published: November 2019

AbstractObjectivesValue‐based pricing of oncology drugs provides a best estimate for the price of a drug, as it relates to the benefits it provides for individual patients. To date, the impact of value‐based pricing to reference cost‐effectiveness thresholds (λ) on individual and population‐level health benefits remains uncharacterized. The current study examined the potential benefits of value‐based pricing by quantifying the incremental net health benefit (INHB) of publicly funded oncology drugs, if funding occurred at manufacturer‐submitted price without value‐based pricing.MethodsPan‐Canadian Oncology Drug Review (pCODR) submissions were reviewed to identify eligible drug indications from which final economic guidance panel reports were reviewed for incremental costs (ΔC) and quality‐adjusted life‐years (ΔQALY) from manufacturer‐submitted, pCODR lower‐limit (pCODR‐LL) and upper‐limit (pCODR‐UL) re‐analyzed estimates. Annual number of cases in Ontario for each drug indication was obtained from population databases. Annual QALY gain per drug indication was determined by (ΔQALY × cases). Population QALY gain/loss in the absence of value‐based pricing to reference λ was estimated by the INHB: (INHB = [ΔQALY − (ΔC/λ)] × cases).ResultsIn total, 34 drug indications (4629 cases) were identified. Annual gain in QALYs for the funded drug indications using manufacturer, pCODR‐LL, and pCODR‐UL estimates was 1851, 1617, and 1301, respectively. At a λ $100 000/QALY, funding in the absence of value‐based pricing resulted in loss of 2311, 2519, and 2604 QALYs. This would result in a provincial net annual loss of 460, 902, and 1303 QALYs.ConclusionsDespite an annual gain in QALY per funded drug indication, a net loss in QALY for the province, in the absence of value‐based pricing, was demonstrated. Supportive evidence exists for value‐based pricing toward the promotion of health benefits for the greater population.
Potent anti‐myeloma activity of the TOPK inhibitor OTS514 in pre‐clinical models
Authors: Stefka Andrew T. , Johnson David , Rosebeck Shaun , Park Jae‐Hyun , Nakamura Yusuke , Jakubowiak Andrzej J. 
Published: November 2019

AbstractMultiple myeloma (MM) continues to be considered incurable, necessitating new drug discovery. The mitotic kinase T‐LAK cell‐originated protein kinase/PDZ‐binding kinase (TOPK/PBK) is associated with proliferation of tumor cells, maintenance of cancer stem cells, and poor patient prognosis in many cancers. In this report, we demonstrate potent anti‐myeloma effects of the TOPK inhibitor OTS514 for the first time. OTS514 induces cell cycle arrest and apoptosis at nanomolar concentrations in a series of human myeloma cell lines (HMCL) and prevents outgrowth of a putative CD138+ stem cell population from MM patient‐derived peripheral blood mononuclear cells. In bone marrow cells from MM patients, OTS514 treatment exhibited preferential killing of the malignant CD138+ plasma cells compared with the CD138− compartment. In an aggressive mouse xenograft model, OTS964 given orally at 100 mg/kg 5 days per week was well tolerated and reduced tumor size by 48%‐81% compared to control depending on the initial graft size. FOXO3 and its transcriptional targets CDKN1A (p21) and CDKN1B (p27) were elevated and apoptosis was induced with OTS514 treatment of HMCLs. TOPK inhibition also induced loss of FOXM1 and disrupted AKT, p38 MAPK, and NF‐κB signaling. The effects of OTS514 were independent of p53 mutation or deletion status. Combination treatment of HMCLs with OTS514 and lenalidomide produced synergistic effects, providing a rationale for the evaluation of TOPK inhibition in existing myeloma treatment regimens.
Whole exome sequencing reveals a de novo missense variant in EEF1A2 in a Rett syndrome‐like patient
Authors: Kaur Simranpreet , Van Bergen Nicole J. , Gold Wendy Anne , Eggers Stefanie , Lunke Sebastian , White Susan M. , Ellaway Carolyn , Christodoulou John 
Published: November 2019

AbstractUsing whole exome sequencing, we found a pathogenic variant in the EEF1A2 gene in a patient with a Rett syndrome‐like (RTT‐like) phenotype, further confirming the association between EEF1A2 and Rett syndrome RTT and RTT‐like phenotypes.
Reductive Cycloisomerization of Diynes by Supported Palladium Catalysts and Subsequent [4+2] Cycloaddition for One‐Pot Synthesis of Cyclohexenes
Authors: Miura Hiroki , Tanaka Yumi , Nakahara Karin , Shishido Tetsuya 
Published: November 2019

AbstractAbstract: Supported Pd nanoparticles catalyzed the reductive cycloisomerization of diynes to give 1,3‐dienes, and subsequent intermolecular [4+2] cycloaddition with dienophiles led to cyclohexene derivatives. Various diynes and dienophiles participated in the one‐pot reaction to give the corresponding products in good to high yields. Al2O3‐supported Pd catalysts were highly tolerant toward air and reusable.
Trifluoromethyl Derivatives of Elusive Fullerene C98
Authors: Tamm Nadezhda B. , Guan Runnan , Yang Shangfeng , Troyanov Sergey I. 
Published: November 2019

AbstractData concerning the isomeric composition of C98 and the chemistry of C98 derivatives are scarce due to very low abundance of C98 in the fullerene soot. Trifluoromethylation of C98‐containing mixtures followed by HPLC separation of CF3 derivatives and single crystal X‐ray diffraction study resulted in structural characterization of four compounds C98(248)(CF3)18/20, C98(116)(CF3)18, and C98(120)(CF3)20. To date, these compounds represent the largest fullerenes isolated as CF3 derivatives with experimentally determined molecular structures. The addition patterns of C98(CF3)18/20 are discussed in detail revealing the stabilizing factors, such as isolated double C=C bonds and benzenoid rings on C98 fullerene cages. A detailed comparison with the addition patterns of the known C98Cln allowed us to contribute to the better understanding the chemistry of elusive C98 fullerene.
Mobile Sensoren für die Biotechnologie – Ortsunabhängige, miniaturisierte Prozessmessung
Authors: Lauterbach Tim , Ziebart Nandor , Bley Thomas , Walther Thomas , Lenk Felix 
Published: November 2019

AbstractAufgrund verschiedenster Reaktorformen im Bereich der Biotechnologie liefern gewöhnliche Stabsonden unzureichend repräsentative Messergebnisse. In dieser Publikation werden neuartige mobile kugelförmige Sensoreinheiten mit einem Gesamtdurchmesser von 7,9 mm vorgestellt. Basierend auf Simulationen wurden diese in ihrer Dichte für die beste Verteilung im wässrigen Medium optimiert. Darüber hinaus wurde ermittelt, welche Auswirkungen unterschiedliche Rührgeschwindigkeiten in typischen Bioreaktoren auf die Verteilung der Sonden haben. Anhand dreier Bioreaktortypen wird die Anwendbarkeit der hier vorgestellten Messsonden gezeigt.
Predicting risk of cardiovascular events 1 to 3 years post‐myocardial infarction using a global registry
Authors: Pocock Stuart J. , Brieger David , Gregson John , Chen Ji Y. , Cohen Mauricio G. , Goodman Shaun G. , Granger Christopher B. , Grieve Richard , Nicolau Jose C. , Simon Tabassome , Westermann Dirk , Yasuda Satoshi , Hedman Katarina , Rennie Kirsten L. , Sundell Karolina Andersson ,   for the TIGRIS Study Investigators
Published: November 2019

AbstractBackgroundRisk prediction tools are lacking for patients with stable disease some years after myocardial infarction (MI).HypothesisA practical long‐term cardiovascular risk index can be developed.MethodsThe long‐Term rIsk, Clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post‐myocardial infarction patients prospective global registry enrolled patients 1 to 3 years post‐MI (369 centers; 25 countries), all with ≥1 risk factor (age ≥65 years, diabetes mellitus requiring medication, second prior MI, multivessel coronary artery disease, or chronic non‐end‐stage kidney disease [CKD]). Self‐reported health was assessed with EuroQoL‐5 dimensions. Multivariable Poisson regression models were used to determine key predictors of the primary composite outcome (MI, unstable angina with urgent revascularization [UA], stroke, or all‐cause death) over 2 years.ResultsThe primary outcome occurred in 621 (6.9%) of 9027 eligible patients: death 295 (3.3%), MI 195 (2.2%), UA 103 (1.1%), and stroke 58 (0.6%). All events accrued linearly. In a multivariable model, 11 significant predictors of primary outcome (age ≥65 years, diabetes, second prior MI, CKD, history of major bleed, peripheral arterial disease, heart failure, cardiovascular hospitalization (prior 6 months), medical management (index MI), on diuretic, and poor self‐reported health) were identified and combined into a user‐friendly risk index. Compared with lowest‐risk patients, those in the top 16% had a rate ratio of 6.9 for the primary composite, and 18.7 for all‐cause death (overall c‐statistic; 0.686, and 0.768, respectively). External validation was performed using the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events registry (c‐statistic; 0.748, and 0.849, respectively).ConclusionsIn patients >1‐year post‐MI, recurrent cardiovascular events and deaths accrue linearly. A simple risk index can stratify patients, potentially helping to guide management.
Association between facility volume and mortality of patients with classic Hodgkin lymphoma
Authors: Goyal Gaurav , Tella Sri Harsha , Funni Shealeigh , Kommalapati Anuhya , Inselman Jonathan W. , Shah Nilay D. , Go Ronald S. , Ansell Stephen M. 
Published: November 2019

BackgroundPrior studies in oncology have shown that a higher annual facility patient volume is associated with reduced mortality. Because classic Hodgkin lymphoma is uncommon but highly curable, this study used the National Cancer Database (2003‐2014) to analyze whether such a relationship exists for this disease.MethodsThe facilities were classified by quartiles, and random intercepts were used to account for clustering of patients within facilities. A Cox regression model was used to determine the volume‐outcome relationship.ResultsThere were 47,633 patients with classic Hodgkin lymphoma treated at 1310 facilities. The first quartile (Q1), which included 58.4% of the facilities, treated 3 or fewer patients per year, whereas the fourth quartile (Q4), which included 5.9% of the facilities, treated more than 9 patients per year. Compared with the patients treated at Q4 facilities, those treated at lower quartile facilities had a higher risk of death (hazard ratio for the third quartile [HR], 1.19; 95% confidence interval [CI], 1.1‐1.29; HR for the second quartile, 1.28; 95% CI, 1.19‐1.38; HR for Q1, 1.29; 95% CI, 1.2‐1.39) after adjustments for all other factors (P < .0001). Compared with facilities treating 10 patients per year, facilities treating 40 patients per year had approximately 27% lower overall mortality rates.ConclusionsPatients with classic Hodgkin lymphoma treated at high‐volume centers had lower overall mortality than those treated at lower volume centers. Because this is a highly curable malignancy, such differences may suggest a benefit from referral to higher volume facilities or the emulation of their care models.
Quantitative associations between health insurance and stage of melanoma at diagnosis among nonelderly adults in the United States
Authors: Abudu Boya , Cook Kaitlyn A. , Gershenwald Jeffrey E. , Cohen Philip R. , Geller Alan C. 
Published: November 2019

BackgroundHealth insurance plays a critical role in the accessibility to and quality of health care for patients with melanoma in the United States. Current knowledge regarding the association between insurance status and stage of melanoma is limited because few studies to date have simultaneously controlled for factors known to influence the risk of diagnosis of late‐stage melanoma. The current study was conducted to examine the association between health insurance status and stage of melanoma at the time of diagnosis in nonelderly adults, accounting for known risk factors for late‐stage diagnosis.MethodsIn this cross‐sectional study, the authors analyzed the National Cancer Data Base for cases of invasive melanoma diagnosed between 2004 and 2015 among individuals aged 26 to 64 years. Using the American Joint Committee on Cancer melanoma staging system, early‐stage melanoma was defined as stage I or stage II whereas late‐stage melanoma was defined as stage III or stage IV. Late‐stage diagnosis was the primary outcome compared across 4 insurance types (private, Medicaid, none, and unknown). Adjusted covariates were age, sex, race/ethnicity, educational level, income, year of diagnosis, number of comorbidities, and facility location. Logistic regression was used for univariable and multivariable analyses.ResultsAmong 177,247 cases, individuals with Medicaid or no health insurance were found to have 3.12 (95% CI, 2.97‐3.28) and 2.21 (95% CI, 2.10‐2.33) times greater odds, respectively, of being diagnosed with late‐stage melanoma compared with individuals with private insurance after adjusting for risk factors in late‐stage diagnosis.ConclusionsFuture investigation into insurance disparities in the diagnosis of late‐stage melanoma may help to prioritize melanoma screening in populations with nonprivate insurance.
Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy‐mediated drug resistance in ovarian cancer cells, xenografts, and patient‐derived xenograft models
Authors: Santiago‐O’Farrill Janice M. , Weroha S. John , Hou Xiaonan , Oberg Ann L. , Heinzen Ethan P. , Maurer Matthew J. , Pang Lan , Rask Philip , Amaravadi Ravi K. , Becker Sarah E. , Romero Ignacio , Rubio Ma Jesús , Matias‐Guiu Xavier , Santacana Maria , Llombart‐Cussac Antonio , Poveda Andrés , Lu Zhen , Bast Robert C. 
Published: November 2019

BackgroundPoly(adenosine diphosphate ribose) polymerase (PARP) inhibitors exhibit promising activity against ovarian cancers, but their efficacy can be limited by acquired drug resistance. This study explores the role of autophagy in regulating the sensitivity of ovarian cancer cells to PARP inhibitors.MethodsInduction of autophagy was detected by punctate LC3 fluorescence staining, LC3I to LC3II conversion on Western blot analysis, and electron microscopy. Enhanced growth inhibition and apoptosis were observed when PARP inhibitors were used with hydroxychloroquine, chloroquine (CQ), or LYS05 to block the hydrolysis of proteins and lipids in autophagosomes or with small interfering RNA against ATG5 or ATG7 to prevent the formation of autophagosomes. The preclinical efficacy of the combination of CQ and olaparib was evaluated with a patient‐derived xenograft (PDX) and the OVCAR8 human ovarian cancer cell line.ResultsFour PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) induced autophagy in a panel of ovarian cancer cells. Inhibition of autophagy with CQ enhanced the sensitivity of ovarian cancer cells to PARP inhibitors. In vivo, olaparib and CQ produced additive growth inhibition in OVCAR8 xenografts and a PDX. Olaparib inhibited PARP activity, and this led to increased reactive oxygen species (ROS) and an accumulation of γ‐H2AX. Inhibition of autophagy also increased ROS and γ‐H2AX and enhanced the effect of olaparib on both entities. Treatment with olaparib increased phosphorylation of ATM and PTEN while decreasing the phosphorylation of AKT and mTOR and inducing autophagy.ConclusionsPARP inhibitor–induced autophagy provides an adaptive mechanism of resistance to PARP inhibitors in cancer cells with wild‐type BRCA, and a combination of PARP inhibitors with CQ or other autophagy inhibitors could improve outcomes for patients with ovarian cancer.
Geographic and demographic features of neuroendocrine tumors in the United States of America: A population‐based study
Authors: Gosain Rohit , Ball Somedeb , Rana Navpreet , Groman Adrienne , Gage‐Bouchard Elizabeth , Dasari Arvind , Mukherjee Sarbajit 
Published: November 2019

BackgroundThe incidence of neuroendocrine tumors (NETs) is rapidly rising. There are very few studies investigating the role of sociodemographic factors in NETs. This study was aimed at examining how geographic and sociodemographic characteristics shape outcomes in the NET population.MethodsA retrospective analysis using the Surveillance, Epidemiology, and End Results database was performed, and the NET patient population from 1973 to 2015 was studied. Univariate and multivariable analyses were performed to evaluate patients' disease‐specific survival (DSS) and overall survival (OS). Geographic and sociodemographic factors, including the location of residence (urban area [UA] vs rural area [RA]), sex, race, insurance status, and marital status, were included in the analysis.ResultsA total of 53,034 patients (5517 in RAs and 47,517 in UAs) were included in the analysis. The incidence of NETs was found to be rising in both RAs and UAs but more rapidly in RAs (with the highest incidence in 2006‐2015: 5.93 per 100,000 in RAs vs 4.10 per 100,000 in UAs). Patients from RAs presented at advanced stages in comparison with patients from UAs (regional, 18% vs 16%; distant, 15% vs 13%; P < .01). In the multivariable model, RA patients had a trend toward poorer OS (hazard ratio, 1.05; P = .053) in comparison with UA patients. The multivariable analysis showed significantly worse DSS and OS for uninsured, single, and male patients in comparison with insured, married, and female patients, respectively.ConclusionsThis study has identified sociodemographic disparities in NET outcomes. Access to health care could be a potential contributing factor, although differences in environmental exposure, health behavior, and tumor biology could also be responsible.
Phase 1 Dose‐Escalation Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Tofacitinib in Japanese Healthy Volunteers
Authors: Miyoshi So , Krishnaswami Sriram , Toyoizumi Shigeyuki , Nakamura Hiroyuki , Zwillich Samuel H. 
Published: November 2019

AbstractThe aim of the study was to characterize the pharmacokinetics, safety, and tolerability of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis in healthy Japanese volunteers, and to compare these outcomes with those of healthy Western volunteers. Twenty‐five volunteers (Japanese, n = 16; Western [white], n = 9) were randomized to receive either 3 escalating single doses of tofacitinib (1, 5, and 30 mg), single‐dose tofacitinib (15 mg) followed by multiple doses (15 mg twice daily for 5 days), or placebo. No significant differences in systemic exposure to tofacitinib were detected between the 2 ethnicities. Following single tofacitinib 1, 5, and 30 mg doses, mean area under the plasma concentration–time curve from time zero to infinity ratio (Japanese/Western) values were 96.6%, 93.5%, and 95.6%, respectively. Similarly, mean maximum observed plasma concentration ratio values were 99.5%, 118%, and 119%, respectively. Mean renal clearance was also similar, ranging across doses from 134 mL/min (5 mg) to 162 mL/min (1 mg) in Japanese volunteers, and 124 mL/min (30 mg) to 160 mL/min (1 mg) in Western volunteers. In both ethnicities, most adverse events were mild. No serious adverse events or deaths were reported. The pharmacokinetics of tofacitinib were well characterized in healthy Japanese volunteers and were similar to those in Western volunteers.
Development of the Counseling Center Assessment of Psychological Symptoms‐Japanese version: Pilot study
Authors: Horita Ryo , Kawamoto Aki , Nishio Akihiro , Sado Tadahiro , Locke Benjamin D. , Yamamoto Mayumi 
Published: November 2019

AbstractThere is currently no reliable and valid multidimensional instrument for measuring psychological symptoms among Japanese university students. The purpose of this pilot study was to translate the Counseling Center Assessment of Psychological Symptoms‐62 (CCAPS‐62) into Japanese and evaluate its validity and reliability. Following robust translation procedures, the CCAPS‐Japanese was created. In the validation study, 2,758 undergraduate students from 11 universities (mean age = 19.08 ± 1.85 years) completed the CCAPS‐Japanese. The results of confirmatory factor analysis supported the theoretical eight‐factor structure model of the CCAPS‐Japanese with the exclusion of seven items. The decision to retain/remove items was made by evaluating factor loadings and model fit indices while considering cultural equivalence and structural validity. Using the finalized 55‐item CCAPS‐Japanese, further analyses demonstrated that the eight subscales had acceptable to good internal consistencies (α = .61–.89). Thus, the tool's validity and reliability were established. The CCAPS‐Japanese may be appropriate for assessing the psychological concerns of Japanese university students.
Natural Kaolin: Sustainable Technology for the Instantaneous and Energy‐Neutral Recycling of Anthropogenic Mercury Emissions
Authors: Ganguly Mainak , Tao Yuanyuan , Lee Bryan , Ariya Parisa A. 
Published: November 2019

AbstractKaolin, a natural and inexpensive clay mineral, is ubiquitous in soil, dirt, and airborne particles. Amongst four commonly available clay minerals, kaolin, as a result of its layered structure, is the most efficient natural gaseous Hg adsorbent to date (Langmuir maximum adsorption capacity Qm=574.08 μg g−1 and Freundlich Qm=756.49 μg g−1). The Hg uptake proceeds by homogeneous monolayer and heterogeneous processes. Hg physisorption on kaolin occurs in the dark, yet the adsorption rate is enhanced upon irradiation. The effects of several metal complexes, salts, halides and solvents on the Hg uptake were examined. The addition of CuCl2 particles leads to a significant enhancement of the Hg uptake capacity (>30 times) within second timescales and without irradiation. The physisorption with kaolin is switched to chemisorption upon the addition of CuCl2 to kaolin. This process is entirely reversible upon the addition of Zn/Sn granules at room temperature without any added energy. However, the investment of a small amount of renewable energy can speed up the process. This technology demonstrates the facile and efficient capture and recycling of elemental Hg0 from air. A wide range of metal particles and diverse physicochemical processes, which include the microphysics of nucleation, are herein examined to explore the potential reaction mechanism by using a suite of complementary analytical techniques. These new mechanistic insights open a new era of energy‐neutral environmental remediation based on natural soil/airborne particles.