bluuebunny/crossref_metadata_2025_split huggingface dataset:
178 Single-Dose Pharmacokinetics of Amphetamine Extended-Release Tablet Compared with Amphetamine Extended-Release Oral Suspension
Authors: Herman Barry K. , Kando Judith C. , King Thomas , Pardo Antonio 
Published: April 2020

Abstract:Objectives:Evaluate comparative bioavailability of single-dose amphetamine extended-release tablet (AMPH ER TAB, Tris Pharma, Inc., Monmouth Junction, NJ) 20 mg, swallowed whole or chewed and amphetamine extended-release oral suspension (AMPH EROS) 2.5 mg/mL; and evaluate whether a PK food effect exists on AMPH ER TAB (contains a 3.2:1 ratio of d- to l-amphetamine).METHODS:Healthy volunteers (18-55 yr) were randomized to 1 dose of AMPH ER TAB 20 mg swallowed (fasted), chewed (fed/fasted), or 20 mg AMPH EROS (fasted).A crossover design was used. Samples were collected each period pre-dose and at time points to 60 h post-dose. D-and l-amphetamine were measured, and PK was calculated (90% CIs of the ratios of the geometric mean plasma levels) for Cmax, AUCt, and AUC0∞. Comparative bioavailability was determined when ratios were within 80 and 125%. Safety was also assessed.RESULTS:32 subjects completed the study. Based on the calculated bioavailability ratios, for AMPH ER TAB swallowed vs. AMPH EROS fasted: d-amphetamine total and peak exposures were found to be similar: AUC0-t: 100.68-108.08%, AUC0-∞:101.47-109.52%, Cmax: 98.10-103.17%. For l-amphetamine, the total and peak exposures were similar: AUC0-t: 100.31-108.57%, AUC0-∞:101.27-111.09%, Cmax: 98.2-103.37%.AMPH ER TAB chewed vs. AMPH EROS fasted: For d-amphetamine, the total and peak exposures were similar: AUC0-t: 99.23-106.62%, AUC0-∞: 99.58-107.59%, Cmax: 99.91-105.14%. For l-amphetamine, the total and peak exposure was similar: AUC0-t: 98.16-106.35%, AUC0-∞: 98.44-108.11%, Cmax: 99.53-104.75%.Food effect: AMPH ER TAB, chewed, fasted vs. fed: For d-amphetamine, the total and peak exposure was similar: AUC0-t: 92.57-99.49%, AUC0-∞: 91.12-98.48%, Cmax: 94.22-99.17%.For l-amphetamine, the total and peak exposure was similar: AUC0-t: 91.27-98.91%, AUC0-∞: 88.44-97.17%, Cmax: 94.52-99.50%).No serious AEs were reported during the conduct of this study, and the AE profiles were observed to be similar in frequency of events and severity to other amphetamine formulations used in ADHD.CONCLUSIONS:Bioavailability of single dose of AMPH ER TAB for both d- and l-amphetamine was comparable, swallowed whole or chewed, to an equivalent 20 mg dose of the reference product AMPH EROS, 2.5 mg/mL fasted, and showed equivalent peak and overall exposure.No food effect was observed for AMPH ER TAB administered chewed. All AEs were mild in severity and AE profiles were similar to other amphetamine formulations used for treatment of ADHD.Funding Acknowledgements:Tris Pharma, Inc.
179 Palatability Assessment of a New Amphetamine Extended-Release Tablet Formulation
Authors: Herman Barry K. , King Thomas R. , Kando Judith C. , Pardo Antonio 
Published: April 2020

Abstract:Background:In 2016, the US FDA issued an industry guidance document “Quality Attribute Considerations for Chewable Tablets” which describes the quality attributes to be considered when developing chewable tablets. It includes recommendations on selection of acceptance criteria for measuring palatability (having a taste acceptable to the patient or has adequate masking). These data are now recommended as part of ANDA submissions. Palatability is a known positive contributing factor to drug adherence and persistence. We summarize here palatability data for a new amphetamine extended-release tablet (Dyanavel XR® Extended Release Tablet; AMPH ER TAB).Methods:This was a 2-arm preplanned secondary analysis from a comparative bioavailability study: single-dose AMPH ER TAB 20 mg chewed under fasting (Treatment A) and fed (Treatment B) conditions. Subjects rated the palatability of AMPH ER TAB (Treatments A+B) through a 5-question palatability questionnaire. The questions included in the palatability questionnaire were as follows:1.Oral sensation/mouth feel of the drug product2.Taste of the drug product3.How strong is the taste?4.Aftertaste of the product5.How strong is the aftertaste?Subjects completed the questionnaire within 10 minutes from the time of drug administration, which was evaluated and scored according to the rubric below:Q1, Q2, Q4: palatability- Very unpleasant (score of 1), Unpleasant (2), No sensation or mouthfeel (3), Pleasant (4), and Very pleasant (5)Q3, Q5 (Taste/aftertaste strength): Very strong (score of 1), Strong (2), Moderate (3), Mild (4), No aftertaste (5).Scores of 1-2 for both categories were Negative; score of 3 was Neutral, and 4-5 were Positive.Results:35 subjects comprised the palatability dataset (completed one question on the questionnaire). In the palatability analysis, for treatments A and B, most of the subjects rated the oral sensation/mouth feel of AMPH ER TAB (Question 1) and the taste of AMPH ER TAB (Question 2) as positive (pleasant to very pleasant) (70.1% and 83.6%, respectively).When evaluating taste strength (Question 3): 43.3% rated the strength as positive (mild/no taste) and 43.3% of subjects rated the strength as neutral (moderate taste). Also, 82.1% rated the aftertaste of AMPH ER TAB (Question 4) as positive (pleasant/very pleasant) and 52.2% rated the strength of the aftertaste as positive (mild/no taste).Conclusion:Most subjects rated the oral sensation and taste as pleasant or very pleasant, whether chewed under fasted conditions or after a meal. With respect to the taste strength, most subjects rated it as moderate (chewed under fasted conditions) or mild/no taste (chewed after a meal). Aftertaste was rated as pleasant or very pleasant in most subjects, with the strength as moderate (chewed under fasted conditions) or mild/no aftertaste (chewed after a meal). AMPH ER Tablets provided an overall pleasant taste and mouthfeel experience for patients.Funding Acknowledgements: Tris Pharma, Inc.
180 Improvement of Sexual Function Observed During Treatment of Major Depressive Disorder with Adjunctive Pimavanserin
Authors: Freeman Marlene P. , Fava Maurizio , Dirks Bryan , Jha Manish K. , Shelton Richard C. , Thase Michael E. , Trivedi Madhukar H. , Papakostas George I. , Liu Keith , Whitworth Troy , Stankovic Srdjan 
Published: April 2020

Abstract:Study Objectives:Sexual dysfunction occurs in 40%-60% of patients with major depressive disorder (MDD), due to either the illness itself and/or the effects of antidepressant treatment. The phase-2 CLARITY trial recently demonstrated the efficacy of adjunctive pimavanserin (PIM) for MDD when added to ongoing selective serotonin or serotonin–norepinephrine reuptake inhibitor (SSRI/SNRI) treatment. No new safety observations were reported in this study. This post-hoc analysis examines the potential impact of PIM treatment on sexual function.Method:Study methodology has been presented previously (APA 2019). Adult male and female patients with moderate-to-severe MDD were randomized to PIM 34 mg/day (n=51) or placebo (PBO, n=152) added to ongoing SSRI/SNRI treatment. Massachusetts General Hospital–Sexual Functioning Inventory (MGH-SFI) and Hamilton Depression Rating Scale, 17-item version (HAMD-17) item 14 (sexual interest) scores were examined by analysis of covariance.Results:Adjunctive PIM resulted in significantly greater 5-week reduction (improvement) relative to SSRI/SNRI treatment plus placebo on mean MGH-SFI scores (difference –0.634, SE 0.167; P<0.001; effect size [ES], Cohen’s d 0.614). Similarly, PIM resulted in greater improvement compared with placebo on individual MGH-SFI items that applied to both males and females: Interest in Sex (P=0.006; ES=0.483), Ability to Get Sexually Aroused/Excited (P=0.001; ES=0.560), Ability to Achieve Orgasm (P<0.001; ES=0.609), Overall Sexual Satisfaction (P=0.003; ES=0.524). HAMD-17 item 14 scores were also significantly more reduced (improved) with PIM (P<0.001; ES=0.574).Conclusions:These results underscore the potential of adjunctive PIM for improving sexual function in patients with MDD and inadequate response to SSRIs/SNRIs. Potential benefits should be confirmed in further studies.Funding Acknowledgements:ACADIA Pharmaceuticals Inc.
190 Treating Fibromyalgia Syndrome through Neuromodulation With Transcranial Magnetic Stimulation
Authors: Keays Ashley C 
Published: April 2020

Abstract:Fibromyalgia Syndrome (FM) affects 2-4% of the US adult population. It is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, disrupted sleep, memory and mood issues. Researchers believe that FM amplifies painful sensations by affecting the way the brain processes pain signals. In recent years there is converging data favoring the theory of a dysregulation of pain processing in the central nervous system of FM patients, particularly associated with an increase in cerebral glutamate levels. Traditional medications have not proven to be enough. Since 2017, Keays Medical Group has used neuromodulation with Transcranial Magnetic Stimulation to treat FM patients with comorbid major depressive disorder. Preliminary results have shown improvement in all standardized scoring measures including FIQ-R, GAD-7 and PHQ-9 when treated with our FMS Protocol.
Pathways to retirement through self-employment
Authors: Ramnath Shanthi , Shoven John B. , Slavov Sita Nataraj 
Published: April 2020

AbstractWe examine the role of self-employment in retirement transitions using a panel of administrative tax data. We find that the hazard of self-employment increases at popular retirement ages associated with Social Security eligibility, particularly for those with greater retirement wealth. Late-career transitions to self-employment are associated with a larger drop in income than similar mid-career transitions. Data from the Health and Retirement Study suggest that hours worked also fall upon switching to self-employment. These results suggest that self-employment at older ages may serve as a ‘bridge job,’ allowing workers to gradually reduce hours and earnings along the pathway to retirement.
Loneliness, hopelessness and suicide in later life: a case–control psychological autopsy study in rural China
Authors: Niu Lu , Jia Cunxian , Ma Zhenyu , Wang Guojun , Sun Bin , Zhang Dexing , Zhou Liang 
Published: April 2020

Abstract

Aims
Loneliness is increasingly recognised as a serious public health issue worldwide. However, there is scarce research addressing the association between loneliness and suicide in older adults in rural China. We set out to examine loneliness and other psychosocial factors in elderly suicide cases and explore their interaction effects.

Methods
Using a 1 : 1 matched case–control design, data were collected from 242 elderly suicide cases and 242 living community controls by psychological autopsy method in rural China, including demographic characteristics, loneliness, depression, hopelessness and social support. The chi-square automatic interaction detection (CHAID) tree model and multivariable logistic regression analysis were used to explore the relationships of these factors and suicide.

Results
The CHAID tree model showed that loneliness, hopelessness and depressive symptoms were closely associated with completed suicide and that loneliness and hopelessness interacted with each other. The result of multivariable logistic regression showed that individuals who were unemployed [odds ratio (OR) = 2.344; 95% confidence interval (CI): 1.233–4.457], living alone (OR = 2.176; 95% CI: 1.113–4.254), had lower levels of subjective social support (OR = 2.185; 95% CI: 1.243–3.843), experienced depressive symptoms (OR = 6.700; 95% CI: 3.405–13.182), showed higher levels of hopelessness (OR = 7.253; 95% CI: 3.764–13.974) and felt higher levels of hopelessness × higher levels of loneliness (OR = 2.446; 95% CI: 1.089–5.492) were significantly associated with an elevated suicide risk in older people in rural China.

Conclusions
Regular evaluation of loneliness, hopelessness and depression can help detect older adults who are at risk of committing suicide. Interventions should target social support systems, particularly among people living alone, to alleviate feelings of loneliness and hopelessness. Treating depression is also key to preventing suicide among elderly people in rural China.
Particle‐Size Distributions and Solubility of Aerosol Iron Over the Antarctic Peninsula During Austral Summer
Authors: Gao Yuan , Yu Shun , Sherrell Robert M. , Fan Songyun , Bu Kaixuan , Anderson James R. 
Published: April 2020

AbstractThis study provides new data on the properties of aerosol iron (Fe) over the Antarctic Peninsula, one of the fastest warming regions on Earth in recent decades. Atmospheric deposition delivers Fe, a limiting micronutrient, to the Southern Ocean, and aerosol particle size influences the air‐to‐sea deposition rate and fractional solubility of aerosol Fe. Size‐segregated aerosols were collected at Palmer Station on the West Antarctic Peninsula during austral summer 2016–2017. Results show single‐mode size distribution of aerosol Fe, peaking at 4.4 μm diameter. The average concentration of total aerosol Fe was 1.3 (±0.40) ng m−3 (range 0.74–1.8 ng m−3). High concentrations of total aerosol Fe occurred in January, implying increased Fe source strength then. Total labile Fe varied between 0.019 and 0.095 ng m−3, and labile Fe (II) accounted for ~90% of the total labile Fe. The average fractional solubility for total Fe was 3.8% (±1.5%) (range 2.5–7.3%). Estimated dry deposition fluxes for the study period were 3.2 μg m−2 year−1 for total labile Fe and 83 μg m−2 year−1 for total Fe in aerosols. We speculate that local and regional dust sources in Antarctica contributed to the observed aerosol Fe in austral summer and that warming on the Antarctic Peninsula during the past half century may have increased the formation of dust sources in this region. The potential biogeochemical impact of atmospheric Fe input to the West Antarctic Peninsula shelf waters and adjacent pelagic surface waters of the Southern Ocean may need to be re‐evaluated.
Vegetation Trajectories and Shortwave Radiative Forcing Following Boreal Forest Disturbance in Eastern Siberia
Authors: Stuenzi S. M. , Schaepman-Strub G. 
Published: April 2020

AbstractMajor boreal forest disturbance and associated carbon emissions have been reported in the coldest region of the Northern Hemisphere. Related biophysical feedbacks to climate remain highly uncertain but might reduce warming effects expected from carbon emissions. This study quantifies albedo change after disturbance, primarily fires, in larch‐dominated forests around Yakutsk as compared to undisturbed areas with natural albedo variability, using satellite‐based time series. The related annual mean shortwave radiative forcing was −6.015 W/m2 for the 13 years following forest disturbance. It was highly negative during snow‐covered months (−3.738 to −13.638 W/m2), but positive (+5.441 W/m2) for the summer months in the first year after disturbance, decreasing afterward and also turning into a negative forcing after 5 years. Forcing by surface shortwave radiation must be considered to assess the impact of boreal forest disturbance on climate and additional feedbacks, such as increased permafrost thaw or transition to alternative ecosystem states.
Magnetic Fabric Constraints on the Cenozoic Compressional Strain Changes in the Northern Qaidam Marginal Thrust Belt and Their Tectonic Implications
Authors: Li Bingshuai , Yan Maodu , Zhang Weilin , Parés Josep M. , Fang Xiaomin , Yang Yongpeng , Zhang Dawen , Guan Chong , Bao Jing 
Published: April 2020

AbstractReconstructing the compressional strain history of the northern Qaidam marginal thrust belt has significant implications for understanding the mountain building processes of the northeastern Tibetan Plateau and the tectonic evolution of the Altyn Tagh Fault. However, the variation of compressional strain in this region has rarely been studied. Here, we present Cenozoic anisotropy of the low‐field magnetic susceptibility records from the fluvial‐lacustrine Hongliugou profile within the middle part of the northern Qaidam marginal thrust belt. The magnetic fabrics of the Shizigou Formation are dominated by a primary sedimentary magnetic fabric, whereas those of the lower Lulehe Formation are undetermined, most likely due to the conglomerate lithology; in contrast, the magnetic fabrics of the middle Lulehe to Shangyoushashan Formations, all of which are dominated by antiferromagnetic hematite and paramagnetic components with crystallographic preferred orientations, are mostly embryonic tectonic fabrics induced by prefolding layer‐parallel shortening. Compared with previously reported paleomagnetic rotation results within the Hongliugou locality, the rotation‐corrected compressional strain directions that are perpendicular to the rotation‐corrected magnetic lineations exhibit a regular trend from nearly N‐S before ~33 Ma to NE‐SW at ~10 Ma. Integrated with other lines of evidence from the northern Qaidam Basin, we attribute the ~45° successive clockwise rotations of the compressional strain directions to the propagation of significant strike‐slip faulting along the Altyn Tagh Fault into the northern Qaidam marginal thrust belt that resulted in significant vertical axis clockwise rotations in the region.
Observing Waves in Sea Ice With ICESat‐2
Authors: Horvat C. , Blanchard‐Wrigglesworth Ed , Petty A. 
Published: April 2020

AbstractThe coupled interaction of ocean surface waves and sea ice is important in determining the thermodynamic and dynamic properties of sea ice and its relationship to the ocean and atmosphere. Wave‐ice interactions create the marginal ice zone (MIZ), a region critically important for ecology, transportation, and the polar energy budget. Typically, the MIZ is defined using satellite products as those regions where sea ice concentration is between 15% and 80%. Here we present a new technique to observe ocean surface waves in sea ice, leveraging NASA's ICESat‐2 satellite laser altimeter, and produce maps of wave‐affected sea ice regions in both hemispheres. Defining a new wave‐based metric for MIZ extent, we find that compared to a concentration‐based metric, wave‐based MIZ estimates are smaller. Further, the wave‐affected MIZ makes up a larger fraction of sea ice extent in winter than in summer, opposite to the seasonal cycle of concentration‐based MIZ.
A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics
Authors: Sánchez Ricardo , Ribera Jordi , Morgades Mireia , Ayala Rosa , Onecha Esther , Ruiz-Heredia Yanira , Juárez-Rufián Alexandra , de Nicolás Rodrigo , Sánchez-Pina José , Vives Susana , Zamora Lurdes , Mercadal Santiago , Coll Rosa , Cervera Marta , García Olga , Ribera Josep-Maria , Martínez-López Joaquín 
Published: April 2020

AbstractBCR-ABL1-like B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains poorly characterized in adults. We sought to establish the frequency and outcome of adolescent and adult BCR-ABL1-like ALL using a novel RNA-Seq signature in a series of patients with BCP-ALL. To this end, we developed and tested an RNA-Seq custom panel of 42 genes related to a BCR-ABL1-like signature in a cohort of 100 patients with BCP-ALL and treated with risk-adapted ALL trials. Mutations related to BCR-ABL1-like ALL were studied in a panel of 33 genes by next-generation sequencing (NGS). Also, CRLF2 overexpression and IKZF1/CDKN2A/B deletions were analyzed. Twenty out of 79 patients (12–84 years) were classified as BCR-ABL1-like (25%) based on heatmap clustering, with significant overexpression of ENAM, IGJ, and CRLF2 (P ≤ 0.001). The BCR-ABL1-like subgroup accounted for 29% of 15–60-year-old patients, with the following molecular characteristics: CRLF2 overexpression (75% of cases), IKZF1 deletions (64%), CDKN2A/B deletions (57%), and JAK2 mutations (57%). Among patients with postinduction negative minimal residual disease, those with the BCR-ABL1-like ALL signature had a higher rate of relapse and lower complete response duration than non-BCR-ABL1-like patients (P = 0.007). Thus, we have identified a new molecular signature of BCR-ABL1-like ALL that correlates with adverse prognosis in adult patients with ALL.
CtBP determines ovarian cancer cell fate through repression of death receptors
Authors: Ding Boxiao , Yuan Fang , Damle Priyadarshan K. , Litovchick Larisa , Drapkin Ronny , Grossman Steven R. 
Published: April 2020

AbstractC-terminal binding protein 2 (CtBP2) is elevated in epithelial ovarian cancer, especially in the aggressive and highly lethal subtype, high-grade serous ovarian cancer (HGSOC). However, whether HGSOC tumor progression is dependent on CtBP2 or its paralog CtBP1, is not well understood. Here we report that CtBP1/2 repress HGSOC cell apoptosis through silencing of death receptors (DRs) 4/5. CtBP1 or 2 knockdown upregulated DR4/5 expression, and triggered autonomous apoptosis via caspase 8 activation, but dependent on cell-type context. Activation of DR4/5 by CtBP1/2 loss also sensitized HGSOC cell susceptibility to the proapoptotic DR4/5 ligand TRAIL. Consistent with its function as transcription corepressor, CtBP1/2 bound to the promoter regions of DR4/5 and repressed DR4/5 expression, presumably through recruitment to a repressive transcription regulatory complex. We also found that CtBP1 and 2 were both required for repression of DR4/5. Collectively, this study identifies CtBP1 and 2 as potent repressors of DR4/5 expression and activity, and supports the targeting of CtBP as a promising therapeutic strategy for HGSOC.
FADS1 promotes the progression of laryngeal squamous cell carcinoma through activating AKT/mTOR signaling
Authors: Zhao Rui , Tian Linli , Zhao Bo , Sun Yanan , Cao Jing , Chen Kexin , Li Fengqing , Li Minghua , Shang Desi , Liu Ming 
Published: April 2020

AbstractMetabolic abnormality is the major feature of laryngeal squamous cell carcinoma (LSCC), however, the underlying mechanism remain largely elusive. Fatty acid desaturase 1 (FADS1), as the key rate-limiting enzyme of polyunsaturated fatty acids (PUFAs), catalyzes dihomo-gamma-linolenic acid (DGLA) to arachidonic acid (AA). In this study, we reported that the expression of FADS1 was upregulated in LSCC, high FADS1 expression was closely associated with the advanced clinical features and poor prognosis of the recurrent LSCC patients after chemotherapy. Liquid chromatograph-mass spectrometry (LC-MS) analysis revealed that FADS1 overexpression induced greater conversion of DGLA to AA, suggesting an increased activity of FADS1. Similarly, the level of prostaglandin E2 (PGE2), a downstream metabolite of AA, was also elevated in cancerous laryngeal tissues. Functional assays showed that FADS1 knockdown suppressed the proliferation, migration and invasion of LSCC cells, while FADS1 overexpression had the opposite effects. Bioinformatic analysis based on microarray data found that FADS1 could activate AKT/mTOR signaling. This hypothesis was further validated by both in vivo and in vitro assays. Hence, our data has supported the viewpoint that FADS1 is a potential promoter in LSCC progression, and has laid the foundation for further functional research on the PUFA dietary supplementation interventions targeting FADS1/AKT/mTOR pathway for LSCC prevention and treatment.