Cost-Effectiveness of Dabigatran versus Genotype-Guided Management of Warfarin Therapy for Stroke Prevention in Patients with Atrial Fibrillation

BACKGROUND: Dabigatran is associated with lower rate of stroke comparing to warfarin when anticoagulation control is sub-optimal. Genotype-guided warfarin dosing and management may improve patient-time in target range (TTR) and therefore affect the cost-effectiveness of dabigatran compared with warfain. We examined the cost-effectiveness of dabigatran versus warfarin therapy with genotype-guided management in patients with atrial fibrillation (AF). METHODOLOGY/PRINCIPAL FINDINGS: A Markov model was designed to compare life-long economic and treatment outcomes of dabigatran (110 mg and 150 mg twice daily), warfarin usual anticoagulation care (usual AC) with mean TTR 64%, and genotype-guided anticoagulation care (genotype-guided AC) in a hypothetical cohort of AF patients aged 65 years old with CHADS(2) score 2. Model inputs were derived from literature. The genotype-guided AC was assumed to achieve TTR = 78.9%, adopting the reported TTR achieved by warfarin service with good anticoagulation control in literature. Outcome measure was incremental cost per quality-adjusted life-year (QALY) gained (ICER) from perspective of healthcare payers. In base-case analysis, dabigatran 150 mg gained higher QALYs than genotype-guided AC (10.065QALYs versus 9.554QALYs) at higher cost (USD92,684 versus USD85,627) with ICER = USD13,810. Dabigatran 110 mg and usual AC gained less QALYs but cost more than dabigatran 150 mg and genotype-guided AC, respectively. ICER of dabigatran 150 mg versus genotype-guided AC would be >USD50,000 (and genotype-guided AC would be most cost-effective) when TTR in genotype-guided AC was >77% and utility value of warfarin was the same or higher than that of dabigatran. CONCLUSIONS/SIGNIFICANCE: The likelihood of genotype-guided anticoagulation service to be accepted as cost-effective would increase if the quality of life on warfarin and dabigatran therapy are compatible and genotype-guided service achieves high TTR (>77%)

Monomeric ephrinB2 binding induces allosteric changes in Nipah virus G that precede its full activation.

Nipah virus is an emergent paramyxovirus that causes deadly encephalitis and respiratory infections in humans. Two glycoproteins coordinate the infection of host cells, an attachment protein (G), which binds to cell surface receptors, and a fusion (F) protein, which carries out the process of virus-cell membrane fusion. The G protein binds to ephrin B2/3 receptors, inducing G conformational changes that trigger F protein refolding. Using an optical approach based on second harmonic generation, we show that monomeric and dimeric receptors activate distinct conformational changes in G. The monomeric receptor-induced changes are not detected by conformation-sensitive monoclonal antibodies or through electron microscopy analysis of G:ephrinB2 complexes. However, hydrogen/deuterium exchange experiments confirm the second harmonic generation observations and reveal allosteric changes in the G receptor binding and F-activating stalk domains, providing insights into the pathway of receptor-activated virus entry.Nipah virus causes encephalitis in humans. Here the authors use a multidisciplinary approach to study the binding of the viral attachment protein G to its host receptor ephrinB2 and show that monomeric and dimeric receptors activate distinct conformational changes in G and discuss implications for receptor-activated virus entry

Neural correlates of positive and negative symptoms through the illness course: an fMRI study in early psychosis and chronic schizophrenia

Psychotic illness is associated with cognitive control deficits and abnormal recruitment of neural circuits subserving cognitive control. It is unclear to what extent this dysfunction underlies the development and/or maintenance of positive and negative symptoms typically observed in schizophrenia. In this study we compared fMRI activation on a standard Stroop task and its relationship with positive and negative symptoms in early psychosis (EP, N = 88) and chronic schizophrenia (CHR-SZ, N = 38) patients. CHR-SZ patients showed reduced frontal, striatal, and parietal activation across incongruent and congruent trials compared to EP patients. Higher positive symptom severity was associated with reduced activation across both trial types in supplementary motor area (SMA), middle temporal gyrus and cerebellum in EP, but not CHR-SZ patients. Higher negative symptom severity was associated with reduced cerebellar activation in EP, but not in CHR-SZ patients. A negative correlation between negative symptoms and activation in SMA and precentral gyrus was observed in EP patients and in CHR-SZ patients. The results suggest that the neural substrate of positive symptoms changes with illness chronicity, and that cognitive control related neural circuits may be most relevant in the initial development phase of positive symptoms. These findings also highlight a changing role for the cerebellum in the development and later maintenance of both positive and negative symptoms

Exploring the band structure of Wurtzite InAs nanowires using photocurrent spectroscopy

We use polarized photocurrent spectroscopy in a nanowire device to investigate the band structure of hexagonal Wurtzite InAs. Signatures of optical transitions between four valence bands and two conduction bands are observed which are consistent with the symmetries expected from group theory. The ground state transition energy identified from photocurrent spectra is seen to be consistent with photoluminescence emitted from a cluster of nanowires from the same growth substrate. From the energies of the observed bands we determine the spin orbit and crystal field energies in Wurtzite InAs. This information is vital to the development of crystal phase engineering of this important III-V semiconductor.ER

Efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2–positive breast cancer

© 2018, Hong Kong Academy of Medicine Press. All rights reserved. Introduction: The management of human epidermal growth factor receptor 2 (HER2)–positive breast cancer has changed dramatically with the introduction and widespread use of HER2-targeted therapies. There is, however, relatively limited real-world information about the effectiveness and safety of trastuzumab emtansine (T-DM1) in Hong Kong Chinese patients. We assessed the efficacy and toxicity profiles among local patients with HER2-positive advanced breast cancer who had received T-DM1 therapy in the second-line setting and beyond. Methods: This retrospective study involved five local centres that provide service for over 80% of the breast cancer population in Hong Kong. The study period was from December 2013 to December 2015. Patients were included if they had recurrent or metastatic histologically confirmed HER2+ breast cancer who had progressed after at least one line of anti-HER2 therapy including trastuzumab. Patients were excluded if they received T-DM1 as first-line treatment for recurrent or metastatic HER2+ breast cancer. Patient charts including biochemical and haematological profiles were reviewed for background information, T-DM1 response, and toxicity data. Adverse events were documented during chemotherapy and 28 days after the last dose of medication. Results: Among 37 patients being included in this study, 28 (75.7%) had two or more lines of anti-HER2 agents and 26 (70.3%) had received two or more lines of palliative chemotherapy. Response assessment revealed that three (8.1%) patients had a complete response, eight (21.6%) a partial response, 11 (29.7%) a stable disease, and 12 (32.4%) a progressive disease; three patients could not be assessed. The median duration of response was 17.3 (95% confidence interval, 8.4-24.8) months. The clinical benefit rate (complete response + partial response + stable disease, ≥12 weeks) was 37.8% (95% confidence interval, 22.2%-53.5%). The median progression-free survival was 6.0 (95% confidence interval, 3.3-9.8) months and the median overall survival had not been reached by the data cut-off date. Grade 3 or 4 toxicities included thrombocytopaenia (13.5%), raised alanine transaminase (8.1%), anaemia (5.4%), and hypokalaemia (2.7%). No patient died as a result of toxicities. Conclusions: In patients with HER2-positive advanced breast cancer who have been heavily pretreated with anti-HER2 agents and cytotoxic chemotherapy, T-DM1 is well tolerated and provided a meaningful progression-free survival of 6 months and an overall survival that has not been reached. Further studies to identify appropriate patient subgroups are warranted.Link_to_subscribed_fulltex

Kinetic Phenomena in Thin Film Electronic Materials

Contains reports on ten research projects.Semiconductor Research Corporation (Grant 83-01-033)National Science Foundation (Grant DMR 81-19285)U.S. Department of Energy (Contract DE-ACO2-82-ER-13019)National Science Foundation (Grant ECS82-05701)International Business Machines, Inc.Dartmouth UniversityJoint Services Electronics Program (Contract DAAG29-83-K-0003