Importance Despite guideline recommendations, many patients discontinue P2Y12 inhibitor therapy earlier than the recommended 1 year after myocardial infarction (MI), and higher-potency P2Y12 ...inhibitors are underutilized. Cost is frequently cited as an explanation for both of these observations. Objective To determine whether removing co-payment barriers increases P2Y12 inhibitor persistence and lowers risk of major adverse cardiovascular events (MACE). Design, Setting, and Participants Cluster randomized clinical trial among 301 hospitals enrolling adult patients with acute MI (June 5, 2015, through September 30, 2016); patients were followed up for 1 year after discharge (final date of follow-up was October 23, 2017), with blinded adjudication of MACE; choice of P2Y12 inhibitor was per clinician discretion. Interventions Hospitals randomized to the intervention (n = 131 6436 patients) provided patients with co-payment vouchers for clopidogrel or ticagrelor for 1 year (median voucher value for a 30-day supply, $137 25th-75th percentile, $20-$339). Hospitals randomized to usual care (n = 156 4565 patients) did not provide study vouchers. Main Outcomes and Measures Independent coprimary outcomes were patient-reported persistence with P2Y12 inhibitor (defined as continued treatment without gap in use ≥30 days) and MACE (death, recurrent MI, or stroke) at 1 year among patients discharged with a prescription for clopidogrel or ticagrelor. Results Among 11 001 enrolled patients (median age, 62 years; 3459 31% women), 10 102 patients were discharged with prescriptions for clopidogrel or ticagrelor (clopidogrel prescribed to 2317 36.0% in the intervention group and 2497 54.7% in the usual care group), 4393 of 6135 patients (72%) in the intervention group used the voucher, and follow-up data at 1 year were available for 10 802 patients (98.2%). Patient-reported persistence with P2Y12 inhibitors at 1 year was higher in the intervention group than in the control group (unadjusted rates, 5340/6135 87.0% vs 3324/3967 83.8%, respectively; P < .001; adjusted difference, 2.3% 95% CI, 0.4% to 4.1%; adjusted odds ratio, 1.19 95% CI, 1.02 to 1.40). There was no significant difference in MACE at 1 year between intervention and usual care groups (unadjusted cumulative incidence, 10.2% vs 10.6%; P = .65; adjusted difference, 0.66% 95% CI, −0.73% to 2.06%; adjusted hazard ratio, 1.07 95% CI, 0.93 to 1.25). Conclusions and Relevance Among patients with MI, provision of vouchers to offset medication co-payments for P2Y12 inhibitors, compared with no vouchers, resulted in a 3.3% absolute increase in patient-reported persistence with P2Y12 inhibitors and no significant reduction in 1-year MACE outcomes.
The TRIPS Agreement (Agreement on Trade related aspects of Intellectual Property Rights) is one the most significant of the multilateral trade agreements under the WTO regime. The TRIPS Agreement ...covers intellectual property areas such as copy right and related rights, trademarks including service marks, geographical indications, industrial designs, patents including the protection of new varieties of plants, the layout-designs of integrated circuits, and undisclosed information. This research paper examines that a strong intellectual property rights protection system in line with the objectives of the TRIPS Agreement is likely to have immense impact on the economy of Pakistan because strong legal framework and judicial system ensures the attraction of foreign trade and investment. A case-law study reveals that the Pakistani courts are now-a-days very much vigilant in reorganization of the intellectual property regime under the multilateral trading system. Moreover, the prevention of abuse of intellectual property rights as envisaged in the TRIPS Agreement is a highly encouraging factor for attracting foreign investment in Pakistan.
Purpose: The study evaluates the performance of alternative variance-covariance estimators as a fundamental ingredient to portfolio optimization.
Methodology: The study estimates eleven covariance ...matrices on the data of Pakistan stock exchange's non-financial sector firms covering the period from July 2006 to June 2020. The accuracy and efficiency of covariance estimators are assessed through two evaluation parameters: root mean square error and minimum variance portfolios (risk behavior).
Main findings: Empirical findings based on evaluation parameters suggest that more complex covariance estimators in the equity market of Pakistan yield no additional financial gains than the equally weighted portfolio of estimators.
Application of the study: As the estimation of the variance-covariance matrix is one of the essential elements of portfolio construction, this study guides investor(s) on selecting an appropriate covariance estimator among eleven estimators endorsed by literature.
Novelty/ originality of the study: Based on detailed analysis, the study documents that investor(s) of the Pakistan stock exchange cannot gain any additional benefit from more complex and tricky methods of variance-covariance estimators compared to a portfolio of estimators for the non-financial sector. Investors are advised to consider the equally weighted portfolio of estimators when formulating their investment strategy.
Purpose: The work empirically investigates the effect of corporate social responsibility (CSR) on information asymmetry (IA).
Methodology: For analysis, the study uses annual data ranging from 2007 ...to 2017, collected from the published reports of companies registered at the Pakistani equity market comprising the non-financial sector. An unbalanced panel of 257 companies with 2383 observations is analyzed using the generalized methods of moment (GMM) technique.
Main findings: In line with stakeholder's theory, results disclose a negative association between the variable of CSR and IA. It suggests that investing in CSR-related activities will reduce the asymmetry of information among managers and shareholders.
Application of the study: Findings of the study uncover the benefits of CSR in relation to IA that must be considered while formulating any strategy both at the governmental and corporate level. Government should facilitate corporations that engage in CSR work while firms must include CSR in their policy-making as it can significantly reduce information asymmetry.
Novelty/ originality of the study: This study provides a deep analysis in the form of behavioural association and the effect of CSR practices on information asymmetry in the context of the Pakistani non-financial sector. The study endorses the concept of CSR practices for the reduction of information asymmetry in Pakistani firms.
The aim of this investigation was to study an association among boron-induced oxidative stress, antioxidant system and polyamine metabolism in cucumber
Cucumis sativus
(L) plants. Furthermore, it was ...also investigated whether chitosan would increase the antioxidant activity and polyamine concentration that could induce tolerance to boron-induced oxidative stress. Cucumber (cv. Sahil) plants were exposed to 0.5, 1.0, and 1.5 mM boron stress at the 16-day stage for one week while receiving nutrient solution. At the 23- and 27-day stages, plants were foliar-treated with chitosan solution (50 and 75 mg L
−1
), and harvested at the 34-day stage to investigate growth, photosynthesis, and biochemical characteristics. Boron stress significantly reduced the growth, total chlorophyll concentration, relative water contents, photosynthesis, stomatal conductance, internal CO
2
concentration, stomatal size, and membrane stability index. However, boron stress elevated the enzymatic activities of various antioxidants, osmolytes, polyamine concentration, H
2
O
2
concentration, lipid peroxidation and electrolyte leakage in leaves. The follow-up spray with chitosan to the plants subjected to boron stress improved growth, relative water contents, green pigments, photosynthetic activity and membrane stability index, and further enhanced the activity of antioxidant enzymes, osmolytes, leaf polyamine concentration, hydrogen peroxide concentration, lipid peroxidation, and electrolyte leakage in the leaves. The augmented level of antioxidant enzymes, root/shoot osmolytes and leaf polyamine concentration might have induced resistance to the boron stressed plants, causing an ameliorated growth, relative water contents, and photosynthesis related characteristics. It is also concluded that chitosan is an eco-friendly alleviator of toxicity caused by boron by enhancing polyamine concentration and strengthening antioxidant defensive system but reducing the boron concentration in plant tissues.
Passband broadening of an AWG (array waveguide grating) demultiplexer with an MMI (multimode interference) coupler connected at the end of a tapered input waveguide is considered. An explicit formula ...based on the field propagation of an approximate Hermit–Gaussian beam is used to calculate quickly and reliably the spectral response of the AWG demultiplexer. The widths of the input waveguide, the output waveguides and the MMI coupler are optimized. The optimal design is verified with the experimental measurement.
Cytomegalovirus (CMV) is a persistent DNA virus that has evolved with humans to establish a finely balanced host-virus relationship. This balance is maintained by host immune surveillance since ...deficiencies in these processes can result in life-threatening disease, as observed in immunologically immature neonates and pharmacologically immunosuppressed transplant recipients. Both T cells and natural killer cells are intimately involved in maintaining asymptomatic infection by specific and non-specific recognition of infected cells. Under pressure from such host immune responses, CMV appears to have evolved elaborate strategies to subvert these responses in order to persist in the host. CMV target antigens are well characterized, with many CD8 T cell and CD4 T cell epitopes reported. This information is now being exploited to treat immunocompromised patients in order to boost virus-specific immunity. This review also discusses our current understanding of how virus carriage may skew lymphocyte populations in immunocompetent subjects and the association of CMV-seropositivity with immunosenescence.
Improvement of potato has been accomplished using conventional and non-conventional approaches coupled with numerous tissue culture procedures. The aim of the present study was to assess the efficacy ...of gibberellic acid (GA3) on the morphogenesis of International Potato Center (CIP) potato explants and acclimatization of plantlets in the field. Nodal segments as an explant source (1–1.5 cm) were isolated from 31 CIP potato plantlets and were inoculated into Murashige and Skoog (MS) medium supplemented with 0.0 (control), 0.1, 0.5, or 1.0 mg L−1of GA3. The variation in growth parameters of the cultivars was then observed. The highest shoot induction occurred in MS medium containing 1.0 mg L−1 GA3 with an increase in the inter-nodal distance between nodes as compared to other treatments. Higher concentration (1.0 mg L−1) of GA3 significantly increased plant height and root length in the treated germplasm however; this concentration was inhibitory to the number of nodes and roots per plant. The number of leaves was significantly increased in plants receiving GA3 treatment at lower concentration (0.1 mg L−1). The 31 CIP genotypes were transplanted to the field and checked for yield quality traits. It was concluded from the results that GA3 had significant effects on morphogenesis and was effective in the acclimatization of CIP potato plantlets in field.
Background:
The poor-risk cytogenetic subgroup of acute myeloid leukaemia (AML) includes various chromosomal aberrations and represents a heterogeneous population of patients with a dismal 10-year ...overall survival. While the success of genetic landscaping studies is encouraging, it is debatable whether genomics, or indeed any single-omics platform alone, is sufficient to capture the biology of a disease that continues to evade our existing treatments so effectively. Instead, we need to develop a much better understanding of the complexity of this subgroup of AMLs: the relationship and interdependencies across biochemical pathways, how these may differ between patients and their impact on the leukemia and normal stem cell compartments. To launch this process, we have completed a multi-omics profiling programme to shed new light on the genetic and biochemical features of poor-risk AML (https://poor-risk-aml.bham.ac.uk/).
Aims: Application of multi-omics and integrative approaches to decipher the complexities of cytogenetically poor-risk AML
Methods: Sample inclusion criteria were based on cytogenetics and availability of sufficient diagnostic bone marrow or peripheral blood material for analysis. The 50 primary AMLs included 17 cases with complex karyotype, 13 -7/del(7), 11 KMT2A rearrangements (with the exception of t(9;11)), 4 t(6;9), 3 -5/de(5), 1 del(17) and 1 inv(3). Profiles consisted of a combination of genomics (whole genome sequencing (WGS, 60X for tumour and 30X for germ-line controls), targeted sequencing of 54 myeloid loci, and total RNA-seq (100 million reads per bulk sample), mass spectrometry proteomics and phosphoproteomics (with >6,000 proteins and > 25,000 phosphorylation sites detected and quantified), mass cytometry (CyTOF, 39 markers), drug screening (ranging from 200-500 approved or investigational compounds) and the selective generation of patient-derived xenograft (PDX) models.
Results: Near complete datasets have been compiled on all 50 primary AMLs, with the exception of WGS analysis where profiling was restricted to cases where corresponding germline DNA was available. Integration of WGS and RNA-seq data identified 122 genes having notable allele-specific expression (ASE) in ≥ 5 samples supported by ≥ 3 SNPs and these included the transcription factor GATA2 and the DNA topoisomerase TOP1MT. Use of RNA fusion capture tools resolved novel inter- and intra- chromosomal gene rearrangements that were confirmed by WGS. The four t(6;9)(p23;q34)/DEK-NUP214 cases, with a mean age of diagnosis of 43.5 years and all harboring FLT3-ITD mutations, arose from the most immature hematopoietic compartment (CD34+CD117+ enrichment) and demonstrated a unique transcriptomic signature, which included upregulation of FOXO3 and GRP56. Collectively, t(6;9) primary samples also showed a selective drug sensitivity to XPO1 (selinexor and eltanexor) and JAK inhibitors (ruxolitinib, tofacitinib and momelotinib) compared to other cytogenetic risk groups. On the other hand, a comparison of in vitro drug sensitivity data with genomic data of our entire cohort of patients demonstrated that TP53 wt AMLs (n=37) were more sensitive to all four MDM2 inhibitors (AMG-232, idasanutlin, SAR405838 and NVP-CGM097) compared to TP53 mutated cases (n=13). Comparisons of transcriptomics with the in vitro sensitivity to drugs included in early/late phase AML clinical trials, identified signatures of response associated with MDM2 and Aurora B kinase (AZD1152-HQPA) inhibitors. Phosphoproteomics analysis and machine learning modeling separated KMT2A rearranged leukemias into 2 discrete groups (group A: MLLT4, MLLT10 and TET1; group B with MLLT6, ELL and SEP9 fusion partners). Functionally, group A presented with elevated HOXA10 protein expression and enhanced in vitro response to genotoxic drugs and cell cycle inhibitors when compared to group B leukemia.
Conclusions: Our study demonstrates the feasibility of simultaneously generating omics data from several different platforms and highlights that a combination of genetic and proteomic profiles may help to inform the choice of therapies based on the underlying biology of a patient's AML.
Wennerberg:Novartis: Research Funding; Pfizer: Honoraria. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding; Innovative Mediicines Initiative project Harmony: Research Funding.
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