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Asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response [MCyR]) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.3 years, asciminib continued to demonstrate superior efficacy and better safety and tolerability than bosutinib. The major molecular response (MMR) rate at week 96 (key secondary endpoint) was 37.6% with asciminib vs 15.8% with bosutinib; the MMR rate difference between the arms, after adjusting for baseline MCyR, was 21.7% (95% CI, 10.53–32.95; two-sided p = 0.001). Fewer grade ≥3 adverse events (AEs) (56.4% vs 68.4%) and AEs leading to treatment discontinuation (7.7% vs 26.3%) occurred with asciminib than with bosutinib. A higher proportion of patients on asciminib than bosutinib remained on treatment and continued to derive benefit over time, supporting asciminib as a standard of care for patients with CML-CP previously treated with ≥2 TKIs.

Asciminib is a first-in-class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P-glycoprotein (P-gp) and possesses pH-dependent solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P-gp inhibitors, CYP3A inducers and acid-reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40 mg). Asciminib exposure (area under the curve [AUC]) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (C

Background: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal–epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety. Methods: This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two-drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator. Results: A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (Cmax) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUCinf) and area under the plasma concentration-time curve from time zero to the last measurable point (AUClast), respectively, with no change in Cmax. Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study. Conclusion: The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.

Antimicrobial resistance (AMR) is a global health emergency. Complementary to developing new drugs, AMR can be monitored and controlled through cost-effective active surveillance of resistance. As an initiative to monitor resistance, countries all across the globe are collecting data using a variety of surveillance tools. Moreover, hospitals routinely collect the AMR data for treatment which is being stored in their Laboratory and Hospital Information systems (LIS-HIS). The generated clinical data is collected & stored in various formats, making it very difficult to analyze and generate national reports. To integrate the stored clinical data for predictive modeling and analysis, there is an immediate need for a one-stop data repository capable of importing and exporting data in simple data exchange formats (CSV/Excel). The paper highlights the design & development of i-DIA, a python-based web API to facilitate the interoperability of AMR data by automatically importing the bulk of medical data from CSV files into generic data management and analysis system. The i-DIA has been integrated and tested with the ICMR’s AMR surveillance network on in-house developed software, i-AMRSS. The i-AMRSS is presently collecting data from 31 laboratories across India and i-DIA has been used to import data generated from LIS & HIS of a few hospitals directly into the system. The paper also proposes the complete web-based framework (an extension of i-DIA) integrated with peer-to-peer system architecture.

Context: In CML-CP, the BCR::ABL1 T315I mutation confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs), except ponatinib and olverembatinib. In a previous analysis of the phase I, dose-escalation trial X2101, asciminib—a BCR::ABL1 inhibitor that binds to the ABL myristoyl pocket—demonstrated efficacy and a favorable safety profile in heavily pretreated patients with T315I-mutated CML. We report updated efficacy and safety data in patients with CML-CP with the T315I mutation (data cutoff: January 6, 2021). Objective: Provide updated safety and efficacy data for patients with T315I-mutated CML-CP after added exposure. Design: Patients with T315I-mutated CML-CP and treated with ≥1 prior TKI were enrolled and received asciminib 200mg twice daily (BID). Results: 48 patients were included; 25 patients (52.1%) received ≥3 prior TKIs. At data cutoff, treatment was ongoing in 27 patients (56.3%). 45 of 48 patients were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR); 3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable patients, 19 (42.2%) achieved MMR by week 24 and 22 (48.9%) by week 96. Evaluable patients included 26 ponatinib-pretreated and 19 ponatinib-naive patients; 34.6% and 68.4%, respectively, achieved MMR by week 96. The probability of maintaining MMR for ≥96 weeks was 84% (95% CI, 68.1%-100.0%). 23 of 37 patients (62.2%) with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS ≤1% by week 96. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added exposure (median duration of exposure, 2.08 years; range, 0.04-4.13 years). The most common (≥10%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations) and thrombocytopenia (14.6%). Arterial occlusive events occurred in 4 patients (8.3%); none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation occurred in 5 patients (10.4%). Only 2 study deaths, both due to COVID-19, occurred in this patient population. Conclusions: After a median exposure of >2 years, asciminib monotherapy 200mg BID exhibited a sustained, favorable safety profile and clinical efficacy in patients with T315I-mutated CML-CP—a population with high unmet medical need. This updated analysis confirms asciminib as a treatment option for patients with T315I-mutated CML-CP, including those previously treated with ponatinib.

Capmatinib, a mesenchymal-epithelial transition factor tyrosine kinase inhibitor, is metabolized by cytochrome P450 (CYP) 3A4 and aldehyde oxidase. In individuals with hepatic impairment, alterations in hepatobiliary excretion and metabolism could lead to higher capmatinib exposure. We compared the pharmacokinetics of a single oral dose of capmatinib 200 mg administered to participants with varying degrees of hepatic impairment vs. matched controls with normal hepatic function.This phase 1, multicentre, open-label, parallel-group study enrolled adult participants with normal hepatic function and mild, moderate and severe hepatic impairments. Eligible participants received a single oral dose of 200 mg capmatinib. The pharmacokinetic parameters of capmatinib were analysed and compared across participants with impaired and normal hepatic function.Of 31 enrolled participants, 29 had an evaluable pharmacokinetic profile: normal (n = 9); mild (n = 6); moderate (n = 8); severe (n = 6). Compared with the normal group, geometric mean (GM) maximum (peak) observed plasma drug concentration after single-dose administration decreased by 27.6% in the mild group (GM ratio [GMR] = 0.724; 90% confidence interval [CI]: 0.476-1.10), by 17.2% in the moderate group (GMR = 0.828; 90% CI: 0.563-1.22) and remained unchanged in the severe group (GMR = 1.02; 90% CI: 0.669-1.55). Compared with the normal group, GM area under the plasma concentration-time curve from time zero to infinity decreased by 23.3% in the mild group (GMR = 0.767; 90% CI: 0.532-1.11), by 8.6% in the moderate group (GMR = 0.914; 90% CI: 0.652-1.28) and increased by 24% in the severe group (GMR = 1.24; 90% CI: 0.858-1.78).Mild, moderate and severe hepatic impairment did not have a clinically relevant impact on capmatinib pharmacokinetics. No new safety findings are reported in this study.

7004 Background: Asciminib is the first BCR::ABL1 inhibitor to specifically target the ABL Myristoyl Pocket (STAMP). In the ASCEMBL primary analysis, asciminib had superior efficacy and better safety/tolerability than BOS in pts with CML-CP after ≥2 prior TKIs. After a median follow-up of 2.3 years (16.5 months’ additional follow-up since primary analysis), we report efficacy and safety results (cutoff: October 6, 2021). Methods: Eligible pts were adults with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 European LeukemiaNet. Pts were randomized 2:1 to asciminib 40 mg twice daily or BOS 500 mg once daily, stratified by major cytogenetic response (MCyR) status (Ph+ metaphases ≤35%) at baseline. The key secondary endpoint was major molecular response (MMR) rate at wk 96. Results: 233 pts were randomized to asciminib (n=157) or BOS (n=76). At cutoff, treatment was ongoing in 84 (53.5%) and 15 (19.7%) pts, respectively; the most common reason for discontinuation was lack of efficacy in 38 (24.2%) and 27 (35.5%) pts, respectively. MMR rate at wk 96 (per ITT) was higher on asciminib (37.6%) than BOS (15.8%). The difference, adjusting for baseline MCyR, was 21.7% (95% CI, 10.5%-33.0%; 2-sided P=.001). More pts on asciminib than BOS, respectively, had BCR::ABL1IS ≤1% (45.1% vs 19.4%) at wk 96. The probability of maintaining MMR and BCR::ABL1IS ≤1% for ≥72 wk was 96.7% (95% CI, 87.4%-99.2%) and 94.6% (95% CI, 86.2%-97.9%), respectively, on asciminib and 92.9% (95% CI, 59.1%-99.0%) and 95.0% (95% CI, 69.5%-99.3%), respectively, on BOS. Median duration of exposure was 103.1 (range, 0.1-201.1) wk on asciminib and 30.5 (range, 1.0-188.3) wk on BOS. Despite the longer duration of asciminib exposure, safety/tolerability of asciminib continued to be better than that of BOS (Table). No new on-treatment deaths were reported since the primary analysis. Most frequent (>10%) grade ≥3 adverse events (AEs) on asciminib vs BOS were thrombocytopenia (22.4%, 9.2%), neutropenia (18.6%, 14.5%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). Conclusions: After >2 years of follow-up, asciminib continued to show superior efficacy and better safety/tolerability vs BOS. Responses were durable, with more pts on asciminib in MMR. Additionally, more pts on asciminib had BCR::ABL1IS ≤1%, a milestone response in later lines associated with improved survival. These results continue to support the use of asciminib as a new CML therapy, with the potential to transform standard of care. Clinical trial information: NCT03106779. [Table: see text]

BACKGROUND Infectious diseases are the major cause of mortality across the globe. Tuberculosis is one such infectious disease which is in the top 10 deaths causing diseases in developing as well as developed countries. The biosensors have emerged as a promising approach to attain the early detection of the pathogenic infection with accuracy and precision. However, the main challenge with biosensors is real time data monitoring preferentially reversible and label free measurements of certain analytes. Integration of biosensor and Artificial Intelligence (AI) approach would enable better acquisition of patient’s data in real time manner enabling automatic detection and monitoring of Mycobacterium tuberculosis (M.tb.) at an early stage. Here we propose a biosensor based smart handheld device that can be designed for automatic detection and real time monitoring of M.tb from varied analytic sources including DNA, proteins and biochemical metabolites. The collected data would be continuously transferred to the connected cloud integrated with AI based clinical decision support systems (CDSS) which may consist of the machine learning based analysis model useful in studying the patterns of disease infestation, progression, early detection and treatment. The proposed system may get deployed in different collaborating centres for validation and collecting the real time data. OBJECTIVE To propose a biosensor based smart handheld device that can be designed for automatic detection and real time monitoring of M.tb from varied analytic sources including DNA, proteins and biochemical metabolites. METHODS The Major challenges for control and early detection of the Mycobacterium tuberculosis were studied based upon the literature survey. Based upon the observed challenges, the biosensor based smart handheld device has been proposed for automatic detection and real time monitoring of M.tb from varied analytic sources including DNA, proteins and biochemical metabolites. RESULTS In this viewpoint, we propose an application based novel approach of combining AI based machine learning algorithms on the real time data collected with the use of biosensor technology which can serve as a point of care system for early diagnosis of the disease which would be low cost, simple, responsive, measurable, can diagnose and distinguish between active and passive cases, include single patient visits, cause considerable inconvenience, can evaluate the cough sample, require minimum material aid and experienced staff, and is user-friendly. CONCLUSIONS In this viewpoint, we propose an application based novel approach of combining AI based machine learning algorithms on the real time data collected with the use of biosensor technology which can serve as a point of care system for early diagnosis of the disease which would be low cost, simple, responsive, measurable, can diagnose and distinguish between active and passive cases, include single patient visits, cause considerable inconvenience, can evaluate the cough sample, require minimum material aid and experienced staff, and is user-friendly.

Altres ajuts: Novartis Pharmaceuticals Corporation. Purpose: In the Phase II GEOMETRY mono-1 study, the potent and selective mesenchymal-epithelial transition (MET) inhibitor capmatinib exhibited considerable efficacy in MET exon 14 skipping (METex14)-mutated metastatic non-small cell lung cancer at a dose of 400 mg BID. The current recommended dose is 400 mg BID in tablet formulation, with or without food. This article reports the pharmacokinetic (PK) profile, safety, and tolerability of capmatinib 300 and 400 mg BID given with food in MET-dysregulated advanced solid tumors. Methods: This multicenter, open-label, Phase I study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose escalation phase, capmatinib tablets were orally administered at a dose of 300 mg BID with food; if tolerated, the dose escalation cohort of 400 mg BID was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK variables, with a secondary objective of safety. Findings: Overall, 35 patients (300 mg BID, n = 8; 400 mg BID, n = 27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy, and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median T for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0 to 5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios, 1.29-1.69), with an increase in exposure (AUC and C) from 300 to 400 mg BID. There were no occurrences of dose-limiting toxicity. All patients experienced at least 1 adverse event, and treatment-related adverse events occurred in 28 patients (80%; 300 mg BID, n = 6; 400 mg BID, n = 22), the most frequent of which were fatigue (37.1%) and nausea (34.3%). Implications: Capmatinib tablet formulation at a dose of up to 400 mg BID with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg BID with or without food. ClinicalTrials.gov identifier: NCT02925104.

Adequate nutrition is generally regarded as a core dimension in any evaluation of well-being. In the context of India, a country with a high prevalence of poor nutrition, there is a dearth of nutrition studies with adequate coverage and comparability. Using primary data on food consumption from a village in a poorer state of India, we study the consumption of five key nutrients, namely, calories, protein, carbohydrates, calcium and iron. Among the various determinants of nutrition, we find that expenditure has a significant impact on nutrition and the expenditure elasticity of nutrition is comparatively high for all the key nutrients. By correcting for potential endogeneity, we demonstrate a causal link from expenditure and food subsidy provided by the public distribution system to nutritional intake. There is some evidence that household characteristics such as household size and gender of the household head matter for nutrition; however, they are not robust under various specifications.

In this paper, the transient solution of the amount of charge in a rechargeable battery of finite capacity is obtained. The level of charge in the battery is governed by different input and output processes and are dependent on the level of charge in the battery. This model has been already discussed in Jones et al. (Fluid queue models of battery life. In: IEEE 19th international symposium on modeling, analysis and simulation of computer and telecommunication systems (MASCOTS), pp. 278–285, 2011), and the distribution of the hitting time was found numerically. In this paper, the method chosen is based on probabilistic approach which allows us to achieve a closed form solution for the distribution of the level of charge in the battery at any time t. Numerical illustrations are presented to verify the analytical results.

EP300 is a member of the EP300/CBP family of lysine acetyltransferases (KATs) with multiple roles in development and physiology. Loss of EP300/CBP activity in humans causes a very rare congenital disorder called Rubinstein Taybi Syndrome (RSTS). The zebrafish genome has two co-orthologs of lysine acetyltransferase EP300 (KAT3B) in zebrafish viz. ep300a and ep300b. Chemical inhibition of Ep300 with C646, a competitive inhibitor and morpholino-based genetic knockdown of ep300a and ep300b cause defects in embryonic development reminiscent of the human RSTS syndrome. Remarkably, overexpression of Ep300a KAT domain results in near complete rescue of the jaw development defects, a characteristic feature of RSTS in human suggesting the dispensability of the protein-interaction and DNA-binding domains for at least some developmental roles of Ep300. We also perform a chemical screen and identify two inhibitors of deacetylases, CHIC35 and HDACi III, that can partially rescue the RSTS-like phenotypes. Thus, modeling rare human genetic disorders in zebrafish allows for functional understanding of the genes involved and can also yield small molecule candidates towards therapeutic goals.

INTRODUCTION: Asciminib is the first BCR-ABL1 inhibitor that potently inhibits kinase activity of the BCR-ABL1 oncoprotein by Specifically Targeting the ABL Myristoyl Pocket (STAMP). The primary analysis from ASCEMBL, a randomized, phase 3 trial, demonstrated that asciminib has superior efficacy and a better safety and tolerability profile than bosutinib (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after ≥2 prior ATP-binding tyrosine kinase inhibitors (TKIs). The major molecular response (MMR) rate at wk 24 was 25.5% with asciminib vs 13.2% with BOS; the difference in MMR rates, after adjusting for major cytogenetic response status at baseline, was 12.2% (95% CI, 2.19-22.30; 2-sided P=.029). Grade ≥3 adverse events (AEs) were reported in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively, and AEs leading to discontinuation in 5.8% and 21.1%, respectively. After a median follow-up of 19.2 months (or 7.5 months' additional follow-up since the primary analysis), we report updated efficacy and safety results from ASCEMBL. METHODS: Adults with CML-CP treated with ≥2 prior TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Eligible pts must have experienced treatment failure (lack of efficacy) per 2013 European LeukemiaNet recommendations for second-line TKI therapy or intolerance of the most recent TKI at screening. Pts intolerant of their most recent TKI were eligible only if they had BCR-ABL1 on the International Scale >0.1% at screening. Pts with known BOS-resistant T315I or V299L mutations were ineligible. The cutoff date for the current analysis was January 6, 2021. RESULTS: A total of 233 pts were randomized to receive either asciminib (n=157) or BOS (n=76). At cutoff, all randomized pts had completed their wk 48 visit or had discontinued earlier. Treatment was ongoing in 89 (56.7%) and 17 (22.4%) pts on asciminib and BOS, respectively; the most common reason for treatment discontinuation was lack of efficacy in 37 (23.6%) and 27 (35.5%) pts, respectively (Table 1). By wk 48, the cumulative incidence of MMR was 33.2% with asciminib and 18.6% with BOS, showing that the difference between the 2 treatment arms observed by wk 24 in the primary analysis was maintained with longer follow-up (Figure 1). The cumulative incidence of BCR-ABL1IS ≤1% by wk 48 in patients without this level of response at baseline was 50.8% with asciminib and 33.7% with BOS. The difference in deep molecular responses (MRs) favoring asciminib vs BOS persisted by wk 48: MR 4 (BCR-ABL1IS ≤0.01%) and MR 4.5 (BCR-ABL1IS ≤0.0032%) rates were 14.0% and 9.6% with asciminib and 6.6% and 2.6% with BOS, respectively. With a longer duration of exposure in the asciminib arm, the safety and tolerability profile in the current analysis remains similar to that at the primary analysis. Median duration of exposure was 67.1 wk (range, 0.1-162.1 wk) for asciminib and 29.7 wk (range, 1.0-149.3 wk) for BOS. By the cutoff date, 91.0% of pts on asciminib and 97.4% of pts on BOS reported ≥1 all-grade AE; 54.5% and 67.1% of pts, respectively, reported ≥1 grade ≥3 AE. No additional fatal events were reported since the primary analysis. Fewer pts in the asciminib (7.1%) than BOS (25.0%) arm experienced AEs leading to treatment discontinuation (Table 2). The most common AEs leading to treatment discontinuation included thrombocytopenia (3.2%) and neutropenia (2.6%) in the asciminib arm and increased alanine aminotransferase (5.3%) and neutropenia (3.9%) in the BOS arm. CONCLUSIONS: Resistant/intolerant CML-CP after 2 lines of TKI treatment remains BCR-ABL1 dependent. The novel STAMP inhibitor asciminib demonstrates continued superior efficacy and a limited adverse event profile; myelosuppression, while more prominent, appears to be early and disease related. Secondary resistance based on loss of MMR is rare. Overall, after a median follow-up of 19.2 months, the positive benefit-risk profile of asciminib vs BOS continues to support the use of asciminib as a new therapy in this heavily pretreated pt population. This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Mauro: Sun Pharma / SPARC: Research Funding; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy. Minami: Takeda: Honoraria; CMIC: Research Funding; Astellas: Honoraria; Ono: Research Funding; Pfizer Japan Inc.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Voloshin: Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Pfizer: Consultancy; Biacad: Consultancy, Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes: Sun Pharma: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Fogliatto: AstraZeneca: Speakers Bureau. Kim: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Paladin: Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding. le Coutre: Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squibb: Honoraria. Saussele: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Pfizer: Honoraria; Roche: Honoraria. Hughes: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Honoraria. Chaudhri: Abbvie: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Garcia Gutierrez: Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Kapoor: Novartis: Current Employment, Current equity holder in publicly-traded company. Allepuz: Novartis: Current Employment, Current equity holder in publicly-traded company. Quenet: Novartis: Current Employment. Bédoucha: Novartis: Current Employment. Boquimpani: Pinth Pharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jansen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP). In adults, 5 TKIs are approved: imatinib, dasatinib, nilotinib, bosutinib and ponatinib. In the pediatric population, however, only imatinib, dasatinib and nilotinib are approved. Pediatric pts have similar cytogenetic and molecular response rates to first-line (1L) imatinib and 1L second-generation TKIs nilotinib and dasatinib as adults. While the safety profiles for TKIs are similar in adult and pediatric pts, growth retardation has been reported specifically in the pediatric population. Therefore, safer and more efficacious options are needed for pediatric pts. Asciminib is an investigational drug that inhibits BCR-ABL1 by specifically targeting the ABL myristoyl pocket (STAMP inhibitor). Asciminib has shown promising efficacy and safety in adults with CML-CP in phase I-III trials, given without food for 1 hour prior and 2 hours after taking asciminib (fasted). In the phase I asciminib monotherapy trial in heavily pretreated adult pts, 48% and 28% without and with T315I mutations, respectively, achieved or maintained major molecular response (MMR) by 12 months. In the phase III ASCEMBL trial for adults with CML-CP who are resistant to or intolerant of ≥2 TKIs, 25.5% of pts on asciminib vs 13.2% of pts on bosutinib achieved MMR at 24 weeks. Here we present the phase Ib/II trial evaluating asciminib monotherapy in pediatric pts. OBJECTIVE: The primary objectives of this study are to characterize the pharmacokinetic (PK) profile of asciminib in pediatric pts and identify a pediatric formulation dose (taken with food) leading to an asciminib exposure comparable to that of 40 mg twice daily (BID) in adult pts (fasted). DESIGN: This is a multicenter, open-label, phase Ib/II study (NCT04925479, Figure 1). Eligible pts have Philadelphia chromosome-positive CML-CP resistant to or intolerant of ≥1 prior TKI, do not bear T315I mutations and are aged ≥1 to In part 1 (dose-determining cohort), 4 to 6 pts aged ≥1 to In part 2 (expansion cohort), the body weight-adjusted dosing determined in part 1 will be used, and the total pts enrolled on pediatric formulation will be increased to 30, including those from part 1 (15 pts aged 1 to The total duration of the study treatment period is 5 years. The primary analysis (primary PK endpoints, safety, and pharmacodynamics) will be assessed after all pts have been on study for 52 weeks or discontinued earlier. A final analysis will be completed after all pts have been on study for 5 years or discontinued earlier. Pts who discontinue the study early will be followed up for survival until the study is complete. MAIN OUTCOMES MEASURES: The primary endpoints include PK parameters. Secondary endpoints include treatment-associated AEs, hematologic and molecular responses, and acceptability and palatability of asciminib (Table 1). CONCLUSIONS: Data from this study will be used to support a strategy of full extrapolation from adult data to use in the pediatric setting. This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Hijiya: Novartis: Consultancy; Stemline Therapeutics: Consultancy. Kapoor: Novartis: Current Employment, Current equity holder in publicly-traded company. Descamps: Novartis: Current Employment. Bayar: Novartis: Current Employment. Ramscar: Novartis: Current Employment.

BACKGROUND: Patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) may be treated with 1 of the 4 tyrosine kinase inhibitors (TKIs) approved for first-line (1L) use: the first-generation TKI imatinib and the second-generation (2G) TKIs bosutinib, dasatinib, and nilotinib. Deep molecular responses (DMRs) are important criteria for attempting treatment-free remission, an important goal for pts in 1L. However, in 1L, only about 30% of pts treated with imatinib and 30%-55% of pts treated with a 2G TKI achieve MR 4.5 (BCR-ABL1levels on the International Scale≤0.0032%). More than 50% of pts with CML-CP treated with imatinib develop resistance or intolerance to therapy. Among pts treated with a 2G TKI in 1L, 30%-40% need to change therapy by 5 years. Therefore, new treatment options are needed to help pts achieve their treatment goals in 1L. The main treatment goal for all pts is achievement of disease control, which potentially requires lifelong treatment. Therefore, highly potent, safe treatment options are needed for newly diagnosed pts with CML-CP. Asciminib is an investigational drug that inhibits the BCR-ABL1 oncoprotein through a novel mechanism of action: specifically targeting the ABL myristoyl pocket (STAMP). Due to asciminib's specifically targeting the ABL kinase family (ABL1, ABL2, BCR-ABL1), asciminib monotherapy offers the potential to improve safety and tolerability vs TKIs that target the adenosine triphosphate binding site of BCR-ABL1 and thus have varying degrees of selectivity toward ABL kinases. Asciminib has shown promising efficacy and safety in heavily pretreated adult pts with CML in phase I and III trials. In a phase III trial for pts with CML-CP treated with ≥2 prior TKIs, major molecular response (MMR) was achieved by 25.5% of pts on asciminib (40 mg twice daily [BID]) vs 13.2% on bosutinib at week 24. In the phase I trial of asciminib monotherapy at doses of 10-200 mg BID and 80-200 mg once daily (QD), 48% of pts with CML-CP treated with ≥2 prior TKIs without T315I mutations achieved or maintained MMR by 12 months. Here we present the upcoming phase III trial evaluating asciminib 80 mg QD monotherapy vs an investigator-selected approved TKI in newly diagnosed adult pts with CML-CP. OBJECTIVE: The primary objectives of this study are to assess the efficacy of asciminib vs an investigator-selected TKI (either imatinib, bosutinib, dasatinib, or nilotinib) in 1L and to compare the efficacy of asciminib within the stratum receiving investigator-selected imatinib in 1L through the primary end point of MMR rates at week 48. DMRs and; other long-term outcomes are also of interest. DESIGN: This is a multicenter, open-label, randomized, phase III study of asciminib at 80 mg QD compared with an approved, investigator-selected TKI (either imatinib, bosutinib, dasatinib, or nilotinib) for adult pts with newly diagnosed CML-CP in 1L (expected N=402; NCT04971226). Pts may not have received prior TKI therapy for CML, with the exception of ≤2 weeks of imatinib therapy and must have Eastern Cooperative Oncology Group performance status (ECOG PS) scores of 0 or 1. Pts who have previously received hydroxyurea or anagrelide may be included. Pts will be randomized 1:1 to the asciminib and investigator-selected TKI arms using 2 strata: European Treatment and Outcome Study (EUTOS) long-term survival (ELTS) risk score and the control arm TKI selected by the investigator prior to randomization (Figure 1). Pts randomized to the investigator-selected TKI arm will receive their selected TKIs at approved doses: imatinib, 400 mg QD; bosutinib, 400 mg QD; dasatinib, 100 mg QD; or nilotinib, 300 mg BID. Pts will remain on study for 5 years after the last pt first treatment has occurred, unless they have discontinued early due to treatment failure, disease progression, intolerance, or investigator or pt decision. Pts who discontinue early will continue to be followed up for survival and disease progression until the end of the study. MAIN OUTCOMES: The primary end point is MMR at week 48. Key secondary end points include MMR at week 96; exploratory end points include biomarker assessments. CONCLUSIONS: This study will assess the efficacy of asciminib 80 mg QD in adult pts with newly diagnosed CML-CP vs currently approved TKIs in 1L. This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Cortes: Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Hochhaus: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Takahashi: Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eizai: Research Funding; Toyamakagaku: Research Funding; Chugai: Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Larson: CVS/Caremark: Consultancy; Gilead: Research Funding; Astellas: Consultancy, Research Funding; Rafael Pharmaceuticals: Research Funding; Epizyme: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Cellectis: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Bombaci: CML Advocates Network: Consultancy, Current Employment, Membership on an entity's Board of Directors or advisory committees, Other: Organizational Grant Funding; MPN Advocates Network: Membership on an entity's Board of Directors or advisory committees, Other: Organizational Grant Funding; AIL - Associazione Italiana contro le Leucemie, i Linfomi e il Mieloma ONLUS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Organizational Grant Funding; CLL Advocate Network: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Organizational Grant Funding; Novartis: Consultancy, Other: Organizational Grant Funding; Jazz: Consultancy, Other: Organizational Grant Funding; Ceogene: Consultancy, Other: Organizational Grant Funding; Incyte: Consultancy, Other: Organizational Grant Funding; Takeda: Consultancy, Other: Organizational Grant Funding. Ramscar: Novartis: Current Employment. Kapoor: Novartis: Current Employment, Current equity holder in publicly-traded company. Ifrah: Novartis: Current Employment. Hughes: Novartis: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria.

An optimized platinum (Pt) doped tin oxide (SnO2) ink was prepared by chemical route and was deposited on low temperature co-fired ceramics (LTCC) micro-hotplate by screen printing. An alkoxide ink was prepared by mixing tin(II) 2-ethylexanoate (17 wt%) with isopropanol (27 wt%) and SnO2 powder (55 wt%). Doping of the ink was done using Pt (1 wt%) which increased the resistance of SnO2 film at room temperature and also reduced the operating temperature. The temperature of ensor was obtained and stabilised using MOSFET based temperature stability circuit. Film characterization was performed using Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray Spectroscopy (EDS) technique. Small grain size and high porosity is the requirement for good sensing. The grain size was found to be in the range of 150-180 nm and the film was sufficiently porous. Resistance change of the film was also investigated in the presence of carbon monoxide (CO) to assure gas sensing.

Circular RNAs are a new addition to the growing list of diverse species of RNAs that are formed by covalent linked 3' and 5' end forming a closed loop structure. Circular RNAs are characteristically resistant to exonuclease treatment and are relatively stable to linear transcripts. Circular RNAs are formed by alternate splicing mechanism but do not follow the canonical order of exons. Backsplice junctions are unique to circRNAs. CircRNAs are shown to possess potential to act as miRNA sponges and control transcription of mRNAs. CircRNAs are also reported as biomarkers for the disease like Alzheimer's, Parkinson's and cancer. A huge number of circRNA transcripts have been identified in model organisms including C.elegans, mouse, Drosophila as well as human. But there are no circular RNAs reported in zebrafish that is a very good model to study developmental stages, cardiovascular and blood-related disorders. In order to use zebrafish as a model organism and study the role of circRNAs in disease, we have used in-house generated RNA-sequencing data for five tissues including blood, brain, muscle, gills and heart. We discarded the reads mapped contiguously and full length over reference genome and identified back-splice junctions for putative circRNA transcripts. We identified a total of 3428 circRNA junctions out of which 78% were tissue specific. We validated 22 selected candidates for 5 tissues based on literature significance. We quantitatively analysed 5 tissue-enriched candidates using Real-time PCR. We also observed that major proportion of circRNAs is originating from protein coding loci. These circRNAs could be used to further study their role in hematopoietic and cardiovascular diseases.

CHD7 mutations are implicated in a majority of cases of the congenital disorder, CHARGE syndrome. CHARGE, an autosomal dominant syndrome, is known to affect multiple tissues including eye, heart, ear, craniofacial nerves and skeleton and genital organs. Using a morpholino-antisense-oligonucleotide-based zebrafish model for CHARGE syndrome, we uncover a complex spectrum of abnormalities in the neural crest and the crest-derived cell types. We report for the first time, defects in myelinating Schwann cells, enteric neurons and pigment cells in a CHARGE model. We also observe defects in the specification of peripheral neurons and the craniofacial skeleton as previously reported. Chd7 morphants have impaired migration of neural crest cells and deregulation of sox10 expression from the early stages. Knocking down Sox10 in the zebrafish CHARGE model rescued the defects in Schwann cells and craniofacial cartilage. Our zebrafish CHARGE model thus reveals important regulatory roles for Chd7 at multiple points of neural crest development viz., migration, fate choice and differentiation and we suggest that sox10 deregulation is an important driver of the neural crest-derived aspects of Chd7 dependent CHARGE syndrome.

Birth death processes with rational birth death rates have been studied by Maki (1976). This paper analyses the steady state behaviour of a fluid queue driven by a finite birth death process with rational birth and death rates. Two specific models are considered and closed form solutions are obtained for the equilibrium distribution of the buffer occupancy by finding the explicit eigenvalues of the underlying tridiagonal matrix. Numerical illustration is presented for different values of the size of the state space of the background process and for different values of the parameter involved.

T-cell acute lymphoblastic leukemias (T-ALLs) are aggressive hematologic tumors that result from the malignant transformation of T-cell progenitors. T-ALLs are classified immunologically into immature (pro- and pre-T), cortical and mature T-ALL. ETP-ALL is a recently described subtype of immature T-ALL. T-ALL is characterized by overexpression of oncogenic transcription factors that drive the malignancy: TAL1, TAL2, LYL1,LMO1, LMO2; TLX1, TLX3, NKX2.1, NKX2.2, NKX2.5, MEF2C and HOX genes. This study was conducted to understand the landscape of protein-coding genes using RNAseq in immature, cortical and mature T-ALL patients in India. This was a prospective study done on 134 T-ALL cases. The T-ALL patients were divided into 2 cohorts: discovery (n=35; immature 13, cortical 17, mature 5) and validation cohort (n=99; immature 45, cortical 44, mature 10). Total RNA seq was done in the discovery cohort. Clinical and prognostic relevance of lesions identified in the discovery cohort were studied in validation cohort. On RNAseq, a total of 2,318 genes were most differentially expressed between the 3 subtypes. In immature T-ALL cases, transcription factors controlling early hematopoiesis (MEF2C, TP63, HHEX, RUNX2, HOXA10, HOXA9, RUNX1T1 and ZBTB16) were highly expressed. LYN, a tyrosine kinase gene was also highly expressed. BAALC and MN1 genes, previously reported in acute myeloid leukemia, but not emphasized in reported genomics studies in the West, were overexpressed. Interestingly, LMO2 was overexpressed in the absence of significant overexpression of LYL1, a gene reported to be critical for oncogenic functions of Lmo2. In cortical T-ALL, the cortical thymocyte-defining CD1A gene was overexpressed. Homoebox domain genes NKX2-1, TLX1, TLX3, involved in T-cell development were overexpressed. In addition, FAT1, FAT3, EREG, CD1C, AKAP-2, IL-4, PRTG, TCL-6, ZP1 and TRAV genes were overexpressed. On examining CD1a+/sCD3+ and CD1a+/sCD3- groups, we found that in contrast to reported literature, TLX1 was highly expressed in the former group and TLX3 in the latter. In mature T-ALL, APC2, BCL3, CCR4, CDKN2A, EML4, HIST1H4G, HIST2H2B, NCOR2, ST20 and TRAV22 genes were overexpressed. Conventional drivers of T-ALL leukemogenesis - LYL1, TAL1 and LMO1 were not differentially expressed in our patients suggesting a difference between Indian and Western T-ALL patients. The clinical significance of expression of MEF2C, BAALC, HHEX, LYL1, TAL1 and FAT1 genes was studied in validation cohort by real-time PCR. High expression of MEF2C and BAALC gene was associated with immature immunophenotype (IPT) as compared to cortical and mature IPT (p=0.009; 0.008, respectively). Patients with ETP-ALL had higher expression of MEF2C and BAALC gene (p=0.018; 0.014, respectively). High MEF2C and BAALC expression were associated with CD34 positivity (p=0.004; 0.032, respectively). High BAALC expression was also associated with aberrant expression of the myeloid markers (p=0.021). Although not statistically significant, high HHEX expression was associated with immature IPT (p=0.072) and ETP-ALL IPT (p=0.06). Although LYL1 expression did not correlate with immature IPT, ETP-ALL was associated with higher LYL1 expression (p=0.039). Higher expression of FAT1 gene was associated with cortical IPT (p=0.026). Low XIST expression was more frequently associated with non-ETP-ALL IPT (p=0.017). TAL1 expression did not correlate with IPT. On survival analysis, only MEF2C gene expression was associated with EFS and OS. Compared to low MEF2C expressors, patients with high MEF2C had a lower event free survival (EFS) (73.58% vs 51.38%, p=0.01). High expression was found to be a significant predictor of overall survival (OS) (81.11% vs 96.43%, p=0.012). MEF2C emerged as driving oncogene in our T-ALL patients which can be used as predictor of EFS and OS. Expression of BAALC, HHEX, LYL1, TAL1, FAT1 and XIST genes did not correlate with EFS and OS. In this first study correlating T-ALL IPT with transcriptome profile in Indian T-ALL patients, we noted interesting differences from the West, potential subjects of further study. MEF2C gene expression emerged as the predictor of poor EFS and OS in T-ALL patients. Lastly, increased expression of LYN gene in our patients suggests that our immature T-ALL patients may benefit from tyrosine kinase inhibitors targeting Lyn. Disclosures No relevant conflicts of interest to declare.

Background: In patients with chronic myeloid leukemia in chronic phase (CML-CP), the efficacy of ATP-competitive tyrosine kinase inhibitors (TKIs) has resulted in treatment-free remission (TFR) as a primary treatment goal for those with a sustained deep molecular response (DMR). However, most patients treated with imatinib fail to achieve a sustained DMR, meaning that they cannot benefit from TFR. Asciminib is a potent and specific inhibitor of BCR-ABL1. Unlike BCR-ABL1 TKIs that target the ATP binding site, asciminib binds to the myristate pocket of ABL1. Preclinical data showed that the combination of asciminib with ATP-competitive TKIs may provide more potent BCR-ABL1 inhibition and prevent emergence of resistance mutations (Wylie et al. Nature. 2017;543:733-737). In an ongoing phase 1 study (NCT02081378), asciminib demonstrated clinical activity and was well tolerated as a single agent (Hughes et al. Blood. 2016;128 [abstract 625]). In the same study, asciminib in combination with imatinib showed promising preliminary efficacy and a good safety profile in patients resistant/intolerant of ≥2 prior TKIs (Cortes et al. HemaSphere. 2019;3(S1) [abstract S388]). These findings informed the dose of asciminib to be further evaluated in combination with imatinib. An ongoing phase 3 study (NCT03106779) is evaluating asciminib vs bosutinib in patients previously treated with ≥2 ATP-binding site TKIs (Mauro et al. J Clin Oncol. 2019;37 [abstract TPS7070]). Here, we describe the ASCiminib add-on 4-arm study evaluating MOlecular REsponse (ASC4MORE) in patients. This is a phase 2 study evaluating the efficacy of adding asciminib to ongoing imatinib therapy in patients with CML-CP who have not achieved DMR with long-term frontline imatinib (CABL001E2201; NCT03578367). Methods: Study participants are aged ≥18 years, have CML-CP, and have been treated with frontline imatinib for ≥12 months. Study entry requires patients to be receiving imatinib 400 mg once daily (QD) at randomization, have BCR-ABL1 transcript levels in the range of ≤1% to >0.01% on the International Scale (IS), no prior achievement of MR4 (BCR-ABL1IS ≤0.01%) confirmed by two consecutive tests, and no prior treatment failure. Overall, ~80 patients will be randomized 1:1:1:1 to one of four arms (Figure): either asciminib 40 mg QD or 60 mg QD added to imatinib 400 mg QD; continued treatment with imatinib 400 mg QD; or switch to nilotinib 300 mg twice daily. Study treatment will continue until treatment resistance or intolerance, or up to 96 weeks after the last randomized patient has begun treatment. The primary objective of this study is to assess whether asciminib add-on to imatinib is more effective than imatinib continuation; the primary endpoint is the rate of MR4.5 (BCR-ABL1IS ≤0.0032%) at 48 weeks. Secondary objectives include: to estimate the efficacy of switch to nilotinib; to estimate the difference in efficacy between asciminib add-on to imatinib and switch to nilotinib; and to characterize the safety of asciminib add-on to imatinib. Exploratory objectives include TFR eligibility at the end of the study and patient-reported outcomes. Patients in the imatinib continuation arm who have not achieved MR4.5 at 48 weeks may cross over to receive add-on asciminib. This study is ongoing, with 23 patients randomized as of 22 July 2019. Disclosures Saglio: BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Celgene: Consultancy. Hughes:Novartis, Bristol-Myers Squibb, Celgene: Research Funding; Novartis, Bristol-Myers Squibb: Consultancy, Other: Travel. Geissler:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Amgen: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Biomarin: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; UCB: Consultancy, Speakers Bureau; Servier: Consultancy. Kapoor:Novartis: Employment. Longin:Novartis: Employment. Mukherjee:Novartis: Employment. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

The management of acute pain in the opioid-tolerant patient is an area in perioperative medicine that is growing, as the use of opioids for chronic noncancer pain has been tolerated in the USA. Adding to this population is an increase in opioid abusers, addicts and those in recovery and maintenance programmes. These patients will continue to present for surgery and with acute pain that anaesthesiologists and other members of the healthcare team must become more adept at managing.This review covers some of the strategies that may be used by practitioners in the management of acute pain in the opioid-tolerant patient. It is important to collect a detailed history of opioid and drugs of abuse, including the timing of the last dose in order to avoid precipitation of withdrawal. The use of multimodal anaesthetic and analgesic strategies is important for both patient safety and satisfaction and can enhance recovery and discharge home.There is a need for more high-level evidence-based guidelines to help practitioners achieve the best care of this growing high-risk population of patients.

Birth death processes with rational birth and death rates have been studied by Maki (1976). In this paper a fluid queue driven by a birth death process with infinite state space and absorption is studied where the birth and death rates are rational functions of linear polynomials. We obtain an explicit transient solution for the fluid queue model using continued fraction approach to solve the underlying system of partial differential equations. For specific value of the parameter the considered model reduces to the model discussed by Parthasarathy, Sericola and Vijayashree (2005) and the results coincide. We also analyze the behavior of the fluid queue in a long run.

The objective of this paper is to study the transient distribution of the buffer content in any intermediate node of a wireless network based on IEEE 802.11 standards. The steady state solution of the discussed model has already been given in Arunachalam et al. (2010). The methodology used, maps the underlying model to a fluid queue model driven by two independent finite state birth-death processes with the aim to simplify the solution which is obtained in closed form with numerical illustration. Along with the buffer occupancy distribution, other performance measures: throughput, server utilisation and expected buffer content are also obtained numerically.

Long non-coding RNAs (lncRNAs) form the largest class of non-protein coding genes in the human genome. While a small subset of well-characterized lncRNAs has demonstrated their significant role in diverse biological functions like chromatin modifications, post-transcriptional regulation, imprinting etc., the functional significance of a vast majority of them still remains an enigma. Increasing evidence of the implications of lncRNAs in various diseases including cancer and major developmental processes has further enhanced the need to gain mechanistic insights into the lncRNA functions. Here, we present a comprehensive review of the various computational approaches and tools available for the identification and annotation of long non-coding RNAs. We also discuss a conceptual roadmap to systematically explore the functional properties of the lncRNAs using computational approaches. Contact: vinods@igib.in