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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.

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.

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.

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.

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.

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.

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.

A large repertoire of gene-centric data has been generated in the field of zebrafish biology. Although the bulk of these data are available in the public domain, most of them are not readily accessible or available in nonstandard formats. One major challenge is to unify and integrate these widely scattered data sources. We tested the hypothesis that active community participation could be a viable option to address this challenge. We present here our approach to create standards for assimilation and sharing of information and a system of open standards for database intercommunication. We have attempted to address this challenge by creating a community-centric solution for zebrafish gene annotation. The Zebrafish GenomeWiki is a ‘wiki’-based resource, which aims to provide an altruistic shared environment for collective annotation of the zebrafish genes. The Zebrafish GenomeWiki has features that enable users to comment, annotate, edit and rate this gene-centric information. The credits for contributions can be tracked through a transparent microattribution system. In contrast to other wikis, the Zebrafish GenomeWiki is a ‘structured wiki’ or rather a ‘semantic wiki’. The Zebrafish GenomeWiki implements a semantically linked data structure, which in the future would be amenable to semantic search. Database URL: http://genome.igib.res.in/twiki

In India, an increasing number of vehicles on the roads, in recent past, have led to an increase in the number of road accidents. There have been alarming statistics regarding the number of accidents per day in India. At least 1,42,000 people died due to road accidents in India in the year 2011. Bad driving, lax traffic control, and poor road conditions are the main reason for this.In this work, we present a mobile phone application that uses combination of in-built sensors, GPS, micro-phone and accelerometer, to detect driving behavior along with road and traffic conditions. This application will prove helpful in detecting bad driving as well as road and traffic conditions in order to assist a willing individual to change his or her driving behavior. The law and enforcement agencies may also use this data in analyzing the ground realities for increasing number of road accidents.

A 30W (peak) S-band helix travelling wave tube (TWT) has been designed and developed. Specialised techniques for the fabrication of gridded gun, rf attenuators and stainless steel to alumina sealing were developed. A number of tubes were successfully fabricated, processed and tested to check the reproducibility of rf output characteristics. The hot test results were found comparable with the predicted results. Computer aided design packages were used to validate the design of the vital components and predict the performance of the TWT.

The regulation of PPAR? and PPAR? at m-RNAs expression level is responsible for Islet ?-cell dysfunction and insulin secretion seen in diabetic rats. Many traditional treatments have been recommended in the alternative system of medicine for the treatment of diabetes mellitus. Stevia rebaudiana and Gurmmar is a nontoxic natural therapeutic agent revealed to own diuretic, hypotensive and hypoglycemic properties. The ground of this study was to examine the anti-hyperglycemic property, expression of m-RNA at PPAR? and PPAR? receptors and islet ?-cells dysfunction of a combined aqueous extracts of Stevia rebaudiana and Gurmmar is on streptozotocin induced diabetic wistar rats. The diabetes induced rats were fed with plant extracts at the increasing dosage of 200mg, 300mg and 500mg of body weight. The combined plant extracts administrated rats revealed a significantly (P

Vane-loaded slow-wave structures (SWS) for travelling-wave tubes (TWT) have been designed using rigorous model of Kravchenko et al [1] and a recently proposed MINV (modified infinite number of vanes) model [2], Two different SWS with six, and nine vanes respectively have been optimised to give a flat dispersion characteristic over about two octaves in S-C band by varying the radial penetration and angular thickness of the vanes. The dispersion characteristics of the cold test models of the two structures have been experimentally measured using the perturbation technique over 2–7 GHz frequency range. The comparison of the results of theoretical MINV and Kravchenko's models with the experimental results indicate that a reasonable prediction of dispersion characteristics can be made with the simpler MINV model in place of using Kravchenko's model, which is based on rigorous field analysis.