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Chemoimmunotherapy regimens have been the standard first-line therapy for patients with chronic lymphocytic leukemia (CLL). For young, fit patients the standard of care is combination of fludarabine, cyclophosphamide, and rituximab (FCR). Based on the preclinical work demonstrating that bendamustine combined with fludarabine resulted in increased DNA damage, we designed a phase I-II clinical trial with fludarabine, bendamustine, and rituximab (FBR) for patients with relapsed/refractory CLL. Treatment consisted of fludarabine 20 mg/m2 daily x 3 days and rituximab 375-500 mg/m2 x 1 day. Phase I included bendamustine at increasing doses of 20, 30, 40, or 50 mg/m2 daily x 3 days; phase II was with FR, and B at the selected dose. DNA damage response (H2AX phosphorylation) was evaluated in a subset of patients. Fifty-one patients were enrolled. The median age was 62 years; median number of prior therapies was 2; 40% had del(11q); and 41 patients had received prior FCR-based therapies. Hematologic toxicity was more common in ≥40 mg/m2 dose cohorts. Maximum tolerated dose (MTD) was not identified. Bendamustine-elicited H2AX phosphorylation was not dose-dependent, but markedly increased after fludarabine. We identified bendamustine 30 mg/m2 as the safe dose for phase II. The overall response rate (ORR) was 67% with 36% complete response (CR) / CR with incomplete count recovery (CRi). Younger patients (

BackgroundClofarabine is a nucleoside analogue with activity in children with acute lymphoblastic leukemia (ALL). Based on the hypothesis that clofarabine inhibits DNA repair after exposure to DNA-damaging agents, we designed a phase I and extension study to evaluate the combination of clofarabine and cyclophosphamide in adult patients with relapsed/refractory ALL.MethodsThe continual reassessment method (CRM) was used to define the maximum tolerated dose (MTD).ResultsFifty patients with a median age of 30 years (range, 21-72 years) were enrolled, 30 of whom were part of the phase I group. Clofarabine 40 mg/m(2) intravenously daily × 3 days and cyclophosphamide 200 mg/m(2) intravenously every 12 hours × 3 days were established as the MTDs. Dose limiting toxicity (DLT) included diarrhea, transaminase elevations, and skin rashes. The response rate of the whole study group was 14%, including 10% of patients who achieved complete remission (CR) or CR without platelet recovery (CRp). Three responses occurred in patients with primary refractory disease. Early mortality (< 30 days) was 6%. The median duration of response was 69 days (range, 5-315 days). Median overall survival was about 3 months. Compared with day 1 (cyclophosphamide alone), H2AX phosphorylation was increased on day 2 when clofarabine and cyclophosphamide were administered as a couplet (n = 8).ConclusionThe combination of clofarabine plus cyclophosphamide at the doses used in this study in a group of heavily pretreated patients with ALL is only moderately effective. Other doses, alternative schedules, or a more favorable patient population may achieve better results.

Approximate Matrix Multiplication (AMM) has emerged as a useful and computationally inexpensive substitute for actual multiplication of large matrices. Randomized as well as deterministic solutions to AMM were provided in the past. The latest work provides a deterministic algorithm that solves AMM more accurately than the other works. It is a streaming algorithm that is both fast and accurate. But, it is less robust to noise and is also liable to have less than optimal performance in the presence of concept drift in the input matrices. We propose an algorithm that is more accurate, robust to noise, invariant to concept drift in the data, while having almost the same running time as the state-of-the-art algorithm. We also prove that theoretical guarantees exist for the proposed algorithm. An empirical performance improvement of up to 90 % is obtained over the previous algorithm. We also propose a general framework for parallelizing the proposed algorithm. The two parallelized versions of the algorithm achieve up to 1.9 x and 3.6 x speedups over the original version of the proposed algorithm. [ABSTRACT FROM AUTHOR]

Guideline Directed Medical Therapy (GDMT) has been revolutionary in improving outcomes of heart failure patients. However, with the addition of more medication classes, the annual cost of these medications on the US healthcare system needs further evaluation. We aim to evaluate the trend of annual cost of GDMT from 2013 to 2021 using the Medicare-part D Database. Using Medicare Part D database (2013–2021), we determined the number of beneficiaries receiving these drugs, the total number of 30-day fills for each medication, and the total annual spending on these medications. Linear regression was used to analyze data using Python Programming Language. P value of less than 0.05 was considered to be statistically significant. The estimated annual Medicare- part D spending on empagliflozin had a 50 % increase in cost between 2020 and 2021, which could be attributed to its FDA approval for heart failure with reduced ejection fraction. Empagliflozin cost Medicare 3.73 billion USD in 2021 alone. In addition, sacubitril-valsartan had a strong trajectory since its introduction to the market in 2015. Since its approval in July 2015, it cost Medicare 4.51 billion USD. The Mineralocorticoid Receptor Antagonist class was the least costly class of GDMT. The rise in the cost of GDMT is not proportionate amongst the different classes of GDMT. Newer classes of medications cast a significant cost on Medicare in recent years. [ABSTRACT FROM AUTHOR]

• A variety of survival prediction model scores designed for critically ill ICU and VA-ECMO patients demonstrated modest discriminatory ability in the current cohort of patients. • The Encourage score, the APACHE II score, and the ACEF score were significantly higher in nonsurvivors to discharge than survivors after VA-ECMO. • The ACEF score, while not designed to predict survival in critically ill patients, demonstrated the best discriminatory ability. • The ACEF score is also the simplest to calculate, an advantage in the emergent setting. Patients undergoing consideration for venoarterial extracorporeal membrane oxygenation (VA-ECMO) require an immediate risk profile assessment in the setting of incomplete information. A number of survival prediction models for critically ill patients and patients undergoing elective cardiac surgery or institution of VA-ECMO support have been designed. We assess the ability of these models to predict outcomes in a cohort of patients undergoing institution of VA-ECMO for cardiogenic shock or cardiac arrest. Fifty-one patients undergoing institution of VA-ECMO support were retrospectively analyzed. APACHE II, SOFA, SAPS II, Encourage, SAVE, and ACEF scores were calculated. Their ability to predict outcomes were assessed. Indications for ECMO support included postcardiotomy shock (25%), ischemic etiologies (39%), and other etiologies (36%). Pre-ECMO arrest occurred in 73% and 41% of patients underwent cannulation during arrest. Survival to discharge was 39%. Three survival prediction model scores were significantly higher in nonsurvivors to discharge than surivors; the Encourage score (25.4 vs 20; p =.04), the APACHE II score (23.6 vs 19.2; p =.05), and the ACEF score (3.1 vs 1.8; p =.03). In ROC analysis, the ACEF score demonstrated the greatest predictive ability with an AUC of 0.7. A variety of survival prediction model scores designed for critically ill ICU and VA-ECMO patients demonstrated modest discriminatory ability in the current cohort of patients. The ACEF score, while not designed to predict survival in critically ill patients, demonstrated the best discriminatory ability. Furthermore, it is the simplest to calculate, an advantage in the emergent setting. [ABSTRACT FROM AUTHOR]

Left ventricular outflow tract obstruction (LVOTO) can be caused by multiple factors. One of the rare causes of LVOTO is preserved anterior mitral valve leaflet and chordal apparatus after mitral valve replacement. We describe a case of a patient with worsening chronic congestive heart failure secondary to LVOTO from systolic anterior motion of residual native anterior mitral leaflet. In this patient, LVOTO was surgically corrected by excision of anterior leaflet and chordal apparatus through the aortic root. [ABSTRACT FROM AUTHOR]

Abstract Drug Named Entity Recognition (DNER) is the process of identifying drug names from unstructured biomedical text. Most of the research works in this area make use of the available benchmark biomedical corpus to train and test the DNER system. In this paper, we propose an interactive biomedical text mining framework to access the scientific abstracts online, to pre-process and to extract drug entity through state – of – art machine learning techniques. This framework facilitates recognizing new drug names from real time biomedical abstracts from PubMed as well as from existing benchmark test datasets. [ABSTRACT FROM AUTHOR]

Abstract Handwritten signatures are very important in our social and legal life for verification and authentication. A signature can be accepted only if it is from the intended person. The probability of two signatures made by the same person being the same is very less. Many properties of the signature may vary even when two signatures are made by the same person. So, detecting a forgery becomes a challenging task. In this paper, a solution based on Convolutional Neural Network (CNN) is presented where the model is trained with a dataset of signatures, and predictions are made as to whether a provided signature is genuine or forged. [ABSTRACT FROM AUTHOR]