A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis

Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2- MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase 1 (sTK1) activity. At data-cutoff, fifty-four patients received a median of 13 cycles (range 2.6-43.5). The rate of G3 + ANC was 21.3% (95% CI: 11.2-36.1%) without G4 in C1, and 40.7% (95% CI: 27.9-54.9%), including 38.9% G3 and 1.8% G4, in all cycles. The clinical benefit rate was 80.4% (95% CI: 66.5-89.7%). The median progression-free survival (mPFS) (95% CI) was 19.75 (12.11-34.89), 33.5 (17.25-not reached [NR]), and 11.96 (10.43-NR) months, in the overall, endocrine sensitive or resistant population, respectively. High sTK1 at baseline, C1 day 15 (C1D15), and C2D1 were independently prognostic for shorter PFS (p = 9.91 × 1

Survey Among Medical Students During COVID-19 Lockdown: The Online Class Dilemma

Background: In view of COVID-19 lockdown in India, many colleges started online classes. This study aimed to evaluate the attitudes of, and the factors affecting, medical students attending online classes during lockdown. Methods: We designed an online questionnaire with open-ended, close-ended, and Likert scale questions. Links to the questionnaires were shared with the medical students who have attended at least one online class during the COVID-19 lockdown period. Respondents were 1061 participants from 30 medical colleges from the states of Kerala and Tamil Nadu in India. Results: The majority of students – 94% (955/1016) – used smartphones to attend online classes. ZOOM/ Skype – by 57.1% (580/1016) – and Google platforms – by 54.4% (553/1016) – were commonly used. Learning at leisure – 44.5% (452/1016) – was the top reason why students liked online classes, whereas network problems – 85.8% (872/1016) – was the top reason why students disliked them. Lack of sufficient interaction – 61.1% (621/1016) was another reason why students disliked online learning. More than half the participants – 51.7% (526/1016) – did not want to continue online classes after COVID-19 lockdown. More students – 55% (558/1016) – favored regular classes than online classes. Conclusion: Students in our survey did not seem favorably disposed to online classes. Network problems experienced by students should be addressed. Furthermore, teachers should try to make the classes more interactive and educational institutions should address the problems pointed out by the students in order to make online classes more effective in the future

DE-STARLITE: A Directed Energy Planetary Defense Mission

This paper presents the motivation behind and design of a directed energy planetary defense system that utilizes laser ablation of an asteroid to impart a deflecting force on the target. The proposed system is called DE-STARLITE for Directed Energy System for Targeting of Asteroids and ExploRation – LITE as it is a small, stand-on unit of a larger standoff DE-STAR system. Pursuant to the stand-on design, ion engines will propel the spacecraft from low-Earth orbit (LEO) to the near-Earth asteroid (NEA). During laser ablation, the asteroid itself becomes the propellant ; thus a very modest spacecraft can deflect an asteroid much larger than would be possible with a system of similar mission mass using ion beam deflection (IBD) or a gravity tractor. DE-STARLITE is capable of deflecting an Apophis-class (325 m diameter) asteroid with a 15-year targeting time. The mission fits within the rough mission parameters of the Asteroid Redirect Mission (ARM) program in terms of mass and size and has much greater capability for planetary defense than current proposals and is readily scalable to the threat. It can deflect all known threats with sufficient warning

Scheduling in a Database-Based Distributed Operating System

Current operating systems date from over 40 years ago and were designed for very different computing requirements, making them ill-equipped to handle serverless workloads as well as modern challenges in scalability, heterogeneity, availability, and security. Hence, we propose a radically new data-centric OS design for serverless computing. This database OS (DBOS) centralizes all cluster state in a uniform data model: database tables stored in a high-performance, distributed, main-memory database management system. Operations on this state will be performed via serverless, stateless tasks. This thesis presents work done to build a preliminary scheduler and to implement and evaluate various global scheduling algorithms. We also demonstrate the performance of a modern DBMS in executing various scheduling operations.M.Eng

Retrospective Analysis of Treatment Patterns and Effectiveness of Palbociclib and Subsequent Regimens in Metastatic Breast Cancer

Cyclin-dependent kinase (CDK) 4/6 inhibitors are now the standard of care for hormone receptor-positive (HR+), HER2-negative (HER-) metastatic breast cancer (MBC). However, guidelines are lacking regarding their optimal sequencing with other available agents. This study examines physician practice patterns and treatment outcomes of palbociclib and subsequent therapies in a real-world setting. A retrospective chart review was conducted for consecutive patients with MBC who received palbociclib between February 2015 and August 2017 at the Alvin J. Siteman Cancer Center. Kaplan-Meier method was used to generate time-to-event curves and estimate median progression-free survival (mPFS). Log-rank test was used to compare differences. A total of 200 patients, with a median age of 59.4 years and a follow-up of 19.5 months, were included. Palbociclib was most frequently combined with letrozole (73.5%), followed by fulvestrant (25%), anastrozole (1%), and tamoxifen (0.5%). Most patients received palbociclib in the endocrine-resistant setting (n=42, n=50, and n=108 in the first-, second-, and subsequent-line settings, respectively), and the fraction of patients receiving palbociclib as first- or second-line therapy increased in recent months ( =.0428). mPFS was 20.7, 12.8, and 4.0 months with palbociclib administered in the first-, second-, and subsequent-line settings, respectively ( <.0001). Incidences of grade 3/4 neutropenia (41.5%) and dose reductions (29%) were comparable to reports in the literature. Among patients whose disease progressed on palbociclib (n=104), the most frequent next-line treatment was capecitabine (n=21), followed by eribulin (n=16), nab-paclitaxel (n=15), and exemestane + everolimus (n=12). mPFS with hormone therapy alone or in combination with targeted agents (n=32) after first-, second-, and subsequent-line palbociclib was 17.0, 9.3, and 4.2 months, respectively ( =.04). mPFS with chemotherapy (n=70) was not reached, 4.7, and 4.1 months after first-, second-, and subsequent-line palbociclib, respectively ( =.56). Palbociclib is effective for HR+/HER2- MBC in real-world practice. Hormone therapy alone or in combination with targeted agents remains an effective option after palbociclib progression

DBOS: a DBMS-oriented operating system

This paper lays out the rationale for building a completely new operating system (OS) stack. Rather than build on a single node OS together with separate cluster schedulers, distributed filesystems, and network managers, we argue that a distributed transactional DBMS should be the basis for a scalable cluster OS. We show herein that such a database OS (DBOS) can do scheduling, file management, and inter-process communication with competitive performance to existing systems. In addition, significantly better analytics can be provided as well as a dramatic reduction in code complexity through implementing OS services as standard database queries, while implementing low-latency transactions and high availability only once.</jats:p

Sphingolipids in Childhood Asthma and Obesity (SOAP Study): A Protocol of a Cross-Sectional Study

Asthma and obesity are two of the most common chronic conditions in children and adolescents. There is increasing evidence that sphingolipid metabolism is altered in childhood asthma and is linked to airway hyperreactivity. Dysregulated sphingolipid metabolism is also reported in obesity. However, the functional link between sphingolipid metabolism, asthma, and obesity is not completely understood. This paper describes the protocol of an ongoing study on sphingolipids that aims to examine the pathophysiology of sphingolipids in childhood asthma and obesity. In addition, this study aims to explore the novel biomarkers through a comprehensive multi-omics approach including genomics, genome-wide DNA methylation, RNA-Seq, microRNA (miRNA) profiling, lipidomics, metabolomics, and cytokine profiling. This is a cross-sectional study aiming to recruit 440 children from different groups: children with asthma and normal weight (n = 100), asthma with overweight or obesity (n = 100), overweight or obesity (n = 100), normal weight (n = 70), and siblings of asthmatic children with normal weight, overweight, or obesity (n = 70). These participants will be recruited from the pediatric pulmonology, pediatric endocrinology, and general pediatric outpatient clinics at Sidra Medicine, Doha, Qatar. Information will be obtained from self-reported questionnaires on asthma, quality of life, food frequency (FFQ), and a 3-day food diary that are completed by the children and their parents. Clinical measurements will include anthropometry, blood pressure, biochemistry, bioelectrical impedance, and pulmonary function tests. Blood samples will be obtained for sphingolipid analysis, serine palmitoyltransferase (SPT) assay, whole-genome sequencing (WGS), genome-wide DNA methylation study, RNA-Seq, miRNA profiling, metabolomics, lipidomics, and cytokine analysis. Group comparisons of continuous outcome variables will be carried out by a one-way analysis of variance or the Kruskal–Wallis test using an appropriate pairwise multiple comparison test. The chi-squared test or a Fisher’s exact test will be used to test the associations between categorical variables. Finally, multivariate analysis will be carried out to integrate the clinical data with multi-omics data. This study will help us to understand the role of dysregulated sphingolipid metabolism in obesity and asthma. In addition, the multi-omics data from the study will help to identify novel genetic and epigenetic signatures, inflammatory markers, and mechanistic pathways that link asthma and obesity in children. Furthermore, the integration of clinical and multi-omics data will help us to uncover the potential interactions between these diseases and to offer a new paradigm for the treatment of pediatric obesity-associated asthma

Assessment of network module identification across complex diseases

International audienc