Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter

BACKGROUND: Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase III randomized CheckMate 548 study was to evaluate RT + TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587). METHODS: Patients (N = 716) were randomized 1:1 to NIVO [(240 mg every 2 weeks × 8, then 480 mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 once daily during RT, then 150-200 mg/m2 once daily on days 1-5 of every 28-day cycle × 6)] or PBO + RT + TMZ following the same regimen. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in patients without baseline corticosteroids and in all randomized patients. RESULTS: As of December 22, 2020, median (m)PFS (blinded independent central review) was 10.6 months (95% CI, 8.9-11.8) with NIVO + RT + TMZ vs 10.3 months (95% CI, 9.7-12.5) with PBO + RT + TMZ (HR, 1.1; 95% CI, 0.9-1.3) and mOS was 28.9 months (95% CI, 24.4-31.6) vs 32.1 months (95% CI, 29.4-33.8), respectively (HR, 1.1; 95% CI, 0.9-1.3). In patients without baseline corticosteroids, mOS was 31.3 months (95% CI, 28.6-34.8) with NIVO + RT + TMZ vs 33.0 months (95% CI, 31.0-35.1) with PBO + RT + TMZ (HR, 1.1; 95% CI, 0.9-1.4). Grade 3/4 treatment-related adverse event rates were 52.4% vs 33.6%, respectively. CONCLUSIONS: NIVO added to RT + TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated or indeterminate MGMT promoter. No new safety signals were observed

Turning to art as a positive way of living with cancer: A qualitative study of personal motives and contextual influences

Why do some women turn to creative art-making after a diagnosis of cancer? Eleven women provided qualitative accounts that were analyzed following guidelines for interpretative phenomenological analysis (IPA). Some described taking up artistic leisure activities initially in order to manage emotional distress. Others emphasized their need for positive well-being, taking up art to experience achievement and satisfaction, to regain a positive identity, and to normalize family dynamics in the context of living with cancer. Participants’ turn to art-making was facilitated by biographical and contextual factors, including pre-existing craft skills, long-standing personal values and coping philosophies, family role models for managing adversity, and the supportive encouragement of family and friends. Other research has acknowledged that positive lifestyle change and post-traumatic growth can occur after a cancer diagnosis, and this study reveals a multi-faceted process. The findings suggest a need for further research into the experiences that facilitate positive lifestyle change and subjective well-being among people who are living with cancer

A preclinical and phase Ib study of palbociclib plus nab-paclitaxel in patients with metastatic adenocarcinoma of the pancreas

PURPOSE: To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m RESULTS: Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis ( CONCLUSIONS: This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met. TRIAL REGISTRATION: Pfizer Inc (NCT02501902). SIGNIFICANCE: In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population

Critical care service delivery across healthcare systems in low-income and low-middle-income countries: Protocol for a systematic review

INTRODUCTION: Critical care in low-income and low-middle income countries (LLMICs) is an underdeveloped component of the healthcare system. Given the increasing growth in demand for critical care services in LLMICs, understanding the current capacity to provide critical care is imperative to inform policy on service expansion. Thus, our aim is to describe the provision of critical care in LLMICs with respect to patients, providers, location of care and services and interventions delivered. METHODS AND ANALYSIS: We will search PubMed/MEDLINE, Web of Science and EMBASE for full-text original research articles available in English describing critical care services that specify the location of service delivery and describe patients and interventions. We will restrict our review to populations from LLMICs (using 2016 World Bank classifications) and published from 1 January 2008 to 1 January 2020. Two-reviewer agreement will be required for both title/abstract and full text review stages, and rate of agreement will be calculated for each stage. We will extract data regarding the location of critical care service delivery, the training of the healthcare professionals providing services, and the illnesses treated according to classification by the WHO Universal Health Coverage Compendium. ETHICS AND DISSEMINATION: Reviewed and exempted by the Stanford University Office for Human Subjects Research and IRB on 20 May 2020. The results of this review will be disseminated through scholarly publication and presentation at regional and international conferences. This review is designed to inform broader WHO, International Federation for Emergency Medicine and partner efforts to strengthen critical care globally. PROSPERO REGISTRATION NUMBER: CRD42019146802

Liquid air as an energy storage:A review

With the increasing demand for energy due to rapid industrialisation and the environmental concerns due to the usage of fossil fuels as the main energy source, there is a shift towards renewable energy. However, the intermittent nature of renewable energy requires energy produced during off-peak hours to be stored. This paper explores the use of liquefied air as an energy storage, the plausibility and the integration of liquefied air into existing framework, the role of liquefied air as an energy storage in addressing the Grand Challenges for Engineering as well as its employability in Malaysia

Measuring the health-related Sustainable Development Goals in 188 countries: a baseline analysis from the Global Burden of Disease Study 2015

Background: In September, 2015, the UN General Assembly established the Sustainable Development Goals (SDGs). The SDGs specify 17 universal goals, 169 targets, and 230 indicators leading up to 2030. We provide an analysis of 33 health-related SDG indicators based on the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015). Methods: We applied statistical methods to systematically compiled data to estimate the performance of 33 health-related SDG indicators for 188 countries from 1990 to 2015. We rescaled each indicator on a scale from 0 (worst observed value between 1990 and 2015) to 100 (best observed). Indices representing all 33 health-related SDG indicators (health-related SDG index), health-related SDG indicators included in the Millennium Development Goals (MDG index), and health-related indicators not included in the MDGs (non-MDG index) were computed as the geometric mean of the rescaled indicators by SDG target. We used spline regressions to examine the relations between the Socio-demographic Index (SDI, a summary measure based on average income per person, educational attainment, and total fertility rate) and each of the health-related SDG indicators and indices. Findings: In 2015, the median health-related SDG index was 59·3 (95% uncertainty interval 56·8–61·8) and varied widely by country, ranging from 85·5 (84·2–86·5) in Iceland to 20·4 (15·4–24·9) in Central African Republic. SDI was a good predictor of the health-related SDG index (r2=0·88) and the MDG index (r2=0·92), whereas the non-MDG index had a weaker relation with SDI (r2=0·79). Between 2000 and 2015, the health-related SDG index improved by a median of 7·9 (IQR 5·0–10·4), and gains on the MDG index (a median change of 10·0 [6·7–13·1]) exceeded that of the non-MDG index (a median change of 5·5 [2·1–8·9]). Since 2000, pronounced progress occurred for indicators such as met need with modern contraception, under-5 mortality, and neonatal mortality, as well as the indicator for universal health coverage tracer interventions. Moderate improvements were found for indicators such as HIV and tuberculosis incidence, minimal changes for hepatitis B incidence took place, and childhood overweight considerably worsened. Interpretation: GBD provides an independent, comparable avenue for monitoring progress towards the health-related SDGs. Our analysis not only highlights the importance of income, education, and fertility as drivers of health improvement but also emphasises that investments in these areas alone will not be sufficient. Although considerable progress on the health-related MDG indicators has been made, these gains will need to be sustained and, in many cases, accelerated to achieve the ambitious SDG targets. The minimal improvement in or worsening of health-related indicators beyond the MDGs highlight the need for additional resources to effectively address the expanded scope of the health-related SDGs

Fourth-order discrete-time variable centre frequency bandpass sigma-delta modulator

Copyright © 2006 IEEEA design for a variable centre frequency bandpass sigma-delta modulator is presented. The modulator is based on a tunable discrete-time resonator using only one control parameter. The noise transfer function of the modulator is controlled by a 4-bit digital signal, which provides nine different centre frequencies distributed between 0.1-0.4 normalized frequencies. The measurement results show a stable modulator at all centre frequenciesY. Zhu, S.F. Al-Sarawi, C. C. Lim, and M.J. Liebel