Paul Brown speaks to Gemma Westcott, Commissioning Editor: Paul Brown has served as the Head of Roche Molecular Diagnostics at Roche Diagnostics Corporation since February 2010 having previously held ...a variety of positions within Roche Pharma. After completing his doctorate in organic chemistry he was awarded a post-doctoral fellowship at the California Institute of Technology in Pasadena, CA, USA, but soon returned to his native UK to join Roche Pharma Research. Paul's first post within Roche was as group leader, doing drug discovery and making new small molecule drugs, but later moved into the business part of the company. Since then, he has enjoyed roles such as lifecycle leader for brands such as Tamiflu(®) and Xenical, vice president of sales and marketing of the pharmaceutical division and most recently general manager of Roche Pharma, Sweden.
This study aimed to identify country-level predictors of COVID-19 mortality, after controlling for diverse potential factors, and utilizing current worldwide mortality data. COVID-19 deaths, as well ...as geographic, demographic, socioeconomic, healthcare, population health, and pandemic-related variables, were obtained for 152 countries. Continuous variables were examined with Spearman's correlation, categorical variables with ANOVA or Welch's Heteroscedastic F Test, and country-level independent predictors of COVID-19 mortality identified by weighted generalized additive models. This study identified independent mortality predictors in six limited models, comprising groups of related variables. However, in the full model, only WHO region, percent of population ≥ 65 years, Corruption Perception Index, hospital beds/100,000 population, and COVID-19 cases/100,000 population were predictive of mortality, with model accounting for 80.7% of variance. These findings suggest areas for focused intervention in the event of similar future public health emergencies, including prioritization of the elderly, optimizing healthcare capacity, and improving deficient health sector-related governance.
Extracellular vesicles are small membrane-enclosed particles released during cell activation or injury. They have been investigated for several decades and found to be secreted in various diseases. ...Their pathogenic role is further supported by the presence of several important molecules among their cargo, including proteins, lipids, and nucleic acids. Many studies have reported enhanced and targeted extracellular vesicle biogenesis in diseases that involve chronic or transient elevation of arterial pressure resulting in endothelial dysfunction, within either the general circulatory system or specific local vascular beds. In addition, several associated pathologic processes have been studied and reported. However, the role of elevated pressure as a common pathogenic trigger across vascular domains and disease chronicity has not been previously described. This review will therefore summarize our current knowledge of the differential and targeted biogenesis of extracellular vesicles in major diseases that are characterized by elevated arterial pressure leading to endothelial dysfunction and propose a unified theory of pressure-induced extracellular vesicle-mediated pathogenesis.
•Extracellular vesicles carry pro-atherogenic cargo including proteins and mRNAs•Endogenous extracellular vesicles also demonstrate angiogenic potential•Extracellular vesicles can be engineered to ...promote neovascularization
Atherogenesis involves a complex multifactorial process including chronic inflammation that requires the participation of several cell types and molecules. In addition to their role in vascular homeostasis, extracellular vesicles also appear to play an important role in atherogenesis, including monocyte transmigration and foam cell formation, SMC proliferation and migration, leukocyte transmigration, and thrombosis. Peripheral arterial disease, a major form of peripheral vascular disease, is characterized by structural or functional impairment of peripheral arterial supply, often secondary to atherosclerosis. Elevated levels of extracellular vesicles have been demonstrated in patients with peripheral arterial disease and implicated in the development of atherosclerosis within peripheral vascular beds. However, extracellular vesicles also appear capable of delivering cargo with atheroprotective effects. This capability has been exploited in vesicles engineered to carry content capable of neovascularization, suggesting potential for therapeutic angiogenesis. This dual capacity holds substantial promise for diagnosis and therapy, including possibly limb- and life-saving options for peripheral arterial disease management.
The current literature compartmentalizes the complex issue of water and wastewater into its discrete components; technology, planning, policy, construction, economics, etc. Considered from the ...perspective of sustainability, however, water in the urban environment must be approached as a single resource that can be continuously reused and recycled. This book will be the first to capture all of the current work on this idea in a single, integrated, plan for designing the water-centric cities of the future. From new construction to the retrofitting of existing systems, this book presents the case for a new urban relationship to water, one with a more sustainableconnection tothe environment and the hydrological cycle. Through case studies of successfully planned and built systems around the world, the book will educate the reader about the need for a new approach to urban water management, and make the case that these changes are not only possible but imperative.
To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors.
ASCO convened an Expert Panel and conducted a systematic review of the literature.
Thirty-two ...randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base.
Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.Additional information is available at www.asco.org/neurooncology-guidelines.
Background
Brain radionecrosis (tissue death caused by radiation) can occur following high‐dose radiotherapy to brain tissue and can have a significant impact on a person's quality of life (QoL) and ...function. The underlying pathophysiological mechanism remains unclear for this condition, which makes establishing effective treatments challenging.
Objectives
To assess the effectiveness of interventions used for the treatment of brain radionecrosis in adults over 18 years old.
Search methods
In October 2017, we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) for eligible studies. We also searched unpublished data through Physicians Data Query, www.controlled‐trials.com/rct, www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials for ongoing trials and handsearched relevant conference material.
Selection criteria
We included randomised controlled trials (RCTs) of any intervention directed to treat brain radionecrosis in adults over 18 years old previously treated with radiation therapy to the brain. We anticipated a limited number of RCTs, so we also planned to include all comparative prospective intervention trials and quasi‐randomised trials of interventions for brain radionecrosis in adults as long as these studies had a comparison group that reflects the standard of care (i.e. placebo or corticosteroids). Selection bias was likely to be an issue in all the included non‐randomised studies therefore results are interpreted with caution.
Data collection and analysis
Two review authors (CC, PB) independently extracted data from selected studies and completed a 'Risk of bias' assessment. For dichotomous outcomes, the odds ratio (OR) for the outcome of interest was reported. For continuous outcomes, treatment effect was reported as mean difference (MD) between treatment arms with 95% confidence intervals (CIs).
Main results
Two RCTs and one prospective non‐randomised study evaluating pharmacological interventions met the inclusion criteria for this review. As each study evaluated a different drug or intervention using different endpoints, a meta‐analysis was not possible. There were no trials of non‐pharmacological interventions that met the inclusion criteria.
A very small randomised, double‐blind, placebo‐controlled trial of bevacizumab versus placebo reported that 100% (7/7) of participants on bevacizumab had reduction in brain oedema by at least 25% and reduction in post‐gadolinium enhancement, whereas all those receiving placebo had clinical or radiological worsening or both. This was an encouraging finding but due to the small sample size we did not report a relative effect. The authors also failed to provide adequate details regarding the randomisation and blinding procedures Therefore, the certainty of this evidence is low and a larger RCT adhering to reporting standards is needed.
An open‐label RCT demonstrated a greater reduction in brain oedema (T2 hyperintensity) in the edaravone plus corticosteroid group than in the corticosteroid alone group (MD was 3.03 (95% CI 0.14 to 5.92; low‐certainty evidence due to high risk of bias and imprecision); although the result approached borderline significance, there was no evidence of any important difference in the reduction in post‐gadolinium enhancement between arms (MD = 0.47, 95% CI ‐ 0.80 to 1.74; low‐certainty evidence due to high risk of bias and imprecision).
In the RCT of bevacizumab versus placebo, all seven participants receiving bevacizumab were reported to have neurological improvement, whereas five of seven participants on placebo had neurological worsening (very low‐certainty evidence due to small sample size and concerns over validity of analyses). While no adverse events were noted with placebo, three severe adverse events were noted with bevacizumab, which included aspiration pneumonia, pulmonary embolus and superior sagittal sinus thrombosis. In the RCT of corticosteroids with or without edaravone, the participants who received the combination treatment were noted to have significantly greater clinical improvement than corticosteroids alone based on LENT/SOMA scale (OR = 2.51, 95% CI 1.26 to 5.01; low‐certainty evidence due to open‐label design). No differences in treatment toxicities were observed between arms.
One included prospective non‐randomised study of alpha‐tocopherol (vitamin E) versus no active treatment was found but it did not include any radiological assessment. As only one included study was a double‐blinded randomised controlled trial, the other studies were prone to selection and detection biases.
None of the included studies reported quality of life outcomes or adequately reported details about corticosteroid requirements.
A limited number of prospective studies were identified but subsequently excluded as these studies had a limited number of participants evaluating different pharmacological interventions using variable endpoints.
Authors' conclusions
There is a lack of good certainty evidence to help quantify the risks and benefits of interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery. In an RCT of 14 patients, bevacizumab showed radiological response which was associated with minimal improvement in cognition or symptom severity. Although it was a randomised trial by design, the small sample size limits the quality of data. A trial of edaravone plus corticosteroids versus corticosteroids alone reported greater reduction in the surrounding oedema with combination treatment but no effect on the enhancing radionecrosis lesion. Due to the open‐label design and wide confidence intervals in the results, the quality of this data was also low. There was no evidence to support any non‐pharmacological interventions for the treatment of radionecrosis. Further prospective randomised studies of pharmacological and non‐pharmacological interventions are needed to generate stronger evidence. Two ongoing RCTs, one evaluating bevacizumab and one evaluating hyperbaric oxygen therapy were identified.
Dietary cadmium (Cd
2+
) intake is implicated in the pathogenesis of hypertension and anaemia, but there is a paucity of information on the haematological changes in hypertensive conditions. This ...study, therefore, aims to evaluate the effects of Cd
2+
on blood pressure (BP) and haematological indices in the Sprague–Dawley rat model. Three cohorts (n = 10 each) of control and Cd
2+
-fed male Sprague–Dawley rats were selected. Cd
2+
-exposed rats received 2.5 or 5 mg/kg b.w. cadmium chloride via gavage thrice-weekly for eight weeks, while control animals received tap water. BP and flow were measured non-invasively from rat tails twice-weekly using a CODA machine, while weights were measured thrice-weekly. Haematological indices were assessed using the Cell-Dyn Emerald Haematology Analyzer. Data were reported as mean ± SEM, and statistically analyzed using One-Way Analysis of Variance. Bonferroni post hoc test was used for multiple comparisons. Cd
2+
-exposure induced hypertension by significantly (p < 0.05) elevating systolic, diastolic, and mean arterial BPs, pulse pressure, and heart rate (HR), and increased (p < 0.05) blood flow. Mean cell volume (MCV) and haemoglobin (MCH) were significantly (p < 0.05) reduced, and red cell distribution width (RDW) significantly (p < 0.01) increased by exposure to 5 mg/kg b.w. Cd
2+
. Haemoglobin concentration (MCHC), haematocrit, haemoglobin, red blood cell, platelet, mean platelet volume, and white blood cell counts were unaffected by Cd
2+
-exposure. Cd
2+
induced hypertension, microcytosis, hypochromicity, and anisocytosis without anaemia, which may be precursor to microcytic anaemia and coronary artery disease. This study is important in Cd
2+
-exposed environments and warrants further investigations.
An estimated 20% of patients with cancer will develop brain metastases. Approximately 200,000 individuals in the United States alone receive whole-brain radiotherapy (WBRT) each year to treat brain ...metastases. Historically, the prognosis of patients with brain metastases has been poor; however, with new therapies, this is changing. Because patients are living longer following the diagnosis and treatment of brain metastases, there has been rising concern about treatment-related toxicities associated with WBRT, including neurocognitive toxicity. In addition, recent clinical trials have raised questions about the use of WBRT. To better understand this rapidly changing landscape, this review outlines the treatment roles and toxicities of WBRT and alternative therapies for the management of brain metastases.
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