Background In the context of clinical research, investigators have historically selected the outcomes that they consider to be important, but these are often discordant with patients’ priorities. ...Efforts to define and report patient-centered outcomes are gaining momentum, though little work has been done in nephrology. We aimed to identify patient and caregiver priorities for outcomes in hemodialysis. Study Design Nominal group technique. Setting & Participants Patients on hemodialysis therapy and their caregivers were purposively sampled from 4 dialysis units in Australia (Sydney and Melbourne) and 7 dialysis units in Canada (Calgary). Methodology Identification and ranking of outcomes. Analytical Approach Mean rank score (of 10) for top 10 outcomes and thematic analysis. Results 82 participants (58 patients, 24 caregivers) aged 24 to 87 (mean, 58.4) years in 12 nominal groups identified 68 outcomes. The 10 top-ranked outcomes were fatigue/energy (mean rank score, 4.5), survival (defined by patients as resilience and coping; 3.7), ability to travel (3.6), dialysis-free time (3.3), impact on family (3.2), ability to work (2.5), sleep (2.3), anxiety/stress (2.1), decrease in blood pressure (2.0), and lack of appetite/taste (1.9). Mortality ranked only 14th and was not regarded as the complement of survival. Caregivers ranked mortality, anxiety, and depression higher than patients, whereas patients ranked ability to work higher. Four themes underpinned their rankings: living well, ability to control outcomes, tangible and experiential relevance, and severity and intrusiveness. Limitations Only English-speaking participants were eligible. Conclusions Although trials in hemodialysis have typically focused on outcomes such as death, adverse events, and biological markers, patients tend to prioritize outcomes that are more relevant to their daily living and well-being. Researchers need to consider interventions that are likely to improve these outcomes and measure and report patient-relevant outcomes in trials, and clinicians may become more patient-orientated by using these outcomes in their clinical encounters.
Plastic contamination is an increasing environmental problem in marine systems where it has spread globally to even the most remote habitats. Plastic pieces in smaller size scales, microplastics ...(particles <5 mm), have reached high densities (e.g., 100 000 items per m3) in waters and sediments, and are interacting with organisms and the environment in a variety of ways. Early investigations of freshwater systems suggest microplastic presence and interactions are equally as far reaching as are being observed in marine systems. Microplastics are being detected in freshwaters of Europe, North America, and Asia, and the first organismal studies are finding that freshwater fauna across a range of feeding guilds ingest microplastics.
Drawing from the marine literature and these initial freshwater studies, we review the issue of microplastics in freshwater systems to summarise current understanding, identify knowledge gaps and suggest future research priorities. Evidence suggests that freshwater systems may share similarities to marine systems in the types of forces that transport microplastics (e.g. surface currents); the prevalence of microplastics (e.g. numerically abundant and ubiquitous); the approaches used for detection, identification and quantification (e.g. density separation, filtration, sieving and infrared spectroscopy); and the potential impacts (e.g. physical damage to organisms that ingest them, chemical transfer of toxicants). Differences between freshwater and marine systems include the closer proximity to point sources in freshwaters, the typically smaller sizes of freshwater systems, and spatial and temporal differences in the mixing/transport of particles by physical forces. These differences between marine and freshwater systems may lead to differences in the type of microplastics present. For example, rivers may show a predictable pattern in microplastic characteristics (size, shape, relative abundance) based on waste sources (e.g. household vs. industrial) adjacent to the river, and distance downstream from a point source.
Given that the study of microplastics in freshwaters has only arisen in the last few years, we are still limited in our understanding of 1) their presence and distribution in the environment; 2) their transport pathways and factors that affect distributions; 3) methods for their accurate detection and quantification; 4) the extent and relevance of their impacts on aquatic life. We also do not know how microplastics might transfer from freshwater to terrestrial ecosystems, and we do not know if and how they may affect human health. This is concerning because human populations have a high dependency on freshwaters for drinking water and for food resources. Increasing the level of understanding in these areas is essential if we are to develop appropriate policy and management tools to address this emerging issue.
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•Microplastics are widely distributed in waters and sediments of rivers and lakes.•Human density and activities influence the types of microplastics present.•Physical forces (e.g., winds, currents) influence distributions.•Organismal impacts may be as wide ranging as those seen for marine taxa.•Future research might investigate whether microplastics will impact humans.
The mammalian brain contains few niches for neural stem cells (NSCs) capable of generating new neurons, whereas other regions are primarily gliogenic. Here we leverage the spatial separation of the ...sub-ependymal zone NSC niche and the olfactory bulb, the region to which newly generated neurons from the sub-ependymal zone migrate and integrate, and present a comprehensive proteomic characterization of these regions in comparison to the cerebral cortex, which is not conducive to neurogenesis and integration of new neurons. We find differing compositions of regulatory extracellular matrix (ECM) components in the neurogenic niche. We further show that quiescent NSCs are the main source of their local ECM, including the multi-functional enzyme transglutaminase 2, which we show is crucial for neurogenesis. Atomic force microscopy corroborated indications from the proteomic analyses that neurogenic niches are significantly stiffer than non-neurogenic parenchyma. Together these findings provide a powerful resource for unraveling unique compositions of neurogenic niches.
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•Proteomics define the NSC niche-specific extracellular matrix•Detergent-solubility profiling reveals extracellular matrix architecture•Transglutaminase 2 regulates neurogenesis•Stiffness is increased in the neurogenic niches of the brain
The physical properties of stem cell niches are thought to mediate important regulatory functions. Here we provide a proteomic resource of the neural stem cell niche in comparison to gliogenic brain parenchyma, highlighting stiffness and the enzyme transglutaminase 2 as key regulators of neurogenesis.
1,4-Dioxane has historically been used to stabilize chlorinated solvents and more recently has been found as a contaminant of numerous consumer and food products. Once discharged into the ...environment, its physical and chemical characteristics facilitate migration in groundwater, resulting in widespread contamination of drinking water supplies. Over one-fifth of U.S. public drinking water supplies contain detectable levels of 1,4-dioxane. Remediation efforts using common adsorption and membrane filtration techniques have been ineffective, highlighting the need for alternative removal approaches. While the data evaluating human exposure and health effects are limited, animal studies have shown chronic exposure to cause carcinogenic responses in the liver across multiple species and routes of exposure. Based on this experimental evidence, the U.S. Environmental Protection Agency has listed 1,4-dioxane as a high priority chemical and classified it as a probable human carcinogen. Despite these health concerns, there are no federal or state maximum contaminant levels for 1,4-dioxane. Effective public health policy for this emerging contaminant requires additional information about human health effects, chemical interactions, environmental fate, analytical detection, and treatment technologies. This review highlights the current state of knowledge, key uncertainties, and data needs for future research on 1,4-dioxane.
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•1,4-Dioxane is an emerging environmental contaminant and a probable carcinogen.•The de minimis cancer risk level is exceeded at 7% of U.S. drinking water sites.•The physicochemical properties challenge detection and remediation of 1,4-dioxane.•This review presents data needed to set an enforceable drinking water standard.
Reactive oxygen species (ROS) are continuously generated within living systems and the inability to manage ROS load leads to elevated oxidative stress and cell damage. Oxidative stress is coupled to ...the oxidative degradation of lipid membranes, also known as lipid peroxidation. This process generates over 200 types of aldehydes, many of which are highly reactive and toxic. Aldehyde dehydrogenases (ALDHs) metabolize endogenous and exogenous aldehydes and thereby mitigate oxidative/electrophilic stress in prokaryotic and eukaryotic organisms. ALDHs are found throughout the evolutionary gamut, from single-celled organisms to complex multicellular species. Not surprisingly, many ALDHs in evolutionarily distant, and seemingly unrelated, species perform similar functions, including protection against a variety of environmental stressors such as dehydration and ultraviolet radiation. The ability to act as an “aldehyde scavenger” during lipid peroxidation is another ostensibly universal ALDH function found across species. Upregulation of ALDHs is a stress response in bacteria (environmental and chemical stress), plants (dehydration, salinity, and oxidative stress), yeast (ethanol exposure and oxidative stress), Caenorhabditis elegans (lipid peroxidation), and mammals (oxidative stress and lipid peroxidation). Recent studies have also identified ALDH activity as an important feature of cancer stem cells. In these cells, ALDH expression helps abrogate oxidative stress and imparts resistance against chemotherapeutic agents such as oxazaphosphorine, taxane, and platinum drugs. The ALDH superfamily represents a fundamentally important class of enzymes that contributes significantly to the management of electrophilic/oxidative stress within living systems. Mutations in various ALDHs are associated with a variety of pathological conditions in humans, highlighting the fundamental importance of these enzymes in physiological and pathological processes.
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► Aldehyde dehydrogenases (ALDHs) metabolize electrophilic aldehydes. ► ALDHs are expressed in all forms of life from simple to complex multicellular organisms. ► ALDHs are elevated by stress in these organisms to protect against oxidative damage. ► Mutations in ALDH genes are associated with a variety of diseases in humans.
Reactive oxygen species (ROS) are continuously generated within living systems and the inability to manage ROS load leads to elevated oxidative stress and cell damage. Oxidative stress is coupled to ...the oxidative degradation of lipid membranes, also known as lipid peroxidation. This process generates over 200 types of aldehydes, many of which are highly reactive and toxic. Aldehyde dehydrogenases (ALDHs) metabolize endogenous and exogenous aldehydes and thereby mitigate oxidative/electrophilic stress in prokaryotic and eukaryotic organisms. ALDHs are found throughout the evolutionary gamut, from single-celled organisms to complex multicellular species. Not surprisingly, many ALDHs in evolutionarily distant, and seemingly unrelated, species perform similar functions, including protection against a variety of environmental stressors such as dehydration and ultraviolet radiation. The ability to act as an "aldehyde scavenger" during lipid peroxidation is another ostensibly universal ALDH function found across species. Upregulation of ALDHs is a stress response in bacteria (environmental and chemical stress), plants (dehydration, salinity, and oxidative stress), yeast (ethanol exposure and oxidative stress), Caenorhabditis elegans (lipid peroxidation), and mammals (oxidative stress and lipid peroxidation). Recent studies have also identified ALDH activity as an important feature of cancer stem cells. In these cells, ALDH expression helps abrogate oxidative stress and imparts resistance against chemotherapeutic agents such as oxazaphosphorine, taxane, and platinum drugs. The ALDH superfamily represents a fundamentally important class of enzymes that contributes significantly to the management of electrophilic/oxidative stress within living systems. Mutations in various ALDHs are associated with a variety of pathological conditions in humans, highlighting the fundamental importance of these enzymes in physiological and pathological processes.
•Recent use and future directions of Crowdsourcing and Open Innovation in drug discovery are presented.•Pharmaceutical companies’ online presentation of their own engagement and use of Open ...Innovation is assessed and compared.•Emergent topics of serendipity in R&D, the digital/physical gap, meta-gaming, and artificial intelligence are introduced.
The past decade has seen significant growth in the use of ‘crowdsourcing’ and open innovation approaches to engage ‘citizen scientists’ to perform novel scientific research. Here, we quantify and summarize the current state of adoption of open innovation by major pharmaceutical companies. We also highlight recent crowdsourcing and open innovation research contributions to the field of drug discovery, and interesting future directions.
Abstract Evidence-based health care decision making requires comparison of all relevant competing interventions. In the absence of randomized controlled trials involving a direct comparison of all ...treatments of interest, indirect treatment comparisons and network meta-analysis provide useful evidence for judiciously selecting the best treatment(s). Mixed treatment comparisons, a special case of network meta-analysis, combine direct evidence and indirect evidence for particular pairwise comparisons, thereby synthesizing a greater share of the available evidence than traditional meta-analysis. This report from the International Society for Pharmacoeconomics and Outcomes Research Indirect Treatment Comparisons Good Research Practices Task Force provides guidance on technical aspects of conducting network meta-analyses (our use of this term includes most methods that involve meta-analysis in the context of a network of evidence). We start with a discussion of strategies for developing networks of evidence. Next we briefly review assumptions of network meta-analysis. Then we focus on the statistical analysis of the data: objectives, models (fixed-effects and random-effects), frequentist versus Bayesian approaches, and model validation. A checklist highlights key components of network meta-analysis, and substantial examples illustrate indirect treatment comparisons (both frequentist and Bayesian approaches) and network meta-analysis. A further section discusses eight key areas for future research.
IMPORTANCE: Men and women develop melanoma at different rates on different body sites, with variation across countries, but explanations for these disparities remain elusive. OBJECTIVE: To test ...whether observed differences in melanoma incidence between men and women vary by population, age, or anatomic site. DESIGN: Cross-sectional analysis of sex- and site-specific temporal trends in melanoma incidence over 3 decades was conducted for men and women diagnosed with invasive melanoma in the US (limited to white race), Canada, Australia, New Zealand, the UK, Sweden, Norway, and Denmark. Using cancer registry data, male to female incidence rate ratios (IRRs) were calculated overall and by anatomic site, and Joinpoint regression models were used to estimate the annual percentage rate changes in sex- and site-specific incidence in each population. Incidence rates were standardized to the US 2000 population. Data on the incidence between January 1, 1982, and December 31, 2015, were obtained; analysis was conducted from March 1 to October 15, 2019. MAIN OUTCOMES AND MEASURES: Male to female IRRs and annual percentage change in rates. RESULTS: Total melanoma incidence was higher in men than women in US individuals (limited to white race), Canada, Australia, and New Zealand, but not in Denmark, the UK, Norway, and Sweden. In all populations, men had higher rates of melanoma of the head and neck and trunk than women (male to female IRR >1), but lower melanoma rates on the lower limbs (ie, male to female IRR approximately 0.5). The male to female IRR increased log linearly with age, with excess melanomas in women younger than 45 years in all populations (eg, IRR for 20-24 y age group, 0.3 in Denmark and 0.7 in Australia), and excess melanomas in men older than 69 years (eg, IRR for 70-74 y age group, 1.1 in Denmark and 2.1 in the US white population). The age at which the melanoma incidence in men exceeded the melanoma incidence in women differed by population, being achieved the earliest in Australia (45-49 years) and latest in Denmark (65-69 years). CONCLUSIONS AND RELEVANCE: In predominantly fair-skinned populations, melanoma incidence appears to differ systematically and consistently between men and women by age and anatomic site.
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