Women and Chronic Renal Failure: Some Neglected Issues

It has been assumed until recently that chronic renal failure is more prevalent among men than among women, but data now indicate that at least half of all renal patients are women. The literature continues to focus on adjustment problems of male patients, especially sexual adjustment and job-loss problems, and to assume that women can adjust more easily because of their ability to maintain the homemaker role. However, women patients whose work status is that of homemaker are found to have the highest depression scores, and job loss results in low satisfaction for those who have held meaningful outside jobs. Women patients are not necessarily more satisfied with their sexual life than are men patients. Questions can also be raised about women patients\u27 access to treatment alternatives associated with optimal patient outcomes

Variation in Isoprene Emission from Quercus rubra: Sources, Causes, and Consequences for Estimating Fluxes

Isoprene is the dominant volatile organic compound produced in many forest systems. Uncertainty in estimates of leaf level isoprene emission rate stems from an insufficient understanding of the patterns and processes controlling isoprene emission capacity in plant leaves. Previous studies suggest that variation in isoprene emission capacity is substantial; however, it is not known at what scale emission capacity is the most variable. Identifying the sources of variation in emission capacity has implications for conducting measurements and for model development, which will ultimately improve emission estimates and models of tropospheric chemistry. In addition, understanding the sources of variation will help to develop a comprehensive understanding of the physiological controls over isoprene emission. This study applied a variance partitioning approach to identify the major sources of variation in isoprene emission capacity from two populations of northern red oak (Quercus rubra) over three growing seasons. Specifically, we evaluated variation due to climate, populations, trees, branches, leaves, seasons, and years. Overall, the dominant source of variation was the effect of a moderate drought event. In the years without drought events, variation among individual trees (intraspecific) explained approximately 60% of the total variance. Within the midseason, isoprene emission capacity of sun leaves varied by a factor of 2 among trees. During the third year a moderate 20-day drought event caused isoprene emission capacity to decrease fourfold, and the relative importance of intraspecific variation was reduced to 24% of total variance. Overall, ambient temperature, light, and a drought index were poor predictors of isoprene emission capacity over a 0 to 14-day period across growing seasons. The drought event captured in this study emphasizes the need to incorporate environmental influences into leaf level emission models

Natural history study of glycan accumulation in large animal models of GM2 gangliosidoses

beta-hexosaminidase is an enzyme responsible for the degradation of gangliosides, glycans, and other glycoconjugates containing beta-linked hexosamines that enter the lysosome. GM2 gangliosidoses, such as Tay-Sachs and Sandhoff, are lysosomal storage disorders characterized by beta-hexosaminidase deficiency and subsequent lysosomal accumulation of its substrate metabolites. These two diseases result in neurodegeneration and early mortality in children. A significant difference between these two disorders is the accumulation in Sandhoff disease of soluble oligosaccharide metabolites that derive from N- and O-linked glycans. In this paper we describe our results from a longitudinal biochemical study of a feline model of Sandhoff disease and an ovine model of Tay-Sachs disease to investigate the accumulation of GM2/GA2 gangliosides, a secondary biomarker for phospholipidosis, bis-(monoacylglycero)-phosphate, and soluble glycan metabolites in both tissue and fluid samples from both animal models. While both Sandhoff cats and Tay-Sachs sheep accumulated significant amounts of GM2 and GA2 gangliosides compared to age-matched unaffected controls, the Sandhoff cats having the more severe disease, accumulated larger amounts of gangliosides compared to Tay-Sachs sheep in their occipital lobes. For monitoring glycan metabolites, we developed a quantitative LC/MS assay for one of these free glycans in order to perform longitudinal analysis. The Sandhoff cats showed significant disease-related increases in this glycan in brain and in other matrices including urine which may provide a useful clinical tool for measuring disease severity and therapeutic efficacy. Finally, we observed age-dependent increasing accumulation for a number of analytes, especially in Sandhoff cats where glycosphingolipid, phospholipid, and glycan levels showed incremental increases at later time points without signs of peaking. This large animal natural history study for Sandhoff and Tay-Sachs is the first of its kind, providing insight into disease progression at the biochemical level. This report may help in the development and testing of new therapies to treat these disorders

Reputation Agent: Prompting Fair Reviews in Gig Markets

Our study presents a new tool, Reputation Agent, to promote fairer reviews from requesters (employers or customers) on gig markets. Unfair reviews, created when requesters consider factors outside of a worker's control, are known to plague gig workers and can result in lost job opportunities and even termination from the marketplace. Our tool leverages machine learning to implement an intelligent interface that: (1) uses deep learning to automatically detect when an individual has included unfair factors into her review (factors outside the worker's control per the policies of the market); and (2) prompts the individual to reconsider her review if she has incorporated unfair factors. To study the effectiveness of Reputation Agent, we conducted a controlled experiment over different gig markets. Our experiment illustrates that across markets, Reputation Agent, in contrast with traditional approaches, motivates requesters to review gig workers' performance more fairly. We discuss how tools that bring more transparency to employers about the policies of a gig market can help build empathy thus resulting in reasoned discussions around potential injustices towards workers generated by these interfaces. Our vision is that with tools that promote truth and transparency we can bring fairer treatment to gig workers.Comment: 12 pages, 5 figures, The Web Conference 2020, ACM WWW 202

Lipidomic Evaluation of Feline Neurologic Disease after AAV Gene Therapy

GM1 gangliosidosis is a fatal lysosomal disorder, for which there is no effective treatment. Adeno-associated virus (AAV) gene therapy in GM1 cats has resulted in a greater than 6-fold increase in lifespan, with many cats remaining alive at \u3e 5.7 years of age, with minimal clinical signs. Glycolipids are the principal storage product in GM1 gangliosidosis whose pathogenic mechanism is not completely understood. Targeted lipidomics analysis was performed to better define disease mechanisms and identify markers of disease progression for upcoming clinical trials in humans. 36 sphingolipids and subspecies associated with ganglioside biosynthesis were tested in the cerebrospinal fluid of untreated GM1 cats at a humane endpoint ( approximately 8 months), AAV-treated GM1 cats ( approximately 5 years old), and normal adult controls. In untreated GM1 cats, significant alterations were noted in 16 sphingolipid species, including gangliosides (GM1 and GM3), lactosylceramides, ceramides, sphingomyelins, monohexosylceramides, and sulfatides. Variable degrees of correction in many lipid metabolites reflected the efficacy of AAV gene therapy. Sphingolipid levels were highly predictive of neurologic disease progression, with 11 metabolites having a coefficient of determination (R(2)) \u3e 0.75. Also, a specific detergent additive significantly increased the recovery of certain lipid species in cerebrospinal fluid samples. This report demonstrates the methodology and utility of targeted lipidomics to examine the pathophysiology of lipid storage disorders

Real-time MR tracking of AAV gene therapy with betagal-responsive MR probe in a murine model of GM1-gangliosidosis

Transformative results of adeno-associated virus (AAV) gene therapy in patients with spinal muscular atrophy and Leber\u27s congenital amaurosis led to approval of the first two AAV products in the United States to treat these diseases. These extraordinary results led to a dramatic increase in the number and type of AAV gene-therapy programs. However, the field lacks non-invasive means to assess levels and duration of therapeutic protein function in patients. Here, we describe a new magnetic resonance imaging (MRI) technology for real-time reporting of gene-therapy products in the living animal in the form of an MRI probe that is activated in the presence of therapeutic protein expression. For the first time, we show reliable tracking of enzyme expression after a now in-human clinical trial AAV gene therapy (ClinicalTrials.gov: NTC03952637) encoding lysosomal acid beta-galactosidase (betagal) using a self-immolative betagal-responsive MRI probe. MRI enhancement in AAV-treated enzyme-deficient mice (GLB-1(-/-)) correlates with betagal activity in central nervous system and peripheral organs after intracranial or intravenous AAV gene therapy, respectively. With \u3e 1,800 gene therapies in phase I/II clinical trials (ClinicalTrials.gov), development of a non-invasive method to track gene expression over time in patients is crucial to the future of the gene-therapy field

Quantifying and Mitigating Motor Phenotypes Induced by Antisense Oligonucleotides in the Central Nervous System [preprint]

Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into the cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. The effect of sugar and phosphate modifications on these phenotypes has not previously been systematically studied. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence acute motor phenotypes. Among sugar analogues, PS-DNA induces the strongest motor phenotype while 2’-substituted RNA modifications improve the tolerability of PS-ASOs. This helps explain why gapmer ASOs have been more challenging to develop clinically relative to steric blocker ASOs, which have a reduced tendency to induce these effects. Reducing the PS content of gapmer ASOs, which contain a stretch of PS-DNA, improves their toxicity profile, but in some cases also reduces their efficacy or duration of effect. Reducing PS content improved the acute tolerability of ASOs in both mice and sheep. We show that this acute toxicity is not mediated by the major nucleic acid sensing innate immune pathways. Formulating ASOs with calcium ions before injecting into the CNS further improved their tolerability, but through a mechanism at least partially distinct from the reduction of PS content. Overall, our work identifies and quantifies an understudied aspect of oligonucleotide toxicology in the CNS, explores its mechanism, and presents platform-level medicinal chemistry approaches that improve tolerability of this class of compounds

Diverse Macrophage Populations Contribute to the Inflammatory Microenvironment in Premalignant Lesions During Localized Invasion.

Myeloid cell heterogeneity remains poorly studied in breast cancer, and particularly in premalignancy. Here, we used single cell RNA sequencing to characterize macrophage diversity in mouse pre-invasive lesions as compared to lesions undergoing localized invasion. Several subpopulations of macrophages with transcriptionally distinct profiles were identified, two of which resembled macrophages in the steady state. While all subpopulations expressed tumor-promoting genes, many of the populations expressed pro-inflammatory genes, differing from reports in tumor-associated macrophages. Gene profiles of the myeloid cells were similar between early and late stages of premalignancy, although expansion of some subpopulations occurred. These results unravel macrophage heterogeneity in early progression and may provide insight into early intervention strategies that target macrophages

Developing a National Implementation Strategy to accelerate Uptake of Evidence-Based Family Caregiver Support in Us Cancer Centers

OBJECTIVE: Characterize key factors and training needs of U.S. cancer centers in implementing family caregiver support services. METHODS: Sequential explanatory mixed methods design consisting of: (1) a national survey of clinicians and administrators from Commission-on-Cancer-accredited cancer centers (N = 238) on factors and training needed for establishing new caregiver programs and (2) qualitative interviews with a subsample of survey respondents (N = 30) to elicit feedback on survey findings and the outline of an implementation strategy to facilitate implementation of evidence-based family caregiver support (the Caregiver Support Accelerator). Survey data was tabulated using descriptive statistics and transcribed interviews were analyzed using thematic analysis. RESULTS: top factors for developing new caregiver programs were that the program be: consistent with the cancer center\u27s mission and strategic plan (87%), supported by clinic leadership (86.5%) and providers and staff (85.7%), and low cost or cost effective (84.9%). top training needs were how to: train staff to implement programs (72.3%), obtain program materials (63.0%), and evaluate program outcomes (62.6%). Only 3.8% reported that no training was needed. Qualitative interviews yielded four main themes: (1) gaining leadership, clinician, and staff buy-in and support is essential; (2) cost and clinician burden are major factors to program implementation; (3) training should help with adapting and marketing programs to local context and culture; and (4) the Accelerator strategy is comprehensive and would benefit from key organizational partnerships and policy standards. CONCLUSION: Findings will be used to inform and refine the Accelerator implementation strategy to facilitate the adoption and growth of evidence-based cancer caregiver support in U.S. cancer centers