"Just trying to adjust to the new reality that seems to be changing every hour": Lessons learned from nation-wide peer meetings on COVID-19 with rural disability service providers.

At the onset of the COVID-19 pandemic, providers of independent living services for rural disabled people were forced to adapt how they conducted their operations. This study is a primary analysis of data based on transcripts from eight meetings of a nationwide network of service providers, who met virtually to provide peer support during the unfolding pandemic. We used qualitative thematic analysis to understand the ways these service providers adapted to address the needs of rural disabled people during the pandemic. Each meeting was attended by Center for Independent Living (CIL) staff members (n = 40 to 150 participants per meeting). We identified four main themes describing organizational adaptations: 1) Providing core services remotely, 2) Regular check-ins, 3) Virtual group meetings became a mainstay of service provision, and 4) Barriers and solutions to virtual connectivity in rural areas. Although this was a predominantly challenging time, CIL staff identified ways their adaptations were beneficial. These included creating new ways to connect, reaching more people with disabilities, and cutting down on commuting time to provide services. CIL staff intended to continue using their adapted strategies and platforms for providing services, and thus projected these benefits would be long-lasting.

Epigenetic vulnerabilities of leukemia harboring inactivating EZH2 mutations.

Epigenetic regulators, such as the polycomb repressive complex 2 (PRC2), play a critical role in both normal development and carcinogenesis. Mutations and functional dysregulation of PRC2 complex components, such as EZH2, are implicated in various forms of cancer and associated with poor prognosis. This study investigated the epigenetic vulnerabilities of acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative disorders (MDS/MPN) by performing a chemical probe screen in patient cells. Paradoxically, we observed increased sensitivity to EZH2 and embryonic ectoderm development (EED) inhibitors in AML and MDS/MPN patient cells harboring EZH2 mutations. Expression analysis indicated that EZH2 inhibition elicited upregulation of pathways responsible for cell death and growth arrest, specifically in patient cells with mutant EZH2. The identified EZH2 mutations had drastically reduced catalytic activity, resulting in lower cellular H3K27me3 levels, and were associated with decreased EZH2 and PRC2 component EED protein levels. Overall, this study provides an important understanding of the role of EZH2 dysregulation in blood cancers and may indicate disease etiology for these poor prognosis AML and MDS/MPN cases.

Handicraft art leisure activities and cognitive reserve.

ObjectiveOlder individuals face a higher likelihood of developing dementia. The rate of cognitive decline resulting from dementia is not equivalent for all, as some patients with dementia are able to function independently longer than others, despite having similar disease burden. The cognitive reserve (CR) theory provides one explanation for the differing rate of decline. CR suggests that there are factors-most notably, educational attainment and occupational attainment-that can protect against the cognitive decline. Although the beneficial effects of these notable CR factors are clear, not all are easily modifiable. Participation in leisure activities may represent a more easily modifiable factor. Some research hints at beneficial effects of leisure activities, although specific leisure activities have not been well examined. The present study examined the relations between handicraft art leisure activities (HALAs) and multiple cognitive domains. MethodArchival WAIS-IV and demographic data for 50 California retirement community residents were examined. ResultsHALA participation accounted for statistically significant variance in working memory performance (R2 = .40, ß = .24%) over and above the established CR factors of age, depression, educational attainment, and occupational attainment. In addition, HALA participation was related to a better ability to perform abstract visual information tasks (Block Design subtest, r = .28, p = .05) and non-verbal reasoning tasks (Visual Puzzles subtest, r = .38, p = .008). ConclusionsHALA participation among older adults could contribute to the retention of cognitive function, supporting the role of HALA participation as a CR factor.

Memory self-efficacy and working memory.

Dementia affects multiple aspects of cognitive functioning, including working memory and executive functioning. Memory self-efficacy (MSE) has previously been related to episodic memory performance and to executive functioning, but little research has examined the relations between MSE and working memory. United States older adults (N = 197) were recruited via MTurk to complete an MSE questionnaire before completing a digit span working memory task. Hierarchical regression results revealed that the model accounted for a significant amount of variance in working memory performance after statistically controlling for several covariates, F(11, 179) = 4.94, p < .001, adjusted R2 = .19. MSE explained a large and unique portion of variance (B = 1.02, SE = 0.17, p < .001). Based on our findings, one's beliefs about their memory are positively associated with their working memory performance. These novel findings provide support for neuropsychologists to consider using MSE measures and utilizing MSE interventions.

Trace Actinide Signatures of a Bulk Neptunium Sample.

In nuclear forensic analyses, measurements of actinide elements in a sample can assist with identifying interdicted or unknown materials. While these radiochemical signatures have been extensively investigated in uranium materials, less is known about bulk neptunium samples. This paper describes the measurement of trace actinide concentrations and isotopic profiles in a 237Np oxide sample. Uranium, plutonium, americium, and curium concentrations and isotopic profiles in the sample were determined and deemed potentially useful for distinguishing different sources of 237Np. Several different potential radiochronometry systems were also investigated; discordant results indicate that the Np sample was never completely purified of other actinide elements, or that subsequent contamination of the sample occurred. Few prior studies of neptunium materials have been reported, and these data suggest that trace actinide constituents could provide unique signatures to identify material out of regulatory control.

Exploring Metro and Non-metro Differences in Satisfaction With Services and Community Participation Among Low-Income Personal Assistance Service Users.

Personal assistance services (PAS) are supports provided by workers to assist disabled people with their activities of daily living. Access to in-home PAS allows people who need assistance with these activities to live in their own homes and communities, rather than moving to congregate living facilities. Because metro and non-metro areas differ in many ways, we explored the following research questions: (1) Are there differences between non-metro and metro PAS users?, (2) What factors are associated with satisfaction with services?, and (3) What factors are associated with satisfaction with community participation?. We randomly surveyed PAS consumers in five states about their experiences with PAS. To answer the first question, we compared metro or non-metro consumers using independent samples t-tests. We found few statistically significant differences between metro and non-metro respondents. To answer the second and third research questions, we conducted linear regressions predicting our dependent variables. In terms of satisfaction with services, our model explained very little of the variance, other than finding that being partnered or married was significantly, positively related to satisfaction with services. In predicting satisfaction with community participation, the model explained about a quarter of the variance, with having fewer disabilities and higher health status predicting more satisfaction. This research indicates that there are few differences between metro and non-metro low-income PAS consumers and that more research is needed to understand what factors are related to satisfaction with services and community participation in this population.

The intersection of disability status and rurality in American Indian/Alaskan Native communities.

There is a noteworthy gap in the literature regarding disability in rural American Indian/Alaskan Native (AI/AN) communities. This is significant, as many tribal lands are in rural areas and AI/AN individuals experience some of the highest prevalence rates of disability. To address this gap, we used descriptive statistics to examine the intersection of AI/AN and rurality in disability prevalence. Results indicate that rural counties have the highest prevalence of disability for both Whites and AI/ANs and that AI/ANs experience higher prevalence rates than Whites. However, further analysis indicates that county makeup (counties with high prevalence of AI/AN in the general population) moderated this relationship. Specifically, rural counties with populations of at least 5% AI/AN had lower prevalence of AI/AN disability compared to counties with populations with less than 5% AI/AN. Further analysis is needed to unpack this relationship, but results might suggest that AI/AN communities may feature resilient and protective attributes, moderating the amount of disability experienced in rural AI/AN communities.

Intersections of Personal Assistance Services for Rural Disabled People and Home Care Workers' Rights.

It is very difficult to find and keep workers to provide home-based care for disabled people, especially in rural places. There is a tension between the rights of disabled people and the rights of home-based personal care workers. In this brief review, we explore the intersections of historical and social forces that shaped federal-level policies for both disability rights and the rights of personal care workers, as well as the current state of the policies. This paper provides a narrow focus on federal policies relevant to both groups, while also considering how the urbancentric nature of advocacy and policymaking has failed to address important issues experienced by rural people. In addition to briefly reviewing relevant federal policies, we also explore sources of support and resistance and how urbanormativity, ableism, and sexism intersect to influence how the needs of people with disabilities and their personal care workers are conceptualized and addressed. We conclude with recommendations for how to better address the needs of rural people with disabilities using home-based personal care services and the workers who provide them.

PRMT5 regulates ATF4 transcript splicing and oxidative stress response.

Protein methyltransferase 5 (PRMT5) symmetrically dimethylates arginine residues leading to regulation of transcription and splicing programs. Although PRMT5 has emerged as an attractive oncology target, the molecular determinants of PRMT5 dependency in cancer remain incompletely understood. Our transcriptomic analysis identified PRMT5 regulation of the activating transcription factor 4 (ATF4) pathway in acute myelogenous leukemia (AML). PRMT5 inhibition resulted in the expression of unstable, intron-retaining ATF4 mRNA that is detained in the nucleus. Concurrently, the decrease in the spliced cytoplasmic transcript of ATF4 led to lower levels of ATF4 protein and downregulation of ATF4 target genes. Upon loss of functional PRMT5, cells with low ATF4 displayed increased oxidative stress, growth arrest, and cellular senescence. Interestingly, leukemia cells with EVI1 oncogene overexpression demonstrated dependence on PRMT5 function. EVI1 and ATF4 regulated gene signatures were inversely correlated. We show that EVI1-high AML cells have reduced ATF4 levels, elevated baseline reactive oxygen species and increased sensitivity to PRMT5 inhibition. Thus, EVI1-high cells demonstrate dependence on PRMT5 function and regulation of oxidative stress response. Overall, our findings identify the PRMT5-ATF4 axis to be safeguarding the cellular redox balance that is especially important in high oxidative stress states, such as those that occur with EVI1 overexpression.

"Less time committed to care": Beliefs About Electronic Visit Verification Among Adults Using Home-Based Personal Assistance Services.

In 2016, the federal government mandated that all Medicaid-funded personal assistance services be documented through an Electronic Visit Verification (EVV) program by January 2020. Most states have asked for extensions due to difficulties in implementation and strong opposition from consumer advocacy groups. Qualitative research has documented various concerns of consumers and consumer advocates. In 2020 (prepandemic), we conducted a mail survey of consumers which included questions regarding familiarity with, and attitudes toward, EVV. Respondents could also write in qualitative comments. This paper explores consumers' perceptions of EVV using four survey items related to fraud, benefits, concerns, and protection and 25 qualitative comments related to these topics. We found that respondents agreed most with statements focused on both concerns with EVV interfering with their care and help in reducing fraud. In general, the most common quantitative response to the statements was indifference. Qualitative comments centered on concerns about EVV interfering with services in a variety of ways, although there were also comments related to EVV being protective, beneficial, or helpful in reducing fraud. We also identified a new category in the qualitative comments about consumers' beliefs that the work done by their personal assistance service workers is underrecognized. We recommend that policy makers and service organizations continue to collect information from consumers as EVV is implemented and altered to both meet the expectations of the legislation and the needs of consumers and workers.

Author Correction: Caenorhabditis elegans is a useful model for anthelmintic discovery.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Adherence to Disease-Modifying Therapies at a Multiple Sclerosis Clinic: The Role of the Specialty Pharmacist.

BACKGROUND: Disease-modifying therapy (DMT) delays disease progression and improves quality of life for patients with multiple sclerosis (MS), but adherence to DMT is often suboptimal. Vanderbilt Specialty Pharmacy (VSP) embeds pharmacists within an outpatient MS clinic to provide medication management and address barriers to adherence. OBJECTIVE: We evaluated rates and predictors of adherence to DMT among patients with MS at an integrated specialty pharmacy. METHODS: We included patients with MS who filled ≥3 DMT prescriptions from VSP during the study period. Adherence was defined as medication possession ratio (MPR) or proportion of days covered (PDC) ≥0.8. Reasons for nonadherence were collected from pharmacy claims and electronic medical records. RESULTS: The study included 653 patients. Average MPR and PDC were 0.93 and 0.94, respectively. Eighty-eight percent of patients achieved MPR ≥0.8; 89% achieved PDC ≥0.8. Using financial assistance and having $0 out-of-pocket cost were associated with higher odds of achieving MPR and PDC ≥0.8 (P < .05). Of the 12% of patients who were nonadherent, most were unreachable for refills. CONCLUSIONS: Ensuring financial assistance and low out-of-pocket costs are associated with high adherence to DMT within an integrated specialty clinic, but more work is needed to address adherence in unreachable patients.

Discovery of a chemical probe for PRDM9.

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.

Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation.

Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.

Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells.

In embryonic stem cells, promoters of key lineage-specific differentiation genes are found in a bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them poised for transcription upon loss of H3K27me3. Whether cancer-initiating cells (C-ICs) have similar epigenetic mechanisms that prevent lineage commitment is unknown. Here we show that colorectal C-ICs (CC-ICs) are maintained in a stem-like state through a bivalent epigenetic mechanism. Disruption of the bivalent state through inhibition of the H3K27 methyltransferase EZH2, resulted in decreased self-renewal of patient-derived C-ICs. Epigenomic analyses revealed that the promoter of Indian Hedgehog (IHH), a canonical driver of normal colonocyte differentiation, exists in a bivalent chromatin state. Inhibition of EZH2 resulted in de-repression of IHH, decreased self-renewal, and increased sensitivity to chemotherapy in vivo. Our results reveal an epigenetic block to differentiation in CC-ICs and demonstrate the potential for epigenetic differentiation therapy of a solid tumour through EZH2 inhibition.

Characterization of inv(3) cell line OCI-AML-20 with stroma-dependent CD34 expression.

Acute myeloid leukemia (AML) is a complex, heterogeneous disease with variable outcomes following curative intent chemotherapy. AML with inv(3) is a genetic subgroup characterized by a very low response rate to current induction type chemotherapy and thus has among the worst long-term survivorship of the AMLs. Here, we describe OCI-AML-20, a new AML cell line with inv(3) and deletion of chromosome 7; the latter is a common co-occurrence in inv(3) AML. In OCI-AML-20, CD34 expression is maintained and required for repopulation in vitro and in vivo. CD34 expression in OCI-AML-20 shows dependence on the co-culture with stromal cells. Transcriptome analysis indicates that the OCI-AML-20 clusters with other AML patient data sets that have poor prognosis, as well as other AML cell lines, including another inv(3) line, MUTZ-3. OCI-AML-20 is a new cell line resource for studying the biology of inv(3) AML that can be used to identify potential therapies for this poor outcome disease.

The novel nematicide wact-86 interacts with aldicarb to kill nematodes.

Parasitic nematodes negatively impact human and animal health worldwide. The market withdrawal of nematicidal agents due to unfavourable toxicities has limited the available treatment options. In principle, co-administering nematicides at lower doses along with molecules that potentiate their activity could mitigate adverse toxicities without compromising efficacy. Here, we screened for new small molecules that interact with aldicarb, which is a highly effective treatment for plant-parasitic nematodes whose toxicity hampers its utility. From our collection of 638 worm-bioactive compounds, we identified 20 molecules that interact positively with aldicarb to either kill or arrest the growth of the model nematode Caenorhabditis elegans. We investigated the mechanism of interaction between aldicarb and one of these novel nematicides called wact-86. We found that the carboxylesterase enzyme GES-1 hydrolyzes wact-86, and that the interaction is manifested by aldicarb's inhibition of wact-86's metabolism by GES-1. This work demonstrates the utility of C. elegans as a platform to search for new molecules that can positively interact with industrial nematicides, and provides proof-of-concept for prospective discovery efforts.

Histone deacetylase and acetyltransferase inhibitors modulate behavioral responses to social stress.

Histone acetylation has emerged as a critical factor regulating learning and memory both during and after exposure to stressful stimuli. There are drugs that we now know affect histone acetylation that are already in use in clinical populations. The current study uses these drugs to examine the consequences of acutely increasing or decreasing histone acetylation during exposure to social stress. Using an acute model of social defeat in Syrian hamsters, we systemically and site-specifically administered drugs that alter histone acetylation and measured subsequent behavior and immediate-early gene activity. We found that systemic administration of a histone deacetylase inhibitor enhances social stress-induced behavioral responses in males and females. We also found that systemic administration completely blocks defeat-induced neuronal activation, as measured by Fos-immunoreactivity, in the infralimbic cortex, but not in the amygdala, after a mild social defeat stressor. Lastly, we demonstrated that site-specific administration of histone deacetylase inhibitors in the infralimbic region of the prefrontal cortex, but not in the basolateral amygdala, mimics the systemic effect. Conversely, decreasing acetylation by inhibiting histone acetyltransferases in the infralimbic cortex reduces behavioral responses to defeat. This is the first demonstration that acute pharmacological manipulation of histone acetylation during social defeat alters subsequent behavioral responses in both males and females. These results reveal that even systemic administration of drugs that alter histone acetylation can significantly alter behavioral responses to social stress and highlight the importance of the infralimbic cortex in mediating this effect.

Improvements in manual dexterity relate to improvements in cognitive planning after assisted cycling therapy (ACT) in adolescents with down syndrome.

We have previously reported beneficial effects of acute (i.e., single session) Assisted Cycling Therapy (ACT) on manual dexterity and cognitive planning ability in adolescents with Down syndrome (DS). In the present study, we report the chronic effects of eight weeks of ACT, voluntary cycling (VC), and no cycling (NC), on the same measures in adolescents with DS. Participants completed 8 weeks of ACT, VC, or NC. Those in the ACT and VC groups completed 30min sessions three times per week on a stationary bicycle. During ACT, the mechanical motor of the bicycle augmented the cadence to a rate which was on average 79% faster than the voluntary cadence. During VC, the participants pedaled at a self-selected rate. Unimanual dexterity scores as measured with the Purdue Pegboard test (PPT) improved significantly more for the ACT and VC groups compared to the NC group. ACT lead to greater improvements than VC and NC in the assembly sub-test, which is a task that requires more advanced temporal and spatial processing. The ACT group improved significantly more than the VC group and non-significantly more than the NC group in cognitive planning ability as measured by the Tower of London test (ToL). There were also significant correlations between the assembly subtest of the PPT and all measures of the ToL. These correlations were stronger during post-testing than pre-testing. Pre-post changes in the combined PPT score and ToL number of correct moves correlated positively in the ACT group. These results support the efficacy of the salutary effects of ACT on global fine motor function and executive function in DS. Additionally, the performance on complex bimanual dexterity tasks appears to be related to the capacity of cognitive planning ability. This research has important implications for persons with movement deficits that affect activities of daily living.

Caenorhabditis elegans is a useful model for anthelmintic discovery.

Parasitic nematodes infect one quarter of the world's population and impact all humans through widespread infection of crops and livestock. Resistance to current anthelmintics has prompted the search for new drugs. Traditional screens that rely on parasitic worms are costly and labour intensive and target-based approaches have failed to yield novel anthelmintics. Here, we present our screen of 67,012 compounds to identify those that kill the non-parasitic nematode Caenorhabditis elegans. We then rescreen our hits in two parasitic nematode species and two vertebrate models (HEK293 cells and zebrafish), and identify 30 structurally distinct anthelmintic lead molecules. Genetic screens of 19 million C. elegans mutants reveal those nematicides for which the generation of resistance is and is not likely. We identify the target of one lead with nematode specificity and nanomolar potency as complex II of the electron transport chain. This work establishes C. elegans as an effective and cost-efficient model system for anthelmintic discovery.