Abstract
Although participation in physical activity is recommended for adults with arthritis, research indicates individuals often stop participating in sports and physically active leisure due to ...the pain and symptoms associated with arthritis (Wilcox et al., 2006). Examining a group of older adults with arthritis, the present study examines motivations and constraints related to participating in sport and physically active leisure as well as how they negotiate constraints. Data (N=1203) were collected through an online questionnaire of adults aged 50 and older in the United States. This study includes individuals reporting a diagnosis of some form of arthritis (n=288; M age = 64.8, SD = 8.08). Approximately 32% self-reported participation in sport in the past 12 months. Descriptive statistics were conducted to explore motivations and constraints to sport involvement. Regressions were run to determine whether constraints and motivations explained adults’ functional mobility and social wellbeing. The most commonly identified motivation for participation was for health purposes (80.2%). Constraints to participation included not being in good enough shape (51.9%) and not having others their age with whom to participate (47.4%). The most commonly identified constraint negotiation was to budget money (51.4%); this is not surprising since sport participation was perceived as expensive (41.3%). Motivations (p<.01) and constraints (p<.001) significantly predicted functional mobility; constraints significantly predicted some aspects of social wellbeing (i.e., coherence, contribution, actualization; p<.05) while constraint negotiation predicted social acceptance (p<.05) and integration (p<.001). Discussion will include implications and strategies for agencies and professionals who work with adults who have arthritis.
Hematopoietic stem cells (HSCs) are genetically heterogeneous with each HSC possessing its own unique mutations. Some mutations confer a fitness advantage, allowing the HSCs harboring them to ...clonally expand. The role of different cellular stressors on this expansion remains unknown, as does the nature of the expanding hematopoietic populations.To address these issues, we designed an error-corrected sequencing assay able to detect somatic variants in 46 genes associated with clonal hematopoiesis or AML/MDS at a variant allele frequency (VAF) of 0.1%. We then characterized clonal hematopoiesis after two distinct types of stress: cytotoxic therapy and hematopoietic transplantation.
We first assessed mobilized pheresis samples from three groups: lymphoma or myeloma patients exposed to cytotoxic therapy (n=81), myeloma patients with no such exposure (n=38), and normal donors (n=19). Prior cytotoxic therapy was associated with a significantly increased incidence of clonal hematopoiesis, which was observed in 66/81 (81.5%) of these patients. In fact, most patients with clonal hematopoiesis after cytotoxic therapy had two or more variants detected (median: 3; range: 1-11), suggesting an expansion of multiple clones. Of the 46 genes assessed, we identified six commonly associated with DNA damage response (TP53, PPM1D, ATM, BRCC3, SRCAP, and RAD21) . Variants in these genes were seen in 36/81 (44%) of patients following cytotoxic therapy compared to only 9/57 (16%; P<0.001) of individuals lacking such exposure. In contrast, variants in the other 40 genes were not significantly increased after cytotoxic therapy. These data suggest that cytotoxic therapy provides a fitness advantage to HSCs harboring mutations in certain genes involved in the DNA damage response.
To investigate the nature of expanded mutant clones, we sorted pheresis samples with DNMT3A (n=2), TP53 (n=3), or PPM1D (n=3) variants into myeloid and lymphoid populations. In general, variants were detected in both myeloid and lymphoid lineages, suggesting that they arose in HSCs. However, in most cases with TP53 or PPM1D mutant clones, the percentage of cells with the identified variant was higher in myeloid versus T cells (median: 14.2-fold; range: 2.3 to 88.3-fold). This may reflect the quicker turnover of myeloid compared to lymphoid populations and short time period (< 1 year in most cases) between cytotoxic therapy initiation and pheresis collection.
We next asked how transplantation influences HSC expansion. We sequenced peripheral blood leukocytes collected 6-12 months after transplantation from 40 of our lymphoma patients (with 104 detected pheresis variants). The VAFs of most of these variants did not change significantly with transplant while variants not initially identified in the pheresis samples often became detectable post-transplant. Several trends were observed. Of 46 DNMT3A variants detected before or after transplant, 15 (32.6%) significantly increased ≥ 2-fold in VAF after transplantation, while 2 (4.3%) decreased. Interestingly, all three clones with R882 codon variants expanded. In contrast, of 21 PPM1D variants, only 2 (9.5%) significantly increased in VAF with transplantation, while 7 (33.3%) decreased (P=0.002). These data suggest that clones expanding after cytotoxic therapy are often long-lived and persist after transplant. As with cytotoxic therapy, the behavior of hematopoietic clones following transplant depends, in part, on what mutations they harbor; however, transplantation-induced selection pressure doesn't necessarily favor the same clones as cytotoxic therapy.
Finally, to assess the leukemic potential of expanded clones following cytotoxic therapy, we sequenced bone marrow samples from 134 t-AML/t-MDS patients. They were enriched in TP53 mutations with 34.3% carrying a mutation in this gene. In contrast, variants in other interrogated DNA damage response genes were infrequent in t-AML/t-MDS despite being common after cytotoxic therapy. For example, although variants in PPM1D were detected in a similar percentage of patients following cytotoxic therapy as those in TP53 (17.3% vs. 21.0%), they were only present in 3.0% of t-AML/t-MDS cases (P = 0.008). In total, our data suggests a model in which distinct clones carrying specific mutations expand in response to different cellular stressors. Each clone differs in its leukemic potential due, in part, to the mutations it harbors.
Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. DiPersio:Magenta Therapeutics: Equity Ownership; Celgene, Bioline, Vasculox, Cellworks, Rivervest: Consultancy; Hemedicus, DAVA Oncology: Speakers Bureau; BMS, Asterias, Amphivena, Bluebird: Other: Travel, Accomodations, Expenses.
Relationships between grandparents and grandchildren provide an excellent framework for integrating family theory and family methodology. Systematic differences as a function of age, gender, life ...expectancy, and health as played out through generations suggest some topics are best studied by disentangling variability between and within families. Using data from 1,345 grandchildren (52% girls, mean age 13.69 years, range 9 to 20) reporting on 3,664 grandparents, we compare results obtained from studying grandparent-grandchild relationships individually and at the family level. Results suggest important predictors of relationship quality at the within-subject and between-subject levels. Future research should more carefully integrate each level into theory and design.
Introduction: The clinical diagnosis of myelodysplastic syndrome (MDS) relies on the presence of persistent cytopenias, not otherwise explained, and evidence of morphologic dysplasia in the bone ...marrow. Low grade MDS (bone marrow blasts <5%) is defined by the presence of morphologic dysplasia in at least 10% of cells in one or more cell lineage. Low grade MDS is particularly challenging to diagnose, as morphologic dysplasia may be subtle and is subject to high inter-observer variability. The ability to diagnose low grade MDS can be improved by incorporating cytogenetic evaluation of the bone marrow, especially in the setting of equivocal morphologic dysplasia. However, many MDS cases (up to 60%) lack cytogenetic abnormalities, limiting the overall utility of cytogenetics. Multiple recent studies have demonstrated that the majority of MDS patients (over 80% in some studies) harbor recurrent somatic mutations in a core group of genes. We sought to determine if targeted DNA sequencing of genes recurrently mutated in MDS and AML could be useful in the evaluation of cytopenic patients with a normal karyotype being evaluated for the possible diagnosis of MDS.
Methods: We screened patients who presented for evaluation of MDS between 2002 and 2014 that had consented for sequencing studies and had banked samples. Patients were selected based on 1) World Health Organization defined cytopenia (WBC <1,800/µL, hemoglobin <10g/dL, platelets <100k/µL) in at least one lineage, 2) bone marrow blasts <5%, 3) WBC <14k/uL, 4) normal cytogenetics, and 5) absence of prior therapy for MDS. Bone marrow specimens were independently re-reviewed by two board certified hematopathologists. DNA was extracted from cryopreserved bone marrow and skin (to serve as a source of normal DNA) and enriched for a panel of 285 commonly mutated myeloid genes. Captured DNA libraries were sequenced on a HiSeq 2500 instrument with 2x101bp reads. The resulting data was analyzed for single nucleotide variants (SNVs) and insertions/deletions (indels) using VarScan2 in paired normal mode.
Results: Thirty-eight patients met the selection criteria, and 30 of these had bone marrow aspirates available for morphologic review and were included in the study. A mean unique coverage depth of 913x was achieved for targeted genes and all reported variants had >50x coverage, variant allele fractions (VAFs) >3%, and minor allele frequencies (MAFs) < 1% in any population. Of the 30 sequenced cases, 25 had a somatic mutation in at least one gene (mean 3.3 mutations/case, range 1-10 mutations/case). The most commonly mutated gene was TET2 (7 cases), followed by ASXL1 (5 cases), EZH2 (4 cases), SRSF2 (4 cases), and U2AF1 (4 cases). Of the 285 sequenced genes, 44 were mutated in at least one case, and 14 were mutated in 2 or more cases. The mean VAF (variant reads/total reads) of detected mutations was 27% (range 3-98%). Morphologic review demonstrated definitive dysplasia (≥10% of cells in least one lineage) made by two pathologists in 18 of 30 cases (supporting the clinical diagnosis of MDS), no dysplasia in 6 of 30 cases, and equivocal dysplasia (where hematopathologists did not agree that dysplasia was ≥10%) in 6 of 30 cases. Thirteen of 18 cases (72%) with definitive dysplasia had a mutation, 5/6 cases (83%) without dysplasia had mutations, and 6/6 (100%) cases with equivocal dysplasia harbored somatic mutations. The mean VAF of mutations was 17.5% in cases without dysplasia, 29% in cases with equivocal dysplasia, and 28% in cases with definitive dysplasia. All of these groups included mutations in canonical MDS genes such as TET2, DNMT3A, SRSF2, RUNX1, and EZH2.
Conclusions: In this cohort of 30 cytopenic patients with normal cytogenetics, 80% harbored a somatic mutation in at least one myeloid-associated gene. Somatic mutations were detected in 5 of 6 cases without definitive dysplasia (<10% dysplasia) and 6 of 6 cases with equivocal dysplasia. Notably, canonical MDS mutations were found even in the absence of dysplasia. These findings suggest that clonal hematopoiesis may be present in the majority of cytopenic patients independent of dysplasia, a finding that requires independent validation. Identification of somatic gene mutations in patients with morphologically equivocal MDS or cytopenic patients without definitive dysplasia provides a means for tracking clonal disease that could be used to monitor patients for subsequent development of definitive MDS.
Duncavage:DI&P Consulting: Consultancy; Cofactor Genomics: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.
Nearly half of rural residents in the USA have at least one chronic condition, and meeting the complex needs of these individuals has become a challenge for the current healthcare system. A ...self-management approach enables individuals with chronic illnesses to gain skills needed to improve the management of their conditions. Rural areas have a higher proportion of individuals who are likely to be affected by chronic conditions. Based on these factors, it is necessary to provide programs to help rural residents self-manage their health. The purpose of this qualitative, exploratory study is to explore the benefits perceived by rural residents due to their participation in six weekly group sessions, which are referred to as the Chronic Disease Self-Management Program (CDSMP).
Individuals who completed the CDSMP were recruited to participate in a focus group regarding their experience with the program. Thirty-four of the 45 respondents (75%) who completed the CDSMP participated in six focus groups. When the respondents returned for the scheduled focus groups, they were asked to share their experience with the CDSMP. Each focus group was located at the same site that housed the program in their community. Phenomenological and consensual qualitative approaches were used in the data analysis for the present study.
The majority (91%) of the participants were female. Of those, 97% were non-Hispanic whites. The mean number of chronic conditions was two, with a range between one and eight chronic conditions per participant. Two prominent themes emerged from the six focus groups: respondent interaction in behavior change and prioritizing health behavior change.
The study findings support that chronic disease self-management programs can initiate positive behavioral changes, and those lifestyle changes can influence and improve the health of rural populations. Similar programs can yield beneficial results on important behavior change for the rural communities, an underserved population with chronic conditions.
Treatment-related acute myeloid leukemia (t-AML) arises as a result of prior exposure to radiation, alkylator chemotherapy or topoisomerase II inhibitors. The overall prognosis is poor, with a median ...survival of only 6-10 months. Genetic background influences the risk of acquiring t-AML, yet specific susceptibility factors have not been wellcharacterized. We utilized a mouse model to identify novel risk factors for t-AML, which allowed us to control for environmental factors and test the effect of different genetic backgrounds. Cohorts of twenty inbred mouse strains (including several genetically diverse wild-derived strains) were treated with N-ethyl-N-nitrosourea (ENU), a potent alkylating agent in mice. As we previously reported, six of these mouse strains were susceptible to alkylator-induced myeloid leukemia. In the current study, we searched for candidate susceptibility factors that could explain this phenotype. Genome-wide association analysis using strain-specific leukemia incidence and a panel of single nucleotide polymorphism (SNP) markers revealed a peak spanning 1.07 Mb on mouse chromosome 3. This region contains six genes, including myeloid leukemia factor 1 (Mlf1). Mlf1 is a strong candidate gene since it is a translocation partner in the rare t(3;5) (q25.1;q34) associated with AML and MDS in which NPM1 is fused to nearly full-length MLF1. We first sequenced the Mlf1 locus in all 20 strains and found SNPs and in/dels at a frequency of 1/100 bp, but no nonsynonymous coding changes. Next, we asked whether Mlf1 is expressed in the cellular compartment relevant for initiation of t-AML. RNA was isolated from bone marrow cells from 18 of the 20 previously characterized strains (N=4 mice per strain) sorted into lineage (GR-1, CD19, B220, CD3, CD4, CD8, TER119, and IL-7Rα) negative/kit+, whole bone marrow, or lineage+ fractions. Quantitative RTPCR analysis demonstrated that Mlf1 is only expressed in the more immature lineage-/kit+ cells. In addition, Mlf1 is expressed in a strain-dependent fashion with a 10-fold difference of expression across strains that ranged from below the level of detection to 2.3% of the GAPDH signal. To further define the pattern of Mlf1 expression, the lineage-/ kit+ population was purified into HSC, CMP, GMP, and MEP subsets. The highest Mlf1 expression was found in the common myeloid progenitors (Lin-/c-Kit+/Sca-1-/CD34+/ FcγR-). There was not a direct correlation between RNA expression levels and t-AML susceptibility. Possible explanations for this discordance include heterogeneity of the cell populations analyzed, differences between cells at baseline vs. after exposure to a genotoxin, and potential differences between MLF1 mRNA and protein levels. Finally, to address how different levels of Mlf1 expression might affect t-AML susceptibility, we utilized an in vitro overexpression assay. Primary bone marrow cells were transduced with either an MLF1 ires YFP-MSCV retrovirus or control YFP-MSCV retrovirus with similar multiplicities of infection. YFP+ cells infected with the control virus expanded to nearly 4-fold greater levels than cells overexpressing MLF1 when analyzed at 72 hours. We show that the decreased accumulation of MLF1-expressing cells is due to, at least in part, a 3.4-fold increase in apoptosis (p<0.001, 44% in MLF1 ires YFP vs.13% in control). We propose a model in which the relative abundance of MLF1 in CMPs is a determinant that influences whether or not cells exposed to genotoxic stress undergo MLF1 induced apoptosis. The identification of the molecular basis of t-AML susceptibility may lead to strategies that reduce the incidence of this disease.
Treatment-related acute myeloid leukemia (t-AML) arises as a result of treating primary malignancies with alkylator chemotherapy drugs and has a poor prognosis. Genetic background influences the risk ...of acquiring t-AML, yet little is known about susceptibility factors. To identify candidate risk factors, cohorts of twenty inbred mouse strains were treated with N-ethyl-N-nitrosourea (ENU), a potent alkylating agent in mice. Six of these mouse strains were susceptible to alkylator-induced leukemia. SWR/J mice were the most susceptible in this relatively small screen. We expanded on that study to characterize SWR/J mice as a susceptible strain to t-AML using 245 mice. Mice were treated with different permutations of steroid treatment to determine the effect they would have on leukemia numbers. In addition to the susceptible strains, quantitative trait loci mapping was used on the initial study to identify genetic components responsible for the leukemic phenotype. This analysis revealed two significant peaks of interest on chromosomes 3 and 14. The 1 Mb region on chromosome 3 contains six genes, one of which was myeloid leukemia factor 1 (Mlf1). In humans, MLF1 waspreviously identified for its involvement in a chromosomal translocation with nucleophosmin (NPM) that is restricted to AML and myelodysplastic (MDS) patients. We show that MLF1 is pro-apoptotic and decreases the viability of hematopoietic cells.
The purpose of the present study is to examine continuity and change in post-retirement leisure, and the relationship of such patterns to subjective well-being (SWB) in two national contexts. ...National data sets from the US (N=430) and Israel (N=383) are used to examine changes in leisure participation and their impact on SWB. Results indicate that in the US there is a general inclination toward continuity, while in Israel there are significant increases in rates and frequency of participation. In Israel some changes in activity are associated with life satisfaction, while in the US no such association is found. These differences are discussed in light of the higher pre-retirement participation in leisure activities in the US and the possibility that adjustment to retirement may be easier in more leisure-oriented societies.
המחקר בדק את שינוי המעורבות בפעילויות פנאי לאחר מות בן-הזוג, וכיצד המעורבות בפעילויות פנאי קשורה לבריאות ותחושת רווחה של האלמנות בתקופת המעבר. המחקר מבוסס על דיווחי 154 אלמנות, בגיל העמידה ומעלה, ...בעלות הכנסה בינונית ומטה, על פעילויות הפנאי שלהן ועל רגשות הרווחה והבריאות שלהן. רוב האלמנות הפחיתו את השתתפותן בפעילויות פנאי. מן הממצאים עולה כי סממנים של דיכאון והתאוששות מן האבידה ניבאו היטב שינוי בהיקף פעילויות הפנאי. ממצא זה תומך בהשערה כי הרגשת רווחה או היעדרות של תחושת רווחה השפיעו באופן הרב ביותר על פעילויות פנאי. זאת לעומת הכיוון ההפוך - מידת ההשפעה של השתתפות (או הפחתה בהשתתפות) בפעילויות פנאי על תחושת רווחה או דיכאון.
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