Michelle Shardell’s research while affiliated with University of Maryland, Baltimore and other places

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Publications (312)


METABOLOMIC AND IMMUNOLOGIC INSIGHTS INTO RACIAL DIFFERENCES IN REPRODUCTIVE AGING
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December 2024

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Innovation in Aging

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Michelle Shardell

Menopause is linked to declining levels of estrogen, loss of protective vaginal lactobacilli, and age-related comorbidities. Vaginal metabolites reflect metabolic activity of the microbiota and human host, along with exogenous influences, and can modify susceptibility to multiple pathologies. Racial/ethnic minorities experience earlier and more intense symptoms of menopause but are underrepresented in reproductive aging studies. To address these gaps, we applied 16S rRNA gene sequencing, untargeted metabolomics, and cytokine profiling to characterize the vaginal microenvironment across reproductive stages, with an emphasis on comparisons between post-menopausal racial/ethnic groups. 476 participants (aged 35-60 years) contributed semiannual person-visits over two years (N=1,153 samples). Bayesian mixed-effects regression of log2-transformed metabolites (n=770) assessed metabolomic differences in samples from pre- (n=287), peri (n=335), and post-menopausal (n=531) participants, 25% of whom were racial/ethnic minorities. Samples collected from post-menopausal participants had distinct metabolomic profiles compared to pre- or peri-menopausal samples (548 metabolites were lower in post-menopausal samples; p< 0.05). After adjustment for vaginal microbiota, post-menopausal samples had lower concentrations of most micronutrients (e.g., vitamins B, C, and D; p< 0.05). Metabolites reflecting epithelial damage and oxidative stress, along with host-produced lysophospholipids (e.g., lactosyl-N-palmitoyl-sphingosine), were highest in samples from post-menopausal participants (p< 0.05), with post-menopausal Black participants having the highest levels (relative to post-menopausal white participants, and non-postmenopausal Black or white participants) (p< 0.05). Lysophospholipids are immunogenic, and many were positively correlated with TNF-α, but negatively correlated with IL-19. Further investigations linking menopause and race/ethnicity with inflammatory or oxidative stress-related metabolites are needed to reduce disparities in healthy reproductive aging.


DETERMINANTS OF RECOVERY IN THE US MEDICARE MINIMUM DATA SET: HANDLING INFORMATIVE OBSERVATION TIMES

December 2024

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Innovation in Aging

Patients with Alzheimer’s Disease (AD) who experience a hip fracture are heterogeneous and understudied; thus, factors that influence these patients’ physical recovery are unknown. Moreover, identifying these factors can help inform personalized care for this population. To fill this gap, we use the US Minimum Data Set (MDS), a federally mandated standardized clinical assessment tool administered by the United States Centers for Medicare and Medicaid Services to facilitate care management for residents in Medicare and Medicaid certified nursing homes. Longitudinal assessments in these real-world data are irregular, and their timing is likely informative, which leads to bias if ignored. Therefore, we introduce and apply a novel joint model for longitudinal outcomes and observation times that includes a shared random effect. Data include 9,545 older adults (76.8% female, 55.7% aged 86+ years, 21.8% Medicaid eligible) in the MDS living with AD who were discharged from the hospital after hip fracture to Medicare and Medicaid certified nursing homes between 2017 and 2022. Barthel Index, a measure of physical function in activities of daily living, was the outcome (range: 0 to 90, higher scores indicate better function). Participants underwent 35,794 assessments over 100 days. Medicaid eligibility and lower cognition measured using the Brief Interview for Mental Status were more strongly associated with worse physical function in the proposed method than in a competing method (p<.05). Findings highlight 1) potential roles of socioeconomic status and heterogeneous cognition in AD in hip fracture recovery, and 2) importance of addressing informative observation times in the MDS.


A NEW ANALYTICAL METHOD FOR RISK FACTOR IDENTIFICATION IN ANALYZING LONGITUDINAL POSTFRACTURE RECOVERY OUTCOMES

December 2024

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1 Read

Innovation in Aging

Hip fracture is a highly disabling event experienced disproportionately by older adults with Alzheimer’s disease or related dementias (ADRD). Older adults with ADRD are up to three times more likely than cognitively intact older adults to sustain a hip fracture, have worse functional outcomes, and spend more than 50 fewer days at home (DAH) in the year after fracture. Given the significant consequences of hip fracture among older adults, improving recovery for those with ADRD is a crucial national priority. However, the population of patients with ADRD is highly heterogeneous, hindering our ability to risk stratify patients and focus interventions on those at highest risk and with greatest likelihood of benefit. We develop a new data science approach to unbiasedly detect high-dimensional patient-level risk factors associated with less DAH, while existing toolboxes may fail to address potential biases from unmeasured hospital-level confounders, informative hospital size, and loss to follow-up in analyzing Medicare claims. Analysis of 16562 Medicare beneficiaries with ADRD, aged 65 or above, and experienced a hip fracture between 2017 and 2019 demonstrated that older age, longer length of stay in the hospital, heavier comorbidity burden, and less days at home before fracture are significantly associated less days spent at home in the 12-month period after hip fracture (p<.05), while existing methods fail to detect some effects. Findings demonstrate that the proposed method can overcome bias in using Medicare data and can lead to findings that may inform target for intervention to promote healthy aging.


FREE TESTOSTERONE, SEX HORMONE BINDING GLOBULIN, AND INCIDENT FRAILTY IN MEN WITH HIV

December 2024

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2 Reads

Innovation in Aging

Background Older men with HIV (MWH) have a higher prevalence of frailty than matched men without HIV, but the underlying mechanisms are unclear. Testosterone (T) contributes to higher muscle (mass, strength), and it binds to sex hormone-binding globulin (SHBG), which regulates testosterone bioavailability to the tissues. Aging MWH experience increase in circulating SHBG and decline in circulating free T concentrations. We hypothesized that these hormonal changes may contribute to the development of frailty in MWH. Methods Free T and SHBG were measured in 306 non-frail MWH (129 robust and 177 prefrail) who had at least one frailty assessment at a semi-annual follow-up visit in the Multicenter AIDS Cohort Study. Marginal structural models were used and adjusted for covariates: age, race, education, comorbidity burden, BMI, smoking status, alcohol use, HIV parameters and loss to follow-up. Results Mean age at baseline was 55±5 years, (median 58 years, Q1=55, Q3=63); follow up frailty assessments visits was 8.5(SD:2.5) years. MWH with low free T (< 50 pg/ml) were more likely to become frail compared to those with free T ≥50 pg/ml (HR,1.58 (95%CI:1.12, 2.24); p-value=0.03). Low free T was also significantly associated with transition from prefrailty to frailty, [< 50 pg/ml: 47%; ≥50 pg/ml:34%], a difference of 12.4% (95% CI:2.9,24.3%). In contrast, SHBG concentrations were not associated incident frailty or transition to frailty. Conclusion Low free T, but not SHBG, predicted incident frailty in men with HIV at high risk of developing frailty, in particular those in the prefrail state.


ASSOCIATION BETWEEN PRE-HIP FRACTURE DEPRESSION AND DAYS AT HOME AFTER FRACTURE AMONG MEDICARE BENEFICIARIES

December 2024

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1 Read

Innovation in Aging

Hip fracture and depression are important public health issues among older adults. Though historically more common in females, hip fracture cases are projected to increase among males, who often experience greater depression severity. Days at home (DAH), a patient-centered metric reflecting fracture recovery, can inform post-surgical treatments for older adults. The association between pre-fracture depression and DAH among hip fracture survivors and potential sex differences remains unexplored. Our cohort included 63,618 community-dwelling Medicare fee-for-service beneficiaries, aged 65+, who underwent hip fracture surgery between 2010 and 2017. Generalized Estimating Equations assessed longitudinal associations between pre-fracture depression at hospital admission and total DAH over 12 months post-discharge, adjusting for covariates. Sex-by-depression interactions were also included, and multiple models were built to identify factors that may explain the primary association. There was no difference in DAH between beneficiaries by depression status in the fully adjusted model. After adjusting for demographic factors (age and sex) and social determinants of health (race, Medicaid dual eligibility, and poverty), those with depression spent 11 fewer average DAH compared to counterparts without depression (incident rate ratio [IRR] = 0.92; 95% CI = 0.91, 0.93; p<.0001). The association was attenuated and not significant after additional adjustment for medical complexities, specifically comorbidities, and facility and geographic factors. The sex-by-depression interaction term was not statistically significant (p=0.38). The association between pre-existing depression and DAH among Medicare beneficiaries with hip fracture underscores the need for early recognition and secondary prevention of depressive symptoms during acute care, which may inform hip fracture treatment.


KNEE OSTEOARTHRITIS: PERCEPTIONS OF PSYCHOSOCIAL CONSEQUENCES, PAIN, AND MANAGEMENT COMPLEXITIES

December 2024

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Innovation in Aging

Knee Osteoarthritis (KOA) afflicts 27 million U.S. adults and has adverse health and psychosocial outcomes. Depression is twice as common among persons with KOA compared to the general population and is a barrier to pain management and physical activity. While guidelines advise depression treatment, directions on co-managing depression and pain are seldom offered; a viable adjunctive treatment, duloxetine, treats both depression and pain, yet is not routinely prescribed and could facilitate physical activity. Progress in reducing KOA distress is hampered by inadequate knowledge of perceptions and experiences of persons’ daily living with KOA especially when pain and depression co-occur. Qualitative interviews were conducted at baseline in a program evaluating aerobic exercise plus duloxetine to learn participants’ perceptions, challenges, and how depression and pain interact in managing KOA. The sample included: n=12 (5 African American, 1 Asian, 6 White) participants, aged 41-71 years (10 female, 2 male) with self-report pain severity, median 3 (scale 0-4) and moderate to severe difficulty with Activities of Daily Living. Analytic strategies featured topic, theme, and critical case comparative methods. Results identified four key constructs: (a) unpredictability and temporal variability of impacts of KOA; (b) management requiring flexible strategies encompassing a wide range of self-image and life domains beyond pain and depression; (c) barriers including concerns with medications; depression eroding energy; a sense of isolation socially and from meaningful activities; and (d) challenges to program participation. Pathways to address the constellation of intersecting domains perceived in living with KOA and treatment program participation are needed.


ASSOCIATION BETWEEN PRE–HIP FRACTURE ANTIDEPRESSANT USE AND HOSPITAL LENGTH OF STAY AMONG MEDICARE BENEFICIARIES

December 2024

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Innovation in Aging

Antidepressants are the first-line treatment for depression among older adults. Their use presents important sex differences and is linked to hospital length of stay (LOS), which can affect hip fracture recovery. Given the push to deprescribe these medications among older adults, exploring the effect of antidepressant use prior to hip fracture among older adults with existing depression is important. Thus, our study examined the association between pre-fracture antidepressant use and hospital LOS among hip fracture survivors, and related sex differences. The sample included 17,936 community-dwelling Medicare fee-for-service beneficiaries with depression and a hospitalization claim for hip fracture surgery between 2010 and 2017. Ordinal logistic regression was used to estimate the association between pre-fracture antidepressant use, measured 6 months prior to fracture, and hospital LOS in days, a categorical outcome variable classified into three groups (1-4, 5-8, and 8+ days) during the 30-day post-fracture period. In the covariate-adjusted model, hip fracture survivors with depression who used antidepressants pre-fracture had 6.7% higher odds of a shorter hospital LOS compared to non-users (odds ratio [OR]=1.07; 95% CI=1.01, 1.13; p=0.03). Males had longer LOS on average (mean=6.02, standard deviation [SD]=4.07) compared to females (mean=5.43, SD=3.17), but the sex-by-antidepressant use interaction was not significant (p=0.83). Treating existing depression with antidepressants was associated with shorter hospital LOS in this sample. The findings suggest a benefit of antidepressant use prior to hip fracture which may inform clinical decision-making surrounding depression management among hip fracture survivors to optimize recovery trajectories.


SEX-SPECIFIC BIOMARKER PREDICTION OF FEMORAL NECK BONE LOSS AFTER HIP FRACTURE

December 2024

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2 Reads

Innovation in Aging

Hip fracture exacerbates age-related inflammation and metabolic dysfunction, which could accelerate bone loss post-fracture. This study aimed to develop biomarker prediction models for declines in femoral neck bone mineral density (BMD) after hip fracture. Participants were Caucasian men (n=99) and women (n=75) from the Baltimore Hip Studies 7th cohort with a hip fracture who were not receiving glucocorticoids, sex-hormone therapy, or bone-active medications. Data were collected at baseline (within 15 days of admission) and 2-, 6-, and 12-months later. Biomarkers were categorized into tertiles: interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), soluble tumor necrosis factor-alpha (TNF-alpha) receptor type 1, estradiol (E), testosterone (T), intact parathyroid hormone (iPTH), sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), C-terminal telopeptide of type I collagen (CTX), and procollagen type I N-propeptide (PINP). Femoral neck BMD was measured using dual energy x-ray absorptiometry. Mixed-effects models adjusted for age, height, and weight estimated 1-year changes in femoral neck BMD after hip fracture. Bone loss was classified as accelerated for intra-individual changes that exceeded the mean decline. Logistic regression models were stratified by biological sex and implemented using stepwise selection. The area under the curve (AUC) estimate among men was 0.68, and biomarkers related to bone loss were E, IGF-1, SHBG, and CTX. Similarly, the AUC metric among women was 0.69, but identified biomarkers were IL-6, iPTH, IGF-1, and SHBG. Findings indicate that both inflammatory and hormonal biomarkers relate to accelerated bone loss post-fracture; however, there are differential associations in physiological mechanisms between men and women.


RED BLOOD CELL DISTRIBUTION WIDTH: FURTHER INSIGHTS

December 2024

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3 Reads

Innovation in Aging

Red blood cell distribution width (RDW) measures erythrocyte size variability and strongly predicts cardiovascular disease (CVD) morbidity and mortality. Our prior cross-sectional analysis showed that inflammation, metabolic rate, and body habitus are independently associated with RDW. To better understand determinants of RDW, we performed a longitudinal analysis associating changes in RDW within the normal range (11.5 - 15.0%) with age, sex, race, and changes in other erythrocyte properties, major CVD risk factors, and other physiologic measures. Data were from 452 men and 482 women, aged 50 to 94 years enrolled in the Baltimore Longitudinal Study of Aging. For each participant and each predictor, change was the regression coefficient of time from a linear model. Coefficients of candidate correlates were then used to predict change in RDW in multiple linear regression models that were reduced by backward selection. In the final model, increasing erythrocyte number (STβ=1.4980, P< 0.001), mean platelet volume (STβ=0.2019, P< 0.001), anion gap (STβ=0.1754, P< 0.001), blood urea nitrogen (STβ=0.0684, P=0.0395), urine albumin-creatinine ratio (STβ=0.1007, P=0.0015), alanine transaminase (STβ=0.1580, P< 0.001), interleukin-6 (STβ=0.2338, P< 0.001), and diastolic blood pressure (STβ=0.0769, P=0.0107) and decreasing glucose (STβ=-0.2425, P< 0.001), vitamin B12 (STβ=-0.1310, P< 0.001), and C-reactive protein (STβ=-0.1801, P< 0.001) were associated with increasing RDW. The association of age with increasing RDW was independently explained by decreasing glucose (STβ=-0.2310, P< 0.001). Taken together, these findings suggest that rising RDW may reflect accelerated aging. Studies in larger, more diverse populations are necessary to confirm these findings and determine their role in mechanisms leading to age-associated increases in RDW.


ASSOCIATION OF KIDNEY MARKERS AND DUAL TRAJECTORIES OF COGNITIVE AND PHYSICAL FUNCTION

December 2024

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2 Reads

Innovation in Aging

The interplay between kidney health and cognitive-physical function has garnered increased attention. Dual trajectories consider simultaneous longitudinal changes in cognitive-physical function. Among participants in the Health, Aging and Body Composition Study with initially fast gait and high cognitive function, we assessed associations between baseline kidney function markers and joint longitudinal cognition-gait trajectories. Grouped-based trajectory analysis performed on modified mini-mental state (years 3, 5, 8, 10) and 20-meter usual gait speed (years 3–6, 8, 10) yielded three dual trajectory groups: Group 1 (n=660; exhibited sustained superior longitudinal cognitive-physical performance), Group 2 (n=744; high sustained cognition and initially lower, steadily declining gait), and Group 3 (n=498; lowest initial cognitive-physical performance, both steeply declining over time). Four sequential multinomial regression models were built. Model 1 showed a higher estimated glomerular filtration rate (ml/min/1.73m2) to be associated with lower odds of Group 3 versus Group 1 (odds ratio[OR]=0.98, 95% confidence interval [CI]: 0.97–0.99) after adjusting for covariates. Model 2 estimated 19% greater odds of Group 2 per log-transformed urine albumin-to-creatinine ratio (mg/g) (OR=1.19, 95%CI: 1.05–1.35) and 35% greater odds of Group 3 (OR=1.35, 95%CI: 1.17–1.55) versus Group 1. In Model 3, 25-hydroxyvitamin D was not significantly associated with cognitive-physical trajectory. Model 4 added parathyroid hormone, alpha-klotho, and fibroblast growth factor 23 (FGF23) (p=0.044 Model 4 versus 3); FGF23 was significantly associated with cognitive-physical trajectory (Group 3 versus 1 per log-transformed FGF23 [pg/mL]: OR=1.51, 95%CI:1.00–2.28). Findings support a potential role of kidney health in dual cognitive-physical performance among initially healthy older adults.


Citations (42)


... In contrast, the vaginal microbiomes of Black women are more likely to be dominated by Gardnerella and "Ca. Lachnocurva vaginae" species, which are associated with bacterial vaginosis [10]. In recent years, substantiated evidence has been reported that links vaginal microbiota disorders to the onset and progression of various gynaecological disorders, including pelvic inflammatory diseases such as CE and salpingitis [11]. ...

Reference:

The Therapeutic Potential of Lactobacillus crispatus for Chronic Endometritis: A Comprehensive Clinical Trial and Experimental Investigation
Correction: Integrating compositional and functional content to describe vaginal microbiomes in health and disease
  • Citing Article
  • Full-text available
  • February 2024

... They maintain the acidic environment of the vagina (pH approximately 4.5) by producing lactic acid, which inhibits the growth of pathogens. Lactobacillus can also produce hydrogen peroxide and bacteriocins, which have antibacterial activity and further enhance the defense against pathogenic microorganisms (25,26). ...

Integrating compositional and functional content to describe vaginal microbiomes in health and disease

... Notably, the rate of colonization with E. coli was inversely associated with the presence of Lactobacilli, and diabetic women treated with insulin showed a 3-fold increased risk of vaginal E. coli colonization compared with women without DM or with DM not treated with insulin [32]. The vaginal microbial composition in 811 female patients by midvaginal sampling was also evaluated, clustering them into different CSTs [33]. Among diabetic patients (45 out of 811), 45 % belonged to CSTs I/II/V (Lactobacillus crispatus, Lactobacillus jensenii or Lactobacillus gasseri), 12 % to CST III (Lactobacillus iners) and 43 % to CST IV, with a low amount of Lactobacillus. ...

202-LB: Association between Diabetes and the Vaginal Microbiota
  • Citing Article
  • June 2023

Diabetes

... The bacterial diversity in the vaginal microbiota is comparatively lower than that found in the intestinal tract. The vaginal environment is primarily regulated by a diverse range of lactic acid bacteria to maintain homeostasis (Brown et al., 2023). However, the vaginal environment in an individual's life is dynamic and presents complex circumstances. ...

Bacterial Vaginosis and Spontaneous Clearance of Chlamydia trachomatis in the Longitudinal Study of Vaginal Flora
  • Citing Article
  • May 2023

The Journal of Infectious Diseases

... 12 A recent metabolomic characterization of memory and gait "dual decline"-a paradigm similar to MCR-demonstrated metabolic alteration among dual decliners indicative of mitochondrial, immune, and cardiovascular dysfunction. 13 Although these findings provide clues about the cause of joint motor and cognitive decline, the primary biological drivers of the MCR phenotype remain unknown. The identification of proteins in blood that are dysregulated in individuals with MCR and MCI syndromes holds promise for better understanding the biology of these pre-dementia syndromes. ...

Plasma metabolomic signatures of dual decline in memory and gait in older adults

GeroScience

... In the PFF cohort, reduced T1, T2, and T3 vertical accelerations and increased T3 jerk were identified in univariate analysis, pointing to altered acceleration patterns during turns. These findings may stem from factors such as residual pain, muscle weakness, altered joint mechanics, or an adaptive gait strategy aimed at minimizing discomfort during turning activities [33,52]. Also, the correlation analysis showed that longer durations, lower vertical angular velocity, and higher jerk during turns were associated with a lower SPPB score, indicating potential connections between impaired turning dynamics and physical performance in individuals with PFF. ...

Predictors of mobility status one year post hip fracture among community-dwelling older adults prior to fracture: A prospective cohort study
  • Citing Article
  • March 2023

Journal of the American Geriatrics Society

... Despite the prevalence of sleep disorder in older adults and the hypothesized critical role of gut microbiota, few studies have investigated the sleep and gut-brain axis relationship in older adults and the results are often conflicting, suggesting the need for more research [8][9][10][11]. For example, neither objective nor subjective sleep quality was significantly associated with microbiota diversity measures in one study [10], while another study found that objective sleep efficiency was a significant predictor of microbiota composition [11]. Sleep is a multidimensional construct, including duration, timing, regularity, efficiency, and subjective satisfaction [12]. ...

Association of subjective and objective measures of sleep with gut microbiota composition and diversity in older men: The Osteoporotic Fractures in Men (MrOS) study
  • Citing Article
  • January 2023

The Journals of Gerontology Series A Biological Sciences and Medical Sciences

... While advancements in living standards and healthcare have contributed to prolonged lifespans, they have also been accompanied by a rising prevalence of chronic diseases and disabilities among older adults. Consequently, the increase in healthy life expectancy has lagged significantly behind the overall growth in lifespan [2,3]. Therefore, investigating the factors contributing to accelerated aging is necessary, as it is closely associated with increased susceptibility to chronic diseases and an increased mortality risk [4]. ...

Longitudinal phenotypic aging metrics in the Baltimore Longitudinal Study of Aging

Nature Aging

... In this demographic, the term "mild" belies the true impact of the injury: up to 55% of these older adults suffer unfavorable outcomes-a significant increase from the 15% reported in younger populations. [1][2][3][4][5][6] These injuries are more frequent and more severe in older adults, leading to extended hospitalizations, an increased likelihood (15-67%) of a transition to nursing homes, and elevated mortality rates. 2 The long-term consequences are profound, with a heightened risk of post-traumatic epilepsy, delayed seizures, and a predisposition to neurodegenerative disorders such as dementia and Parkinson's disease, with respective increased risks of 26% and 44%. 5 Managing TBIs in this age group is further complicated by preexisting comorbidities, polypharmacy, and an increased potential for drug interactions. [1][2][3][4][5][6] Women, who are particularly underrepresented in pre-clinical animal model studies despite accounting for 62% of injuries in those older than 85, face unique challenges. ...

Traumatic Brain Injury and Risk of Long-Term Nursing Home Entry among Older Adults: An Analysis of Medicare Administrative Claims Data
  • Citing Article
  • July 2022

Journal of Neurotrauma

... It is also argued that because stress and depression are both associated with the development of later life medical co-morbidities, as well as the possible onset and worsening of osteoarthritis pain, disability, and poor health, plus possible excess opioid usage [66], very careful evaluation to tease out the presence of physical symptoms, versus emotional distress, followed by interventions such as relaxation, is strongly indicated [67], and may be especially helpful in reducing osteoarthritis related disability, among those who are over-anxious and/ or chronically ill. In turn, therapies that foster feelings of efficacy and confidence and engage the mental and social capacities of the arthritis sufferer are expected to positively impact overall well-being, including walking ability as well as mental health status [68][69][70][71]. Educational approaches that can foster both a more positive outlook, as well as an individual's self-management capacity, may similarly heighten the life quality of the individual osteoarthritic patient who feels sad and distressed, especially those older adults with little social support or negative views, those with a family history of psychiatric problems, those with long standing medical conditions, those experiencing prolonged stress, and those with limited resources. ...

POS1138 PERSISTENCY OF DEPRESSIVE SYMPTOMS AND PHYSICAL PERFORMANCE IN KNEE OSTEOARTHRITIS
  • Citing Article
  • June 2022

Annals of the Rheumatic Diseases