Introduction Diabetes and osteoarthritis (OA) are prevalent chronic conditions, often occurring concurrently and complicating patient management. While the individual impact of each condition on functional impairment is well documented, their combined effect remains poorly understood. This study aims to elucidate the relationship between diabetes and OA-related functional impairment. Methodology This was a cross-sectional study of 290 participants with unilateral knee OA. Their demographic, clinical, and diabetes data were collected. Functional impairment was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index-Center for Rheumatic Diseases (WOMAC-CRD). Statistical analyses investigated the relationships between diabetes, OA severity, and functional impairment. Result Diabetic participants showed significantly worse physical function and overall disability, with lower WOMAC-CRD scores. Mean WOMAC-CRD pain scores were 6.46 (SD = 1.088) and 6.48 (SD = 1.101) for the diabetic and non-diabetic groups, respectively. Mean WOMAC-CRD stiffness scores were 6.48 (SD = 1.101) and 6.56 (SD = 1.083) for diabetic and non-diabetic groups. Diabetic participants had a mean WOMAC-CRD physical function score of 55.93 (SD = 2.484), compared to 64.02 (SD = 2.542) for non-diabetic participants. The mean total WOMAC score was 68.80 (SD = 2.857) for diabetic participants and 77.06 (SD = 2.933) for non-diabetic participants. Longer diabetes duration correlated negatively with physical function and total WOMAC scores. Discussion The findings suggest that diabetes exacerbates functional impairment in OA patients, particularly affecting physical function and overall disability. Chronic inflammation and the accumulation of advanced glycation end-products may contribute to the observed deterioration in joint function. Conclusion Integrated management strategies addressing both diabetes and OA are essential for optimizing patient care.

OBJECTIVE: Our current study aimed to investigate the determinants of dementia among the oldest old using longitudinal data from a representative sample covering both community-dwelling and institutionalized individuals.
METHODS: Longitudinal representative data were taken from the \"Survey on quality of life and subjective well-being of the very old in North Rhine-Westphalia (NRW80+)\" that surveyed community-dwelling and institutionalized individuals aged 80 years and above (n = 1,296 observations in the analytic sample), living in North Rhine-Westphalia (most populous state of Germany). The established DemTect was used to measure cognitive impairment (i.e., probable dementia). A logistic random effects model was used to examine the determinants of probable dementia.
RESULTS: The mean age was 86.3 years (SD: 4.2 years). Multiple logistic regressions revealed that a higher likelihood of probable dementia was positively associated with lower education (e.g., low education compared to medium education: OR: 3.31 [95% CI: 1.10-9.98]), a smaller network size (OR: 0.87 [95% CI: 0.79-0.96]), lower health literacy (OR: 0.29 [95% CI: 0.14-0.60]), and higher functional impairment (OR: 13.45 [3.86-46.92]), whereas it was not significantly associated with sex, age, marital status, loneliness, and depressive symptoms in the total sample. Regressions stratified by sex were also reported.
CONCLUSIONS: Our study identified factors associated with dementia among the oldest old. This study extends current knowledge by using data from the oldest old; and by presenting findings based on longitudinal, representative data (also including individuals residing in institutionalized settings).
CONCLUSIONS: Efforts to increase, among other things, formal education, network size, and health literacy may be fruitful in postponing dementia, particularly among older women. Developing health literacy programs, for example, may be beneficial to reduce the burden associated with dementia.

OBJECTIVE: Rehabilitation services are recommended by clinical practice guidelines following breast cancer treatment, yet little is known about how utilization may vary by patient-level characteristics which we aimed to study using SEER-Medicare data.
METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database was used to identify non-metastatic breast cancer survivors aged ≥ 66 years diagnosed between 2011 and 2016. Rehabilitation services delivered 0-11 months post-diagnosis were identified via outpatient or physician visit claims. Descriptive statistics and associations between patient characteristics and rehabilitation services were calculated using modified Poisson models estimating relative risk (RR) and corresponding 95% confidence intervals (CIs).
RESULTS: Of 55,539 breast cancer survivors, 33% (n = 18,244) had received any type of rehabilitative services. Survivors were a mean age of 75 years (SD 6.7), 88% White, 86% urban-dwelling, and 21% Medicare/Medicaid dually enrolled. In adjusted models, patients aged > 75 vs. ≤ 75 were 6% (RR 0.94, 95% CI 0.92-0.96) less likely to have received rehabilitative services. Survivors in an area with greater educational attainment vs. less educational attainment, White vs. non-White, or living in a rural vs. urban area were 26% (1.26, CI 1.22-1.30), 6% (1.06, CI 1.02-1.11), and 6% (1.06, CI 1.02-1.10) more likely to have received rehabilitative services, respectively.
CONCLUSIONS: The largest differences in rehabilitation utilization were observed for survivors of differing educational and treatment statuses.
CONCLUSIONS: Further research is needed on barriers, access, and delivery of rehabilitation services, specifically for breast cancer survivors who are older-aged, non-White, or Medicare/Medicaid dual eligible.

UNASSIGNED: Treatment-resistant depression (TRD) is defined as the failure of at least two antidepressants in adequate doses and timing during a major depressive episode. Esketamine intranasal (ESK-IN) has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of TRD in combination with other antidepressants.
UNASSIGNED: To assess the effectiveness and tolerability of a sample of TRD patients who received treatment with ESK-IN as part of the compassionate use program.
UNASSIGNED: A retrospective, observational study was carried out on patients with a diagnosis of TRD enrolled in the early access program of ESK-IN in nine centers. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS) at four time points: baseline, 28, 90, and 180 days of treatment.
UNASSIGNED: The sample included 71 patients (70% women) with a mean baseline MADRS score of 38.27 ± 5.9 and total or partial work disability rates of 85%. ESK-IN treatment was associated with a statistically and clinically significant reduction in the severity of depressive symptoms at all time points assessed. The presence of side effects was common but the majority were mild in severity and resolved after the observation period. Those patients who received psychotherapy in combination with ESK-IN showed a significantly lower MADRS score at 90 and 180 days than those patients who did not undergo psychotherapy.
UNASSIGNED: ESK-IN has proven to be effective and safe in a clinical sample of patients with severe TRD. To optimize clinical outcomes, the pharmacological treatment for TRD should always be integrated into a comprehensive therapeutic plan that encompasses strategies such as psychotherapy, social support, and family interventions.

UNASSIGNED: Objectively measuring Parkinson\'s disease (PD) signs and symptoms over time is critical for the successful development of treatments aimed at halting the disease progression of people with PD.
UNASSIGNED: To create a clinical trial simulation tool that characterizes the natural history of PD progression and enables a data-driven design of randomized controlled studies testing potential disease-modifying treatments (DMT) in early-stage PD.
UNASSIGNED: Data from the Parkinson\'s Progression Markers Initiative (PPMI) were analyzed with nonlinear mixed-effect modeling techniques to characterize the progression of MDS-UPDRS part I (non-motor aspects of experiences of daily living), part II (motor aspects of experiences of daily living), and part III (motor signs). A clinical trial simulation tool was built from these disease models and used to predict probability of success as a function of trial design.
UNASSIGNED: MDS-UPDRS part III progresses approximately 3 times faster than MDS-UPDRS part II and I, with an increase of 3 versus 1 points/year. Higher amounts of symptomatic therapy is associated with slower progression of MDS-UPDRS part II and III. The modeling framework predicts that a DMT effect on MDS-UPDRS part III could precede effect on part II by approximately 2 to 3 years.
UNASSIGNED: Our clinical trial simulation tool predicted that in a two-year randomized controlled trial, MDS-UPDRS part III could be used to evaluate a potential novel DMT, while part II would require longer trials of a minimum duration of 3 to 5 years underscoring the need for innovative trial design approaches including novel patient-centric measures.
To develop effective medicines that can slow down or stop the progression of Parkinson’s disease (PD), it is important to accurately understand how the disease worsens over time. We used data from an observational study, led by the Michael J. Fox Foundation, called the Parkinson’s Progression Markers Initiative (PPMI) to understand the natural progression of  PD. We simulated clinical trials on a computer using different scales to measure the progression of PD. We specifically looked at a physician-reported measure MDS-UPDRS part III, and at a patient-reported measure MDS-UPDRS part II of how PD symptoms worsen over time. To measure the effect of a new medicine slowing down the progression of PD using patient-reported measure MDS-UPDRS part II, we estimate that we may need to conduct a clinical trial of at least 3 to 5 years. On the other hand, to measure an effect using physician-reported measure MDS-UPDRS part III, the duration of the trial could be shorter than 2 years. We were also able to show that worsening recorded by the physician-reported measure MDS-UPDRS part III could be predictive of a later worsening recorded by the patient-reported measure MDS-UPDRS part II. We concluded that MDS-UPDRS part III may be a good endpoint for a clinical trial of a reasonable duration and that MDS-UPDRS part II could be measured in longer studies, for example, open-label extensions.

UNASSIGNED: Prolonged confinement can lead to personal deterioration at various levels. We studied this phenomenon during the nationwide COVID-19 lockdown in a functionally dependent population of the Orcasitas neighborhood of Madrid, Spain, by measuring their ability to perform basic activities of daily living and their mortality rate.
UNASSIGNED: A total of 127 patients were included in the Orcasitas cohort. Of this cohort, 78.7% were female, 21.3% were male, and their mean age was 86 years. All participants had a Barthel index of ≤ 60. Changes from pre- to post-confinement and 3 years afterward were analyzed, and the effect of these changes on survival was assessed (2020-2023).
UNASSIGNED: The post-confinement functional assessment showed significant improvement in independence over pre-confinement for both the Barthel score (t = -5.823; p < 0.001) and the classification level (z = -2.988; p < 0.003). This improvement progressively disappeared in the following 3 years, and 40.9% of the patients in this cohort died during this period. These outcomes were associated with the Barthel index (z = -3.646; p < 0.001) and the level of dependence (hazard ratio 2.227; CI 1.514-3.276). Higher mortality was observed among men (HR 1.745; CI 1.045-2.915) and those with severe dependence (HR 2.169; CI 1.469-3.201). Setting the cutoff point of the Barthel index at 40 provided the best detection of the risk of death associated with dependence.
UNASSIGNED: Home confinement and the risk of death due to the COVID-19 pandemic awakened a form of resilience in the face of adversity among the population of functionally dependent adults. The Barthel index is a good predictor of medium- and long-term mortality and is a useful method for detecting populations at risk in health planning. A cutoff score of 40 is useful for this purpose. To a certain extent, the non-institutionalized dependent population is an invisible population. Future studies should analyze the causes of the high mortality observed.

Traumatic brain injury (TBI) is a significant public health concern characterized by a complex cascade of cellular events. TBI induces adenosine monophosphate-activated protein kinase (AMPK) dysfunction impairs energy balance activates inflammatory cytokines and leads to neuronal damage. AMPK is a key regulator of cellular energy homeostasis during inflammatory responses. Recent research has revealed its key role in modulating the inflammatory process in TBI. Following TBI the activation of AMPK can influence various important pathways and mechanisms including metabolic pathways and inflammatory signaling. Our study investigated the effects of post-TBI loss of AMPK function on functional outcomes inflammasome activation, and inflammatory cytokine production. Male C57BL/6 adult wild-type (WT) and AMPK knockout (AMPK-KO) mice were subjected to a controlled cortical impact (CCI) model of TBI or sham surgery. The mice were tested for behavioral impairment at 24 h post-TBI thereafter, mice were anesthetized, and their brains were quickly removed for histological and biochemical evaluation. In vitro we investigated inflammasome activation in mixed glial cells stimulated with lipopolysaccharides+ Interferon-gamma (LI) (0.1 μg/20 ng/ml LPS/IFNg) for 6 h to induce an inflammatory response. Estimating the nucleotide-binding domain, leucine-rich-containing family pyrin domain containing western blotting ELISA and qRT-PCR performed 3 (NLRP3) inflammasome activation and cytokine production. Our findings suggest that TBI leads to reduced AMPK phosphorylation in WT mice and that the loss of AMPK correlates with worsened behavioral deficits at 24 h post-TBI in AMPK-KO mice as compared to WT mice. Moreover compared with the WT mice AMPK-KO mice exhibit exacerbated NLRP3 inflammasome activation and increased expression of proinflammatory mediators such as IL-1b IL-6 TNF-a iNOS and Cox 2. These results align with the in vitro studies using brain glial cells under inflammatory conditions, demonstrating greater activation of inflammasome components in AMPK-KO mice than in WT mice. Our results highlighted the critical role of AMPK in TBI outcomes. We found that the absence of AMPK worsens behavioral deficits and heightens inflammasome-mediated inflammation thereby exacerbating brain injury after TBI. Restoring AMPK activity after TBI could be a promising therapeutic approach for alleviating TBI-related damage.

BACKGROUND: Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking.
METHODS: Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case-control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed.
RESULTS: Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, V ˙ e, V ˙ O2, V ˙ CO2, V ˙ T, HR, O2pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for V ˙ e/ V ˙ CO2, PetCO2, O2pulse, work, V ˙ O2 and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1.
CONCLUSIONS: Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered.
BACKGROUND: ClinicalTrials.gov, retrospectively registered, ID# NCT04026425, date of registration: 2019-07-17.

BACKGROUND: Functional capacity impairment is a crucial consequence of chronic obstructive pulmonary disease (COPD). Although it can be identified with simple tests, such as the sit-to-stand tests, its prevalence, relation with disease severity, and the characteristics of people presenting this impairment remain unknown.
OBJECTIVE: To explore the functional capacity of people with COPD.
METHODS: A cross-sectional study with people with COPD and age-/sex-matched healthy controls was conducted. Functional capacity was assessed with the 5-repetitions (5-STS) and the 1-minute (1-minSTS) sit-to-stand tests. People with COPD were grouped according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifications. Comparisons between people with COPD and healthy controls, and among GOLD groups were established. Associations between symptoms, muscle strength, quality of life, and measures of functional capacity were explored.
RESULTS: 302 people with COPD [79% male; mean (SD) 68 (10) years old] and 304 healthy controls [75% male; 66 (9) years old] were included. 23% of people with COPD presented impairment in the 5-STS and 33% in the 1-minSTS. People with COPD from all GOLD classifications presented significantly lower functional capacity than healthy controls (5-STS: COPD median [1st quartile; 3rd quartile] 8.4 [6.7; 10.6] versus healthy 7.4 [6.2; 9.3] s; 1-minSTS: COPD 27 [21; 35] vs healthy 35 [29; 43] reps). Correlations with symptoms, muscle strength, and quality of life were mostly weak (5-STS: rs [-0.34; 0.33]; 1-minSTS: rs [-0.47; 0.40]).
CONCLUSIONS: People with COPD have decreased functional capacity independently of their GOLD classifications. The prevalence of functional impairment is 23-33%. Because impaired functional capacity is a treatable trait not accurately reflected by other outcomes, comprehensive assessment and management is needed.

BACKGROUND: Low neighborhood socioeconomic status is associated with adverse health outcomes, but its association with health care costs in older adults is uncertain.
OBJECTIVE: To estimate the association of neighborhood Area Deprivation Index (ADI) with total, inpatient, outpatient, skilled nursing facility (SNF), and home health care (HHC) costs among older community-dwelling Medicare beneficiaries, and determine whether these associations are explained by multimorbidity, phenotypic frailty, or functional impairments.
METHODS: Four prospective cohort studies linked with each other and with Medicare claims.
METHODS: In total, 8165 community-dwelling fee-for-service beneficiaries (mean age 79.2 years, 52.9% female).
METHODS: ADI of participant residence census tract, Hierarchical Conditions Category multimorbidity score, self-reported functional impairments (difficulty performing four activities of daily living), and frailty phenotype. Total, inpatient, outpatient, post-acute SNF, and HHC costs (US 2020 dollars) for 36 months after the index examination.
RESULTS: Mean incremental annualized total health care costs adjusted for age, race/ethnicity, and sex increased with ADI ($3317 [95% CI 1274 to 5360] for the most deprived vs least deprived ADI quintile, and overall p-value for ADI variable 0.009). The incremental cost for the most deprived vs least deprived ADI quintile was increasingly attenuated after separate adjustment for multimorbidity ($2407 [95% CI 416 to 4398], overall ADI p-value 0.066), frailty phenotype ($1962 [95% CI 11 to 3913], overall ADI p-value 0.22), or functional impairments ($1246 [95% CI -706 to 3198], overall ADI p-value 0.29).
CONCLUSIONS: Total health care costs are higher for older community-dwelling Medicare beneficiaries residing in the most socioeconomically deprived areas compared to the least deprived areas. This association was not significant after accounting for the higher prevalence of phenotypic frailty and functional impairments among residents of socioeconomically deprived neighborhoods.