Second Primary Malignancies of the Bones and Joints: More Common than Expected in Osteosarcoma Patients.

BACKGROUND: Osteosarcoma is the most common primary bone tumor in children, adolescents, and young adults. Second primary malignancies (SPMs) are a potential serious long-term event that can occur in osteosarcoma survivors. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results 18 database was queried for all osteosarcoma cases from 2000 through 2015. Standardized incidence ratio (SIR) and absolute excess risk (AER) of SPM per 10,000 persons (AER) relative to representative population-level data were calculated across for various anatomic locations. RESULTS: In total, 3438 patients with osteosarcoma were identified. Of these patients, 79 (2.3%) developed SPMs, with an SIR of 2.84 (95% confidence interval [CI] 2.35 to 3.39, P < 0.0001) and an AER of 44.96. The most common SPMs were tumors of the bones or joints (SIR 73.07, CI, 38.90 to 124.94, P < 0.0001, AER 7.48), tumors of soft tissues including the heart (SIR 15.19, CI, 5.58 to 33.07, P < 0.0001, AER 3.27), and leukemia (SIR 22.28, CI, 15.03 to 31.80, P < 0.0001, AER 16.74). CONCLUSION: The overall incidence of SPMs in osteosarcoma survivors was significantly higher than would otherwise be expected for this population. Considering the occurrence and targeting surveillance for SPM in the osteosarcoma patient population is warranted.

A Qualitative Study of "What Matters" to Older Adults in the Emergency Department.

INTRODUCTION: The "4Ms" model - What Matters, Medication, Mentation, and Mobility - is increasingly gaining attention in age-friendly health systems, yet a feasible approach to identifying what matters to older adults in the emergency department (ED) is lacking. Adapting the "What Matters" questions to the ED setting, we sought to describe the concerns and desired outcomes of both older adult patients seeking ED care and their treating clinicians. METHODS: We conducted 46 dyadic semi-structured interviews of cognitively intact older adults and their treating clinicians. We used the "What Matters" conversation guide to explore patients' 1) concerns and 2) desired outcomes. We then asked analogous questions to each patient's treating clinician regarding the patient's priorities. Interviews were professionally transcribed and coded using an inductive approach of thematic analysis to identify emergent themes. RESULTS: Interviews with older adults lasted a mean of three minutes, with a range of 1-8 minutes. Regarding patients' concerns, five themes emerged from older adults: 1) concern through a family member or outpatient clinician recommendation; 2) no concern, with a high degree of trust in the healthcare system; 3) concerns regarding symptom cause identification; 4) concerns regarding symptom resolution; and 5) concerns regarding preservation of their current status. Regarding desired outcomes, five priority themes emerged among older adults: 1) obtaining a diagnosis; 2) returning to their home environment; 3) reducing or resolving symptoms; 4) maintaining self-care and independence; and 5) gaining reassurance. Responding to what they believed mattered most to older adult patients, ED clinicians believed that older adults were concerned primarily about symptom cause identification and resolution and primarily desired a return to the home environment and symptom reduction. CONCLUSION: This work identifies concerns and desired outcomes of both older adult patients seeking ED care and their treating clinicians as well as the feasibility of incorporating the "What Matters" questions within ED clinical practice.

Physical Activity as a Predictor of Cognitive Decline in an Elderly Essential Tremor Cohort: A Prospective, Longitudinal Study.

Background: Essential tremor (ET), one of the most common neurological diseases, is associated with cognitive impairment. Surprisingly, predictors of cognitive decline in ET remain largely unidentified, as longitudinal studies are rare. In the general population, however, lower physical activity has been linked to cognitive decline. Objectives: To determine whether baseline physical activity level is a predictor of cognitive decline in ET. Methods: One hundred and twenty-seven ET cases (78.1 ± 9.5 years, range = 55-95), enrolled in a prospective, longitudinal study of cognition. At baseline, each completed the Physical Activity Scale for the Elderly (PASE), a validated, self-rated assessment of physical activity. Cases underwent an extensive battery of motor-free neuropsychological testing at baseline, 1.5 years, and 3 years, which incorporated assessments of cognitive subdomains. Generalized estimating equations (GEEs) were used to assess the predictive utility of baseline physical activity for cognitive change. Results: Mean follow-up was 2.9 ± 0.4 years (range = 1.3-3.5). In cross-sectional analyses using baseline data, lower physical activity was associated with lower overall cognitive function as well as lower cognitive scores in numerous cognitive domains (memory, language, executive function, visuospatial function and attention, all p < 0.05). In adjusted GEE models, lower baseline physical activity level significantly predicted overall cognitive decline over time (p=0.047), and declines in the subdomains of memory (p = 0.001) and executive function (p = 0.03). Conclusions: We identified reduced physical activity as a predictor of greater cognitive decline in ET. The identification of risk factors often assists clinicians in determining which patients are at higher risk of cognitive decline over time. Interventional studies, to determine whether increasing physical activity could modify the risk of developing cognitive decline in ET, may be warranted.

Baseline Infection Burden and Cognitive Function in Elders with Essential Tremor.

Background: Patients with essential tremor (ET) have an increased risk of cognitive impairment, yet little is known about the predictors of cognitive decline in these patients. Exposures to infectious agents throughout the lifespan may impact the later development of cognitive impairment. For example, high Infection exposure has been associated with lower cognitive performance in Alzheimer's and Parkinson's disease. However, this predictor has not been examined in ET. Objectives: To determine whether a higher baseline infection burden is associated with worse cognitive performance at baseline and greater cognitive decline over time in an ET cohort. Method/Design: 160 elderly non-demented ET participants (80.0 ± 9.5 years) underwent an extensive cognitive evaluation at three time points. At baseline, participants completed an infection burden questionnaire (t-IBQ) that elicited information on previous exposure to infectious agents and number of episodes per disease. Analysis of covariance and generalized estimated equations (GEEs) were used. Results: Overall, infection burden was not associated baseline cognitive performance. Adjusted GEE models for repeated measures yielded a significant time interaction between moderate infection burden at baseline and better performance in the attention domain over time (p = 0.013). Previous history of rubella was associated with faster rate of decline in visuospatial performance (p = 0.046). Conclusion: The data were mixed. Moderate self-reported infection burden was associated with better attention performance over time. Self-reported history of rubella infection was related to lower visuospatial performance over time in this cohort. Follow-up studies with additional design elements would be of value.

Effect of relative social rank within a social hierarchy on neural activation in response to familiar or unfamiliar social signals.

Competent social functioning of group-living species relies on the ability of individuals to detect and utilize conspecific social cues to guide behavior. Previous studies have identified numerous brain regions involved in processing these external cues, collectively referred to as the Social Decision-Making Network. However, how the brain encodes social information with respect to an individual's social status has not been thoroughly examined. In mice, cues about an individual's identity, including social status, are conveyed through urinary proteins. In this study, we assessed the neural cFos immunoreactivity in dominant and subordinate male mice exposed to familiar and unfamiliar dominant and subordinate male urine. The posteroventral medial amygdala was the only brain region that responded exclusively to dominant compared to subordinate male urine. In all other brain regions, including the VMH, PMv, and vlPAG, activity is modulated by a combination of odor familiarity and the social status of both the urine donor and the subject receiving the cue. We show that dominant subjects exhibit robust differential activity across different types of cues compared to subordinate subjects, suggesting that individuals perceive social cues differently depending on social experience. These data inform further investigation of neurobiological mechanisms underlying social-status related brain differences and behavior.

The spiral axis: A comparison of unaffected first-degree relatives of essential tremor cases vs. controls.

We previously observed that during a spiral drawing task, in essential tremor (ET) cases, the tremor wave forms align along a single predominant axis. This interesting clinical feature can distinguish ET from dystonia cases. We now investigate whether the unaffected relatives of ET cases also express this trait, albeit perhaps in a milder form. To address our aim, we assessed the spiral axis in 237 unaffected first-degree relatives of ET cases (FD-ET), comparing them to 105 controls (Co). A movement disorder neurologist assessed four hand drawn spirals for the presence of a single identifiable tremor orientation axis. A spiral axis score (range = 0-4 [a single axis on 4 spirals]) was assigned to each enrollee. FD-ET had higher spiral axis scores than Co. In a contingency table, the distribution of spiral axis scores differed in the two groups: FD-ET (highest) and Co (lowest) (ordinal chi-square test p = 0.014). Furthermore, when spiral axis scores were examined as a continuous measure, the groups differed (Mann-Whitney test p = 0.03) - with the means being 0.51 (FD-ET) and 0.26 (Co). These data have scientific implications. They (1) show that such axes are more common in relatives of ET cases than controls, and (2) raise the possibility that the spiral axis may be an early subclinical feature of ET.

Prospective Longitudinal Study of Gait and Balance in a Cohort of Elderly Essential Tremor Patients.

Background: Essential tremor (ET) encompasses a variety of features, including tremor, cognitive dysfunction, and gait and balance impairments. Gait and balance impairments in ET are often mild, but they can be severe and are, in some cases, associated with functional sequelae in terms of increased fall risk and reduced balance confidence. Previous research on gait and balance in ET has been limited to cross-sectional comparisons. There have been no longitudinal studies or prospective studies. As such, our understanding of natural history and possible predictors of declines in ET-related gait and balance impairments is incomplete. Objectives: We (1) present natural history data on the change in gait and balance measures over time, (2) provide estimates of annual rate of change in each gait and balance metric, and (3) examine the relationship between baseline clinical predictors and changes in gait and balance over time. Methods: 149 ET participants (mean age 78.7 years), enrolled in a prospective, longitudinal, clinical-pathological study, underwent an extensive evaluation of cognition, tremor, and gait and balance at three distinct intervals performed every 18 months. Gait and balance measures included a combination of performance-based tests (e.g., tandem gait, tandem stance) and self-reported assessments (e.g., number of falls, use of a walking aid). Results: Between the baseline and final assessments, numerous balance and gait measures showed evidence of decline and annual rates of change were quantified for each. We examined the predictive utility of clinical variables at baseline for five gait and balance outcomes, with global cognition and executive function standing out as the most consistent predictors. Conclusions: We present a much-needed look into the course of disease for elderly patients with ET, focusing on changes observed in gait and balance and the predictors of these changes. These results also add another dimension to the relevance of cognitive impairment observed in ET; such impairment can now be viewed as predictive of poorer gait and balance over time in ET. These findings are a useful tool for clinicians, patients, and their families to better understand and plan for changing disease-features over time.

Subtle Cerebellar Features in Relatives of Essential Tremor Cases.

Background: Essential tremor (ET) cases often exhibit a range of mild cerebellar signs. Their unaffected relatives have been shown in prior studies to exhibit subtle (i.e., preclinical) disease features. Objective: To quantify subtle cerebellar signs in unaffected first-degree relatives of ET cases stratified based on their tremor severity. Methods: Two hundred sixty-nine first-degree relatives of ET cases, none of whom reported tremor or a diagnosis of ET, or were diagnosed with ET based on detailed neurological examination, were stratified based on total tremor score (TTS) into two groups (lower TTS vs. higher TTS) and quartiles. Changes in gait, balance, and intention tremor were quantified on neurological examination. Results: Higher TTS performed worse on the tandem stance task (p = 0.011). When stratified into TTS quartiles, higher quartile was associated with worse performance in tandem stance (p = 0.011) and stance with feet together (p = 0.028). Similarly, intention tremor in the arms (p = 0.0002) and legs (p = 0.047) were higher in the groups with more tremor. Discussion: The links between ET and the cerebellum are multiple. These data provide intriguing evidence that subtle cerebellar signs (i.e., changes in balance and intention tremor) are more prevalent among first-degree relatives of ET cases with more tremor (i.e., those who may be themselves on the pathway to developing ET). These data contribute to a better characterization of what may be an early subclinical stage of the disease.

Rate of progression from mild cognitive impairment to dementia in an essential tremor cohort: A prospective, longitudinal study.

BACKGROUND: Essential tremor (ET), among the most common neurological diseases, is associated with cognitive dysfunction. Yet, nearly all knowledge of ET-related cognitive impairment is static and cross-sectional (e.g., prevalence), with virtually no dynamic information (i.e., course and progression, conversion rates, and clinical outcomes). OBJECTIVES: To quantify the rate of progression from mild cognitive impairment (MCI) to dementia in a cohort of elderly ET cases. METHODS: 167 ET cases, enrolled in a prospective, longitudinal, clinical-pathological study, underwent an extensive neuropsychological testing battery at baseline (T1), 1.5 years (T2), and 3 years (T3). Results of these assessments informed clinical diagnoses of normal cognition (ET-NC), MCI (ET-MCI), and dementia (ET-D). RESULTS: At baseline, 26 cases (82.7 ± 7.7 years) were diagnosed with ET-MCI and were available for follow-up at T2. At T2, three of 26 (11.5%) had converted to ET-D. At the start of T2, 23 cases (83.6 ± 7.7 years) were diagnosed with ET-MCI and were available for follow-up at T3. At T3, six of 23 (26.1%) converted to ET-D. The average annual conversion rate from ET-MCI to ET-D was 12.5%. CONCLUSIONS: The study of cognitive impairment in ET is a nascent field, with limited data. We show that the conversion rate from ET-MCI to ET-dementia was 12.5%. Available studies on historical controls have reported conversion rates of 2.6-6.3%. Data such as these systematically fill gaps in knowledge, creating a scientifically-derived knowledge base to guide physicians and patients in clinical settings.