Retrospective studies of inpatients with cancer suggest that a cancer diagnosis confers a high risk of falls. In adults with advanced cancer, we aimed to prospectively document the incidence of ...falls, identify the risk factors, and determine if falls in this population occur predominantly in older patients.
Patients admitted consecutively to community and inpatient palliative care services with metastatic or locoregionally advanced cancer who were mobile without assistance were recruited. Risk-factor assessment was conducted on initial encounter. Patients underwent follow-up via weekly telephone contact for 6 months or until time of fall or death. Relationship between covariates and time to fall was examined using hazard ratios (HRs) derived from univariate and multivariate Cox proportional hazards models.
Of 185 participants (52.4% men; mean age 68 ± standard deviation of 12.6 years), 50.3% fell; 35 (53%) of 66 participants age < 65 years and 58 (48.7%) of 119 age ≥ 65 years fell; 61.3% of falls occurred in the community; 42% resulted in injury. Median time to fall was 96 days (95% CI, 64.66 to 127.34). Primary brain tumor or brain metastasis (HR 2.5; P = .002), number of falls in the preceding 3 months (HR, 1.27; P = .005), severity of depression (HR, 1.12; P = .012), benzodiazepine dose (HR, 1.05; P = .004), and cancer-related pain (HR, 1.96; P = .024) were independently associated with time to fall in multivariate analysis.
Fifty percent of adults with advanced cancer, regardless of age, will experience a fall associated with high risk of physical injury. There is a compelling need to assess the efficacy of assessment and management of modifiable fall risk factors in patients with advanced cancer.
In the healthcare sector, patients can be categorized into clinical risk groups, which are based, in part, on multiple chronic conditions. Population-based measures of clinical risk groups for ...population health planning, however, are not available. Using responses of working-age adults (19-64 years old) from the Behavioral Risk Factor Surveillance System for survey years 2015-2017, a population-based measure of chronic disease severity (CDS) was developed as a proxy for clinical risk groups. Four categories of CDS were developed: low, medium-low, medium-high, and high, based on self-reported diagnoses of multiple chronic conditions, weighted by hospitalization costs. Prevalence estimates of CDS were prepared, by population demographics and state characteristics, and CDS association with perceived health-related quality of life (HRQOL) was evaluated. Age-adjusted CDS varied from 72.9% (95% CI: 72.7-73.1%) for low CDS, to 21.0% (95% CI: 20.8-21.2%), 4.4% (95% CI: 4.3-4.5%) and 1.7% (95% CI: 1.6-1.8%) for medium-low, medium-high, and high CDS, respectively. The prevalence of high CDS was significantly greater (p < 0.05) among older adults, those living below the federal poverty level, and those with disabilities. The adjusted odds of fair/poor perceived HRQOL among adults with medium-low or medium-high/high CDS were 2.39 times (95% CI: 2.30-2.48) or 6.53 times (95% CI: 6.22-6.86) higher, respectively, than adults with low CDS. Elevated odds of fair/poor HRQOL with increasing CDS coincided with less prevalence of high CDS among men, minority race/ethnicities, and adults without insurance, suggesting a link between CDS and risk of mortality. Prevalence of high CDS was significantly higher (p < 0.05) in states with lower population density, lower per capita income, and in states that did not adopt the ACA. These results demonstrate the relevance of a single continuous population-based measure of chronic disease severity for health planning at the state, regional, and national levels.
Objectives
Abnormal beliefs and delusions have been reported in some people with dementia, however, the prevalence of delusions, and their neurocognitive basis has been underexplored. This study ...aimed to examine the presence, severity, content and neural correlates of delusions in a large, well‐characterised cohort of dementia patients using a transdiagnostic, cross‐sectional approach.
Methods
Four‐hundred and eighty‐seven people with dementia were recruited: 102 Alzheimer's disease, 136 behavioural‐variant frontotemporal dementia, 154 primary progressive aphasia, 29 motor neurone disease, 46 corticobasal syndrome, 20 progressive supranuclear palsy. All patients underwent neuropsychological assessment and brain magnetic resonance imaging, and the Neuropsychiatric Inventory was conducted with an informant, by an experienced clinician.
Results
In our cohort, 48/487 patients (10.8%) had delusions. A diagnosis of behavioural‐variant frontotemporal dementia (18.4%) and Alzheimer's disease (11.8%) were associated with increased risk of delusions. A positive gene mutation was observed in 11/27 people with delusions. Individuals with frequent delusions performed worse on the Addenbrooke's Cognitive Examination (p = 0.035), particularly on the orientation/attention (p = 0.022) and memory (p = 0.013) subtests. Voxel‐based morphometry analyses found that increased delusional psychopathology was associated with reduced integrity of the right middle frontal gyrus, right planum temporale and left anterior temporal pole.
Conclusion
Our results demonstrate that delusions are relatively common in dementia and uncover a unique cognitive and neural profile associated with the manifestation of delusions. Clinically, delusions may lead to delayed or misdiagnosis. Our results shed light on how to identify individuals at risk of neuropsychiatric features of dementia, a crucial first step to enable targeted symptom management.
Key points
Delusions showed high prevalence, occurring in 10% of all dementia syndromes.
Behavioural‐variant frontotemporal dementia had an increased risk of delusions.
Most patients experience polythematic delusions, often and of ranging severity, with delusions being related to more severe attention, orientation and memory deficits.
Delusions were more common in people with strong family history/genetic mutations.
Objective:
Frontotemporal lobar degeneration (FTLD) is the most common cause of early‐onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) ...comprise trans‐activating response element (TAR) DNA binding protein (TDP‐43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD‐MND pedigree with no mutations in known dementia genes.
Methods:
A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation.
Results:
We identified a nonpolymorphic mutation (c.672*51G>T) in the 3′‐untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD‐MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4‐fold, corresponding with a significant 1.5‐fold to 2‐fold change in the SIGMAR1 transcript or Sigma‐1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP‐43 or FUS but not Sigma‐1. Overexpression of SIGMAR1 shunted TDP‐43 and FUS from the nucleus to the cytoplasm by 2.3‐fold and 5.2‐fold, respectively. Treatment of cells with Sigma‐1 ligands significantly altered translocation of TDP‐43 by up to 2‐fold.
Interpretation:
SIGMAR1 is a causative gene for familial FTLD‐MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma‐1 drugs as potential treatments for the TDP‐43/FUS proteinopathies. Ann Neurol 2010;68:639–649
Abstract The Palliative Prognostic Index (PPI) was devised and validated in patients with cancer in a hospice inpatient unit in Japan. The aim of this study was to test its accuracy in a different ...population, in a range of care settings and in those receiving palliative chemotherapy and radiotherapy. The information required to calculate the PPI was recorded for patients referred to a hospital-based consultancy palliative care service, a hospice home care service, and a hospice inpatient unit. One hundred ninety-four patients were included in the study, 43% of whom were receiving chemotherapy /or radiotherapy or both. Use of the PPI split patients into three subgroups based on PPI score. Group 1 corresponded to patients with PPI ≤ 4, median survival 68 days (95% confidence interval CI 52, 115 days). Group 2 corresponded to those with PPI > 4 and ≤6, median survival 21 days (95% CI 13, 33), and Group 3 corresponded to patients with PPI > 6, median survival five days (95% CI 3, 11). Using the PPI, survival of less than three weeks was predicted with a positive predictive value of 86% and negative predictive value of 76%. Survival of less than six weeks was predicted with a positive predictive value of 91% and negative predictive value of 64%. The PPI is quick and easy to use, and can be applied to patients with cancer, in hospital, in hospice, and at home. It may be used by general physicians to achieve prognostic accuracy comparable, if not superior, to that of physicians experienced in oncology and palliative care, and by oncology and palliative care specialists, to improve the accuracy of their survival predictions.
Background
Identified genetic mutations account for ∼50% of familial frontotemporal dementia (FTD) and ∼70% of familial amyotrophic lateral sclerosis (ALS) cases, however, for the remainder of ...patients the origin of the disease is uncertain. Post‐mortem, affected neurons from 97% of ALS and ∼50% of FTD patients show cytoplasmic mislocalisation of the typically nuclear proteins, TDP‐43 and/or FUS. We exploited this predominant neuropathological feature to develop a high‐throughput, automated method for the quantification of cytoplasmic TDP‐43 and FUS in human cell lines.
Method
Utilising fluorescently tagged cDNA constructs to identify cells of interest, fluorescence intensity of TDP‐43 or FUS in the nucleus and cytoplasm of HEK293 and SH‐SY5Y cells was measured from confocal microscope images using the freely available analysis software, CellProfiler. The assay was validated using known ALS‐causative mutations in the genes encoding TDP‐43 (TARDBP) and FUS, and pharmacological interventions known to cause TDP‐43 and FUS mislocalisation. The ability of the assay to detect effects of a secondary gene on endogenous TDP‐43 was tested using CYLD wild‐type and mutant constructs.
Results
Expression of known TARDBP and FUS mutations showed significantly higher cytoplasmic to nuclear ratios when compared to wild‐type protein. Treatment with apoptosis inducers MG132 and staurosporine induced a similar effect. Lastly, we recapitulated the effect of the CYLD FTD‐ALS mutation p.M719V on TDP‐43 mislocalisation, as observed previously by manual counting of primary mouse neurons Dobson‐Stone et al 2020, Brain 143:783‐799.
Conclusion
The current study validates our methodology as a novel in vitro technique for the quantification of TDP‐43 or FUS mislocalisation that can be used to rapidly and systematically assess the pathogenicity of predicted FTD/ALS gene variants. This methodology can be employed to aid genetic diagnosis of patients carrying novel variants in known FTD/ALS genes, and in the prioritisation of novel candidate genes for further functional analysis.
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