Medication management error types: Associations with mild cognitive impairment subtype.

Objective: Medication management errors are suspected to be prevalent among older adults with mild cognitive impairment (MCI). This study examined types of simulated medication-taking errors in cognitively normal older adults (CN; n = 131), single domain amnestic MCI (sdMCI, n = 91), and multi-domain MCI (mdMCI, n = 44). Errors were measured using the medication management ability assessment (MMAA). Methods: 266 participants seen for neuropsychological evaluation (94.4% White, 57.9% female, average age = 72, average education = 14 years) completed the MMAA (version 4.1), a performance-based task of medication management. Group differences in MMAA total scores, accuracy, and error types were evaluated using Kruskall-Wallis H tests. This study was the first to explore a newly operationalized error, perseverations, caused by taking a specific dose ≥2 times during the simulation. Results: CN and sdMCI groups had higher MMAA total scores than individuals with mdMCI, indicating better overall performance. The mdMCI group made a higher number of omission errors (missed pills) than other groups, but no differences were found for commission errors (extra pills). The sdMCI group made more perseverative errors compared to the CN group. Conclusions: Individuals with mdMCI made more simulated medication management errors than CN and sdMCI groups, indicating that they may be most vulnerable to difficulties in medication management. In contrast, sdMCI individuals were more likely to make perseverative errors, which may reflect a tendency towards overcompensation of memory loss. Future studies should assess whether MMAA performance is associated with patterns of real-world medication-taking in more diverse samples of older adults.

Lower odds of successful community discharge after medical hospitalization for Veterans with schizophrenia: A retrospective cohort study of national data.

Medical comorbidity, particularly cardiovascular diseases, contributes to high rates of hospital admission and early mortality in people with schizophrenia. The 30 days following hospital discharge represents a critical period for mitigating adverse outcomes. This study examined the odds of successful community discharge among Veterans with schizophrenia compared to those with major affective disorders and those without serious mental illness (SMI) after a heart failure hospital admission. Data for Veterans hospitalized for heart failure were obtained from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services between 2011 and 2019. Psychiatric diagnoses and medical comorbidities were assessed in the year prior to hospitalization. Successful community discharge was defined as remaining in the community without hospital readmission, death, or hospice for 30 days after hospital discharge. Logistic regression analyses adjusting for relevant factors were used to examine whether individuals with a schizophrenia diagnosis showed lower odds of successful community discharge versus both comparison groups. Out of 309,750 total Veterans in the sample, 7377 (2.4%) had schizophrenia or schizoaffective disorder and 32,472 (10.5%) had major affective disorders (bipolar disorder or recurrent major depressive disorder). Results from adjusted logistic regression analyses demonstrated significantly lower odds of successful community discharge for Veterans with schizophrenia compared to the non-SMI (Odds Ratio [OR]: 0.63; 95% Confidence Interval [CI]: 0.60, 0.66) and major affective disorders (OR: 0.65, 95%; CI: 0.62, 0.69) groups. Intervention efforts should target the transition from hospital to home in the subgroup of Veterans with schizophrenia.

Serious mental illness is associated with elevated risk of hospital readmission in veterans with heart failure.

OBJECTIVE: Adults with serious mental illness (SMI) have high rates of cardiovascular disease, particularly heart failure, which contribute to premature mortality. The aims were to examine 90- and 365-day all-cause medical or surgical hospital readmission in Veterans with SMI discharged from a heart failure hospitalization. The exploratory aim was to evaluate 180-day post-discharge engagement in cardiac rehabilitation, an effective intervention for heart failure. METHODS: This study used administrative data from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services between 2011 and 2019. SMI status and medical comorbidity were assessed in the year prior to hospitalization. Cox proportional hazards models (competing risk of death) were used to evaluate the relationship between SMI status and outcomes. Models were adjusted for VHA hospital site, demographics, and medical characteristics. RESULTS: The sample comprised 189,767 Veterans of which 23,671 (12.5%) had SMI. Compared to those without SMI, Veterans with SMI had significantly higher readmission rates at 90 (16.1% vs. 13.9%) and 365 (42.6% vs. 37.1%) days. After adjustment, risk of readmission remained significant (90 days: HR: 1.07, 95% CI: 1.03, 1.11; 365 days: HR: 1.10, 95% CI: 1.07, 1.12). SMI status was not significantly associated with 180-day cardiac rehabilitation engagement (HR: 0.98, 95% CI: 0.91, 1.07). CONCLUSIONS: Veterans with SMI and heart failure have higher 90- and 365-day hospital readmission rates even after adjustment. There were no differences in cardiac rehabilitation engagement based on SMI status. Future work should consider a broader range of post-discharge interventions to understand contributors to readmission.

Cognitive dispersion is related to subtle objective daily functioning changes in older adults with and without cognitive impairment.

Early detection of cognitive and functional decline is difficult given that current tools are insensitive to subtle changes. The present study evaluated whether cognitive dispersion on neuropsychological testing improved prediction of objectively assessed daily functioning using unobtrusive monitoring technologies. Hierarchical linear regression was used to evaluate whether cognitive dispersion added incremental information beyond mean neuropsychological performance in the prediction of objectively assessed IADLs (i.e., computer use, pillbox use, driving) in a sample of 104 community-dwelling older adults without dementia (Mage = 74.59, 38.5% Female, 90.4% White). Adjusting for age, sex, education, and mean global cognitive performance, cognitive dispersion improved prediction of average daily computer use duration (R2 Δ = 0.100, F Change, p = 0.005), computer use duration variability (R2 Δ = 0.089, F Change p = 0.009), and average daily duration of nighttime driving (R2 Δ = 0.072, F Change p = 0.013). These results suggest cognitive dispersion may improve prediction of objectively assessed functional changes in older adults without dementia.

Remote and in-clinic digital cognitive screening tools outperform the MoCA to distinguish cerebral amyloid status among cognitively healthy older adults.

INTRODUCTION: We evaluated the accuracy of remote and in-person digital tests to distinguish between older adults with and without AD pathological change and used the Montreal Cognitive Assessment (MoCA) as a comparison test. METHODS: Participants were 69 cognitively normal older adults with known beta-amyloid (Aß) PET status. Participants completed smartphone-based assessments 3×/day for 8 days, followed by TabCAT tasks, DCTclock™, and MoCA at an in-person study visit. We calculated the area under the curve (AUC) to compare task accuracies to distinguish Aß status. RESULTS: Average performance on the episodic memory (Prices) smartphone task showed the highest accuracy (AUC = 0.77) to distinguish Aß status. On in-person measures, accuracy to distinguish Aß status was greatest for the TabCAT Favorites task (AUC = 0.76), relative to the DCTclockTM (AUC = 0.73) and MoCA (AUC = 0.74). DISCUSSION: Although further validation is needed, our results suggest that several digital assessments may be suitable for more widespread cognitive screening application.

Comparing Lookback Periods to Ascertain Alzheimer's Disease and Related Dementias.

Claims data are a valuable resource for studying Alzheimer's disease and related dementias (ADRD). Alzheimer's disease and related dementias is often identified using a list of claims codes and a fixed lookback period of 3 years of data. However, a 1-year lookback or an approach using all-available lookback data could be beneficial based on different research questions. Thus, the purpose of this study was to compare 1-year and all-available lookback approaches to ascertaining ADRD compared to the standard 3-year approach. Using a cohort of Veterans hospitalized for heart failure (N = 373, 897), our results suggested high agreement (93% or greater) between the lookback periods. The 1-year lookback period had lower sensitivity (60%) and underestimated the prevalence of ADRD. These results suggest that 1-year and all-available lookback periods are viable approaches when using claims data.

Oncolytic BHV-1 Is Sufficient to Induce Immunogenic Cell Death and Synergizes with Low-Dose Chemotherapy to Dampen Immunosuppressive T Regulatory Cells.

Immunogenic cell death (ICD) can switch immunologically "cold" tumors "hot", making them sensitive to immune checkpoint inhibitor (ICI) therapy. Many therapeutic platforms combine multiple modalities such as oncolytic viruses (OVs) and low-dose chemotherapy to induce ICD and improve prognostic outcomes. We previously detailed many unique properties of oncolytic bovine herpesvirus type 1 (oBHV) that suggest widespread clinical utility. Here, we show for the first time, the ability of oBHV monotherapy to induce bona fide ICD and tumor-specific activation of circulating CD8+ T cells in a syngeneic murine model of melanoma. The addition of low-dose mitomycin C (MMC) was necessary to fully synergize with ICI through early recruitment of CD8+ T cells and reduced infiltration of highly suppressive PD-1+ Tregs. Cytokine and gene expression analyses within treated tumors suggest that the addition of MMC to oBHV therapy shifts the immune response from predominantly anti-viral, as evidenced by a high level of interferon-stimulated genes, to one that stimulates myeloid cells, antigen presentation and adaptive processes. Collectively, these data provide mechanistic insights into how oBHV-mediated therapy modalities overcome immune suppressive tumor microenvironments to enable the efficacy of ICI therapy.

Longitudinal Predictors of Informant-Rated Everyday Function in Mild Cognitive Impairment.

OBJECTIVE: To examine predictors of informant-reported everyday functioning in mild cognitive impairment (MCI) and relations between everyday function and conversion to dementia. METHODS: Informants of participants (n = 2614) with mild cognitive impairment (MCI) were administered the Functional Activities Questionnaire (FAQ). Changes in dimensions of functional ability as determined by an exploratory factor analysis (EFA) were examined over 3 years and participant predictors of change were examined using multilevel modeling (MLM). RESULTS: The FAQ consisted of 3 factors, multistep, finance, and memory/orientation daily tasks. Impairment in memory/orientation tasks was significantly higher than impairment in multistep tasks. Worse functioning was associated with greater depression, worse memory, worse speed/EF, higher years of education and identifying as White. There was variability in some of these associations with different FAQ factors. Impairments in financial and memory/orientation daily tasks predicted follow-up conversion to dementia. CONCLUSIONS: Depression, speed/EF, and memory are consistently associated with domains of everyday functioning. Race, education, and age may be more variability associated with everyday functioning. Specific attention should be paid to subtle declines in the financial and memory/orientation domains as they may uniquely predict future dementia development. Depression may be a modifiable risk factor associated with functional impairment over time.

Mentorship in clinical neuropsychology: Survey of current practices, cultural responsiveness, and untapped potential.

INTRODUCTION: Neuropsychology trainees have identified mentorship as an important factor in their training. Limited past work has been conducted on mentorship within neuropsychology, and there is a need to better understand the experiences and perspectives of neuropsychology mentors. METHOD: Self-identified mentors in clinical neuropsychology completed a survey about their mentorship practices, including culturally responsive mentorship, as well as perceived barriers and challenges to providing effective mentorship. Themes were derived using qualitative analyses for free response questions, and descriptive statistics were calculated for quantitative variables. RESULTS: Mentors identified assessment, professionalism, and ethics as top priorities in mentorship, which may reflect the overlap within neuropsychology of assessment supervision and mentoring. Reported best practices included being self-aware and engaging in a personalized approach to mentorship relationships that varies depending upon the needs of the mentee. A majority reported that their training program is not diverse and they themselves do not mentor trainees from diverse backgrounds which provides a clear area for targeted efforts to recruit and retain diversity in the discipline. Mentors described practices related to discussing diversity-related differences with their trainees including self-disclosure, creating a safe space for conversations, and tailoring discussions to the individual trainee. They reported an interest in more training on how to engage in culturally competent mentorship. Two barriers to providing effective mentorship identified most by mentors were time constraints and a lack of training. CONCLUSIONS: These results highlight a variety of perspectives and approaches to mentorship, which may be beneficial for mentors to consider as they reflect on their mentorship practices and/or for trainees as part of their professional development toward becoming future mentors themselves. These results also highlight the need for a greater emphasis on mentorship training within neuropsychology, including training in culturally responsive mentorship practices.

IFNAR blockade synergizes with oncolytic VSV to prevent virus-mediated PD-L1 expression and promote antitumor T cell activity.

Oncolytic virotherapies have shown excellent promise in a variety of cancers by promoting antitumor immunity. However, the effects of oncolytic virus-mediated type I interferon (IFN-I) production on antitumor immunity remain unclear. Recent reports have highlighted immunosuppressive functions of IFN-I in the context of checkpoint inhibitor and cell-based therapies. In this study, we demonstrate that oncolytic virus-induced IFN-I promotes the expression of PD-L1 in tumor cells and leukocytes in a IFN receptor (IFNAR)-dependent manner. Inhibition of IFN-I signaling using a monoclonal IFNAR antibody decreased IFN-I-induced PD-L1 expression and promoted tumor-specific T cell effector responses when combined with oncolytic virotherapy. Furthermore, IFNAR blockade improved therapeutic response to oncolytic virotherapy in a manner comparable with PD-L1 blockade. Our study highlights a critical immunosuppressive role of IFN-I on antitumor immunity and uses a combination strategy that improves the response to oncolytic virotherapy.

A Combination of Chemotherapy and Oncolytic Virotherapy Sensitizes Colorectal Adenocarcinoma to Immune Checkpoint Inhibitors in a cDC1-Dependent Manner.

Immune checkpoint therapy has shown great promise in the treatment of cancers with a high mutational burden, such as mismatch repair-deficient colorectal carcinoma (dMMR CRC). However, many patients fail to respond to immune checkpoint therapy. Using a mouse model of dMMR CRC, we demonstrated that tumors can be further sensitized to immune checkpoint therapy by using a combination of low-dose chemotherapy and oncolytic HSV-1. This combination induced the infiltration of CD8+ and CD4+ T cells into the tumor and the upregulation of gene signatures associated with the chemoattraction of myeloid cell subsets. When combined with immune checkpoint therapy, the combination promoted the infiltration of activated type 1 conventional dendritic cells (cDC1s) into the tumor. Furthermore, we found this combination strategy to be dependent on cDC1s, and its therapeutic efficacy to be abrogated in cDC1-deficient Batf3-/- mice. Thus, we demonstrated that the adjuvanticity of dMMR CRCs can be improved by combining low-dose chemotherapy and oncolytic HSV-1 in a cDC1-dependent manner.

Beyond depression: examining the role of anxiety and anxiety sensitivity on subjective cognition and functioning in older adults.

OBJECTIVES: Subjective cognitive difficulties in the elderly may serve as potential risk-factors for future, objective decline and conversion to neurodegenerative disorders (e.g., mild cognitive impairment [MCI] and dementia). Though these subjective declines have been associated with depression, and to a lesser extent, anxiety, it is unknown if related constructs (e.g. anxiety sensitivity) and specific kinds of worries (e.g. worry about developing dementia, health anxiety) are related to subjective declines. The current study sought to examine if cognitive concerns related to anxiety sensitivity, dementia worry, and health anxiety added incremental validity beyond general symptoms of anxiety and depression in predicting subjective cognition and functioning in a sample of older adults. METHODS: Participants were 429 older adults who were at least 60 years old. Participants completed questionnaires on subjective cognition, subjective everyday function, anxiety, depression, anxiety sensitivity, dementia worry, and health anxiety via Qualtrics Panels. Hierarchical multiple regressions were conducted. RESULTS: Our variables of interest (anxiety sensitivity, dementia worry, and health anxiety) added significant variance in predicting subjective cognition and everyday function. Specifically, anxiety sensitivity was related to subjective cognition and functioning, while dementia worry and health anxiety were variably associated. CONCLUSION: Our results suggest that constructs related to anxiety and worry have a significant relationship with subjective cognition and function in older adults beyond general symptoms of depression and anxiety. Future work should examine if interventions and education may help to decrease anxiety sensitivity and worry about dementia respectively in older adults, which may in tern protect against future subjective declines.

Representation of U.S. Black Americans in neuropsychology research: How well do our reporting practices show that Black lives matter?

OBJECTIVE: Black American individuals comprise about 13% of the population in the United States (U.S.). It is estimated by 2045, approximately 50% of U.S. residents will belong to an ethnic minority group underscoring the importance of the provision of culturally competent services. The present study provides a critical/systematic review of the literature to examine the representation of Black Americans in recent neuropsychological research in U.S. neuropsychology journals. We examined the representation of U.S. Black American individuals across journals, year of study, and by study sample. METHOD: We evaluated 1,151 journal articles published in 4 neuropsychology journals published in 2011, 2014, 2017 and 2019. Articles were coded for reporting of age, sex/gender, years of education, ethnicity/race, and if race was a focus of the study. We also recorded sample size and type of sample. RESULTS: Out of the 397 articles meeting inclusion criteria, 37.5% did not report ethnic or racial demographic information. Additionally, 96% of the articles were not racially/ethnically focused. Black participants comprised 10.7% of participants in articles that reported race/ethnicity. The proportion of Black participants increased by 3.7% between 2011 and 2019. CONCLUSION: Our results demonstrate the underrepresentation of U.S. Black Americans in neuropsychological research over the targeted years. This highlights our shortcomings as a field in demonstrating the importance of including Black Americans in research.

Multimethod assessment of driving in older adults using a novel driving simulator.

Driving simulators may be an effective means of assessing driving performance, however many are cost-prohibitive. The present pilot study examined whether a novel, cost-effective driving simulator (Assetto Corsa (AC)) may be useful in the evaluation of older adults' driving performance, and explore associations among various driving safety indicators. A community sample of older adults completed a battery of cognitive measures, several self-reported driving measures, and a novel driving simulator task (AC). Simple attention, executive functioning, and processing speed were associated with simulator performance variables. Lower self-rated driving safety was associated with slower simulated driving. Additionally, several cognitive domains were associated with perceptions about driving-related safety and driving-related legal repercussions (e.g., traffic tickets). Findings suggested that associations between cognitive tests with AC were less robust than those found in other simulator studies. Novel associations between cognitive performance and self-reported driving were identified; however, given the small sample size of this study, such associations should be explored further.

Response to FEC Chemotherapy and Oncolytic HSV-1 Is Associated with Macrophage Polarization and Increased Expression of S100A8/A9 in Triple Negative Breast Cancer.

The era of immunotherapy has seen an insurgence of novel therapies driving oncologic research and the clinical management of the disease. We have previously reported that a combination of chemotherapy (FEC) and oncolytic virotherapy (oHSV-1) can be used to sensitize otherwise non-responsive tumors to immune checkpoint blockade and that tumor-infiltrating B cells are required for the efficacy of our therapeutic regimen in a murine model of triple-negative breast cancer. In the studies herein, we have performed gene expression profiling using microarray analyses and have investigated the differential gene expression between tumors treated with FEC + oHSV-1 versus untreated tumors. In this work, we uncovered a therapeutically driven switch of the myeloid phenotype and a gene signature driving increased tumor cell killing.

Immune checkpoint blockade in triple negative breast cancer influenced by B cells through myeloid-derived suppressor cells.

Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. Clinical trials for TNBC employing immune checkpoint blockade in combination with chemotherapy show modest prognostic benefit, but the percentage of patients that respond to treatment is low, and patients often succumb to relapsed disease. Here, we show that a combination immunotherapy platform utilizing low dose chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) increases tumor-infiltrating lymphocytes, in otherwise immune-bare tumors, allowing 60% of mice to achieve durable tumor regression when treated with immune checkpoint blockade. Whole-tumor RNA sequencing of mice treated with FEC + oHSV-1 shows an upregulation of B cell receptor signaling pathways and depletion of B cells prior to the start of treatment in mice results in complete loss of therapeutic efficacy and expansion of myeloid-derived suppressor cells. Additionally, RNA sequencing data shows that FEC + oHSV-1 suppresses genes associated with myeloid-derived suppressor cells, a key population of cells that drive immune escape and mediate therapeutic resistance. These findings highlight the importance of tumor-infiltrating B cells as drivers of antitumor immunity and their potential role in the regulation of myeloid-derived suppressor cells.

Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low, and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabeled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.

Disaster stressors and psychological well-being in older adults after a flood.

We examined the inoculation and stress sensitization explanations concerning mental health outcomes in 223 predominately middle-aged and older adults after a flood (M age = 49.6 years, SD = 17.7 years, range: 18-88 years). In multiple linear regression models, having flood damage was associated with higher levels of posttraumatic stress disorder (PTSD) and depressive symptoms, while social support was associated with fewer symptoms. Greater lifetime trauma and flood-related stress were associated with more symptoms of depression and PTSD, respectively. Older age was associated with more religious coping and fewer depressive and worry symptoms. Future directions for research on postdisaster vulnerabilities and resilience are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Neuroimaging, Behavioral, and Gait Correlates of Fall Profile in Older Adults.

Prior research has suggested that measurements of brain functioning and performance on dual tasks (tasks which require simultaneous performance) are promising candidate predictors of fall risk among older adults. However, no prior study has investigated whether brain function measurements during dual task performance could improve prediction of fall risks and whether the type of subtasks used in the dual task paradigm affects the strength of the association between fall characteristics and dual task performance. In this study, 31 cognitively normal, community-dwelling older adults provided a self-reported fall profile (number of falls and fear of falling), completed a gait dual task (spell a word backward while walking on a GaitRite mat), and completed a supine dual task (rhythmic finger tapping with one hand while completing the AX continuous performance task (AX-CPT) with the other hand) during functional magnetic resonance imaging (fMRI). Gait performance, AX-CPT reaction time and accuracy, finger tapping cadence, and brain functioning in finger-tapping-related and AX-CPT-related brain regions all showed declines in the dual task condition compared to the single task condition. Dual-task gait, AX-CPT and finger tapping performance, and brain functioning were all independent predictors of fall profile. No particular measurement domain stood out as being the most strongly associated measure with fall variables. Fall characteristics are determined by multiple factors; brain functioning, motor task, and cognitive task performance in challenging dual-task conditions all contribute to the risk of falling.