Prioritising Key Concepts for informed health choices in cancer: An evidence-based online educational programme.

Objective: The overabundance of health misinformation has undermined people's capacity to make evidence-based, informed choices about their health. Using the Informed Health Choices (IHC) Key Concepts (KCs), we are developing a two-stage education programme, Informed Health Choices-Cancer (IHC-C), to provide those impacted by cancer with the knowledge and skills necessary to think critically about the reliability of health information and claims and make well-informed choices. Stage 1 seeks to prioritise the most relevant Key Concepts. Methods: A project group and a patient and carer participation group completed a two-round prioritisation process. The process involved disseminating pre-reading materials, training sessions, and a structured judgement form to evaluate concepts for inclusion. Data from each round were analysed to reach a consensus on the concepts to include. Results: Fourteen participants were recruited and completed the first-round prioritisation. Fifteen participants undertook the second-round prioritisation. Nine Key Concepts were selected for the programme across five training sessions and two consensus meetings. Conclusion: The prioritised concepts identified represent the most pertinent aspects of cancer-related information for those impacted by the disease. By incorporating these concepts into educational materials and communication strategies, healthcare providers and organisations can potentially help cancer patients, survivors, and their loved ones to recognise and combat cancer-related misinformation more effectively. Innovation: This study introduces a participatory prioritisation process, which integrates the expertise of healthcare professionals with the insights of patients and carers, thereby enhancing the programme's relevance and applicability.

In silico analysis of overall survival with YBX1 in male and female solid tumours.

The Y-box binding protein-1 (YBX1) gene codes for a multifunctional oncoprotein that is increasingly being linked to the regulations of many aspects of cancer cell biology. Disparities in treatment outcomes between male and female cancer patients are increasingly reported. This study aimed to examine the relationship between YBX1 expression and overall survival in male and female patients with solid tumours. Overall survival and YBX1 expression data for cohorts of male and female cancer patients obtained from freely available databases were analysed with a cox proportional hazard model with covariates of biological sex and YBX1 expression. Kaplan-Meier curves and Violin plots were constructed for segregated male and female cohorts. High YBX1 expression was significantly associated with poor survival in 2 female-only and 4 mixed-sex cancer sites. In female lung cancer patients, better survival and lower YBX1 expression were identified. The clinical importance of YBX1 expression in cancer ought to be evaluated in a sex-specific manner, especially in lung cancer.

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

Is biomedical research self-correcting? Modelling insights on the persistence of spurious science.

The reality that volumes of published biomedical research are not reproducible is an increasingly recognized problem. Spurious results reduce trustworthiness of reported science, increasing research waste. While science should be self-correcting from a philosophical perspective, that in insolation yields no information on efforts required to nullify suspect findings or factors shaping how quickly science may be corrected. There is also a paucity of information on how perverse incentives in the publishing ecosystem favouring novel positive findings over null results shape the ability of published science to self-correct. Knowledge of factors shaping self-correction of science remain obscure, limiting our ability to mitigate harms. This modelling study introduces a simple model to capture dynamics of the publication ecosystem, exploring factors influencing research waste, trustworthiness, corrective effort and time to correction. Results from this work indicate that research waste and corrective effort are highly dependent on field-specific false positive rates and time delays to corrective results to spurious findings are propagated. The model also suggests conditions under which biomedical science is self-correcting and those under which publication of correctives alone cannot stem propagation of untrustworthy results. Finally, this work models a variety of potential mitigation strategies, including researcher- and publisher-driven interventions.

Impact of human papillomavirus age-related prevalence and vaccination levels on interpretation of cervical screening modalities: a modelling study.

OBJECTIVE: Cervical screening is a life-saving intervention, which reduces the incidence of and mortality from cervical cancer in the population. Human papillomavirus (HPV) based screening modalities hold unique promise in improving screening accuracy. HPV prevalence varies markedly by age, as does resultant cervical intraepithelial neoplasia (CIN), with higher rates recorded in younger women. With the advent of effective vaccination for HPV drastically reducing prevalence of both HPV and CIN, it is critical to model how the accuracy of different screening approaches varies with age cohort and vaccination status. This work establishes a model for the age-specific prevalence of HPV factoring in vaccine coverage and predicts how the accuracy of common screening modalities is affected by age profile and vaccine uptake. DESIGN: Modelling study of HPV infection rates by age, ascertained from European cohorts prior to the introduction of vaccination. Reductions in HPV due to vaccination were estimated from the bounds predicted from multiple modelling studies, yielding a model for age-varying HPV and CIN grades 2 and above (CIN2+) prevalence. SETTING: Performance of both conventional liquid-based cytology (LBC) screening and HPV screening with LBC reflex (HPV reflex) was estimated under different simulated age cohorts and vaccination levels. PARTICIPANTS: Simulated populations of varying age and vaccination status. RESULTS: HPV-reflex modalities consistently result in much lower incidence of false positives than LBC testing, with an accuracy that improves even as HPV and CIN2+ rates decline. CONCLUSIONS: HPV-reflex tests outperform LBC tests across all age profiles, resulting in greater test accuracy. This improvement is especially pronounced as HPV infection rates fall and suggests HPV-reflex modalities are robust to future changes in the epidemiology of HPV.

Region of Attainable Redaction, an extension of Ellipse of Insignificance analysis for gauging impacts of data redaction in dichotomous outcome trials.

In biomedical science, it is a reality that many published results do not withstand deeper investigation, and there is growing concern over a replicability crisis in science. Recently, Ellipse of Insignificance (EOI) analysis was introduced as a tool to allow researchers to gauge the robustness of reported results in dichotomous outcome design trials, giving precise deterministic values for the degree of miscoding between events and non-events tolerable simultaneously in both control and experimental arms (Grimes, 2022). While this is useful for situations where potential miscoding might transpire, it does not account for situations where apparently significant findings might result from accidental or deliberate data redaction in either the control or experimental arms of an experiment, or from missing data or systematic redaction. To address these scenarios, we introduce Region of Attainable Redaction (ROAR), a tool that extends EOI analysis to account for situations of potential data redaction. This produces a bounded cubic curve rather than an ellipse, and we outline how this can be used to identify potential redaction through an approach analogous to EOI. Applications are illustrated, and source code, including a web-based implementation that performs EOI and ROAR analysis in tandem for dichotomous outcome trials is provided.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases.

Type 2 diabetes mellitus (T2DM) and hypertension are risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, PVS in the white matter (wmPVS) or basal ganglia (bgPVS), and diffusion metrics in white matter. Patients with T2DM had greater wmPVS volume and there were greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found indirect effects of T2DM on volumes of other SVD and diffusion markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, and progression of deep lacunes over 1 year, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal mechanisms that mediate the impact of T2DM on cerebral small vessels.

White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases.

BACKGROUND: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases. METHODS: Five hundred thirteen participants with one of these conditions, i.e. Alzheimer's Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson's Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory - Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss. RESULTS: Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson's disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. CONCLUSIONS: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.

Rare neurovascular genetic and imaging markers across neurodegenerative diseases.

INTRODUCTION: Cerebral small vessel disease (SVD) is common in patients with cognitive impairment and neurodegenerative diseases such as Alzheimer's and Parkinson's. This study investigated the burden of magnetic resonance imaging (MRI)-based markers of SVD in patients with neurodegenerative diseases as a function of rare genetic variant carrier status. METHODS: The Ontario Neurodegenerative Disease Research Initiative study included 520 participants, recruited from 14 tertiary care centers, diagnosed with various neurodegenerative diseases and determined the carrier status of rare non-synonymous variants in five genes (ABCC6, COL4A1/COL4A2, NOTCH3/HTRA1). RESULTS: NOTCH3/HTRA1 were found to significantly influence SVD neuroimaging outcomes; however, the mechanisms by which these variants contribute to disease progression or worsen clinical correlates are not yet understood. DISCUSSION: Further studies are needed to develop genetic and imaging neurovascular markers to enhance our understanding of their potential contribution to neurodegenerative diseases.

Validation of the Rainbow Model of Integrated Care Measurement Tool in Parkinson's Disease.

BACKGROUND: Integrated care is essential for improving the management and health outcomes for people with Parkinson's disease (PD); reliable and objective measures of care integration are few. OBJECTIVE: The aim of this study was to test the psychometric properties of the Rainbow Model of Integrated Care Measurement Tool (RMIC-MT, provider version) for healthcare professionals involved in PD care. METHODS: A cross-sectional survey was administered online to an international network representing 95 neurology centers across 41 countries and 588 healthcare providers. Exploratory factor analysis with principal axis extraction method was used to assess construct validity. Confirmatory factor analysis was used to evaluate model fit of the RMIC-MT provider version. Cronbach's alpha was used to assess the internal consistency reliability. RESULTS: Overall, 371 care providers (62% response rate) participated in this study. No item had psychometric sensitivity problems. Nine factors (professional coordination, cultural competence, triple aims outcome, system coordination, clinical coordination, technical competence, community-centeredness, person-centeredness, and organizational coordination) with 42 items were determined by exploratory factor analysis. Cronbach's alpha ranged from 0.76 (clinical coordination) to 0.94 (system coordination) and showed significant correlation among all items in the scale (>0.4), indicating good internal consistency reliability. The confirmatory factor analysis model passed most goodness-of-fit tests, thereby confirming the factor structure of nine categories with a total of 40 items. CONCLUSIONS: The results provide evidence for the construct validity and other psychometric properties of the provider version of the RMIC-MT to measure integrated care in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases.

Oculomotor tasks generate a potential wealth of behavioural biomarkers for neurodegenerative diseases. Overlap between oculomotor and disease-impaired circuitry reveals the location and severity of disease processes via saccade parameters measured from eye movement tasks such as prosaccade and antisaccade. Existing studies typically examine few saccade parameters in single diseases, using multiple separate neuropsychological test scores to relate oculomotor behaviour to cognition; however, this approach produces inconsistent, ungeneralizable results and fails to consider the cognitive heterogeneity of these diseases. Comprehensive cognitive assessment and direct inter-disease comparison are crucial to accurately reveal potential saccade biomarkers. We remediate these issues by characterizing 12 behavioural parameters, selected to robustly describe saccade behaviour, derived from an interleaved prosaccade and antisaccade task in a large cross-sectional data set comprising five disease cohorts (Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and cerebrovascular disease; n = 391, age 40-87) and healthy controls (n = 149, age 42-87). These participants additionally completed an extensive neuropsychological test battery. We further subdivided each cohort by diagnostic subgroup (for Alzheimer's disease/mild cognitive impairment and frontotemporal dementia) or degree of cognitive impairment based on neuropsychological testing (all other cohorts). We sought to understand links between oculomotor parameters, their relationships to robust cognitive measures, and their alterations in disease. We performed a factor analysis evaluating interrelationships among the 12 oculomotor parameters and examined correlations of the four resultant factors to five neuropsychology-based cognitive domain scores. We then compared behaviour between the abovementioned disease subgroups and controls at the individual parameter level. We theorized that each underlying factor measured the integrity of a distinct task-relevant brain process. Notably, Factor 3 (voluntary saccade generation) and Factor 1 (task disengagements) significantly correlated with attention/working memory and executive function scores. Factor 3 also correlated with memory and visuospatial function scores. Factor 2 (pre-emptive global inhibition) correlated only with attention/working memory scores, and Factor 4 (saccade metrics) correlated with no cognitive domain scores. Impairment on several mostly antisaccade-related individual parameters scaled with cognitive impairment across disease cohorts, while few subgroups differed from controls on prosaccade parameters. The interleaved prosaccade and antisaccade task detects cognitive impairment, and subsets of parameters likely index disparate underlying processes related to different cognitive domains. This suggests that the task represents a sensitive paradigm that can simultaneously evaluate a variety of clinically relevant cognitive constructs in neurodegenerative and cerebrovascular diseases and could be developed into a screening tool applicable to multiple diagnoses.

Classification and staging of Parkinson's disease using video-based eye tracking.

INTRODUCTION: 83% of those diagnosed with Parkinson's Disease (PD) eventually progress to PD with mild cognitive impairment (PD-MCI) followed by dementia (PDD) - suggesting a complex spectrum of pathology concomitant with aging. Biomarkers sensitive and specific to this spectrum are required if useful diagnostics are to be developed that may supplement current clinical testing procedures. We used video-based eye tracking and machine learning to develop a simple, non-invasive test sensitive to PD and the stages of cognitive dysfunction. METHODS: From 121 PD (45 Cognitively Normal/45 MCI/20 Dementia/11 Other) and 106 healthy controls, we collected video-based eye tracking data on an interleaved pro/anti-saccade task. Features of saccade, pupil, and blink behavior were used to train a classifier to predict confidence scores for PD/PD-MCI/PDD diagnosis. RESULTS: The Receiver Operator Characteristic Area Under the Curve (ROC-AUC) of the classifier was 0.88, with the cognitive-dysfunction subgroups showing progressively increased AUC, and the AUC of PDD being 0.95. The classifier reached a sensitivity of 83% and a specificity of 78%. The confidence scores predicted PD motor and cognitive performance scores. CONCLUSION: Biomarkers of saccade, pupil, and blink were extracted from video-based eye tracking to create a classifier with high sensitivity to the landscape of PD cognitive and motor dysfunction. A complex landscape of PD is revealed through a quick, non-invasive eye tracking task and our model provides a framework for such a task to be used as a supplementary screening tool in the clinic.

White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative.

BACKGROUND AND PURPOSE: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years. METHODS: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale. RESULTS: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline. CONCLUSION: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology.

Neuropsychiatric Symptom Burden across Neurodegenerative Disorders and its Association with Function.

OBJECTIVE: Neuropsychiatric symptoms (NPS) are prevalent in neurodegenerative disorders, however, their frequency and impact on function across different disorders is not well understood. We compared the frequency and severity of NPS across Alzheimer's disease (AD) (either with mild cognitive impairment or dementia), Cerebrovascular disease (CVD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and explored the association between NPS burden and function. METHODS: We obtained data from Ontario Neurodegenerative Disease Research Initiative (ONDRI) that included following cohorts: AD (N = 111), CVD (N = 148), PD (N = 136), FTD (N = 50) and ALS (N = 36). We compared the frequency and severity of individual NPS (assessed by the neuropsychiatric inventory questionnaire) across cohorts using generalized estimating equations and analysis of variance. Second, we assessed the relationship of NPS burden with instrumental (iADLs) and basic (ADLs) activities of living across cohorts using multivariate linear regression while adjusting for relevant demographic and clinical covariates. RESULTS: Frequency of NPS varied across cohorts (χ2(4) = 34.4, p < .001), with post-hoc tests showing that FTD had the greatest frequency as compared to all other cohorts. The FTD cohort also had the greatest severity of NPS (H(4) = 34.5, p < .001). Further, there were differences among cohorts in terms of the association between NPS burden and ADLs (F(4,461) = 3.1, p = 0.02). Post-hoc comparisons suggested that this finding was driven by the FTD group, however, the differences did not remain significant following Bonferroni correction. There were no differences among cohorts in terms of the association between NPS burden and IADLs. CONCLUSIONS: NPS frequency and severity are markedly greater in FTD as compared to other neurodegenerative diseases. Further, NPS burden appears to be associated differently with function across neurodegenerative disorders, highlighting the need for individualized clinical interventions.

Interpersonal Psychotherapy for Depression in Parkinson's Disease: A Feasibility Study.

Individuals living with Parkinson's disease (PD) experience interpersonal stressors that contribute to depressive risk. Interpersonal psychotherapy (IPT) emphasizes the bidirectional relationship between interpersonal stressors and mood may therefore be a suitable treatment for PD-depression. The primary aim of this study was to evaluate the feasibility of delivering 12 sessions of IPT to depressed PD patients and explore the need for modifications. A secondary aim was to obtain descriptive information about efficacy outcomes. The study used a pre-post design without a comparison group. Participants were 12 PD patients with a major depressive disorder. IPT was well accepted and tolerated by patients and required minimal modifications. Compliance with session attendance and completion of study questionnaires were excellent and treatment satisfaction was high. Depression scores declined from baseline to endpoint, with 7 patients meeting criteria for remission at endpoint. Findings are encouraging and a larger randomized controlled trial is currently underway to ascertain if IPT is an efficacious treatment for PD-depression.

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.