Cancer-related cognitive impairment as a key contributor to psychopathology in cancer survivors: implications for prevention, treatment and supportive care.

A significant proportion of cancer survivors will experience some form of mental health compromise across domains including mood, anxiety, psychosis, eating disorders, and substance use. This psychopathology within cancer survivors is related to a range of negative outcomes and can also have a substantial negative impact on quality of life. Along with psychopathology, cognitive impairments are also commonly experienced, resulting in deficits in memory, reasoning, decision-making, speed of processing, and concentration, collectively referred to as cancer-related cognitive impairment (CRCI). Within the non-oncology literature, cognitive deficits are consistently demonstrated to be a key transdiagnostic aetiological feature of psychopathology, functionally contributing to the development and perpetuation of symptoms. Whilst there is an acknowledgement of the role mental health concerns might play in the development of and perception of CRCI, there has been limited acknowledgement and research exploring the potential for CRCI to functionally contribute toward the development of transdiagnostic psychopathology in cancer survivors beyond simply psychosocial distress. Given the theoretical and empirical evidence suggesting cognitive deficits to be an aetiological factor in psychopathology, we provide a rationale for the potential for CRCI to be a factor in the development and perpetuation of transdiagnostic psychopathology in cancer survivors. This potential functional association has significant implications for risk identification, prevention, treatment, and supportive cancer care approaches regarding psychopathology in cancer survivorship. We conclude by providing directions for future research in this area.

Validating the PROMIS cognitive function short form in cancer survivors.

PURPOSE: The Patient-Reported Outcome Measurement Information System Cognitive Function Short Form 8a  (PROMIS Cog) could provide a shorter, useful alternative to the often used Functional Assessment of Cancer Therapy - Cognition (FACT-Cog) in research and clinical care. This study aimed to determine the convergent validity and internal reliability of the PROMIS Cog in 3 separate samples of breast cancer survivors and to explore clinical cut points. METHODS: Data from three samples of breast cancer survivors were used for this secondary analysis. Convergent validity was determined by evaluating correlation strength among the derived PROMIS Cog and measures of depression, anxiety, stress, fatigue, sleep, loneliness, the FACT-Cog . Clinical cut-points for the PROMIS Cog were determined by plotting the receiver operating characteristic curves. RESULTS: 3 samples of breast cancer survivors (N = 471, N = 132, N = 90) were included. Absolute values of correlations demonstrating convergent validity ranged from 0.21 to 0.82, p's < 0.001, and were comparable to correlations with the full FACT-Cog 18 item perceived cognitive impairments (PCI) scale. ROC curve plots indicated a clinical cut off < 34 for the combined sample. CONCLUSION: The 8-item PROMIS Cog demonstrated good convergent validity and internal reliability in breast cancer survivors, comparable to the 18-item FACT-Cog PCI. The PROMIS Cog 8a is a brief self-report measure that can be easily incorporated into cancer-related cognitive impairment research designs or used in clinical settings.

Cisheteronormativity and its influence on the psychosocial experience of LGBTQ+ people with cancer: A qualitative systematic review.

OBJECTIVE: Cisheteronormativity refers to the relationship of heterosexual and cisgender privilege stemming from patriarchy. Although studies have shown that cisheteronormativity can impact health outcomes for lesbian, gay, bisexual, transgender, queer and other sexual, gender diverse, and gender nonconforming (LGBTQ+) people, the specific impact on cancer care has not been described. We synthesized the qualitative evidence on how cisheteronormativity impacts the psychosocial experience of LGBTQ+ people with cancer. METHODS: We conducted a historic search in the CINAHL, LGBT+ Health, PsycInfo, and PubMed databases. Qualitative studies that described the psychosocial experience of LGBTQ+ people with cancer were included. After appraising the quality of the publications, 11 articles were included. Then, we conducted inductive nominal coding, taxonomic analysis, and thematic synthesis. RESULTS: Two main themes emerged, (1) Cisheteronormativity as a social determinant of health, and (2) Cancer, sexual orientation, and gender: Associations and introjections. The themes comprise four categories and 13 subcategories that describe the impact of cisheteronormativity on the cancer experience of LGBTQ+ people. CONCLUSION: Cisheteronormativity within the healthcare system impacts the psychosocial experience of LGBTQ+ people with cancer. Understanding how these gender biases, norms, and social expectations impact the cancer experience is necessary to transform social norms and promote health equity.

Patient reported outcomes affecting quality of life in socioeconomically disadvantaged cancer patients.

PURPOSE: The aim of this study was to identify correlates of quality of life (QOL) for socioeconomically disadvantaged cancer patients receiving care in the "safety net" health system. DESIGN: This cross-sectional study used linear regressions to determine the effect of patient reported outcome measures (PRO) on QOL.Sample/Methods: Cancer patients (n = 115) receiving drug therapy completed a series of PROs including: Functional Assessment of Cancer Therapy (FACT-G), PROMIS (Anxiety, Depression, Fatigue, Pain Interference, and Physical Function), and the Comprehensive Score for Financial Toxicity. FINDINGS: More than 60% of patients reported an annual income below $24,999. Forty-five percent of patients were either uninsured or county-funded. Depression, pain, and financial toxicity were found to be consistently significant correlates of QOL.Implications: Cancer patients with existing financial strain have unique psychosocial stressors. This study provides insight into the relationship between these stressors, and the need for targeted screening and intervention that address such aspects of care.

Neurocognitive Impairment After Hematopoietic Stem Cell Transplant for Hematologic Malignancies: Phenotype and Mechanisms.

Hematopoietic stem cell transplant (HSCT) plays a central role in the treatment of hematologic cancers. With the increasing survival of patients after HSCT, survivorship issues experienced by this population have become an important outcome. Cognitive impairment is an established sequela of HSCT, with studies to date establishing its presence, associated risk factors, and clinical phenotype. There are multiple potential contributors to cognitive impairment after HSCT. Efforts are ongoing to further characterize its clinical phenotype, associated biomarkers, and biologic underpinnings. A fundamental knowledge of post-HSCT cognitive impairment is of value for all clinicians who interface with this population, and further academic efforts are needed to more fully understand the impact of this cancer treatment on brain health. IMPLICATIONS FOR PRACTICE: As survival outcomes after hematopoietic stem cell transplant (HSCT) improve, an awareness of the post-treatment challenges faced by this population has become central to its care. HSCT can have a sustained and broad impact on brain health, causing cognitive dysfunction, fatigue, disturbed mood, and sleep. In affected patients, autonomy, return to work, relationships, and quality of life may all be affected. A fundamental fluency in this area is important for clinicians interfacing with HSCT survivors, facilitating the identification and management of cognitive dysfunction and concurrent symptom clusters, and stimulating interest in these sequelae as areas for future clinical research.

Lessons learned from eight teams: The value of pilot and feasibility studies in self-management science.

Designing and conducting effective intervention research is an important domain of nursing science. Nurse scientists have long recognized people with chronic conditions need effective self-management strategies across the lifespan, so they have led the way in establishing theoretical and practical grounds for the science of self-management. Guidance from pilot and feasibility research for self-management interventions is scarce. Documented exemplars of successes and failures in pilot and feasibility study designs are scant in the literature. The purpose of this paper is to illustrate methodological approaches using pilot and feasibility examples. To maximize collective lessons learned in self-management science study design, features of our pilot and feasibility research strategies that yielded both desirable and undesirable outcomes are described, analyzed, and paired with alternative solutions. A National Institute of Nursing Research P30 grant center, awarded grants to 8 pilot investigators to pilot self-management interventions. A wide variety of chronic conditions were addressed, including heart failure, chronic kidney disease, multiple sclerosis, diabetes, and HIV. The investigators provided their experiences of study implementation. Common themes across the studies were identified. There were four lessons learned from these studies: 1) maximize resources and develop enough evidence for subsequent studies; 2) embed patient-centered feasibility within implementation testing with new patient populations; 3) develop a flexible participant recruitment plan to allow for adjustments when unexpected barriers arise; and 4) define study-specific data collection procedures to demonstrate feasibility. Researchers conducting preliminary small-scale self-management intervention research must balance resources to develop and implement interventions to meet pilot and feasibility objectives.

Predicting Patient Reported Outcomes of Cognitive Function Using Connectome-Based Predictive Modeling in Breast Cancer.

Being able to predict who will likely experience cancer related cognitive impairment (CRCI) could enhance patient care and potentially reduce economic and human costs associated with this adverse event. We aimed to determine if post-treatment patient reported CRCI could also be predicted from baseline resting state fMRI in patients with breast cancer. 76 newly diagnosed patients (n = 42 planned for chemotherapy; n = 34 not planned for chemotherapy) and 50 healthy female controls were assessed at 3 times points [T1 (prior to treatment); T2 (1 month post chemotherapy); T3 (1 year after T2)], and at yoked intervals for controls. Data collection included self-reported executive dysfunction, memory function, and psychological distress and resting state fMRI data converted to connectome matrices for each participant. Statistical analyses included linear mixed modeling, independent t tests, and connectome-based predictive modeling (CPM). Executive dysfunction increased over time in the chemotherapy group and was stable in the other two groups (p < 0.001). Memory function decreased over time in both patient groups compared to controls (p < 0.001). CPM models successfully predicted executive dysfunction and memory function scores (r > 0.31, p < 0.002). Support vector regression with a radial basis function (SVR RBF) showed the highest performance for executive dysfunction and memory function (r = 0.68; r = 0.44, p's < 0.001). Baseline neuroimaging may be useful for predicting patient reported cognitive outcomes which could assist in identifying patients in need of surveillance and/or early intervention for treatment-related cognitive effects.

Biomarkers panels can predict fatigue, depression and pain in persons living with HIV: A pilot study.

BACKGROUND: Persons living with HIV experience high symptom burden that can negatively impact medication adherence, work productivity, and quality of life. Symptoms are highly subjective, which can lead to under- or improper treatment. The purpose of this exploratory study was to examine relationships between circulating biomarkers representative of inflammatory, coagulation, and vascular function pathways and prevalent HIV symptoms. SETTING AND SAMPLE: Adults >18 years who were diagnosed with HIV and spoke English for this cross-sectional study were recruited from community clinics and organizations. METHODS: Symptom burden was measured with the HIV Symptom Index; depression with the Patient Health Questionnaire. Human multiplex kits were used to determine serum concentrations of select biomarkers representing inflammatory, coagulation, and vascular function pathways. The biomarkers were included as features in machine learning models to determine which biomarkers predicted the most prevalent HIV symptoms (fatigue and muscle/joint pain) and the symptom of depression. RESULTS: Participants (N = 32) were representative of the local population of people with HIV, being mostly Black (54.4%) and male (60.6%). Depression was predicted by age, gender, glucose, hemoglobin A1c, and inflammation. Muscle/joint pain was predicted by adiponectin, C-reactive protein, and serum amyloid A (SAA). Fatigue was predicted by adiponectin, SAA, and soluble interleukin-1 receptor type II (sIL-1RII). CONCLUSION: Biomarker clusters can be a tool to monitor symptoms. Adding an objective measure to subjective patient experiences could improve management and monitoring of symptoms. Defining a biomarker cluster for the objective assessment of HIV symptoms warrants further investigation; however, the presence of comorbid conditions needs to be controlled.

An initial investigation of the reliability and validity of the Compensatory Cognitive Strategies Scale.

Although many cognitive performance tests and self-reported cognitive concerns scales have been used to evaluate cognitive functioning, fewer measures assess the use of compensatory cognitive strategies for daily activities among those experiencing mild levels of cognitive impairment. The Compensatory Cognitive Strategies Scale was developed to measure frequency of self-reported cognitive strategies to decrease distractions, organise and sequence activities, and to utilise newly available computer aids to assist memory among those with multiple sclerosis (MS). Cronbach's alpha, a measure of internal consistency reliability, was .89 and .90 in two different samples. Concurrent validity was supported by the total score's moderate correlation with the MMQ-Strategy Scale (rs = .67) and by a statistically significant increase in total scores for those who had participated in an intervention designed to improve their cognitive abilities. Correlations were stronger with another strategy measure than with measures of other constructs such as health-promoting behaviours, thus supporting the scales convergent versus divergent validity. These initial findings suggest that the Compensatory Cognitive Strategies Scale may be useful to both researchers and clinicians working to build compensatory strategies for day-to-day functioning among those with mild cognitive impairment.

Relationships between self-reported sleep quality components and cognitive functioning in breast cancer survivors up to 10 years following chemotherapy.

OBJECTIVE: Links have been made between aspects of sleep quality and cognitive function in breast cancer survivors (BCS), but findings are heterogeneous. The objective of this study is to examine relationships between specific sleep quality components (latency, duration, efficiency, daytime sleepiness, sleep disturbance, use of sleep aids) and cognitive impairment (performance and perceived), and determine which sleep quality components are the most significant contributors to cognitive impairments in BCS 6 months to 10 years post chemotherapy. METHODS: Women 21 to 65 years old with a history of non-metastatic breast cancer following chemotherapy completion were recruited. Data collection included surveys to evaluate sleep quality and perceived cognitive impairments, and neuropsychological testing to evaluate verbal fluency and memory. Descriptive statistics, bivariate correlations, and hierarchical multiple regression were calculated. RESULTS: Ninety women (mean age 49) completed data collection. Moderate significant correlations were found between daytime dysfunction, sleep efficiency, sleep latency, and sleep disturbance and perceived cognitive impairment (Rs = -0.37 to -0.49, Ps < .00049), but not objective cognitive performance of verbal fluency, memory, or attention. After accounting for individual and clinical characteristics, the strongest predictors of perceived cognitive impairments were daytime dysfunction, sleep efficiency, and sleep disturbance. CONCLUSIONS: Findings support links between sleep quality and perceived cognitive impairments in BCS and suggest specific components of sleep quality (daytime dysfunction, sleep efficiency, and sleep disturbance) are associated with perceived cognitive functioning in this population. Findings can assist clinicians in guiding survivors to manage sleep and cognitive problems and aid in the design of interventional research.

Modifiable factors and cognitive dysfunction in breast cancer survivors: a mixed-method systematic review.

PURPOSE: It is unknown why some breast cancer survivors experience cancer-related cognitive impairments (CRCI) after cancer treatment, and modifiable risk factors for CRCI remain to be explicated. This mixed-method systematic review synthesizes quantitative and qualitative evidence for relationships between modifiable factors and CRCI in breast cancer survivors who receive chemotherapy as part of their treatment. METHODS: Keyword Searches of PubMed/Medline, PsychINFO, and CINAHL were performed for January 2005 through June 2015. Studies that provided data on associations between modifiable biological, behavioral, environmental, and psychosocial factors and cognition were included. RESULTS: Twenty-two quantitative studies and five qualitative studies were identified after applying inclusion and exclusion criteria yielding evidence for significant relationships among modifiable biological (inflammatory cytokines), behavioral (sleep quality, physical activity), and psychosocial (stress, distress, affect) factors and CRCI. CONCLUSION: Many women unfortunately experience CRCI after breast cancer chemotherapy, with limited treatment options available to improve cognitive function. This review synthesizes current evidence to support the associations between modifiable factors and CRCI and can inform research to evaluate these factors prospectively. The clinical implications of these findings suggest that lifestyle factors such as physical activity, stress management, and sleep quality may be appropriate targets for behavioral interventions to improve cognitive function following breast cancer chemotherapy; however, further research is necessary.

An Exploratory Analysis of Contributors to Cognitive Functioning Among Sexual and Gender Minority Individuals Who Had COVID-19.

Sexual and gender minority (SGM) individuals face mental health disparities. However, research analyzing SGM people's mental health after a COVID-19 diagnosis is scarce. In this secondary analysis of a remote study, we 1) examined associations between cognitive and psychosocial health and 2) explored differences between these health outcomes among SGM (n = 14) and heterosexual cisgender (n = 64) U.S. adults who had COVID-19. We used the Patient Reported Outcome Measures Information System (PROMIS) v2.0 to assess subjective cognition and the BrainCheck cognitive test to analyze objective cognition. We administered the Perceived Stress Scale and PROMIS 57 Profile V.2.0 to measure psychosocial health. SGM COVID-19 survivors had worse scores in depression, anxiety, sleep disturbance, pain, stress, and objective cognition than heterosexual cisgender participants (p-values < .05). Objective cognition was associated with age, SGM classification, racial or ethnic minority classification, income, comorbidities, COVID-19 severity, number of symptoms, and pain (|0.137| < r < |0.373|, p-values < .05). Subjective cognition was associated with comorbidities, number of symptoms, depression, anxiety, sleep disturbance, pain, and stress (|0.158| < r < |0.537|, p-values < .05). Additional studies are needed to expand what is known about post-COVID-19 health disparities and to guide policies and interventions that promote cognitive functioning.

Subjective cancer-related cognitive impairments and salience network connectivity in breast cancer survivors.

PURPOSE: Little is known about the neural basis of subjective cancer-related cognitive changes. The purpose of this study was to explore salience network connectivity in relation to subjective executive and memory dysfunction in breast cancer survivors compared to controls. METHODS: A retrospective cross-sectional analysis of neuroimaging, subjective cognitive, clinical, and demographic data in chemotherapy-treated primary breast cancer survivors compared to frequency matched controls was used. Functional connectivity within salience network hubs (anterior cingulate, bilateral insula) was determined using resting state functional MRI. Mann-Whitney U tests were used to evaluate group differences and Spearman's rho correlations were examined among the behavioral measures and salience network connectivity. RESULTS: We included 65 breast cancer survivors and 71 controls. Survivors demonstrated greater subjective executive dysfunction and memory complaints (p < .001) and lower salience network connectivity (p < .05) than controls. Executive functioning correlated with bilateral insula and left anterior cingulate connectivity (rho > - 0.29, p < .05). Distress did not correlate with salience network connectivity. CONCLUSION: These findings suggest that salience network connectivity may represent a biomarker of subjective cancer-related cognitive changes. IMPLICATIONS FOR CANCER SURVIVORS: Subjective cancer-related cognitive changes are common following treatment and associated with objective changes in brain connectivity.

Neuroimaging based biotypes for precision diagnosis and prognosis in cancer-related cognitive impairment.

Cancer related cognitive impairment (CRCI) is commonly associated with cancer and its treatments, yet the present binary diagnostic approach fails to capture the full spectrum of this syndrome. Cognitive function is highly complex and exists on a continuum that is poorly characterized by dichotomous categories. Advanced statistical methodologies applied to symptom assessments have demonstrated that there are multiple subclasses of CRCI. However, studies suggest that relying on symptom assessments alone may fail to account for significant differences in the neural mechanisms that underlie a specific cognitive phenotype. Treatment plans that address the specific physiologic mechanisms involved in an individual patient's condition is the heart of precision medicine. In this narrative review, we discuss how biotyping, a precision medicine framework being utilized in other mental disorders, could be applied to CRCI. Specifically, we discuss how neuroimaging can be used to determine biotypes of CRCI, which allow for increased precision in prediction and diagnosis of CRCI via biologic mechanistic data. Biotypes may also provide more precise clinical endpoints for intervention trials. Biotyping could be made more feasible with proxy imaging technologies or liquid biomarkers. Large cross-sectional phenotyping studies are needed in addition to evaluation of longitudinal trajectories, and data sharing/pooling is highly feasible with currently available digital infrastructures.

Assessing cancer-related cognitive function in the context of everyday life using ecological mobile cognitive testing: A protocol for a prospective quantitative study.

Objective: Millions of cancer survivors are at risk for cancer-related cognitive impairment (CRCI), yet accurate and accessible assessments of cognitive functioning remain limited. Ecological mobile cognitive testing (EMCT) could offer a solution. This paper presents the protocol for a study that aims to (1) establish the reliability and validity of EMCT to assess CRCI in breast cancer survivors, and (2) prospectively evaluate within-person processes (and interactions) among context, mood, and behavior that explain cognitive variability, everyday functioning, and quality of life of cancer survivors. Methods: Participants will include breast cancer survivors (>21 years old) who are within 5 years of completing chemotherapy treatment. Participants will complete two virtual visits (baseline, follow-up) 2 months apart to assess self-reported cognitive symptoms and cognitive performance, sociodemographic characteristics, clinical history, everyday functioning, and quality of life. Between virtual visits, EMCT will be used to sample cognitive functioning every other day (28 times total). We will use linear mixed-effect regressions and single-level multiple regression models to analyze the data. Results: We anticipate a minimum of 124 breast cancer survivors enrolling and completing data collection. Study results will be published in peer-reviewed scientific journals. Conclusions: Our findings will have broad implications for assessing CRCI in an ecologically valid and person-centered way using EMCT. We aim to provide this protocol to aid researchers who would like to apply this approach to their studies.

Clinical, psychosocial, and sociodemographic factors of sexual and gender minority groups with cancer: A systematic review.

PURPOSE: Psychosocial health varies depending on demographic and clinical factors and the social context in which individuals grow and live. Sexual and gender minority (SGM) populations experience health disparities due to systemic factors that privilege cisgender and heterosexual identities. We reviewed the literature on the psychosocial, sociodemographic, and clinical factors in SGM groups with cancer and described the associations among these factors. METHODS: We conducted a systematic review according to Fink's methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines in the PubMed, PsycInfo, Cumulative Index of Nursing and Allied Health Literature, and LGBTQ+ Life databases. Quantitative articles published in English or Spanish were included. Grey literature and studies with participants in hospice care were excluded. The quality of the publications was assessed with the Joanna Briggs Institute criticalappraisal tools. RESULTS: The review included 25 publications. In SGM groups, systemic cancer treatment was associated with worse psychosocial outcomes; and older age, employment, and higher income were associated with better psychosocial outcomes. CONCLUSIONS: SGM groups with cancer are different from their heterosexual cisgender peers in sociodemographic, psychosocial, and clinical factors. Clinical and sociodemographic factors are associated with psychosocial outcomes among SGM individuals with cancer.

Comparing Fatigue, Loneliness, Daytime Sleepiness, and Stress in Younger and Older Breast Cancer Survivors: A Cross-Sectional Analysis.

BACKGROUND: Breast cancer treatment can negatively affect psychosocial outcomes for breast cancer survivors (BCS), but these outcomes present differently for younger and older survivors. OBJECTIVES: The objective of this study was to compare psychosocial outcomes between younger and older BCS and identify predictors of loneliness in younger BCS. METHODS: This cross-sectional descriptive study of 90 BCS evaluated data on sociodemographic and clinical characteristics and self-reported measures of psychosocial outcomes (fatigue, depressive symptoms, anxiety, loneliness, daytime sleepiness, and stress). Participants were dichotomized into two groups by age (aged less than 50 years and aged 50 years or older). Descriptive statistics, bivariate correlations, and multiple regression were also examined. FINDINGS: Younger BCS reported greater fatigue, loneliness, daytime sleepiness, and stress than older BCS. No between-group differences were found in depressive symptoms or anxiety. Having children and less time since chemotherapy completion were significant predictors of less loneliness in younger BCS.

Self-Reported Cognitive Function in Persons with Nonneurological Chronic Diseases: A Systematic Review.

Background: Globally, one in three adults has a chronic condition. Many chronic diseases that are not neurological in nature (e.g., diabetes and heart failure) are increasingly associated with cognitive symptoms. However, the instruments used to assess cognitive symptoms in those with nonneurologic chronic illness are heterogeneous, and questions remain as to how cognitive symptoms may be related to demographic and clinical outcome variables, neurocognitive test performance, and other patient-reported outcomes. In this review, we describe associations among self-reported cognitive function, cognitive performance, and additional patient-reported outcomes as well as how cognitive symptoms are measured in nonneurologic chronic illness. Method: Multiple databases (PubMed, Medline, CINAHL, PsycInfo, EMBASE, SCOPUS, the Cochrane Library, and Academic Search Complete) were searched for studies from 1990 to 2020 that provided data on self-reported cognitive symptoms in those with nonneurological chronic conditions. Initial search yielded 304 articles, of which 32 met inclusion criteria. Quality assessment was conducted using the Critical Appraisal Skills Programme. Results: Thirty-two total studies were included: twenty cross-sectional, 10 longitudinal, and 2 randomized controlled trials. The tools used to assess self-reported cognitive function in the studies were heterogeneous: 28 unique tools were used. Thirty studies examined associations among self-reported cognitive function and other patient-reported outcomes. In 19 there were significant associations. Six studies showed no significant associations between neuropsychological tests and self-reported cognitive function; another 6 studies found a significant association. Conclusion: Tools to assess cognitive symptoms were heterogeneous. In most studies, self-reported cognitive symptoms were not correlated with neuropsychological test results, but the majority of studies found a strong association between self-reported cognitive function and other patient-reported outcomes. Implications. Consensus on measuring cognitive symptoms would facilitate cross-study comparisons and facilitate scientific progress in those with nonneurological chronic conditions. Based on these results, there is a need to establish a standardized approach for self-reported cognitive function measurement in patients with nonneurologic chronic illness.