GDF-15 is associated with sarcopenia and frailty in acutely admitted older medical patients.

BACKGROUND: Growth differentiation factor-15 (GDF-15) has been associated with senescence, lower muscle strength, and physical performance in healthy older people. Still, it is not clear whether GDF-15 can be utilized as a biomarker of sarcopenia and frailty in the early stages of hospitalization. We investigated the association of plasma GDF-15 with sarcopenia and frailty in older, acutely admitted medical patients. METHODS: The present study is based on secondary analyses of cross-sectional data from the Copenhagen PROTECT study, a prospective cohort study including 1071 patients ≥65 years of age admitted to the acute medical ward at Copenhagen University Hospital, Bispebjerg, Denmark. Muscle strength was assessed using handgrip strength, and lean mass was assessed using direct segmental multifrequency bioelectrical impedance analyses and used to clarify the potential presence of sarcopenia defined according to guidelines from the European Working Group on Sarcopenia in Older People. Frailty was evaluated using the Clinical Frailty Scale. Plasma GDF-15 was measured using electrochemiluminescence assays from Meso Scale Discovery (MSD, Rockville, MD, USA). RESULTS: We included 1036 patients with completed blood samples (mean age 78.9 ± 7.8 years, 53% female). The median concentration of GDF-15 was 2669.3 pg/mL. Systemic GDF-15 was significantly higher in patients with either sarcopenia (P < 0.01) or frailty (P < 0.001) compared with patients without the conditions. Optimum cut-off points of GDF-15 relating to sarcopenia and frailty were 1541 and 2166 pg/mL, respectively. CONCLUSIONS: Systemic GDF-15 was higher in acutely admitted older medical patients with sarcopenia and frailty compared with patients without. The present study defined the optimum cut-off for GDF-15, related to the presence of sarcopenia and frailty, respectively. When elevated above the derived cutoffs, GDF-15 was strongly associated with frailty and sarcopenia in both crude and fully adjusted models.

Feasibility of Assessing Older Patients in the Acute Setting: Findings From the Copenhagen PROTECT Study.

OBJECTIVES: Older patients are typically underrepresented in clinical trials despite representing a major proportion of the patient population. We aim to describe the feasibility of performing body composition measures, physical function measures, and patient-reported questionnaires within the first 24 hours of admission in a large sample of older acutely admitted medical patients. In addition, we aim to characterize patients with missing measurements. DESIGN: Secondary analyses of cross-sectional data from a cohort study. SETTING AND PARTICIPANTS: A total of 1071 acutely admitted patients aged ≥65 years from the acute medical ward at Bispebjerg Hospital, were enrolled within the first 24 hours of hospitalization. METHODS: Body composition was investigated using direct segmental multifrequency bioelectrical impedance analyses (DSM-BIA) and physical function was assessed using hand grip strength (HGS) and the 30-second sit-to-stand test (STS). The orientation-memory-concentration test (OMC) was used to evaluate the prevalence of cognitive impairments within 24 hours of hospitalization, and the OMC in conjunction with the Strength, Assistance walking, Rise from a chair, Climb stairs, and Falls questionnaire (SARC-F) was used to assess the feasibility of patient-reported outcomes (PROs). RESULTS: Mean age was 78.8 ± 7.8 years (53.0% female). HGS was performed in 96.2% of the enrolled patients, whereas the PRO, 30-second STS, and DSM-BIA were performed in 91.2%, 69.2%, and 59.8% of patients, respectively. The main barrier for performing the 30-second STS and body composition measurements was an inability to mobilize the patient from the hospital bed. CONCLUSIONS AND IMPLICATIONS: The assessment of HGS and PROs show excellent feasibility in clinical research including older patients, even when the patients are enrolled and tested within 24 hours of an acute admission. Assessments of DSM-BIA and the 30-second STS show good feasibility but are less feasible in immobile patients often presenting as more frail, weaker, and cognitively impaired.

Comparison of two frailty screening tools for acutely admitted elderly patients.

INTRODUCTION: Frailty is a clinical syndrome that arises due to age-related decline, diseases, malnutrition and lifestyle. Two major perspectives on frailty exists: frailty as a phenotype and frailty as an accumulation of deficits. The two types are measured by Fried's Phenotype (FP) and the Clinical Frailty Scale (CFS), respectively. The aim of this study was to investigate which model best predicts 90-day mortality in elderly patients acutely admitted to an emergency department in Denmark. METHODS: This study comprised a prospective cohort with the following inclusion criteria: age > 65 years, acute admission and admission >24 h. Bispebjerg Hospital, Odense University Hospital and Hospital of Southwest Jutland participated in the study. The FP and the CFS were measured in all patients. Descriptive statistics, relative risk (RR), odds ratio (OR), risk difference and receiver-operating characteristics (ROC) analysis were performed. The outcome was 90-day mortality. RESULTS: A total of 1,030 patients participated (mean age: 78.2 years, 54% female). Among these, 221 were frail by the FP (score > 3) and 555 participants were frail by the CFS (score > 5). Within 90 days, 128 died. The analyses revealed significant associations between frailty and 90-day mortality. For the FP, the RR was 2.67 (95% confidence interval (CI): 1.93-3.69), p less-than 0.001; and for the CFS, the RR was 4.12 (95% CI: 2.65-6.42), p less-than 0.001. The adjusted OR for the CFS was 4.38 (95% CI: 2.68-7.13); for the FP, 3.88 (95% CI: 2.51-6.01). CONCLUSION: A significant association existed between frailty and 90-day mortality in the Danish cohort. However, the CFS is a better predictor of 90-day mortality the FP. Even so, the CFS still has a lack of sensitivity and specificity. FUNDING: none TRIAL REGISTRATION. not relevant.

Biomarkers for length of hospital stay, changes in muscle mass, strength and physical function in older medical patients: protocol for the Copenhagen PROTECT study-a prospective cohort study.

INTRODUCTION: Sarcopenia is generally used to describe the age-related loss of muscle mass and strength believed to play a major role in the pathogenesis of physical frailty and functional impairment that may occur with old age. The knowledge surrounding the prevalence and determinants of sarcopenia in older medical patients is scarce, and it is unknown whether specific biomarkers can predict physical deconditioning during hospitalisation. We hypothesise that a combination of clinical, functional and circulating biomarkers can serve as a risk stratification tool and can (i) identify older acutely ill medical patients at risk of prolonged hospital stays and (ii) predict changes in muscle mass, muscle strength and function during hospitalisation. METHOD AND ANALYSIS: The Copenhagen PROTECT study is a prospective cohort study consisting of acutely ill older medical patients admitted to the acute medical ward at Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark. Assessments are performed within 24 hours of admission and include blood samples, body composition, muscle strength, physical function and questionnaires. A subgroup of patients transferred to the Geriatric Department are included in a smaller geriatric cohort and have additional assessments at discharge to evaluate the relative change in circulating biomarker concentrations, body composition, muscle strength and physical function during hospitalisation. Enrolment commenced 4 November 2019, and proceeds until August 2021. ETHICS AND DISSEMINATION: The study protocol has been approved by the local ethics committee of Copenhagen and Frederiksberg (H-19039214) and the Danish Data Protection Agency (P-2019-239) and all experimental procedures were performed in accordance with the Declaration of Helsinki. Findings from the project, regardless of the outcome, will be published in relevant peer-reviewed scientific journals in online (www.clinicaltrials.gov). TRIAL REGISTRATION NUMBER: NCT04151108.

Comparison between temporal and rectal temperature measurement.

INTRODUCTION: Various digital thermometers for non-invasive use have been used increasingly in Danish hospitals, including the temporal artery thermometer (TAT). However, previous studies have concluded that the accuracy of the TAT is unsatisfying for paediatric, surgical, cancer and intensive care patients. The purpose of this study was to compare the accuracy of the TAT with that of a conventional rectal thermometer (REC) within acutely admitted medical patients at an emergency department. METHODS: This was a prospective, comparative study. For two months, 381 patients were included. At a maximum interval of seven minutes, the temperature was measured first with a temporal artery thermometer and then with an REC. The measurements were analysed in a Bland-Altman plot, and the sensitivity and specificity of the TAT were calculated. RESULTS: The differences between the TAT and the REC ranged from -1.7 °C to 1.7 °C. The mean of the difference was drawn in the Bland-Altman plot through 0.17 with a standard deviation of ± 0.47. The sensitivity and specificity were calculated to 67% and 96%, respectively. CONCLUSIONS: Based on this study, we do not recommend the use of the TAT as an alternative to an REC for non-invasive measuring of the body temperature in acutely admitted medical patients. FUNDING: All authors received honoraria from The Capital Region of Denmark. TRIAL REGISTRATION: Study procedures were approved by the local ethical committee and submitted to www.clinicaltrials.org (NCT01817881).

Predictors of Acute Kidney Injury After Hip Fracture in Older Adults.

INTRODUCTION: This study aimed to investigate the prevalence of acute kidney injury (AKI) following hip fracture surgery in geriatric patients and to identify predictors for development of AKI with a focus on possible preventable risk factors. METHODS: In this retrospective cohort study, we reviewed electronic medical records of all patients above 65 years of age who underwent hip fracture surgery at Copenhagen University Hospital, Bispebjerg, Denmark, in 2018. Acute kidney injury was assessed according to the Kidney Disease Improving Global Outcomes guidelines. Multivariate logistic regression analyses were used to identify independent risk factors for AKI. RESULTS: Postoperative AKI developed in 28.4% of the included patients (85/299). Acute kidney injury was associated with increased length of admission (11.3 vs 8.7 days, P < .001) and 30-day mortality (18/85 vs 16/214, P = .001). In multivariable analysis, higher age (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.01-1.08, P = .004), heart disease (OR: 1.78, 95% CI: 1.01-3.11, P = .045), and postoperative blood transfusion (OR: 1.84, 95% CI: 1.01-3.36, P = .048) were associated with AKI. Moreover, a higher postoperative C-reactive protein (199.0 ± 99.9 in patients with AKI, 161.3 ± 75.2 in patients without AKI) and lower postoperative diastolic blood pressure were observed in patients developing AKI. DISCUSSION AND CONCLUSION: Acute kidney injury was common following hip fracture surgery and associated with longer admissions and increased mortality. Patients developing AKI were older and showed several postoperative similarities, including higher C-reactive protein, lower postoperative diastolic pressure, and the need for blood transfusion.

Predictive validity of the CriSTAL tool for short-term mortality in older people presenting at Emergency Departments: a prospective study.

ABSTRACT: To determine the validity of the Australian clinical prediction tool Criteria for Screening and Triaging to Appropriate aLternative care (CRISTAL) based on objective clinical criteria to accurately identify risk of death within 3 months of admission among older patients. METHODS: Prospective study of ≥ 65 year-olds presenting at emergency departments in five Australian (Aus) and four Danish (DK) hospitals. Logistic regression analysis was used to model factors for death prediction; Sensitivity, specificity, area under the ROC curve and calibration with bootstrapping techniques were used to describe predictive accuracy. RESULTS: 2493 patients, with median age 78-80 years (DK-Aus). The deceased had significantly higher mean CriSTAL with Australian mean of 8.1 (95% CI 7.7-8.6 vs. 5.8 95% CI 5.6-5.9) and Danish mean 7.1 (95% CI 6.6-7.5 vs. 5.5 95% CI 5.4-5.6). The model with Fried Frailty score was optimal for the Australian cohort but prediction with the Clinical Frailty Scale (CFS) was also good (AUROC 0.825 and 0.81, respectively). Values for the Danish cohort were AUROC 0.764 with Fried and 0.794 using CFS. The most significant independent predictors of short-term death in both cohorts were advanced malignancy, frailty, male gender and advanced age. CriSTAL's accuracy was only modest for in-hospital death prediction in either setting. CONCLUSIONS: The modified CriSTAL tool (with CFS instead of Fried's frailty instrument) has good discriminant power to improve prognostic certainty of short-term mortality for ED physicians in both health systems. This shows promise in enhancing clinician's confidence in initiating earlier end-of-life discussions.

Efficacy of a tool to predict short-term mortality in older people presenting at emergency departments: Protocol for a multi-centre cohort study.

BACKGROUND: Prognostic uncertainty inhibits clinicians from initiating timely end-of-life discussions and advance care planning. This study evaluates the efficacy of the CriSTAL (Criteria for Screening and Triaging to Appropriate aLternative care) checklist in emergency departments. METHODS: Prospective cohort study of patients aged ≥65 years with any diagnosis admitted via emergency departments in ten hospitals in Australia, Denmark and Ireland. Electronic and paper clinical records will be used to extract risk factors such as nursing home residency, physiological deterioration warranting a rapid response call, personal history of active chronic disease, history of hospitalisations or intensive care unit admission in the past year, evidence of proteinuria or ECG abnormalities, and evidence of frailty to be concurrently measured with Fried Score and Clinical Frailty Scale. Patients or their informal caregivers will be contacted by telephone around three months after initial assessment to ascertain survival, self-reported health, post-discharge frailty and health service utilisation since discharge. Logistic regression and bootstrapping techniques and AUROC curves will be used to test the predictive accuracy of CriSTAL for death within 90 days of admission and in-hospital death. DISCUSSION: The CriSTAL checklist is an objective and practical tool for use in emergency departments among older patients to determine individual probability of death in the short-term. Its validation in this cohort is expected to reduce clinicians' prognostic uncertainty on the time to patients' death and encourage timely end-of-life conversations to support clinical decisions with older frail patients and their families about their imminent or future care choices.

Indoor mobility-related fatigue and muscle strength in nonagenarians: a prospective longitudinal study.

BACKGROUND AND AIMS: Mobility-related fatigue is an important indicator of functional decline in old age, however, very little is known about fatigue in the oldest old population segment. The aim of this study was to examine the association between indoor mobility-related fatigue and muscle strength decline in nonagenarians. METHODS: The study is based on a prospective longitudinal study of all Danes born in 1905 and assessed in 1998, 2000 and 2003, and includes 92- to 93-year-old persons who were independent of help in basic indoor mobility at baseline (n = 1,353). Fatigue was assessed at baseline and defined as a subjective feeling of fatigue when transferring or walking indoors. The outcome measure, maximum grip strength, was measured at each measurement point. RESULTS: Grip strength declined throughout the study in participants with and without fatigue, but those reporting fatigue had significantly (P < .001) lower muscle strength during the entire study period. Longitudinal analyses indicated slightly slower decline in muscle strength among participants with fatigue compared to those without; however, observed selective dropout of participants with fatigue and poor performance at baseline needs to be considered when interpreting the results. Accordingly, participants without fatigue had significantly higher chances of being alive and having muscle strength above gender-specific median at first (RR 1.32, 95 % CI 1.07-1.58), second (RR 1.51, 1.06-1.96) and third (RR 1.39, 1.01-1.97) measurement points. CONCLUSIONS: Indoor mobility-related fatigue in advanced later life should not merely be considered as an unpleasant symptom, but rather an indicator of physical impairment, and consequently declined physiological reserve.

Fatigue, general health, and ischemic heart disease in older adults.

BACKGROUNDS: Fatigue has been shown to predict ischemic heart disease (IHD) and mortality in nonsmoking middle-aged men free of cardiovascular disease. The aim of this study was to investigate the predictive value of fatigue for IHD and general health in nondisabled individuals free of cardiovascular disease and older than 70 years. METHODS: The study population was drawn from The Longitudinal Study of Aging Danish Twins. In total, 1,696 participants were followed up for 2-10 years by questionnaires and 10-16 years through registries. Kaplan Meier, Cox Proportional Hazard and logistic regression were used to analyze data. Fatigue was measured with the mobility-tiredness scale, and multivariable-adjusted models included age, sex, socioeconomic position, life style factors, and depression symptomatology. Good general health was defined as no hospitalization due to IHD, no self-reported IHD-related diagnoses, no use of heart medication, sustained good mobility, and participation at follow-up. IHD was defined as first hospitalization due to IHD (ICD10: I20-I25) or death due to IHD as primary cause. RESULTS: Participants without fatigue had higher chances of a sustained good general health at 2 (odds ratio [OR] = 1.45 confidence interval [CI] 95%: 1.08-1.93) and 4 years of follow-up (OR = 1.55 CI 95%: 1.11-2.16), compared with participants with fatigue. Further, participants with fatigue had a significantly higher hazard of IHD during the 10-16 years of follow-up (hazard ratio [HR] = 1.47 CI 95%: 1.08-2.00) compared with participants without fatigue. CONCLUSION: We concluded that fatigue in nondisabled older adults free of cardiovascular disease is an early predictor for development of subsequent poor general health and IHD.

Do negative aspects of social relations influence fatigue? A cross-sectional study on a non-clinical sample of middle-aged Danish men.

OBJECTIVE: Fatigue is a common complaint among young and old adults and may be associated with negative aspects of social relations. Hence, the purpose of this study was to explore the association between demands from and conflicts with different sources of social relations and fatigue. METHODS: The study was based on sub-populations of the 6292 members of the Danish Metropolit Cohort. The cohort comprises men born in 1953 in the Copenhagen Metropolitan area who participated in a questionnaire survey in 2004. Data were analysed using χ(2)-tests and multivariable logistic regression. RESULTS: The results showed that demands from and conflicts with children were independently associated with fatigue in a dose-response pattern. The adjusted odds ratio for fatigue was 1.48 (95% CI: 1.01-2.17) when the men experienced frequent demands from children and 1.89 (95% CI: 1.17-3.06) when they had frequent conflicts with their children. Crude analyses of demands from or conflicts with spouse, relatives or friends, respectively showed associations with fatigue compared to no demands or no conflicts. However, adjustment for depression and physical chronic disease cancelled out these associations. CONCLUSION: We concluded that middle-aged Danish men, who had frequent negative social interactions with their children, more frequently experienced fatigue. However, negative social interactions with spouse, relatives or friends were not associated with fatigue.

The predictive value of fatigue for nonfatal ischemic heart disease and all-cause mortality.

OBJECTIVE: To investigate whether fatigue predicts nonfatal ischemic heart disease (IHD) and all-cause mortality in middle-aged men. METHODS: The study population consisted of 5216 middle-aged men born in the Copenhagen metropolitan area in 1953. At baseline, men free of angina pectoris and previous IHD were asked if they felt fatigued. Information on IHD diagnosis and all-cause mortality was register based. The Cox proportional hazard model was used to test the association at 4-year follow-up. RESULTS: Fatigue was associated with hospitalization for nonfatal IHD (hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.09-3.61) and all-cause mortality (HR = 3.99, 95% CI = 2.27-7.02). These associations became nonsignificant in multivariable-adjusted models (HR = 1.57, 95% CI = 0.82-3.01 and HR = 1.90, 95% CI = 0.95-3.80). Imputation of missing data did not modify conclusions. Fatigue was a strong independent predictor of first hospitalization for nonfatal IHD among nonsmoking men (HR = 6.00, 95% CI = 2.00-18.04), and the fatigue-by-smoking status interaction was significant (p = .04). Findings should be interpreted with caution because of the small number of participants with IHD (n = 21, 1.5%). Compared to nonfatigued nonsmokers, both fatigued nonsmokers and fatigued smokers had higher hazard of dying (HR = 4.99, 95% CI = 1.31-19.09 and HR = 3.74, 95% CI = 1.32-10.57, respectively), although the fatigue-by-smoking status interaction was not significant (p = .12). CONCLUSIONS: Fatigue is a potential risk indicator for IHD and mortality. Further research is needed to establish the role of smoking and other life-style characteristics.

Fatigability in basic indoor mobility in nonagenarians.

OBJECTIVES: To evaluate the prevalence and associated health factors of indoor mobility-related fatigability in nonagenarians. DESIGN: A cross-sectional observational study of all Danes born in 1905 and assessed in 1998. SETTING: Community, sheltered housing and nursing homes. PARTICIPANTS: Individuals aged 92 and 93 (N = 1,181) who were independent of help in basic indoor mobility. MEASUREMENTS: Fatigability in basic indoor mobility was defined as a subjective feeling of fatigue when transferring or walking indoors. Other standardized assessments include self-report measures of medical history and performance-based assessments of walking speed and maximum handgrip strength. RESULTS: Twenty-six percent of participants reported fatigability when transferring or walking indoors; fatigability was more common in participants living in sheltered housing (32%) than in those living independently (23%, P < .001). Cardiovascular diseases, musculoskeletal pain, medications, walking speed, and depressive symptoms were independently associated with fatigability. CONCLUSION: Fatigability in basic everyday mobility is common in nondisabled nonagenarians. The results also indicate important associations between fatigability and potentially modifiable health factors.

Differential associations between white blood cell counts and fatigue in young and older adults.

BACKGROUND AND AIMS: The aims of this exploratory study were to study whether fatigue might be related to the cellular immune system by 1) analysing if the number of white blood cell subsets are related to fatigue and 2) if possible relationships vary in younger and older community-dwelling individuals. METHODS: The participants were recruited from nine general practitioners in Aarhus County, Denmark and included 196 individuals aged 20-35 years and 314 individuals aged 70-85 years. The white blood cell counts included number of total leukocytes, lymphocytes, monocytes, neutrophils, eosinophils, and basophils. General fatigue was measured by a question from the SF-12 Vitality-Scale and mobility-related fatigue by the Avlund Mob-T Scale. RESULTS: Total number of lymphocytes was associated with fatigue in the old sample, both in the crude and adjusted analyses. Total number of leukocytes and netrophils were associated with fatigue in both age groups in the crude analyses. In the old sample the estimates were attenuated to non-significance when adjusting for physical activity and disability. In the young sample the estimates stayed statistically significant in the fully adjusted analyses regarding number of neutrophils, while the associations between fatigue and number of leukocytes were attenuated to non-significance when adjusting for depressive mood. CONCLUSION: Total number of leukocytes, lymphocytes and neutrophils were associated with fatigue in both age groups, while the explanatory factors for the associations differed by age group, in that the associations were partly explained by physical activity and disability in the old sample and partly by depressive mood in the young sample. The findings provide initial insight into the potential role of leukocyte, neutrophil and lymphocyte counts in the development of fatigue.

Are acceptance rates of a national preventive home visit programme for older people socially imbalanced?: a cross sectional study in Denmark.

BACKGROUND: Preventive home visits are offered to community dwelling older people in Denmark aimed at maintaining their functional ability for as long as possible, but only two thirds of older people accept the offer from the municipalities. The purpose of this study is to investigate 1) whether socioeconomic status was associated with acceptance of preventive home visits among older people and 2) whether municipality invitational procedures for the preventive home visits modified the association. METHODS: The study population included 1,023 community dwelling 80-year-old individuals from the Danish intervention study on preventive home visits. Information on preventive home visit acceptance rates was obtained from questionnaires. Socioeconomic status was measured by financial assets obtained from national registry data, and invitational procedures were identified through the municipalities. Logistic regression analyses were used, adjusted by gender. RESULTS: Older persons with high financial assets accepted preventive home visits more frequently than persons with low assets (adjusted OR = 1.5 (CI95%: 1.1-2.0)). However, the association was attenuated when adjusted by the invitational procedures. The odds ratio for accepting preventive home visits was larger among persons with low financial assets invited by a letter with a proposed date than among persons with high financial assets invited by other procedures, though these estimates had wide confidence intervals. CONCLUSION: High socioeconomic status was associated with a higher acceptance rate of preventive home visits, but the association was attenuated by invitational procedures. The results indicate that the social inequality in acceptance of publicly offered preventive services might decrease if municipalities adopt more proactive invitational procedures.

Mobility-related fatigue, walking speed, and muscle strength in older people.

BACKGROUND: Fatigue is an important early marker of functional decline among older people, but the mechanisms underlying this association are not fully understood. The purpose of the present study was to examine the association between mobility-related fatigue and walking speed and to test the degree to which muscle strength accounts for this association. METHODS: The study is based on baseline (n = 523) and 5-year follow-up data (n = 292) from a cohort of 75-year-old persons. Standardized assessments include self-report measures of mobility-related fatigue (score range 0-6) and medical history, as well as performance-based assessment of walking speed and maximal isometric strength of knee extension, body extension, and handgrip. RESULTS: In the cross-sectional baseline analysis, one unit increase in fatigue score was associated with 0.03 m/s (ß = -.03, p < .001) and 0.05 m/s (ß = -.05, p < .001) slower maximum walking speed among women and men, respectively, while adjusting for important covariates. Among women, muscle strength accounted up to 21% and among men up to 24% for the association. In the prospective analysis, fatigue at baseline was predictive of change in walking speed among men (ß = -.04, p < .001) but not among women (ß = -.005, p = .64). Among men, muscle strength accounted up to 15% for the association between baseline fatigue and change in maximum walking speed. CONCLUSIONS: Mobility-related fatigue is associated with slower walking speed in older adults. The results suggest that muscle strength is one of the underlying factors explaining this association.