Weight loss, visit-to-visit body weight variability and cognitive function in older individuals.

OBJECTIVE: to investigate the association between variability and loss of body weight with subsequent cognitive performance and activities of daily living in older individuals. DESIGN: cross-sectional cohort study. SETTING: PROspective Study of Pravastatin in the Elderly at Risk, multicentre trial with participants from Scotland, Ireland and the Netherlands. SUBJECTS: 4,309 participants without severe cognitive dysfunction (mean age 75.1 years, standard deviation (SD) = 3.3), at higher risk for cardiovascular disease (CVD). METHODS: body weight was measured every 3 months for 2.5 years. Weight loss was defined as an average slope across all weight measurements and as ≥5% decrease in baseline body weight during follow-up. Visit-to-visit variability was defined as the SD of weight measurements (kg) between visits. Four tests of cognitive function were examined: Stroop test, letter-digit coding test (LDCT), immediate and delayed picture-word learning tests. Two measures of daily living activities: Barthel Index (BI) and instrumental activities of daily living (IADL). All tests were examined at month 30. RESULTS: both larger body weight variability and loss of ≥5% of baseline weight were independently associated with worse scores on all cognitive tests, but minimally with BI and IADL. Compared with participants with stable weight, participants with significant weight loss performed 5.83 seconds (95% CI 3.74; 7.92) slower on the Stroop test, coded 1.72 digits less (95% CI -2.21; -1.13) on the LDCT and remembered 0.71 pictures less (95% CI -0.93; -0.48) on the delayed picture-word learning test. CONCLUSION: in older people at higher risk for CVD, weight loss and variability are independent risk-factors for worse cognitive function.

Design and rationale of a routine clinical care pathway and prospective cohort study in older patients needing intensive treatment.

BACKGROUND: Treatment decisions concerning older patients can be very challenging and individualised treatment plans are often required in this very heterogeneous group. In 2015 we have implemented a routine clinical care pathway for older patients in need of intensive treatment, including a comprehensive geriatric assessment (CGA) that was used to support clinical decision making. An ongoing prospective cohort study, the Triaging Elderly Needing Treatment (TENT) study, has also been initiated in 2016 for participants in this clinical care pathway, to study associations between geriatric characteristics and outcomes of treatment that are relevant to older patients. The aim of this paper is to describe the implementation and rationale of the routine clinical care pathway and design of the TENT study. METHODS: A routine clinical care pathway has been designed and implemented in multiple hospitals in the Netherlands. Patients aged ≥70 years who are candidates for intensive treatments, such as chemotherapy, (chemo-)radiation therapy or major surgery, undergo frailty screening based on the Geriatric 8 (G-8) questionnaire and the Six-Item Cognitive Impairment Test (6CIT). If screening reveals potential frailty, a CGA is performed. All patients are invited to participate in the TENT study. Clinical data and blood samples for biomarker studies are collected at baseline. During follow-up, information about treatment complications, hospitalisations, functional decline, quality of life and mortality is collected. The primary outcome is the composite endpoint of functional decline or mortality at 1 year. DISCUSSION: Implementation of a routine clinical care pathway for older patients in need of intensive treatment provides the opportunity to study associations between determinants of frailty and outcomes of treatment. Results of the TENT study will support individualised treatment for future patients. TRIAL REGISTRATION: The study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107 . Date of registration: 22-10-2019.

Patterns and characteristics of cognitive functioning in older patients approaching end stage kidney disease, the COPE-study.

BACKGROUND: The prevalence of impaired cognitive functioning in older patients with end stage kidney disease (ESKD) is high. We aim to describe patterns of memory, executive function or psychomotor speed and to identify nephrologic, geriatric and neuroradiologic characteristics associated with cognitive impairment in older patients approaching ESKD who have not yet started with renal replacement therapy (RRT). METHODS: The COPE-study (Cognitive Decline in Older Patients with ESRD) is a prospective cohort study including 157 participants aged 65 years and older approaching ESKD (eGFR ≤20 ml/min/1.73 m2) prior to starting with RRT. In addition to routinely collected clinical parameters related to ESKD, such as vascular disease burden and parameters of metabolic disturbance, patients received a full geriatric assessment, including extensive neuropsychological testing. In a subgroup of patients (n = 93) a brain MRI was performed. RESULTS: The median age was 75.3 years. Compared to the normative data of neuropsychological testing participants memory performance was in the 24th percentile, executive function in the 18th percentile and psychomotor speed in the 20th percentile. Independent associated characteristics of impairment in memory, executive and psychomotor speed were high age, low educational level and low functional status (all p-values < 0.003). A history of vascular disease (p = 0.007) and more white matter hyperintensities on brain MRI (p = 0.013) were associated with a lower psychomotor speed. CONCLUSION: Older patients approaching ESKD have a high prevalence of impaired memory, executive function and psychomotor speed. The patterns of cognitive impairment and brain changes on MRI are suggestive of vascular cognitive impairment. These findings could be of potentially added value in the decision-making process concerning patients with ESKD.

Knee extension strength measurements should be considered as part of the comprehensive geriatric assessment.

BACKGROUND: Comprehensive geriatric assessment (CGA) generally includes handgrip strength (HGS) as a measure of overall muscle strength that is associated with various health characteristics in geriatric outpatients. Whether this is also true for knee extension strength (KES) is yet unknown. This study aims to compare the associations between health characteristics from the CGA with both HGS and KES in geriatric outpatients. METHODS: Data were retrieved from a cross-sectional study. A total of 163 community-dwelling older adults referred to a geriatric outpatient clinic of a middle-sized teaching hospital were included. Health characteristics included physical, nutritional, social, psychological, diseases, cognitive, and behavioural factors. HGS and KES were assessed three times for each limb and the best performance was used for analysis. Sex-specific z-scores of HGS and KES were used to allow comparison of effect estimates. Associations between health characteristics with standardized HGS and KES were analysed with linear regression adjusted for age, sex and further adjustment for standardized KES (for model of HGS) or standardized HGS (for model of KES). RESULTS: Physical, nutritional and psychological health characteristics were positively associated with both HGS and KES after adjustment for age and sex, with overall stronger associations with KES compared to HGS. All significant associations with HGS were lost after further adjustment for KES; significant associations with KES remained after further adjustment for HGS, except for nutritional characteristics. CONCLUSIONS: Stronger associations of health characteristics with KES compared to HGS indicate its additional value and therefore inclusion of KES in the CGA is recommended.

Blood pressure change does not associate with Center of Pressure movement after postural transition in geriatric outpatients.

BACKGROUND: Orthostatic hypotension (OH), a blood pressure drop after postural change, is associated with impaired standing balance and falls in older adults. This study aimed to assess the association between blood pressure (BP) and a measure of quality of standing balance, i.e. Center of Pressure (CoP) movement, after postural change from supine to standing position in geriatric outpatients, and to compare CoP movement between patients with and without OH. METHODS: In a random subgroup of 75 consecutive patients who were referred to a geriatric outpatient clinic, intermittent BP measurements were obtained simultaneously with CoP measurements in mediolateral and anterior-posterior direction directly after postural change during 3 min of quiet stance with eyes open on a force plate. Additional measurements of continuous BP were available in n = 38 patients. Associations between BP change during postural change and CoP movement were analyzed using Spearman correlation. Mann-Whitney-U tests were used to compare CoP movement between patients with OH and without OH, in which OH was defined as a BP drop exceeding 20 mmHg of systolic BP (SBP) and/or 10 mmHg of diastolic BP (DBP) within 3 min after postural change. RESULTS: OH measured intermittently was found in 8 out of 75 (11%) and OH measured continuously in 22 out of 38 patients (57.9%). BP change did not associate with CoP movement. CoP movement did not differ significantly between patients with and without OH. CONCLUSIONS: Results do not underpin the added value of CoP movement measurements in diagnosing OH in a clinical setting. Neither could we identify the role of CoP measurements in the understanding of the relation between OH and impaired standing balance.

Early prediction of hospital admission for emergency department patients: a comparison between patients younger or older than 70 years.

OBJECTIVE: The aim of this study was to develop models that predict hospital admission to ED of patients younger and older than 70 and compare their performance. METHODS: Prediction models were derived in a retrospective observational study of all patients≥18 years old visiting the ED of a university hospital during the first 6 months of 2012. Patients were stratified into two age groups (<70 years old and ≥70 years old). Multivariable logistic regression analysis was used to identify predictors of hospital admission among factors available immediately after patient arrival to the ED. Validation of the prediction models was performed on patients presenting to the ED during the second half of the year 2012. RESULTS: 10 807 patients were included in the derivation and 10 480 in the validation cohorts. The strongest independent predictors of hospital admission among the 8728 patients <70 years old were age, sex, triage category, mode of arrival, performance of blood tests, chief complaint, ED revisit, type of specialist, phlebotomised blood sample and all vital signs. The area under the curve (AUC) of the validation cohort for those <70 years old was 0.86 (95% CI 0.85 to 0.87). Among the 2079 patients ≥70 years, the same factors were predictive, except for gender, type of specialist and heart rate; the AUC was 0.77 (95% CI 0.75 to 0.79). The prediction models could identify a group of 10% of patients with the highest risk in whom hospital admission was predicted at ED triage, with a positive predictive value (PPV) of 71% (95% CI 68% to 74%) in younger patients and PPV of 87% (95% CI 81% to 92%) in older patients. CONCLUSION: Demographic and clinical factors readily available early in the ED visit can be useful in identifying patients who are likely to be admitted to the hospital. While the model for the younger patients had a higher AUC, the model for older patients had a higher PPV in identifying the patients at highest risk for admission. Of note, heart rate was not a useful predictor in the older patients.

Association between changes in brain microstructure and cognition in older subjects at increased risk for vascular disease.

BACKGROUND: The purpose of this study is to investigate whether changes in brain microstructure, detected by magnetization transfer imaging, are associated with cognition in older subjects at increased risk for vascular disease. METHODS: One hundred ninety three nondemented subjects (105 men, mean age 77 ± 3 years) from the Prospective Study of Pravastatin in the Elderly at Risk were included. To assess cross-sectional associations between magnetization transfer ratio (MTR) peak height and cognitive test scores, general linear model multivariate analysis was performed. Models were adjusted for age, sex, education level, vascular risk factors, individual white matter lesion volume, and brain atrophy. A repeated measures general linear model was used to investigate whether MTR peak height relates to cognitive test performance at baseline and 3.3-year follow-up. RESULTS: Cross-sectionally, MTR peak height was associated with performance on the STROOP test (unstandardized ß = -0.27, p = 0.045), delayed Picture Word Learning (PWL) test (ß = 0.48, p = 0.007), and the Letter Digit Coding test (ß = 1.1, p = 0.006). Repeated measures general linear model analysis showed that individuals with low MTR peak height at baseline performed worse on the STROOP test compared to subjects with intermediate MTR peak height (mean time to complete the test at baseline and follow-up, lower versus middle tertile of MTR peak height: 61.6 versus 52.7 s, p = 0.019) or compared to subjects with high MTR peak height (p = 0.046). Similarly, low MTR peak height was associated with worse performance on the immediate (lower versus middle tertile, p = 0.023; lower versus higher tertile, p = 0.032) and delayed PWL test (lower versus middle, p = 0.004; lower versus higher, p = 0.012) at baseline and follow-up testing. CONCLUSIONS: MTR peak height is associated with cognitive function in older subjects at increased risk for vascular disease.

Performance of Cockcroft-Gault, MDRD, and CKD-EPI in estimating prevalence of renal function and predicting survival in the oldest old.

BACKGROUND: The question for prevalence estimation and validation of the various eGFRs in old age is still under debate. To assess renal function with increasing age, we estimated mean eGFR, in subjects aged 20-85 years. Furthermore, we assessed prevalence of eGFR in a population-based sample of 85 year olds and investigated the performance of these eGFRs in predicting mortality in the oldest old. METHODS: Renal function with increasing age was assessed in subjects aged 20-85 years from the Bronovo Study Cohort. We estimated prevalences of eGFRs and mortality risks in a population-based study of persons aged 85 years and older, the Leiden 85-plus Study. The GFRs were estimated by three different formulas. RESULTS: After the age of 70 years, the C-G tended to give relatively lower eGFRs. An eGFR < 60 was found in 90% of the subjects aged 85 years as calculated by C-G, in 55% of the subjects using MDRD and in 68% of the 85 year old subjects as calculated by CKD-EPI. When renal function was <30 ml/min/1.73 m2, an increased mortality risk was observed by C-G (HR 1.9 (95% CI 1.1-3.3)), by MDRD (HR 3.5 (95% CI 1.8-6.7)), whereas by CKD-EPI significance was not reached (HR 2.4 (95% CI 0.9-6.4)). CONCLUSIONS: Our study demonstrates that in subjects above age 70, C-G gives lower estimates of renal function when compared to MDRD and CKD-EPI. Furthermore, prevalence of renal dysfunction (CKD stage 1-3) at age 85 years was highest for C-G (90%), lowest for MDRD (55%), and 68% for CKD-EPI. Moreover, we found that in subjects aged 85 years MDRD predicted mortality best.

Neurovascular coupling in early stage dementia - A case-control study.

Cerebral amyloid angiopathy (CAA) is frequently found post mortem in Alzheimer's dementia, but often undetected during life especially since in vivo hallmarks of CAA and its vascular damage become overt relatively late in the disease process. Decreased neurovascular coupling to visual stimulation has been put forward as an early MRI marker for CAA disease severity. The current study investigates the role of neurovascular coupling in AD related dementia and its early stages. We included 25 subjective cognitive impairment, 33 mild cognitive impairment and 17 dementia patients and 44 controls. All participants underwent magnetic resonance imaging of the brain and neuropsychological assessment. Univariate general linear modeling analyses were used to assess neurovascular coupling between patient groups and controls. Moreover, linear regression analyses was used to assess the associations between neurovascular coupling and cognition. Our data show that BOLD amplitude is lower in dementia (mean 0.8 ± 0.2, p = 0.001) and MCI patients (mean 0.9 ± 0.3, p = 0.004) compared with controls (mean 1.1 ± 0.2). A low BOLD amplitude was associated with low scores in multiple cognitive domains. We conclude that cerebrovascular dysfunction, most likely due CAA, is an important comorbidity in early stages of dementia and has an independent effect on cognition.

No increased mortality risk in older persons with unexplained anaemia.

BACKGROUND: in older persons, anaemia is associated with a number of unfavourable outcomes. In approximately 30% of older persons with anaemia, the cause of the anaemia is unexplained. We assessed the clinical differences between subjects with explained and unexplained anaemia and investigated whether these subjects have different mortality patterns compared with subjects without anaemia. DESIGN: observational prospective follow-up study. SETTING: the Leiden 85-plus study. PARTICIPANTS: four hundred and ninety-one persons aged 86 years. METHODS: the study population was divided in three groups: (i) no anaemia (reference group, n=377), (ii) explained anaemia (iron deficiency, folate deficiency, vitamin B12 deficiency, signs of myelodysplastic syndrome or renal failure, n=74) and (iii) unexplained anaemia, (n=40). Mortality risks were estimated with Cox-proportional hazard models. RESULTS: haemoglobin levels were significantly lower in subjects with explained anaemia than in subjects with unexplained anaemia (P<0.01). An increased risk for mortality was observed in subjects with explained anaemia [HR: 1.93 (95% CI: 1.47-2.52), P<0.001], but not in subjects with unexplained anaemia [HR: 1.19 (95% CI: 0.85-1.69), P=0.31]. Adjusted analyses (sex, co-morbidity, MMSE, institutionalised and smoking) did not change the observed associations for both explained and unexplained anaemic subjects. CONCLUSION: older subjects with unexplained anaemia had similar survival compared with non-anaemic subjects. Increased mortality risks were observed in subjects with explained anaemia compared with non-anaemic subjects.

Temporal relationship between handgrip strength and cognitive performance in oldest old people.

BACKGROUND: cognitive decline and muscle weakness are prevalent health conditions in elderly people. We hypothesised that cognitive decline precedes muscle weakness. OBJECTIVE: to analyse the temporal relationship between cognitive performance and handgrip strength in oldest old people. DESIGN: prospective population-based 4-year follow-up study. SUBJECTS: a total of 555 subjects, all aged 85 years at baseline, were included into the study. METHODS: handgrip strength measured at age 85 and 89 years. Neuropsychological test battery to assess global cognitive performance, attention, processing speed and memory at baseline and repeated at age 89 years. Associations between handgrip strength and cognitive performance were analysed by repeated linear regression analysis adjusted for common confounders. RESULTS: at age 85 and 89 years, better cognitive performance was associated with higher handgrip strength (all, P<0.03), except for attention. There was no longitudinal association between baseline handgrip strength and cognitive decline (all, P>0.10), except for global cognitive performance (P=0.007). Better cognitive performance at age 85 years was associated with slower decline in handgrip strength (all, P<0.01) after adjustment for common confounders. CONCLUSION: baseline cognitive performance was associated with decline in handgrip strength, whereas baseline handgrip strength was not associated with cognitive decline. Our results suggest that cognitive decline precedes the onset of muscle weakness in oldest old people.

Thyroid Function and Risk of Anemia: A Multivariable-Adjusted and Mendelian Randomization Analysis in the UK Biobank.

CONTEXT: Thyroid dysfunction is associated with higher anemia prevalence, although causality remains unclear. OBJECTIVE: This study aimed to investigate the association between thyroid function and anemia. METHODS: This cross-sectional and Mendelian randomization study included 445 482 European participants from the UK Biobank (mean age 56.77 years (SD 8.0); and 54.2% women). Self-reported clinical diagnosis of hypothyroidism was stated by 21 860 (4.9%); self-reported clinical diagnosis of hyperthyroidism by 3431 (0.8%). Anemia, defined as hemoglobin level of < 13 g/dL in men and < 12 g/dL in women, was present in 18 717 (4.2%) participants. RESULTS: In cross-sectional logistic regression analyses, self-reported clinical diagnoses of hypo- and hyperthyroidism were associated with higher odds of anemia (OR 1.12; 95% CI, 1.05-1.19 and OR 1.09; 95% CI, 0.91-1.30), although with wide confidence intervals for hyperthyroidism. We did not observe an association of higher or lower genetically influenced thyrotropin (TSH) with anemia (vs middle tertile: OR for lowest tertile 0.98 [95% CI, 0.95-1.02]; highest tertile 1.02 [95% CI, 0.98-1.06]), nor of genetically influenced free thyroxine (fT4) with anemia. Individuals with genetic variants in the DIO3OS gene implicated in intracellular regulation of thyroid hormones had a higher anemia risk (OR 1.05; 95% CI, 1.02-1.10); no association was observed with variants in DIO1 or DIO2 genes. CONCLUSION: While self-reported clinical diagnosis of hypothyroidism was associated with higher anemia risk, we did not find evidence supporting a causal association with variation of thyroid function within the euthyroid range. However, intracellular regulation of thyroid hormones might play a role in developing anemia.

Diastolic carotid artery wall shear stress is associated with cerebral infarcts and periventricular white matter lesions.

BACKGROUND AND PURPOSE: Low wall shear stress (WSS) is an early marker in the development of vascular lesions. The present study aims to assess the relationship between diastolic and systolic WSS in the internal carotid artery and periventricular (PWML), deep white matter lesions, and cerebral infarcts (CI). METHODS: Early, mid, and late diastolic and peak systolic WSS were derived from shear rate obtained by gradient echo phase contrast magnetic resonance sequences multiplied by individually modeled viscosity. PWML, deep white matter lesions, and CI were derived from proton density (PD), T2, and fluid attenuated inversion recovery (FLAIR) MRI in 329 participants (70-82 years; PROSPER baseline). Analyses were adjusted, if appropriate, for age, gender, intracranial volume, and multiple cardiovascular risk factors. RESULTS: Mid-diastolic WSS was significantly correlated with the presence of PWML (B=-10.15; P=0.006) and CI (B=-2.06; P=0.044), but not with deep white matter lesions (B=-1.30; P=0.050; adjusted for age, gender, WML, and intracranial volume). After adjustment for cardiovascular risk factors, these correlations weakened but remained significant. Systolic WSS was not correlated with any of the cerebrovascular parameters. CONCLUSIONS: This study is the first to our knowledge to present a cross-sectional correlation between carotid artery WSS and cerebrovascular pathology such as PWML and CI in a large population. Furthermore, it shows that diastolic hemodynamics may be more important than systolic or mean hemodynamics. Future studies exploring vascular hemodynamic damage should focus on diastolic WSS.

Persistent epigenetic differences associated with prenatal exposure to famine in humans.

Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development. Although the mechanisms behind these relationships are unclear, an involvement of epigenetic dysregulation has been hypothesized. Here we show that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944-45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for periconceptional exposure, reinforcing that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.

Determining the frequency of thyroid parameter measurements following rhTSH administration in a healthy, older population.

Serial thyroid hormone measurement in blood following recombinant human thyroid stimulating hormone (rhTSH) administration has not been studied extensively in healthy, older populations. Current methods involve measurement of thyroid hormones mostly at 4 to 24 hours following rhTSH administration. We tailored existing protocols to measure thyroid hormones at high frequencies following 0.1mg rhTSH intramuscular (i.m.) administration to identify optimal measurement points in our healthy, older population. We designed a method with frequent blood sampling in the first 8 hours, followed by blood sampling at 24, 48 and 72 hours after rhTSH administration to measure TSH, thyroxine (T4), free T4 (fT4), triiodothyronine (T3), free T3 (fT3) and thyroglobulin (Tg). In total, we performed a series of 17 blood withdrawals in four consecutive days. Following 0.1mg rhTSH (i.m.) administration, mean thyroid parameters showed great inter-individual variation and variation over time. Mean TSH concentration showed the greatest variation in the first 8 hours following rhTSH administration. Mean T4, fT4, T3 and fT3 started showing variation from 2 hours after rhTSH administration, and were less variable than mean TSH concentration. Mean Tg was only variable at later time points, namely 24, 48 and 72 hours after rhTSH administration. In this novel method with high frequency blood sampling following 0.1mg rhTSH (i.m.) administration, we identify optimal time points for measuring thyroid gland output in a healthy, older population. Our methods and findings may be informative for further thyroid but also other hormonal axis studies.•Thyroid metabolism•Blood sampling frequency•Geriatrics and longevity.

Familial longevity is associated with lower baseline bone turnover but not differences in bone turnover in response to rhTSH.

CONTEXT: Offspring from long-lived families have a different thyroid status than controls, characterised by higher circulating levels of thyroid stimulating hormone (TSH) and similar levels of thyroid hormone. Expression of the TSH receptor has previously been observed on various extrathyroidal tissues, including bone. However, potential physiological consequences of differences in circulating TSH as observed in familial longevity on bone tissue remain unclear. OBJECTIVE: Based on the hypothesis that TSH may inhibit bone resorption, we explored whether offspring of long-lived families have lower bone turnover than controls at baseline as well as following a challenge with recombinant human TSH (rhTSH). METHODS: Bone turnover markers CTX and P1NP were measured in fasted morning samples from 14 offspring and 12 controls at baseline and at 24 hour intervals following 0.1 mg rhTSH i.m. administration for four consecutive days. RESULTS: At baseline, mean (SEM) CTX was 0.32 (0.03) ng/ml in offspring and 0.50 (0.04) ng/ml in controls, p < 0.01, whereas mean (SEM) P1NP was 39.6 (3.2) ng/ml in offspring and 61.8 (6.6) ng/ml in controls, p < 0.01. Following rhTSH administration, both CTX and P1NP levels transiently increased over time and normalized towards baseline after 72 h (general linear modelling: CTX time p = 0.01, P1NP time p < 0.01); the response was similar between offspring and controls. CONCLUSIONS: Bone turnover markers were lower at baseline in offspring from long-lived families than in controls but increased similarly following an rhTSH challenge.

Prognostic Factors for Short-term Recovery of Independence in a Multistate Model for Patients With a Hip Fracture.

OBJECTIVES: This study investigates the transitions of community-dwelling patients with a proximal femoral fracture towards recovery of independence using multistate modeling. The prognostic value of factors affecting the short-term rate of recovery of independence in activities of daily living was assessed for the resilient portion of the population. DESIGN: An inception cohort was recruited between 2016 and 2019. SETTING AND PARTICIPANTS: Only community-dwelling older patients admitted with a proximal femoral fracture were included. MEASURES: Follow-up was performed at 6 weeks and 3 months, when the patients' living situation and level of independence were recorded. Multistate modeling was used to study the transition rates of the population through prespecified states of the recovery process. Using this model, prognostic factors for the recovery of independence were identified for resilient patients (defined as those patients who managed to return home at any point in the follow-up after discharge). RESULTS: A total of 558 patients were included, and 218 (40.9%) recovered to prefracture levels of independence. Of the resilient patients, 20.7% were discharged home directly, and 79.3% via a rehabilitation home. In this patient group, a more favorable American Society of Anesthesiologists classification, better prefracture mobility, and the absence of a prefracture fear of falling were statistically significantly associated with a successful recovery. A low level of prefracture independence was inversely associated, meaning that patients with a low level of prefracture independence had a higher chance of successful recovery. CONCLUSIONS AND IMPLICATIONS: This study identified 4 factors with an independent prognostic value for the recovery of independence in resilient patients after a proximal femoral fracture. These factors could be used to construct clinical profiles that contribute to the assessment of the patient's post-acute care needs and recovery capacity. In addition, multistate modeling has been shown to be an effective and versatile tool in the study of recovery prognostics.

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

KIF6 Trp719Arg polymorphism and the effect of statin therapy in elderly patients: results from the PROSPER study.

BACKGROUND: Statin therapy has been found to substantially and significantly reduce coronary events in carriers of the KIF6 719Arg variant (rs20455) but not in noncarriers. We investigated whether, among the elderly, statin therapy also significantly reduced coronary events in carriers but not in noncarriers. DESIGN AND METHODS: Among 5,752 patients of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study, we assessed the effect of pravastatin, compared with placebo, on coronary events according to 719Arg carrier status using proportional hazards models. RESULTS: Since benefit from statin therapy in elderly patients has been primarily shown among those with prior vascular disease, we performed analyses in PROSPER patients with prior disease and found that pravastatin therapy significantly reduced events in 719Arg carriers [hazards ratio (HR): 0.66, 95% confidence interval (CI): 0.52-0.86] but not in noncarriers (HR: 0.94, 95% CI: 0.69-1.28), P=0.09 for interaction between treatment and carrier status. Among those without prior disease, no significant benefit was observed in either carriers or noncarriers. Among those with prior vascular disease in the placebo arm, Trp719Arg heterozygotes were at significantly greater risk, compared with noncarriers (HR: 1.36, 95% CI: 1.03-1.81, P=0.03); the HR of 719Arg carriers, compared with noncarriers, was 1.28 (95% CI: 0.98-1.69, P=0.07). CONCLUSION: Elderly carriers of the KIF6 719Arg variant with prior vascular disease received significant benefit from pravastatin therapy; no benefit was observed in noncarriers with prior disease or in those without prior disease (carriers or noncarriers).