Search

Introduction: The prevalence of depressive symptoms and cognitive decline increases with age, reducing quality of life. However, the temporal relationship between the two remains elusive. Objectives: We aimed to explore the temporal relationship between depressive symptoms and cognitive decline in individuals aged 85 years, during up to 5 years follow-up. Methods: Participants eligible for this study were selected from the Leiden 85-plus Study, who participated for at least 3 follow-up measurements. Depressive symptoms were assessed at baseline and at follow-up in a period of 6 yearly assessments, utilizing the 15-item Geriatric Depression Scale (GDS-15). Cognitive decline was measured through various tests including the Mini Mental State Exam (MMSE), Stroop Test, Letter Digit Coding Test, and immediate and delayed recall using the 12-word learning test. Dynamic Time Warping (DTW) analysis was employed to model their temporal dynamics, in undirected and directed analysis, to ascertain whether depressive symptoms precede cognitive decline, or vice versa. Results: The study included a total of 325 (54.2%) of 599 patients, of whom 68.0% were female, 45.0% with intermediate to higher education, and all aged 85 years. Depressive symptoms and cognitive functioning significantly covaried in time, and directed analyses showed that depressive symptoms preceded most of the parameters of cognitive decline in the oldest old. Of the 15 GDS symptoms, those with the strongest outstrength were worthlessness, hopelessness, low happiness, dropping activities/interests, and low satisfaction with life (all p<.01). Conclusions: We found a strong temporal link between depressive symptoms and subsequent cognitive decline in a population of the oldest old. This highlights the importance of a holistic approach that considers both mental and cognitive well-being in the aging population. As depressive symptoms were an early indicator of cognitive decline, it is of importance that healthcare professionals recognize and address depressive symptoms early to allow for appropriate interventions and support, to potentially mitigate the impact on cognitive decline. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

Background: Common and plantar warts are caused by human papillomaviruses (HPV). Mode of transmission of wart HPVs within families is largely unknown. Objective: To demonstrate similarity of HPV type(s) among wart cases, family members and household linen. Methods: In a cross‐sectional study, swabs taken from 123 warts and foreheads of 62 index patients and 157 family members and from 58 kitchen towels and 59 bathroom mats were tested for DNA of 23 cutaneous wart‐associated HPV types. Generalized estimating equations (GEE) were used to estimate the chance of detecting the same HPV type as was found in the index patients on the family contacts and on the kitchen towels and bathroom mats. Results: HPV1, HPV2, HPV27 and HPV57 were the most prevalent types in the warts of the index patients. Altogether, 60 (42.3%) of the 142 family members without warts had HPV DNA on their foreheads. When HPV1 and HPV2 were found in the warts, these types were also frequently (>50%) found on the foreheads of index patients and their family members, as well as on the kitchen towels and the bathroom mats. HPV27 and HPV57 were less frequently found (<25%) on foreheads and linen. No associations were found for age, sex and site of HPV DNA presence. Conclusion: Dissemination of skin wart‐causing HPV types, from wart cases to household contacts and linen, such as kitchen towels and bathroom mats, is more likely for HPV1 and HPV2 than for HPV27 and HPV57. The role of towels and bathroom mats in HPV transmission deserves further investigation. Linked Commentary A. Kreuter and U. Wieland. J Eur Acad Dermatol Venereol 2022; 36: 11–12. https://doi.org/10.1111/jdv.17820. [ABSTRACT FROM AUTHOR]

Background: Managing older patients with acute pulmonary embolism (PE) is challenging due to their underrepresentation in clinical trials, comorbidities, and increased complication risk., Objectives: To evaluate risk assessment and management outcomes in older patients with PE focusing on home and reperfusion treatment., Methods: A retrospective analysis was conducted on patients aged 70 years or older diagnosed with acute PE at an academic medical center (2015-2022)., Results: In total, 242 patients with a mean age of 77 years were included. All 59 patients with negative Hestia criteria were discharged ≤24 hours, and in total, 81 patients (35%) received home treatment. Among these 14-day mortality and recurrent venous thromboembolism were 0% and major bleeding occurred in 1.3% (1 patient, 95% CI: 0.11-6.1). European Society of Cardiology risk classification showed 9 low-risk (3.9%), 199 intermediate-risk (87%), and 20 high-risk (8.8) patients with PE. In 5 of the 20 high-risk patients, hypotension was mainly caused by another condition, that is, sepsis. Eight high-risk patients received reperfusion therapy. The 14-day mortality rate was 51% in high-risk patients (95% CI: 27-71); 5 of 8 patients receiving reperfusion treatment died within 5 days. Patients with an Acute Presenting Older Patient score of ≥45% had higher 14-day mortality (28%; 95% CI: 12-46) compared with <45% (3.2%; 95% CI: 0.85-8.3; hazard ratios: 10.2; 95% CI: 2.6-39)., Conclusion: Selecting for home treatment using Hestia criteria was safe for older patients with PE in our cohort. Mortality in the high-risk group was high also when receiving reperfusion treatment. The European Society of Cardiology risk classification and Acute Presenting Older Patient score identified patients at higher mortality risk, suggesting their potential utility in clinical decision-making., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Given the growing population of older persons, medical students need to develop an appropriate professional identity to comply with older persons' healthcare needs. In this study, we explored the needs and expectations of older persons regarding their doctor to gain more insight into the characteristics of this professional identity., Design: A qualitative study based on a constructivist research paradigm was conducted, based on individual semistructured, in-depth interviews using a letter as a prompt, and focus groups. Thematic analysis was applied to structure and interpret the data., Setting and Participants: Our study population consisted of older persons, aged 65 years and above, living at home in the South-West of the Netherlands, with no apparent cognitive or hearing problems and sufficient understanding of the Dutch language to participate in writing, talking and reflecting. The in-depth interviews took place at the participant's home or the Leiden University Medical Center (LUMC), and the focus groups were held at the LUMC., Results: The older persons shared and reflected on what they need and expect from the doctor who takes care of them. Four major themes were identified: (1) personal attention, (2) equality, (3) clarity and (4) reasons why., Conclusion: Increasing complexity, dependency and vulnerability that arise at an older age, make it essential that a doctor is familiar with the older person's social context, interacts respectfully and on the basis of equality, provides continuity of care and gives clarity and perspective. To this end, the doctor has to be caring, involved, patient, honest and self-aware. Participation in a community of practice that provides the context of older persons' healthcare may help medical students develop a professional identity that is appropriate for this care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Viral mutations and improved prevention or treatment options may have changed the association of frailty with mortality throughout the COVID-19 pandemic. We investigated how associations of frailty with in-hospital mortality changed throughout the pandemic in older people hospitalised for COVID-19., Methods: The COVID-OLD study included COVID-19 patients aged ≥ 70 years hospitalised during the first (early 2020), second (late 2020), third (late 2021) or fourth wave (early 2022). Based on the clinical frailty scale, patients were categorised as fit (1-3), pre-frail (4-5) or frail (6-9). Associations of frailty with in-hospital mortality were assessed with pairwise comparisons with fit as reference category and modelled using binary logistic regression adjusted for age and sex., Results: This study included 2362 patients (mean age 79.7 years, 60% men). In the first wave, in-hospital mortality was 46% in patients with frailty and 27% in fit patients. In-hospital mortality decreased in each subsequent wave to 25% in patients with frailty and 11% in fit patients in the fourth wave. After adjustments, an overall higher risk of in-hospital mortality was found in frail (OR 2.26, 95% CI: 1.66-3.07) and pre-frail (OR 1.73, 95% CI: 1.27-2.35) patients compared to fit patients, which did not change over time (p for interaction = 0.74)., Conclusions: Frailty remained associated with a higher risk of in-hospital mortality throughout the entire COVID-19 pandemic, although overall in-hospital mortality rates decreased. Frailty therefore remains a relevant risk factor in all stages of a pandemic and is important to consider in prevention and treatment guidelines for future pandemics., (© 2024. The Author(s).)

Background: The prevalence of depressive symptoms and cognitive decline increases with age. We investigated their temporal dynamics in individuals aged 85 and older across a 5-year follow-up period., Methods: Participants were selected from the Leiden 85-plus study and were eligible if at least three follow-up measurements were available (325 of 599 participants). Depressive symptoms were assessed at baseline and at yearly assessments during a follow-up period of up to 5 years, using the 15-item Geriatric Depression Scale (GDS-15). Cognitive decline was measured through various tests, including the Mini Mental State Exam, Stroop test, Letter Digit Coding test and immediate and delayed recall. A novel method, dynamic time warping analysis, was employed to model their temporal dynamics within individuals, in undirected and directed time-lag analyses, to ascertain whether depressive symptoms precede cognitive decline in group-level aggregated results or vice versa., Results: The 325 participants were all 85 years of age at baseline; 68% were female, and 45% received intermediate to higher education. Depressive symptoms and cognitive functioning significantly covaried in time, and directed analyses showed that depressive symptoms preceded most of the constituents of cognitive impairment in the oldest old. Of the GDS-15 symptoms, those with the strongest outstrength, indicating changes in these symptoms preceded subsequent changes in other symptoms, were worthlessness, hopelessness, low happiness, dropping activities/interests, and low satisfaction with life (all P's < 0.01)., Conclusion: Depressive symptoms preceded cognitive impairment in a population based sample of the oldest old., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: Based on observational studies and randomised controlled trials (RCTs), the benefit-harm balance of antihypertensive treatment in older adults with dementia is unclear., Objective: To assess whether discontinuing antihypertensive treatment reduces neuropsychiatric symptoms (NPSs) and maintains quality of life (QoL) in nursing home residents with dementia., Design: Open-label, blinded-outcome RCT. Randomisation 1:1, stratified by nursing home organisation and baseline NPS. Trial registration: NL7365., Subjects: Dutch long-term care residents with moderate-to-severe dementia and systolic blood pressure (SBP) ≤160 mmHg during antihypertensive treatment. Exclusion criteria included heart failure NYHA-class-III/IV, recent cardiovascular events/procedures or life expectancy <4 months (planned sample size n = 492)., Measurements: Co-primary outcomes NPS (Neuropsychiatric Inventory-Nursing Home [NPI-NH]) and QoL (Qualidem) at 16 weeks., Results: From 9 November 2018 to 4 May 2021, 205 participants (median age 85.8 [IQR 79.6-89.5] years; 79.5% female; median SBP 134 [IQR 123-146] mmHg) were randomised to either antihypertensive treatment discontinuation (n = 101) or usual care (n = 104). Safety concerns, combined with lacking benefits, prompted the data safety and monitoring board to advice a premature cessation of randomisation. At 16-week follow-up, no significant differences were found between groups for NPI-NH (adjusted mean difference 1.6 [95% CI -2.3 to 5.6]; P = 0.42) or Qualidem (adjusted mean difference - 2.5 [95% CI -6.0 to 1.0]; P = 0.15). Serious adverse events (SAEs) occurred in 36% (discontinuation) and 24% (usual care) of the participants (adjusted hazard ratio 1.65 [95% CI 0.98-2.79]). All 32-week outcomes favoured usual care., Conclusion: Halfway through this study, a non-significant increased SAE risk associated with discontinuing antihypertensive treatment was observed, and an associated interim analysis showed that significant worthwhile health gain for discontinuation of antihypertensive treatment was unlikely. This unbeneficial benefit-harm balance shows that discontinuation of antihypertensive treatment in this context does not appear to be either safe or beneficial enough to be recommended in older adults with dementia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: Subclinical thyroid diseases are often the subject of debate concerning their clinical significance, the appropriateness of diagnostic testing, and possible treatment. This systematic review addresses the variation in international guidelines for subclinical hyperthyroidism, focusing on diagnostic workup, treatment, and follow-up recommendations., Methods: Following the PRISMA guidelines, we searched PubMed, Embase, and guideline-specific databases and included clinical practice guidelines with recommendations on subclinical hyperthyroidism. Guideline recommendations were extracted, and quality assessment was performed using selected questions of the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument., Results: Of the 2624 records screened, 22 guidelines were included, which were published between 2007 and 2021. Guideline quality was generally intermediate to low. Diagnostic approaches differed substantially, particularly in the extent of recommended testing. Treatment initiation depended on TSH levels, age, and comorbidities, but the level of detail regarding defining precise comorbidities varied. Recommendations for monitoring intervals for follow-up ranged from 3 to 12 months., Conclusion: This review underscores the existing variability in (inter)national guidelines concerning subclinical hyperthyroidism. There isa need for clear recommendations in guidelines considering diagnostic workup, treatment, and follow-up of subclinical hyperthyroidism. In order to establish this, future research should focus on determining clear and evidence-based intervention thresholds.

Introduction: The LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the association between LIBRA scores and incident dementia is moderated by geographical location or sociodemographic characteristics., Methods: We combined data from 21 prospective cohorts across six continents (N = 31,680) and conducted cohort-specific Cox proportional hazard regression analyses in a two-step individual participant data meta-analysis., Results: A one-standard-deviation increase in LIBRA score was associated with a 21% higher risk for dementia. The association was stronger for Asian cohorts compared to European cohorts, and for individuals aged ≤75 years (vs older), though only within the first 5 years of follow-up. No interactions with sex, education, or socioeconomic position were observed., Discussion: Modifiable risk and protective factors appear relevant for dementia risk reduction across diverse geographical and sociodemographic groups., Highlights: A two-step individual participant data meta-analysis was conducted. This was done at a global scale using data from 21 ethno-regionally diverse cohorts. The association between a modifiable dementia risk score and dementia was examined. The association was modified by geographical region and age at baseline. Yet, modifiable dementia risk and protective factors appear relevant in all investigated groups and regions., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The benefit of levothyroxine treatment of subclinical hypothyroidism (SCH) is subject to debate. This study compared treatment satisfaction between older adults with SCH using levothyroxine or placebo. Methods: We analyzed pooled individual participant data from two randomized, double-blind, placebo-controlled trials investigating the effects of levothyroxine treatment in older adults with SCH. Community-dwelling participants aged ≥65 years, with SCH (persistent thyrotropin levels 4.60-19.99 mIU/L for >3 months and normal free T4 level), were included. Intervention dose titration until thyrotropin levels normalized, with a mock dose adjustment of placebo. Treatment satisfaction was determined during the final study visit using the Treatment Satisfaction Questionnaire for Medication (TSQM), encompassing perceived effectiveness, side effects, convenience, and global satisfaction, along with the participants' desire to continue study medication after the trial. Results: We included 536 participants. At baseline, the median (interquartile range [IQR]) age was 74.9 (69.7-81.4) years, and 292 (55%) were women. The median (IQR) thyrotropin levels were 5.80 (5.10-7.00) mIU/L at baseline in both groups; at final visit, 4.97 (3.90-6.35) mIU/L in the placebo and 3.24 (2.49-4.41) mIU/L in the levothyroxine group. After treatment, the groups did not differ significantly in global satisfaction (mean difference [CI] -1.1 [-4.5 to 2.1], p = 0.48), nor in any other domain of treatment satisfaction. These results held true regardless of baseline thyrotropin levels or symptom burden. No major differences were found in the numbers of participants who wished to continue medication after the trial (levothyroxine 35% vs. placebo 27%), did not wish to continue (levothyroxine 27% vs. placebo 30%), or did not know (levothyroxine 37% vs. placebo 42%) ( p = 0.14). In a subpopulation with high symptom burden from hypothyroid symptoms at baseline, those using levothyroxine more often desired to continue the medication after the trial than those using placebo (mean difference [CI]: -21.1% [-35.6% to -6.5%]). Conclusion: These pooled data from two RCTs showed no major differences in treatment satisfaction between older adults receiving levothyroxine or placebo. This finding has important implications for decision-making regarding initiating levothyroxine treatment for SCH. Our findings generally support refraining from routinely prescribing levothyroxine in older adults with SCH.

Background: Literature relating older people's goals of care to their varying frailty status is scarce., Objective: To investigate goals of care in case of acute and/or severe disease in relationship to frailty status among the general older population., Method: Older people aged ≥70 in the Netherlands completed a questionnaire. They were divided into three subgroups based on a self-reported Clinical Frailty Scale: fit (CFS 1-3), mildly frail (CFS 4-5) and severely frail (CFS 6-8). Seven goals were graded as unimportant (1-5), somewhat important (6-7) or very important (8-10): extending life, preserving quality of life (QoL), staying independent, relieving symptoms, supporting others, preventing hospital admission and preventing nursing home admission., Results: Of the 1,278 participants (median age 76 years, 63% female), 57% was fit, 32% mildly frail and 12% severely frail. Overall, participants most frequently considered preventing nursing home admission as very important (87%), followed by staying independent (84%) and preserving QoL (83%), and least frequently considered extending life as very important (31%). All frailty subgroups reported similar preferences out of the surveyed goals as the overall study population. However, participants with a higher frailty status attached slightly less importance to each individual goal compared with fit participants (Ptrend-values ≤ 0.037)., Conclusion: Preferred goals of care are not related to frailty status, while the importance ascribed to individual goals is slightly lower with higher frailty status. Future research should prioritise outcomes related to the shared goals of fit, mildly frail and severely frail older people to improve personalised medicine for older patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Objectives: To systematically evaluate the performance of COVID-19 prognostic models and scores for mortality risk in older populations across three health-care settings: hospitals, primary care, and nursing homes., Study Design and Setting: This retrospective external validation study included 14,092 older individuals of ≥70 years of age with a clinical or polymerase chain reaction-confirmed COVID-19 diagnosis from March 2020 to December 2020. The six validation cohorts include three hospital-based (CliniCo, COVID-OLD, COVID-PREDICT), two primary care-based (Julius General Practitioners Network/Academisch network huisartsgeneeskunde/Network of Academic general Practitioners, PHARMO), and one nursing home cohort (YSIS) in the Netherlands. Based on a living systematic review of COVID-19 prediction models using Prediction model Risk Of Bias ASsessment Tool for quality and risk of bias assessment and considering predictor availability in validation cohorts, we selected six prognostic models predicting mortality risk in adults with COVID-19 infection (GAL-COVID-19 mortality, 4C Mortality Score, National Early Warning Score 2-extended model, Xie model, Wang clinical model, and CURB65 score). All six prognostic models were validated in the hospital cohorts and the GAL-COVID-19 mortality model was validated in all three healthcare settings. The primary outcome was in-hospital mortality for hospitals and 28-day mortality for primary care and nursing home settings. Model performance was evaluated in each validation cohort separately in terms of discrimination, calibration, and decision curves. An intercept update was performed in models indicating miscalibration followed by predictive performance re-evaluation., Main Outcome Measure: In-hospital mortality for hospitals and 28-day mortality for primary care and nursing home setting., Results: All six prognostic models performed poorly and showed miscalibration in the older population cohorts. In the hospital settings, model performance ranged from calibration-in-the-large -1.45 to 7.46, calibration slopes 0.24-0.81, and C-statistic 0.55-0.71 with 4C Mortality Score performing as the most discriminative and well-calibrated model. Performance across health-care settings was similar for the GAL-COVID-19 model, with a calibration-in-the-large in the range of -2.35 to -0.15 indicating overestimation, calibration slopes of 0.24-0.81 indicating signs of overfitting, and C-statistic of 0.55-0.71., Conclusion: Our results show that most prognostic models for predicting mortality risk performed poorly in the older population with COVID-19, in each health-care setting: hospital, primary care, and nursing home settings. Insights into factors influencing predictive model performance in the older population are needed for pandemic preparedness and reliable prognostication of health-related outcomes in this demographic., Competing Interests: Declaration of competing interest All authors have completed the International Committee of Medical Journals Editors uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: funding from the Netherlands Organisation for Scientific Research (ZonMw). KJ and FW have received grants from the program Leren van Data by theDutch Ministry of Health, Welfare and Sport(grantnumber:329517); all declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The broad concept of health as "the ability to adapt and self-manage in the face of social, physical and emotional challenges" has been operationalized by "Positive Health," a framework increasingly used in the Netherlands. We explored to what degree the impact of the COVID-19 pandemic and preventive measures on Positive Health differed between community-dwelling older adults without, with mild and with complex health problems, as well as differences flowing from their use of preventive measures., Methods: During the second wave in the Netherlands (November 2020-February 2021), a convenience sample of adults aged ≥65 years completed an online questionnaire. Positive Health impact was measured based on self-reported change of current health status, across six dimensions, compared to before the pandemic (decreased/unchanged/increased). The complexity of health problems (past month) was assessed using the validated ISCOPE tool, comparing subgroups without, with mild or with complex health problems. High use of preventive measures was defined as ≥9 of 13 measures and compared to low use (<9 measures)., Results: Of the 2397 participants (median age 71 years, 60% female, and 4% previous COVID-19 infection), 31% experienced no health problems, 55% mild health problems, and 15% complex health problems. Overall, participants reported a median decrease in one Positive Health dimension (IQR 1-3), most commonly in social participation (68%). With an increasing complexity of health problems, subjective Positive Health declined more often across all six dimensions, ranging from 3.3% to 57% in those without, from 22% to 72% in those with mild, and from 47% to 75% in those with complex health problems (p-values for trend <0.001; independent of age and sex). High users of preventive measures more often experienced declined social participation (72% vs. 62%, p < 0.001) and a declined quality of life (36% vs. 30%, p = 0.007) than low users, especially those with complex health problems., Conclusion: As the complexity of health problems increased, the adverse impact of the COVID-19 pandemic and related preventive measures was experienced more frequently across all dimensions of Positive Health. Acknowledging this heterogeneity is pivotal to the effective targeting of prevention and healthcare to those most in need., (© 2023 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background: During the COVID-19 pandemic, older patients in primary care were triaged based on their frailty or assumed vulnerability for poor outcomes, while evidence on the prognostic value of vulnerability measures in COVID-19 patients in primary care was lacking. Still, knowledge on the role of vulnerability is pivotal in understanding the resilience of older people during acute illness, and hence important for future pandemic preparedness. Therefore, we assessed the predictive value of different routine care-based vulnerability measures in addition to age and sex for 28-day mortality in an older primary care population of patients with COVID-19., Methods: From primary care medical records using three routinely collected Dutch primary care databases, we included all patients aged 70 years or older with a COVID-19 diagnosis registration in 2020 and 2021. All-cause mortality was predicted using logistic regression based on age and sex only (basic model), and separately adding six vulnerability measures: renal function, cognitive impairment, number of chronic drugs, Charlson Comorbidity Index, Chronic Comorbidity Score, and a Frailty Index. Predictive performance of the basic model and the six vulnerability models was compared in terms of area under the receiver operator characteristic curve (AUC), index of prediction accuracy and the distribution of predicted risks., Results: Of the 4,065 included patients, 9% died within 28 days after COVID-19 diagnosis. Predicted mortality risk ranged between 7-26% for the basic model including age and sex, changing to 4-41% by addition of comorbidity-based vulnerability measures (Charlson Comorbidity Index, Chronic Comorbidity Score), more reflecting impaired organ functioning. Similarly, the AUC of the basic model slightly increased from 0.69 (95%CI 0.66 - 0.72) to 0.74 (95%CI 0.71 - 0.76) by addition of either of these comorbidity scores. Addition of a Frailty Index, renal function, the number of chronic drugs or cognitive impairment yielded no substantial change in predictions., Conclusion: In our dataset of older COVID-19 patients in primary care, the 28-day mortality fraction was substantial at 9%. Six different vulnerability measures had little incremental predictive value in addition to age and sex in predicting short-term mortality., (© 2024. The Author(s).)

Context: With age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown., Objective: To investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism., Design: Pooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial)., Setting: Community-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom., Participants: The pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included., Main Outcome Measures: Incidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization., Results: In the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization., Conclusion: Because TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment., Trial Registration: ClinicalTrials.gov, NCT01660126 and Netherlands Trial Register, NTR3851., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Rationale & Objective: Apathy reflects diminished motivation, goal-directed behavior, and emotions, as well as less engagement in social interactions. Apathy overlaps with depression and is associated with cognitive decline. In the older individuals with chronic kidney disease (CKD), both depression and cognitive impairments are common, but apathy symptoms have been underreported. We investigated the occurrence of apathy symptoms and their associations with physical and cognitive functioning, health-related quality of life (HRQoL), and mortality in older patients with CKD., Study Design: Prospective observational cohort study., Setting & Participants: 180 outpatients aged≥65 years with estimated glomerular filtration rate≤20mL/min/1.73m 2 from 5 Dutch nephrology centers., Exposure: Apathy symptoms at baseline were considered present when a Geriatric Depression Scale's 3-item apathy subscale score was≥2 points., Outcome: Physical and cognitive functioning, HRQoL (assessed in annual geriatric assessments), and 4-year mortality., Analytical Approach: Linear regression for cross-sectional associations, linear regression models for longitudinal associations, and Cox regression models for mortality over 4 years of observation., Results: Apathy symptoms were present in 64 patients (36%; 67% men; median age 75.5 years), of whom 32 (50%) had no depressive symptoms. At baseline, the presence of apathy symptoms was associated with significantly more frailty, more functional dependence, less physical capacity, lower visuoconstructive performance, worse delayed recall, and lower HRQoL scores. The presence of apathy symptoms at baseline was also associated with a higher mortality risk (hazard ratio, 2.3 [95% CI, 1.3-4.2], P=0.005 adjusted for age, sex, and high education level), but not with changes in physical and cognitive functioning or HRQoL during the follow-up period., Limitations: Risk of selection bias and residual confounding., Conclusions: Apathy symptoms were highly prevalent and associated with concurrent lower physical and cognitive status, lower HRQoL, and increased mortality. These findings highlight apathy as a potentially important clinical phenotype in older CKD patients., Plain-Language Summary: We observed that older kidney patients often present apathy symptoms, such as less motivation, fewer goal-directed behaviors, fewer emotions, and less social engagement. Prior research has not extensively described apathy in kidney disease. We investigated the link between apathy symptoms and poor outcomes. We measured physical functioning, cognitive functioning, and quality of life. We learned that one-third of our older kidney patients showed symptoms of apathy, only half of whom had symptoms of depression. Patients with apathy symptoms showed lower quality of life and lower physical and cognitive performance. They also had a higher risk of death. These findings highlight the need for awareness of apathy symptoms in older kidney patients., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Falls and consequent injuries are prevalent in older adults. In this group, half of injury-related hospitalizations are associated with falls and the rate of falls increases with age. The evidence on the role of blood pressure and the use of antihypertensive treatment on the risk of falls remains unclear in oldest-old adults (≥85 years)., Objectives: To examine the association between systolic blood pressure (SBP) and incident falls with medical consequences in oldest-old adults and to analyse whether this association is modified by the use of antihypertensive treatments or the presence of cardiovascular disease., Methods: We analysed data from the Leiden 85-plus Study, a prospective, population-based cohort study with adults aged ≥85 years and a 5-year follow-up. Falls with medical consequences were reported by the treating physician of participants. We assessed the association between time-updated systolic blood pressure and the risk of falling over a follow-up period of five years using generalized linear mixed effects models with a binomial distribution and a logit link function. Subgroup analyses were performed to examine the role of antihypertensive treatment and the difference between participant with and without cardiovascular disease., Results: We analysed data from 544 oldest-old adults, 242 (44.4%) of which used antihypertensives. In 81 individuals (15%) ≥1 fall(s) were reported during the follow-up period. The odds for a fall decreased by a factor of 0.86 (95% CI 0.80 to 0.93) for each increase in blood pressure by 10 mmHg. This effect was specific to blood pressure values above 130mmHg. We did not find any evidence that the effect would be modified by antihypertensive treatment, but that there was a tendency that it would be weaker in participants with cardiovascular disease (OR 0.81, 95% CI 0.72 to 0.90 per 10mmHg) compared to those without cardiovascular disease (OR 0.94, 95% CI 0.84 to 1.05 per 10mmHg)., Conclusion: Our results point towards a possible benefit of higher blood pressure in the oldest-old with respect to falls independent of the use of antihypertensive treatments., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2023 Röthlisberger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT 4 ) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT 4 based on the risk of cardiovascular disease and mortality., Methods: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT 4 , and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT 4 , thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576., Findings: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT 4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT 4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT 4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT 4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality., Interpretation: There was a J-shaped association of FT 4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT 4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT 4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes., Funding: None., Competing Interests: Declaration of interests TIMK reports personal fees from IBSA, Meck, Berlin-Chemie, and Quidel; is an unpaid co-chair of the American Thyroid Association guidelines on thyroid and pregnancy. BBY reports grants from National Health and Medical Research Council, Fremantle Hospital Medical Research Foundation, and Ada Bartholomew Medical Research Trust. NR reports a grant from the Swiss National Science Foundation. SR reports a grant for an investigator-initiated trial by Merck; manufacturer of levothyroxine and speaker fees from Merck, Abbott Pharmaceuticals, IBSA (makers of levothyroxine). JWJ reports research grants from or was a speaker (with or without lecture fees) at (Continuing Medical Education accredited) meetings sponsored or supported by Abbott, Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Edwards Lifesciences, GE Healthcare, Johnson and Johnson, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme. DCB reports research grants from the National institutes of Health. DF reports a research grant from DFG SFB TR 296 LOCOTACT. RGJW reports a research grant from the Novo Nordisk Foundation Challenge Programme (NNF17OC0027812). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In the general population, an increase in low-density lipoprotein cholesterol (LDL-C) predicts higher cardiovascular disease risk, and lowering LDL-C can prevent cardiovascular disease and reduces mortality risk. Interestingly, in cohort studies that include very old populations, no or inverse associations between LDL-C and mortality have been observed. This study aims to investigate whether the association between LDL-C and mortality in the very old is modified by a composite fitness score., Methods: A 2-stage meta-analysis of individual participant data from the 5 observational cohort studies. The composite fitness score was operationalized by performance on a combination of 4 markers: functional ability, cognitive function, grip strength, and morbidity. We pooled hazard ratios (HR) from Cox proportional-hazards models for 5-year mortality risk for a 1 mmol/L increase in LDL-C. Models were stratified by high/low composite fitness score., Results: Composite fitness scores were calculated for 2 317 participants (median 85 years, 60% females participants), of which 994 (42.9%) had a high composite fitness score, and 694 (30.0%) had a low-composite fitness score. There was an inverse association between LDL-C and 5-year mortality risk (HR 0.87 [95% CI: 0.80-0.94]; p < .01), most pronounced in participants with a low-composite fitness score (HR 0.85 [95% CI: 0.75-0.96]; p = .01), compared to those with a high composite fitness score (HR = 0.98 [95% CI: 0.83-1.15]; p = .78), the test for subgroups differences was not significant., Conclusions: In this very old population, there was an inverse association between LDL-C and all-cause mortality, which was most pronounced in participants with a low-composite fitness scores., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Introduction: Sex differences in dementia risk, and risk factor (RF) associations with dementia, remain uncertain across diverse ethno-regional groups., Methods: A total of 29,850 participants (58% women) from 21 cohorts across six continents were included in an individual participant data meta-analysis. Sex-specific hazard ratios (HRs), and women-to-men ratio of hazard ratios (RHRs) for associations between RFs and all-cause dementia were derived from mixed-effect Cox models., Results: Incident dementia occurred in 2089 (66% women) participants over 4.6 years (median). Women had higher dementia risk (HR, 1.12 [1.02, 1.23]) than men, particularly in low- and lower-middle-income economies. Associations between longer education and former alcohol use with dementia risk (RHR, 1.01 [1.00, 1.03] per year, and 0.55 [0.38, 0.79], respectively) were stronger for men than women; otherwise, there were no discernible sex differences in other RFs., Discussion: Dementia risk was higher in women than men, with possible variations by country-level income settings, but most RFs appear to work similarly in women and men., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Aims: Mendelian randomization confirmed multiple risk factors for primary events of coronary artery disease (CAD), but no such studies have been performed on recurrent major coronary events despite interesting insights derived from other designs. We examined the associations between genetically-influenced classical cardiovascular risk factors and the risk of recurrent major coronary events in a cohort of CAD patients., Methods: We included all first-time CAD cases (defined as angina pectoris, chronic ischemic heart disease or acute myocardial infarction) of European ancestry from the UK Biobank. Cases were followed till the end of follow-up, death or when they developed a recurrent major coronary event (chronic ischemic heart disease or acute myocardial infarction). Standardized weighted genetic risk scores were calculated for body mass index (BMI), systolic blood pressure, LDL cholesterol and triglycerides., Results: From a total of 22,949 CAD patients (mean age at first diagnosis 59.8 (SD 7.3) years, 71.1% men), 12,539 (54.6%) reported a recurrent major coronary event within a period of maximum 17.8 years. One standard deviation higher genetically-determined LDL cholesterol was associated with a higher risk of a recurrent major coronary event (odds ratio: 1.08 [95% confidence interval: 1.05, 1.11]). No associations were observed for genetically-influenced BMI (1.00 [0.98, 1.03]), systolic blood pressure (1.01 [0.98, 1.03]) and triglycerides (1.02 [0.995, 1.05])., Conclusions: Despite the use risk-reducing medications following a first coronary event, this study provided genetic evidence that, of the classical risk factors, mainly high LDL cholesterol was associated with a higher risk of developing recurrent major coronary events., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: As unplanned Emergency Department (ED) return visits (URVs) are associated with adverse health outcomes in older adults, many EDs have initiated post-discharge interventions to reduce URVs. Unfortunately, most interventions fail to reduce URVs, including telephone follow-up after ED discharge, investigated in a recent trial. To understand why these interventions were not effective, we analyzed patient and ED visit characteristics and reasons for URVs within 30 days for patients aged ≥ 70 years., Methods: Data was used from a randomized controlled trial, investigating whether telephone follow-up after ED discharge reduced URVs compared to a satisfaction survey call. Only observational data from control group patients were used. Patient and index ED visit characteristics were compared between patients with and without URVs. Two independent researchers determined the reasons for URVs and categorized them into: patient-related, illness-related, new complaints and other reasons. Associations were examined between the number of URVs per patient and the categories of reasons for URVs., Results: Of the 1659 patients, 222 (13.4%) had at least one URV within 30 days. Male sex, ED visit in the 30 days before the index ED visit, triage category "urgent", longer length of ED stay, urinary tract problems, and dyspnea were associated with URVs. Of the 222 patients with an URV, 31 (14%) returned for patient-related reasons, 95 (43%) for illness-related reasons, 76 (34%) for a new complaint and 20 (9%) for other reasons. URVs of patients who returned ≥ 3 times were mostly illness-related (72%)., Conclusion: As the majority of patients had an URV for illness-related reasons or new complaints, these data fuel the discussion as to whether URVs can or should be prevented., Trial Registration: For this cohort study, we used data from a randomized controlled trial (RCT). This trial was pre-registered in the Netherlands Trial Register with number NTR6815 on the 7 th of November 2017., (© 2023. The Author(s).)

Background: Many older persons use the thyroid hormone levothyroxine which is often continued for life. Scientifically, there is much uncertainty whether simple continuation is the optimal approach. First, the physical need for levothyroxine can decrease with age thereby posing a higher risk of overtreatment and adverse effects. Second, large trials in subclinical hypothyroidism have shown no benefit for the use of levothyroxine. Interestingly, guidelines do not address re-evaluation of the indication. This self-controlled trial aims to determine the effects of discontinuation of levothyroxine treatment in older adults., Methods and Analysis: Participants are community-dwelling subjects aged ≥60 years using levothyroxine continuously at a stable dosage of ≤150 µg and a level of thyroid-stimulating hormone (TSH) <10 mU/L. After a control period of 12 weeks, levothyroxine treatment is discontinued gradually using a stepwise approach with regular monitoring of thyroid function guided by their GP. The primary outcome is the proportion of participants withdrawn from levothyroxine while maintaining a free T4 level within the reference range and a TSH level <10 mU/L, 52 weeks after the start of discontinuation. Secondary outcomes are compared with the control period (self-controlled) and include among others, the effects on thyroid-specific and general health-related quality of life. Furthermore, patients' attitudes towards deprescribing and regret regarding discontinuing levothyroxine treatment will be recorded. A total of 513 participants will be recruited to estimate the expected proportion of 50% with a 95% CI ranging from 45% to 55%., Ethics and Dissemination: Approval was obtained from the institutional Medical Ethics Committee. The Older People Advisory Board Health and Well-being has reviewed the research proposal and their comments were used for improvement. In line with the funding policies of the grant organisation funding this study, the study results will be proactively disseminated to the general public and key public health stakeholders., Trial Registration Number: NL7978; NCT05821881., Competing Interests: Competing interests: Ravensberg receives a grant from ZonMw (839110026) during the conduct of the study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: The COVID-19 pandemic has a large impact worldwide and is known to particularly affect the older population. This paper outlines the protocol for external validation of prognostic models predicting mortality risk after presentation with COVID-19 in the older population. These prognostic models were originally developed in an adult population and will be validated in an older population (≥ 70 years of age) in three healthcare settings: the hospital setting, the primary care setting, and the nursing home setting., Methods: Based on a living systematic review of COVID-19 prediction models, we identified eight prognostic models predicting the risk of mortality in adults with a COVID-19 infection (five COVID-19 specific models: GAL-COVID-19 mortality, 4C Mortality Score, NEWS2 + model, Xie model, and Wang clinical model and three pre-existing prognostic scores: APACHE-II, CURB65, SOFA). These eight models will be validated in six different cohorts of the Dutch older population (three hospital cohorts, two primary care cohorts, and a nursing home cohort). All prognostic models will be validated in a hospital setting while the GAL-COVID-19 mortality model will be validated in hospital, primary care, and nursing home settings. The study will include individuals ≥ 70 years of age with a highly suspected or PCR-confirmed COVID-19 infection from March 2020 to December 2020 (and up to December 2021 in a sensitivity analysis). The predictive performance will be evaluated in terms of discrimination, calibration, and decision curves for each of the prognostic models in each cohort individually. For prognostic models with indications of miscalibration, an intercept update will be performed after which predictive performance will be re-evaluated., Discussion: Insight into the performance of existing prognostic models in one of the most vulnerable populations clarifies the extent to which tailoring of COVID-19 prognostic models is needed when models are applied to the older population. Such insight will be important for possible future waves of the COVID-19 pandemic or future pandemics., (© 2023. The Author(s).)

Objectives: The benefit-risk ratio of many interventions remains unclear in older adults with dementia. Efforts for more representative trial inclusion are made; however, recruiting and particularly gaining informed consent remains complex. For research participation, dementia compels the designation of a legal guardian (LG) to give proxy consent. To advance future trial development, we aimed to provide more insights into the factors that affect the proxy decision-making process in dementia research., Design: A qualitative analysis of semi-structured interviews about proxy decision-making on participation in dementia research., Setting and Participants: LGs of nursing home residents that gave (n = 19) and refrained from giving (n = 18) proxy consent for a clinical trial (the Danton study) in the Netherlands., Methods: Verbatim transcripts were thematically analyzed by using a preliminary deductive framework with room for induction of additional emerging themes, being an overall abductive approach. Based on that theme list, related factors of the decision-making process were grouped into overarching levels and merged into a step-by-step process., Results: When discussing proxy decision-making on the participation of an older adult with dementia in a clinical trial, LGs described interconnected factors on the level of the study and patient. Past experiences and attitudes of the LG influenced the weighing of these study- and patient-related factors, leading to a preliminary decision. Other proxies and treating health care professionals (HCPs) were named as important other stakeholders of the decision-making process., Conclusions and Implications: When giving proxy consent for research participation, LGs weigh study- and patient-related factors, leading to an initial benefit-risk evaluation. This weighing process is influenced by LG-related factors and can be modulated by other proxies or treating HCPs, leading to a definitive decision. Although insights into these underlying mechanisms could facilitate the proxy decision-making process for both LGs and researchers, treating HCPs could act as an independent party., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: loss of skeletal muscle function, strength and mass is common in older adults, with important socioeconomic impacts. Subclinical hypothyroidism is common with increasing age and has been associated with reduced muscle strength. Yet, no randomized placebo-controlled trial (RCT) has investigated whether treatment of subclinical hypothyroidism affects muscle function and mass., Methods: this is an ancillary study within two RCTs conducted among adults aged ≥65 years with persistent subclinical hypothyroidism (thyrotropin (TSH) 4.60-19.99 mIU/l, normal free thyroxine). Participants received daily levothyroxine with TSH-guided dose adjustment or placebo and mock titration. Primary outcome was gait speed at final visit (median 18 months). Secondary outcomes were handgrip strength at 1-year follow-up and yearly change in muscle mass., Results: we included 267 participants from Switzerland and the Netherlands. Mean age was 77.5 years (range 65.1-97.1), 129 (48.3%) were women, and their mean baseline TSH was 6.36 mIU/l (standard deviation [SD] 1.9). At final visit, mean TSH was 3.8 mIU/l (SD 2.3) in the levothyroxine group and 5.1 mIU/l (SD 1.8, P < 0.05) in the placebo group. Compared to placebo, participants in the levothyroxine group had similar gait speed at final visit (adjusted between-group mean difference [MD] 0.01 m/s, 95% confidence interval [CI] -0.06 to 0.09), similar handgrip strength at one year (MD -1.22 kg, 95% CI -2.60 to 0.15) and similar yearly change in muscle mass (MD -0.15 m2, 95% CI -0.49 to 0.18)., Conclusions: in this ancillary analysis of two RCTs, treatment of subclinical hypothyroidism did not affect muscle function, strength and mass in individuals 65 years and older., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)