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Background: Guidelines and studies provide conflicting information on whether type 2 diabetes (T2D) should be considered a coronary heart disease risk (CHD) equivalent in older adults., Methods: We synthesized participant-level data on 82,723 individuals aged ≥65 years from five prospective studies in two-stage meta-analyses. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of T2D (presence versus absence) on a primary composite outcome defined as cardiovascular events or all-cause mortality. Secondary outcomes were the components of the composite. We evaluated CHD risk equivalence by comparing outcomes between individuals with T2D but no CHD versus CHD but no T2D., Results: The median age of participants was 71 years, 20% had T2D and 17% had CHD at baseline. A total of 29,474 participants (36%) experienced the composite outcome. Baseline T2D was associated with higher risk of cardiovascular events or all-cause mortality versus no T2D (HR 1.44, 95% CI [1.40-1.49]). The association was weaker in individuals aged ≥75 years versus 65-74 years (HR 1.32 [1.19-1.46] vs. 1.56 [1.50-1.62]; p-value for interaction = .032). Compared to individuals with CHD but no T2D, individuals with T2D but no CHD had a similar risk of the composite outcome (HR 0.95 [0.85-1.07]), but a lower risk of cardiovascular events (HR 0.76 [0.59-0.98])., Conclusions: T2D was associated with increased risk of cardiovascular events and all-cause mortality in older adults, but T2D without CHD conferred lower risk of cardiovascular events compared to CHD without T2D. Our results suggest that T2D should not be considered a CHD risk equivalent in older adults., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Introduction: Cerebral Small-Vessel Disease (CSVD) is a complex condition affecting the brain's vascular network, linked to cognitive and physical decline, cerebrovascular disease, and death. This study assesses the relationship between CSVD (composite and individual features) and all-cause mortality in a large cohort of geriatric outpatients., Methods: Data from 1305 geriatric outpatients (mean age 78 ± 7; 51 % female) in the Amsterdam Ageing cohort were analysed. CSVD presence was based on brain imaging (MRI or CT), defined by a Fazekas score ≥ 2, presence of ≥1 lacunes, or (in MRI) ≥ 3 microbleeds. Mortality data (February 2016 - January 2024) was sourced from the Dutch Municipality Register. The relationship between CSVD and all-cause mortality was evaluated using a Cox proportional-hazards model, adjusting for key confounders., Results: At baseline, 835 (64 %) of the 1305 patients had CSVD. During a median follow-up of 3.1 years (IQR 1.6-4.6 years), all-cause mortality was 40 % (333 patients) in the CSVD group and 26 % (121 patients) in the non-CSVD group, corresponding with incidence rates of 137 and 78 per 1000 patient-years, respectively. The age- and sex-adjusted hazard ratio for mortality in the CSVD group was 1.6 (95 % CI: 1.3-2.0). This association remained significant after adjusting for cardiovascular disease and its risk factors, physical function (gait speed), and cognitive function (MMSE)., Conclusion: Radiographic CSVD presence is prevalent and its integration into daily care is important as it is independently linked to increased all-cause mortality in geriatric outpatients., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Guidelines suggest indefinite anticoagulation after unprovoked venous thromboembolism (VTE) unless the bleeding risk is high, yet there is no consistent guidance on assessing bleeding risk., Objectives: This study aimed to evaluate the performance of 5 bleeding risk tools (RIETE, VTE-BLEED, CHAP, VTE-PREDICT, and ABC-Bleeding)., Methods: PLATO-VTE, a prospective cohort study, included patients aged ≥40 years with a first unprovoked VTE. Risk estimates were calculated at VTE diagnosis and after 3 months of treatment. Primary outcome was clinically relevant bleeding, as per International Society on Thrombosis and Haemostasis criteria, during 24-month follow-up. Discrimination was assessed by the area under the receiver operating characteristic curve (AUROC). Patients were classified as having a "high risk" and "non-high risk" of bleeding according to predefined thresholds; bleeding risk in both groups was compared by hazard ratios (HRs)., Results: Of 514 patients, 38 (7.4%) had an on-treatment bleeding. AUROCs were 0.58 (95% CI, 0.48-0.68) for ABC-Bleeding, 0.56 (95% CI, 0.46-0.66) for RIETE, 0.53 (95% CI, 0.43-0.64) for CHAP, 0.50 (95% CI, 0.41-0.59) for VTE-BLEED, and 0.50 (95% CI, 0.40-0.60) for VTE-PREDICT. The proportion of high-risk patients ranged from 1.4% with RIETE to 36.9% with VTE-BLEED. The bleeding incidence in the high-risk groups ranged from 0% with RIETE to 13.0% with ABC-Bleeding, and in the non-high-risk groups, it varied from 7.7% with ABC-Bleeding to 9.6% with RIETE. HRs ranged from 0.93 (95% CI, 0.46-1.9) for VTE-BLEED to 1.67 (95% CI, 0.86-3.2) for ABC-Bleeding. Recalibration at 3-month follow-up did not alter the results., Conclusion: In this cohort, discrimination of currently available bleeding risk tools was poor. These data do not support their use in patients with unprovoked VTE., Competing Interests: Declaration of competing interests N.A.M.G., A.-M.L.B., S.S.W., N.K., F.I.M., M.J.L.P., M.t.W, J.M.M.B.O., E.P., V.S.-L., and P.M.M.B. have no competing interests to disclose. M.C. has received research funding from BMS, Pfizer, and LEO Pharma. He has also received Honoria from Bayer, BMS, Pfizer, Servier, and LEO Pharma. A.D. has received research funding from BMS-Pfizer and Honoria from Bayer, BMS-Pfizer, Servier, and LEO Pharma. L.J.-P. has received research funding from LEO Pharma and MSD. He has also received honoraria from Bayer Hispania, Actelion, Pfizer, Rovi, LEO Pharma, Menarini, and MSD. M.D. has received research funding from LEO Pharma and honoraria and consultancy fees from Daiichi Sankyo, Bayer, BMS-Pfizer, Sanofi, and LEO Pharma outside the submitted work. W.A. has received research funding from Bayer and honoraria from Bayer, BMS-Pfizer, Aspen, Sanofi, Janssen, Werfen, LEO Pharma, and Portola. J.B.-W. has received research funding from Bayer, Daiichi Sankyo, Pfizer, and Portola/Alexion. He has also received honoraria from Bayer, Daiichi Sankyo, Pfizer, and Portola/Alexion. T.V. has served as a speaker and/or advisor for Boehringer Ingelheim, Daiichi Sankyo, BMS/Pfizer, Bayer, Sanofi, and LEO Pharma. F.A.K. reports research grants from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Daiichi Sankyo, Actelion, the Dutch Thrombosis Association, and the Dutch Heart foundation. B.C. reports speakers’ fees from Daiichi Sankyo and Sanofi. V.E.A.G. reports lecture fees from Novo Nordisk, and funding of studies by Dutch Thrombosis Foundation, AstraZeneca, and Zambon. H.B. reports consulting fees from Daiichi Sankyo, Bayer Healthcare, BMS/Pfizer, Boehringer Ingelheim, Portola, Medscape, Eli Lilly, Sanofi Aventis, and Ionis. N.v.E. has received advisory board honoraria from Daiichi Sankyo, Bayer, and LEO Pharma, which were transferred to his institute. P.W.K. received research grants from Daiichi Sankyo and Roche Diagnostics., (Copyright © 2024. Published by Elsevier Inc.)

Background and Purpose: The Total Calcification Score (TCS) is a visual rating scale to measure Primary Familial Brain Calcification (PFBC) related calcification severity on Computed Tomography (CT). We investigated the inter-and intrarater agreement of a modified TCS., Materials and Methods: Patients aged ≥18 years with PFBC or Fahr's syndrome who visited the outpatient clinic of a Dutch academic hospital were included. The TCS was modified, for example by adding hippocampal calcification, and ranged from 0 to 95 points. Fifteen raters evaluated all CTs, of whom three evaluated the CTs twice. Their Entrustable Professional Activity (EPA) level ranged from II (medical student) to V (neuroradiologist). Agreement was assessed using the intraclass correlation coefficient (ICC) for the total score. Kendall's W and weighted Cohen's Kappa were used to determine the inter- and intrarater agreement for individual locations, respectively., Results: Forty patients were included (mean age 60 years, 53% female). The median modified TCS was 34 (range 4-76). For all EPA levels, the interrater agreement of the modified TCS was excellent (ICC=0.97 (95% CI 0.95-0.98)). Kendall's W's were good to excellent for commonly affected locations, but poor to moderate for less commonly affected locations for raters with lower levels of expertise. The intrarater agreement of the modified TCS was excellent. Kappa's of most locations were substantial to almost perfect., Conclusions: The modified TCS can be used with excellent reproducibility of the overall amount of brain calcifications and with limited training, although for some individual calcification locations more expertise is needed., Abbreviations: CI, Confidence Interval; CT, Computed Tomography; EPA, Entrustable Professional Activity; IBGC, Idiopathic Basal Ganglia Calcification; ICC, Intraclass Correlation Coefficient; IQR, Interquartile Range; PFBC, Primary Familial Brain Calcification; SD, Standard Deviation, TCS, Total Calcification Score; UMCU, University Medical Center Utrecht., Competing Interests: The authors declare no conflicts of interest related to the content of this article., (© 2024 by American Journal of Neuroradiology.)

Background: It is unclear whether patients with basal ganglia calcifications (BGC) should undergo infectious disease testing as part of their diagnostic work-up. We investigated the occurrence of possibly associated infections in patients with BGC diagnosed with Fahr's disease or syndrome and consecutively performed a systematic review of published infectious diseases associated with BGC. Methods: In a cross-sectional study, we evaluated infections in non-immunocompromised patients aged ≥ 18 years with BGC in the Netherlands, who were diagnosed with Fahr's disease or syndrome after an extensive multidisciplinary diagnostic work-up. Pathogens that were assessed included the following: Brucella sp., cytomegalovirus, human herpesvirus type 6/8, human immunodeficiency virus (HIV), Mycobacterium tuberculosis , rubella virus, and Toxoplasma gondii . Next, a systematic review was performed using MEDLINE and Embase (2002-2023). Results: The cross-sectional study included 54 patients (median age 65 years). We did not observe any possible related infections to the BGC in this population. Prior infection with Toxoplasma gondii occurred in 28%, and in 94%, IgG rubella antibodies were present. The positive tests were considered to be incidental findings by the multidisciplinary team since these infections are only associated with BGC when congenitally contracted and all patients presented with adult-onset symptoms. The systematic search yielded 47 articles, including 24 narrative reviews/textbooks and 23 original studies (11 case series, 6 cross-sectional and 4 cohort studies, and 2 systematic reviews). Most studies reported congenital infections associated with BGC (cytomegalovirus, HIV, rubella virus, Zika virus). Only two studies reported acquired pathogens (chronic active Epstein-Barr virus and Mycobacterium tuberculosis ). The quality of evidence was low. Conclusions: In our cross-sectional study and systematic review, we found no convincing evidence that acquired infections are causing BGC in adults. Therefore, we argue against routine testing for infections in non-immunocompromised adults with BGC in Western countries.

Background: Orthostatic hypotension (OH), an impaired blood pressure (BP) response to postural change, has been associated with cognitive decline and dementia, possibly through cerebral small vessel disease (CSVD). We hypothesized that longer duration of BP drop and a larger BP drop is associated with increased risk of CSVD., Methods: This cross-sectional study included 3971 memory clinic patients (mean age 68 years, 45% female, 42% subjective cognitive complaints, 17% mild cognitive impairment, 41% dementia) from the Amsterdam Ageing Cohort and Amsterdam Dementia Cohort. Early OH (EOH) was defined as a drop in BP of ±20 mmHg systolic and/or 10 mmHg diastolic only at 1 min after standing, and delayed/prolonged OH (DPOH) at 1 and/or 3 min after standing. Presence of CSVD [white matter hyperintensities (WMH), lacunes, microbleeds] was assessed with MRI ( n  = 3584) or CT brain (n = 389)., Results: The prevalence of early OH was 9% and of delayed/prolonged OH 18%. Age- and sex-adjusted logistic regression analyses showed that delayed/prolonged OH, but not early OH, was significantly associated with a higher burden of WMH (OR, 95%CI: 1.21, 1.00-1.46) and lacunes (OR, 95%CI 1.34, 1.06-1.69), but not microbleeds (OR, 95%CI 1.22, 0.89-1.67). When adjusting for supine SBP, these associations attenuated (ORs, 95%CI for WMH 1.04, 0.85-1.27; for lacunes 1.21, 0.91-1.62; for microbleeds 0.95, 0.68-1.31). A larger drop in SBP was associated with increased risk of WMH and microbleeds, however, when adjusted for supine SBP, this effect diminished., Conclusions: Among memory clinic patients, DPOH is more common than EOH. While longer duration and larger magnitude of BP drop coincided with a higher burden of CSVD, these associations were largely explained by high supine BP., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Older adults at the Emergency Department (ED) often present with nonspecific complaints (NSC) such as 'weakness' or 'feeling unwell'. Health care workers may underestimate illness in patients with NSC, leading to adverse health outcomes. This study compares characteristics and outcomes of NSC-patients versus specific complaints (SC) patients., Methods: Cohort study in patients ≥ 70 years in two Dutch EDs. NSC was classified according to the BANC-study-framework based on the medical history in the ED letter, before additional diagnostics took place. A second classification was performed at the end of the ED visit/hospital admission. Primary outcomes were functional decline, institutionalization, and mortality at 30 days., Results: 26% (n = 228) of a total of 888 included patients presented with NSC. Compared with SC-patients, NSC-patients were older, more frail, and more frequently female. NSC-patients had a higher risk of functional decline and institutionalization at 30 days (adjusted ORs 1.84, 95% CI 1.27 - 2.72, and 2.46, 95% CI 1.51-4.00, respectively), but not mortality (adjusted OR 1.26, 95% CI 0.58 - 2.73). Reclassification to a specific complaint after the ED visit or hospital admission occurred in 54% of NSC-patients., Conclusion: NSC occur especially in older, frail female patients and are associated with an increased risk of functional decline and institutionalization, even after adjustment for worse baseline status. In half of the patients, a specific complaint revealed during ED or hospital stay. Physicians at the ED should consider NSC as a red flag needing appropriate observation and evaluation of underlying serious conditions and needs of this vulnerable patient group., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To extend our investigation of cardiovascular diseases (CVD) in rheumatoid arthritis (RA) patients to a follow up of more than 20 years, with a special focus on patients without prevalent CVD., Methods: The CARRÉ study is an ongoing prospective cohort study on CV endpoints in RA patients. Results were compared to those of a reference cohort (n = 2484) enriched for type 2 diabetes mellitus (DM). Hazard ratios (HR) for RA and DM patients compared to non-RA/-DM controls were calculated with cox proportional hazard models, and adjusted for baseline SCORE1 (estimated 10-year CVD mortality risk based on CV risk factors)., Results: 238 RA patients, 117 DM patients and 1282 controls, without prevalent CVD at baseline were included. Analysis of events in these patients shows that after adjustment, no relevant 'RA-specific' risk remains (HR 1.16; 95%CI 0.88 - 1.53), whereas a 'DM-specific' risk is retained (1.73; 1.24 - 2.42). In contrast, adjusted analyses of all cases confirm the presence of an 'RA-specific' risk (1.50; 1.19 - 1.89)., Conclusions: In RA patients without prevalent CVD the increased CVD risk is mainly attributable to increased presence of traditional risk factors. After adjustment for these factors, an increased risk attributable to RA only was thus preferentially seen in the patients with prevalent CVD at baseline. As RA treatment has improved, this data suggests that the 'RA-specific' effect of inflammation is preferentially seen in patients with prevalent CVD. We suggest that with modern (early) treatment of RA, most of the current increased CVD risk is mediated through traditional risk factors., Competing Interests: Declaration of Competing Interests None., (Copyright © 2022. Published by Elsevier Inc.)

There is a clear increase in cardiovascular risk with increasing age. However, in relative terms the contribution of individual cardiovascular risk factors such as BMI or blood pressure to the occurrence of cardiovascular disease weakens with age. Whether these weaker associations are causal or driven by other confounding factors is unclear. If such associations are indeed causal, this would imply that cardiovascular risk factors require less intensive treatment with ageing. A recent study using mendelian randomization techniques confirmed that the causal relationship of cardiovascular risk factors with the occurrence of coronary artery disease weakens with age. In this article we discuss the possible contribution of mendelian randomization studies in studying casual relationships between cardiovascular risk factors and cardiovascular disease. We also comment on what the possible consequences are for cardiovascular risk management in older people in daily clinical practice.

To meet the end-of-life needs of all patients, ongoing conversations about values and preferences regarding end-of-life care are essential. Aspects of social identity are associated with disparities in end-of-life care outcomes. Therefore, accounting for patient diversity in advance care planning and end-of-life conversations is important for equitable end-of-life practices. We conducted 16 semi-structured interviews to explore how Dutch healthcare professionals and researchers conceptualized diversity in advance care planning and end-of-life conversations and how they envision diversity-responsive end-of-life care and research. Using thematic discourse analysis, we identified five 'diversity discourses': the categorical discourse; the diversity as a determinant discourse; the diversity in norms and values discourse; the everyone is unique discourse, and the anti-essentialist discourse. These discourses may have distinct implications for diversity-responsive end-of-life conversations, care and research. Awareness and reflection on these discourses may contribute to more inclusive end-of-life practices., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Older adults at the emergency department (ED) with polypharmacy, comorbidity, and frailty are at risk of adverse health outcomes. We investigated the association of polypharmacy with adverse health outcomes, in relation to comorbidity and frailty., Methods: This is a prospective cohort study in ED patients  ≥ 70 years. Non-polypharmacy was defined as 0-4 medications, polypharmacy 5-9 and excessive polypharmacy ≥ 10. Comorbidity was classified by the Charlson comorbidity index (CCI). Frailty was defined by the Identification of Seniors At Risk-Hospitalized Patients (ISAR-HP) score. The primary outcome was 3-month mortality. Secondary outcomes were readmission to an ED/hospital ward and a self-reported fall < 3 months. The association between polypharmacy, comorbidity and frailty was analyzed by logistic regression., Results: 881 patients were included. 43% had polypharmacy and 18% had excessive polypharmacy. After 3 months, 9% died, 30% were readmitted, and 21% reported a fall. Compared with non-polypharmacy, the odds ratio (OR) for mortality ranged from 2.62 (95% CI 1.39-4.93) in patients with polypharmacy to 3.92 (95% CI 1.95-7.90) in excessive polypharmacy. The OR weakened after adjustment for comorbidity: 1.80 (95% CI 0.92-3.52) and 2.32 (95% CI 1.10-4.90). After adjusting for frailty, the OR weakened to 2.10 (95% CI 1.10-4.00) and OR 2.40 (95% CI 1.15-5.02). No significant association was found for readmission or self-reported fall., Conclusions: Polypharmacy is common in older patients at the ED. Polypharmacy, and especially excessive polypharmacy, is associated with an increased risk of mortality. The observed association is complex given the confounding effect of comorbidity and frailty., (© 2022. The Author(s).)

Introduction: Orthostatic hypotension is a common condition associated with an increased mortality risk. This study investigates this association specifically in geriatric outpatients and additionally focuses on the duration and magnitude of orthostatic hypotension., Methods: In this observational prospective cohort study with geriatric outpatients from the Amsterdam Ageing cohort, we differentiated orthostatic hypotension in early orthostatic hypotension (EOH) and delayed/prolonged orthostatic hypotension (DPOH). The magnitude of drop in both SBP and DBP after either 1 or 3 min was quantified. Mortality data was obtained from the Dutch municipal register. Cox proportional hazard models were used to determine the association between orthostatic hypotension and mortality, adjusted for sex and age (model 1), additionally adjusted for orthostatic hypotension-inducing drugs + SBP (model 2) and the presence of cardiovascular disease and diabetes (model 3). Stratified analyses in patients with geriatric deficits were performed., Results: We included 1240 patients (mean age 79.4 ± 6.9 years, 52.6% women). Prevalence of orthostatic hypotension was 443 (34.9%); 148 (11.9%) patients had EOH and 285 (23%) DPOH. DPOH was associated with a higher mortality risk [hazard ratio, 95% CI 1.69 (1.28-2.22)] whereas EOH was not associated with mortality risk. This association did not differ in patients with geriatric deficits. Furthermore, the magnitude of drop in both SBP and DBP was associated with a higher mortality risk., Conclusion: The presence of DPOH and the magnitude of both systolic and diastolic orthostatic hypotension are related to an increased mortality risk in geriatric outpatients. Whether the duration of orthostatic hypotension and magnitude of the drop in blood pressure is causally related to mortality risk or whether it is a sign of decreased resilience remains to be elucidated., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: This study aimed to investigate the interrelation between slowing in walking, thinking and mood, and their relationship with cerebral small vessel disease (CSVD) in a geriatric population., Design: Cross-sectional study., Setting and Participants: 566 geriatric outpatients from the Amsterdam Aging Cohort (49% female; age 79 ±6 years), who visited the Amsterdam UMC geriatric outpatient memory clinic., Methods: Patients underwent a comprehensive geriatric assessment, brain imaging, and a neuropsychological assessment as part of medical care. Three slowing aspects were investigated: gait speed, processing speed, and apathy symptoms (higher scores indicating more advanced slowing). We visually rated CSVD [white matter hyperintensities (WMHs), strategic lacunes, and microbleeds] on brain imaging., Results: Regression analyses showed that slowing in walking (gait speed) was associated with slowing in thinking [processing speed; β = 0.35, 95% confidence interval (CI) 0.22, 0.48] and slowing in mood (apathy symptoms; β = 0.21, 95% CI 0.13, 0.30), independent of important confounders. Large confluent areas of WMH (Fazekas 3) were associated with all slowing aspects: gait speed (β = 0.49, 95% CI 0.28, 0.71), processing speed (β = 0.36, 95% CI 0.19, 0.52) and apathy symptoms (β = 0.30, 95% CI 0.09, 0.51). In addition, in patients with more slowing aspects below predefined cutoffs, severe WMH was more common. Presence of ≥3 microbleeds was associated with apathy symptoms (β = 0.39, 95% CI 0.12, 0.66), whereas lacunes were not associated with slowing., Conclusions and Implications: This study provides evidence that slowing in walking, thinking, and mood are closely related and associated with CSVD. This phenotype or geriatric syndrome could be helpful to identify and characterize patients with CSVD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Frailty is associated with a higher risk of mortality, but not much is known about underlying pathways of the frailty-mortality association. In this study, we explore a wide range of possible mediators of the relation between frailty and mortality. Data were used from the Longitudinal Aging Study Amsterdam (LASA). We included 1477 older adults aged 65 years and over who participated in the study in 2008-2009 and linked their data to register data on mortality up to 2015. We examined a range of lifestyle, social, psychological, cognitive, and physical factors as potential mediators. All analyses were stratified by sex. We used causal mediation analyses to estimate the indirect effects in single-mediator analyses. Statistically significant mediators were then included in multiple-mediator analyses to examine their combined effect. The results showed that older men (OR = 2.79, 95% CI = 1.23;6.34) and women (OR = 2.31, 95% CI = 1.24;4.30) with frailty had higher odds of being deceased 6 years later compared to those without frailty. In men, polypharmacy (indirect effect OR = 1.21, 95% CI = 1.03;1.50) was a statistically significant mediator in this association. In women, polypharmacy, self-rated health, and multimorbidity were statistically significant mediators in the single-mediator models, but only the indirect effect of polypharmacy remained in the multiple-mediator model (OR = 1.16, 95% CI = 1.03;1.38). In conclusion, of many factors that were considered, we identified polypharmacy as explanatory factor of the association between frailty and mortality in older men and women. This finding has important clinical implications, as it suggests that targeting polypharmacy in frail older adults could reduce their risk of mortality., Competing Interests: 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., (© 2021 The Author(s).)

Purpose: Delay of routine medical care during the COVID-19 pandemic may have serious consequences for the health and functioning of older adults. The aim of this study was to investigate whether older adults reported cancellation or avoidance of medical care during the first months of the COVID-19 pandemic, and to explore associations with health and socio-demographic characteristics., Methods: Cross-sectional data of 880 older adults aged ≥ 62 years (mean age 73.4 years, 50.3% female) were used from the COVID-19 questionnaire of the Longitudinal Aging Study Amsterdam, a cohort study among community-dwelling older adults in the Netherlands. Cancellation and avoidance of care were assessed by self-report, and covered questions on cancellation of primary care (general practitioner), cancellation of hospital outpatient care, and postponed help-seeking. Respondent characteristics included age, sex, educational level, loneliness, depression, anxiety, frailty, multimorbidity and information on quarantine., Results: 35% of the sample reported cancellations due to the COVID-19 situation, either initiated by the respondent (12%) or by healthcare professionals (29%). Postponed help-seeking was reported by 8% of the sample. Multimorbidity was associated with healthcare-initiated cancellations (primary care OR = 1.92, 95% CI = 1.09-3.50; hospital OR = 1.86, 95% CI = 1.28-2.74) and respondent-initiated hospital outpatient cancellations (OR = 2.02, 95% CI = 1.04-4.12). Depressive symptoms were associated with postponed help-seeking (OR = 1.15, 95% CI = 1.06-1.24)., Conclusion: About one third of the study sample reported cancellation or avoidance of medical care during the first months of the pandemic, and this was more common among those with multiple chronic conditions. How this impacts outcomes in the long term should be investigated in future research., (© 2021. The Author(s).)

Optimizing emergency care for the aging population is an important future challenge, as the proportion of older patients at the emergency department (ED) rapidly increases. Older patients, particularly those who are frail, have a high risk of adverse outcomes after an ED visit, such as functional decline, institutionalization, and death. The ED can have a key position in identifying frail older patients who benefit most from comprehensive geriatric care [including delirium preventive measures, early evaluation of after-discharge care, and a comprehensive geriatric assessment (CGA)]. However, performing extensive frailty assessment is not suitable at the ED. Therefore, quick and easy-to-use instruments are needed to identify older patients at risk for adverse outcomes. This narrative review outlines the importance and complexity of frailty assessment at the ED. It aligns the available screening instruments, including clinical judgment as frailty assessment, and summarizes arguments for and against frailty assessment at the ED., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: assess how many patients with low ambulatory diastolic blood pressure (DBP) are not identified when relying on office DBP alone, and thus have 'masked diastolic hypotension'., Design: cross-sectional, retrospective cohort study., Setting: academic hospital., Subjects: 848 patients treated for hypertension who received ambulatory blood pressure monitoring (ABPM)., Methods: cut-off value between on- and off-target systolic blood pressure (SBP): 140 mmHg. Cut-off for low office and/or ambulatory DBP: DBP ≤ 70 mmHg. 'Masked diastolic hypotension' was defined as office DBP > 70 mmHg and mean ambulatory DBP ≤ 70 mmHg., Results: mean age of the sample was 60 ± 13 years, 50% was female, 37% had diabetes, 42% preexisting cardiovascular disease (CVD), mean office blood pressure (BP) was 134/79 mmHg. In all patients (n = 848), low office DBP was present in n = 84(10%), while n = 183(22%) had low ambulatory DBP. In all patients with normal-to-high office DBP (n = 764), n = 122(16%) had 'masked diastolic hypotension'. In this group, ambulatory DBP was 14-19 mmHg lower than office DBP. Patients with low ambulatory DBP were older, had more (cardiovascular) comorbidities, and used more (antihypertensive) drugs. Antihypertensive drugs were lowered or discontinued in 30% of all patients with 'masked diastolic hypotension' due to side effects., Conclusions: 'masked diastolic hypotension' is common among patients treated for hypertension, particularly in older patients with CVD (e.g. coronary artery disease, diabetes), patient groups in which the European Society of Cardiology/Hypertension guideline advises to prevent low DBP. Although it remains to be examined at which BP levels the harms of low DBP outweigh the benefits of lowering SBP, our observations are aimed to increase awareness among physicians., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: This study aims to assess the presence of geriatric domain impairments in an older heart failure (HF) outpatient population and to relate these domain impairments with 1 year mortality risk in comparison with a geriatric outpatient population without HF., Methods and Results: Data were used from two different prospective cohort studies: 241 outpatients with HF (mean age 78 ± 9 years, 48% female) and 686 geriatric outpatients (mean age 80 ± 7 years, 55% female). We similarly assessed the following geriatric domains in both cohorts: physical function, nutritional status, polypharmacy, cognitive function, and activities in daily living. Cox proportional hazards analyses were used to relate individual domains to 1 year mortality risk in both populations and to compare 1 year mortality risk between both populations. Of the patients with HF, 34% had impairments in ≥3 domains, compared with 38% in geriatric patients. One-year mortality rates were 13% and 8%, respectively, in the HF and geriatric populations; age-adjusted and sex-adjusted hazard ratio (95% confidence interval) for patients with HF compared with geriatric patients was 1.7 (1.3-2.6). The individual geriatric domains were similarly associated with 1 year mortality risk in both populations. Compared with zero to two impaired domains, age-adjusted and sex-adjusted mortality risk (hazard ratio, 95% confidence interval) for three, four, or five impaired domains ranged from 1.6 (0.6-4.2) to 6.5 (2.1-20.1) in the HF population and from 1.4 (0.7-2.9) to 7.9 (2.9-21.3) in the geriatric population., Conclusions: In parallel with geriatric patients, patients with HF often have multiple geriatric domain impairments that adversely affect their prognosis. This similarity together with the findings that patients with HF have a higher 1 year mortality risk than a general geriatric population supports the integration of a multi-domain geriatric assessment in outpatient HF care., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Given the link between systemic inflammation, body composition and insulin resistance (IR), anti-inflammatory therapy may improve IR and body composition in inflammatory joint diseases. This study assesses the IR and beta cell function in rheumatoid arthritis (RA) patients with active disease compared to osteoarthritis (OA) patients and investigates the effect of anti-TNF treatment on IR, beta cell function and body composition in RA. 28 Consecutive RA patients starting anti-TNF treatment (adalimumab), and 28 age, and sex-matched patients with OA were followed for 6 months. Exclusion criteria were use of statins, corticosteroids, and cardiovascular or endocrine co-morbidity. Pancreatic beta cell function and IR, using the homeostasis model assessment (HOMA2), and body composition, using dual-energy X-ray absorptiometry (DXA) were measured at baseline and 6 months. At baseline, IR [1.5 (1.1-1.8) vs. 0.7 (0.6-0.9), 100/%S] and beta cell function (133% vs. 102%) were significantly (p < 0.05) higher in RA patients with active disease as compared to OA patients. After 6 months of anti-TNF treatment, IR [1.5 (1.1-1.8) to 1.4 (1.1-1.7), p = 0.17] slightly improved and beta cell function [133% (115-151) to 118% (109-130), p <0.05] significantly improved. Improvement in IR and beta cell function was most pronounced in RA patients with highest decrease in CRP and ESR. Our observations indicate that IR and increased beta cell function are more common in RA patients with active disease. Anti-TNF reduced IR and beta cell function especially in RA patients with highest decrease in systemic inflammation and this effect was not explained by changes in body composition.

Introduction: In older patients, life expectancy is determined by a complex interaction of multiple geriatric domains. A comprehensive geriatric assessment (CGA) captures different geriatric domains. Yet, if and how components of the CGA are related to mortality in an outpatient geriatric setting is unknown. In the Amsterdam Ageing Cohort, we therefore studied distribution and accumulation of geriatric domain deficits in relation to mortality., Methods: All patients received a CGA as part of standard care, independent of referral reason. We summarized deficits on the CGA, using predefined cutoffs, in 5 geriatric domains: somatic, mental, nutritional, physical, and social domain. Information on mortality was obtained from the Dutch municipal register. We used age- and sex-adjusted Cox proportional hazards analyses to relate the separate domains and accumulation of impaired domains to overall mortality., Results: From the 1,055 geriatric outpatients (53% female; age 79 ± 7 years), 172 patients (16%) had died after 1.7 ± 1.1 years. In 626 patients (59%), 3 or more domains were impaired. All domains were independently associated with mortality, with the highest hazard for the somatic domain (HR 3.7 [1.7-8.0]) and the lowest hazard for the mental domain (HR 1.5 [1.1-12.0]). In addition, accumulation of impaired domains showed a gradually increased mortality risk, ranging from HR 2.2 (0.8-6.1) for 2 domains to HR 9.6 (3.7-24.7) for all 5 domains impaired., Conclusions: This study provides evidence that impairment in multiple geriatric domains is highly prevalent and independently and cumulatively associated with mortality in an outpatient geriatric setting., (© 2021 The Author(s)Published by S. Karger AG, Basel.)

Aims: Preliminary evidence from animal and human studies shows that gut microbiota composition and levels of microbiota-derived metabolites, including short-chain fatty acids (SCFAs), are associated with blood pressure (BP). We hypothesized that faecal microbiota composition and derived metabolites may be differently associated with BP across ethnic groups., Methods and Results: We included 4672 subjects (mean age 49.8 ± 11.7 years, 52% women) from six different ethnic groups participating in the HEalthy Life In an Urban Setting (HELIUS) study. The gut microbiota was profiled using 16S rRNA gene amplicon sequencing. Associations between microbiota composition and office BP were assessed using machine learning prediction models. In the subgroups with the largest associations, faecal SCFA levels were compared in 200 subjects with lower or higher systolic BP. Faecal microbiota composition explained 4.4% of the total systolic BP variance. Best predictors for systolic BP included Roseburia spp., Clostridium spp., Romboutsia spp., and Ruminococcaceae spp. Explained variance of the microbiota composition was highest in Dutch subjects (4.8%), but very low in South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan and Turkish descent groups (explained variance <0.8%). Faecal SCFA levels, including acetate (P < 0.05) and propionate (P < 0.01), were lower in young Dutch participants with low systolic BP., Conclusions: Faecal microbiota composition is associated with BP, but with strongly divergent associations between ethnic groups. Intriguingly, while Dutch participants with lower BP had higher abundances of several SCFA-producing microbes, they had lower faecal SCFA levels. Intervention studies with SCFAs could provide more insight in the effects of these metabolites on BP., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Physical frailty screening is more commonly performed at outpatient heart failure (HF) clinics. However, this does not incorporate other common geriatric domains. This study assesses whether a multidomain geriatric assessment, in comparison with HF severity or physical frailty, is associated with short-term adverse outcomes., Methods and Results: This is a prospective cohort study of 197 patients with HF (mean age 78, 44% female) attending outpatient HF clinics. HF severity was assessed with New York Heart Association class (I-II versus III-IV) and N-terminal pro b-type natriuretic peptide levels. Physical frailty was assessed with the Fried frailty criteria (not frail, pre-frail, and frail). The following geriatric domains were assessed: physical function, nutrition, polypharmacy, cognition, and dependency in activities of daily living. Logistic regression analyses adjusted for age, sex, diabetes and kidney function assessed 3 month risk of adverse health outcomes (emergency department visits, hospital admissions, and/or death) according to HF severity, physical frailty, and number of affected domains. Number (%) of patients with HF with no, 1, 2, and ≥3 domains affected were 36 (18%), 61 (31%), 58 (29%), and 42 (21%). Seventy-four adverse outcomes were experienced in 50 patients at follow-up. Severity of HF and physical frailty were not significantly associated with an increased risk of adverse health outcomes. However, increasing number of affected domains were significantly associated with an increased risk of adverse outcomes. Compared with no domains affected, odds ratios (95% confidence interval) for 1, 2, and ≥3 domains were 1.8 (0.5-6.5), 4.5 (1.3-15.4), and 7.2 (2.0-26.3) (P-trend <0.01). Further adjustment for HF severity and frailty status slightly attenuated the effect estimates (P-trend 0.02)., Conclusions: Having limitations in multiple domains appears more strongly associated with short-term adverse outcomes than HF severity and physical frailty. This may illustrate the potential added value of a multidomain geriatric assessment in the evaluation and treatment of patients with HF with respect to relevant short-term health outcomes., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objective: Cardiovascular (CV) disease (CVD) risk is increased in rheumatoid arthritis (RA). However, longterm followup studies investigating this risk are scarce., Methods: The CARRÉ (CARdiovascular research and RhEumatoid arthritis) study is a prospective cohort study investigating CVD and its risk factors in 353 patients with longstanding RA. CV endpoints were assessed at baseline and 3, 10, and 15 years after the start of the study and are compared to a reference cohort (n = 2540), including a large number of patients with type 2 diabetes (DM)., Results: Ninety-five patients with RA developed a CV event over 2973 person-years, resulting in an incidence rate of 3.20 per 100 person-years. Two hundred fifty-seven CV events were reported in the reference cohort during 18,874 person-years, resulting in an incidence rate of 1.36 per 100 person-years. Age- and sex-adjusted HR for CV events were increased for RA (HR 2.07, 95% CI 1.57-2.72, p < 0.01) and DM (HR 1.51, 95% CI 1.02-2.22, p = 0.04) compared to the nondiabetic participants. HR was still increased in RA (HR 1.82, 95% CI 1.32-2.50, p < 0.01) after additional adjustment for CV risk factors. Patients with both RA and DM or insulin resistance had the highest HR for developing CVD (2.21, 95% CI 1.01-4.80, p = 0.046 and 2.67, 95% CI 1.30-5.46, p < 0.01, respectively)., Conclusion: The incidence rate of CV events in established RA was more than double that of the general population. Patients with RA have an even higher risk of CVD than patients with DM. This risk remained after adjustment for traditional CV risk factors, suggesting that systemic inflammation is an independent contributor to CV risk.

Acutely ill older adults are at high risk of adverse health outcomes, including loss of function, loss of independence, and mortality. Screening instruments may aid the identification of older adults who are at high risk of negative health outcomes. An extensive geriatric examination, by means of the Comprehensive Geriatric Assessment (CGA), and fit-for-purpose interventions, such as drawing an inventory of the required aftercare, instructions upon discharge, and Advance Care Planning (ACP) can all contribute to improved outcomes. The implementation of screening for vulnerability in the emergency department requires a tailored approach. The current screening instruments differ in terms of target population, moment of application, outcome measures and predictive properties. The APOP screener has been developed and validated in Dutch hospitals. A screening instrument is always part of a broader repertoire, such as education, awareness, adjustment of care processes and protocols, and implementation of appropriate interventions, all aimed at improving outcomes for acutely ill older adults.

Background: Dutch cardiovascular risk management guidelines state almost every older adult (≥70 years) is eligible for a lipid lowering drug (LLD). However, life expectancy, frailty or comorbidities may influence this treatment decision., Objective: investigate how many older adults, according to age, frailty (Drubbel-frailty index) and comorbidities were prescribed LLDs., Methods: data of 244,328 adults ≥70 years from electronic health records of 415 Dutch general practices from 2011-15 were used. Number of LLD prescriptions in patients with (n = 55,309) and without (n = 189,019) cardiovascular disease (CVD) was evaluated according to age, frailty and comorbidities., Results: about 69% of adults ≥70 years with CVD and 36% without CVD were prescribed a LLD. LLD prescriptions decreased with age; with CVD: 78% aged 70-74 years and 29% aged ≥90 years were prescribed a LLD, without CVD: 37% aged 70-74 years and 12% aged ≥90 years. In patients with CVD and within each age group, percentage of LLD prescriptions was 20% point(pp) higher in frail compared with non-frail. In patients without CVD, percentage of LLD prescriptions in frail patients was 11pp higher in adults aged 70-74 years and 40pp higher in adults aged ≥90 years compared to non-frail. Similar trends were seen in the analyses with number of comorbidities., Conclusion: in an older population, LLD prescriptions decreased with age but-contrary to our expectations-LLD prescriptions increased with higher frailty levels., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Orthostatic hypotension (OH) has been cross-sectionally and longitudinally related to dementia in the general population. Whether OH contributes to clinical progression to mild cognitive impairment (MCI) or dementia is less certain. Also, differences in risk of progression between patients with early OH (EOH) versus delayed and/or prolonged OH (DPOH) are unclear., Objective: Assess the prevalence of EOH and DPOH, investigate the longitudinal association between EOH and DPOH and either incident MCI or dementia., Methods: 1,882 patients from the Amsterdam Dementia Cohort [64±8 years; 43% female; n = 500 with subjective cognitive decline (SCD), n = 341 MCI, n = 758 Alzheimer's disease (AD), n = 49 vascular dementia (VaD), n = 146 frontotemporal dementia (FTD), n = 88 Lewy body dementia (DLB)]. Definition OH: systolic blood pressure (BP) drop≥20 mmHg and/or a diastolic BP drop≥10 mmHg at 1 and/or 3 minutes after standing. EOH: OH only at 1 minute, DPOH: OH at (1 and) 3 minutes., Results: Prevalence OH: 19% SCD, 28% MCI, 41% dementia. Compared to SCD, odds of having OH were highest in patients with VaD and DLB; ORs (95% CI) were 2.6 (1.4-4.7) and 5.1 (3.1-8.4), respectively. After a mean (SD) follow-up of 2.2 (1.4) years, 105 (22%) of SCD or MCI patients showed clinical progression. Compared to patients without OH, those with DPOH had an increased risk of progression; hazard ratio (95% CI) was 1.7 (1.1-2.7), and those with EOH did not; 0.8 (0.3-1.9)., Conclusion: Compared to SCD, prevalence of OH was higher in MCI and highest in dementia, particularly in VaD and DLB. DPOH, more likely associated with autonomic dysfunction, is a risk factor for incident MCI or dementia.

The risk of cardiovascular disease (CVD) can be reduced by lowering cholesterol, even at old age. However, there is a large spread in the level of risk of CVD in the elderly. Competing risks, time-to-benefit of the medication in relation to patient life expectancy and frailty must be taken into account when deciding whether or not to prescribe a cholesterol-lowering drug. When estimating cardiovascular risk in the elderly, one should use an age-adjusted individualized risk score that takes into account competing risks. In the case of energetic elderly people without vascular disease, one should start with cholesterol-lowering drugs only if they have a high risk of cardiovascular morbidity, for example, because of diabetes mellitus or very high blood pressure. Cholesterol-lowering drugs should not be prescribed to frail elderly people without vascular disease. A cholesterol-lowering drug should be started or continued in elderly patients with vascular disease. It should be stopped in case of unpleasant side effects or if life expectancy is no more than 1 to 2 years.

To evaluate aortic stiffness in patients with ankylosing spondylitis (AS) using cardiovascular magnetic resonance (CMR) and to assess its association with AS characteristics and left ventricular (LV) remodeling. In this prospective study, 14 consecutive AS patients were each matched to two controls without cardiovascular symptoms or known cardiovascular disease who underwent CMR imaging for the assessment of aortic arch pulse wave velocity (PWV) at 1.5 Tesla. To enhance comparability of the samples, matching was done with replacement resulting in 20 unique controls. Only AS patients with abnormal findings on screening echocardiography were included in this exploratory study. Cine CMR was used to assess LV geometry and systolic function, and late gadolinium enhancement was performed to determine the presence of myocardial hyperenhancement (i.e., fibrosis). Aortic arch PWV was significantly higher in the AS group compared with the control group (median 9.7 m/s, interquartile range [IQR] 7.1 to 11.8 vs. 6.1 m/s, IQR 4.6 to 7.6 m/s; p < 0.001). PWV was positively associated with functional disability as measured by BASFI (R: 0.62; p = 0.018). Three patients (21%) with a non-ischemic pattern of hyperenhancement showed increased PWV (11.7, 12.3, and 16.5 m/s) as compared to the 11 patients without hyperenhancement (9.0 m/s, IQR 6.6 to 10.5 m/s; p = 0.022). PWV was inversely associated with LV ejection fraction (R: - 0.63; p = 0.015), but was not found to be statistically correlated to LV volumes or mass. Aortic arch PWV was increased in our cohort of patients with AS. Higher PWV in the aortic arch was associated with functional disability, the presence of non-ischemic hyperenhancement, and reduced LV systolic function.

Background: Early detection of vulnerable older adults at the emergency department (ED) and implementation of targeted interventions to prevent functional decline may lead to better patient outcomes., Objective: To assess the level of agreement between four frequently used screening instruments: ISAR-HP, VMS, InterRAI ED Screener and APOP., Methods: Observational prospective cohort study in patients ≥ 70 years attending Dutch ED., Results: The prevalence of vulnerability ranged from 19% (APOP) to 45% (ISAR-HP). Overall there was a moderate agreement between the screening instruments (Fleiss Kappa of 0.42 (p<0.001))., Conclusion: Depending on the screening instrument used, either only a small percentage or almost as many as half of the presenting patients will be eligible for targeted interventions, leading to large dissimilarities in working processes, resources and costs.

Objective: To assess the 10-year cardiovascular (CV) risk score and to identify treatment and undertreatment of CV risk factors in patients with established RA., Methods: Demographics, CV risk factors and prevalence of cardiovascular disease (CVD) were assessed by questionnaire. To calculate the 10-year CV risk score according to the Dutch CV risk management guideline, systolic blood pressure was measured and cholesterol levels were determined from fasting blood samples. Patients were categorized into four groups: indication for treatment but not treated; inadequately treated, so not meeting goals (systolic blood pressure ⩽140 mmHg and/or low-density lipoprotein ⩽2.5 mmol/l); adequately treated; or no treatment necessary., Results: A total of 720 consecutive RA patients were included, 375 from Reade and 345 from the Antonius Hospital. The mean age of patients was 59 years (s.d. 12) and 73% were female. Seventeen per cent of the patients had a low 10-year CV risk (<10%), 21% had an intermediate risk (10-19%), 53% a high risk (⩾20%) and 9% had CVD. In total, 69% had an indication for preventive treatment (cholesterol-lowering or antihypertensive drugs). Of those, 42% received inadequate treatment and 40% received no treatment at all., Conclusion: Optimal CV risk management remains a major challenge and better awareness and management are urgently needed to reduce the high risk of CVD in the RA population., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: To evaluate cardiac involvement in patients with ankylosing spondylitis using cardiac magnetic resonance (CMR)., Methods: Patients with ankylosing spondylitis without cardiovascular symptoms or known cardiovascular disease were screened by transthoracic echocardiography (TTE) for participation in this exploratory CMR study. We prospectively enrolled 15 ankylosing spondylitis patients with an abnormal TTE for further tissue characterisation using late gadolinium enhancement (LGE) and T1 mapping. T1 mapping was used to calculate myocardial extracellular volume (ECV). Disease activity was assessed by C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) measurements., Results: In the total of 15 included patients, 14 had a complete CMR exam (mean age 62 years, 93% male and mean disease duration 21 years). Left ventricular (LV) diastolic dysfunction was the most common finding on TTE (79%), followed by aortic root dilatation (14%), right ventricular (RV) dilatation (7%) and RV dysfunction (7%). CMR revealed focal hyperenhancement in three patients (21%), all with a particular pattern of enhancement. LV dysfunction, as defined by a LV ejection fraction below 55%, was observed in five patients (36%). Myocardial ECV was correlated with the CRP concentration (R=0.78, p<0.01) and ESR level (R S =0.73, p<0.01)., Conclusions: In patients with ankylosing spondylitis, CMR with cine imaging and LGE identified global LV dysfunction and focal areas of hyperenhancement. Myocardial ECV, quantified by CMR T1 mapping, was associated with the degree of disease activity. These results may suggest the presence of cardiac involvement in ankylosing spondylitis and may show the potential of ECV as a marker for disease monitoring., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)