Empagliflozin does not change cardiac index nor systemic vascular resistance but rapidly improves left ventricular filling pressure in patients with type 2 diabetes: a randomized controlled study.

BACKGROUND: In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that immediate hemodynamic effects may play a role. However, hitherto no data exist on early effects of SGLT2 inhibitors on hemodynamic parameters and cardiac function. Thus, this study examined early and delayed effects of empagliflozin treatment on hemodynamic parameters including systemic vascular resistance index, cardiac index, and stroke volume index, as well as echocardiographic measures of cardiac function. METHODS: In this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Hemodynamic and echocardiographic parameters were assessed after 1 day, 3 days and 3 months of treatment. RESULTS: Baseline characteristics were not different in the empagliflozin (n = 22) and placebo (n = 20) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; day 1: 48.4 ± 34.7 g/24 h; p < 0.001) as well as urinary volume (1740 ± 601 mL/24 h to 2112 ± 837 mL/24 h; p = 0.011) already after one day compared to placebo. Treatment with empagliflozin had no effect on the primary endpoint of systemic vascular resistance index, nor on cardiac index, stroke volume index or pulse rate at any time point. In addition, echocardiography showed no difference in left ventricular systolic function as assessed by left ventricular ejections fraction and strain analysis. However, empagliflozin significantly improved left ventricular filling pressure as assessed by a reduction of early mitral inflow velocity relative to early diastolic left ventricular relaxation (E/e') which became significant at day 1 of treatment (baseline: 9.2 ± 2.6; day 1: 8.5 ± 2.2; p = 0.005) and remained apparent throughout the study. This was primarily attributable to reduced early mitral inflow velocity E (baseline: 0.8 ± 0.2 m/s; day 1: 0.73 ± 0.2 m/sec; p = 0.003). CONCLUSIONS: Empagliflozin treatment of patients with T2D has no significant effect on hemodynamic parameters after 1 or 3 days, nor after 3 months, but leads to rapid and sustained significant improvement of diastolic function. Trial registration EudraCT Number: 2016-000172-19; date of registration: 2017-02-20 (clinicaltrialregister.eu).

Effects of empagliflozin on erythropoiesis in patients with type 2 diabetes: Data from a randomized, placebo-controlled study.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to significantly reduce hospitalization for heart failure (HHF) and cardiovascular (CV) mortality in various CV outcome trials in patients with and without type 2 diabetes mellitus (T2D). SGLT2 inhibition further increased haemoglobin and haematocrit levels by an as yet unknown mechanism, and this increase has been shown to be an independent predictor of the CV benefit of these agents, for example, in the EMPA-REG OUTCOME trial. The present analysis of the EMPA haemodynamic study examined the early and delayed effects of empagliflozin treatment on haemoglobin and haematocrit levels, in addition to measures of erythropoiesis and iron metabolism, to better understand the underlying mechanisms. In this prospective, placebo-controlled, double-blind, randomized, two-arm parallel, interventional and exploratory study, 44 patients with T2D were randomized into two groups and received empagliflozin 10 mg or placebo for a period of 3 months in addition to their concomitant medication. Blood and urine was collected at baseline, on Day 1, on Day 3 and after 3 months of treatment to investigate effects on haematological variables, erythropoietin concentrations and indices of iron stores. Baseline characteristics were comparable in the empagliflozin (n = 20) and placebo (n = 22) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; Day 1: 48.4 ± 34.7 g/24 h; P < 0.001) as well as urinary volume (baseline: 1740 ± 601 mL/24 h; Day 1: 2112 ± 837 mL/24 h; P = 0.011) already after 1 day and throughout the 3-month study period, while haematocrit and haemoglobin were only increased after 3 months of treatment (haematocrit: baseline: 40.6% ± 4.6%; Month 3: 42.2% ± 4.8%, P < 0.001; haemoglobin: baseline: 136 ± 19 g/L; Month 3: 142 ± 25 g/L; P = 0.008). In addition, after 3 months, empagliflozin further increased red blood cell count (P < 0.001) and transferrin concentrations (P = 0.063) and there was a trend toward increased erythropoietin levels (P = 0.117), while ferritin (P = 0.017), total iron (P = 0.053) and transferrin saturation levels (P = 0.030) decreased. Interestingly, the increase in urinary glucose excretion significantly correlated with the induction of erythropoietin in empagliflozin-treated patients at the 3-month timepoint (Spearman rho 0.64; P = 0.008). Empagliflozin increased haemoglobin concentrations and haematocrit with a delayed time kinetic, which was most likely attributable to increased erythropoiesis with augmented iron utilization and not haemoconcentration. This might be attributable to reduced tubular glucose reabsorption in response to SGLT2 inhibition, possibly resulting in diminished cellular stress as a mechanism for increased renal erythropoietin secretion.

Screen-detected atrial fibrillation predicts mortality in elderly subjects.

AIMS: Current guidelines recommend opportunistic screening for atrial fibrillation (AF) but the prognosis of individuals is unclear. The aim of this investigation is to determine prevalence and 1-year outcome of individuals with screen-detected AF. METHODS AND RESULTS: We performed a prospective, pharmacy-based single time point AF screening study in 7107 elderly citizens (≥65 years) using a hand-held, single-lead electrocardiogram (ECG) device. Prevalence of AF was assessed, and data on all-cause death and hospitalization for cardiovascular (CV) causes were collected over a median follow-up of 401 (372; 435) days. Mean age of participants was 74 ± 5.9 years, with 58% (N = 4130) of female sex. Automated heart rhythm analyses identified AF in 432 (6.1%) participants, with newly diagnosed AF in 3.6% of all subjects. During follow-up, 62 participants (0.9%) died and 390 (6.0%) were hospitalized for CV causes. Total mortality was 2.3% in participants with a screen-detected AF and 0.8% in subjects with a normal ECG [hazard ratio (HR) 2.94; 95% confidence interval (CI) 1.49-5.78; P = 0.002]; hospitalization for CV causes occurred in 10.6% and 5.5%, respectively (HR 2.08; 95% CI 1.52-2.84; P < 0.001). Compared with subjects without a history of AF at baseline and a normal ECG, participants with newly diagnosed or known AF had a significantly higher mortality risk with HRs of 2.64 (95% CI 1.05-6.66; P = 0.04) and 2.68 (95% CI 1.44-4.97; P = 0.002), respectively. After multivariable adjustment, screen-detected AF remained a significant predictor of death or hospitalization for CV causes. CONCLUSION: Pharmacy-based, automated AF screening in elderly citizens identified subjects with unknown AF and an excess mortality risk over the next year.

EULAR/eumusc.net standards of care for rheumatoid arthritis: cross-sectional analyses of importance, level of implementation and care gaps experienced by patients and rheumatologists across 35 European countries.

OBJECTIVE: As part of European League against Rheumatism (EULAR)/European Musculoskeletal Conditions Surveillance and Information Network, 20 user-focused standards of care (SoCs) for rheumatoid arthritis (RA) addressing 16 domains of care were developed. This study aimed to explore gaps in implementation of these SoCs across Europe. METHODS: Two cross-sectional surveys on the importance, level of and barriers (patients only) to implementation of each SoC (0-10, 10 highest) were designed to be conducted among patients and rheumatologists in 50 European countries. Care gaps were calculated as the difference between the actual and maximum possible score for implementation (ie, 10) multiplied by the care importance score, resulting in care gaps (0-100, maximal gap). Factors associated with the problematic care gaps (ie, gap≥30 and importance≥6 and implementation<6) and strong barriers (≥6) were further analysed in multilevel logistic regression models. RESULTS: Overall, 26 and 31 countries provided data from 1873 patients and 1131 rheumatologists, respectively. 19 out of 20 SoCs were problematic from the perspectives of more than 20% of patients, while this was true for only 10 SoCs for rheumatologists. Rheumatologists in countries with lower gross domestic product and non-European Union countries were more likely to report problematic gaps in 15 of 20 SoCs, while virtually no differences were observed among patients. Lack of relevance of some SoCs (71%) and limited time of professionals (66%) were the most frequent implementation barriers identified by patients. CONCLUSIONS: Many problematic gaps were reported across several essential aspects of RA care. More efforts need to be devoted to implementation of EULAR SoCs.

Individual-level and country-level socioeconomic determinants of disease outcomes in SpA: multinational, cross-sectional study (ASAS-COMOSPA).

OBJECTIVE: To explore the independent contribution of individual-level and country level socioeconomic status (SES) determinants to disease activity and physical function in patients with spondyloarthritis (SpA). METHODS: Data from the cross-sectional, multinational (n=22 countries worldwide) COMOSPA (COMOrbidities in SpA) study were used. Contribution of individual SES factors (gender, education) and country of residence to Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Functional Index (BASFI) was explored in multilevel regression models, adjusting for clinical and demographic confounders. Next, the additional effects of national macroeconomic indicators (gross domestic product [GDP], Human Development Index, healthcare expenditure and Gini index) were explored. The mediating role of uptake of biologic disease-modifying antirheumatic drugs between education or GDP and ASDAS was explored by testing indirect effects. RESULTS: In total, 3370 patients with SpA were included: 65% were male, with a mean age of 43 (SD 14), ASDAS of 2.0 (SD 1.1) and BASFI score of 3.1 (SD 2.7). In adjusted models, patients with low education and female patients had an OR of 1.7 (95% CI 1.3 to 2.2) and an OR of 1.7 (95% CI 1.4 to 2.0), respectively, of having ASDAS ≥2.1. They also reported slightly worse function. Large country differences were observed independent of individual SES and clinical confounders. Patients from less SES developed countries have worse ASDAS, while patterns for BASFI were insignificant. Uptake of biologicals did not mediate the relationship between individual-level or country-level SES and disease activity. CONCLUSIONS: Individual-level and country-level health inequalities exist also among patients with SpA. Women and lower educated persons had worse disease activity and somewhat worse physical function. While patients in less socioeconomically developed countries had higher disease activity, they reported similar physical function.

Patients with rheumatoid arthritis facing sick leave or work disability meet varying regulations: a study among rheumatologists and patients from 44 European countries.

OBJECTIVES: To describe and explore differences in formal regulations around sick leave and work disability (WD) for patients with rheumatoid arthritis (RA), as well as perceptions by rheumatologists and patients on the system's performance, across European countries. METHODS: We conducted three cross-sectional surveys in 50 European countries: one on work (re-)integration and social security (SS) system arrangements in case of sick leave and long-term WD due to RA (one rheumatologist per country), and two among approximately 15 rheumatologists and 15 patients per country on perceptions regarding SS arrangements on work participation. Differences in regulations and perceptions were compared across categories defined by gross domestic product (GDP), type of social welfare regime, European Union (EU) membership and country RA WD rates. RESULTS: Forty-four (88%) countries provided data on regulations, 33 (75%) on perceptions of rheumatologists (n=539) and 34 (77%) on perceptions of patients (n=719). While large variation was observed across all regulations across countries, no relationship was found between most of regulations or income compensation and GDP, type of SS system or rates of WD. Regarding perceptions, rheumatologists in high GDP and EU-member countries felt less confident in their role in the decision process towards WD (ß=-0.5 (95% CI -0.9 to -0.2) and ß=-0.5 (95% CI -1.0 to -0.1), respectively). The Scandinavian and Bismarckian system scored best on patients' and rheumatologists' perceptions of regulations and system performance. CONCLUSIONS: There is large heterogeneity in rules and regulations of SS systems across Europe in relation to WD of patients with RA, and it cannot be explained by existing welfare regimes, EU membership or country's wealth.

Deriving common comorbidity indices from the MedDRA classification and exploring their performance on key outcomes in patients with rheumatoid arthritis.

OBJECTIVE: To develop algorithms for calculating the Rheumatic Diseases Comorbidity Index (RDCI), Charlson-Deyo Index (CDI) and Functional Comorbidity Index (FCI) from the Medical Dictionary for Regulatory Activities (MedDRA), and to assess how these MedDRA-derived indices predict clinical outcomes, utility and health resource utilization (HRU). METHODS: Two independent researchers linked the preferred terms of the MedDRA classification into the conditions included in the RDCI, the CDI and the FCI. Next, using data from the Norwegian Register-DMARD study (a register of patients with inflammatory joint diseases treated with DMARDs), the explanatory value of these indices was studied in models adjusted for age, gender and DAS28. Model fit statistics were compared in generalized estimating equation (prediction of outcome over time) models using as outcomes: modified HAQ, HAQ, physical and mental component summary of SF-36, SF6D and non-RA related HRU. RESULTS: Among 4126 patients with RA [72% female, mean (s.d.) age 56 (14) years], median (interquartile range) of RDCI at baseline was 0.0 (1.0) [range 0-6], CDI 0.0 (0.0) [0-7] and FCI 0.0 (1.0) [0-6]. All the comorbidity indices were associated with each outcome, and differences in their performance were moderate. The RDCI and FCI performed better on clinical outcomes: modified HAQ and HAQ, hospitalization, physical and mental component summary, and SF6D. Any non-RA related HRU was best predicted by RDCI followed by CDI. CONCLUSION: An algorithm is now available to compute three commonly used comorbidity indices from MedDRA classification. Indices performed comparably well in predicting a variety of outcomes, with the CDI performing slightly worse when predicting outcomes reflecting functioning and health.

Emergence times and airway reactions during general anaesthesia with remifentanil and a laryngeal mask airway: A multicentre randomised controlled trial.

BACKGROUND: Avoidance of airway complications and rapid emergence from anaesthesia are indispensable for the use of a laryngeal mask airway (LMA). Evidence from adequately powered randomised studies with a low risk of bias for the optimal anaesthetic in this context is limited. OBJECTIVE: We tested the hypothesis that when using remifentanil-based intra-operative analgesia, desflurane would be the most suitable anaesthetic: with noninferiority in the occurrence of upper airway complications and superiority in emergence times compared with sevoflurane or propofol. DESIGN: A randomised, multicentre, partially double-blinded, three-arm, parallel-group study. SETTING: Two university and two regional German hospitals, from February to October 2015. PATIENTS: A total of 352 patients (age 18 to 75 years, ASA physical status I to III, BMI less than 35 kg m and fluent in German) were enrolled in this study. All surgery was elective with a duration of 0.5 to 2 h, and general anaesthesia with a LMA was feasible. INTERVENTION: The patients were randomised to receive desflurane, sevoflurane or propofol anaesthesia. MAIN OUTCOME MEASURES: This study was powered for the primary outcome 'time to state date of birth' and the secondary outcome 'intra-operative cough'. Time to emergence from anaesthesia and the incidence of upper airway complications were assessed on the day of surgery. RESULTS: The primary outcome was analysed for 343 patients: desflurane (n=114), sevoflurane (n=111) and propofol (n=118). The desflurane group had the fastest emergence. The mean (± SD) times to state the date of birth following desflurane, sevoflurane and propofol were 8.1 ±â€Š3.6, 10.1 ±â€Š4.0 and 9.8 ±â€Š5.1 min, respectively (P < 0.01). There was no difference in upper airway complications (cough and laryngospasm) across the groups, but these complications were less frequent than in previous studies. CONCLUSION: When using a remifentanil infusion for intra-operative analgesia in association with a LMA, desflurane was associated with a significantly faster emergence and noninferiority in the incidence of intra-operative cough than either sevoflurane or Propofol. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02322502; EudraCT identifier: 2014-003810-96.

Mobile access to virtual randomization for investigator-initiated trials.

Background/aims Randomization is indispensable in clinical trials in order to provide unbiased treatment allocation and a valid statistical inference. Improper handling of allocation lists can be avoided using central systems, for example, human-based services. However, central systems are unaffordable for investigator-initiated trials and might be inaccessible from some places, where study subjects need allocations. We propose mobile access to virtual randomization, where the randomization lists are non-existent and the appropriate allocation is computed on demand. Methods The core of the system architecture is an electronic data capture system or a clinical trial management system, which is extended by an R interface connecting the R server using the Java R Interface. Mobile devices communicate via the representational state transfer web services. Furthermore, a simple web-based setup allows configuring the appropriate statistics by non-statisticians. Our comprehensive R script supports simple randomization, restricted randomization using a random allocation rule, block randomization, and stratified randomization for un-blinded, single-blinded, and double-blinded trials. For each trial, the electronic data capture system or the clinical trial management system stores the randomization parameters and the subject assignments. Results Apps are provided for iOS and Android and subjects are randomized using smartphones. After logging onto the system, the user selects the trial and the subject, and the allocation number and treatment arm are displayed instantaneously and stored in the core system. So far, 156 subjects have been allocated from mobile devices serving five investigator-initiated trials. Conclusion Transforming pre-printed allocation lists into virtual ones ensures the correct conduct of trials and guarantees a strictly sequential processing in all trial sites. Covering 88% of all randomization models that are used in recent trials, virtual randomization becomes available for investigator-initiated trials and potentially for large multi-center trials.

Survey of Non-Rigid Registration Tools in Medicine.

We catalogue available software solutions for non-rigid image registration to support scientists in selecting suitable tools for specific medical registration purposes. Registration tools were identified using non-systematic search in Pubmed, Web of Science, IEEE Xplore® Digital Library, Google Scholar, and through references in identified sources (n = 22). Exclusions are due to unavailability or inappropriateness. The remaining (n = 18) tools were classified by (i) access and technology, (ii) interfaces and application, (iii) living community, (iv) supported file formats, and (v) types of registration methodologies emphasizing the similarity measures implemented. Out of the 18 tools, (i) 12 are open source, 8 are released under a permissive free license, which imposes the least restrictions on the use and further development of the tool, 8 provide graphical processing unit (GPU) support; (ii) 7 are built on software platforms, 5 were developed for brain image registration; (iii) 6 are under active development but only 3 have had their last update in 2015 or 2016; (iv) 16 support the Analyze format, while 7 file formats can be read with only one of the tools; and (v) 6 provide multiple registration methods and 6 provide landmark-based registration methods. Based on open source, licensing, GPU support, active community, several file formats, algorithms, and similarity measures, the tools Elastics and Plastimatch are chosen for the platform ITK and without platform requirements, respectively. Researchers in medical image analysis already have a large choice of registration tools freely available. However, the most recently published algorithms may not be included in the tools, yet.

In wealthier countries, patients perceive worse impact of the disease although they have lower objectively assessed disease activity: results from the cross-sectional COMORA study.

OBJECTIVES: To investigate patterns in patient-reported and physician-reported disease outcomes in patients with rheumatoid arthritis (RA) from countries with different level of socioeconomic development. METHODS: Data from a cross-sectional multinational study (COMOrbidities in RA) were used. Contribution of socioeconomic welfare (gross domestic product (GDP); low vs high) of country of residence to physician-reported (tender joint count, swollen joint count (SJC), erythrocyte sedimentation rate, disease activity score based on 28 joints assessment (DAS28)-3v based on these three components and physician global assessment) and patient-reported (modified Health Assessment Questionnaire (mHAQ), patient global assessment and fatigue) disease outcomes was explored in linear regressions, adjusting for relevant confounders. RESULTS: In total, 3920 patients with RA from 17 countries (30 to 411 patients per country) were included, with mean age of 56 years (SD13) and 82% women. Mean SJC varied between 6.7 (Morocco) and 0.9 (The Netherlands), mean mHAQ ranged between 0.7 (Taiwan) and 1.5 (The Netherlands). Venezuela had the lowest (1.7) and the Netherlands the highest score on fatigue (5.0). In fully adjusted models, lower GDP was associated with worse physician-reported outcomes (1.85 and 2.84 more swollen and tender joints, respectively, and 1.0 point higher DAS28-3v), but only slightly worse performance-based patient-reported outcome (0.15 higher mHAQ), and with better evaluation-based patient-reported outcomes (0.43 and 0.97 points lower on patient global assessment and fatigue, respectively). CONCLUSIONS: In patients with RA, important differences in physician-reported and patient-reported outcomes across countries were seen, with overall a paradox of worse physician-reported outcomes but better patient-reported outcomes in low-income countries, while results indicate that these outcomes in multinational studies should be interpreted with caution. Research on explanatory factors of this paradox should include non-disease driven cultural factors influencing health.

Lower education and living in countries with lower wealth are associated with higher disease activity in rheumatoid arthritis: results from the multinational COMORA study.

OBJECTIVES: To investigate the relationship of socioeconomic status (SES) on an individual and country level with disease activity in rheumatoid arthritis (RA) and explore the mediating role of uptake of costly biological disease-modifying antirheumatic drugs (bDMARDs) in this relationship. METHODS: Data from a cross-sectional multinational study (COMOrbidities in RA) were used. Contribution of individual socioeconomic factors and country of residence to disease activity score with 28-joint assessment (DAS28) was explored in regression models, adjusting for relevant clinical confounders. Next, country of residence was replaced by gross domestic product (GDP) (low vs high) to investigate the contribution of SES by comparing R(2) (model fit). The mediating role of uptake of bDMARDs in the relationship between education or GDP and DAS28 was explored by testing indirect effects. RESULTS: In total, 3920 patients with RA were included (mean age 56 (SD 13) years, 82% women, mean DAS28 3.7 (1.6)). After adjustment, women (vs men) and low-educated (vs university) patients had 0.35 higher DAS28. Adjusted country differences in DAS28, compared with the Netherlands (lowest DAS28), varied from +0.2 (France) to +2.4 (Egypt). Patients from low GDP countries had 0.98 higher DAS28. No interactions between individual-level and country-level variables were observed. A small mediation effect of uptake of bDMARDs in the relationship between education and DAS28 (7.7%) and between GDP and DAS28 (6.7%) was observed. CONCLUSIONS: Female gender and lower individual or country SES were independently associated with DAS28, but did not reinforce each other. The association between lower individual SES (education) or lower country welfare (GDP) with higher DAS28 was partially mediated by uptake of bDMARDs.

In rheumatoid arthritis, country of residence has an important influence on fatigue: results from the multinational COMORA study.

OBJECTIVES: To investigate the relationship between country of residence and fatigue in RA, and to explore which country characteristics are related to fatigue. METHODS: Data from the multinational COMORA study were analysed. Contribution of country of residence to level of fatigue [0-10 on visual analogue scale (VAS)] and presence of severe fatigue (VAS ⩾ 5) was explored in multivariable linear or logistic regression models including first socio-demographics and objective disease outcomes (M1), and then also subjective outcomes (M2). Next, country of residence was replaced by country characteristics: gross domestic product (GDP), human development index (HDI), latitude (as indicator of climate), language and income inequality index (gini-index). Model fit (R(2)) for linear models was compared. RESULTS: A total of 3920 patients from 17 countries were included, mean age 56 years (s.d. 13), 82% females. Mean fatigue across countries ranged from 1.86 (s.d. 2.46) to 4.99 (s.d. 2.64) and proportion of severe fatigue from 14% (Venezuela) to 65% (Egypt). Objective disease outcomes did not explain much of the variation in fatigue ([Formula: see text] = 0.12), while subjective outcomes had a strong negative impact and partly explained the variation in fatigue ([Formula: see text]= 0.27). Country of residence had a significant additional effect (increasing model fit to [Formula: see text] = 0.20 and [Formula: see text] = 0.36, respectively). Remarkably, higher GDP and better HDI were associated with higher fatigue, and explained a large part of the country effect. Logistic regression confirmed the limited contribution of objective outcomes and the relevant contribution of country of residence. CONCLUSION: Country of residence has an important influence on fatigue. Paradoxically, patients from wealthier countries had higher fatigue.

Less educated and older patients have reduced access to biologic DMARDs even in a country with highly developed social welfare (Norway): results from Norwegian cohort study NOR-DMARD.

OBJECTIVE: To explore whether age, gender or education influence the time until initiation of the first bDMARD in patients with RA. METHODS: Data from the Norwegian Register of DMARDs collected between 2000 and 2012 were used. Only DMARD-naïve patients with RA starting their first conventional synthetic DMARD were included in the analyses. The start of the first bDMARD was the main outcome of interest. Cox regression analyses were used to explore the impact of education, age and gender on the start of a first bDMARD, adjusting for confounders, either at baseline or varying over time (time-varying model). RESULTS: Of 1946 eligible patients [mean (s.d.) age: 55 (14) years, 68% females], 368 (19%) received a bDMARD during follow-up (mean 2.6 years). In the baseline prediction model, older age [Hazard Ratio (HR) 0.97, 95% CI: 0.96, 0.98], lower education [HR = 0.76 and 0.68 for low and intermediate education levels vs college/university education, respectively (P = 0.01)] and female gender [only in the period 2000-03, HR = 0.61 (95% CI: 0.41, 0.91)] were associated with a lower hazard ratio to start a bDMARD. The time-varying model provided overall consistent results, but the effect of education was only relevant for older patients (>57 years) and became more pronounced by the end of the decade. CONCLUSIONS: Less educated and older patients have disadvantages with regard to access to costly treatments, even in a country with highly developed welfare like Norway. Females had lower access in the beginning of the 2000s, but access had improved by the end of the decade.

Fluctuations in patient reported disease activity, pain and global being in patients with ankylosing spondylitis.

OBJECTIVE: To evaluate in patients with AS (i) the fluctuation in self-reported disease activity (BASDAI), patient global well-being [visual analogue scale (VAS)-global] and spinal pain (VAS-pain) during 2 years of follow-up on a group level and (ii) the clinical relevance of these fluctuations on a patient level. METHODS: Dutch patients from the Outcome in AS International Study cohort completed patient-reported outcome measures every 2 months over 2 years. On the group level, mixed linear models were used to analyse whether the outcome measures were constant over time. On a patient level, relevant changes in scores were assessed by the frequency in which changes would exceed predefined cut-off values (>1.0 or >2.0 on a 0-10 scale) during the 2 years of follow-up using 2-, 4-, 6-, 12- or 24-month assessments. RESULTS: Ninety patients [median age 47.3 years (sd 11.4), 67.8% male, symptom duration 25.2 years (sd 11.3)] were included. On the group level, the outcome measures remained constant over time. However, large fluctuations were found on the patient level. For example, using 2 month intervals, 92% and 69% of the patients had at least one change of > 1.0 or > 2.0, respectively, in the BASDAI during the 2 year follow-up. When prolonging the interval, the proportion of changes exceeding the cut-off decreased, indicating that information is lost. Similar results were found for the VAS-global and VAS-pain. CONCLUSION: Substantial fluctuations in BASDAI, VAS-global and VAS-pain were found in individuals over time. With longer intervals, fewer fluctuations were observed, indicating that relevant changes might be missed.

Polymorphisms in genes of the renin-angiotensin-aldosterone system and renal cell cancer risk: interplay with hypertension and intakes of sodium, potassium and fluid.

Hypertension is an established risk factor for renal cell cancer (RCC). The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and is closely linked to hypertension. RAAS additionally influences homeostasis of electrolytes (e.g. sodium and potassium) and fluid. We investigated single nucleotide polymorphisms (SNPs) in RAAS and their interactions with hypertension and intakes of sodium, potassium and fluid regarding RCC risk in the Netherlands Cohort Study (NLCS), which was initiated in 1986 and included 120,852 participants aged 55 to 69 years. Diet and lifestyle were assessed by questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the SEQUENOM® MassARRAY® platform for a literature-based selection of 13 candidate SNPs in seven key RAAS genes. After 20.3 years of follow-up, Cox regression analyses were conducted using a case-cohort approach including 3,583 subcohort members and 503 RCC cases. Two SNPs in AGTR1 were associated with RCC risk. AGTR1_rs1492078 (AA vs. GG) decreased RCC risk [hazard ratio (HR) (95% confidence interval (CI)): 0.70(0.49-1.00)], whereas AGTR1_rs5186 (CC vs. AA) increased RCC risk [HR(95%CI): 1.49(1.08-2.05)]. Associations were stronger in participants with hypertension. The RCC risk for AGT_rs3889728 (AG + AA vs. GG) was modified by hypertension (p interaction = 0.039). SNP-diet interactions were not significant, although HRs suggested interaction between SNPs in ACE and sodium intake. SNPs in AGTR1 and AGT influenced RCC susceptibility, and their effects were modified by hypertension. Sodium intake was differentially associated with RCC risk across genotypes of several SNPs, yet some analyses had probably inadequate power to show significant interaction. Results suggest that RAAS may be a candidate pathway in RCC etiology.

Relationship between types of radiographic damage and disability in patients with rheumatoid arthritis in the EURIDISS cohort: a longitudinal study.

OBJECTIVE: The aim of this study was to assess if any of the different types of radiographic damage [true joint space narrowing (JSN), (sub)luxation and erosions] are preferentially related to disability in patients with RA. METHODS: Longitudinal data from 167 RA patients from the European Research on Incapacitating Diseases and Social Support study over 10 years were analysed to investigate the relationship between the three types of radiographic damage and disability [grip strength, HAQ and the dexterity scale in the Arthritis Impact Measurement Scales (AIMS)]. A longitudinal analysis including separate models per type of damage and joint group and combined models including all information was conducted. RESULTS: All types of damage were inversely related to grip strength in the analysis of separate models, but only true JSN independently remained statistically significant in the combined analysis [ß = -0.087 (95% CI -0.151, -0.022)]. Neither JSN, (sub)luxation nor erosions were associated with HAQ score, while erosions were associated with AIMS dexterity only in the analysis of separate models. After stratifying for hand joint group, erosions at MCP joints [ß = -0.288 (95% CI -0.556, -0.019)] and true JSN at the wrist [ß = -0.132 (95% CI -0.234, -0.030)] were significantly related to grip strength. Erosions at the PIP [ß = 0.017 (95% CI 0.005, 0.028)] and MCP joints [ß = 0.114 (95% CI 0.010, 0.217)] was the only type of damage associated with HAQ and AIMS dexterity, respectively. CONCLUSION: All types of radiographically visible joint damage interfere with important aspects of physical functions. True JSN is most closely related to hand function.

Occupational asbestos exposure and risk of esophageal, gastric and colorectal cancer in the prospective Netherlands Cohort Study.

The evidence for an association between occupational asbestos exposure and esophageal, gastric and colorectal cancer is limited. We studied this association specifically addressing risk differences between relatively low and high exposure, risk associated with cancer subtypes, the influence of potential confounders and the interaction between asbestos and smoking in relation to cancer risk. Using the Netherlands Cohort Study (n = 58,279 men, aged 55-69 years at baseline), asbestos exposure was estimated by linkage to a job-exposure matrix. After 17.3 years of follow-up, 187 esophageal, 486 gastric and 1,724 colorectal cancer cases were available for analysis. The models adjusted for age and family history of cancer showed that mainly (prolonged) exposure to high levels of asbestos was statistically significantly associated with risk of esophageal adenocarcinoma (EAC), total and distal colon cancer and rectal cancer. For overall gastric cancer and gastric non-cardia adenocarcinoma (GNCA), also exposure to lower levels of asbestos was associated. Additional adjustment for lifestyle confounders, especially smoking status, yielded non-significant associations with overall gastric cancer and GNCA in the multivariable-adjusted model, except for the prolonged highly exposed subjects (tertile 3 vs. never: HR 2.67, 95% CI: 1.11-6.44 and HR 3.35, 95% CI: 1.33-8.44, respectively). No statistically significant additive or multiplicative interaction between asbestos and smoking was observed for any of the studied cancers. This prospective population-based study showed that (prolonged) high asbestos exposure was associated with overall gastric cancer, EAC, GNCA, total and distal colon cancer and rectal cancer.

Vegetable, fruit and nitrate intake in relation to the risk of Barrett's oesophagus in a large Dutch cohort.

There are few epidemiological data on the dietary risk factors of Barrett's oesophagus, a precursor of oesophageal adenocarcinoma. The present study investigated the association between vegetable, fruit and nitrate intake and Barrett's oesophagus risk in a large prospective cohort. The Netherlands Cohort Study recruited 120,852 individuals aged 55-69 years in 1986. Vegetable and fruit intake was assessed using a 150-item FFQ, and nitrate intake from dietary sources and drinking water was determined. After 16.3 years of follow-up, 433 cases (241 men and 192 women) of Barrett's oesophagus with specialised intestinal metaplasia and 3717 subcohort members were analysed in a case-cohort design using Cox proportional hazards models while adjusting for potential confounders. Men exhibited a lower risk of Barrett's oesophagus in the highest v. the lowest quintile of total (multivariable-adjusted hazard ratio (HR): 0.66, 95% CI 0.43, 1.01), raw (HR 0.63, 95% CI 0.40, 0.99), raw leafy (HR 0.55, 95% CI 0.36, 0.86) and Brassica (HR 0.64, 95% CI 0.41, 1.00) vegetable intake. No association was found for other vegetable groups and fruits. No significant associations were found between vegetable and fruit intake and Barrett's oesophagus risk among women. Total nitrate intake was inversely associated with Barrett's disease risk in men (HR 0.50, 95% CI 0.25, 0.99) and positively associated with it in women (HR 3.77, 95% CI 1.68, 8.45) (P for interaction = 0.04). These results suggest that vegetable intake may contribute to the prevention of Barrett's oesophagus. The possible differential effect in men and women should be evaluated further.

Preoperative Midazolam and Patient-Centered Outcomes of Older Patients: The I-PROMOTE Randomized Clinical Trial.

Importance: The effect of oral midazolam premedication on patient satisfaction in older patients undergoing surgery is unclear, despite its widespread use. Objective: To determine the differences in global perioperative satisfaction in patients with preoperative administration of oral midazolam compared with placebo. Design, Setting, and Participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial was conducted in 9 German hospitals between October 2017 and May 2019 (last follow-up, June 24, 2019). Eligible patients aged 65 to 80 years who were scheduled for elective inpatient surgery for at least 30 minutes under general anesthesia and with planned extubation were enrolled. Data were analyzed from November 2019 to December 2020. Interventions: Patients were randomized to receive oral midazolam, 3.75 mg (n = 309), or placebo (n = 307) 30 to 45 minutes prior to anesthesia induction. Main Outcomes and Measures: The primary outcome was global patient satisfaction evaluated using the self-reported Evaluation du Vécu de l'Anesthésie Generale (EVAN-G) questionnaire on the first postoperative day. Key secondary outcomes included sensitivity and subgroup analyses of the primary outcome, perioperative patient vital data, adverse events, serious complications, and cognitive and functional recovery up to 30 days postoperatively. Results: Among 616 randomized patients, 607 were included in the primary analysis. Of these, 377 (62.1%) were male, and the mean (SD) age was 71.9 (4.4) years. The mean (SD) global index of patient satisfaction did not differ between the midazolam and placebo groups (69.5 [10.7] vs 69.6 [10.8], respectively; mean difference, -0.2; 95% CI, -1.9 to 1.6; P = .85). Sensitivity (per-protocol population, multiple imputation) and subgroup analyses (anxiety, frailty, sex, and previous surgical experience) did not alter the primary results. Secondary outcomes did not differ, except for a higher proportion of patients with hypertension (systolic blood pressure ≥160 mm Hg) at anesthesia induction in the placebo group. Conclusion and Relevance: A single low dose of oral midazolam premedication did not alter the global perioperative patient satisfaction of older patients undergoing surgery or that of patients with anxiety. These results may be affected by the low dose of oral midazolam. Further trials-including a wider population with commonplace low-dose intravenous midazolam and plasma level measurements-are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03052660.