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.

Poor reporting quality of randomized controlled trials comparing treatments of COVID-19-A retrospective cross-sectional study on the first year of publications.

INTRODUCTION: Transparent and complete reporting of randomized controlled trials (RCTs) is essential for critical scientific appraisal of the results. It has been argued whether publications during the COVID-19 pandemic have met reporting standards. In this study, we assessed reporting adherence of RCTs on treatment interventions in COVID-19 patients to the CONSORT checklist and discuss which lessons can be learned to improve reporting in the future. METHODS: This was a retrospective, cross-sectional study performed at the University Hospital RWTH Aachen, Germany. We conducted a pragmatic systematic literature search in the PubMed database to identify RCTs on treatment interventions in COVID-19 patients in the first year of publications on the topic (March 2020-February 2021). We investigated the adherence of each publication to the CONSORT checklist and assessed the association between specific predictors and percentage adherence in an exploratory multivariable regression model. RESULTS: We analyzed 127 RCTs and found that the median percentage adherence to the CONSORT checklist was 54.3% [IQR 38.9 to 65.7]. In the exploratory multivariable regression model, the impact factor (highest tertile of impact factor compared to lowest tertile ß = 21.77, 95% CI 13.89 to 29.66, p<0.001; middle tertile compared lowest tertile ß = 11.79, 95% CI 5.74 to 17.84, p<0.001)) and authors' referral to the CONSORT statement (ß = 9.29, 95% CI 2.98 to 15.60, p = 0.004) were associated with a higher percentage adherence to the CONSORT checklist. CONCLUSION: The reporting quality of RCTs on treatment interventions in COVID-19 patients during the first year of publications was poor. Measures to improve reporting quality are urgently needed.

Empagliflozin reduces markers of acute kidney injury in patients with acute decompensated heart failure.

AIMS: In this prospective, placebo-controlled, double-blind, exploratory study, we examined early and more delayed effects of empagliflozin treatment on haemodynamic parameters (primary endpoint: cardiac output) and kidney function including parameters of acute kidney injury (AKI) in patients with acute decompensated heart failure (HF). METHODS AND RESULTS: Patients with acute decompensated HF with or without diabetes were randomized to empagliflozin 10 mg or placebo for 30 days. Haemodynamic, laboratory, and urinary parameters were assessed after 6 h, 1 day, 3 days, 7 days, and 30 days of treatment. Median time between hospital admission and randomization was 72 h. Baseline characteristics were not different in the empagliflozin (n = 10) and placebo (n = 9) groups. Empagliflozin led to a significant increase in urinary glucose excretion throughout the study (baseline: 37 ± 15 mg/24 h; Day 1: 14 565 ± 8663 mg/24 h; P = 0.001). Empagliflozin did not affect the primary endpoint of cardiac index or on systemic vascular resistance index at any time point. However, empagliflozin significantly reduced parameters of AKI (urinary TIMP-2 and IGFBP7 by NephroCheck® as indicators of tubular kidney damage), which became significant after 3 days of treatment [placebo: 1.1 ± 1.1 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.02] and remained significant at the 7 day time point [placebo: 2.5 ± 3.8 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.003]. CONCLUSIONS: In this study, empagliflozin treatment did not affect haemodynamic parameters but significantly reduced markers of tubular injury in patients with acute decompensated HF.

Effects of COPD on Left Ventricular and Left Atrial Deformation in Patients with Acute Myocardial Infarction: Strain Analysis Using Speckle-Tracking Echocardiography.

Myocardial strain analysis, which describes myocardial deformation (shortening or lengthening), provides more detailed information about left ventricular (LV) and atrial (LA) functions than conventional echocardiography and delivers prognostic information. To analyze the effects of COPD on left heart function upon acute myocardial infarction (AMI), consecutive AMI patients were retrospectively screened, and patients were included if a post-AMI echocardiography and results of recent pulmonary function tests (PFTs) were available. Strain analysis was performed by a cardiologist who was blinded to clinical information. Overall, 109 AMI patients were included (STEMI: 38%, non-STEMI: 62%). COPD patients (41%) had significantly more impaired LV "global-longitudinal-strain" (LV-GLS) compared to non-COPD patients (−15 ± 4% vs. −18 ± 4%; p < 0.001, respectively), even after adjusting for LV-ejection-fraction (LVEF) and age (mean estimated difference: 1.7%, p = 0.009). Furthermore, COPD patients had more impaired LA strain (LAS) than non-COPD patients in all cardiac cycle phases (estimated mean differences after adjusting for LVEF and age: during reservoir phase: −7.5% (p < 0.001); conduit phase: 5.5% (p < 0.001); contraction phase: 1.9% (p = 0.034)). There were no correlations between PFT variables and strain values. In conclusion, the presence of COPD was associated with more impaired LV and LA functions after AMI, as detected by strain analysis, which was independent of age, LVEF, and PFT variables.

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.

Effects of Transcatheter Mitral Valve Repair Using MitraClip® Device on Sleep Disordered Breathing in Patients with Mitral Valve Regurgitation.

Sleep disordered breathing (SDB) is common among patients with valvular heart disease, and successful valve surgery could reduce SDB severity. However, data about the effects of transcatheter mitral valve repair on SDB are scarce. Therefore, mitral regurgitation (MR) patients undergoing MitraClip-placement were prospectively enrolled. Before MitraClip-placement, daytime sleepiness and sleep quality were assessed using the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI), respectively; and all patients underwent SDB screening using five-channel respiratory polygraphy. After 3-6 months, patients had a similar reassessment including: ESS, PSQI, and respiratory polygraphy. 67 patients were included (77 ± 8years). Despite normal sleepiness scores, 41 patients (61%) had SDB with apnea-hypopnea-index (AHI) ≥ 15 h before MitraClip-placement, of whom only three patients had known SDB previously. Compared to patients without SDB, patients with SDB had similar sleepiness scores but higher NT-proBNP values at baseline (4325 vs. 1520 pg/mL, p < 0.001). At follow-up, there were significant AHI improvements among patients with SDB (p = 0.013). However, there were no significant sleepiness score changes. In conclusion, the prevalence of SDB among MitraClip candidates is very high even in those without daytime sleepiness. MR patients with SDB have higher NT-proBNP values, which may reflect a worse prognosis. MitraClip-placement may improve the underlying SDB, which could be an additional benefit of the procedure.

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).

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.

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.

Impact of PReOperative Midazolam on OuTcome of Elderly patients (I-PROMOTE): study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Premedication of surgical patients with benzodiazepines has become questionable regarding risk-benefit ratio and lack of evidence. Though preoperative benzodiazepines might alleviate preoperative anxiety, a higher risk for adverse events is described, particularly for elderly patients (≥ 65 years). Several German hospitals already withhold benzodiazepine premedication from elderly patients, though evidence for this approach is lacking. The patient-centred outcome known as global postoperative patient satisfaction is recognised as a substantial quality indicator of anaesthesia care incorporated by the American Society of Anesthesiologists. Therefore, we aim to assess whether the postoperative patient satisfaction after premedication with placebo compared to the preoperative administration of 3.75 mg midazolam in elderly patients differs. METHODS: This study is a multicentre, randomised, placebo-controlled, double-blinded, two-arm parallel, interventional trial, conducted in nine German hospitals. In total 614 patients (≥ 65-80 years of age) undergoing elective surgery with general anaesthesia will be randomised to receive either 3.75 mg midazolam or placebo. The primary outcome (global patient satisfaction) will be assessed with the validated EVAN-G questionnaire on the first postoperative day. Secondary outcomes will be assessed until the first postoperative day and then 30 days after surgery. They comprise among other things: functional and cognitive recovery, postoperative delirium, health-related quality of life assessment, and mortality or new onset of serious cardiac or pulmonary complications, acute stroke, or acute kidney injury. Analysis will adhere to the intention-to-treat principle. The primary outcome will be analysed with the use of mixed linear models including treatment effect and study centre as factors and random effects for blocks. Exploratory adjusted and subgroup analyses of the primary and secondary outcomes with regard to gender effects, frailty, pre-operative anxiety level, patient demographics, and surgery experience will also be performed. DISCUSSION: This is, to the best of our knowledge, the first study analysing patient satisfaction after premedication with midazolam in elderly patients. In conclusion, this study will provide high-quality data for the decision-making process regarding premedication in elderly surgical patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03052660 . Registered on 14 February 2017. EudraCT 2016-004555-79 .

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.

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.

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.

Large country differences in work outcomes in patients with RA - an analysis in the multinational study COMORA.

BACKGROUND: We aimed to explore whether country of residence or specific country characteristics are associated with work outcomes in rheumatoid arthritis (RA). METHODS: Data from the 17 countries participating in the Comorbidities in RA (COMORA) study were used. Work outcomes were measured by the Work Productivity and Activity Impairment Questionnaire, addressing employment (yes/no), absenteeism (percentage of time; 3 categories) and presenteeism (percentage of at-work productivity restrictions; 4 categories). Contribution of country of residence, gross domestic product (GDP), Human Development Index (HDI), unemployment rate, social protection expenditures (SPE) or world region to work outcomes was investigated in adjusted (ordered) logistic regressions. RESULTS: The patients (n = 2395) were younger than 60 years; mean age 48 (SD 9.2) years, 1972 (84%) female and 1065 (45%) employed. Large country differences were found. Taking the country with the best work outcome as reference, Moroccan patients had the lowest odds of being employed (OR 0.2 (95% CI 0.1; 0.3) vs. Germany) and highest odds of absenteeism (OR 13.2 (3.6; 48.3) vs. Japan). Patients in Taiwan had the highest odds of presenteeism (OR 13.0 (5.5; 30.9) vs. Venezuela). All country indices except SPE were associated with work outcomes. For example, patients in low-GDP countries had lower odds of employment (OR 0.6 (0.5; 0.8)), higher odds of absenteeism (OR 2.8 (2.0; 4.1)), but lower odds of presenteeism (OR 0.5 (0.4; 0.7)) compared to higher-GDP countries. CONCLUSION: Substantial differences in work outcomes among patients with RA were observed between countries. Lower economic wealth and human development of countries were associated with worse employment and higher absenteeism, but lower presenteeism.

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.

Promoter CpG island methylation in ion transport mechanisms and associated dietary intakes jointly influence the risk of clear-cell renal cell cancer.

Background: Sodium intake, but not potassium or fluid intake, has been associated with higher renal cell cancer (RCC) risk. However, risk factors may differ by molecular subtypes of the tumour. In renal physiology, electrolyte and water homeostasis is facilitated by ion transport mechanisms (ITM). Aberrant regulation of ITM genes, for example by promoter CpG island methylation, may modify associations between sodium, potassium and fluid intake and RCC risk. Methods: We identified ARHGDIG , ATP1A1 , SCNN1B and SLC8A3 as ITM genes exhibiting RCC-specific promoter methylation and down-regulation. Methylation-specific polymerase chain reaction (PCR) was used to analyse promoter CpG island methylation in tumour DNA of 453 RCC cases from the Netherlands Cohort Study ( n = 120 852) after 20.3 years of follow-up. Diet was measured at baseline using food-frequency questionnaires. Cox regression analyses were restricted to clear-cell (cc)RCC ( n = 306) and stratified by tumours with no, low (1 gene) and high (≥ 2 genes) methylation. Results: Sodium intake (high vs low) increased ccRCC risk particularly in tumours with a high methylation index: hazard ratio (HR) [95% confidence interval (CI)]: 2.04 (1.16-3.58), whereas heterogeneity across the methylation index was not significant ( P -heterogeneity = 0.26). Potassium intake was differentially associated with ccRCC risk ( P -heterogeneity = 0.008); the risk for high (vs low) potassium intake was low for unmethylated tumours [HR (95% CI): 0.60 (0.36-1.01)], but high for tumours with a high methylation index [HR (95% CI): 1.60 (0.96-2.65)]. Risks similarly differed for fluid intake, though not significantly ( P -heterogeneity = 0.54). Conclusions: Our findings suggest for the first time that dietary intakes are differentially associated with ccRCC risk according to molecular subtypes defined by ITM gene-specific promoter methylation.

Potential role of gene-environment interactions in ion transport mechanisms in the etiology of renal cell cancer.

We investigated the ion transport mechanism (ITM) in renal cell cancer (RCC) etiology using gene-environment interactions between candidate single nucleotide polymorphisms (SNPs) and associated environmental factors, including dietary intakes of sodium, potassium and fluid, hypertension and diuretic medication. A literature-based selection of 13 SNPs in ten ITM genes were successfully genotyped in toenail DNA of 3,048 subcohort members and 419 RCC cases from the Netherlands Cohort Study. Diet and lifestyle were measured with baseline questionnaires. Cox regression analyses were conducted for main effects and gene-environment interactions. ADD1_rs4961 was significantly associated with RCC risk, showing a Hazard Ratio (HR) of 1.24 (95% confidence intervals (CI): 1.01-1.53) for the GT + TT (versus GG) genotype. Four of 65 tested gene-environment interactions were statistically significant. Three of these interactions clustered in SLC9A3_rs4957061, including the ones with fluid and potassium intake, and diuretic medication. For fluid intake, the RCC risk was significantly lower for high versus low intake in participants with the CC genotype (HR(95% CI): 0.47(0.26-0.86)), but not for the CT + TT genotype (P-interaction = 0.002). None of the main genetic effects and gene-environment interactions remained significant after adjustment for multiple testing. Data do not support the general hypothesis that the ITM is a disease mechanism in RCC etiology.