Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease.

INTRODUCTION: Micro- and macrovascular complications are common among persons with type 2 diabetes. Recently there has been growing interest to investigate the potential of circulating small non-coding RNAs (sncRNAs) as contributors to the development of diabetic complications. In this study we investigate to what extent circulating sncRNAs levels associate with prevalent diabetic kidney disease (DKD) in persons with type 2 diabetes. METHODS: Plasma sncRNAs levels were determined using small RNA-seq, allowing detection of miRNAs, snoRNAs, piRNAs, tRNA fragments, and various other sncRNA classes. We tested for differentially expressed sncRNAs in persons with type 2 diabetes, with DKD (n = 69) or without DKD (n = 405). In secondary analyses, we also tested the association with eGFR, albuminuria (UACR), and the plasma proteome. RESULTS: In total seven sncRNAs were negatively associated with prevalent DKD (all PFDR ≤ 0.05). Including one microRNA (miR-143-5p), five snoRNAs (U8, SNORD118, SNORD24, SNORD107, SNORD87) and a piRNA (piR-019825 | DQ597218). Proteomic analyses showed that the seven sncRNAs, and especially the piRNA piR-019825, were associated with plasma levels of 24 proteins of which several have known associations with kidney function including TNF sR-I (TNFRFS1A), DAN (NBL1) and cystatin C (CST3). CONCLUSION: We have identified novel small non-coding RNAs, primarily from classes other than microRNAs, that are associated with diabetic kidney disease. Our results show that the involvement of small non-coding RNAs in DKD goes beyond the already known microRNAs and also involves other classes of sncRNA, in particular snoRNAs and the piRNA piR-019825, that have never been studied before in relation to kidney function.

Towards trust-based governance of health data research.

Developments in medical big data analytics may bring societal benefits but are also challenging privacy and other ethical values. At the same time, an overly restrictive data protection regime can form a serious threat to valuable observational studies. Discussions about whether data privacy or data solidarity should be the foundational value of research policies, have remained unresolved. We add to this debate with an empirically informed ethical analysis. First, experiences with the implementation of the General Data Protection Regulation (GDPR) within a European research consortium demonstrate a gap between the aims of the regulation and its effects in practice. Namely, strictly formalised data protection requirements may cause routinisation among researchers instead of substantive ethical reflection, and may crowd out trust between actors in the health data research ecosystem; while harmonisation across Europe and data sharing between countries is hampered by different interpretations of the law, which partly stem from different views about ethical values. Then, building on these observations, we use theory to argue that the concept of trust provides an escape from the privacy-solidarity debate. Lastly, the paper details three aspects of trust that can help to create a responsible research environment and to mitigate the encountered challenges: trust as multi-agent concept; trust as a rational and democratic value; and trust as method for priority setting. Mutual cooperation in research-among researchers and with data subjects-is grounded in trust, which should be more explicitly recognised in the governance of health data research.

In RA patients without prevalent CVD, incident CVD is mainly associated with traditional risk factors: A 20-year follow-up in the CARRÉ cohort study.

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.

Temporal variation in out-of-hospital cardiac arrest occurrence in individuals with or without diabetes.

OBJECTIVE: Out-of-hospital cardiac arrest (OHCA) occurrence has been shown to exhibit a circadian rhythm, following the circadian rhythm of acute myocardial infarction (AMI) occurrence. Diabetes mellitus (DM) is associated with changes in circadian rhythm. We aimed to compare the temporal variation of OHCA occurrence over the day and week between OHCA patients with DM and those without. METHODS: In two population-based OHCA registries (Amsterdam Resuscitation Studies [ARREST] 2010-2016, n = 4163, and Danish Cardiac Arrest Registry [DANCAR], 2010-2014, n = 12,734), adults (≥18y) with presumed cardiac cause of OHCA and available medical history were included. Single and double cosinor analysis was performed to model circadian variation of OHCA occurrence. Stratified analysis of circadian variation was performed in patients with AMI as immediate cause of OHCA. RESULTS: DM patients (22.8% in ARREST, 24.2% in DANCAR) were older and more frequently had cardiovascular risk factors or previous cardiovascular disease. Both cohorts showed 24 h-rhythmicity, with significant amplitudes in single and double cosinor functions (P-range < 0.001). In both registries, a morning peak (10:00-11:00) and an evening peak (20:00-21:00) was observed in both DM and non-DM patients. No septadian variation was observed in either DM or non-DM patients (P-range 0.13-84). CONCLUSIONS: In these two population-based OHCA registries, we observed a similar circadian rhythm of OHCA occurrence in DM and non-DM patients.

The effect of the localisation of an underlying ST-elevation myocardial infarction on the VF-waveform: A multi-centre cardiac arrest study.

INTRODUCTION: In cardiac arrest, ventricular fibrillation (VF) waveform characteristics such as amplitude spectrum area (AMSA) are studied to identify an underlying myocardial infarction (MI). Observational studies report lower AMSA-values in patients with than without underlying MI. Moreover, experimental studies with 12-lead ECG-recordings show lowest VF-characteristics when the MI-localisation matches the ECG-recording direction. However, out-of-hospital cardiac arrest (OHCA)-studies with defibrillator-derived VF-recordings are lacking. METHODS: Multi-centre (Amsterdam/Nijmegen, the Netherlands) cohort-study on the association between AMSA, ST-elevation MI (STEMI) and its localisation. AMSA was calculated from defibrillator pad-ECG recordings (proxy for lead II, inferior vantage point); STEMI-localisation was determined using ECG/angiography/autopsy findings. RESULTS: We studied AMSA-values in 754 OHCA-patients. There were statistically significant differences between no STEMI, anterior STEMI and inferior STEMI (Nijmegen: no STEMI 13.0mVHz [7.9-18.6], anterior STEMI 7.5mVHz [5.6-13.8], inferior STEMI 7.5mVHz [5.4-11.8], p = 0.006. Amsterdam: 11.7mVHz [5.0-21.9], 9.6mVHz [4.6-17.2], and 6.9mVHz [3.2-16.0], respectively, p = 0.001). Univariate analyses showed significantly lower AMSA-values in inferior STEMI vs. no STEMI; there was no significant difference between anterior and no STEMI. After correction for confounders, adjusted absolute AMSA-values were numerically lowest for inferior STEMI in both cohorts, and the relative differences in AMSA between inferior and no STEMI was 1.4-1.7 times larger than between anterior and no STEMI. CONCLUSION: This multi-centre VF-waveform OHCA-study showed significantly lower AMSA in case of underlying STEMI, with a more pronounced difference for inferior than for anterior STEMI. Confirmative studies on the impact of STEMI-localisation on the VF-waveform are warranted, and might contribute to earlier diagnosis of STEMI during VF.

Resuscitation with an AED: putting the data to use.

The increased use of the automated external defibrillator (AED) contributes to the rising survival rate after sudden cardiac arrest in the Netherlands. When used, the AED records the unconscious person's medical data (heart rhythm and information about cardiopulmonary resuscitation), which may be important for further diagnosis and treatment. In practice, ethical and legal questions arise about what can and should be done with these 'AED data'. In this article, the authors advocate the development of national guidelines on the handling of AED data. These guidelines should serve two purposes: (1) to safeguard that data are handled carefully in accordance with data protection principles and the rules of medical confidentiality; and (2) to ensure nationwide availability of data for care of patients who survive resuscitation, as well as for quality monitoring of this care and for related scientific research. Given the medical ethical duties of beneficence and fairness, existing (sometimes lifesaving) information about AED use ought to be made available to clinicians and researchers on a structural basis. Creating a national AED data infrastructure, however, requires overcoming practical and organisational barriers. In addition, further legal study is warranted.

Comorbidity and survival in the pre-hospital and in-hospital phase after out-of-hospital cardiac arrest.

INTRODUCTION: Cumulative disease burden may be associated with survival chances after out-of-hospital cardiac arrest (OHCA). The relative contributions of cumulative disease burden on survival rates at the pre-hospital and in-hospital phases of post-resuscitation care are unknown. METHODS: The association between cumulative comorbidity burden as measured by the Charlson Comorbidity Index (CCI) and pre-hospital and in-hospital survival rates was studied using data (2010-2014) from a prospective OHCA registry in the Netherlands. The association between CCI and survival rate (overall survival [OHCA-hospital discharge], pre-hospital survival [OHCA-hospital admission] and in-hospital survival [hospital admission-hospital discharge]) was assessed using logistic regression analyses. The relative contributions of CCI on pre-hospital and in-hospital survival rates were determined using the Nagelkerke test. RESULTS: We included 2510 OHCA patients aged ≥18y. CCI was significantly associated with overall survival rate (OR 0.71; 95%CI 0.61-0.83; P < 0.01). CCI was not associated with pre-hospital survival rate (OR 0.96; 95%CI 0.76-1.23; P = 0.92) whereas high CCI was significantly associated with low in-hospital survival rate (OR 0.41; 95%CI 0.27-0.62; P = 0.01). The relative contributions of CCI on pre-hospital and in-hospital survival were 1.1% and 8.1%, respectively. CONCLUSION: Pre-existing high comorbidity burden plays a modest role in reducing survival rate after OHCA, and only in the in-hospital phase. The present study offers data that may guide clinicians in discussing resuscitation options during advance care planning with patients with high comorbidity burden. This may be helpful in creating a patients' informed choice.

The challenges and possibilities of public access defibrillation.

Out-of-hospital cardiac arrest (OHCA) is a major health problem that affects approximately four hundred and thousand patients annually in the United States alone. It is a major challenge for the emergency medical system as decreased survival rates are directly proportional to the time delay from collapse to defibrillation. Historically, defibrillation has only been performed by physicians and in-hospital. With the development of automated external defibrillators (AEDs), rapid defibrillation by nonmedical professionals and subsequently by trained or untrained lay bystanders has become possible. Much hope has been put to the concept of Public Access Defibrillation with a massive dissemination of public available AEDs throughout most Western countries. Accordingly, current guidelines recommend that AEDs should be deployed in places with a high likelihood of OHCA. Despite these efforts, AED use is in most settings anecdotal with little effect on overall OHCA survival. The major reasons for low use of public AEDs are that most OHCAs take place outside high incidence sites of cardiac arrest and that most OHCAs take place in residential settings, currently defined as not suitable for Public Access Defibrillation. However, the use of new technology for identification and recruitment of lay bystanders and nearby AEDs to the scene of the cardiac arrest as well as new methods for strategic AED placement redefines and challenges the current concept and definitions of Public Access Defibrillation. Existing evidence of Public Access Defibrillation and knowledge gaps and future directions to improve outcomes for OHCA are discussed. In addition, a new definition of the different levels of Public Access Defibrillation is offered as well as new strategies for increasing AED use in the society.

In-Hospital Haloperidol Use and Perioperative Changes in QTc-Duration.

OBJECTIVES: Haloperidol may prolong ECG QTc-duration but is often prescribed perioperatively to hip-fracture patients. We aimed to determine (1) how QTc-duration changes perioperatively, (2) whether low-dose haloperidol-use influences these changes, and (3) which clinical variables are associated with potentially dangerous perioperative QTc-prolongation (PD-QTc; increase >50 ms or to >500 ms). DESIGN: Prospective cohort study. SETTING: Tertiary university teaching-hospital. PARTICIPANTS: Patients enrolled in a randomized controlled clinical trial of melatonin versus placebo on occurrence of delirium in hip-fracture patients. MEASUREMENTS: Data from ECGs made before and after hip surgery (1-3 days and/or 4-6 days post-surgery) were analyzed. QTc-duration was measured by hand, blinded for haloperidol and pre/post-surgery status. Clinical variables were measured at baseline. Mixed model analysis was used to estimate changes in QTc-duration. Risk-factors for PD-QTc were estimated by logistic regression analysis. RESULTS: We included 89 patients (mean age 84 years, 24% male); 39 were treated with haloperidol. Patients with normal pre-surgery QTc-duration (male ≤430 ms, female ≤450 ms) had a significant increase (mean 12 ms, SD 28) in QTc-duration. A significant decrease (mean 19 ms, SD 34) occurred in patients with prolonged pre-surgery QTc-duration (male >450ms, female >470 ms). Haloperidol-use did not influence the perioperative course of the QTc-interval (p=0.351). PD-QTc (n=8) was not associated with any of the measured risk-factors. CONCLUSION: QTc-duration changed differentially, increasing in patients with normal, but decreasing in patients with abnormal baseline QTc-duration. PD-QTc was not associated with haloperidol-use or other risk-factors. Low-dose oral haloperidol did not affect perioperative QTc-interval.

Increased prevalence of ECG markers for sudden cardiac arrest in refractory epilepsy.

BACKGROUND AND AIM: People with epilepsy are at increased risk of sudden cardiac arrest (SCA) due to ECG-confirmed ventricular tachycardia/fibrillation, as seen in a community-based study. We aimed to determine whether ECG-risk markers of SCA are more prevalent in people with epilepsy. METHODS: In a cross-sectional, retrospective study, we analysed the ECG recordings of 185 people with refractory epilepsy and 178 controls without epilepsy. Data on epilepsy characteristics, cardiac comorbidity, and drug use were collected, and general ECG variables (heart rate (HR), PQ and QRS intervals) assessed. We analysed ECGs for three markers of SCA risk: severe QTc prolongation (male >450 ms, female >470 ms), Brugada ECG pattern, and early repolarisation pattern (ERP). Multivariate regression models were used to analyse differences between groups, and to identify associated clinical and epilepsy-related characteristics. RESULTS: People with epilepsy had higher HR (71 vs 62 bpm, p<0.001) and a longer PQ interval (162.8 vs 152.6 ms, p=0.001). Severe QTc prolongation and ERP were more prevalent in people with epilepsy (QTc prolongation: 5% vs 0%; p=0.002; ERP: 34% vs 13%, p<0.001), while the Brugada ECG pattern was equally frequent in both groups (2% vs 1%, p>0.999). After adjustment for covariates, epilepsy remained associated with ERP (ORadj 2.4, 95% CI 1.1 to 5.5) and severe QTc prolongation (ORadj 9.9, 95% CI 1.1 to 1317.7). CONCLUSIONS: ERP and severe QTc prolongation appear to be more prevalent in people with refractory epilepsy. Future studies must determine whether this contributes to increased SCA risk in people with epilepsy.

Genetic, clinical and pharmacological determinants of out-of-hospital cardiac arrest: rationale and outline of the AmsteRdam Resuscitation Studies (ARREST) registry.

INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) is a major public health problem. Recognising the complexity of the underlying causes of OHCA in the community, we aimed to establish the clinical, pharmacological, environmental and genetic factors and their interactions that may cause OHCA. METHODS AND ANALYSIS: We set up a large-scale prospective community-based registry (AmsteRdam Resuscitation Studies, ARREST) in which we prospectively include all resuscitation attempts from OHCA in a large study region in the Netherlands in collaboration with Emergency Medical Services. Of all OHCA victims since June 2005, we prospectively collect medical history (through hospital and general practitioner), and current and previous medication use (through community pharmacy). In addition, we include DNA samples from OHCA victims with documented ventricular tachycardia/fibrillation during the resuscitation attempt since July 2007. Various study designs are employed to analyse the data of the ARREST registry, including case-control, cohort, case only and case-cross over designs. ETHICS AND DISSEMINATION: We describe the rationale, outline and potential results of the ARREST registry. The design allows for a stable and reliable collection of multiple determinants of OHCA, while assuring that the patient, lay-caregiver or medical professional is not hindered in any way. Such comprehensive data collection is required to unravel the complex basis of OHCA. Results will be published in peer-reviewed journals and presented at relevant scientific symposia.

Reduced in-hospital survival rates of out-of-hospital cardiac arrest victims with obstructive pulmonary disease.

AIM: Out-of-hospital cardiac arrest (OHCA) due to sustained ventricular tachycardia/fibrillation (VT/VF) is common and often lethal. Patient's co-morbidities may determine survival after OHCA, and be instrumental in post-resuscitation care, but are poorly studied. We aimed to study whether patients with obstructive pulmonary disease (OPD) have a lower survival rate after OHCA than non-OPD patients. METHODS: We performed a community-based cohort study of 1172 patients with non-traumatic OHCA with ECG-documented VT/VF between 2005 and 2008. We compared survival to emergency room (ER), to hospital admission, to hospital discharge, and at 30 days after OHCA, of OPD-patients and non-OPD patients, using logistic regression analysis. We also compared 30-day survival of patients who were admitted to hospital, using multivariate logistic regression analysis. RESULTS: OPD patients (n=178) and non-OPD patients (n=994) had comparable survival to ER (75% vs. 78%, OR 0.9 [95% CI: 0.6-1.3]) and to hospital admission (56% vs. 57%, OR 1.0 [0.7-1.4]). However, survival to hospital discharge was significantly lower among OPD patients (21% vs. 33%, OR 0.6 [0.4-0.9]). Multivariate regression analysis among patients who were admitted to hospital (OPD: n=100, no OPD: n=561) revealed that OPD was an independent determinant of reduced 30-day survival rate (39% vs. 59%, adjusted OR 0.6 [0.4-1.0, p=0.035]). CONCLUSION: OPD-patients had lower survival rates after OHCA than non-OPD patients. Survival to ER and to hospital admission was not different between both groups. However, among OHCA victims who survived to hospital admission, OPD was an independent determinant of reduced 30-day survival rate.

Observation of hydrophobic-like behavior in geometrically patterned hydrophilic microchannels.

We present our observation of meta-hydrophobicity, where geometrically patterned surfaces make hydrophilic microchannels exhibit hydrophobic-like behaviors. We analyze the wetting-induced energy decrease that results from the surface geometries and experimentally demonstrate how those geometries can modulate the dynamics of capillary-driven wetting and evaporation-driven drying of microfluidic systems. Our results also show that the modulated wetting dynamics can be employed to generate regulated patterns of microbubbles.