Epitranscriptomic events such as adenosine‐to‐inosine (A‐to‐I) RNA editing by ADAR can recode mRNAs to translate novel proteins. Editing of the mRNA that encodes actin crosslinking protein Filamin A (FLNA) mediates a Q‐to‐R transition in the interactive C‐terminal region. While FLNA editing is conserved among vertebrates, its physiological function remains unclear. Here, we show that cardiovascular tissues in humans and mice show massive editing and that FLNA RNA is the most prominent substrate. Patient‐derived RNA‐Seq data demonstrate a significant drop in FLNA editing associated with cardiovascular diseases. Using mice with only impaired FLNA editing, we observed increased vascular contraction and diastolic hypertension accompanied by increased myosin light chain phosphorylation, arterial remodeling, and left ventricular wall thickening, which eventually causes cardiac remodeling and reduced systolic output. These results demonstrate a causal relationship between RNA editing and the development of cardiovascular disease indicating that a single epitranscriptomic RNA modification can maintain cardiovascular health.

BackgroundVesicovaginal fistulas (VVF) are the most commonly acquired fistulas of the urinary tract, but we lack a standardized algorithm for their management. Surgery is the most commonly preferred approach to treat women with primary VVF following benign gynaecologic surgery.ObjectiveTo carry out a systematic review and meta-analysis on the effectiveness of operative techniques or conservative treatment for patients with postsurgical VVF. Our secondary objective was to define the surgical time and determine the types of study designs.MethodsPubMed, Old Medline, Embase and Cochrane Central Register of Controlled Trials were used as data sources. This systematic review was modelled on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, including a registration number (CRD42012002097).ResultsWe reviewed 282 full text articles to identify 124 studies for inclusion. In all, 1379/1430 (96.4%) patients were treated surgically. Overall, the transvaginal approach was performed in the majority of patients (39%), followed by a transabdominal/transvesical route (36%), a laparoscopic/robotic approach (15%) and a combined transabdominal-transvaginal approach in 3% of cases. Success rate of conservative treatment was 92.86% (95%CI: 79.54–99.89), 97.98% in surgical cases (95% CI: 96.13–99.29) and 91.63% (95% CI: 87.68–97.03) in patients with prolonged catheter drainage followed by surgery. 79/124 studies (63.7%) provided information for the length of follow-up, but showed a poor reporting standard regarding prognosis. Complications were studied only selectively. Due to the inconsistency of these data it was impossible to analyse them collectively.ConclusionsAlthough the literature is imprecise and inconsistent, existing studies indicate that operation, mainly through a transvaginal approach, is the most commonly preferred treatment strategy in females with postsurgical VVF. Our data showed no clear odds-on favorite regarding disease management as well as surgical approach and current evidence on the surgical management of VVF does not allow any accurate estimation of success and complication rates. Standardisation of the terminology is required so that VVF can be managed with a proper surgical treatment algorithm based on characteristics of the fistula.

ObjectivesTo examine whether a mixed lipid emulsion reduces the incidence of parenteral nutrition associated cholestasis (PNAC) in extremely low birth weight (ELBW, <1000 g) infants.Study designThis double-blind randomized trial of 230 ELBW infants (June 2012-October 2015) was performed at a single level IV neonatal intensive care unit. Patients received either a mixed lipid emulsion composed of soybean oil, medium chain triglycerides, olive oil, and fish oil-(intervention) or a soybean oil-based lipid emulsion (control) for parenteral nutrition. The primary outcome measure was PNAC (conjugated bilirubin >1.5 mg/dL [25 μmol/L] at 2 consecutive measurements). The study was powered to detect a reduction of PNAC from 25% to 10%.ResultsReasons for noneligibility of 274 infants screened were refusal to participate (n = 16), death (n = 10), withdrawal of treatment (n = 5), higher order multiples (n = 9), and parents not available for consent (n = 4). Intention to treat analysis was carried out in 223 infants (7 infants excluded after randomization). Parenteral nutrition associated cholestasis was 11 of 110 (10.1%) in the intervention and 18 of 113 (15.9%) in the control group (P = .20). Multivariable analyses showed no statistically significant difference in the intention to treat (aOR 0.428, 95% CI 0.155-1.187; P = .10) or per protocol population (aOR 0.457, 95% CI 0.155-1.347; P = .16). There was no statistically significant effect on any other neonatal morbidity.ConclusionsThe incidence of parenteral nutrition associated cholestasis was not significantly reduced using a mixed lipid emulsion in ELBW infants.Trial RegistrationClinicalTrials.gov NCT01585935.

Background: Immunoadsorption (IAS) and therapeutic plasma exchange (TPE) are considered safe although fibrinogen is removed. To date no comparison of fibrinogen reduction and associated risk of bleeding in apheresis exists. Methods: Retrospective analysis of TPE, three IAS adsorbers, and combined TPE/IAS regarding fibrinogen reduction and bleeding incidence in 67 patients (1,032 treatments). Results: TPE and TPE/IAS reduced fibrinogen by 64 ± 11% and 58 ± 9%, leading to concentrations <100 mg/dl in 20 and 17% of treatments, respectively. IAS decreased fibrinogen less than TPE (26 ± 6%, p < 0.0001), resulting in fibrinogen concentrations <100 mg/dl in 1% of treatments. The processed volume correlated with reduction in TPE (r = 0.64, p < 0.01), but not in IAS. Bleeding occurred in 1.3% (IAS), 2.3% (TPE) and 3.1% (TPE/IAS) of treatments. Conclusion: Hypofibrinogenemia occurs in 20% of patients after TPE and TPE/IAS, but rarely after IAS. IAS removes fibrinogen independently of volume processed. Overall, bleeding is rare in apheresis.

MRP-8/14 in saliva might be a potential diagnostic parameter for periodontal disease.

AimTo prospectively monitor subclinical changes in capillary perfusion and retinal layer thickness in patients with type 2 diabetes and early diabetic retinal disease over 2 years.MethodsIn this longitudinal study we performed biannual retinal vascular imaging using optical coherence tomography angiography (RTVue) to analyse the foveal avascular zone (FAZ) area, perimeter, acircularity index (AI) and parafoveal superficial/deep vessel density (VD). Spectral-domain optical coherence tomography (Spectralis) was used to measure the thickness of nine macular layers and the peripapillary nerve fibre layer.ResultsAmong 117 eyes (58 left) of 59 patients (21 female), 105 had no diabetic retinopathy (DR), 6 mild and 6 moderate non-proliferative DR at baseline. We found DR progression in 13 eyes at year 2. The FAZ area (+0.008±0.002 mm2/year, p<0.0001), perimeter (+0.036±0.010 mm/year, p=0.006) and AI (+0.005±0.002/year, p=0.0280) increased significantly. A pronounced decrease was found in the superficial (−1.425±0.290%/year, p<0.0001) but not the deep VD. Inner neuroretinal loss was confined to the ganglion cell (−0.539±0.150 µm/year, p=0.0004) and the inner plexiform layer (−0.361±0.127 µm/year, p=0.0045). In the outer retina, we observed a statistically significant decrease in thickness in the outer plexiform, photoreceptor layer and pigment epithelium of −0.921±0.161 µm/year, −0.325±0.139 µm/year and −0.385±0.084 µm/year, respectively.ConclusionSubclinical signs of microangiopathy and neurodegeneration appear in parallel and are highly progressive even in the earliest stages of diabetic retinal disease.Trial registration number EudraCT20156000239634.

Three-dimensional gait analysis is capable of assessing dynamic load characteristics and the resulting compensatory effects of lower limb malalignment, which are generally not reflected in static imaging. This study determined differences in gait parameters in the frontal and transverse plane between patients and controls in order to identify compensatory mechanisms, and to correlate radiographic measurements and gait parameters in a consecutive series of children with idiopathic genu valgum. Thirty-three patients (mean age 12.3 years) were retrospectively reviewed and compared to a healthy control group. Children with genu valgum demonstrated significantly decreased internal knee valgus moments, shifting into varus moments. Furthermore, significantly different transverse plane gait patterns (decreased external knee rotation, increased external hip rotation) were observed. These patterns showed a relevant influence on the frontal knee moments, with knee rotation and foot progression angle showing the highest predictive value for changes and possible compensation of frontal knee moments. The correlation between commonly used radiographic measurements (i.e., mechanical axis deviation) and findings of the gait analysis was only low. Besides showing decreased internal knee valgus moments, our results suggest that considerable compensatory gait mechanisms may be present in children with idiopathic genu valgum to reduce joint loading. ß

Odor (including flavor) perception plays a major role in dietary behavior. Orthonasal olfactory function (OOF) has been shown to decrease in obese subjects. Changes in retronasal olfactory function (ROF) after weight loss and in the individual significance of olfaction (ISO) in obesity are yet to be investigated. Firstly, 15 obese subjects were recruited in a pilot study and supported to conventionally lose weight. OOF (Sniffin’ Sticks) was measured at the beginning and after 5.6 ± 1.3 months. Eleven subjects re-visited but barely lost weight and no major changes in OOF were observed. Secondly, the body-mass-index (BMI), OOF, and ROF (Candy Smell Test, CST) were recorded in subjectively olfactory-healthy subjects (SOHSs) and additionally the ISO questionnaire was collected in patients with olfactory dysfunction (OD). BMI correlated significantly negatively with odor discrimination (p = 0.00004) in 74 SOHSs and negatively with CST (p < 0.0001) in 66 SOHSs. In 48 SOHSs, there was a gender difference in ISO scores (p = 0.034), but no significant correlation with BMI was found (p > 0.05). ISO scores were significantly higher in 52 OD patients in comparison to SOHSs (p = 0.0382). Not only OOF but also ROF may decline with higher BMI. ISO does not seem to alter with BMI, but olfaction becomes more important once it is consciously impaired.