Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease

Background: Gaucher disease (GD) is the most common inherited lysosomal storage disorder in humans, caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). GD is clinically heterogeneous and although the type of GBA1 mutation plays a role in determining the type of GD, it does not explain the clinical variability seen among patients. Cumulative evidence from recent studies suggests that GBA2 could play a role in the pathogenesis of GD and potentially interacts with GBA1. Methods: We used a framework of functional and genetic approaches in order to further characterize a potential role of GBA2 in GD. Glucosylceramide (GlcCer) levels in spleen, liver and brain of GBA2-deficient mice and mRNA and protein expression of GBA2 in GBA1-deficient murine fibroblasts were analyzed. Furthermore we crossed GBA2-deficient mice with conditional Gba1 knockout mice in order to quantify the interaction between GBA1 and GBA2. Finally, a genetic approach was used to test whether genetic variation in GBA2 is associated with GD and/or acts as a modifier in Gaucher patients. We tested 22 SNPs in the GBA2 and GBA1 genes in 98 type 1 and 60 type 2/3 Gaucher patients for single-and multi-marker association with GD. Results: We found a significant accumulation of GlcCer compared to wild-type controls in all three organs studied. In addition, a significant increase of Gba2-protein and Gba2-mRNA levels in GBA1-deficient murine fibroblasts was observed. GlcCer levels in the spleen from Gba1/Gba2 knockout mice were much higher than the sum of the single knockouts, indicating a cross-talk between the two glucosylceramidases and suggesting a partially compensation of the loss of one enzyme by the other. In the genetic approach, no significant association with severity of GD was found for SNPs at the GBA2 locus. However, in the multi-marker analyses a significant result was detected for p.L444P (GBA1) and rs4878628 (GBA2), using a model that does not take marginal effects into account. Conclusions: All together our observations make GBA2 a likely candidate to be involved in GD etiology. Furthermore, they point to GBA2 as a plausible modifier for GBA1 in patients with GD

Covid-19 triage in the emergency department 2.0: how analytics and AI transform a human-made algorithm for the prediction of clinical pathways

The Covid-19 pandemic has pushed many hospitals to their capacity limits. Therefore, a triage of patients has been discussed controversially primarily through an ethical perspective. The term triage contains many aspects such as urgency of treatment, severity of the disease and pre-existing conditions, access to critical care, or the classification of patients regarding subsequent clinical pathways starting from the emergency department. The determination of the pathways is important not only for patient care, but also for capacity planning in hospitals. We examine the performance of a human-made triage algorithm for clinical pathways which is considered a guideline for emergency departments in Germany based on a large multicenter dataset with over 4,000 European Covid-19 patients from the LEOSS registry. We find an accuracy of 28 percent and approximately 15 percent sensitivity for the ward class. The results serve as a benchmark for our extensions including an additional category of palliative care as a new label, analytics, AI, XAI, and interactive techniques. We find significant potential of analytics and AI in Covid-19 triage regarding accuracy, sensitivity, and other performance metrics whilst our interactive human-AI algorithm shows superior performance with approximately 73 percent accuracy and up to 76 percent sensitivity. The results are independent of the data preparation process regarding the imputation of missing values or grouping of comorbidities. In addition, we find that the consideration of an additional label palliative care does not improve the results

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Radiofrequency Pulmonary Vein Isolation without Esophageal Temperature Monitoring: Contact-Force Characteristics and Incidence of Esophageal Thermal Damage

Esophageal thermal lesions following pulmonary vein isolation (PVI) for atrial fibrillation (AF) potentially harbor lethal complications. Radiofrequency (RF)-PVI using contact force-technology can reduce collateral damage. We evaluated the incidence of endoscopically detected esophageal lesions (EDEL) and the contribution of contact force to esophageal lesion formation without esophageal temperature monitoring. One hundred and thirty-one AF patients underwent contact force-guided RF-PVI. Contact force, energy, force-time-integral, and force-power-time-integral were adopted. During PVI at the posterior segment of the wide antral circumferential line, limits were set for energy (30 W), duration (30 s) and contact force (40 g). Ablations were analyzed postero-superior and -inferior around PVs. Endoscopy within 120 h identified EDEL in six patients (4.6%). In EDEL(+), obesity was less frequent (17% vs. 68%, p = 0.018), creatinine was higher (1.55 ± 1.18 vs. 1.07 ± 0.42 mg/dL, p = 0.016), and exclusively at the left postero-inferior site, force-time-integral and force-power-time-integral were greater (2973 ± 3267 vs. 1757 ± 1262 g·s, p = 0.042 and 83,547 ± 105,940 vs. 43,556 ± 35,255 g·J, p = 0.022, respectively) as compared to EDEL(−) patients. No major complications occurred. At 12 months, arrhythmia-free survival was 74%. The incidence of EDEL was low after contact force-guided RF-PVI. Implementing combined contact force-indices on the postero-inferior site of left-sided PVs may reduce EDEL

Patient delay and benefit of timely reperfusion in ST-segment elevation myocardial infarction

Background In patients with ST-segment elevation myocardial infarction (STEMI), it is unknown how patient delay modulates the beneficial effects of timely reperfusion.Aims To assess the prognostic significance of a contact-to-balloon time of less than 90 min on in-hospital mortality in different categories of symptom-onset-to-first-medical-contact (S2C) times.Methods A total of 20 005 consecutive patients from the Feedback Intervention and Treatment Times in ST-segment Elevation Myocardial Infarction (FITT-STEMI) programme treated with primary percutaneous coronary intervention (PCI) were included.Results There were 1554 deaths (7.8%) with a J-shaped relationship between mortality and S2C time. Mortality was 10.0% in patients presenting within 1 hour, and 4.9%, 6.0% and 7.3% in patient groups with longer S2C intervals of 1–2 hours, 2–6 hours and 6–24 hours, respectively. Patients with a short S2C interval of less than 1 hour (S2C<60 min) had the highest survival benefit from timely reperfusion with PCI within 90 min (OR 0.27, 95% CI 0.23 to 0.31, p<0.0001) as compared with the three groups with longer S2C intervals of 1 hour<S2C≤2 hours (OR 0.44, 95% CI 0.33 to 0.59, p<0.0001), 2 hours<S2C≤6 hours (OR 0.49, 95% CI 0.38 to 0.64, p<0.0001) and 6 hours<S2C≤24 hours (OR 0.42, 95% CI 0.30 to 0.58, p<0.0001).Conclusions Timely reperfusion with a contact-to-balloon time of less than 90 min is most effective in patients presenting with short S2C intervals of less than 1 hour, but has also beneficial effects in patients with S2C intervals of up to 24 hours.Trial registration number NCT00794001