Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: Rationale and Methodology for the DETECT Study From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer

Pancreatogenic diabetes mellitus is most commonly the result of chronic pancreatitis but can also occur secondary to pancreatic cancer. The early identification of pancreatogenic diabetes and distinction from the more prevalent type 2 diabetes are clinically significant; however, currently, there is no validated method to differentiate these diabetes subtypes. We describe a study, "Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: the DETECT study," that seeks to address this knowledge gap. The DETECT study is a multicenter study that will examine differences in hormone and glucose excursions after a mixed meal test. The study will also create a biorepository that will be used to evaluate novel diagnostic biomarkers for differentiating these diabetes subtypes

Safety and efficacy of intra-arterial fibrinolytics as adjunct to mechanical thrombectomy : a systematic review and meta-analysis of observational data

Background Achieving the best possible reperfusion is a key determinant of clinical outcome after mechanical thrombectomy (MT). However, data on the safety and efficacy of intra-arterial (IA) fibrinolytics as an adjunct to MT with the intention to improve reperfusion are sparse. Methods We performed a PROSPERO-registered (CRD42020149124) systematic review and meta-analysis accessing MEDLINE, PubMed, and Embase from January 1, 2000 to January 1, 2020. A random-effect estimate (Mantel-Haenszel) was computed and summary OR with 95% CI were used as a measure of added IA fibrinolytics versus control on the risk of symptomatic intracranial hemorrhage (sICH) and secondary endpoints (modified Rankin ScalePeer reviewe

Safety and efficacy of intra-arterial fibrinolytics as adjunct to mechanical thrombectomy: A systematic review and meta-analysis of observational data

Background: Achieving the best possible reperfusion is a key determinant of clinical outcome after mechanical thrombectomy (MT). However, data on the safety and efficacy of intra-arterial (IA) fibrinolytics as an adjunct to MT with the intention to improve reperfusion are sparse. Methods: We performed a PROSPERO-registered (CRD42020149124) systematic review and meta-analysis accessing MEDLINE, PubMed, and Embase from January 1, 2000 to January 1, 2020. A random-effect estimate (Mantel-Haenszel) was computed and summary OR with 95% CI were used as a measure of added IA fibrinolytics versus control on the risk of symptomatic intracranial hemorrhage (sICH) and secondary endpoints (modified Rankin Scale ≤2, mortality at 90 days). Results: The search identified six observational cohort studies and three observational datasets of MT randomized-controlled trial data reporting on IA fibrinolytics with MT as compared with MT alone, including 2797 patients (405 with additional IA fibrinolytics (100 urokinase (uPA), 305 tissue plasminogen activator (tPA)) and 2392 patients without IA fibrinolytics). Of 405 MT patients treated with additional IA fibrinolytics, 209 (51.6%) received prior intravenous tPA. We did not observe an increased risk of sICH after administration of IA fibrinolytics as adjunct to MT (OR 1.06, 95% CI 0.64 to 1.76), nor excess mortality (0.81, 95% CI 0.60 to 1.08). Although the mode of reporting was heterogeneous, some studies observed improved reperfusion after IA fibrinolytics. Conclusion: The quality of evidence regarding peri-interventional administration of IA fibrinolytics in MT is low and limited to observational data. In highly selected patients, no increase in sICH was observed, but there is large uncertainty

Decline in subarachnoid haemorrhage volumes associated with the first wave of the COVID-19 pandemic

BACKGROUND: During the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study\u27s objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines. METHODS: We conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March-31 May 2020. The prior 1-year control period (1 March-31 May 2019) was obtained to account for seasonal variation. FINDINGS: There was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI -24.3% to -20.7%, p\u3c0.0001). Embolisation of ruptured aneurysms declined with 1170-1035 procedures, respectively, representing an 11.5% (95%CI -13.5% to -9.8%, p=0.002) relative drop. Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations, a 24.9% relative decline (95% CI -28.0% to -22.1%, p\u3c0.0001). A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1% (95% CI 32.3% to 50.6%, p=0.008) despite a decrease in SAH admissions in this tertile. INTERPRETATION: There was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction

Performance of the RACE Prehospital Triage Score During Working and Nonworking Hours

Background Prehospital triage scores aim to identify large vessel occlusions (LVOs) in the field; however, their real‐world performance and accuracy across a 24‐hour period remains unknown. In this study, we compare the positive predictive value of the prehospital Rapid Arterial occlusion Evaluation (RACE) score for the detection of LVO during working hours and nonworking hours. Methods We performed a retrospective review of all patients presenting with a RACE score of ≥5 at one comprehensive and one thrombectomy‐capable hospital between July 2015 and December 2019. Patients were dichotomized to those presenting during “working hours” (7:00 am to 6:00 pm on weekdays) or “nonworking hours” (6:01 pm to 6:59 am on weekdays or anytime during weekends). The primary outcome was diagnosis of LVO. Secondary outcomes included diagnosis of acute neurovascular syndromes, door‐to‐treatment time metrics, and a modified Rankin Scale of ≤2 in those undergoing mechanical thrombectomy. Results Of the 701 patients with RACE score ≥5, 687 patients were included (355 nonworking hours and 332 working‐hours cohorts). Mean age was 71 and 72 years in the nonworking hours and working hours groups, respectively (P=0.13). Median National Institutes of Health Stroke Scale and baseline demographics were comparable between the 2 groups. There was no significant difference in the diagnosis of LVO (36.3% versus 34.6%; P=0.69) or final discharge diagnosis. The positive predictive value of the RACE score for the detection of an acute neurovascular syndrome (transient ischemic attack and stroke) was improved during nonworking hours (76.3% versus 67.8%; P=0.01). In patients undergoing mechanical thrombectomy, rates of good clinical outcome were similar (44.7% versus 48%; P=0.76), despite the shorter door‐to‐groin‐puncture and revascularization times during working hours. Conclusions The RACE score shows a consistent positive predictive value in determining LVO during working and nonworking hours. However, it is more accurate in determining acute neurovascular syndromes during nonworking hours, which is driven by a decrease in stroke mimics during this time

Abstract 1122‐000243: Capacity and Characteristics of Thrombectomy Centers World‐wide Using the MT2020+ Global Thrombectomy Tracking Smartphone App

Introduction : Mechanical thrombectomy (MT) has been established as a first line therapy for large vessel occlusion stroke; however, MT remains underutilized globally with massive disparity in access based on country income level. Mission Thrombectomy 2020+ (MT2020+) is a global alliance and campaign that aims to reduce this disparity and democratize MT access for patients. A novel smartphone application, Global Thrombectomy Tracking App, was designed to characterize thrombectomy centers on a global‐level and numerically track MT cases in near real‐time. Methods : The MT2020 App was launched in November 2019. To gain insight into local systems of care, neurointerventionalists were prompted to participate in an optional 11‐question survey over a 19‐month period. Questions pertained to population density, organizational structure, academic affiliation, available imaging modalities, tPA usage, and case volumes. Results : Of 338 active users from 9 countries, 49‐neurointerventionalists participated in the survey. The majority (71.5%) practiced in large metropolis with population >1‐million, of which 16.3% were in mega‐cities (>10‐million). The centers were government funded (46.9%), private (40.8%) or charitable (12.2%). Most were academic hospitals (81.6%) with neurointerventional trainees (55.1%). At most centers (87.7%), IV‐tPA was available with annual treatment rate >5% for 55.1%. Most centers (57.1%) utilize additional CT perfusion scans prior to MT. For 69.3% respondents, the annual MT case volume was between 10–100 cases. Conclusions : Our survey analysis shows that the global MT tracking APP can generate important thrombectomy capacity and characteristics at regional levels on a global scale, which can be used for targeted funding and resource allocation to accelerate access to MT

Structural basis for recognition of phosphodiester-containing lysosomal enzymes by the cation-independent mannose 6-phosphate receptor

Mannose 6-phosphate (Man-6-P)-dependent trafficking is vital for normal development. The biogenesis of lysosomes, a major cellular site of protein, carbohydrate, and lipid catabolism, depends on the 300-kDa cation-independent Man-6-P receptor (CI-MPR) that transports newly synthesized acid hydrolases from the Golgi. The CI-MPR recognizes lysosomal enzymes bearing the Man-6-P modification, which arises by the addition of GlcNAc-1-phosphate to mannose residues and subsequent removal of GlcNAc by the uncovering enzyme (UCE). The CI-MPR also recognizes lysosomal enzymes that elude UCE maturation and instead display the Man-P-GlcNAc phosphodiester. This ability of the CI-MPR to target phosphodiester-containing enzymes ensures lysosomal delivery when UCE activity is deficient. The extracellular region of the CI-MPR is comprised of 15 repetitive domains and contains three distinct Man-6-P binding sites located in domains 3, 5, and 9, with only domain 5 exhibiting a marked preference for phosphodiester-containing lysosomal enzymes. To determine how the CI-MPR recognizes phosphodiesters, the structure of domain 5 was determined by NMR spectroscopy. Although domain 5 contains only three of the four disulfide bonds found in the other seven domains whose structures have been determined to date, it adopts the same fold consisting of a flattened β-barrel. Structure determination of domain 5 bound to N-acetylglucosaminyl 6-phosphomethylmannoside, along with mutagenesis studies, revealed the residues involved in diester recognition, including Y679. These results show the mechanism by which the CI-MPR recognizes Man-P-GlcNAc-containing ligands and provides new avenues to investigate the role of phosphodiester-containing lysosomal enzymes in the biogenesis of lysosomes