Granular Assembly of α-Synuclein Leading to the Accelerated Amyloid Fibril Formation with Shear Stress

α-Synuclein participates in the Lewy body formation of Parkinson's disease. Elucidation of the underlying molecular mechanism of the amyloid fibril formation is crucial not only to develop a controlling strategy toward the disease, but also to apply the protein fibrils for future biotechnology. Discernable homogeneous granules of α-synuclein composed of approximately 11 monomers in average were isolated in the middle of a lag phase during the in vitro fibrillation process. They were demonstrated to experience almost instantaneous fibrillation during a single 12-min centrifugal membrane-filtration at 14,000×g. The granular assembly leading to the drastically accelerated fibril formation was demonstrated to be a result of the physical influence of shear force imposed on the preformed granular structures by either centrifugal filtration or rheometer. Structural rearrangement of the preformed oligomomeric structures is attributable for the suprastructure formation in which the granules act as a growing unit for the fibril formation. To parallel the prevailing notion of nucleation-dependent amyloidosis, we propose a double-concerted fibrillation model as one of the mechanisms to explain the in vitro fibrillation of α-synuclein, in which two consecutive concerted associations of monomers and subsequent oligomeric granular species are responsible for the eventual amyloid fibril formation

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Postoperative outcomes in oesophagectomy with trainee involvement

BACKGROUND: The complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting. METHODS: Data from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups. RESULTS: Of 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005). CONCLUSION: Trainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery

PP 221 IMPAIRED AORTIC ELASTIC PROPERTIES IN PATIENTS WITH CHRONIC GRAFT VERSUS HOST DISEASE

Objectives: Graft-versus-host disease (GVHD), which develops as a result of the immunologic response that donor T-lymphocytes generate against host tissue following hematopoietic stem cell transplantation (HSCT), is the leading cause of morbidity and mortality in these patients. The aim of this study is the investigate relation between aortic wall stiffness and duration of the disease in patients with chronic GVHD. Methods: The study population included 32 patients (18 men; mean age, 36.9 +/- 12.5 years, and mean disease duration = 14.7 +/- 2.9 months) who received HSCT and was diagnosed with GVHD and 44 patients (23 men; mean age, 35.2 +/- 9.6 years, and mean disease duration = 13.5 +/- 2.4 months) who did not develop GVHD following HSCT. All patients underwent baseline echocardiography before HSCT and were followed. After approximately 10-14 months following HSCT, these patients were divided into two groups based on whether they had developed chronic GVHD, and were compared to aortic stiffness parameters and cardiac functions. Results: There was no change in basal characteristics, laboratory and echocardiographic findings, and aortic stiffness parameters in both groups before HSCT (P > 0.05). After HSCT, the mean aortic strain and distensibility values of the chronic GVHD patients were significantly lower, compared with the non-GVHD patients (9.8 +/- 3.2% vs. 12.9 +/- 5.0%, P = 0.002 and 4.1 +/- 1.5 x 10(-6) cm(2)/dyn vs. 5.3 +/- 2.1 x 10(-6) cm(2)/dyn; P = 0.005, respectively). In addition, aortic stiffness index was increased in the chronic GVHD group compared with non-GVHD group (2.7 +/- 1.7 vs. 2.0 +/- 0.8, P = 0.03). Conclusion: Aortic stiffness measurements were significantly different in chronic GVHD group compared to non-GVHD group and these findings suggested useful explanation for the potential mechanism about the development of disease. (Echocardiography 2011;28:1011-1018