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BACKGROUND: The Diabetes Prevention Program (DPP) has been translated into digital formats. We report an economic evaluation of a digital DPP implemented in a large, integrated health care system. METHODS: Patients (n = 4148) were invited to participate in digital DPP based on clinical characteristics (HbA1c 5.7%–6.4% and body mass index ≥ 30 kg/m(2)) assessed using electronic medical record data. Using a propensity score we matched (1:1) enrolled and not enrolled patients for a total of 784. We identified high-risk patients (ie, above the 50th percentile of risk; n = 202) by calculating each patient’s 2-year of developing diabetes. We report the cost of the intervention and the costs of medical care over 12- and 24-month follow-up, and the incremental cost-effectiveness ratio as the cost per additional kilogram weight loss at 24 months. RESULTS: At 12 months, enrolled patients had lower total costs ($6,926, 95% CI $5,681–$8,171) than not enrolled patients ($7,538, 95% CI $6,293–$8,783). This pattern attenuated slightly at 24 months (enrolled = $16,255, 95% CI $14,097–$18,412; not enrolled = $16,688, 95% CI $14,531–$18,846). We found an incremental cost-effectiveness ratio of $81.92 per additional kilogram weight loss. For high-risk patients, the digital DPP group had, on average, lower costs and greater weight loss. We found a 55% chance of the digital DPP program being cost-effective at a willingness-to-pay of $150 per additional kilogram of weight loss; at the same willingness-to-pay, there is a 60% chance in the high-risk subgroup. Limitations include the nonrandomized design and potential volunteer bias. CONCLUSION: Digital DPP had a favorable cost-effectiveness profile compared to other lifestyle interventions.

Purpose Incisional hernias often follow open abdominal surgery. A small-stitch–small-bite suture might close the incision durably. We analyzed specific details of this closure technique and assessed their influence on the closure stability. Methods The effects of cyclic loads, simulating coughs were investigated on a bench test. We prepared porcine bellies in the median line and bovine flanks parallel to the muscle fibers with 15 cm long incisions. Then we punched round or rhomboid defects with a diameter of 5–10 cm into the center of the incision. Monomax® 2–0 and Maxon® 1 and 2–0 were used as suture materials. We tested the durability of the closure with pressure impacts of 210 mmHg repeated 425 times. Throughout the experiments, we modified the suturing technique, the surgeon, the tissue tension, the defect size and shape and the suture diameter. Results Standardizing the suture technique improved the durability of the closure significantly. Any other variations showed minor influences after standardization. All incisions with round defects up to 7.5 cm width withstood 425 impacts using standardized suturing. Unstandardized sutures failed in all cases. When closing an incision with a 10 cm wide defect, the tissues ruptured frequently next to the suture line. We defined criteria to standardize this suturing technique. For the first time, we developed a suture factor related to the durability of a sutured tissue closure. We integrated the suture factor into the concept of biomechanically durable repairs. Conclusions Suturing the abdominal wall with a standardized suturing technique improves its durability significantly.

The American College of Surgeons National Surgical Quality Improvement Program was established to help participating hospitals track and report surgical complications with the goal of improving surgical care. We sought to determine whether this has led to improvements in surgical outcomes for pancreatic malignancies.Patients with pancreatic malignancies who underwent surgical resection were identified from the American College of Surgeons National Surgical Quality Improvement Program database (2006-2019). Thirty-day postoperative major morbidity and mortality were analyzed by year. Major morbidity included organ and deep surgical site infection, venous thromboembolism, cardiac event, pneumonia, acute renal failure, sepsis, and respiratory failure.Of the 28,888 patients identified, 51% were male, the median age was 68, 74.3% underwent a pancreaticoduodenectomy, and 25.7% underwent a distal pancreatectomy. Among patients who underwent a pancreaticoduodenectomy, there was a significant increase in major morbidity (annual percent change 0.77, P = .012) driven by increases in organ space surgical site infection (annual percent change 3.52, P.001) and venous thromboembolism (annual percent change 4.72, P = .005). However, there was a decrease in postoperative mortality (annual percent change -4.58, P = .001). For distal pancreatectomy patients, there was no change in rates of overall major morbidity (annual percent change -1.35, P = .08) or mortality (annual percent change -3.21, P = .25).Although major morbidity and mortality have not significantly changed for distal pancreatectomy patients, mortality has steadily decreased for patients undergoing pancreaticoduodenectomy, despite an increase in major morbidity. Whether this trend reflects a change in patient selection, an increase in detection of postoperative morbidities and/or an improvement in mitigation of these morbidities warrants further study.

The present study focuses on the weldability of hot-rolled Fe–Mn–Al–Ni shape memory alloy sheets by vacuum electron beam welding. Tailored process-specific welding parameters, such as preheating with electron beam or beam oscillation during welding, allowed defect-free joining with very thin weld seams and heat-affected zones. By applying a post-weld cyclic heat treatment, abnormal grain growth can be promoted across the weld seams. However, regardless of the selected welding parameters, some specimens are characterized by the formation of smaller grains within the former fusion zone. In situ incremental strain tests reveal that the former fusion zone has only a minor influence on the functional properties and is not responsible for structural failure. Thus, electron beam welding is a promising welding technology for joining Fe–Mn–Al–Ni shape memory alloys.

Intraperitoneal drain placement decreases morbidity and mortality in patients who develop a clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD). It is unknown whether multiple drains mitigate CR-POPF better than a single drain. We hypothesized that multiple drains decrease the complication burden more than a single drain in cases at greater risk for CR-POPF.The Fistula Risk Score (FRS), mitigation strategies (including number of drains placed), and clinical outcomes were obtained from a multi-institutional database of PDs performed from 2003 to 2020. Outcomes were compared between cases utilizing 0, 1, or 2 intraperitoneal drains. Multivariable regression analysis was used to evaluate the optimal drainage approach.A total of 4,292 PDs used 0 (7.3%), 1 (45.2%), or 2 (47.5%) drains with an observed CR-POPF rate of 9.6%, which was higher in intermediate/high FRS zone cases compared with negligible/low FRS zone cases (13% vs 2.4%, P.001). The number of drains placed also correlated with FRS zone (median of 2 in intermediate/high vs 1 in negligible/low risk cases). In intermediate/high risk cases, the use of 2 drains instead of 1 was not associated with a reduced rate of CR-POPF, average complication burden attributed to a CR-POPF, reoperations, or mortality. Obviation of drains was associated with significant increases in complication burden and mortality - regardless of the FRS zone.In intermediate/high risk zone cases, placement of a single drain or multiple drains appears to mitigate the complication burden while use of no drains is associated with inferior outcomes.

INTRODUCTION: Implementation of a Diabetes Prevention Program (DPP) in both in-person and digital health-care settings has been increasing. The purpose of this article is to describe the protocol of a mixed-methods, natural experiment study designed to evaluate the implementation of DPP in a large, integrated health system. METHODS: Kaiser Permanente Northwest patients who were 19 to 75 years with prediabetes (hemoglobin A1c or glycated hemoglobin, 5.7–6.4) and obesity (body mass index ≥ 30 kg/m(2)) were invited, via the Kaiser Permanente Northwest patient portal, to participate in the digital (n = 4124) and in-person (n = 2669) DPP during 2016 through 2018. Primary (weight) and secondary (hemoglobin A1c or glycated hemoglobin level) outcome data will be obtained from electronic health records. A cost-effectiveness analysis as well as qualitative interviews with patients (enrolled and not enrolled in the DPP) and stakeholders will be conducted to examine further implementation, acceptability, and sustainability. CONCLUSION: The mixed-methods, natural experiment design we will use to evaluate Kaiser Permanente Northwest’s implementation of the digital and in-person DPP builds on existing evidence related to the effectiveness of these two DPP delivery modes and will contribute new knowledge related to best practices for implementing and sustaining the DPP within large health systems over the long term.

Figure S1. Sample cohort of this study, which included 204 subjects in total. Workflow shows patient cohorts involved in each classification. * indicated 8 patients repeated in the discovery set and the training set. ** indicated 32 locally advanced patients that were not used in the occult metastases detection as training set did not have locally advanced PDAC patients.

Pancreatic cancer is lethal because of its invasiveness, rapid progression, and profound resistance to chemotherapy and radiation therapy. To identify the molecular mechanisms underlying this, we have examined the expression and potency of three major death receptors: tumor necrosis factor receptor (TNF-R), TNF-related apoptosis-inducing ligand receptor (TRAIL-R), and Fas in mediating cytotoxicity in four invasive pancreatic cancer cell lines. We have analyzed the expression of major antiapoptotic factors, cell cycle regulators and death receptor decoys (DcR) in comparison with normal pancreas tissues and five other human malignant tumor cell lines. We have found that different pancreatic cancer cell lines coexpress high-level TRAIL-R, Fas, and TNF-R1 but are strongly resistant to apoptosis triggered by the death receptors. DcR2 and DcR3 overexpression may partly contribute to the resistance of pancreatic cancer cells to TRAIL-R– and Fas-mediated cytotoxicity. Bcl-XL and Bcl-2 are predominantly overexpressed in pancreatic cancer cell lines, respectively. Bcl-XL is also predominantly overexpressed in prostate, colorectal, and intestinal cancer cells. The knockdown of the predominant Bcl-XL overexpression significantly reduces the viability of pancreatic cancer cells to TNFα- and TRAIL-mediated apoptosis by sublethal-dose single and combined antitumor drugs, including geldanamycin, PS-341, Trichostatin A, and doxorubicine. Geldanamyin and PS-341 synergistically block NFκB activation, suppress Akt/PKB pathway, and down-regulate Bcl-XL, Bcl-2, cIAP-1, and cyclin D1 expression. This combined regimen dramatically enhances TRAIL cytotoxic effects and breaks through chemoresistance. Bcl-XL plays a vital role in pancreatic cancer chemoresistance. Geldanamycin, PS-341, and TRAIL triple combination may be a novel therapeutic strategy for pancreatic cancer.

Supplementary Figures 1 and 2 from Predominant Bcl-XL Knockdown Disables Antiapoptotic Mechanisms: Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Based Triple Chemotherapy Overcomes Chemoresistance in Pancreatic Cancer Cells In vitro

Supplementary Figure 3 from Predominant Bcl-XL Knockdown Disables Antiapoptotic Mechanisms: Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Based Triple Chemotherapy Overcomes Chemoresistance in Pancreatic Cancer Cells In vitro

Supplementary Data Legends from Predominant Bcl-XL Knockdown Disables Antiapoptotic Mechanisms: Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Based Triple Chemotherapy Overcomes Chemoresistance in Pancreatic Cancer Cells In vitro

Background: The association between intraoperative estimated blood loss and outcomes after pancreatoduodenectomy has, thus far, been rarely explored. Methods: In total, 7,706 pancreatoduodenectomies performed at 18 international institutions composing the Pancreas Fistula Study Group were examined (2003-2020). High estimated blood loss (>700 mL) was defined as twice the median. Propensity score matching (1:1 exact-match) was employed to adjust for variables associated with high estimated blood loss and clinically relevant pancreatic fistula occurrence. The study was powered to detect a 33% clinically relevant pancreatic fistula increase in the high estimated blood loss group, with a = 0.05 and b = 0.2. Results: The propensity score model included 966 patients with high estimated blood loss and 966 patients with lower estimated blood loss; all covariate imbalantces were solved. Patients with high estimated blood loss patients experienced higher clinically relevant pancreatic fistula rates (19.4 vs 12.6%, odds ratio 1.66; P < .001), as well as higher severe complication rates (27.8 vs 15.6%), transfusions (50.1 vs 14.3%), reoperations (9.2 vs 4.0%), intensive care unit transfers (9.9 vs 4.8%) and 90-day mortality (4.7 vs 2.0%, all P < .001). High estimated blood loss was an independent predictor for clinically relevant pancreatic fistula (odds ratio 1.78, 95% confidence interval 1.37-2.32), as were prophylactic Octreotide administration (odds ratio 1.95, 95% confidence interval 1.46-2.61) and soft pancreatic texture (odds ratio 5.32, 95% confidence interval 3.74-5.57; all P < .001). Moreover, a second model including 1,126 pancreatoduodenectomies was derived including vascular resections as additional confounder (14.0% vascular resections performed in each group). On multivariable regression, high estimated blood loss was confirmed an independent predictor for clinically relevant pancreatic fistula reduction (odds ratio 1.80, 95% confidence interval 1.32-2.4 4; P < .001), whereas vascular resection was not (odds ratio 0.64, 95% confidence interval 0.34-1.88; P 1/4 .156). Conclusion: This study better establishes the relationship between estimated blood loss and outcomes after pancreatoduodenectomy. Despite inherent contributions to blood loss, its minimization is an actionable opportunity for clinically relevant pancreatic fistula reduction and performance optimization in pancreatoduodenectomy. Accordingly, practical insights are offered to achieve this goal. (c) 2021 Elsevier Inc. All rights reserved.

Suppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash detrimental behavioral actions and addiction. Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. In a mouse model using two-photon calcium imaging in vivo, we identify paraventricular thalamostriatal neuronal ensembles that are inhibited upon sucrose self-administration and seeking, yet these neurons are tonically active when behavior is suppressed by a fear-provoking predator odor, a pharmacological stressor, or inhibitory learning. Electrophysiological, optogenetic, and chemogenetic experiments reveal that thalamostriatal neurons innervate accumbal parvalbumin interneurons through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking regardless of the behavioral suppressor administered. Furthermore, systemic or intra-accumbal opioid injections rapidly dysregulate thalamostriatal ensemble dynamics, weaken thalamostriatal synaptic innervation of downstream neurons, and unleash reward-seeking behaviors in a manner that is reversed by genetic deletion of thalamic µ-opioid receptors. Overall, our findings reveal a thalamostriatal to parvalbumin interneuron circuit that is both required for the suppression of reward seeking and rapidly disengaged by opioids.

Patient education and resources that address barriers to health literacy to improve understanding in pancreatic cancer are limited. We evaluated the impact and outcomes benefits of Animated Pancreas Patient (APP) cancer educational modules (APP website and YouTube).A retrospective study of APP metrics and utilization data from September 2013 to February 2021 was conducted. We evaluated audience reach and calculated top views by media type (animation/expert video/patient video/slideshow) and top retention videos from the modules.During the study period, APP had 4,551,079 views worldwide of which 2,757,064 unique visitors or 60% were from the United States. Of these, 54% were patients, 17% were family members or caregivers, 16% were health care providers, and 13% were other. The most popular topic viewed among the animations was "Understanding Clinical Trials" (n = 182,217), and the most common expert video viewed was "What are the different stages of pancreatic cancer?" (n = 15,357).Pancreatic cancer patient education using APP's visual formats of learning demonstrated a wide reach and had a significant impact on improved understanding among patients, families, and caregivers. Continued efforts should be made to provide patient resources that address health literacy, better quality of life and improved health outcomes in pancreatic cancer.

Aim Has standardization of criteria of a small-stitch-small-bite suture (SSSB) a significant influence on its durability? Material and Methods Porcine abdominal walls and bovine flanks were used as model tissues. We cut a median 15 cm long incision into the tissues. Then we punched an additional round (5–10 cm wide) or rhomboid (5×15 cm) defect in the middle of the incision. Monomax® and Maxon® USP 1 and 2–0 sutures were used in a running technique with a suture to incison lengths above 4:1. The mesh-tissue compounds were investigated on our self-built hydraulic bench test simulating coughs. Cyclic pressure impacts were repeatedly delivered peaking around 210 mmHg. In each of twenty experimental series, ten preparations were loaded 425 times. Results Standardized SSSB sutures using 2–0 Monomax® with a suture-incision-ratio of 4.5 : 1 can give a durable closure of a large defect in thin, elastic tissues. Under other conditions, suture lines can reopen. Standardization of the suturing technique significantly increased the durability (p = 0.00008). Defect shape is important since the larger rhomboid defects were easier to close compared to the smaller, 5 cm wide, round defects (SSSB: p = 0.00018; LSLB: p = 0.00906). Discussion After standardization, insignificant influences on the durability were exerted by the suture material and diameter, the bite and stitch size (small versus large), the surgeon, the tissue elasticity and tension and the defect size. Conclusions A standardized suturing technique was developed. The standardization improved the durability of a suture repair significantly.

Background Health insurance plans are increasingly offering mailed fecal immunochemical test (FIT) programs for colorectal cancer (CRC) screening, but few studies have compared the outcomes of different program models (eg, invitation strategies). Methods This study compares the outcomes of 2 health plan-based mailed FIT program models. In the first program (2016), FIT kits were mailed to all eligible enrollees; in the second program (2018), FIT kits were mailed only to enrollees who opted in after an outreach phone call. Participants in this observational study included dual-eligible Medicaid/Medicare enrollees who were aged 50 to 75 years and were due for CRC screening (1799 in 2016 and 1906 in 2018). Six-month FIT completion rates, implementation outcomes (eg, mailed FITs sent and reminders attempted), and program-related health plan costs for each program are described. Results All 1799 individuals in 2016 were sent an introductory letter and a FIT kit. In 2018, all 1906 were sent an introductory letter, and 1905 received at least 1 opt-in call attempt, with 410 (21.5%) sent a FIT. The FIT completion rate was 16.2% (292 of 1799 [95% CI, 14.5%-17.9%]) in 2016 and 14.6% (278 of 1906 [95% CI, 13.0%-16.2%]) in 2018 (P = .36). The overall implementation costs were higher in 2016 ($40,156) than 2018 ($34,899), with the cost per completed FIT slightly higher in 2016 ($138) than 2018 ($126). Conclusions An opt-in mailed FIT program achieved FIT completion rates similar to those of a program mailing to all dual-eligible Medicaid/Medicare enrollees. Lay summary Health insurance plans can use different program models to successfully mail fecal test kits for colorectal cancer screening to dual-eligible Medicaid/Medicare enrollees, with nearly 1 in 6 enrollees completing fecal testing.

Background Despite abundant, high-level scientific evidence, there is no consensus regarding the prevention, mitigation, and management of clinically relevant pancreatic fistula after pancreatoduodenectomy. The aim of the present investigation is three-fold: (1) to analyze the multiple decision-making points for pancreatico-enteric anastomotic creation and fistula mitigation and management after pancreatoduodenectomy, (2) to reveal the practice of contemporary experts, and (3) to indicate avenues for future research to reduce the burden of clinically relevant pancreatic fistula. Methods A 109-item questionnaire was sent to a panel of international pancreatic surgery experts, recognized for their clinical and scientific authority. Their practice habits and thought processes regarding clinically relevant pancreatic fistula risk assessment, anastomotic construction, application of technical adjuncts, and mitigation strategies, as well as postoperative management, was explored. Sixteen clinical vignettes were presented to reveal their certain approaches to unique situations—both common and uncommon. Results Sixty experts, with a cumulative 48,860 pancreatoduodenectomies, completed the questionnaire. Their median pancreatectomy/pancreatoduodenectomy case volume was 1,200 and 705 procedures, respectively, with a median career duration of 22 years and 200 indexed publications. Although pancreatico-jejunostomy reconstruction with transperitoneal drainage is the standard operative approach for most authorities, uncertainty emerges regarding the employment of objective risk stratification and adaptation of practice to risk. Concrete suggestions are offered to inform decision-making in intimidating circumstances. Early drain removal is frequently embraced, while a step-up approach is unanimously invoked to treat severe clinically relevant pancreatic fistula. Conclusion A comprehensive conceptual framework of 4 sequential phases of decision-making is proposed—risk assessment, anastomotic technique, mitigation strategy employment, and postoperative management. Basic science studies and outcome analyses are proposed for improvement.

Electron beam powder bed fusion (E-PBF) is a well-known additive manufacturing process. Components are realized based on layer-by-layer melting of metal powder. Due to the high degree of design freedom, additive manufacturing came into focus of tooling industry, especially for tools with sophisticated internal cooling channels. The present work focuses on the relationships between processing, microstructure evolution, chemical composition and mechanical properties of a high alloyed tool steel AISI H13 (1.2344, X40CrMoV5-1) processed by E-PBF. The specimens are free of cracks, however, lack of fusion defects are found upon use of non-optimized parameters finally affecting the mechanical properties detrimentally. Specimens built based on suitable parameters show a relatively fine grained bainitic/martensitic microstructure, finally resulting in a high ultimate strength and an even slightly higher failure strain compared to conventionally processed and heat treated AISI H13.

Gef��rdert im Rahmen des Projekts DEAL, Deutsche Forschungsgemeinschaft (project number 400008732)

The present study aims at identifying and analyzing challenges and prospects related to the use of pseudoelastic shape memory alloys for well-established double shear connections in timber engineer...

Introduction: In the setting of metastatic pancreatic adenocarcinoma (mPDAC), lower baseline plasma KRAS mutation levels have been associated with improved survival. While tissue-agnostic, plasma-based copy number instability (CNI) has been demonstrated as an early indicator of response to immunotherapy for some solid tumors, it has not been assessed for patients with mPDAC, nor in combination with KRAS mutations for patients receiving standard of care chemo/radiotherapy. Here we evaluate the combination of mutant KRAS (mKRAS) and CNI detection in plasma as a predictor of overall and progression-free survival (OS/PFS) in mPDAC patients who received standard of care therapy. Methods: Cell-free DNA was extracted from plasma and libraries prepared at baseline (Week 0) and weeks 8, 16 and 24 on therapy, and analyzed by next-generation sequencing (CNI) and droplet digital PCR (mKRAS). Descriptive statistics were computed for variables including CNI (score is a measure of circulating tumor DNA) and mKRAS variant allele fraction. Detection was defined as above the limit of detection (mKRAS=0.13%) and above the 95th percentile of the value in normal individuals (CNI=24). Therapy response was assessed by OS and PFS. Results: 196 plasma samples from 64 mPDAC patients were analyzed. When dichotomized as detectable vs undetectable, CNI alone was significantly associated with OS at all on-therapy timepoints but not baseline, whereas mKRAS was significantly associated with OS for all 4 timepoints (Table 1). Detection of both CNI and mKRAS in combination was strongly associated with worse OS at all timepoints, yielding the highest HR. Similar results were obtained when mKRAS and CNI were dichotomized at their respective median values or with PFS as the clinical endpoint. Conclusions: Combined CNI and mKRAS detection at baseline and on-therapy may provide a strong and early indication of worse prognosis for patients with mPDAC. Table 1. Association of CNI and mKRAS with Overall Survival (HazardRatio [95% CI], log-rank p-value) Timepoint CNI mKRAS CNI and KRAS Baseline/Week 0 1.54 [0.89-2.68], 0.1 2.05 [1.12-3.78], 0.02 2.50 [1.46-4.28], 0.0006 Week 8 1.78 [0.99-3.18], 0.05 2.21 [1.19-4.08], 0.01 9.81 [3.40-28.28], Citation Format: Samuele Cannas, Jacob E. Till, Kristine Kim, Michael J. LaRiviere, Charles M. Vollmer, Jennifer R. Eads, Thomas B. Karasic, Peter J. O'Dwyer, Charles J. Schneider, Ursina R. Teitelbaum, Kim A. Reiss Binder, Mark H. O'Hara, Douglas T. Ross, Kim McGregor, Kirsten Bornemann-Kolatzki, Ekkehard Schütz, Julia Beck, Erica L. Carpenter. Liquid biopsy signature combining copy number instability and mutant KRAS detection is associated with survival for patients with metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1043.

In the present study, Iron-based FeMnAlNi and Cobalt-based CoNiGa shape-memory alloys (SMA) were processed by laser metal deposition for the first time. The materials show susceptibility to cracking upon processing when unheated substrates are employed. Pre-heating of the substrate materials eliminated cracking completely and enabled robust deposition of thin-wall structures. Microstructural analysis using optical microscopy revealed different microstructural evolution for the two materials considered.

Objective The goal of this study was to investigate the effect of progranulin insufficiency on extracellular vesicles (EVs), a heterogeneous population of vesicles that may contribute to progression of neurodegenerative disease. Loss‐of‐function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD), and brains from GRN carriers with FTD (FTD‐GRN) exhibit signs of lysosomal dysfunction. Lysosomal dysfunction may induce compensatory increases in secretion of exosomes, EVs secreted from the endolysosomal system, so we hypothesized that progranulin insufficiency would increase EV levels in the brain. Methods We analyzed levels and protein contents of brain EVs from Grn–/– mice, which model the lysosomal abnormalities of FTD‐GRN patients. We then measured brain EVs in FTD‐GRN patients. To assess the relationship of EVs with symptomatic disease, we measured plasma EVs in presymptomatic and symptomatic GRN mutation carriers. Results Grn–/– mice had elevated brain EV levels and altered EV protein contents relative to wild‐type mice. These changes were age‐dependent, occurring only after the emergence of pathology in Grn–/– mice. FTD‐GRN patients (n = 13) had elevated brain EV levels relative to controls (n = 5). Symptomatic (n = 12), but not presymptomatic (n = 7), GRN carriers had elevated plasma EV levels relative to controls (n = 8). Interpretation These data show that symptomatic FTD‐GRN patients have elevated levels of brain and plasma EVs, and that this effect is modeled in the brain of Grn–/– mice after the onset of pathology. This increase in EVs could influence FTD disease progression, and provides further support for EVs as potential FTD biomarkers.

To investigate the role of intraoperative estimated blood loss (EBL) on development of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD).Minimizing EBL has been shown to decrease transfusions and provide better perioperative outcomes in PD. EBL is also felt to be influential on CR-POPF development.This study consists of 5534 PDs from a 17-institution collaborative (2003-2018). EBL was progressively categorized (≤150mL; 151-400mL; 401-1,000 mL;1,000 mL). Impact of additive EBL was assessed using 20 3- factor fistula risk score (FRS) scenarios reflective of endogenous CR-POPF risk.CR-POPF developed in 13.6% of patients (N = 753) and median EBL was 400 mL (interquartile range 250-600 mL). CR-POPF and Grade C POPF were associated with elevated EBL (median 350 vs 400 mL, P = 0.002; 372 vs 500 mL, P0.001, respectively). Progressive EBL cohorts displayed incremental CR-POPF rates (8.5%, 13.4%, 15.2%, 16.9%; P0.001). EBL400mL was associated with increased CR-POPF occurrence in 13/20 endogenous risk scenarios. Moreover, 8 of 10 scenarios predicated on a soft gland demonstrated increased CR-POPF incidence. Hypothetical projections demonstrate significant reductions in CR-POPF can be obtained with 1-, 2-, and 3-point decreases in FRS points attributed to EBL risk (12.2%, 17.4%, and 20.0%; P0.001). This is especially pronounced in high-risk (FRS7-10) patients, who demonstrate up to a 31% reduction (P0.001). Surgeons in the lowest-quartile of median EBL demonstrated CR-POPF rates less than half those in the upper-quartile (7.9% vs 18.8%; P0.001).EBL independently contributes significant biological risk to CR-POPF. Substantial reductions in CR-POPF occurrence are projected and obtainable by minimizing EBL. Decreased individual surgeon EBL is associated with improvements in CR-POPF.