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Introduction: Pancreatic cancer remains one of the deadliest cancers in the United States. Some types of pancreatic cysts, which are being detected more frequently and often incidentally on imaging, have the potential to develop into pancreatic cancer and thus provide a valuable window of opportunity for cancer interception. Although racial disparity in pancreatic cancer has been described, little is known regarding health disparities in pancreatic cancer prevention. In the present study, we investigate potential health disparities along the continuum of care for pancreatic cancer., Methods: The racial and ethnic composition of pancreatic patients at high-volume centers in Indiana were evaluated, representing patients undergoing surgery for pancreatic cancer (n=390), participating in biobanking (972 pancreatic cancer patients and 1984 patients with pancreatic disease), or being monitored for pancreatic cysts at an early detection center (n=1514). To assess racial disparities and potential differences in decision-making related to pancreatic cancer prevention and early detection, an exploratory online survey was administered through a volunteer registry (n=708).  Results: We show that despite comprising close to 10% or 30% of the Indiana or Indianapolis population, respectively, African Americans make up only about 4-5% of our study cohorts consisting of patients undergoing pancreatic surgery or participating in biobanking and early detection. Analysis of online survey results revealed that given the hypothetical situation of being diagnosed with a pancreatic cyst or pancreatic cancer, the vast majority of respondents (>90%) would agree to undergo surveillance or surgery, respectively, regardless of race. Only a minority (3-12%) acknowledged any significant transportation, financial, or emotional barriers that would impact a decision to undergo surveillance or surgery. This suggests that the observed racial disparities may be due in part to the existence of other barriers that lie upstream of this decision point., Conclusion: Racial disparities exist not only for pancreatic cancer but also at earlier points along the continuum of care such as prevention and early detection. To our knowledge, this is the first study to document racial disparity in the management of patients with pancreatic cysts who are at risk of developing pancreatic cancer. Our results suggest that improving access to information and care for such at-risk individuals may lead to more equitable outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Yip-Schneider et al.)

This study introduces a hybrid analytical super-resolution (SR) pipeline aimed at enhancing the resolution of medical magnetic resonance imaging (MRI) scans. The primary objective is to overcome the limitations of clinical MRI resolution without the need for additional expensive hardware. The proposed pipeline involves three key steps: pre-processing to re-slice and register the image stacks; SR reconstruction to combine information from three orthogonal image stacks to generate a high-resolution image stack; and post-processing using an artefact reduction convolutional neural network (ARCNN) to reduce the block artefacts introduced during SR reconstruction. The workflow was validated on a dataset of six knee MRIs obtained at high resolution using various sequences. Quantitative analysis of the method revealed promising results, showing an average mean error of 1.40 ± 2.22% in voxel intensities between the SR denoised images and the original high-resolution images. Qualitatively, the method improved out-of-plane resolution while preserving in-plane image quality. The hybrid SR pipeline also displayed robustness across different MRI sequences, demonstrating potential for clinical application in orthopaedics and beyond. Although computationally intensive, this method offers a viable alternative to costly hardware upgrades and holds promise for improving diagnostic accuracy and generating more anatomically accurate models of the human body.

Background: Increasing evidence implicates microbiome involvement in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Studies suggest that reflux of gut or oral microbiota can lead to colonization in the pancreas, resulting in dysbiosis that culminates in release of microbial toxins and metabolites that potentiate an inflammatory response and increase susceptibility to PDAC. Moreover, microbe-derived metabolites can exert direct effector functions on precursors and cancer cells, as well as other cell types, to either promote or attenuate tumor development and modulate treatment response., Content: The occurrence of microbial metabolites in biofluids thereby enables risk assessment and prognostication of PDAC, as well as having potential for design of interception strategies. In this review, we first highlight the relevance of the microbiome for progression of precancerous lesions in the pancreas and, using liquid chromatography-mass spectrometry, provide supporting evidence that microbe-derived metabolites manifest in pancreatic cystic fluid and are associated with malignant progression of intraductal papillary mucinous neoplasm(s). We secondly summarize the biomarker potential of microbe-derived metabolite signatures for (a) identifying individuals at high risk of developing or harboring PDAC and (b) predicting response to treatment and disease outcomes., Summary: The microbiome-derived metabolome holds considerable promise for risk assessment and prognostication of PDAC., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Stakeholders in the modeling and simulation (M&S) community organized a workshop at the 2019 Annual Meeting of the Orthopaedic Research Society (ORS) entitled "Reproducibility in Modeling and Simulation of the Knee: Academic, Industry, and Regulatory Perspectives." The goal was to discuss efforts among these stakeholders to address irreproducibility in M&S focusing on the knee joint. An academic representative from a leading orthopedic hospital in the United States described a multi-institutional, open effort funded by the National Institutes of Health to assess model reproducibility in computational knee biomechanics. A regulatory representative from the United States Food and Drug Administration indicated the necessity of standards for reproducibility to increase utility of M&S in the regulatory setting. An industry representative from a major orthopedic implant company emphasized improving reproducibility by addressing indeterminacy in personalized modeling through sensitivity analyses, thereby enhancing preclinical evaluation of joint replacement technology. Thought leaders in the M&S community stressed the importance of data sharing to minimize duplication of efforts. A survey comprised 103 attendees revealed strong support for the workshop and for increasing emphasis on computational modeling at future ORS meetings. Nearly all survey respondents (97%) considered reproducibility to be an important issue. Almost half of respondents (45%) tried and failed to reproduce the work of others. Two-thirds of respondents (67%) declared that individual laboratories are most responsible for ensuring reproducible research whereas 44% thought that journals are most responsible. Thought leaders and survey respondents emphasized that computational models must be reproducible and credible to advance knee M&S., (© 2023 Orthopaedic Research Society.)

Background/objectives: Pancreatic serous cystic neoplasms (SCN) present a diagnostic challenge given their increasing frequency of detection and benign nature yet relatively high rate of misdiagnosis. Here, imaging and analyses associated with EUS-guided fine-needle aspiration (EUS-FNA) are evaluated for their ability to provide a correct preoperative diagnosis of SCN., Methods: A surgical cohort with confirmed pathological diagnosis of SCN (n = 62) and a surveillance cohort with likely SCN (n = 31) were assessed for imaging (CT/MRI/EUS) and EUS-FNA-based analyses (cytology/DNA analysis for Von Hippel-Lindau [VHL] gene alterations/biomarkers)., Results: In the surgical cohort, CT/MRI and EUS respectively predicted SCN in 4 of 58(7%) and 19 of 62(31%). Cyst fluid cytology and VHL alterations predicted SCN in 1 of 51(2%) and 5 of 21(24%), respectively. High specificity cyst fluid biomarkers (vascular endothelial growth factor [VEGF]/glucose/carcinoembryonic antigen [CEA]/amylase) correctly identified SCN in 25 of 27(93%). In the surveillance cohort, cyst fluid biomarkers predicted SCN in 12 of 12(100%) while VHL alterations identified SCN 3 of 10(30%)., Conclusion: High specificity cyst fluid biomarkers provided the most sensitive means of diagnosing SCN preoperatively. To obtain a preoperative diagnosis of SCN at the highest level of certainty, a multidisciplinary approach should be taken to inform appropriate SCN management., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: The accurate identification of mucinous pancreatic cystic lesions (PCLs) is paramount for cancer risk stratification. Cyst fluid carcinoembryonic antigen (CEA), the only routinely used test, requires high volumes and has low sensitivity. We aimed to compare the performance of two investigational small-volume biomarkers, glucose and the protease gastricsin, to CEA for PCL classification., Methods: We obtained cyst fluid samples from 81 patients with pathologically confirmed PCLs from four institutions between 2003 and 2016. Gastricsin activity was measured using an internally quenched fluorescent substrate. Glucose levels were measured with a standard glucometer. CEA levels were obtained from the medical record. Models using Classification and Regression Trees were created to predict mucinous status. Model performance was evaluated using nested cross-validation., Results: Gastricsin activity, CEA, and glucose levels from patients with mucinous (n = 50) and nonmucinous (n = 31) PCLs were analyzed. Area under the curve (AUC) was similar for individual classifiers (gastricsin volume normalized [GVN] 0.88; gastricsin protein concentration normalized [GPN] 0.95; glucose 0.83; CEA 0.84). The combination of two classifiers did not significantly improve AUC, with CEA + GVN (0.88) performing similarly to CEA + GPN (0.95), GVN + glucose (0.87), GPN + glucose (0.95), and CEA + glucose (0.84). The three-analyte combination performed similarly to single and dual classifiers (GPN + glucose + CEA AUC 0.95; GVN + glucose + CEA AUC 0.87). After multiple comparison corrections, there were no significant differences between the individual, dual, and triple classifiers., Conclusions: Gastricsin and glucose performed similarly to CEA and required <5% of the volume required for CEA; these classifiers may be useful in patients with limited cyst fluid. Future multicenter prospective studies are needed to validate and compare these novel small-volume biomarkers., (Copyright © 2022. Published by Elsevier Inc.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that is often detected at an advanced stage. Earlier diagnosis of PDAC is key to reducing mortality. Circulating biomarkers such as microRNAs are gaining interest, but existing technologies require large sample volumes, amplification steps, extensive biofluid processing, lack sensitivity, and are low-throughput. Here, we present an advanced nanoplasmonic sensor for the highly sensitive, amplification-free detection and quantification of microRNAs (microRNA-10b, microRNA-let7a) from unprocessed plasma microsamples. The sensor construct utilizes uniquely designed -ssDNA receptors attached to gold triangular nanoprisms, which display unique localized surface plasmon resonance (LSPR) properties, in a multiwell plate format. The formation of -ssDNA/microRNA duplex controls the nanostructure-biomolecule interfacial electronic interactions to promote the charge transfer/exciton delocalization processes and enhance the LSPR responses to achieve attomolar (10 -18 M) limit of detection (LOD) in human plasma. This improve LOD allows the fabrication of a high-throughput assay in a 384-well plate format. The performance of nanoplasmonic sensors for microRNA detection was further assessed by comparing with the qRT-PCR assay of 15 PDAC patient plasma samples that shows a positive correlation between these two assays with the Pearson correlation coefficient value >0.86. Evaluation of >170 clinical samples reveals that oncogenic microRNA-10b and tumor suppressor microRNA-let7a levels can individually differentiate PDAC from chronic pancreatitis and normal controls with >94% sensitivity and >94% specificity at a 95% confidence interval (CI). Furthermore, combining both oncogenic and tumor suppressor microRNA levels significantly improves differentiation of PDAC stages I and II versus III and IV with >91% and 87% sensitivity and specificity, respectively, in comparison to the sensitivity and specificity values for individual microRNAs. Moreover, we show that the level of microRNAs varies substantially in pre- and post-surgery PDAC patients ( n = 75). Taken together, this ultrasensitive nanoplasmonic sensor with excellent sensitivity and specificity is capable of assaying multiple biomarkers simultaneously and may facilitate early detection of PDAC to improve patient care.

The functional relationship between bone and cartilage is modulated by mechanical factors. Scarce data exist on the relationship between bone shape and the spatial distribution of cartilage thickness. The aim of the study was to characterise the coupled variation in knee bone morphology and cartilage thickness distributions in knees with healthy cartilage and investigate this relationship as a function of sex, height, body mass, and age. MR images of 51 knees from young adults (28.4 ± 4.1 years) were obtained from a previous study and used to train a statistical shape model of the femur, tibia, and patella and their cartilages. Five multiple linear regression models were fitted to characterise morphology as a function of sex, height, body mass, and age. A logistic regression classifier was fitted to characterise morphological differences between males and females, and tenfold cross-validation was performed to evaluate the models' performance. Our results showed that cartilage thickness and its distribution were coupled to bone morphology. The first five shape modes captured over 90% of the variance and described coupled changes to the bone and spatial distribution of cartilage thickness. Mode 1 (size) was correlated to sex (p < 0.001) and height (p < 0.0001). Mode 2 (aspect ratio) was also correlated to sex (p = 0.006) and height (p = 0.017). Mode 4 (condylar depth) was correlated to sex only (p = 0.024). A logistic regression model trained on modes 1, 2, and 4 could classify sex with an accuracy of 92.2% (95% CI [81.1%, 97.8%]). No other modes were influenced by sex, height, body mass, or age. This study demonstrated the coupled relationship between bone and cartilage, showing that cartilage is thicker with increased bone size, diaphysis size, and decreased femoral skew. Our results show that sex and height influence bone shape and the spatial distribution of cartilage thickness in a healthy young adult population, but body mass and age do not., (© 2022. The Author(s).)

Background: The decision to routinely leave a nasogastric tube after pancreatoduodenectomy remains controversial. We sought to determine the impact of immediate nasogastric tube removal versus early nasogastric tube removal (<24 h) on postoperative outcomes., Methods: A retrospective review of our institution's prospective ACS-NSQIP database identified patients that underwent pancreatoduodenectomy from 2015 to 2018. Outcomes were compared among patients with immediate nasogastric tube removal versus early nasogastric tube removal., Results: A total of 365 patients were included in primary analysis (no nasogastric tube, n = 99; nasogastric tube removed <24 h, n = 266). Thirty-day mortality and infectious, renal, cardiovascular, and pulmonary morbidity were similar in comparing those with no nasogastric tube versus early nasogastric tube removal on univariable and multivariable analyses (P > 0.05). Incidence of delayed gastric emptying (11.1 versus 13.2%) was similar between groups. Patients with no nasogastric tube less frequently required nasogastric tube reinsertion (n = 4, 4%) compared to patients with NGT <24 h (n = 39, 15%) (OR = 3.83, 95% CI [1.39-10.58]; P = 0.009)., Conclusion: Routine gastric decompression can be safely avoided after uneventful pancreaticoduodenectomy., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Purpose: Assess the relationship between MRI-derived pancreatic fat fraction and risk of malignancy in intraductal papillary mucinous neoplasm (IPMN)., Methods: MRIs of patients with IPMN who underwent pancreaticoduodenectomy were analyzed. IPMN with low-grade dysplasia (n = 29) were categorized as low-risk while IPMN at high risk of malignancy consisted of those with high-grade dysplasia/invasive carcinoma (n = 33). Pancreatic fat-fraction (FF mean ) was measured using the 2-point Dixon-method. Images were evaluated for the high-risk stigmata and worrisome features according to the revised 2017 Fukuoka consensus criteria. Data on serum CA19-9, Diabetes Mellitus (DM) status, body mass index (BMI), and histological chronic pancreatitis were obtained., Results: A significant difference in FF mean was found between the high-risk IPMN (11.45%) and low-risk IPMN (9.95%) groups (p = 0.027). Serum CA19-9 level (p = 0.021), presence of cyst wall enhancement (p = 0.029), and solid mass (p = 0.008) were significantly associated with high-risk IPMN. There was a significant correlation between FF mean and mural nodule size (r = 0.36, p ˂ 0.01), type 2 DM (r = 0.34, p ˂ 0.01), age (r = 0.31, p ˂ 0.05), serum CA 19-9 (r = 0.30, p ˂ 0.05), cyst diameter (r = 0.30, p ˂ 0.05), and main pancreatic duct diameter (r = 0.26, p ˂ 0.05). Regression analysis revealed FF mean (OR 1.103, p = 0.035) as an independent predictive variable of high-risk IPMN., Conclusion: FF mean is significantly associated with high-risk IPMN and an independent predictor of IPMN malignant risk. FF mean may have clinical utility as a biomarker to complement the current IPMN treatment algorithm and improve clinical decision making regarding the need for surgical resection or surveillance., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The primate thumb plays a central role in grasping and the basal trapeziometacarpal (TMC) joint is critical to its function. The TMC joint morphology varies across primates, yet little is known about form-function interaction within in the TMC joint. The purpose of this study was to investigate how stress distributions within the joint differ between five grasping types commonly employed by bonobos ( Pan paniscus ). Five cadaveric bonobo forearms were CT scanned in five standardized positions of the hand as a basis for the generation of parametric finite element models to compare grasps. We have developed a finite element analysis (FEA) approach to investigate stress distribution patterns in the TMC joint associated with each grasp type. We hypothesized that the simulated stress distributions for each position would correspond with the patterns expected from a saddle-shaped joint. However, we also expected differences in stress patterns arising from instraspecific variations in morphology. The models showed a high agreement between simulated and expected stress patterns for each of the five grasps (86% of successful simulations), while partially (52%) and fully (14%) diverging patterns were also encountered. We identified individual variations of key morphological features in the bonobo TMC joint that account for the diverging stress patterns and emphasized the effect of interindividual morphological variation on joint functioning. This study gives unprecedented insight in the form-function interactions in the TMC joint of the bonobo and provides an innovative FEA approach to modelling intra-articular stress distributions, a valuable tool for the study of the primate thumb biomechanics., Competing Interests: The authors declare there are no competing interests., (©2021 van Leeuwen et al.)

Background: Pancreatic cysts are incidentally detected in up to 13% of patients undergoing radiographic imaging. Of the most frequently encountered types, mucin-producing (mucinous) pancreatic cystic lesions may develop into pancreatic cancer, while nonmucinous ones have little or no malignant potential. Accurate preoperative diagnosis is critical for optimal management, but has been difficult to achieve, resulting in unnecessary major surgery. Here, we aim to develop an algorithm based on biomarker risk scores to improve risk stratification., Study Design: Patients undergoing surgery and/or surveillance for a pancreatic cystic lesion, with diagnostic imaging and banked pancreatic cyst fluid, were enrolled in the study after informed consent (n = 163 surgical, 67 surveillance). Cyst fluid biomarkers with high specificity for distinguishing nonmucinous from mucinous pancreatic cysts (vascular endothelial growth factor [VEGF], glucose, carcinoembryonic antigen [CEA], amylase, cytology, and DNA mutation) were selected. Biomarker risk scores were used to design an algorithm to predict preoperative diagnosis. Performance was tested using surgical (retrospective) and surveillance (prospective) cohorts., Results: In the surgical cohort, the biomarker algorithm outperformed the preoperative clinical diagnosis in correctly predicting the final pathologic diagnosis (91% vs 73%; p < 0.000001). Specifically, nonmucinous serous cystic neoplasms (SCN) and mucinous cystic neoplasms (MCN) were correctly classified more frequently by the algorithm than clinical diagnosis (96% vs 30%; p < 0.000008 and 92% vs 69%; p = 0.04, respectively). In the surveillance cohort, the algorithm predicted a preoperative diagnosis with high confidence based on a high biomarker score and/or consistency with imaging from ≥1 follow-up visits., Conclusions: A biomarker risk score-based algorithm was able to correctly classify pancreatic cysts preoperatively. Importantly, this tool may improve initial and dynamic risk stratification, reducing overdiagnosis and underdiagnosis., (Copyright © 2021 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: As the world responds to COVID-19 and aims for the Sustainable Development Goals, the potential for primary healthcare (PHC) is substantial, although the trends and effectiveness of PHC expenditure are unknown. We estimate PHC expenditure for each low-income and middle-income country between 2000 and 2017 and test which health outputs and outcomes were associated with PHC expenditure., Methods: We used three data sources to estimate PHC expenditures: recently published health expenditure estimates for each low-income and middle-income country, which were constructed using 1662 country-reported National Health Accounts; proprietary data from IQVIA to estimate expenditure of prescribed pharmaceuticals for PHC; and household surveys and costing estimates to estimate inpatient vaginal delivery expenditures. We employed regression analyses to measure the association between PHC expenditures and 15 health outcomes and intermediate health outputs., Results: PHC expenditures in low-income and middle-income countries increased between 2000 and 2017, from $41 per capita (95% uncertainty interval $33-$49) to $90 ($73-$105). Expenditures for low-income countries plateaued since 2014 at $17 per capita ($15-$19). As national income increased, the proportion of health expenditures on PHC generally decrease; however, the fraction of PHC expenditures spent via ambulatory care providers grew. Increases in the fraction of health expenditures on PHC was associated with lower maternal mortality rate (p value≤0.001), improved coverage of antenatal care visits (p value≤0.001), measles vaccination (p value≤0.001) and an increase in the Health Access and Quality index (p value≤0.05). PHC expenditure was not systematically associated with all-age mortality, communicable and non-communicable disease (NCD) burden., Conclusion: PHC expenditures were associated with maternal and child health but were not associated with reduction in health burden for other key causes of disability, such as NCDs. To combat changing disease burdens, policy-makers and health professionals need to adapt primary healthcare to ensure continued impact on emerging health challenges., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Introduction: National Health Accounts are a significant source of health expenditure data, designed to be comprehensive and comparable across countries. However, there is currently no single repository of this data and even when compiled major gaps persist. This research aims to provide policymakers and researchers with a single repository of available national health expenditures by healthcare functions (ie, services) and providers of such services. Leveraging these data within statistical methods, a complete set of detailed health expenditures is estimated., Methods: A methodical compilation and synthesis of all available national health expenditure reports including disaggregation by healthcare functions and providers was conducted. Using these data, a Bayesian multivariate regression analysis was implemented to estimate national-level health expenditures by the cross-classification of functions and providers for 195 countries, from 2000 to 2017., Results: This research used 1662 country-years and 110 070 data points of health expenditures from existing National Health Accounts. The most detailed country-year had 52% of the categories of interest reported. Of all health functions, curative care and medical goods were estimated to make up 51.4% (uncertainty interval (UI) 33.2% to 59.4%) and 17.5% (UI 13.0% to 26.9%) of total global health expenditures in 2017, respectively. Three-quarters of the global health expenditures are allocated to three categories of providers: hospital providers (35.4%, UI 30.3% to 38.9%), providers of ambulatory care (25.5%, UI 21.1% to 28.8%) and retailers of medical goods (14.4%, UI 12.4% to 16.3%). As gross domestic product increases, countries spend more on long-term care and less on preventive care., Conclusion: Disaggregated estimates of health expenditures are often unavailable and unable to provide policymakers and researchers a holistic understanding of how expenditures are used. This research aggregates reported data and provides a complete time-series of estimates, with uncertainty, of health expenditures by health functions and providers between 2000 and 2017 for 195 countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: In patients undergoing pancreatoduodenectomy, non-home discharge is common and often results in an unnecessary delay in hospital discharge. This study aimed to develop and validate a preoperative prediction model to identify patients with a high likelihood of non-home discharge following pancreatoduodenectomy., Methods: Patients undergoing pancreatoduodenectomy from 2013 to 2018 were identified using an institutional database. Patients were categorized according to discharge location (home vs. non-home). Preoperative risk factors, including social determinants of health associated with non-home discharge, were identified using Pearson's chi-squared test and then included in a multiple logistic regression model. A training cohort composed of 80% of the sampled patients was used to create the prediction model, and validation carried out using the remaining 20%. Statistical significance was defined as P < 0.05., Results: Seven hundred sixty-six pancreatoduodenectomy patients met the study criteria for inclusion in the analysis (non-home, 126; home, 640). Independent predictors of non-home discharge on multivariable analysis were age, marital status, mental health diagnosis, functional health status, dyspnea, and chronic obstructive pulmonary disease. The prediction model was then used to generate a nomogram to predict likelihood of non-home discharge. The training and validation cohorts demonstrated comparable performances with an identical area under the curve (0.81) and an accuracy of 84%., Conclusion: A prediction model to reliably assess the likelihood of non-home discharge after pancreatoduodenectomy was developed and validated in the present study.

Objective: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression., Design: We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples., Results: Our multiregion whole exome sequencing identified KLF4 , a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs., Conclusion: Hotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway., Competing Interests: Competing interests: LDW receives research support from Applied Materials. VBG is an employee of Personal Genome Diagnostics. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aim: We created a novel, preoperative wellness program (WP) that promotes recovery. This study assessed its impact on patient outcomes after pancreatectomy., Patients and Methods: Pancreatoduodenectomies (PD) and distal pancreatectomies (DP) performed from 2015 to 2018 were reviewed using our institutional NSQIP database. Patients in the WP had their medical conditions optimized and were provided with the following: chlorhexidine, topical mupirocin, incentive spirometer, and immune-nutrition supplements., Results: Out of a total of 669 pancreatectomy patients (411 PD, 258 DP), 308 were enrolled in the WP (188 PD, 120 DP). In the PD subgroup, on multivariable analysis (MVA), the WP patients had shorter lengths of hospital stay (LOS) (12 vs. 10 days, p<0.001). On MVA, WP patients had less post-op transfusion (20 vs. 10%, p=0.027). For the combined groups on MVA, LOS continued to be significant (OR=0.89, 95%CI=0.82-0.97, p<0.007)., Conclusion: A preoperative patient centered WP may reduce the length of stay.

Background & Aims: There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established., Methods: CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined., Results: In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection., Conclusion: CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Vascular endothelial growth factor (VEGF)-A is known to play key biological roles in angiogenesis and vascular permeability. We previously identified VEGF-A as an accurate biomarker of benign pancreatic cystic lesions known as serous cystic neoplasms (SCN). In the present study, we seek to further characterize the expression of VEGF-A and its splice isoforms in different pancreatic cysts including SCN. Patients undergoing surgery were consented for the collection of pancreatic cystic lesion tissue (SCN, pseudocysts, mucinous cysts) and normal adjacent pancreas as well as pancreatic cyst fluid. Following RNA isolation from the tissues, relative VEGF-A gene expression was quantitatively analyzed using real-time PCR (qPCR), and VEGF-A isoform expression was evaluated by reverse transcriptase (RT)-PCR. Relative VEGF-A gene expression was significantly increased in SCN, demonstrating transcriptional upregulation in SCN compared to other pancreatic cyst tissues (P < 0.0001). VEGF-189, -165, -145, and -121 splice variants were detected in both normal adjacent pancreas and pancreatic cystic lesions; the novel VEGF-111 isoform was variably expressed in normal and cyst tissues. Finally, VEGF isoform levels in pancreatic cyst fluid were measured by isoform-specific ELISAs. VEGF-165, -145, and -121 proteins were present in pancreatic cyst fluids; VEGF-165 levels were significantly higher in SCN cyst fluid. Thus, multiple VEGF isoforms were expressed in normal pancreas and pancreatic cysts. Of particular interest are VEGF-145 and -111, which have not previously been described in human pancreas where they may exhibit unique biological activities in health and/or disease., Competing Interests: Declaration of competing interest The authors have no conflict of interests to report., (Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Background: Recognition of the impact of social determinants on health care and surgical outcomes is imperative to improve patient care. This study aims to examine the impact social determinants have on hospital length of stay (LOS) after pancreatoduodenectomy (PD)., Methods: Retrospective review of a prospective American College of Surgeons-National Surgical Quality Improvement Program database identified patients who underwent PD from 2013 to 2018. Patients were categorized by insurance type (public/private/multiple), and electronic medical record review was performed to obtain distance from home, marital status, and race. Public insurance included Medicare and Medicaid; multiple types were defined as public insurance supplemented by a private insurance. Univariable analysis was used to identify potential confounders. Significant differences (P < 0.05) were controlled for using multivariable regression models to examine the effect of variables on LOS., Results: About 813 PDs were included (n = 341 public; n = 238 private; and n = 234 multiple). Patients with public insurance had significantly longer LOS than patients with private on univariate (P < 0.001) and multivariable analyses (P = 0.021) (8 versus 7 d). Patients with multiple insurance types showed significantly increased LOS compared with patients with private on univariable (P < 0.001) and multivariable analyses (P = 0.006) (8 versus 7 d). Single patients had significantly longer LOS compared with married patients on univariable (P = 0.012) and multivariable analyses (P = 0.005) (8 versus 7 d). Distance from home, race, gender, or age did not have a significant impact on LOS., Conclusions: Single patients and patients with public or multiple insurance types are more likely to have longer hospital LOS after PD. These findings will enable physicians to identify patients at risk and target them for enhanced recovery programming., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This study evaluated closure techniques and incisional surgical site complications (SSCs) and incisional surgical site infections (SSIs) after pancreaticoduodenectomy (PD)., Methods: Retrospective review of open PDs from 2015 to 2018 was performed. Outcomes were compared among closure techniques (subcuticular + topical skin adhesive (TSA); staples; subcuticular only). SSCs were defined as abscess, cellulitis, seroma, or fat necrosis. SSIs were defined according to the National Surgical Quality Improvement Program (NSQIP)., Results: Patients with subcuticular + TSA (n = 205) were less likely to develop an incisional SSC (9.8%) compared to staples (n = 139) (20.1%) and subcuticular (n = 74) (16.2%) on univariable analysis (P = 0.024). Multivariable analysis revealed no statistically significant difference in incisional SSC between subcuticular + TSA and subcuticular (P = 0.528); a significant difference remained between subcuticular + TSA and staples (P = 0.014). Unadjusted median length of stay (LOS) (days) was significantly longer for staples (9) vs. subcuticular (8) vs. subcuticular + TSA (7); P < 0.001. Incisional SSIs were evaluated separately according to the NSQIP definition. When comparing rates, the subcuticular + TSA group experienced lower incisional SSIs compared to the other two techniques (4.9% vs. 10.1%, 10.8%). However, this difference was not statistically significant by either univariable or multivariable analysis., Conclusions: Subcuticular suture + TSA reduces the risk of incisional SSCs when compared to staples alone after pancreaticoduodenectomy., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: A proteomic discovery study was performed to determine if urine possesses a unique biosignature that could form the basis for a noninvasive test able to predict intraductal papillary mucinous neoplasm (IPMN) dysplasia., Methods: Urine was collected from patients undergoing surgery for IPMN (72 low/moderate, 27 high-grade/invasive). Quantitative mass spectrometry-based proteomics was performed. Proteins of interest were identified by differential expression analysis followed by principal component analysis., Results: Proteomics identified greater than 4800 urinary proteins. Low/moderate and high-grade/invasive IPMN were distinguished by 188 proteins (P < 0.05). Following principal component analysis and heatmap visualization, vitamin D binding protein (DBP), apolipoprotein A1 (APOA1), and alpha-1 antitrypsin (A1AT) were selected. The proteomic abundance of DBP (median [interquartile range]) was significantly higher for high-grade/invasive than for low/moderate IPMN (219,735 [128,882-269,943] vs. 112,295 [77,905-180,773] normalized reporter ion intensity units; P = 0.001). Similarly, APOA1 was more abundant in the high-grade/invasive than low/moderate groups (235,420 [144,933-371,247] vs 150,095 [103,419-236,591]; P = 0.0007) as was A1AT (567,514 [358,544-774,801] vs 358,393 [260,850-477,882]; P = 0.0006)., Conclusions: Urinary DBP, APOA1, and A1AT represent potential biomarker candidates that may provide a noninvasive means of predicting IPMN dysplastic grade.

Background: Intraductal papillary mucinous neoplasms (IPMN) are precursors of pancreatic cancer. Potential biomarkers of IPMN progression have not been identified in urine. A few urinary biomarkers were reported to be predictive of pancreatic ductal adenocarcinoma (PDAC). Here, we seek to assess their ability to detect high-risk IPMN., Methods: Urine was collected from patients undergoing pancreatic resection and healthy controls. TIMP-1(Tissue Inhibitor of Metalloproteinase-1), LYVE-1(Lymphatic Vessel Endothelial Receptor 1), and PGEM(Prostaglandin E Metabolite) levels were determined by ELISA and analyzed by Kruskal-Wallis., Results: Median urinary TIMP-1 levels were significantly lower in healthy controls (n = 9; 0.32 ng/mg creatinine) compared to PDAC (n = 13; 1.95) but not significantly different between low/moderate-grade (n = 20; 0.71) and high-grade/invasive IPMN (n = 20; 1.12). No significant difference in urinary LYVE-1 was detected between IPMN low/moderate (n = 16; 0.37 ng/mg creatinine) and high/invasive grades (n = 21; 0.09). Urinary PGEM levels were not significantly different between groups., Conclusions: Urinary TIMP-1, LYVE-1, and PGEM do not correlate with malignant potential of pancreatic cysts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: We sought to determine if interleukin (IL)-1β and prostaglandin E2 (PGE2) (inflammatory mediators in pancreatic fluid) together with serum carbohydrate antigen (CA) 19-9 could better predict intraductal papillary mucinous neoplasm (IPMN) dysplasia than individual biomarkers alone., Methods: Pancreatic cyst fluid (n = 92) collected via endoscopy or surgery (2003-2016) was analyzed for PGE2 and IL-1β (enzyme-linked immunosorbent assay). Patients had surgical pathology-proven IPMN. Threshold values (PGE2 [>1100 pg/mL], IL-1β [>20 pg/mL], and serum CA 19-9 [>36 U/mL]) were determined., Results: Levels of IL-1β were higher in high-grade dysplasia (HGD)/invasive-IPMN (n = 42) compared with low/moderate IPMN (n = 37) (median [range], 54.6 [0-2671] vs 5.9 [0-797] pg/mL; P < 0.001; area under curve [AUC], 0.766). Similarly, PGE2 was higher in HGD/invasive IPMN (n = 45) compared with low/moderate IPMN (n = 47) (median [range], 1790 [20-15,180] vs. 140 [10-14,630] pg/mL; P < 0.001; AUC, 0.748). Presence of elevated PGE2 and IL-1β (AUC, 0.789) provided 89% specificity and 82% positive predictive value (PPV) for HGD/invasive IPMN. Elevated levels of all 3 provided 100% specificity and PPV for HGD/invasive IPMN., Conclusions: Cyst fluid PGE2, IL-1β, and serum CA 19-9 in combination optimize specificity and PPV for HGD/invasive IPMN and may help build a panel of markers to predict IPMN dysplasia.

Background: For pancreatic cysts with negative cytology, Integrated Molecular Pathology (IMP) is a malignancy risk score integrating clinical criteria with pancreatic cyst fluid DNA profiling. Aside from main pancreatic duct (MPD) diameter, integrated clinical criteria are not International Consensus Guidelines High-Risk Stigmata. We predicted exclusion of clinical criteria except MPD diameter could simplify the IMP and better distinguish invasive/malignant disease., Methods: Records of >1100 patients with IPMN were reviewed retrospectively. Sensitivity, specificity, and accuracy of conventional IMP for invasive/malignant disease was compared to DNA profile including only MPD ≥10mm (IMP-10.) Invasive outcomes were invasive-IPMN/adenocarcinoma on surgical pathology, pathologic or radiographic evidence of invasive/metastatic disease during surveillance. Malignant outcomes included high grade dysplastic IPMN (HGD-IPMN)., Results: 225 patients who met study criteria underwent 283 IMP evaluations: 98 followed by surgery, 185 followed by ≥ 23 months surveillance. IMP-10 had greater specificity (90.1% vs. 73.7%) and accuracy (89.8% vs. 74.2%) for invasive disease compared to IMP in surgery + surveillance patients, but lower sensitivity (77.8% vs. 88.9%). Trends were similar in surgery patients alone and malignant outcome analyses., Conclusion: IMP-10 excludes less-reliable clinical factors resulting in greater accuracy in predicting invasive/malignant disease and fewer patients with benign disease being recommended for surgery., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The most common type of mucinous pancreatic cyst that may progress to pancreatic cancer is intraductal papillary mucinous neoplasm (IPMN). Low-risk IPMN with low-/moderate-grade dysplasia may be safely watched, whereas high-risk IPMN with high-grade dysplasia or invasive components should undergo resection. However, there is currently no reliable means of making this distinction. We hypothesize that blood concentrations of insulin resistance biomarkers may aid in the differentiation of low- and high-risk IPMN., Methods: Plasma/serum was collected from consented patients undergoing pancreatic resection. IPMN diagnosis and dysplastic grade were confirmed by surgical pathology. The study included 235 IPMN (166 low/moderate grade, 39 high grade, 30 invasive). Circulating levels of leptin, branched chain amino acids (BCAA), and retinol-binding protein-4 (RBP-4) were measured by enzyme-linked immunoassay and correlated with surgical pathology., Results: Circulating leptin levels (mean ± SE) were significantly higher in patients with low/moderate IPMN than in high-grade/invasive IPMN (15,803 ± 1686 vs. 10,275 ± 1228 pg/ml; p = 0.0086). Leptin levels were positively correlated with BMI (r = 0.65, p < 0.0001) and were higher in females (p < 0.0001). Stratified analysis showed that mean leptin levels were significantly different between low/moderate and high/invasive IPMNs only in females (24,383 ± 2748 vs. 16,295 ± 2040 pg/ml; p = 0.020). Conversely, circulating BCAA levels were lower in low/moderate IPMN than in high-grade/invasive IPMN (0.38 ± 0.007 vs. 0.42 ± 0.01 mM; p = 0.011). No significant differences in RBP-4 levels were observed., Conclusions: Circulating leptin in females and BCAA correlates with IPMN dysplastic grade and, if combined with clinical characteristics, have the potential to improve clinical decision-making.

Background: IPMNs are cystic pancreatic lesions with variable malignant potential. Thrombospondin-2 (THBS2)-an endogenous, anti-angiogenic matrix glycoprotein-may modulate tumor progression. We hypothesized that circulating levels of THBS2 could aid in preoperative prediction of malignant IPMN., Methods: Preoperative serum/plasma samples were procured from patients undergoing surgery. Circulating levels of THBS2 were measured (enzyme-linked immunosorbent assay) and compared to surgical pathology IPMN dysplastic grade., Results: 164 patients underwent THBS2 testing (100 Low/Moderate-IPMN; 64 High-Grade/Invasive-IPMN). Circulating THBS2 (mean ± SD) was greater in High-Grade/Invasive-IPMN than Low/Moderate-grade IPMN (26.6 ± 12.7 ng/mL vs. 20.4 ± 8.2 ng/mL; P < 0.001). THBS2 (AUC = 0.65) out-performed CA19-9 (n = 144; AUC = 0.59) in predicting IPMN grade. The combination of THBS2, CA19-9, radiographic main-duct involvement, main-duct diameter, age, sex, and BMI (AUC 0.82; n = 137) provided a good prediction model for IPMN grade., Conclusion: Circulating THBS2 is correlated with IPMN dysplasia grade. THBS2 alone did not strongly predict IPMN grade but rather strengthened prediction models for High-Grade/Invasive IPMN when combined with other clinical/biomarker data., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Predicting malignancy in intraductal papillary mucinous neoplasm remains challenging. Integrated molecular pathology combines pancreatic fluid DNA and clinical factors into a malignant potential score. We sought to determine the utility of DNA components alone in predicting high-grade dysplasia/invasive disease., Methods: We reviewed prospectively the records from 1,106 patients with intraductal papillary mucinous neoplasm. We excluded non-intraductal papillary mucinous neoplasm cases and cases with definitive malignant cytology. A total 225 patients had 283 DNA profiles (98 followed by surgery, 185 followed by ≥23-month surveillance). High-grade dysplasia/invasive outcomes were high-grade dysplasia, intraductal papillary mucinous neoplasm-invasive, and adenocarcinoma on surgical pathology or mesenteric or vascular invasion, metastases, or biopsy with high-grade dysplasia or adenocarcinoma during surveillance., Results: High-quantity DNA predicted (P = .004) high-grade dysplasia/invasive disease outcomes with sensitivity of 78.3%, but 52.7% specificity, indicating benign cases may exhibit high-quantity DNA. High clonality loss of heterozygosity of tumor suppressor genes was 98.0% specific, strongly predicted high-grade dysplasia/invasive disease but lacked sensitivity (20.0%). High-quantity DNA + high clonality loss of heterozygosity had 99.0% specificity for high-grade dysplasia/invasive disease. KRAS mutation alone did not predict high-grade dysplasia/invasive disease, but, when combined with high-quantity DNA (specificity 84.7%) and high clonality loss of heterozygosity (specificity 99.0%) strongly predicted high-grade dysplasia/invasive outcomes., Conclusion: Certain DNA components are highly specific for high-grade dysplasia/invasive disease and may indicate aggressive lesions, requiring resection when cytology fails., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The most widely accepted biochemical test for preoperative differentiation of mucinous from benign, nonmucinous pancreatic cysts is cyst fluid carcinoembryonic antigen. However, the diagnostic accuracy of carcinoembryonic antigen ranges from 70% to 86%. Based on previous work, we hypothesize that pancreatic cyst fluid glucose may be an attractive alternative to carcinoembryonic antigen., Methods: Pancreatic cyst fluid was collected during endoscopic or operative intervention. Diagnoses were pathologically confirmed. Glucose and carcinoembryonic antigen were measured using a patient glucometer and automated analyzer/enzyme-linked immunosorbent assay. Sensitivity, specificity, accuracy, and receiver operator characteristic analyses were performed., Results: Cyst fluid samples from 153 patients were evaluated (mucinous: 25 mucinous cystic neoplasms, 77 intraductal papillary mucinous neoplasms, 4 ductal adenocarcinomas; nonmucinous: 21 serous cystic neoplasms, 9 cystic neuroendocrine tumors, 14 pseudocysts, 3 solid pseudopapillary neoplasms). Median cyst fluid glucose was lower in mucinous versus nonmucinous cysts (19 vs 96 mg/dL; P < .0001). With a threshold of ≤ 50 mg/dL, cyst fluid glucose was 92% sensitive, 87% specific, and 90% accurate in diagnosing mucinous pancreatic cysts. In comparison, cyst fluid carcinoembryonic antigen with a threshold of >192 ng/mL was 58% sensitive, 96% specific, and 69% accurate. Area under the curve for glucose and CEA were similar at 0.91 and 0.92., Conclusion: Cyst fluid glucose has significant advantages over carcinoembryonic antigen and should be considered for use as a routine diagnostic test for pancreatic mucinous cysts., (Copyright © 2017. Published by Elsevier Inc.)

Despite dramatic growth between 1990 and 2010, development assistance for health from high-income countries and development agencies to low- and middle-income countries has stagnated, and proposed cuts make future funding uncertain. To further understand international financial flows for health, we examined international contributions from major donor countries. Our findings showed that the United States provided more development assistance for health than any other country, but it provided less than others relative to national population, government spending, and income. Norway, Denmark, Luxembourg, and the United Kingdom stand out when the provision of health assistance is considered relative to these other factors. Seventeen of twenty-three countries did not reach a target that corresponds to an international goal. If all twenty-three countries had reached this goal, an additional $13.3 billion would have been available for global health in 2016. Systematic efforts are needed to encourage countries to meet these targets. Sustained health improvement in low- and middle-income countries will benefit greatly from ongoing international support.

Importance: Health care spending in the United States increased substantially from 1995 to 2015 and comprised 17.8% of the economy in 2015. Understanding the relationship between known factors and spending increases over time could inform policy efforts to contain future spending growth., Objective: To quantify changes in spending associated with 5 fundamental factors related to health care spending in the United States: population size, population age structure, disease prevalence or incidence, service utilization, and service price and intensity., Design and Setting: Data on the 5 factors from 1996 through 2013 were extracted for 155 health conditions, 36 age and sex groups, and 6 types of care from the Global Burden of Disease 2015 study and the Institute for Health Metrics and Evaluation's US Disease Expenditure 2013 project. Decomposition analysis was performed to estimate the association between changes in these factors and changes in health care spending and to estimate the variability across health conditions and types of care., Exposures: Change in population size, population aging, disease prevalence or incidence, service utilization, or service price and intensity., Main Outcomes and Measures: Change in health care spending from 1996 through 2013., Results: After adjustments for price inflation, annual health care spending on inpatient, ambulatory, retail pharmaceutical, nursing facility, emergency department, and dental care increased by $933.5 billion between 1996 and 2013, from $1.2 trillion to $2.1 trillion. Increases in US population size were associated with a 23.1% (uncertainty interval [UI], 23.1%-23.1%), or $269.5 (UI, $269.0-$270.0) billion, spending increase; aging of the population was associated with an 11.6% (UI, 11.4%-11.8%), or $135.7 (UI, $133.3-$137.7) billion, spending increase. Changes in disease prevalence or incidence were associated with spending reductions of 2.4% (UI, 0.9%-3.8%), or $28.2 (UI, $10.5-$44.4) billion, whereas changes in service utilization were not associated with a statistically significant change in spending. Changes in service price and intensity were associated with a 50.0% (UI, 45.0%-55.0%), or $583.5 (UI, $525.2-$641.4) billion, spending increase. The influence of these 5 factors varied by health condition and type of care. For example, the increase in annual diabetes spending between 1996 and 2013 was $64.4 (UI, $57.9-$70.6) billion; $44.4 (UI, $38.7-$49.6) billion of this increase was pharmaceutical spending., Conclusions and Relevance: Increases in US health care spending from 1996 through 2013 were largely related to increases in health care service price and intensity but were also positively associated with population growth and aging and negatively associated with disease prevalence or incidence. Understanding these factors and their variability across health conditions and types of care may inform policy efforts to contain health care spending.

Background: With the increased frequency of diagnostic imaging, pancreatic cysts are now detected in >3% of American adults. Most of these are intraductal papillary mucinous neoplasms (IPMNs) with well-established but variable malignant potential. A biomarker that predicts malignant potential or dysplastic grade would help determine which IPMNs require removal and which can be observed safely. We previously reported that pancreatic fluid prostaglandin E 2 (PGE 2 ) levels might have promise as a predictor of IPMN dysplasia and we seek to validate those results in the current study., Study Design: Pancreatic cyst/duct fluid was prospectively collected from 100 patients with IPMN undergoing pancreatic resection. Surgical pathology revealed 47 low-/moderate-grade, 34 high-grade, and 20 invasive IPMNs. The PGE 2 levels were assessed by ELISA and correlated with IPMN dysplasia grade, demographics, clinical radiologic/pathologic variables, acute/chronic pancreatitis, and NSAID use., Results: Mean pancreatic cyst fluid PGE 2 levels in high-grade and invasive IPMNs were significantly higher than low-/moderate-grade IPMNs (3.5 and 4.4 pg/μL, respectively, vs 1.2 pg/μL; p < 0.0016). At a threshold of 1.1 pg/μL, PGE 2 was 63% sensitive, 79% specific, and 71% accurate for detection of high-grade/invasive IPMNs. When tested in the subset of IPMN patients with preoperative pancreatic cyst fluid CEA >192 ng/mL, PGE 2 at a threshold of 0.5 pg/μL demonstrated 78% sensitivity, 100% specificity, and 86% accuracy for detection of high-grade/invasive IPMN., Conclusions: Our results validate pancreatic cyst fluid PGE 2 as an indicator of IPMN dysplasia, especially in select patients with preoperative pancreatic cyst fluid CEA >192 ng/mL. The inclusion of PGE 2 /CEA in a diagnostic biomarker panel can facilitate more optimal treatment stratification of IPMN patients., (Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types., Competing Interests: Conflict of interest statement: C.M.S. and M.T.Y.-S. are founders and coowners of B9, Inc. and have no conflicts of interest with respect to the new technology described in this article. N.P., K.W.K., and B.V. are founders of Personal Genome Diagnostics, Inc. and PapGene, Inc. K.W.K. and B.V. are members of the Scientific Advisory Board of Sysmex-Inostics and Morphotek. B.V. is also a member of the Scientific Advisory Board of Exelixis GP. These companies and others have licensed technologies from Johns Hopkins, including those related to early diagnostics. N.P., K.W.K., and B.V. are the inventors of some of these technologies and receive equity or royalties from their licenses. The terms of these arrangements are being managed by the university in accordance with its conflict of interest policies. N.P., K.W.K., and B.V. have no conflicts of interest with respect to the new technology described in this article, as defined by the Johns Hopkins University policy on conflict of interest.

Under-five mortality in Zambia has declined since 1990, with reductions accelerating after 2000. Zambia's scale-up of malaria control is viewed as the driver of these gains, but past studies have not fully accounted for other potential factors. This study sought to systematically evaluate the impact of malaria vector control on under-five mortality. Using a mixed-effects regression model, we quantified the relationship between malaria vector control, other priority health interventions, and socioeconomic indicators and district-level under-five mortality trends from 1990 to 2010. We then conducted counterfactual analyses to estimate under-five mortality in the absence of scaling up malaria vector control. Throughout Zambia, increased malaria vector control coverage coincided with scaling up three other interventions: the pentavalent vaccine, exclusive breast-feeding, and prevention of mother-to-child transmission of HIV services. This simultaneous scale-up made statistically isolating intervention-specific impact infeasible. Instead, in combination, these interventions jointly accelerated declines in under-five mortality by 11% between 2000 and 2010. Zambia's scale-up of multiple interventions is notable, yet our findings highlight challenges in quantifying program-specific impact without better health data and information systems. As countries aim to further improve health outcomes, there is even greater need-and opportunity-to strengthen routine data systems and to develop more rigorous evaluation strategies.

Purpose: Pancreatic cysts are estimated to be present in 2%-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts. Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 μL of cyst fluid. Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity. Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions. Clin Cancer Res; 23(16); 4865-74. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Accurate differentiation of pancreatic cystic lesions is important for pancreatic cancer early detection and prevention as well as avoidance of unnecessary surgical intervention. Serous cystic neoplasms (SCN) have no malignant potential, but may mimic premalignant mucinous cystic lesions: mucinous cystic neoplasm (MCN) and intraductal papillary mucinous neoplasm (IPMN). We recently identified vascular endothelial growth factor (VEGF)-A as a novel pancreatic fluid biomarker for SCN. We hypothesize that combining cyst fluid carcinoembryonic antigen (CEA) with VEGF-A will improve the diagnostic accuracy of VEGF-A., Methods: Pancreatic cyst/duct fluid was collected from consenting patients undergoing surgical cyst resection with corresponding pathologic diagnoses. Pancreatic fluid VEGF-A and CEA levels were detected by ELISA., Results: One hundred forty-nine patients with pancreatic cystic lesions met inclusion criteria. Pathologic diagnoses included pseudocyst (n=14), SCN (n=26), MCN (n=40), low/moderate grade IPMN (n=34), high grade IPMN (n=20), invasive IPMN (n=10) and solid pseudopapillary neoplasm (n=5). VEGF-A was significantly elevated in SCN cyst fluid compared to all other diagnoses (p<0.001). With a threshold of >5,000 pg/ml, VEGF-A alone has 100% sensitivity and 83.7% specificity to distinguish SCN from other cystic lesions. With a threshold of ≤10ng/ml, CEA alone identifies SCN with 95.5% sensitivity and 81.5% specificity. Sensitivity and specificity of the VEGF-A/CEA combination are 95.5% and 100% respectively. The c-statistic increased from 0.98 to 0.99 when CEA was added to VEGF-A alone in the ROC analysis., Conclusions: Although VEGF-A alone is a highly accurate test for SCN, the combination of VEGF-A with CEA approaches the gold-standard of pathologic diagnosis, thus importantly avoiding false positives. Patients with a positive test indicating benign SCN can be spared a high risk surgical pancreatic resection., (Copyright © 2017. Published by Elsevier Inc.)

Background: Disbursements of development assistance for health (DAH) have risen substantially during the past several decades. More recently, the international community's attention has turned to other international challenges, introducing uncertainty about the future of disbursements for DAH., Methods: We collected audited budget statements, annual reports, and project-level records from the main international agencies that disbursed DAH from 1990 to the end of 2015. We standardised and combined records to provide a comprehensive set of annual disbursements. We tracked each dollar of DAH back to the source and forward to the recipient. We removed transfers between agencies to avoid double-counting and adjusted for inflation. We classified assistance into nine primary health focus areas: HIV/AIDS, tuberculosis, malaria, maternal health, newborn and child health, other infectious diseases, non-communicable diseases, Ebola, and sector-wide approaches and health system strengthening. For our statistical analysis, we grouped these health focus areas into two categories: MDG-related focus areas (HIV/AIDS, tuberculosis, malaria, child and newborn health, and maternal health) and non-MDG-related focus areas (other infectious diseases, non-communicable diseases, sector-wide approaches, and other). We used linear regression to test for structural shifts in disbursement patterns at the onset of the Millennium Development Goals (MDGs; ie, from 2000) and the global financial crisis (impact estimated to occur in 2010). We built on past trends and associations with an ensemble model to estimate DAH through the end of 2040., Findings: In 2015, US$36·4 billion of DAH was disbursed, marking the fifth consecutive year of little change in the amount of resources provided by global health development partners. Between 2000 and 2009, DAH increased at 11·3% per year, whereas between 2010 and 2015, annual growth was just 1·2%. In 2015, 29·7% of DAH was for HIV/AIDS, 17·9% was for child and newborn health, and 9·8% was for maternal health. Linear regression identifies three distinct periods of growth in DAH. Between 2000 and 2009, MDG-related DAH increased by $290·4 million (95% uncertainty interval [UI] 174·3 million to 406·5 million) per year. These increases were significantly greater than were increases in non-MDG DAH during the same period (p=0·009), and were also significantly greater than increases in the previous period (p<0·0001). Between 2000 and 2009, growth in DAH was highest for HIV/AIDS, malaria, and tuberculosis. Since 2010, DAH for maternal health and newborn and child health has continued to climb, although DAH for HIV/AIDS and most other health focus areas has remained flat or decreased. Our estimates of future DAH based on past trends and associations present a wide range of potential futures, although our mean estimate of $64·1 billion (95% UI $30·4 billion to $161·8 billion) shows an increase between now and 2040, although with a large uncertainty interval., Interpretation: Our results provide evidence of two substantial shifts in DAH growth during the past 26 years. DAH disbursements increased faster in the first decade of the 2000s than in the 1990s, but DAH associated with the MDGs increased the most out of all focus areas. Since 2010, limited growth has characterised DAH and we expect this pattern to persist. Despite the fact that DAH is still growing, albeit minimally, DAH is shifting among the major health focus areas, with relatively little growth for HIV/AIDS, malaria, and tuberculosis. These changes in the growth and focus of DAH will have critical effects on health services in some low-income countries. Coordination and collaboration between donors and domestic governments is more important than ever because they have a great opportunity and responsibility to ensure robust health systems and service provision for those most in need., Funding: Bill & Melinda Gates Foundation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To better understand the global response to HIV/AIDS, this study tracked development assistance for HIV/AIDS at a granular, program level., Methods: We extracted data from the Institute for Health Metrics and Evaluation's Financing Global Health 2015 report that captured development assistance for HIV/AIDS from 1990 to 2015 for all major bilateral and multilateral aid agencies. To build on these data, we extracted additional budget data, and disaggregated development assistance for HIV/AIDS into nine program areas, including prevention, treatment, and health system support., Results: Since 2000, $109.8 billion of development assistance has been provided for HIV/AIDS. Between 2000 and 2010, development assistance for HIV/AIDS increased at an annualized rate of 22.8%. Since 2010, the annualized rate of growth has dropped to 1.3%. Had development assistance for HIV/AIDS continued to climb after 2010 as it had in the previous decade, $44.8 billion more in development assistance would have been available for HIV/AIDS. Since 1990, treatment and prevention were the most funded HIV/AIDS program areas receiving $24.6 billion and $22.7 billion, respectively. Since 2010, these two program areas and HIV/AIDS health system strengthening have continued to grow, marginally, with majority support from the US government and the Global Fund. An average of $252.9 of HIV/AIDS development assistance per HIV/AIDS prevalent case was disbursed between 2011 and 2013., Conclusion: The scale-up of development assistance for HIV/AIDS from 2000 to 2010 was unprecedented. During this period, international donors prioritized HIV/AIDS treatment, prevention, and health system support. Since 2010, funding for HIV/AIDS has plateaued.

A systematic study to identify the factors influencing the cytotoxicity of α-methylene-γ-hydroxy esters against three pancreatic cancer cell lines (Panc-1, MIA-PaCa-2, and BxPC-3) has established that, in addition to Michael acceptor abilities, the possibility to lactonize to α-methylene-γ-butyrolactones is as important. The substitution pattern and the number of carbons between the hydroxy and ester moieties also influence the bio-activity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Characterizing the morphology of the carpometacarpal (CMC) joint bones and how they vary across the population is important for understanding the functional anatomy and pathology of the thumb. The purpose of this paper was to develop a statistical shape model of the trapezium and first metacarpal bones to characterize the size and shape of the whole bones across a cohort of 50. We used this shape model to investigate the effects of sex and age on the size and shape of the CMC joint bones and the articulating surface area of the CMC joint. We hypothesized that women have similar shape trapezium and first metacarpal bones compared to men, following scaling for overall size. We also hypothesized that age would be a significant predictor variable for CMC joint bone changes. CT image data and segmented point clouds of 50 CMC bones from healthy adult men and women were obtained from an ongoing study and used to generate two statistical shape models. Statistical analysis of the principal component weights of both models was performed to investigate morphological sex and age differences. We observed sex differences, but were unable to detect any age differences. Between men and women the only difference in morphology of the trapezia and first metacarpal bones was size. These findings confirm our first hypothesis, and suggest that the women have similarly shaped trapezium and first metacarpal bones compared to men. Furthermore, our results reject our second hypothesis, indicating that age is a poor predictor of CMC joint morphology., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Mucinous pancreatic cysts (intraductal papillary mucinous neoplasm and mucinous cystic neoplasm) have the potential to progress to invasive pancreatic adenocarcinoma, presenting an opportunity for early detection, prevention, and cure. Serous cystic neoplasms (SCN) have no malignant potential, but can mimic mucinous pancreatic cysts on imaging. Therefore, identification of biomarkers that can distinguish between cystic lesions is critically important. We hypothesize that vascular endothelial growth factor (VEGF)-A levels in pancreatic fluid correlate with pathologic diagnosis., Study Design: Pancreatic cyst/duct fluid samples were prospectively collected from patients undergoing pancreatic resection and correlated with surgical pathology. VEGF levels were detected by ELISA. VEGF-A and VEGF receptor 2 expression in pancreatic tissue was localized by immunohistochemistry. Genetic alterations of the von Hippel-Lindau gene were determined by targeted next-generation sequencing., Results: Eighty-seven patients met inclusion criteria for enrollment. Final pathologic diagnoses included pseudocyst (n = 9), SCN (n = 17), mucinous cystic neoplasm (n = 24), low/moderate grade intraductal papillary mucinous neoplasm (n = 16), high-grade/invasive intraductal papillary mucinous neoplasm (n = 10), and pancreatic ductal adenocarcinoma (n = 11). VEGF-A was significantly upregulated in SCN cyst fluid compared with all other diagnoses (p < 0.0001). With a cut-off of 8,500 pg/mL, VEGF-A has 100% sensitivity and 97% specificity as an SCN biomarker. VEGF-A and VEGF receptor 2 are overexpressed in SCN cyst tissue. VEGF-C was also significantly elevated in SCN cyst fluid (p < 0.0001). With a cut-off set at 200 pg/mL, VEGF-C identifies SCN with 100% sensitivity and 90% specificity. The presence of a von Hippel-Lindau mutation in SCN cyst tissue correlates with elevated cyst fluid VEGF levels., Conclusions: This is the first report of a cyst fluid protein biomarker that can positively identify SCN. The ability to distinguish SCN from premalignant/malignant pancreatic cysts can spare the cost and risk of surveillance and surgical intervention in select patients., (Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Alcohol consumption promotes hepatocellular carcinoma (HCC). The responsible mechanisms are not well understood. Hepatocarcinogenesis increases with age and is enhanced by factors that impose a demand for liver regeneration. Because alcohol is hepatotoxic, habitual alcohol ingestion evokes a recurrent demand for hepatic regeneration. The alcohol-preferring (P) rat model mimics the level of alcohol consumption by humans who habitually abuse alcohol. Previously, we showed that habitual heavy alcohol ingestion amplified age-related hepatocarcinogenesis in P rats, with over 80% of alcohol-consuming P rats developing HCCs after 18 months of alcohol exposure, compared with only 5% of water-drinking controls., Methods: Herein, we used quantitative real-time PCR and quantitative immunocytochemistry to compare liver tissues from alcohol-consuming P rats and water-fed P rat controls after 6, 12, or 18 months of drinking. We aimed to identify potential mechanisms that might underlie the differences in liver cancer formation and hypothesized that chronic alcohol ingestion would activate Hedgehog (HH), a regenerative signaling pathway that is overactivated in HCC., Results: Chronic alcohol ingestion amplified age-related degenerative changes in hepatocytes, but did not cause appreciable liver inflammation or fibrosis even after 18 months of heavy drinking. HH signaling was also enhanced by alcohol exposure, as evidenced by increased levels of mRNAs encoding HH ligands, HH-regulated transcription factors, and HH target genes. Immunocytochemistry confirmed increased alcohol-related accumulation of HH ligand-producing cells and HH-responsive target cells. HH-related regenerative responses were also induced in alcohol-exposed rats. Three of these processes (i.e., deregulated progenitor expansion, the reverse Warburg effect, and epithelial-to-mesenchymal transitions) are known to promote cancer growth in other tissues., Conclusions: Alcohol-related changes in Hedgehog signaling and resultant deregulation of liver cell replacement might promote hepatocarcinogenesis., (Copyright © 2013 by the Research Society on Alcoholism.)