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Introduction Lumen apposing metal stents (LAMS) have been used increasingly for drainage of pancreatic fluid collections (PFC). We present an international, multicenter study evaluating the safety and efficacy of LAMS in PFCs. Methods Consecutive patients undergoing LAMS placement for PFC at 12 international centers were included ( ClinicalTrials.gov NCT01522573). Demographics, clinical history, and procedural details were recorded. Technical success was defined as successful LAMS deployment. Clinical success was defined as PFC resolution at three-month follow-up. Results 192 patients were included (140 males (72.9%), mean-age 53.8 years), with mean follow-up of 4.2 months ± 3.8. Mean PFC size was 11.9 cm (range 2–25). The median number of endoscopic interventions was 2 (range 1–14). Etiologies for PFC were gallstone (n = 82, 42.7%), alcohol (n = 50, 26%), idiopathic (n = 26, 13.5%), and other (n = 34, 17.7%). Technical success was achieved in 189 patients (98.4%). Clinical success was observed in 125 of 135 patients (92.6%). Adverse events included bleeding (n = 11, 5.7), infection (n = 2, 1%), and perforation (n = 2, 1%). Three or more endoscopy sessions were a positive predictor for PFC resolution and the only significant predictor for AEs. Conclusion LAMS has a high technical and clinical success rate with a low rate of AEs. PFC drainage via LAMS provides a minimally invasive, safe, and efficacious procedure for PFC resolution.

Mammography guidelines have weakened in response to evidence that mammograms diagnose breast cancers that would never eventually cause symptoms, a phenomenon called "overdiagnosis." Given concerns about overdiagnosis, instead of recommending mammograms, US guidelines encourage women aged 40-49 to get them as they see fit. To assess whether these guidelines target women effectively, I propose an approach that examines mammography behavior within an influential clinical trial that followed participants long enough to find overdiagnosis. I find that women who are more likely to receive mammograms are healthier and have higher socioeconomic status. More importantly, I find that the 20-year level of overdiagnosis is at least 3.5 times higher among women who are most likely to receive mammograms. At least 36% of their cancers are overdiagnosed. These findings imply that US guidelines encourage mammograms among healthier women who are more likely to be overdiagnosed by them. Guidelines in other countries do not.

INTRODUCTION Gene fusions are often disease-defining events in cancer. The mutational processes that give rise to fusions, their timing relative to initial diagnosis, and whether they change at relapse are largely unknown. Mutational processes leave distinct marks in the tumor genome, meaning that DNA sequencing can be used to reconstruct how fusions are generated. A prototypical fusion-driven tumor is Ewing sarcoma (ES), a bone cancer predominantly affecting children and young adults. ES is defined by fusions involving EWSR1 , a gene encoding an RNA binding protein, and genes encoding E26 transformation-specific (ETS) transcription factors such as FLI1 . We sought to reconstruct the genomic events that give rise to EWSR1-ETS fusions in ES and chart their evolution from diagnosis to relapse. RATIONALE We studied the processes underpinning gene fusions in ES using the whole-genome sequences of 124 primary tumors. We determined the timing of the emergence of EWSR1 fusions relative to other mutations. To measure ongoing mutation rates and evolutionary trajectories of ES, we studied the genomes of primary tumors, tumors at relapse, and metastatic tumors. RESULTS We found that EWSR1-ETS , the key ES fusion, arises in 42% of cases via complex, loop-like rearrangements called chromoplexy, rather than by simple reciprocal translocations. Similar loops forming canonical fusions were found in three other sarcoma types. Timing the emergence of loops revealed that they occur as bursts in early replicating DNA, as a primary event in ES development. Additional gene disruptions are generated concurrently with the fusions within the loops. Chromoplexy-generated EWSR1 fusions appear to be associated with an aggressive form of the disease and a higher chance of relapse. Numerous mutations present in every cell of the primary were absent at relapse, demonstrating that the primary and relapsed diseases evolved independently. This divergence occurs after formation of an ancestral clone harboring EWSR1 fusions. Importantly, we determined that divergence of the primary tumor and the future relapsed tumor occurs 1 to 2 years before initial diagnosis, as estimated from the number of cell division–associated mutations. CONCLUSION Our findings provide insights into the pathogenesis and natural history of human sarcomas. They reveal complex DNA rearrangements to be a mutational process underpinning gene fusions in a large proportion of ES. Similar observations in other fusion-defined sarcoma types indicate that this process operates more generally. Such complex rearrangements occur preferentially in early replicating and transcriptionally active genomic regions, as evidenced by the additional genes disrupted. EWSR1 fusions arising from chromoplexy correlated with worse clinical outcomes. Formation of the EWSR1 fusion genes is a primary event in the life history of ES. We found evidence of a latency period between this seeding event and diagnosis. This is in keeping with the often-indolent nature of symptoms before clinical disease presentation.

A fundamental concern for researchers who analyze and design experiments is that the estimate obtained from the experiment might not be externally valid for other policies of interest. Researchers often attempt to assess external validity by comparing data from an experiment to external data. In this paper, I discuss approaches from the treatment effects literature that researchers can use to begin the examination of external validity internally, within the data from a single experiment. I focus on presenting the approaches simply using stylized examples.

A headline result from the Oregon Health Insurance Experiment is that emergency room (ER) utilization increased. A seemingly contradictory result from the Massachusetts health reform is that ER utilization decreased. I reconcile both results by identifying treatment effect heterogeneity within the Oregon experiment and extrapolating it to Massachusetts. Even though Oregon compliers increased their ER utilization, they were adversely selected relative to Oregon never takers, who would have decreased their ER utilization. Massachusetts expanded coverage from a higher level to healthier compliers. Therefore, Massachusetts compliers are comparable to a subset of Oregon never takers, which can reconcile the results.

BACKGROUND Fully-covered self-expandable metal stents (FCSEMS) have been used in benign biliary diseases although reported data is limited. These devices are most commonly used to treat biliary leaks, strictures, or both. The aim of this study was to evaluate effectiveness of FCSEMS in treating benign biliary disease and recognize the associated complications. METHODS We performed a multicenter longitudinal retrospective cohort study of patients with benign biliary disease needing FCSEMS between 2011 and 2016. Descriptive statistics were performed using SPSS version 24 (SPSS Inc, Chicago, IL, USA) and continuous variables were presented as mean±standard deviation. RESULTS 75, 57% M/43% F, with a mean age of 58.5±14.9 years, were included. 64 (85%) had benign strictures, 7 patients had leaks, and 4 patients had both a leak and a stricture. Chronic pancreatitis was the most common cause of BBS (47%) and cholecystectomy was the most common cause of leaks. FCSEMS placement was technically successful in all patients. Four patients died of unrelated causes. A recurrent stricture was observed in 24 (32%) of the patients. Recurrent strictures were most commonly seen in patients with chronic pancreatitis 12/35 (34%). Stent migration occurred in 8/75 patients (10.7%). Seven patients (9.3%) had adverse events, acute pancreatitis (N.=4) was most common. CONCLUSIONS FCSEMS are safe and effective for treating biliary strictures and leaks. We report decreased rates of stent migration compared to previous studies. Prospective studies are needed to compare plastic stents with FCSEMS, determine optimal stent in-dwell times and cost effectiveness of FCSEMS.

Background and Objectives: The ability to obtain adequate tissue of solid pancreatic lesions by EUS-guided remains a challenge. The aim of this study was to compare the performance characteristics and safety of EUS-FNA for evaluating solid pancreatic lesions using the standard 22-gauge needle versus a novel EUS biopsy needle. Methods: This was a multicenter retrospective study of EUS-guided sampling of solid pancreatic lesions between 2009 and 2015. Patients underwent EUS-guided sampling with a 22-gauge SharkCore (SC) needle or a standard 22-gauge FNA needle. Technical success, performance characteristics of EUS-FNA, the number of needle passes required to obtain a diagnosis, diagnostic accuracy, and complications were compared. Results: A total of 1088 patients (mean age = 66 years; 49% female) with pancreatic masses underwent EUS-guided sampling with a 22-gauge SC needle (n = 115) or a standard 22-gauge FNA needle (n = 973). Technical success was 100%. The frequency of obtaining an adequate cytology by EUS-FNA was similar when using the SC and the standard needle (94.1% vs. 92.7%, respectively). The sensitivity, specificity, and diagnostic accuracy of EUS-FNA for tissue diagnosis were not significantly different between two needles. Adequate sample collection leading to a definite diagnosis was achieved by the 1st, 2nd, and 3rd pass in 73%, 92%, and 98% of procedures using the SC needle and 20%, 37%, and 94% procedures using the standard needle (P < 0.001), respectively. The median number of passes to obtain a tissue diagnosis using the SC needle was significantly less as compared to the standard needle (1 and 3, respectively; P < 0.001). Conclusions: The EUS SC biopsy needle is safe and technically feasible for EUS-FNA of solid pancreatic mass lesions. Preliminary results suggest that the SC needle has a diagnostic yield similar to the standard EUS needle and significantly reduces the number of needle passes required to obtain a tissue diagnosis.

Insurance induces a well-known tradeoff between the welfare gains from risk protection and the welfare losses from moral hazard. Empirical work traditionally estimates each side of the tradeoff separately, potentially yielding mutually inconsistent results. I develop a nonlinear budget set model of health insurance that allows for the calculation of both sides of the tradeoff simultaneously, allowing for a relationship between moral hazard and risk protection. An important feature of this model is that it considers nonlinearities in the consumer budget set that arise from deductibles, coinsurance rates, and stoplosses that alter moral hazard as well as risk protection relative to no insurance. I illustrate the properties of my model by estimating it using data on employer sponsored health insurance from a large firm. Within my empirical context, the average deadweight losses from moral hazard substantially outweigh the average welfare gains from risk protection. However, the welfare impact of moral hazard and risk protection are both small relative to transfers from the government through the tax preference for employer sponsored health insurance and transfers from some agents to other agents through a common premium.

Signaling via the pre-T cell antigen receptor (pre-TCR) and the receptor Notch1 induces transient self-renewal (β-selection) of TCRβ(+) CD4(-)CD8(-) double-negative stage 3 (DN3) and DN4 progenitor cells that differentiate into CD4(+)CD8(+) double-positive (DP) thymocytes, which then rearrange the locus encoding the TCR α-chain (Tcra). Interleukin 7 (IL-7) promotes the survival of TCRβ(-) DN thymocytes by inducing expression of the pro-survival molecule Bcl-2, but the functions of IL-7 during β-selection have remained unclear. Here we found that IL-7 signaled TCRβ(+) DN3 and DN4 thymocytes to upregulate genes encoding molecules involved in cell growth and repressed the gene encoding the transcriptional repressor Bcl-6. Accordingly, IL-7-deficient DN4 cells lacked trophic receptors and did not proliferate but rearranged Tcra prematurely and differentiated rapidly. Deletion of Bcl6 partially restored the self-renewal of DN4 cells in the absence of IL-7, but overexpression of BCL2 did not. Thus, IL-7 critically acts cooperatively with signaling via the pre-TCR and Notch1 to coordinate proliferation, differentiation and Tcra recombination during β-selection.

Background: Acinar cell cystadenoma is a rare pancreatic cyst that has been described in several case reports. This lesion may be incidental or asymptomatic, occurs predominately in females, and has a mean age of onset in the fourth decade. Case Presentation: A previously healthy 14-year-old male presented with abdominal pain. He was found to have a pancreatic cystic lesion on ultrasound and cross-sectional imaging. His diagnosis remained uncertain despite additional analysis, including endoscopic ultrasound with fine-needle aspiration. The patient underwent successful laparoscopic excision for definitive diagnosis and management with an unremarkable postoperative course. He was diagnosed with a multilocular acinar cell cystadenoma. Conclusion: Acinar cell cystadenoma is a rare pancreatic cyst whose true malignant potential is unknown. Although there are no formal recommendations for post-operative monitoring and the true risk of recurrence is unknown, we recommended every other year magnetic resonance imaging/magnetic resonance cholangiopancreatography for postresection surveillance for this patient due to the theoretical risk of recurrence with malignant transformation.

Objective: To determine if an implanted neuroprosthesis for restoration of an effective cough is less costly than conventional methods of respiratory management. Methods: Nonrandomized clinical trial of participants (N = 14) with spinal cord injury (SCI) using the Cough Stimulator device in the inpatient hospital setting for Cough Stimulator implantation and outpatient hospital or residence for follow-up. A neuroprosthesis was implanted for restoration of an effective cough. The annual costs associated with respiratory management, without (pre implantation) and with (post implantation) the neuroprosthesis, were examined over a 4-year period. Results: The total cost related to implantation of the Cough Stimulator was $59,891, with no maintenance costs over subsequent years. The incidence of respiratory tract infections and the need for caregiver support fell significantly following implantation. The costs associated with respiratory tract infections fell significantly from a mean of $36,406 ± 11,855/year to $13,284 ± 7,035/year (p < .05) pre and post implantation, respectively. Costs fell further to $8,817 ± 5,990 and $4,467 ± 4,404 following the 2nd and 3rd years post implantation (p < .05), respectively. The costs associated with caregiver support fell significantly from $25,312 ± 8,019/year to $2,630 ± 2,233/year (p < .05) pre and post implantation, respectively, and remained low in subsequent years (p < .05). Other costs related to secretion management fell significantly and remained low in subsequent years (p < .05). Break-even analysis demonstrated that this point was reached in the first year. Conclusion: The results of this investigation demonstrate that implantation and use of the Cough Stimulator resulted in significant reductions in the overall costs of respiratory management in this patient population.

While restoration of inspiratory muscle function to restore breathing in ventilator-dependent spinal cord injured (SCI) subjects is an important clinical modality, restoration of expiratory muscle function may be even more important. Due to paralysis of this muscle group, individuals with SCI are unable to cough effectively, increasing their risk of atelectasis and respiratory tract infections. Restoration of an effective cough has the potential to reduce the incidence of aspiration, need for caregiver support, the occurrence of bronchitis and pneumonia and, also to improve life quality. Current methods of respiratory secretion management produce short-term benefits but are cumbersome, labor intensive, and costly. And, despite use of these methods, respiratory complications remain a major cause of morbidity and mortality in this patient population. Several methods have been proposed to restore expiratory muscle function including magnetic stimulation, surface abdominal muscle stimulation, and spinal cord stimulation (SCS). While each of these methods have their own advantages and disadvantages, SCS has been most thoroughly evaluated, demonstrating that SCS is safe, portable, and effective. Utilizing disc electrodes which are surgically implanted on the epidural dorsal surface of the lower thoracic spinal cord, SCS results in expiratory pressure generation and peak expiratory airflows comparable to that observed in normal subjects. Cough efforts can be generated repetitively and on demand to facilitate expectoration of secretions. Use of this method has been shown to virtually eliminate the need for caregiver support and markedly reduce the incidence of respiratory tract infections. Moreover, a cost benefit analysis has demonstrated that the break-even point for implantation of this device is achieved within the first year. Future developments of this method include use of wire electrodes, which can be implanted using minimally invasive techniques, which eliminate the need for hospitalization and should markedly reduce the costs of the procedure. Ultimately, restoration of an effective cough holds promise to improve life quality and reduce the morbidity and mortality in subjects with SCI.

We develop a model of selection that incorporates a key element of recent health reforms: an individual mandate. We identify a set of key parameters for welfare analysis, allowing us to model the welfare impact of the actual policy as well as to estimate the socially optimal penalty level. Using data from Massachusetts, we estimate the key parameters of the model. We compare health insurance coverage, premiums, and insurer average health claim expenditures between Massachusetts and other states in the periods before and after the passage of Massachusetts health reform. In the individual market for health insurance, we find that premiums and average costs decreased significantly in response to the individual mandate; consistent with an initially adversely selected insurance market. We are also able to recover an estimated willingness-to-pay for health insurance. Combining demand and cost estimates as sufficient statistics for welfare analysis, we find an annual welfare gain of $335 dollars per person or $71 million annually in Massachusetts as a result of the reduction in adverse selection. We also find evidence for smaller post-reform markups in the individual market, which increased welfare by another $107 dollars per person per year and about $23 million per year overall. To put this in perspective, the total welfare gains were 8.4% of medical expenditures paid by insurers. Our model and empirical estimates suggest an optimal mandate penalty of $2,190. A penalty of this magnitude would increase health insurance to near universal levels. Our estimated optimal penalty is higher than the individual mandate penalty adopted in Massachusetts but close to the penalty implemented under the ACA.

In persons with spinal cord injury, lower thoracic low-frequency spinal cord stimulation (LF-SCS; 50 Hz, 15 mA) is a useful method to restore an effective cough. Unfortunately, the high-stimulus-amplitude requirements and potential activation of pain fibers significantly limit this application in persons with intact sensation. In this study, the mechanism of the expiratory muscle activation, via high-frequency SCS (HF-SCS; 500 Hz, 1 mA) was evaluated in dogs. In group 1, the effects of electrode placement on airway pressure generation (P) was evaluated. Maximal P occurred at the T9–T10 level with progressive decrements in P at more rostral and caudal levels for both LF-SCS and HF-SCS. In group 2, electromyographic (EMG) latencies of internal intercostal muscle (II) activation were evaluated before and after spinal root section and during direct motor root stimulation. Onset time of II EMG activity during HF-SCS was significantly longer (3.84 ± 1.16 ms) than obtained during direct motor root activation (1.61 ± 0.10 ms). In group 3, P and external oblique (EO) EMG activity, before and after sequential spinal section at the T11–T12 level, were evaluated. Bilateral dorsal column section significantly reduced EO EMG activity below the section and resulted in a substantial fall in P. Subsequent lateral funiculi section completely abolished those activities and resulted in further reductions in P. We conclude that 1) activation of the expiratory muscles via HF-SCS is dependent entirely on synaptic spinal cord pathways, and 2) HF-SCS at the T9 level produces a comparable level of muscle activation with that achieved with LF-SCS but with much lower stimulus amplitudes. NEW & NOTEWORTHY The findings in the present study suggest that lower thoracic high-frequency spinal cord stimulation with low stimulus currents results in sufficient activation of the expiratory muscles via spinal circuitry to produce large positive airway pressures sufficient to generate an effective cough mechanism. This method, therefore, may be applied in patient populations with intact sensation such as stroke and amyotrophic lateral sclerosis to restore an effective cough.

We uncover political dynamics that reward and reinforce increases in US health spending by studying the passage of the 2003 Medicare Modernization (MMA). We focus on a provision added to the MMA, which allowed hospitals to apply for temporary Medicare payment increases. Hospitals represented by members of Congress who voted ‘Yea’ to the MMA were more likely to receive payment increases. The payment increases raised local health spending and led to suggestive increases in health sector employment. Members of Congress representing hospitals that got a payment increase received large increases in campaign contributions before and after the program was extended.

Background and Aims The obesity epidemic has led to increased use of Roux-en-Y gastric bypass (RYGB). These patients have an increased incidence of pancreaticobiliary diseases, yet standard ERCP is not possible because of surgically altered gastroduodenal anatomy. Laparoscopy-assisted ERCP (LA-ERCP) has been proposed as an option, but supporting data are derived from single-center small case series. Therefore, we conducted a large multicenter study to evaluate the feasibility, safety, and outcomes of LA-ERCP. Methods This is a retrospective cohort study of adult patients with RYGB who underwent LA-ERCP in 34 centers. Data on demographics, indications, procedure success, and adverse events were collected. Procedure success was defined when all the following were achieved: reaching the papilla, cannulating the desired duct, and providing endoscopic therapy as clinically indicated. Results A total of 579 patients (median age, 51; 84% women) were included. Indication for LA-ERCP was biliary in 89%, pancreatic in 8%, and both in 3%. Procedure success was achieved in 98%. Median total procedure time was 152 minutes (interquartile range [IQR], 109-210), with a median ERCP time of 40 minutes (IQR, 28-56). Median hospital stay was 2 days (IQR, 1-3). Adverse events were 18% (laparoscopy related, 10%; ERCP related, 7%; both, 1%) with the clear majority (92%) classified as mild/moderate, whereas 8% were severe and 1 death occurred. Conclusions Our large multicenter study indicates that LA-ERCP in patients with RYGB is feasible with a high procedure success rate comparable with that of standard ERCP in patients with normal anatomy. The ERCP-related adverse events rate is comparable with conventional ERCP, but the overall adverse event rate was higher because of the added laparoscopy-related events.

Numerous studies have demonstrated the effect of lung volume on prolongation of duration of expiration (TE) with limited understanding of the TE shortening and termination of expiration as observed in newborn. In 14 dogs, the effects of varied onset of lung inflation during expiration on the TE were evaluated. When lung inflation was applied in the first part of expiration (20-60% of TE) TE was lengthened. However, in the second portion (60-80% of TE) of expiration, lung inflation either terminated or prolonged TE; whereas in the last portion of expiration (80-90% of TE), lung inflation tended to terminate expiration prematurely. The effects were abolished after bilateral vagotomy. We postulate that prolongation of TE relates to the Breuer-Hering inflation reflex, which increases the time needed for a passive expiration; whereas the ability to shorten TE could relate to Head's paradoxical reflex acting to initiate inspiration or to activate inspiratory motor activity to brake expiratory flow as occurs in the newborn.

Background and Aims: ERCP is challenging in patients with Roux-en-Y gastric bypass (RYGB) anatomy. EUS-guided gastrogastrostomy (GG) creation is a promising novel technique to access the excluded stomach to facilitate conventional ERCP. We aimed to compare procedural outcomes and adverse events (AEs) between EUS-guided GG-assisted ERCP (EUS-GG-ERCP) and enteroscopy-assisted ERCP (e-ERCP) in patients with RYGB. Methods: Patients with RYGB anatomy who underwent EUS-GG-ERCP or e-ERCP between 2014 and 2016 at 5 tertiary centers were included. The primary outcome was technical success of ERCP, defined as successful cannulation of the selected duct with successful intervention as intended. Secondary outcomes included total procedural time (in the EUS-GG group, total procedural time included EUS-GG creation plus ERCP procedure time), length of hospital stay, and rate/severity of AEs graded according to the American Society for Gastrointestinal Endoscopy lexicon. Results: A total of 60 patients (mean age, 57.2 ± 13.2; 75% women) were included, of whom 30 (50%) underwent EUS-GG-ERCP and 30 (50%) underwent e-ERCP (double-balloon enteroscope ERCP, 19; single-balloon enteroscope ERCP, 11). The technical success rate was significantly higher in the EUS-GG-ERCP versus the e-ERCP group (100% vs 60.0%, P

Current diagnostic testing is inadequate to determine the malignant potential of pancreatic cysts, resulting in overcautious patient management. Integrated molecular pathology (IMP) testing combines molecular analysis with first-line test results (cytology, imaging, and fluid chemistry) to assess the malignant potential of pancreatic cysts. This multicenter study aimed to determine the diagnostic accuracy of IMP for pancreatic adenocarcinoma, and the utility of IMP testing under current guideline recommendations for managing pancreatic cysts.Patients who had undergone previous IMP testing as prescribed by their physician and for whom clinical outcomes were available from retrospective record review were included (n = 492). Performance was determined by correlation between clinical outcome and previous IMP diagnosis ("benign"/"statistically indolent" vs. "statistically higher risk [SHR]"/ "aggressive") or an International Consensus Guideline (Sendai 2012) criteria model for "surveillance" vs. "surgery." The Cox proportional hazards model determined hazard ratios for malignancy.Benign and statistically indolent IMP diagnoses had a 97 % probability of benign follow-up for up to 7 years and 8 months from initial IMP testing. SHR and aggressive diagnoses had relative hazard ratios for malignancy of 30.8 and 76.3, respectively (both P 0.0001). Sendai surveillance criteria had a 97 % probability of benign follow-up for up to 7 years and 8 months, but for surgical criteria the hazard ratio was only 9.0 (P 0.0001). In patients who met Sendai surgical criteria, benign and statistically indolent IMP diagnoses had a 93 % probability of benign follow-up, with relative hazard ratios for SHR and aggressive IMP diagnoses of 16.1 and 50.2, respectively (both P 0.0001).IMP more accurately determined the malignant potential of pancreatic cysts than a Sendai 2012 guideline management criteria model. IMP may improve patient management by justifying more relaxed observation in patients meeting Sendai surveillance criteria. IMP can more accurately differentiate between the need for surveillance or surgery in patients meeting Sendai surgical criteria.

Background and Aim Osteopontin (OPN) is a phosphoprotein that activates pathways that induce cancer cell survival and metastasis. Our aim was to examine the expression pattern of OPN splice variants a, b, and c in fine-needle aspirates and to determine their correlation with stage-adjusted pancreatic ductal adenocarcinoma (PDA) survival. Methods Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was performed in patients with solid pancreatic masses. The tissue was collected and analyzed for the expression of OPN isoforms by reverse transcription–polymerase chain reaction. Survival curves of stages and overexpression of OPN splice variants (a, b, c) were estimated according to the Kaplan–Meier and the log-rank test. Results EUS-FNA was performed in 46 patients with solid pancreatic lesions (40 PDA and 6 chronic pancreatitis). OPNa was highly expressed in 39/40 (98%), OPNb in 24/40 (60%), while OPNc was present in 10/40 (25%) of PDA samples. The median survival was lower in patients whose fine-needle aspiration (FNA) samples expressed OPNb than those without (406 days vs 749 days, P = 0.049). There was no significant difference in survival in patients with OPNc. Cox proportional hazard model demonstrated that OPNb expression had a trend toward decrease overall survival (P = 0.06), with these patients having a hazard of death three times higher than those without. OPNc was found to significantly correlate with metastatic disease (P = 0.009) in PDA patients. Conclusions Our data show for the first time that in FNA samples, there is a strong association between OPNc and presence of metastasis in PDA, and OPNb and poor survival.

Only a few studies comparing flea composition on the coast and in the mountains have been conducted. We investigated differences in flea communities infesting small mammals in selected habitats in northern, central and southern Poland. We predicted: (1) a greater number of flea species in the southeastern Poland and a lower number in the north; (2) a greater number of flea species in fertile and wet habitats than in poor and arid habitats; (3) a low similarity of flea species between flea communities in western and eastern Poland. We found negative effect of increasing latitude on flea species richness. We suppose that the mountains providing a variety of environments and the limits of the geographic ranges of several flea subspecies in southeastern Poland, result in a higher number of flea species. There was positive effect of increasing wetness of habitat on flea species richness. We found a high diversity in flea species composition between western and eastern Poland (beta diversity = 11) and between central and eastern Poland (beta diversity = 12). Re-colonization of Poland by small mammals and their ectoparasites from different (western and eastern) refugies can affect on this high diversity of flea species. grant no. SFRH/BD/ 31602/2006 from the Science and Technology Foundation (Portuguese Ministry of Science, Technology and Higher Education); budget of the Department of Systematic Zoology (Faculty of Biology AMU, Poznań) Parasitology Research

Notch activation plays an important role in T cell development and mature T cell differentiation. In this study, we investigated the role of Notch activation in a mouse model of respiratory syncytial virus (RSV)–exacerbated allergic airway disease. During RSV exacerbation, in vivo neutralization of a specific Notch ligand, Delta-like ligand (Dll)-4, significantly decreased airway hyperreactivity, mucus production, and Th2 cytokines. Lunatic Fringe (Lfng), a glycosyltransferase that enhances Notch activation by Dll4, was increased during RSV exacerbation. Lfng loss of function in Th2-skewed cells inhibited Dll4-Notch activation and subsequent IL-4 production. Further knockdown of Lfng in T cells in CD4Cre+Lfngfl/fl mice showed reduced Th2 response and disease pathology during RSV exacerbation. Finally, we identified STAT5-binding cis-acting regulatory element activation as a critical driver of Lfng transcriptional activation. These data demonstrate that STAT5-dependent amplification of Notch-modifying Lfng augments Th2 response via Dll4 and is critical for amplifying viral exacerbation during allergic airway disease.

Molecular characterization of pediatric low-grade gliomas (pLGG) have identified recurrent alterations, most commonly involving BRAF and NF1, which have been exploited to aid in diagnosis and treatment decisions. However, a significant portion do not have these canonical alterations, and the genetics and clinical course of these tumors remains unknown. We molecularly characterized a cohort of 986 patients diagnosed at SickKids from 1990–2017 with comprehensive long-term clinical data. For the rare non-canonical alterations uncovered, data was supplemented with cases from the Taskforce. Within the SickKids cohort, 72% were driven by canonical alterations in either BRAF (38% fusions, 16% V600E) or NF1 (18%). 11.5% were driven via recurrent non-canonical events involving FGFR1 (6%), FGFR2 (1%), MYB (1%), MYBL1 (1%), H3F3A (2%) or IDH1 (0.5%). The Taskforce supplemented cohort revealed that most FGFR1/2 fusions (n=51) were hemispheric and benign, with no deaths observed. In contrast, FGFR1 activating mutations (n=29) were commonly observed as a second hit, occurred throughout the neuraxis, and at an older age. These tumors were more aggressive, having a poor response to therapy and resulting in death. MYB/MYBL1 alterations (n=19) were seen exclusively in angiocentric gliomas and diffuse astrocytomas, respectively. Both are primarily hemispheric and often occur as massive lesions in childhood, yet have excellent long-term outcome. IDH1 (n=8) was seen mostly in adolescents (15–18 years). Importantly, several had a long history of seizures and presented with small lesions years prior to surgery. While all tumours eventually progressed, some (n=6) are alive up to 13 years post diagnosis. H3F3A driven pLGGs (n=12) progressed early, (median 11 months) and all patients succumbed to their disease. The work here represents the largest cohort of non-canonical pLGGs assembled. Our work supports a diagnostic workflow which includes these alterations, and we provide preliminary clinical features of these tumors to better equip practicing clinicians.

In this paper I examine the effects that state policy decisions have had on the early impact of the Affordable Care Act (ACA) using data through the first half of 2014. I focus on the individual health insurance market, which includes plans purchased through exchanges as well as plans purchased directly from insurers. In this market, at least 13.2 million people were covered in the second quarter of 2014, representing an increase of at least 4.2 million beyond pre-ACA state-level trends. I use data on coverage, premiums, and costs and a model developed by Martin Hackmann, Jonathan Kolstad, and myself (forthcoming) to calculate changes in selection and markups, which allow me to estimate the welfare impact of the ACA on participants in the individual health insurance market in each state. I then focus on comparisons across groups of states. The estimates from my model imply that market participants in the five “direct enforcement” states—those that ceded all enforcement of the ACA to the federal government—are experiencing welfare losses of approximately $245 per participant on an annualized basis, relative to participants in all other states. The estimates also imply that the impact of setting up a state exchange depends meaningfully on how well the exchange functions. Market participants in the six states that had severe exchange glitches are experiencing welfare losses of approximately $750 per participant on an annu-alized basis, relative to participants in other states with their own exchanges. Although the national impact of the ACA is likely to change over the course of 2014 as coverage, costs, and premiums evolve, I expect that the differential impacts that are observed across states will persist through the rest of 2014.

Background and aims Limited data are available regarding fully covered metal stents in the management of malignant distal biliary strictures. The aim of this study was to evaluate the safety of a fully covered self-expanding metal stent (FCSEMS) with flared ends, in treating malignant biliary strictures. We report our long-term retrospective analysis from 6 centers. Methods A total of 260 patients (142 males, median age 68 y) underwent endoscopic retrograde cholangiopancreatography with placement of FCSEMS (WallFlex; Boston Scientific, Natick, MA) for the palliation of obstructive jaundice in the setting of pancreatic adenocarcinoma (169), metastatic disease (36), cholangiocarcinoma (23), ampullary cancer (19), or other (13). Patients were evaluated clinically in follow-up and biochemical tests of liver function were obtained. Data were recorded for the following variables: patient survival, duration of stent patency, the need for subsequent biliary intervention, and complications. Results A total of 266 FCSEMS were placed in 260 patients. There was a median survival of 100 days (range, 7 to 531 d). There was a mean follow-up of 134±118 days (range, 4 to 519 d). Biliary decompression was successful in 252 patients (97%). At the end of the study period, 121 were alive with a patent stent, 65 patients died with a patent stent, 40 patients were successfully bridged to surgery, 8 patients had their patent stent removed and had no need for further stenting, and 18 patients were lost to follow-up. Five patients who had a successfully placed FCSEMS were considered a failure due to the following reason: migration (2), cholangitis (1), stent occlusion (1), and removal for management of proximal biliary obstruction (1). Two additional patients experienced migration that did not require FCSEMS removal or replacement. Stent replacement was required in 10 patients, of whom 6 had a second FCSEMS placed. The remaining 4 were in the failure group and underwent replacement with either uncovered stents or plastic stents. Other complications, managed conservatively, included pain (2), postendoscopic retrograde cholangiopancreatography pancreatitis (4), fever (1), retroperitoneal perforation (1), and postsphincterotomy bleeding (1). The mean patency duration was 328 days (SE 19.04). The patency percentage was 83% at 3 months, 63% at 6 months, and 48.5% at 12 months. Conclusions In the management of malignant distal biliary strictures, the fully covered WallFlex stent has acceptable patency and complication rates. Further long-term prospective data are required to confirm this observation.

Diaphragm pacing is a clinically useful modality providing artificial ventilatory support in patients with ventilator dependent spinal cord injury. Since this technique is successful in providing full-time ventilatory support in only ~50% of patients, better methods are needed. In this paper, we review a novel method of inspiratory muscle activation involving the application of electrical stimulation applied to the ventral surface of the upper thoracic spinal cord at high stimulus frequencies (300 Hz). In an animal model, high frequency spinal cord stimulation (HF-SCS) results in synchronous activation of both the diaphragm and inspiratory intercostal muscles. Since this method results in an asynchronous pattern of EMG activity and mean peak firing frequencies similar to those observed during spontaneous breathing, HF-SCS is a more physiologic form of inspiratory muscle activation. Further, ventilation can be maintained on a long-term basis with repetitive stimulation at low stimulus amplitudes (

As demonstrated in a canine model, high frequency spinal cord stimulation (HF-SCS) is a novel and more physiologic method of electrical activation of the inspiratory muscles compared to current techniques. The dog model, however, has significant limitations due to cost and societal concerns. Since the rodent respiratory system is also a relevant model for the study of neuronal circuitry function, the aims of the present study were to a) assess the effects of HF-SCS and b) determine the methodology of application of this technique in rats. In 9 Sprague Dawley rats, diaphragm multiunit and single motor unit EMG activity were assessed during spontaneous breathing and HF-SCS applied on the ventral epidural surface of the spinal cord at the T2 level following C1 spinal section. As in dogs, HF-SCS results in the activation of the diaphragm at physiological firing frequencies and the generation of large inspired volumes. Mean maximum firing frequencies of the diaphragm during spontaneous breathing and HF-SCS were 23.3 ± 1.4 Hz (range: 9.8–51.6 Hz) and 26.6 ± 1.3 Hz; range: 12.0–72.9 Hz, respectively, at comparable inspired volumes. Moreover, HF-SCS was successful in pacing these animals over a 60-min period without evidence of system fatigue. Our results suggest that, similar to the dog model, HF-SCS in the rat results in the activation of spinal cord tracts which synapse with the phrenic motoneuron pool, allowing the processing of the stimulus and consequent physiologic activation of the inspiratory muscles. The rat may be a useful model for further studies evaluating phrenic motoneuron physiology.

Background & Aims Most patients with hilar cholangiocarcinomas present with unresectable tumors, so only palliative biliary drainage with self-expanding metal stents (SEMS) is possible. Stents eventually cease to function because of tumor overgrowth and/or other causes, so it is important to identify factors that affect stent patency and failure. We examined the patency of endoscopically placed SEMS in patients with hilar cholangiocarcinoma and factors associated with patency. Methods We performed a retrospective study of 120 consecutive patients (mean age, 67 ± 14.6 years; 74 male) who presented with obstructive jaundice from hilar cholangiocarcinoma and underwent bilateral SEMS from September 2006 through April 2012 at 2 US tertiary medical centers. We collected data on patient demographics and survival, success of stent placement and function, and immediate adverse events. The primary outcome was duration of stent patency (time from insertion to failure). Results Thirty-eight patients had stage 1 hilar cholangiocarcinomas, 45 had stage 2, 12 had stage 3, and 25 had stage 4. The median length of the hilar stricture was 9 mm (range, 8–50 mm). The stent was successfully passaged across the stricture in all patients and was functional in 115; its median length was 8 mm (range, 8–10 mm), and diameter was 80 mm (range, 60–100 mm). Fourteen patients had immediate adverse events, including perforation (n = 2), bleeding (n = 2), pancreatitis (n = 9), and cholangitis (n = 1). Median survival was 17 weeks (range, 1–211 weeks), and 50 patients had stent occlusion. On Kaplan–Meier analysis, the median time from stent placement to occlusion was 17 weeks (range, 1–104 weeks). More patients with stage 3 or 4 tumors (64%) had SEMS occlusion than patients with stage 1 or 2 tumors (28%) in univariate analysis ( P = .017). In multivariate analysis, only cancer stage was independently and significantly associated with patency ( P = .006; hazard ratio, 2.77); age, sex, length of stricture, and SEMS diameter and length were not. Conclusions The cumulative patency of bilateral SEMS for hilar cholangiocarcinoma significantly decreases as tumor stage increases. Age, sex, length of stricture, and SEMS diameter and length are not associated with SEMS patency.

To use subharmonic imaging (SHI) to depict the vascularity of pancreatic masses compared to contrast-enhanced endoscopic ultrasound (EUS) and pathologic results.Sixteen patients scheduled for biopsy of a pancreatic mass were enrolled in an Institutional Review Board-approved study. Pulse-inversion SHI (transmitting/receiving at 2.5/1.25 MHz) was performed on a LOGIQ 9 system (GE Healthcare, Milwaukee, WI) with a 4C transducer, whereas contrast harmonic EUS (transmitting/receiving at 4.7/9.4 MHz) was performed with a radial endoscope (GF-UTC180; Olympus Corporation, Tokyo, Japan) connected to a ProSound SSD α-10 scanner (Hitachi Aloka, Tokyo, Japan). Two injections of the contrast agent Definity (Lantheus Medical Imaging, North Billerica, MA) were administrated (0.3-0.4 and 0.6-0.8 mL for EUS and SHI, respectively). Contrast-to-tissue ratios (CTRs) in the mass and an adjacent vessel were calculated. Four physicians independently scored the images (benign to malignant) for diagnostic accuracy and inter-reader agreement.One patient dropped out before imaging, leaving 11 adenocarcinomas, 1 gastrointestinal stromal tumor with pancreatic infiltration, and 3 benign masses. Marked subharmonic signals were obtained in all patients, with intratumoral blood flow clearly visualized with SHI. Significantly greater CTRs were obtained in the masses with SHI than with EUS (mean ± SD, 1.71 ± 1.63 versus 0.63 ± 0.89; P = .016). There were no differences in the CTR in the surrounding vessels or when grouped by pathologic results (P .60). The accuracies for contrast EUS and SHI were low (53%), albeit with a greater κ value for SHI (0.34) than for EUS (0.13).Diagnostic accuracy of contrast EUS and transabdominal SHI for assessment of pancreatic masses was quite low in this pilot study. However, SHI had improved tumoral CTRs relative to contrast EUS.

Spinal cord stimulation (SCS, 50Hz) is a useful method to restore an effective cough in persons with spinal cord injury (SCI). However, high stimulus amplitudes and potential activation of pain fibers, significantly limits this application. It is our hypothesis that high frequency SCS (HF-SCS), with low stimulus amplitudes may provide the same level of expiratory muscle activation. In 6 dogs, the effects of SCS, with varying stimulus parameters on positive pressure (P) generation was evaluated. At any given level of stimulus current, mean P was largest at 500Hz, compared to all other stimulus frequencies. For example, with stimulation at 1mA and frequencies of 200, 500 and 600Hz, P were 25±3, 58±4, 51±6cmH2O, respectively. By comparison, P achieved with conventional SCS parameters was 61±5cmH2O. HF-SCS results in a comparable P compared to that achieved with conventional stimulus parameters but with much lower stimulus amplitudes. This method may be useful to restore cough even in subjects with intact sensation.