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Cytotoxic T lymphocytes (CTLs) play an integral role in the adaptive immune response by killing infected cells. Antigen presenting cells (APCs), such as dendritic cells, present pathogenic peptides to the T cell receptor on the CTL surface and co-stimulatory signals required for complete activation. Activated CTLs secrete lytic granules containing enzymes that trigger target cell death at the CTL-target contact, also known as the immune synapse (IS). The actin and microtubule cytoskeletons are instrumental in the killing of CTL targets. Lytic granules are transported along microtubules to the IS, where granule secretion is facilitated by actin depletion and recovery. Furthermore, actomyosin contractility promotes target cell death by mediating mechanical force exertion at the IS. Recent studies have shown that inflammatory cytokines produced by APCs, such as interleukin-12 (IL-12), act as a third signal for CTL activation and enhance CTL proliferation and effector function. However, the biophysical mechanisms mediating such enhanced effector function remain unclear. We hypothesized that the third signal for CTL activation, IL-12, modulates cytoskeletal dynamics and force exertion at the IS, thus potentiating CTL effector function. Here, we used live cell total internal reflection fluorescence (TIRF) microscopy to study actomyosin and microtubule dynamics at the IS of murine primary CTLs activated in the presence of peptide-MHC and co-stimulation alone (two signals), or additionally with IL-12 (three signals). We found that three signal-activated CTLs have altered actin flows, myosin dynamics and microtubule growth rates as compared to two signal-activated CTLs. We further showed that lytic granules in three-signal activated CTLs are less clustered and have lower velocities than in two-signal activated CTLs. Finally, we used traction force microscopy to show that three signal-activated CTLs exert greater traction forces than two signal-activated CTLs. Our results demonstrate that activation of CTLs in the presence of IL-12 leads to differential modulation of the cytoskeleton, thereby augmenting the mechanical response of CTLs to their targets. This indicates a potential physical mechanismviawhich the third signal can enhance the CTL response.

Challenges for data storage during drug development have become increasingly complex as the pharmaceutical industry expands in an environment that requires on-demand availability of data and resources for users across the globe. While the efficiency and relative low cost of cloud services have become increasingly attractive, hesitancy toward the use of cloud services has decreased and there has been a significant shift toward real-world implementation. Within GxP laboratories, the considerations for cloud storage of data include data integrity and security, as well as access control and usage for users around the globe. In this review, challenges and considerations when using cloud storage options for the storage of laboratory-based GxP data are discussed and best practices are defined.

Background: Previous pilot research has investigated differences in elbow valgus torque between the “tall and fall” (TF) and “drop and drive” (DD) pitching styles. Whether one of these pitching styles is associated with a greater rate of ulnar collateral ligament reconstruction (UCLR) is currently unknown. Purpose: To determine the proportion of Major League Baseball (MLB) pitchers using the TF and DD pitching styles who underwent UCLR over a 10-year period. Study Design: Cross-sectional study; Level of evidence, 3. Methods: The demographic characteristics of pitchers who underwent UCLR between 2007 and 2017 were obtained via the open-source database MLB Player Analysis Tommy John Surgery List. Other information, such as previous UCLR and pitching videos and graphics, was obtained from other open-source databases. A comprehensive, 2-dimensional, kinesiology-based multicomponent definition of each pitching style was formulated and used to categorize the included pitchers into the TF and DD groups. Statistical comparisons and contrasts were made using chi-square and Pearson correlation tests. Results: Included were 223 MLB pitchers (mean ± SD age, 27.5 ± 3.6 years; body mass index [BMI], 27.6 ± 2.2; throwing velocity, 92.9 ± 2.6 mph [149.5 ± 4.2 km/h]) who underwent UCLR between 2007 and 2017. Of these pitchers, 162 were categorized as TF pitchers (72.6%) and 61 as DD pitchers (27.4%). Pitching velocity for injured pitchers was significantly correlated to BMI ( P < .001). We found no significant associations of pitching style with year of UCLR ( P = .941), BMI ( P = .549), age ( P = .647), handedness ( P = .501), or average pitch velocity ( P = .921). Conclusion: The study findings demonstrated that a higher proportion of UCL-injured MLB pitchers (72.6%) used the TF pitching style. Further research is needed to explore the potential association between pitching style and UCL injury.

The Prostate Protocol PDF book written by Dr. Scott Davis MD… It addresses the main cause of a disorder which affects a large percentage of the male population in the US. The Prostate Protocol PDF book describes in detail the principles that you should incorporate into your lifestyle. The Prostate Protocol PDF book allows the reader to effectively face the causes and symptoms of this problem.

Evidence has demonstrated that biosynthetic glue for laparoscopic inguinal hernia repair results in decreased pain. However, the two glue sub-types (biologic—fibrin based; synthetic—cyanoacrylate based) have never been compared. This study aims to assess the outcomes of those subtypes. A systematic review of the MEDLINE database was undertaken. Randomized trials assessing the outcomes of laparoscopic inguinal hernia repair with penetrating and glue fixation methods were considered for inclusion and data analysis. Thirteen trials involving 1947 laparoscopic inguinal hernia repairs were identified with eight trials utilizing fibrin and five trials utilizing cyanoacrylate. There were no differences in recurrence or wound infection between the glue subtypes when compared individually to penetrating fixation alone or indirectly to each other. There were non-significant trends in reduction of hematoma and seroma for both glue subtypes when compared to penetrating fixation (OR 0.73, 95% CI 0.39–1.40). There was a significant reduction in urinary retention with glue fixation (pooled results of both sub-types) when compared to penetrating fixation (OR 0.33, 95% CI 0.13–0.83). Glue fixation in laparoscopic inguinal hernia repair reduces the incidence of urinary retention and may reduce the rate of hematoma or seroma formation. As there are no differences in outcomes when comparing fibrin or cyanoacrylate glue, surgeons should choose the glue that is available at the lowest cost at their respective institutions.

Introduction The purpose of this study is to assess how the Hirsch Index (h-index) and other academic metrics change over time for academic minimally invasive surgeons (MIS). Methods Through the Fellowship Council's website, MIS program-directors and associate program-directors were identified in 2017 and again in 2018. Using the Scopus database, the number of publications, citations, self-citations, and h-indices were calculated. Results A total of 222 surgeons were included. The median increase of publications, citations, and h-index were 4, 134, and 1, respectively. 75% of surgeons (166/222) saw their h-index increase. In 2017, 26% of surgeons (57/222) had an increase of their h-index due to self-citation. One-year later, 35% of those surgeons (20/57) no longer demonstrated that change. Conclusion Self-citation remains infrequent within MIS. The h-index of most surgeons will increase over one-year. Many surgeons demonstrating an increase in h-index due to self-citation will see that change eliminated over time.

Background Ionizing radiation is a known cause of female breast cancer, but there have been few studies of the risk after prolonged radiation exposure at low dose rates. Methods This population-based case-control study estimated breast cancer risk after ∼25 years’ exposure to radiation from the Chernobyl accident. Cases (n = 468) were women ≤55 years old when first diagnosed with invasive breast cancer during October 2008 through February 2013, who lived in Bryansk Oblast, Russia at the time of the accident and their diagnoses. Controls, individually matched to cases on birth year, administrative district of residence and urban vs non-urban settlement during the accident, were women without breast cancer who lived in Bryansk Oblast at the time of the accident and on their cases’ diagnosis dates (n = 468). Subjects were interviewed regarding residence, dietary and food source histories to support individualized estimation of their radiation doses to the breast, which ranged from 0.04 − 41 centigray (cGy) (mean 1.3 cGy). Results In multivariable analyses, the odds ratio for breast cancer risk was 3.0 [95% confidence interval (CI): 1.3, 7.0] and 2.7 (95% CI: 1.0, 7.3) in the seventh and eighth dose octiles, respectively, relative to the lowest octile. Analyses of dose effect modification suggested that radiation-related risk may have been higher in women who were younger at the time of the accident and/or at the time of diagnosis. Conclusions This study suggests that prolonged exposure to ionizing radiation at low dose rates can increase risk of breast cancer.

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in either PKD1 or PKD2 genes, is one of the most common human monogenetic disorders and the leading genetic cause of end-stage renal disease. Unfortunately, treatment options for ADPKD are limited. Here we report the discovery and characterization of RGLS4326, a first-in-class, short oligonucleotide inhibitor of microRNA-17 (miR-17), as a potential treatment for ADPKD. RGLS4326 is discovered by screening a chemically diverse and rationally designed library of anti-miR-17 oligonucleotides for optimal pharmaceutical properties. RGLS4326 preferentially distributes to kidney and collecting duct-derived cysts, displaces miR-17 from translationally active polysomes, and de-represses multiple miR-17 mRNA targets including Pkd1 and Pkd2. Importantly, RGLS4326 demonstrates a favorable preclinical safety profile and attenuates cyst growth in human in vitro ADPKD models and multiple PKD mouse models after subcutaneous administration. The preclinical characteristics of RGLS4326 support its clinical development as a disease-modifying treatment for ADPKD., Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of end-stage renal disease with limited treatment options. Here the authors discover and characterize a microRNA inhibitor as a potential treatment for ADPKD.

Objective Pulmonary embolism (PE) following laparoscopic paraesophageal hernia repair (PEHR) is rare but occurs at a higher frequency than other laparoscopic procedures. We describe a series of patients who developed PEs after PEHR in hopes of capturing potential risk factors for further study. Materials and methods Five cases of PE after PEHR were observed between 2017 and 2018. Individual and perioperative risk factors, and postoperative courses were reviewed. Results Patients had a mean age of 73 years (range, 59 to 86). All were female. Two patients presented acutely. Three patients underwent revisional surgery. The average procedure duration was 248 minutes (range, 162 to 324). All patients had gastrostomy tubes placed. The diagnosis of PE occurred within 3 to 19 days postoperatively. Four were treated with 3 months of oral anticoagulation; 1 was managed expectantly. Conclusions Highly complex cases, marked by revisional status, need for mesh, large hernia size, and percutaneous endoscopic gastrostomy placement are likely at increased risk for PEs. Preoperative venous thromboembolism chemoprophylaxis should be considered in the majority of laparoscopic PEHR patients.

This paper measures the effect of monetary tightening in key advanced economies on net capital flows around the world. Measuring this effect is complicated by the fact that the domestic monetary policies of affected economies respond endogenously to the foreign tightening shock. Using a structural VAR framework with quarterly panel data we estimate the impulse responses of domestic policy variables and net capital flows to a foreign monetary tightening shock. We find that the endogenous response of domestic monetary policy depends on each economy’s capital account openness and exchange rate regime. We use a method to compute counterfactual impulse responses for net capital outflows under the assumption that the domestic policy rate does not respond to foreign monetary tightening. Our results suggests that failing to account for the endogenous response of domestic monetary policy biases down the estimated elasticity of net capital flows to foreign interest rates by as much as one-third for countries with open capital accounts.

Based on concerns about the item response theory (IRT) linking approach used in the Programme for International Student Assessment (PISA) until 2012 as well as the desire to include new, more compl...

The mechanisms of early failures in dental implant osseointegration are unclear. A possible cause of low levels of bone formation is lubricant contamination on implants during insertion. To explore the impact of lubricant contamination on dental implants, we used 5 New Zealand rabbits and inserted 2 implants per tibia in each animal for a total of 4 implants per animal (20 implants in total). In general, bicorticalization was achieved. The first implant was placed as suggested by the manufacturer with no lubricant used (control). The second implant was placed using a freshly lubricated contra-angle handpiece, which was used only for the test implants. Implant allocation was randomized, and the examining histologist was blinded to the results. All implants were placed by the same surgeon. The animals were maintained in accordance with animal experimentation guidelines. None of the implants failed to osseointegrate. Moreover, no significant difference was observed between the test and control groups. Based on the results of this study, the use of rotary instrument mineral oil lubricant did not jeopardize the osseointegration of dental implants in New Zealand rabbits.

Objective We evaluated 1-year outcomes after platinum chromium everolimus-eluting stents (PtCr-EES) in small versus non-small coronary arteries within a large, diverse sample of men, women, and minorities. Background There exists limited outcomes data on the use of second-generation drug-eluting stent to treat small diameter coronary arteries. Methods We pooled patients from the PLATINUM Diversity and PROMUS Element Plus stent registries. Small-vessel percutaneous coronary intervention (SV-PCI) was defined as ≥1 target lesion with reference vessel diameter (RVD) ≤2.5 mm. Endpoints included major adverse cardiac event (MACE; death, myocardial infarction [MI] or target vessel revascularization [TVR]), target vessel failure (TVF; death related to the target vessel, target vessel MI or TVR) and definite/probable stent thrombosis (ST). Multivariable Cox regression was used to risk-adjust outcomes. Results We included 4,155/4,182 (99%) patients with available RVD, of which 1,607 (39%) underwent small-vessel PCI. SV-PCI was not associated with increased MACE (adjHR 1.02; 95%CI 0.81-1.30) or TVF (adjHR 1.07; 95%CI 0.82-1.39). MI risk was lower in white men compared to women and minorities, both in the setting of SV-PCI (adjHR 0.41; 95%CI 0.23-0.74 and adjHR 0.39; 95%CI 0.20-0.75, respectively) and for non-SV-PCI (adjHR 0.61; 95%CI 0.38-0.99 and adjHR 0.45; 95%CI 0.27-0.74, respectively). There was no significant interaction between RVD and sex or minority status for any endpoint. Conclusion In a large diverse contemporary PCI outcomes database, SV-PCI with PtCr-EES was not associated with increased MACE or TVR and did not account for the increased MI risk noted in women and minorities compared to white men.

The correlation between capital inflows and outflows has increased substantially over time in a sample of 127 advanced and developing countries. We provide evidence that this is a result of an increase in financial globalization (stock of external assets and liabilities). This dominates the effect of an increase in trade globalization (exports plus imports), which reduces the correlation between capital inflows and outflows. In the context of a two-country model with 8 shocks we show that the theoretical impact of financial and trade globalization on the correlation between capital inflows and outflows is consistent with the data.

Seawater chlorination is widely used for coastal, marine industries for the prevention of fouling. Using a choice chamber system, we investigated the influence of chlorinated seawater at typical concentrations occurring near chlorinated cooling water discharges, on the behaviour of juvenile seabass (Dicentrachus labrax). These studies showed that there was evidence of an effect of chlorination, with models predicting 22% fewer fish present in the chlorine dosed chamber compared to the undosed chamber in all control runs (mean number of fish in the dosed chamber in all control runs was 2.23 in comparison to 1.74 when chlorine was present). These data suggest that when food is available D. labrax will enter areas that are at mean chlorination levels of 0.04 mg l−1, which are typical close to the discharge of power station cooling water but are more likely to move away once the food supply is reduced.

Performance feedback through peer coaching and rigorous self-assessment is a critical part of technical skills improvement. However, formal collaborative programs using operative video-based skills assessments to generate peer coaching feedback have only been validated among attending surgeons. In this study, we developed a unique longitudinal, simulation video-based laparoscopic skills resident curriculum using video-based peer coaching and evaluated its association with skills acquisition among surgical trainees.The laparoscopic simulation curriculum consists of a pre-practice laparoscopic skill video recording, followed by receipt of directed coaching and feedback on performance from a faculty coach, a peer coach, and self-coaching. Residents then completed 6 weeks of feedback-directed practice and submitted a second post-practice laparoscopic skill video recording of the same skill, which was evaluated by a minimally invasive surgery expert grader. All general surgery residents in a single institution were enrolled, with 107 residents completing the curriculum in its initial 2 years.Overall, more than two-thirds of residents achieved skills proficiency on their expert assessments, with similar rates of residents achieving skills proficiency at all postgraduate year levels. Significant improvements between the pre-practice assessments and post-practice assessments were most frequently seen in the instrument handling, precision, and motionflow categories (P.05 each). Faculty provided the highest number and proportion of closed-loop comments; residents' self-coaching feedback had the lowest number of closed-loop comments, with 83% of self-assessments containing none.In this study, we describe the successful implementation of a longitudinal laparoscopic skills video-based coaching curriculum designed to improve residents' laparoscopic technical abilities through iterative directed practice supplemented by formative closed-loop feedback. This feasible, reproducible, and low-cost simulation curriculum can be adapted to other training programs and skills acquisition endeavors. This program also prepares trainees for ongoing performance feedback after completion of residency through rigorous self-assessment and peer-to-peer coaching.

This chapter lays out the historical development of Niebuhr’s thought on war and peace in the context of American history and religious thought. It argues that in his early thought he accepts the received wisdom concerning early Christian non-violence, a position that led him to join the “Fellowship of Reconciliation” in 1928. With the Japanese incursions into China in the early 1930s, however, his position began to shift in ways captured in his early exchange with his brother, H. Richard Niebuhr. By the time he delivered the Gifford Lectures, at the very beginning of the Second World War, he has rejected pacifism and begun to develop the positions associated with ‘Christian Realism’. This extended into the early period of nuclear deterrence, though with increasing qualification. By the early 1960s, the perceived lack of restraint led Paul Ramsey to turn to the Catholic just war tradition to articulate a Reformation doctrine of principled love that could clarify which uses of force were acceptable and which had to be rejected. The tradition of Niebuhr persists, however, in such thinkers as John Carlson, whose Christian realist account of war and peace draws directly from Niebuhr and his legacy.

The collateral channel, whereby an increase in residential house prices leads to an increase in commercial property prices, loosening firm borrowing constraints and increasing firm investment, is weaker when residential and commercial real estate are imperfect substitutes. We enrich the DSGE model of the collateral channel in Liu, Wang, and Zha (2013) by adding a land development sector to allow residential and commercial land to be imperfect substitutes. Bayesian estimation of our structural model based on aggregate U.S. data indicates imperfect substitution between the two types of land. With variance decompositions and impulse responses, we show that the strength of the collateral channel linking residential house prices and firm investment is weaker when the two types of land are imperfect substitutes. When residential and commercial land are assumed to be perfect substitutes, shocks to residential real estate demand explain 20-30% of the variance of total output and 30-40% of the total investment, but with the imperfect degree of substitution that we estimate, the same shocks explain less than 10% of the variance of output and 12-15% of investment.

Background A hyperkinetic gallbladder is defined as a hepatobiliary iminodiacetic acid (HIDA) scan ejection fraction (EF) of >80%. This condition is poorly described, and there is no current consensus on optimal management. The intent of this study was to determine if cholecystectomy improves symptoms in patients with a hyperkinetic gallbladder when compared to those managed nonoperatively and if there were variables predictive of symptom improvement with or without cholecystectomy. Materials and Methods This retrospective study included patients from 3 academic hospitals in the Atlanta metro area between the years 2006 and 2018. All patients with an EF >80% were included. Following voluntary exclusion patients were contacted by phone. Each patient was administered a questionnaire regarding their surgical history, medical management, and current symptom profile via Otago score. Institutional Institutional Review Board approval was obtained. Results 4785 HIDA scans were performed, and 194 reported an EF >80% (incidence 15.7%). 96% of these scans were reported as normal by the radiologist. 68 patients were able to be contacted by phone and completed the questionnaire. 18 patients underwent cholecystectomy, and 89% reported that their symptoms attributed to gallbladder disease were no longer present. 50 patients did not undergo cholecystectomy, and alternate diagnoses, medication prescriptions, diet modification, emergency department visits, and Otago score were higher in this cohort. Discussion Patients who undergo cholecystectomy for a diagnosis of hyperkinetic gallbladder, on average, report improvement in symptoms when compared to patients managed nonoperatively. This study supports the practice of reporting and managing hyperkinetic gallbladders as a pathologic entity.

This paper shows how foreign exchange intervention can be used to avoid a sudden stop in capital flows in a small open emerging market economy. The model is based around the concept of an under-borrowing equilibrium defined by Schmitt-Grohe and Uribe (2020). With a low elasticity of substitution between traded and non-traded goods, real exchange rate depreciation may generate a precipitous drop in aggregate demand and a tightening of borrowing constraints, leading to an equilibrium with an inefficiently low level of borrowing. The central bank can preempt this deleveraging cycle through foreign exchange intervention. Intervention is effective due to frictions in private international financial intermediation. Reserve accumulation has ex ante benefits by reducing the risk of a sudden stop, while intervention has ex-post benefits by limiting inefficient deleveraging. But intervention itself faces constraints. When the central bank’s stock of reserves is low, even foreign exchange intervention cannot prevent a sudden stop.

Background During the COVID-19 pandemic, prioritization of care and utilization of scarce resources are daily considerations in healthcare systems that have never experienced these issues before. Elective surgical cases have been largely postponed, and surgery departments are struggling to correctly and equitably determine which cases need to proceed. A resource to objectively prioritize and track time sensitive cases would be useful as an adjunct to clinical decision-making. Methods A multidisciplinary working group at Emory Healthcare developed and implemented an adjudication tool for the prioritization of time sensitive surgeries. The variables identified by the team to form the construct focused on the patient’s survivability according to actuarial data, potential impact on function with delay in care, and high-level biology of disease. Implementation of the prioritization was accomplished with a database design to streamline needed communication between surgeons and surgical adjudicators. All patients who underwent time sensitive surgery between 4/10/20 and 6/15/20 across 5 campuses were included. Results The primary outcomes of interest were calculated patient prioritization score and number of days until operation. 1767 cases were adjudicated during the specified time period. The distribution of prioritization scores was normal, such that real-time adjustment of the empiric algorithm was not required. On retrospective review, as the patient prioritization score increased, the number of days to the operating room decreased. This confirmed the functionality of the tool and provided a framework for organization across multiple campuses. Conclusions We developed an in-house adjudication tool to aid in the prioritization of a large cohort of canceled and time sensitive surgeries. The tool is relatively simple in its design, reproducible, and data driven which allows for an objective adjunct to clinical decision-making. The database design was instrumental in communication optimization during this chaotic period for patients and surgeons.

Multiple medication changes are common after bariatric surgery, but pharmacist assistance in this setting is not well described. This study evaluated the feasibility and effectiveness of a pharmacy-led initiative for facilitating discharge medicine reconciliation after bariatric surgery.A standardized post-operative pharmacy consult evaluation was conducted on bariatric surgery inpatients at a single academic center starting 1/2/2019. Retrospective chart review evaluated patient characteristics, medication changes, and 30-day outcomes pre-intervention (7/2018-12/2018) and post-intervention (1/2019-12/2019). Two-sample t tests or binomial tests were used for continuous or categorical variables, respectively; a p-value of 0.05 was deemed statistically significant.A total of 353 patients were identified for study inclusion (n = 158 pre-intervention, n = 195 post-intervention) with a mean age of 45 years, 87% female, and 71% sleeve gastrectomy. Overall pharmacy consultation compliance was 94% with 77.0% of home medication recommendations followed. Non-narcotic pain medication prescription use significantly increased (39% pre- vs. 54% post-intervention; p 0.001). At discharge, the average number of changed or new medications significantly increased (3.7 ± 1.2 pre- vs. 4.2 ± 1.8 post-intervention; p = 0.003) while the average number of stopped medications was similar (1.2 ± 1.5 pre- vs. 1.5 ± 1.9 post-intervention; p = 0.09). Anti-hypertensive medications were decreased or stopped substantially more often with pharmacist input (44.7% pre- vs. 85.4% post-intervention; p 0.001). Three medication-related readmissions happened pre-intervention with none post-intervention. Outpatient medication-related phone calls did considerably increase (31% pre- vs. 39% post-intervention; p = 0.04), while overall 30-day readmissions significantly decreased (7.6% pre- vs. 1.5% post-intervention; p = 0.04).Inpatient pharmacy consultation facilitated rapid alteration to more appropriate therapy for hypertension management and significantly increased use of non-narcotic pain medications upon discharge among bariatric surgery patients. Improved protocol adherence is anticipated with program maturity and patient education interventions will be deployed to address outpatient phone calls.

Changes in housing demand can have a macroeconomic effect through the collateral channel, where the change in residential real estate prices is associated with a change in commercial real estate prices, affecting firm collateral and thus firm investment. We argue that this channel is weaker when residential and commercial real estate are poor substitutes. Using cross-state heterogeneity in the strength of zoning regulations as a proxy for heterogeneity in the substitutability of residential and commercial real estate, we first show with firm level data that the strength of local zoning regulations has a negative effect on the estimated increase in firm investment following an increase in local residential real estate prices. We then construct a DSGE model where land has both residential and commercial uses and estimate it using Bayesian techniques and U.S. macroeconomic data. We find the average elasticity of substitution between commercial and residential real estate in the U.S. to be around 0.35, but in states with strong zoning restrictions it can be as low as 0.16 and in states with weak zoning restrictions it can be as high as 0.66. Simulations of the model show how these differences in zoning restrictions can affect the transmission of a housing demand shock to the macroeconomy.

Water Quality issues in many Pacific countries are rising, with the increase in coastal populations and associated urban runoff but management requires contamination issues in the aquatic environment to be identified and prioritised. In Vanuatu and Solomon Islands there are few laboratories and resources to assess for the presence or impact of complex chemical contaminants. The extent and impact of chemical contamination of the marine and coastal environment is poorly described. Passive chemical samplers were used to measure a range of aquatic pollutants around the capital cities, Honiara (Solomon Islands) and Port Vila (Vanuatu). We detected a range of chemicals indicative of agricultural and industrial contamination and a few sites had concerning concentrations of specific hydrocarbons and pesticides. The rapid ecotoxicology test, Microtox, indicated toxic impacts in rivers, coastal sites and urban drains This work provides new data on chemical contamination and possible impacts of that contamination for both countries. The techniques could be applied widely across the region to generate critical data for environmental management, guide monitoring efforts and measure the impact of policy or land-use changes.

Esophagogastric junction obstruction (EGJO) post-fundoplication (PF) is difficult to identify with currently available tests. We aimed to assess the diagnostic accuracy of EGJ opening on functional lumen imaging probe (FLIP) and dilation outcome in FLIP-detected EGJO in PF dysphagia.We prospectively collected data on PF patients referred to Esophageal Clinic over 18 months. EGJO diagnosis was made by (a) endoscopist's description of a narrow EGJ/wrap area, (b) appearance of wrap obstruction or contrast/tablet retention on esophagram, or (c) EGJ-distensibility index (DI) 2.8 mmTwenty-six patients were included, of whom 17 (65%) had a low EGJ-DI. No patients had a hiatal hernia greater than 3 cm. Dysphagia was the primary symptom in 17/26 (65%). In 85% (κ = 0.677) of cases, EGJ assessment (tight vs. open) was congruent between the combination of endoscopy (n = 26) and esophagram (n = 21) vs. EGJ-DI (n = 26) on FLIP. Follow-up data were available in 11 patients who had dilation based on a low EGJ-DI (4 with 20 mm balloon and 7 with ≥ 30 mm balloon). Overall, the mean % improvement in dysphagia was 60% (95% CI 37.7-82.3%, p = 0.0001). Nine out of 11 patients, including 6 out of 7 undergoing pneumatic dilation, had improvement ≥ 50% in dysphagia (mean % improvement 72.2%; 95% CI 56.1-88.4%, p = 0.0001).Functional lumen imaging probe is an accurate modality for evaluating for EGJ obstruction PF. FLIP may be used to select patients who may benefit from larger diameter dilation.

Tacrolimus (TAC) is the most important agent for maintenance immunosuppression and prevention of immunologic injury to the renal allograft, yet there remains no consensus on how best to monitor drug therapy. Both high TAC intrapatient variability and low TAC time in therapeutic range (TTR) have been associated with risk of de novo donor-specific antibodies (dnDSA). In this study, we hypothesized that the risk associated with high TAC coefficient of variation (CV) is a result of low TAC TTR rather than the variability itself.We analyzed the risk of dnDSA, acute rejection, or death-censored graft loss by non-dosed-corrected TAC CV and TAC TTR during the first posttransplant year in a cohort of 538 patients with a median follow-up period of 4.1 years.Patients with CV44.2% and TTR40% (high intrapatient variability and low TTR) had a high risk of dnDSA (adjusted OR = 4.93, 95% confidence interval = 2.02-12.06, P0.001) and death-censored graft loss by 5 years (adjusted HR = 4.00, 95% confidence interval = 1.31-12.24, P = 0.015) when compared with patients with CV44.2% and TTR ≥40% (high intrapatient variability and optimal TTR), while the latter patients had similar risk to patients with CV44.2% (lower intrapatient variability).These data suggest that previously reported immunologic risk associated with high TAC intrapatient variability is due to time outside of therapeutic range rather than variability in and of itself when evaluating absolute non-dose-corrected TAC levels irrespective of reason or indication.

Uranium is naturally found in the environment as a radioactive metal element with high concentrations in the Southwestern US. In this region is the Navajo Nation, which spans approximately 69,930 square kilometers. A decay product of uranium is radon gas, a lung carcinogen that has no color, odor, or taste. Radon gas may pass from soil into homes, and, indoor accumulation has been associated with geographical location, seasonality, home construction materials, and home ventilation. A home and indoor radon survey was conducted from November 2014 through May 2015, with volunteers who reported residence on the Navajo Nation. Home geolocation, structural characteristics, temperature (&deg, C) during radon testing, and elevation (meters) were recorded. Short-term indoor radon kits were used to measure indoor radon levels. 51 homes were measured for indoor radon levels, with an arithmetic mean concentration of 60.5 Becquerels per cubic meter (Bq/m3) (SD = 42.7). The mean indoor radon concentrations (Bq/m3) by house type were: mobile, 29.0 (SD = 22.9), wood, 58.6 (SD = 36.0), hogan, 74.0 (SD = 0.0), homes constructed of cement and wood, 82.6 (SD = 3.5), and homes constructed of concrete and cement, 105.7 (SD = 55.8). A key observation is that house construction type appears to be associated with the mean home indoor radon concentration. This observation has been published in that the basic structural make-up of the home may affect home ventilation and therefore indoor radon concentration levels.

Individuals with progressive advanced chronic kidney disease (CKD) have a number of treatment modalities to consider before reaching end-stage renal disease. As CKD reaches stage 4, and particularly as glomerular filtration rate approaches 20 mL/min, patients should be informed of kidney transplantation as a treatment option, provided education regarding the transplant process, and be referred to a transplant center unless there are clear contraindications or comorbidities that preclude consideration. There is an unfortunate and dramatic disparity between those who are eligible for transplantation and those who receive a transplant, due in part to referral biases, the comparative shortage of deceased donors, and a lack of acceptance or awareness of living kidney donation as an option. This chapter reviews the transplant landscape, discusses the procedural and pathophysiological considerations for kidney transplantation, and outlines the transplant evaluation process, including inclusion and exclusion criteria.

The collateral channel, whereby an increase in residential house prices leads to an increase in commercial property prices, loosening firm borrowing constraints and increasing firm investment, is weaker when residential and commercial real estate are imperfect substitutes. We enrich the DSGE model of the collateral channel in Liu, Wang, and Zha (2013) by adding a land development sector to allow residential and commercial land to be imperfect substitutes. Bayesian estimation of our structural model based on aggregate U.S. data indicates imperfect substitution between the two types of land. With variance decompositions and impulse responses, we show that the strength of the collateral channel linking residential house prices and firm investment is weaker when the two types of land are imperfect substitutes. When residential and commercial land are assumed to be perfect substitutes, shocks to residential real estate demand explain 20-30% of the variance of output and 30-40% of the variance of investment, but with the imperfect degree of substitution that we estimate, the same shocks explain less than 10% of the variance of output and 12-15% of investment.

Adopting a single instead of multiple targets can be an effective way to overcome the classic time-inconsistency problem. The choice of a single mandate depends on the trade openness and the credibility. Reduced-form empirical results show as central banks become less credible, they are more likely to adopt a pegged exchange rate, and the tendency to peg depends on trade openness. In a model with “loose commitment,” as credibility falls, either an inflation target or a pegged exchange rate is more likely to be adopted.Arelatively closed (highly open) economywould adopt an inflation target (exchange rate peg).

The recently published NCRP Commentary No. 27 evaluated the new information from epidemiologic studies as to their degree of support for applying the linear nonthreshold (LNT) model of carcinogenic effects for radiation protection purposes (NCRP 2018 Implications of Recent Epidemiologic Studies for the Linear Nonthreshold Model and Radiation Protection, Commentary No. 27 (Bethesda, MD: National Council on Radiation Protection and Measurements)). The aim was to determine whether recent epidemiologic studies of low-LET radiation, particularly those at low doses and/or low dose rates (LD/LDR), broadly support the LNT model of carcinogenic risk or, on the contrary, demonstrate sufficient evidence that the LNT model is inappropriate for the purposes of radiation protection. An updated review was needed because a considerable number of reports of radiation epidemiologic studies based on new or updated data have been published since other major reviews were conducted by national and international scientific committees. The Commentary provides a critical review of the LD/LDR studies that are most directly applicable to current occupational, environmental and medical radiation exposure circumstances. This Memorandum summarises several of the more important LD/LDR studies that incorporate radiation dose responses for solid cancer and leukemia that were reviewed in Commentary No. 27. In addition, an overview is provided of radiation studies of breast and thyroid cancers, and cancer after childhood exposures. Non-cancers are briefly touched upon such as ischemic heart disease, cataracts, and heritable genetic effects. To assess the applicability and utility of the LNT model for radiation protection, the Commentary evaluated 29 epidemiologic studies or groups of studies, primarily of total solid cancer, in terms of strengths and weaknesses in their epidemiologic methods, dosimetry approaches, and statistical modelling, and the degree to which they supported a LNT model for continued use in radiation protection. Recommendations for how to make epidemiologic radiation studies more informative are outlined. The NCRP Committee recognises that the risks from LD/LDR exposures are small and uncertain. The Committee judged that the available epidemiologic data were broadly supportive of the LNT model and that at this time no alternative dose-response relationship appears more pragmatic or prudent for radiation protection purposes.

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

The mammalian target of rapamycin (mTOR) pathway has been shown to be central to cyst formation and growth in patients with autosomal dominant polycystic kidney disease (ADPKD). Drugs that suppress mTOR signaling are frequently used as antiproliferative agents for maintenance immunosuppression in patients who have undergone kidney transplantation. The aim of this study was to determine the effect of sirolimus, an mTOR inhibitor, on cyst volume regression in patients with ADPKD who have undergone renal transplantation.In this single-center, prospective, open-label, parallel-group, randomized trial, 23 adult patients with ADPKD who successfully underwent renal transplantation from 2008 to 2012 were subsequently randomized (on a 1:1 basis) to a maintenance immunosuppression regimen with either sirolimus (sirolimus, tacrolimus, prednisone) or mycophenolate (mycophenolate, tacrolimus, prednisone). Total kidney volumes were measured by means of high-resolution magnetic resonance imaging within 2 weeks after transplantation and at 1 year. The primary end point was change in total kidney volume at 1 year.Sixteen patients completed the 1-year study (8 patients in each group). There was a decrease in kidney volume in both the sirolimus group (percentage change from baseline, 20.5%; P .001) and mycophenolate group (percentage change from baseline, 17%; P = .048), but there was no significant difference in percentage change of total kidney volume between the groups (P = .665).In ADPKD patients at 1 year after kidney transplantation, there was a similar decrease in polycystic kidney volume in patients receiving an immunosuppression regimen containing sirolimus compared with patients receiving mycophenolate.

Background: Patients with prior Roux-en-Y gastric bypass (RYGB) operations for weight loss present reconstruction challenges during a pancreaticoduodenectomy (PD). With over 60,000 RYGB performed annually, the increasing odds of encountering such patients during a PD make it imperative to understand the RYGB anatomy and anticipate reconstruction options. This article describes the possible reconstruction options and their rationale. Methods: We reviewed our PD reconstruction options, compared them to what have been described in the literature, and derived a consensus from internal conferences comprising bariatric and hepatopancreatobiliary surgeons to describe known reconstruction options. Results: In general, reconstruction options can include one of three options: (1) remnant gastrectomy, (2) preservation of gastric remnant, or (3) reversal of gastric bypass. Conclusion: This article describes individualized reconstruction options for RYGB patients undergoing PD. The reconstruction options can ...