Benchmark dose profiles for bivariate exposures.

While benchmark dose (BMD) methodology is well-established for settings with a single exposure, these methods cannot easily handle multidimensional exposures with nonlinear effects. We propose a framework for BMD analysis to characterize the joint effect of a two-dimensional exposure on a continuous outcome using a generalized additive model while adjusting for potential confounders via propensity scores. This leads to a dose-response surface which can be summarized in two dimensions by a contour plot in which combinations of exposures leading to the same expected effect are identified. In our motivating study of prenatal alcohol exposure, cognitive deficits in children are found to be associated with both the frequency of drinking as well as the amount of alcohol consumed on each drinking day during pregnancy. The general methodological framework is useful for a broad range of settings, including combinations of environmental stressors, such as chemical mixtures, and in explorations of the impact of dose rate rather than simply cumulative exposure on adverse outcomes.

Extrahepatic biliary tract tuberculosis: A case report and literature review.

INTRODUCTION: Tuberculosis is a chronic infectious disease that often has a latent period after the initial infection. Tuberculosis most often affects the lungs but it can also affect other parts of the body. Vietnam is in pandemic area of tuberculosis. CASE REPORT: We present a rare case of a 42-year-old male patient admitted to the hospital with a history of progressive jaundice. Magnetic resonance imaging (MRI) revealed a 26 × 33 mm tuberculous mass located at the intersection between the cystic duct and the common hepatic duct, leading to dilation of the intrahepatic biliary ducts on both sides. Initially diagnosed with a Klatskin type II tumor, the patient underwent surgery to remove the mass and create a biliary-enteric anastomosis. However, the pathological report of the postoperative specimens concluded a diagnosis of necrotizing granulomatous inflammation caused by tuberculosis. CASE DISCUSSION: Obstructive jaundice secondary to tuberculosis is a rare condition that can be caused due to the tuberculous enlargement of the pancreatic head, tuberculous lymphadenitis, tuberculous biliary strictures, or a tuberculous retroperitoneal mass. Extrapulmonary tuberculosis usually results from hematogenous dissemination or contiguous spread from adjacent organs. Symptoms vary depending on the affected organ but typically include fever, fatigue, and weight loss. Hepatobiliary tuberculosis is usually secondary to pulmonary or gastrointestinal tuberculosis. CONCLUSION: Hepatobiliary tuberculosis is a rare disease that affects the liver and bile duct system. It is difficult to diagnose because it does not have any specific symptoms and can be easily misdiagnosed with other diseases.

Outcomes of laparoscopic choledochotomy using cholangioscopy via percutaneous-choledochal tube for the treatment of hepatolithiasis and choledocholithiasis: A preliminary Vietnamese study.

Backgrounds/Aims: Hepatolithiasis and choledocholithiasis are frequent pathologies and unfortunately, with the current treatment strategies, the recurrence incidence is still high. This study aimed to assess the outcomes of laparoscopic choledochotomy using cholangioscopy via the percutaneous-choledochal tube for the treatment of hepatolithiasis and choledocholithiasis in Vietnamese patients. Methods: A cross-sectional study of patients with hepatolithiasis and/or choledocholithiasis who underwent laparoscopic choledochotomy using intraoperative cholangioscopy via percutaneous-choledochal tube at the Department of Hepatopancreatobiliary Surgery, 108 Military Central Hospital, from June 2017 to March 2020. Results: A total of 84 patients were analyzed. Most patients were females (56.0%) with a median age of 55.56 years. Among them, 41.8% of patients had previous abdominal operations, with 33.4% having choledochotomy. All patients underwent successful laparoscopic common bile duct exploration followed by T-tube drainage without needing to convert to open surgery. Most patients (64.3%) had both intrahepatic and extrahepatic stones. The rate of stones ≥ 10 mm in diameter was 64.3%. Biliary strictures were observed in 19.1% of patients during cholangioscopy. Complete removal of stones was achieved in 54.8% of patients. Intraoperative complications were encountered in two patients, but there was no need to change the strategy. The mean operating time was 121.85 ± 30.47 minutes. The early postoperative complication rate was 9.6%, and all patients were managed conservatively. The residual stones were removed through the T-tube tract by subsequent choledochoscopy in 34/38 patients, so the total success rate was 95.2%. Conclusions: Laparoscopic choledochotomy combined with cholangioscopy through the percutaneous-choledochal tube is a safe and effective strategy for hepatolithiasis and/or choledocholithiasis, even in patients with a previous choledochotomy.

Additional hepatic artery embolization after liver venous deprivation for right hepatectomy: A case report.

Post hepatectomy Liver Failure (PHLF) is a fatal complication, especially after major liver resection. Insufficient remnant liver volume is a common cause of postoperative liver failure. Many strategies have been applied to induce the remnant liver hypertrophy: Portal vein embolization (PVE), PVE combined with hepatic vein embolization (LVD), two staged liver resection, Associated liver partition with portal vein ligation for staged hepatectomy (ALPPS). We present a case of a 39-year-old male patient who underwent LVD for preoperative liver hypertrophy. After LVD, the patient underwent additional artery embolization, and the patient's remaining liver volume increased by 63.2% in 7 weeks. The patient underwent a right hepatectomy and was discharged after 10 days, with no complications of postoperative liver failure. Simultaneous portal and hepatic vein embolization is a technique that has been applied recently because it can significantly promote the speed and extent of liver hypertrophy before major liver resection compared to portal vein embolization procedure alone. In this case, additional hepatic artery embolization may be an important factor lead to hypertrophy of the remnant liver, thereby shortening the waiting time for surgery and reducing the risk of tumor progression. Liver venous deprivation is safe and feasible to perform. Additional hepatic artery embolization may accelerate the hypertrophy of the remnant liver.

A dose-response analysis of the effects of prenatal alcohol exposure on cognitive development.

BACKGROUND: Most studies of the effects of prenatal alcohol exposure (PAE) on cognitive function have assumed that the dose-response curve is linear. However, data from a few animal and human studies suggest that there may be an inflection point in the dose-response curve above which PAE effects are markedly stronger and that there may be differences associated with pattern of exposure, assessed in terms of alcohol dose per drinking occasion and drinking frequency. METHODS: We performed second-order confirmatory factor analysis on data obtained at school age, adolescence, and early adulthood from 2227 participants in six US longitudinal cohorts to derive a composite measure of cognitive function. Regression models were constructed to examine effects of PAE on cognitive function, adjusted for propensity scores. Analyses based on a single predictor (absolute alcohol (AA)/day) were compared with analyses based on two predictors (dose/occasion and drinking frequency), using (1) linear models and (2) nonparametric general additive models (GAM) that allow for both linear and nonlinear effects. RESULTS: The single-predictor GAM model showed virtually no nonlinearity in the effect of AA/day on cognitive function. However, the two-predictor GAM model revealed differential effects of maternal drinking pattern. Among offspring of infrequent drinkers, PAE effects on cognitive function were markedly stronger in those whose mothers drank more than ~3 drinks/occasion, and the effect of dose/occasion was strongest among the very frequent drinkers. Frequency of drinking did not appear to alter the PAE effect on cognitive function among participants born to mothers who limited their drinking to ~1 drink/occasion or less. CONCLUSIONS: These findings suggest that linear models based on total AA/day are appropriate for assessing whether PAE affects a given cognitive outcome. However, examination of alcohol dose/occasion and drinking frequency is needed to fully characterize the impact of different levels of alcohol intake on cognitive impairment.

Rapid depletion of "catch-and-release" anti-ASGR1 antibody in vivo.

Targeting antigens with antibodies exhibiting pH/Ca2+-dependent binding against an antigen is an attractive strategy to mitigate target-mediated disposition and antigen buffering. Studies have reported improved serum exposure of antibodies exhibiting pH/Ca2+-binding against membrane-bound receptors. Asialoglycoprotein receptor 1 (ASGR1) is a membrane-bound receptor primarily localized in hepatocytes. With a high expression level of approximately one million receptors per cell, high turnover, and rapid recycling, targeting this receptor with a conventional antibody is a challenge. In this study, we identified an antibody exhibiting pH/Ca2+-dependent binding to ASGR1 and generated antibody variants with increased binding to neonatal crystallizable fragment receptor (FcRn). Serum exposures of the generated anti-ASGR1 antibodies were analyzed in transgenic mice expressing human FcRn. Contrary to published reports of increased serum exposure of pH/Ca2+-dependent antibodies, the pH/Ca2+-dependent anti-ASGR1 antibody had rapid serum clearance in comparison to a conventional anti-ASGR1 antibody. We conducted sub-cellular trafficking studies of the anti-ASGR1 antibodies along with receptor quantification analysis for mechanistic understanding of the rapid serum clearance of pH/Ca2+-dependent anti-ASGR1 antibody. The findings from our study provide valuable insights in identifying the antigens, especially membrane bound, that may benefit from targeting with pH/Ca2+-dependent antibodies to obtain increased serum exposure.

Bayesian outcome selection modeling.

In psychiatric and social epidemiology studies, it is common to measure multiple different outcomes using a comprehensive battery of tests thought to be related to an underlying construct of interest. In the research that motivates our work, researchers wanted to assess the impact of in utero alcohol exposure on child cognition and neuropsychological development, which are evaluated using a range of different psychometric tests. Statistical analysis of the resulting multiple outcomes data can be challenging, because the outcomes measured on the same individual are not independent. Moreover, it is unclear, a priori, which outcomes are impacted by the exposure under study. While researchers will typically have some hypotheses about which outcomes are important, a framework is needed to help identify outcomes that are sensitive to the exposure and to quantify the associated treatment or exposure effects of interest. We propose such a framework using a modification of stochastic search variable selection, a popular Bayesian variable selection model and use it to quantify an overall effect of the exposure on the affected outcomes. The performance of the method is investigated empirically and an illustration is given through application using data from our motivating study.

Automated buffer preparation using quaternary valve in fast performance liquid chromatography for protein purification from a cell membrane.

There is a great need for high-throughput protein purification to produce protein molecules for research and therapeutics. Although there have been significant advancements made in automated multi-step chromatography and preparative in-process design-of-experiment (DOE) capabilities in commercial fast performance liquid chromatography (FPLC) instruments, almost all commercial FPLCs rely on a binary buffer mixing system, which hinders automated buffer preparation. Nevertheless, current-generation FPLCs are equipped with a quaternary mixer designed for limited in-line buffer preparation and preparative pH scouting DOE experiments. We decided to leverage the quaternary mixing capability by extending and re-programming AkTA Avant's quaternary valve into an automated in-process buffer preparation system to simplify automated purification requiring complex washing steps. We accomplished this by using two extra inlet valves, a sample valve, and versatile valve to split inputs of the quaternary valve into software-selectable stock solutions of pH buffers, salts, eluents, and additives. We also devised a new flow scheme to perform automated two-step chromatography using only one versatile valve. This was accomplished by using only stock parts and software to facilitate reproduction. To demonstrate the versatility and capability of the system, we purified a transmembrane protein that requires a detergent to stay soluble and needs an in-column, high-salt washing step to achieve high purity.

Novel protein therapeutic joint retention strategy based on collagen-binding Avimers.

Designing drugs to treat diseases associated with articular joints, particularly those targeting chondrocytes, is challenging due to unique local environmental constraints including the avascular nature of cartilage, the absence of a closed joint compartment, and a highly cross-linked extracellular matrix. In an effort to address these challenges, we developed a novel strategy to prolong residence time of intra-articularly administered protein therapeutics. Avimer domains are naturally found in membrane polypeptides and mediate diverse protein-protein interactions. Screening of a phage Avimer domain library led to identification of several low affinity type II collagen-binding Avimers. Following several rounds of mutagenesis and reselection, these initial hits were transformed to high affinity, selective type II collagen-binding Avimers. One such Avimer (M26) persisted in rat knees for at least 1 month following intra-articular administration. Fusion of this Avimer to a candidate therapeutic payload, IL-1Ra, yielded a protein construct which simultaneously bound to type II collagen and to IL-1 receptor. In vitro, IL-1Ra_M26 bound selectively to cartilage explants and remained associated even after extensive washing. Binding appeared to occur preferentially to pericellular regions surrounding chondrocytes. An acute intra-articular IL-1-induced IL-6 challenge rat model was employed to assess in vivo pharmacodynamics. Whereas both IL-1Ra_M26 and native IL-1Ra inhibited IL-6 output when co-administered with the IL-1 challenge, only IL-1Ra_M26 inhibited when administered 1 week prior to IL-1 challenge. Collagen-binding Avimers thus represent a promising strategy for enhancing cartilage residence time of protein therapeutics. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1238-1247, 2018.