Association between Helicobacter pylori infection, MASLD, and liver fibrosis in patients with severe obesity: a single-center experience.

BACKGROUND AND METHODS: Our study sought to evaluate if an association exists between Helicobacter pylori (H. pylori), metabolic dysfunction- associated steatotic liver disease (MASLD), and liver fibrosis in patients with severe obesity (BMI > 35). Our retrospective study included 584 patients over the age of 18 years with severe obesity, who underwent preoperative liver transient elastography (VCTE), upper endoscopy, blood work, and intra-operative liver biopsy concurrent with bariatric surgery at a single institution from July 2020 to September 2021. Liver fibrosis scores including FIB-4, APRI, NAFLD fibrosis score, BARD score, AST: ALT ratio, and NAFLD activity score (NAS) were calculated from the laboratory results and liver biopsy findings. The presence or absence of H. pylori was determined based on gastric biopsies obtained during upper endoscopy. Other variables collected included age, gender, mean preoperative weight, BMI, and the presence or absence of comorbidities. Student's t-test and non-parametric testing were used for the analysis of continuous variables and Chi-square analysis was used for categorical data. RESULTS: Of the 584 patients, 14.7% were H. pylori positive and 85.3% were negative. Liver fibrosis scores including FIB-4, APRI, and NAFLD fibrosis scores were significantly higher in the positive group (p < 0.05), but there was no difference in AST: ALT ratio and BARD score. A significantly higher VCTE steatosis and fibrosis scores were noted in the H. pylori-positive group (p < 0.05). Similarly, a significantly higher NAS (NAFLD activity score) on liver biopsies was noted in the positive group, with all the individual components of NAS (steatosis, lobular inflammation, and hepatocyte ballooning) being significantly higher in the positive group (p < 0.05). A significantly higher incidence of fibrosis on liver biopsies was noted in the positive group overall and across all stages of fibrosis (p < 0.05). There were no significant differences between the groups in relation to gender, mean weight, BMI, presence of comorbidities including Diabetes Mellitus, and laboratory values. CONCLUSION: Our study demonstrates that H. pylori colonization or infection is associated with a higher risk of development of MASLD and progression to fibrosis. Further, population-based studies are needed to corroborate our findings.

Recommendations for a standardized publication protocol for a QSP model.

Development of a Quantitative Systems Pharmacology (QSP) model is a long process with many iterative steps. Lack of standard practices for publishing QSP models has resulted in limited model reproducibility within the field. Multiple studies have identified that model reproducibility is a large challenge, especially for QSP models. This work aimed to investigate the causes of QSP model reproducibility issues and suggest standard practices as a potential solution to ensure QSP models are reproducible. In addition, a protocol is suggested as a guidance towards better publication strategy across journals, hoping to enable QSP knowledge preservation.

A framework for simplification of quantitative systems pharmacology models in clinical pharmacology.

Quantitative systems pharmacology (QSP) is a relatively new discipline within modelling and simulation that has gained wide attention over the past few years. The application of QSP models spans drug-target identification and validation, through all drug development phases as well as clinical applications. Due to their detailed mechanistic nature, QSP models are capable of extrapolating knowledge to predict outcomes in scenarios that have not been tested experimentally, making them an important resource in experimental and clinical pharmacology. However, these models are complicated to work with due to their size and inherent complexity. This makes many applications of QSP models for simulation, parameter estimation and trial design computationally intractable. A number of techniques have been developed to simplify QSP models into smaller models that are more amenable to further analyses while retaining their accurate predictive capabilities. Different simplification techniques have different strengths and weaknesses and hence different utilities. Understanding the utilities of different methods is essential for selection of the best method for a particular situation. In this paper, we have created an overall framework for model simplification techniques that allows a natural categorisation of methods based on their utility. We provide a brief description of the concept underpinning the different methods and example applications. A summary of the utilities of methods is intended to provide a guide to modellers in their model endeavours to simplify these complicated models.

Current practices for QSP model assessment: an IQ consortium survey.

Quantitative Systems Pharmacology (QSP) modeling is increasingly applied in the pharmaceutical industry to influence decision making across a wide range of stages from early discovery to clinical development to post-marketing activities. Development of standards for how these models are constructed, assessed, and communicated is of active interest to the modeling community and regulators but is complicated by the wide variability in the structures and intended uses of the underlying models and the diverse expertise of QSP modelers. With this in mind, the IQ Consortium conducted a survey across the pharmaceutical/biotech industry to understand current practices for QSP modeling. This article presents the survey results and provides insights into current practices and methods used by QSP practitioners based on model type and the intended use at various stages of drug development. The survey also highlights key areas for future development including better integration with statistical methods, standardization of approaches towards virtual populations, and increased use of QSP models for late-stage clinical development and regulatory submissions.

Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection.

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent. CONCLUSION: Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000).

Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients Coinfected With Hepatitis C Virus and Human Immunodeficiency Virus Type 1: The EXPEDITION-2 Study.

Background: Once-daily glecaprevir coformulated with pibrentasvir (glecaprevir/pibrentasvir) demonstrated high rates of sustained virologic response 12 weeks after treatment (SVR12) in patients with hepatitis C virus (HCV) genotype 1-6 infection. This phase 3 study evaluated the efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV genotype 1-6 and human immunodeficiency virus type 1 (HIV-1) coinfection, including patients with compensated cirrhosis. Methods: EXPEDITION-2 was a phase 3, multicenter, open-label study evaluating glecaprevir/pibrentasvir (300 mg/120 mg) in HCV genotype 1-6/HIV-1-coinfected adults without and with compensated cirrhosis for 8 and 12 weeks, respectively. Patients were either HCV treatment-naive or experienced with sofosbuvir, ribavirin, or interferon, and antiretroviral therapy (ART) naive or on a stable ART regimen. Treatment-experienced genotype 3-infected patients were excluded. The primary endpoint was the SVR12 rate. Results: In total, 153 patients were enrolled, including 16 (10%) with cirrhosis. The SVR12 rate was 98% (n = 150/153; 95% confidence interval, 95.8-100), with no virologic failures in 137 patients treated for 8 weeks. One genotype 3-infected patient with cirrhosis had on-treatment virologic failure. Most adverse events were mild in severity; 4 patients (2.6%) had serious adverse events, all deemed unrelated to glecaprevir/pibrentasvir. Treatment discontinuation was rare (<1%). All patients treated with ART maintained HIV-1 suppression (<200 copies/mL) during treatment. Conclusions: Glecaprevir/pibrentasvir for 8 weeks in noncirrhotic and 12 weeks in cirrhotic patients is a highly efficacious and well-tolerated treatment for HCV/HIV-1 coinfection, regardless of baseline HCV load or prior treatment with interferon or sofosbuvir. Clinical trial registration: NCT02738138.

Application of Adaptive DP-optimality to Design a Pilot Study for a Clotting Time Test for Enoxaparin.

PURPOSE: Dosing of enoxaparin, like other anticoagulants, may result in bleeding following excessive doses and clot formation if the dose is too low. We recently showed that a factor Xa based clotting time test could potentially assess the effect of enoxaparin on the clotting system. However, the test did not perform well in subsequent individuals and effectiveness of an exogenous phospholipid, Actin FS, in reducing the variability in the clotting time was assessed. The aim of this work was to conduct an adaptive pilot study to determine the range of concentrations of Xa and Actin FS to take forward into a proof-of-concept study. METHODS: A nonlinear parametric function was developed to describe the response surface over the factors of interest. An adaptive method was used to estimate the parameters using a D-optimal design criterion. In order to provide a reasonable probability of observing a success of the clotting time test, a P-optimal design criterion was incorporated using a loss function to describe the hybrid DP-optimality. RESULTS: The use of adaptive DP-optimality method resulted in an efficient estimation of model parameters using data from only 6 healthy volunteers. The use of response surface modelling identified a range of sets of Xa and Actin FS concentrations, any of which could be used for the proof-of-concept study. CONCLUSIONS: This study shows that parsimonious adaptive DP-optimal designs may provide both precise parameter estimates for response surface modelling as well as clinical confidence in the potential benefits of the study.

Development and evaluation of a prototype of a novel clotting time test to monitor enoxaparin.

PURPOSE: Dosing of the anticoagulant enoxaparin may result in bleeding following excessive doses or thrombosis if dose is too low. Rarely, anti-Xa activity is used to assess the dose for enoxaparin, but its utility to predict clotting or bleeding remains uncertain. We aimed to develop a clotting time test to monitor enoxaparin therapy. METHODS: A previously developed mathematical model of the coagulation network was used to identify suitable targets for monitoring enoxaparin therapy. In vitro experiments were then carried out to demonstrate proof of mechanism of the clotting time test activated by the new target activator. RESULTS: Using the mathematical model, we identified Xa as a plausible activating agent for a clotting time test for enoxaparin. In vitro experiments showed a prolongation of the Xa clotting time of 4.6-fold in the presence of enoxaparin (0.5 IU/ml) where 10 nM Xa was used to activate clotting. CONCLUSIONS: Using both simulations and in vitro experiments, we provide a proof of mechanism for the Xa clotting time (XaCT) test, which can be considered for further development to provide a biomarker of the effect of enoxaparin on the clotting system.

An Unusual Cause of Ascites in Liver Cirrhosis: Peritoneal Tuberculosis.

Peritoneal tuberculosis is a rare disease with increasing incidence in recent years, especially in patients with an immunocompromised state and liver cirrhosis. We report the case of a 37-year-old male with a known history of liver cirrhosis who presented to the hospital with abdominal pain, abdominal distension, and was diagnosed with peritoneal tuberculosis. The diagnosis was made based on findings from a CT of the abdomen and histopathological findings of peritoneal tissue biopsy. He was started on ethambutol, isoniazid, pyrazinamide, and rifampin for six months.

Quantitative Systems Pharmacology Approaches for Immuno-Oncology: Adding Virtual Patients to the Development Paradigm.

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies. However, the current drug-development approach of exploiting a vast number of possible combination targets and dosing regimens has proven to be challenging and is arguably inefficient. In particular, the unprecedented number of clinical trials testing different combinations may no longer be sustainable by the population of available patients. Further development in IO requires a step change in selection and validation of candidate therapies to decrease development attrition rate and limit the number of clinical trials. Quantitative systems pharmacology (QSP) proposes to tackle this challenge through mechanistic modeling and simulation. Compounds' pharmacokinetics, target binding, and mechanisms of action as well as existing knowledge on the underlying tumor and immune system biology are described by quantitative, dynamic models aiming to predict clinical results for novel combinations. Here, we review the current QSP approaches, the legacy of mathematical models available to quantitative clinical pharmacologists describing interaction between tumor and immune system, and the recent development of IO QSP platform models. We argue that QSP and virtual patients can be integrated as a new tool in existing IO drug development approaches to increase the efficiency and effectiveness of the search for novel combination therapies.

Binding of lopinavir to human alpha1-acid glycoprotein and serum albumin.

HIV protease inhibitors are an important component of highly active antiretroviral therapy used to treat pregnant women infected with HIV. They have a low placental transfer and are highly plasma protein bound. This study was carried out to determine the unbound fraction of lopinavir in cord blood, and to characterize the binding of lopinavir to alpha(1)-acid glycoprotein (AAG) and human serum albumin (HSA), and displacement by ritonavir. Serum was obtained from cord blood from placentas obtained after cesarean section of healthy, non-HIV-infected women (n = 4). The unbound fraction of lopinavir in serum obtained from this cord blood was 0.022 +/- 0.011%. The unbound fraction of lopinavir in separately obtained maternal serum samples (n = 4) was 0.89 +/- 0.12%, which was not significantly different from that observed with cord serum samples. Varying concentrations of lopinavir, AAG, and HSA in buffer solutions were then used to characterize the lopinavir binding. The data were fit to obtain the number of binding sites (N) and equilibrium dissociation constant (K(D)). Binding of lopinavir to AAG (7-23 microM) was saturable with K(D) of 5.0 +/- 1.1 microM and N of 1.2 +/- 0.2. At low HSA concentrations (15-152 microM), lopinavir binding K(D) was 24.3 +/- 8.7 microM and N was 1.1 +/- 0.4; however, at 758 microM, lopinavir binding was essentially unsaturable. Lopinavir binding to AAG and HSA was not sensitive to ritonavir, and, thus, efforts to enhance fetal exposure to lopinavir should be focused on other issues such as efflux transporters.

Performance of a Multidisciplinary Pancreatic Cancer Conference in Predicting and Managing Resectable Pancreatic Cancer.

OBJECTIVES: Surgery is the curative treatment for pancreatic ductal adenocarcinoma (PDA). Guidelines recommend utilizing a multidisciplinary pancreatic cancer conference (MDPC) in treatment; however, data are limited. The objective of this study was to assess the accuracy of an MDPC. METHODS: Patients with PDA presented at an MDPC were prospectively collected from April 2013 to August 2016. Patients were included if the MDPC predicted them to have resectable PDA and underwent upfront surgery. Secondary aims were to compare differences in tumor characteristics, time to surgery, and resection rates with patients prior to MDPC implementation (pre-MDPC). RESULTS: A total of 278 patients were presented at the MDPC. After excluding borderline and nonresectable cases, 91 patients were predicted as resectable on evaluation, and 70 were fit for surgery. The MDPC predicted resection in 91.4%. The MDPC had larger tumor size (32.6 vs 24.0 mm), greater proportion of stage II tumor, and a shorter time from diagnosis to resection (27.3 vs 35.5 days) compared with the pre-MDPC. Microscopically negative resections were similar between MDPC and pre-MDPC (85.9% vs 88.0%) despite advanced tumor size and stage. CONCLUSIONS: The MDPC demonstrates a high resection rate. Compared with a pre-MDPC, MDPC provides shorter time to surgery and selects for advanced tumors.

Endoscopic ultrasound guided fine-needle aspiration vs core needle biopsy for solid pancreatic lesions: Comparison of diagnostic accuracy and procedural efficiency.

BACKGROUND: Endoscopic ultrasound (EUS) guided core needle biopsies (CNB) are increasingly being performed to diagnose solid pancreatic lesions. However, studies have been conflicting in terms of CNB improving diagnostic accuracy and procedural efficiency vs fine-needle aspiration (FNA), which this study aims to elucidate. METHODS: Data were prospectively collected on consecutive patients with solid pancreatic or peripancreatic lesions at a single tertiary care center from November 2015 to November 2016 that underwent either FNA or CNB. Patient demographics, characteristics of lesions, diagnostic accuracy, final and follow-up pathology, use of rapid on-site evaluation (ROSE), complications, and procedure variables were obtained. RESULTS: A total of 75 FNA and 48 CNB were performed; of these, 13 patients had both. Mean passes were lower with CNB compared to FNA (2.4 vs 2.9, P = .02). Use of ROSE was higher for FNA (97.3% vs 68.1%, P = .001). Mean procedure time was shorter with CNB (34.1 minutes vs 51.2 minutes, P = .02) and diagnostic accuracy was similar (89.2% vs 89.4%, P = .98). There was no difference in diagnostic accuracy when ROSE was performed for CNB vs not performed (93.5% vs 85.7%, P = .58). Additionally, diagnostic accuracy of combined FNA and CNB procedures was 92.3%, which was comparable to FNA (P = .73) or CNB (P = .52) alone. CONCLUSION: FNA and CNB had comparable safety and diagnostic accuracy. Use of CNB resulted in less number of passes and shorter procedure time as compared to FNA. Moreover, diagnostic accuracy for CNB with or without ROSE was similar.

An Evaluation of a Factor Xa-Based Clotting Time Test for Enoxaparin: A Proof-of-Concept Study.

A well-accepted test for monitoring anticoagulation by enoxaparin is not currently available. As inadequate dosing may result in thrombosis or bleeding, a clinical need exists for a suitable test. Previous in silico and in vitro studies have identified factor Xa as an appropriate activating agent, and the phospholipid Actin FS as a cofactor for a Xa clotting time (TenaCT) test. A proof-of-concept study was designed to (1) explore the reproducibility of the TenaCT test and (2) explore factors that could affect the performance of the test. In vitro clotting time tests were carried out using plasma from 20 healthy volunteers. The effect of enoxaparin was determined at concentrations of 0.25, 0.50, and 1.0 IU/mL. Clotting times for the volunteers were significantly prolonged with increasing enoxaparin concentrations. Clotting times were significantly shortened for frozen plasma samples. No significant differences in prolongation of clotting times were observed between male and female volunteers or between the 2 evaluated age groups. The clotting times were consistent between 2 separate occasions. The TenaCT test was able to distinguish between the subtherapeutic and therapeutic concentrations of enoxaparin. Plasma should not be frozen prior to performing the test, without defining a frozen plasma reference range. This study provided proof-of-concept for a Xa-based test that can detect enoxaparin dose effects, but additional studies are needed to further develop the test.

Esophageal Lichen Planus: Understanding a Potentially Severe Stricturing Disease.

A 67-year-old woman with a long-standing history of recurrent dysphagia and esophageal strictures failed to respond to aggressive antireflux management. She required multiple dilations for symptomatic strictures that were discovered throughout the esophagus. Intralesional, topical, and systemic glucocorticoid therapies were utilized without resolution in symptoms. Several years after initial presentation, histopathology ultimately demonstrated lichenoid features and a diagnosis of esophageal lichen planus (ELP) was confirmed. However, as her symptoms had already become significantly disabling with severe strictures that carried an increased risk of endoscopic complications with dilation, she ultimately decided to undergo an esophagectomy for definitive treatment. Moreover, ELP may often go unrecognized for several years. Clinicians should consider ELP in the differential for dysphagia in middle- to elderly-aged women with or without a known history of lichen planus (LP) especially for those with findings of multiple or proximal strictures.

Intrasperm Ca2+ modulation and human ejaculated sperm viability: influence of miconazole, clotrimazole and loperamide.

Elevation of intrasperm Ca(2+) is reported to influence viability of ejaculated spermatozoa. Human spermatozoa possess inositol triphosphate (IP(3))-sensitive Ca(2+) stores, which can be targeted for increasing intrasperm Ca(2+) level. The influence of agents affecting Ca(2+) homeostasis has been investigated. Miconazole nitrate, clotrimazole and loperamide hydrochloride produced a dose- and time-dependent decrease in viability, each requiring respectively 0.5, 1.0 and 1.0 mM for producing death of all sperm cells immediately upon addition to ejaculated human semen samples. The reduction in sperm viability was accompanied by elevation of intrasperm Ca(2+) and was not affected by presence or absence of extracellular Ca(2+). Significantly (P<0.05) less time was required for producing complete loss of sperm viability and increasing intrasperm Ca(2+) when any of these drugs was added to sperm cells previously treated with selected agents affecting Ca(2+) homeostasis. This enhanced spermicidal activity of miconazole, clotrimazole and loperamide appeared to be due to further mobilization of Ca(2+) from partially depleted intrasperm Ca(2+) stores. Synergism of spermicidal activity and intrasperm Ca(2+) elevation by miconazole or clotrimazole was observed when Ca(2+) efflux from sperm cells was simultaneously inhibited by 2',4'-dichlorobenzamil hydrochloride, a Na(+)-Ca(2+) exchange inhibitor. The spermicidal activity of miconazole, clotrimazole or loperamide due to elevation of intrasperm Ca(2+) and its synergism, therefore, has great potential for exploitation of these drugs as contact spermicides.

Immunoglobulin G4 (IgG4)-associated pouchitis - Part of IgG4 related disease? A case series and review of the literature.

BACKGROUND AND AIMS: IgG4-mediated pouchitis was first described in 2011. The aetiology and pathogenesis of IgG4-associated pouchitis is unknown. Over the last four years, less than seventy cases of IgG-associated pouchitis have been reported from a pouchitis clinic in Cleveland. METHODS: We report the first two cases of IgG4-associated pouchitis from our inflammatory bowel disease clinic and outside of Cleveland. CONCLUSION: This highlights the fact that this entity could be more common than we think. It is important for general gastroenterologists to think about IgG4-mediated disease if the patient has refractory pouchitis, so early diagnosis and referral can be made. This would avoid the cost of expensive therapy and minimize antibiotic use which is what happened in our cases prior to this diagnosis being made.