Non-alcoholic steatohepatitis (NASH) results from inflammation and hepatocyte injury in the setting of hepatic steatosis. Non-alcoholic steatohepatitis increases the risk of progression to liver fibrosis and cirrhosis, and is the most rapidly growing etiology for liver failure and indication for liver transplantation in the USA. Weight loss and lifestyle modification remain the standard first-line treatment, as no USA Food and Drug Administration-approved pharmacotherapy currently exists. The past decade has seen an explosion of interest in drug development targeting pathologic pathways in non-alcoholic steatohepatitis, with numerous phase 2 and 3 trials currently in progress. Here, we concisely review the major targets and mechanisms of action by class, summarize results from completed pivotal phase 2 studies, and provide a detailed outline of key active studies with trial data for drugs in development, including obeticholic acid, elafibranor, cenicriviroc and selonsertib.

When cells are subject to endoplasmic reticulum (ER) stress due to inflammation, inadequate nutrition or infection, a characteristic environment of glucose starvation, acidosis and hypoxia is created. All the conditions cited contribute to ER stress as well as the unfolded protein response (UPR). The UPR is active in a variety of human tumor types. Depending on the severity of ER stress, the UPR can exert a cytoprotective function by resolving the misfolded or unfolded protein, further reducing the ER protein load in mild stress, or by sending signal to cells to undergo cell death by apoptosis in the severe condition. Recent studies suggest that the glucose-regulated protein (GRP)78, or immunoglobulin heavy chain binding protein (BiP), not only confers an advantage to cell survival through an anti-apoptotic function but also may improve cell proliferation and angiogenesis. Understanding how the UPR can induce adaptation to chronic stress instead of apoptosis in cells will be of invaluable significance toward finding a cure for ER stress-associated diseases. This review covers what is known about the adaptive responses of cells when facing ER stress and how these information may lead to discoveries of novel treatments for various related disorders. Studies have suggested that ER stress promotes tissue remodeling under a variety of conditions and through several mechanisms, including activation of apoptosis, epithelial-mesenchymal transition, and enhanced inflammatory response. This review also focuses on the major cell components in the gut, primarily epithelial cells and mesenchymal cells, for which a myriad of evidence suggests that sustained ER stress causes epithelial cell damage along with resultant mucosal barrier dysfunction, stimulates mesenchymal cell differentiation, and induces myofibroblasts activation and their secretion of excess extracellular protein leading to matrix collagen-rich tissue formation. Several key questions are still not answered by the fibrosis research and are discussed in this review: for example, the mechanisms of ER stress induction and the specific signaling pathway(s) activated by which UPR leads to development of organ fibrosis, or how to maintain ER stress at a basal level instead of exacerbating its physiological role that is otherwise necessary to maintain intracellular homeostasis. Ultimately, further investigations are needed to bridge the gap between our current understanding of ER stress mechanisms and to identify efficient anti-fibrotic therapeutic regimens.

Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to NAFLD-related liver cirrhosis and is a main cause of chronic liver diseases. Patients with nonalcoholic steatohepatitis and fibrosis are at a great risk of the progression to cirrhosis or hepatocellular carcinoma, both of which are tightly associated with liver-related mortality. Liver biopsy is still the gold standard for the diagnosis of NAFLD, but some defects, such as serious complications, sampling error and variability in histologic evaluation among pathologists, remain problematic. Therefore, noninvasive, repeatable and accurate diagnostic methods are urgently needed. Ultrasonography is a well-established and lower-cost imaging technique for the diagnosis of hepatic steatosis, especially suitable for population census, but limited by its low sensitivity to diagnose mild steatosis and being highly operator-dependent. Computed tomography also lacks the sensitivity to detect mild steatosis and small changes in fat content, and presents a potential radiation hazard. Controlled attenuation parameter based on the FibroScan® technology is a promising tool for noninvasive semiquantitative assessment of liver fat content, but the accuracy rate depends on the operator’s expertise and is affected by age, width of the intercostal space, skin capsular distance and body mass index. Magnetic resonance imaging and magnetic resonance spectroscopy are regarded as the most accurate quantitative methods for measuring liver fat content in clinical practice, especially for longitudinal follow up of NAFLD patients. In this review, we mainly introduce the current imaging methods that are in use for evaluation of liver fat content and we discuss the advantages and disadvantages of each method.

Adoption of the model for end-stage liver disease score by Organ Procurement and Transplant Network (OPTN) deceased donor liver allocation policy in 2002 has led to an increase in the number of simultaneous liver kidney (SLK) transplantation. Since kidney function recovery following liver transplantation is difficult to predict, allocation of the kidney for SLK transplantation thus far has not been based on much rationale and evidence. Lack of OPTN policy towards SLK organ allocation has resulted in great variations among transplant centers regarding SLK transplantation. Increasing use of kidneys towards SLK transplantation diverts deceased donor kidneys away from candidates awaiting kidney-alone transplantation. Recently OPTN/United Network of Organ Sharing has implemented medical eligibility criteria for adult SLK transplantation which also includes a concept of safety net. Implementation of the new policy is a move in a positive direction, providing consistency in our practice and evidence-based guidelines in selecting candidates for SLK transplantation. This policy needs to be monitored prospectively and modified based on new data that will emerge over time. This review outlines the literature on SLK transplantation and efforts towards developing rational policy on SLK organ allocation.

Background and Aims: Recurrent hepatitis C (HCV) disease in liver transplant (LT) recipients is associated with significant morbidity and mortality. With the availability of noninterferon-based therapy, eliminating HCV may be achievable in LT recipients.

Methods: We studied all consecutive recipients who underwent LT at the University of California Los Angeles between January 2005 and June 2017. We collected data on date of transplant and last follow-up, as well as laboratory values. We also recorded type and timing of antiviral therapy relative to LT. Analyses were performed to assess the proportion of LT recipients who are viremic after transplant.

Results: Six hundred thirty-four patients underwent LT with a diagnosis of HCV. There was a statistically significant trend for patients to be cured before (p < 0.001) and after liver transplantation (p < 0.001) for the study period of 2014 to 2016 relative to 2005 and 2013, respectively. Of the 634 recipients eligible for therapy, 8% and 74% were treated within 12 months of transplant for the study periods 2005 to 2013 and 2014 to 2016, respectively. There was a significant decrease between the two study periods in the proportion of patients undergoing re-LT 1 year after the original LT: 5.5% (n = 28/510) and 1.5% (n = 2/124) respectively for study periods 2005 to 2013 and 2014 to 2016 respectively (p = 0.011).

Conclusions: The proportion of LT recipients who are viremic has decreased over time. Eliminating HCV in LT recipients is feasible after the introduction of direct-acting agents. Curing HCV should translate to improved clinical outcomes in LT recipients who were transplanted for HCV infection with longer follow-up. Preliminary results suggest the decreased need for transplant in the direct-acting agents era.

Asymptomatic bacteriuria (ASB) poses a serious health problem to pregnant women and fetuses. However, in most developing countries, routine screening for ASB and antimicrobial sensitivity test are rarely performed. This study, therefore, aimed to determine the best diagnostic method for routine screening of ASB and antimicrobial susceptibility pattern among pregnant women attending an antenatal clinic in the Ashanti Region of Ghana.

Urine samples from 412 pregnant women between the ages of 16 and 45 years-old attending antenatal clinic at Anglogold Ashanti Health Foundation Hospital and Ellolab Diagnostic Centre were screened for ASB by microscopy, dipstick urinalysis and bacteria culture. Susceptibility of the positive isolates were assessed against commonly used antimicrobial agents, adopting the disc diffusion test method.

Of the 412 pregnant women screened, 72 tested positive for ASB by the urine culture method, which translates into an overall prevalence of 17.5%. There was no association between age, marital status, occupation, parity, educational background nor duration of pregnancy with ASB (p > 0.05). Additionally, dipstick urinalysis was found to be a better diagnostic method than microscopy. The most isolated bacteria were Escherichia coli (62.5%) and Klebsiella pneumoniae (30.6%), and nitrofurantoin and nalidixic acid were the most effective antimicrobial agents.

Routine urine culture and antimicrobial susceptibility test should be carried out on all pregnant women attending antenatal clinic to detect possible ASB and prescribe appropriate drugs, such as nitrofurantoin and nalidixic acid, to prevent any related complications. However, in health centers that lack bacterial culture facilities, dipstick urinalysis should be the preferred screening option.

Regional anesthesia is the preferred modality for obstetric patients undergoing cesarean section due to the risks associated with general anesthesia in pregnant women. Single-shot spinal anesthesia is usually administered, which may be associated with post-block maternal hypotension, despite adequate intravenous fluid therapy. This is deleterious for the uteroplacental circulation, leading to poor outcomes in both the mother and fetus. There are several vasopressors which are used for treatment of these hypotensive episodes. Mephentermine is a sympathomimetic, having both direct and indirect actions. It has many side effects, however, including increased risks of arrhythmias, hypertension, central nervous system stimulation and abuse potential. Yet, it is still used in many developing countries, due to low cost and easy availability. We hereby report a case of rhythm disturbance with missed beats following use of mephentermine to counter hypotension after spinal anesthesia for cesarean section. The rhythm disturbance had a spontaneous resolution, with the patient maintaining hemodynamic stability during and after the episode.

Electromagnetic fields have been evaluated in multiple environments as a source of incidental exposure as well as a therapeutic treatment modality. At low levels and in specific therapies, electromagnetic fields have been found to be safe and may have positive effects on human physiology that improve disease course or alter the severity of some ailments. We conducted a study to investigate whether a commercial Federal Drug Administration-approved electromagnetic field generator device used for stress reduction and relaxation has the capability to impart a measurable impact on the cardiac autonomic nervous system.

This study was designed as a randomized double-blind, sham-stimulation controlled study in healthy subjects. The stimulation or treatment was the application of parasympathetic-targeted electromagnetic fields through the Federal Drug Administration-approved Resonator® device for 60 m. The primary measurements of treatment effect were heart rate variability (measured at baseline and every 15 m) and salivary cortisol (pre- and postapplication). The active treatment consisted of two sessions, 60 m in duration. The electromagnetic field algorithm applied was A160 (3.1 × 10−8 to 3.2 × 10−8 Gauss, frequency range of 0.857–0.859 Hz). All participants received both a sham and an active treatment session, the order of which was randomized.

A total of 28 patients completed both sessions. The measured difference in cortisol between the groups was not statistically significant (p = 0.66). There was a trend towards decreased cortisol levels over time in both groups (p = 0.09 for time trend). Measured heart rate variability showed a nonsignificant reduction in low frequency to high frequency ratio (low frequency/high frequency) at 60 m.

While the results were nonsignificant, the trend towards a reduction in low frequency/high frequency is suggestive of a delayed electromagnetic field effect. This study is hypothesis-generating since additional research is needed to either adjust the electromagnetic field treatment dose/duration during sessions or delay the final data collection of heart rate variability and salivary cortisol until hours after the active treatment.

Malaria and tuberculosis remain endemic in tropical regions and most often coexist, increasing the burden of malaria mortality due to unintended interactions of the co-administered drugs employed in the management of the infections. Rifampicin (RIF) and amodiaquine (ADQ) are likely to be administered concurrently in the treatment of patients with tuberculosis and malaria. The metabolism of ADQ is mediated principally by CYP2C8, while RIF is a known inducer of this enzyme. This study, therefore, investigated the effect of RIF on the disposition of ADQ, a major partner drug in the first-line treatment against uncomplicated malaria in line with the World Health Organization recommendations.

Sixteen healthy volunteers received oral 150 mg dose of RIF daily for 5 days with or without oral 600 mg single dose of ADQ on the fifth day (5th dose) with a 4-week wash out period, in a crossover fashion. Blood samples were collected at predetermined time intervals of 0, 1, 2, 4, 6, 8, 12, 24, 36 and 48 h. Plasma samples were analyzed for ADQ and its major metabolite desethylamodiaquine using a validated RP-high-performance liquid chromatography. Pharmacokinetic parameters were obtained using appropriate software and subjected to appropriate statistical analysis.

Coadministration of ADQ and RIF resulted in significant decreases in the critical pharmacokinetic parameters of ADQ, such as area under the curve (AUC0–∞) of about 66%, time to peak plasma concentration (Tmax) of about 10%, maximum plasma concentration of about 44%, and elimination half-life of about 55%, while the AUC0–∞ and Tmax of the main metabolite desethylamodiaquine increased about 2-fold and 3-fold respectively during the coadministration of RIF with ADQ. The metabolic ratio increased significantly, from 1.55 to 2.68. The AUC0–∞ and Tmax of the drug ADQ, as well as the maximum concentration of both the drug and its metabolite fell outside the point of estimates of the test/reference ratio of the geometric means of 80–125% of bioequivalence range.

An interaction was established during coadministration of RIF and ADQ, confirming RIF as a strong inducer of CYP2C8 in vivo, which may lead to malaria therapeutic failure or adverse drug reactions with ADQ and contribute to the rate at which resistance to ADQ develops.

Sterol regulator element binding proteins (SREBPs) are a family of transcription factors involved in the biogenesis of cholesterol, fatty acids and triglycerides. They also regulate physiological functions of many organs, such as thyroid, brain, heart, pancreas and hormone synthesis. Beside the physiological effects, SREBPs participate in some pathological processes, diabetes, endoplasmic reticulum stress, atherosclerosis and chronic kidney disease associated with SREBP expression changes. In the liver, SREBPs are involved in the pathogenesis of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hepatitis and hepatic cancer. There are several SREBP inhibitors that have potential for treating obesity, diabetes and cancer. This review assesses the recent findings about the roles of SREBPs in the physiology of organs’ function and pathogenesis of liver diseases.

Syphilitic hepatitis in adults is not frequently found in the population and is easily misdiagnosed. The incidence of viral hepatitis is increasing year by year, concomitantly increasing the importance of obtaining a systematic understanding of the clinical features and treatment strategies for this disease. There is, however, a lack of published definitive data regarding the clinical characteristics, diagnosis and standard treatment options for this disease. Searches were made using the MEDLINE database of PubMed and OVID for syphilitic hepatitis publications from 1951 to 2017 in an attempt to analyze and summarize the clinical characteristics.

Despite significant improvements in outcomes after liver transplantation, many patients continue to die on the waiting list, while awaiting an available organ for transplantation. Organ shortage is not only due to an inadequate number of available organs, but also the inability to adequately assess and evaluate these organs prior to transplantation. Over the last few decades, ex-vivo perfusion of the liver has emerged as a useful technique for both improved organ preservation and assessment of organs prior to transplantation. Large animal studies have shown the superiority of ex-vivo perfusion over cold static storage. However, these studies have not, necessarily, been translatable to human livers. Small animal studies have been essential in understanding and improving this technology. Similarly, these results have yet to be translated into clinical use. A few Phase 1 clinical trials have shown promise and confirmed the viability of this technology. However, more robust studies are needed before ex-vivo liver perfusion can be widely accepted as the new clinical standard of organ preservation. Here, we aimed to review all relevant large and small animal research, as well as human liver studies on normothermic ex-vivo perfusion, and to identify areas of deficiency and opportunities for future research endeavors.

Background and Aims: Sustained virologic response is evaluated by single-step reverse transcription (SRT) PCR assay, which assesses hepatitis C virus (HCV) clearance from plasma but not from tissues such as peripheral blood mononuclear cells (PBMCs). Persistence of HCV RNA in PBMCs beyond end of treatment (EOT) is associated with nonresponse. Our goal was to measure intra-PBMC HCV RNA levels during oral antiviral therapy according to the HCV therapy follow-up fractionation (CTF2) protocol.

Methods: Compensated chronic HCV patients (n = 2 78 SRT-PCR positive) were scheduled to receive oral antiviral therapy. Subjects were followed-up by SRT and intra-PBMCs HCV RNA PCR at the end of the 2nd, 6th, 10th, 14th, 18th and 24th weeks to evaluate virus clearance from plasma and PBMCs, respectively. The CTF2 protocol evaluated SRT and PBMC PCR status at each follow-up point for determining therapy continuation or interruption to address cost effectiveness.

Results: All patients tested negative by SRT PCR after therapy for 2 weeks. Application of the CTF2 protocol revealed: a) increasing HCV clearance rate from 75.9% at the end of 10th week to 90.3% at the end of 24th week (p < 0.00001); b) faster clearance of HCV from plasma compared to PBMCs at each point of follow-up until the 18th week (p < 0.05); c) higher viral elimination rates diagnosed by PBMC HCV RNA PCR(−) compared to PBMC HCV RNA PCR(+) from the 6th to 24th week of treatment (p < 0.0001); d) higher over-time increase curve of combined plasma and PBMC HCV RNA determined negativity compared to the decline in positivity curves by PBMC PCR at the 6th-18th week compared to the 24th week (p < 0.01)—these results validated treatment continuation; and e) solitary evaluation of EOT sustained HCV infection and relapses by PBMC HCV RNA (p < 0.001).

Conclusions: Early elimination of serum and tissue (PBMC) HCV infection by oral antiviral therapy can be achieved and evaluated during a cost-effective CTF2 protocol application.

Long QT syndrome (LQTS) is a rare primary cardiac electrophysiological disorder with characteristic symptoms of syncope, tachyarrhythmia and torsades-de-pointes. It is the outcome of mutations in genes encoding ion channels that function as voltage regulators. Heat shock protein (HSP) 90 is a molecular chaperone that plays vital roles in a variety of cellular processes, one of which is folding of nascent polypeptide chains into their native forms. The main objective of this study was to screen for HSP90 Q488H (C > G) polymorphism in patients with LQTS and identify its risk towards LQTS manifestation.

Allele-specific PCR was employed to genotype 49 LQTS patients, 71 first-degree relatives (FDRs) and 219 controls for the HSP90 Q488H polymorphism. The genotypes were statistically evaluated to assess their association with the risk of LQTS. Further, bioinformatic analysis was performed to validate the statistical findings.

Genotyping and statistical evaluation revealed a significant association of the CG genotype with LQTS, pointing towards a heterozygote disadvantage in the patients. The GG and CG genotypes showed a significant association with LQTS in the FDRs. Secondary pre-mRNA structure of the variant allele ‘G’ was found to be more stable than the wild-type structure.

Individuals harboring the heterozygous “CG” genotype are at increased risk for LQTS. In the FDRs, especially, the females harboring the “CG” and “GG” genotypes could transmit the risk allele to the future generation, giving rise to a disadvantage towards LQTS. It is imperative that all FDRs undergo carrier detection and/or prenatal diagnosis to prevent the recurrence of dominant-negative effect leading to sudden cardiac death events among the current and future generations.

The present study deals with a computational model of the transport and retention of drug within the arterial wall eluted from a drug-eluting stent, to enhance our understanding of the performance of this device. We considered a two-species model (free and bound) incorporating a reversible reaction to describe drug interactions with the constituents of the arterial wall. An axisymmetric model of drug delivery from a pair of stent struts has been developed, where the transport of free drug is modelled as an unsteady reaction-diffusion process, while the bound drug, assuming complete immobilization in the tissue, is modeled as an unsteady reaction process. The model also took into account a second-order binding process that describes a saturating reversible binding and time-dependent release kinetics of the drug-eluting stent. Considering that diffusion takes place over a tortuous path in a porous media, the effects of porosity and tortuosity on diffusion cannot be ruled out from this present investigation.

An explicit finite-difference scheme is leveraged to tackle numerically the governing equations of motion, together with the physiologically realistic boundary conditions.

The quantitative effects of significant factors, such as Peclet number (PeT), Damköhler number (Da), tortuosity, porosity, interstrut distance and time-dependent release kinetics of drug-eluting stent, on the distribution and retention of drug are determined graphically.

Predicted results are consistent with several existing results in the literature, which certainly validates the applicability of the model considered.

The CYP2C19*2 allele is associated with reduced clopidogrel bioactivation, increasing the risk of complications after percutaneous coronary intervention (PCI), particularly stent thrombosis. Recently published data suggests that CYP2C19*2 allele carriers have a higher risk for in-stent restenosis (ISR) after endovascular treatment. Very few studies have investigated the relationship between CYP2C19*2 and coronary ISR, with no significant association reported. The objective of this study was to assess the relationship between CYP2C19*2 allele carrier status and coronary ISR.

Patients with previous PCI with stenting and who were scheduled for elective PCI after coronary angiogram were recruited from the cardiac catheterization suite over a 12-month period. The angiography report of each patient was perused to identify patients requiring PCI due to ISR. For patients with angiography-confirmed ISR, date of previous PCI to the restenosed stent was noted. CYP2C19*2 genotyping was undertaken using a TaqMan® Drug Metabolism assay. The association between CYP2C19*2 allele carrier status and incidence of coronary ISR within 1 year was assessed using Fisher’s exact test (p < 0.05 significance) and by calculating the odds ratio (OR) with a 95% confidence interval (CI).

Of the 82 patients with previous PCI, 29 (35.4%) had angiography-confirmed ISR (12 carriers, 17 non-carriers of CYP2C19*2). In 13 (44.8%) of these patients, the restenosed stent was deployed within 1 year and the patients were on clopidogrel therapy at the time of repeat PCI (8 carriers, 5 non-carriers of CYP2C19*2). The association between CYP2C19*2 allele carrier status and ISR within 1 year was not statistically significant (Fisher’s exact p = 0.067; OR: 4.80, 95% CI: 0.98–23.54, p = 0.053).

Despite a higher proportion of CYP2C19*2 allele carriers exhibiting ISR within 1 year compared to non-carriers, the association was not statistically significant. This result may be attributed to the small sample size, and larger prospective studies are recommended to further assess this association.