Miracle-dz/UniFAR-FTUs huggingface dataset:
Human drug‐induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump

Drug‐induced liver injury (DILI) accounts for 20‐40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound‐ and/or patient‐specific. Compound‐specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy‐dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR‐LTKB), the inhibitory properties of 24 Most‐DILI‐, 28 Less‐DILI‐, and 20 No‐DILI‐concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs. Conclusion: These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient‐specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI. (Hepatology 2014;60:1015–1022)
Respirable dust and silica exposure among World Trade Center cleanup workers

ABSTRACT The cleanup effort following the destruction of the World Trade Center (WTC) was unprecedented and involved removal of 1.8 million tons of rubble over a nine-month period. Work at the site occurred 24 hr a day, 7 days a week and involved thousands of workers during the process. The Occupational Safety and Health Administration (OSHA) conducted personal and area exposure sampling during the cleanup of the site. Secondary data analysis was performed on OSHA air sampling data for respirable dust and silica from September 2001 to June 2002 at the WTC recovery site to characterize workers' exposure. Results for silica and respirable particulate were stratified by area and personal samples as well as job task for analysis. Of 1108 samples included in the analysis, 693 were personal and 415 were area. The mean result for personal silica samples was 42 μg/m3 (Range: 4.2–1800 μg/m3). Workers identified as drillers had the highest mean silica exposure (72 μg/m3; range: 5.8–800 μg/m3) followed by workers identified as dock builders (67 μg/m3; range: 5.8–670 μg/m3). The mean result for personal samples for respirable particulate was 0.44 mg/m3 (range: 0.00010–13 mg/m3). There were no discernable trends in personal respirable dust and silica concentrations with date.
Endovascular Aortic Aneurysm Repair and the Role of Ultrasound Surveillance

The endovascular revolution is underway. Endovascular or catheter-based techniques have the potential to supersede many major open vascular procedures in a similar way to laparoscopic surgery, which has replaced many traditional abdominal operations. There have been dramatic advances in the types of vascular disorders that can be treated by endovascular technology. These include endoluminal stenting of arteries and veins, the exclusion of aneurysms by covered stents and possibly most importantly, the treatment of abdominal aortic aneurysms (AAA) by endovascular aortic aneurysm repair (EVAR) using endovascular stent grafts. In the UK, vascular surgeons have been learning catheter-based techniques with the help of the vascular radiologists, and it is not uncommon to see the vascular radiologist and surgeon working together in the operating theatre or angiography department. It is likely that there will be continuing integration between these specialities.
HepG2 cells mount an effective antiviral interferon‐lambda based innate immune response to hepatitis C virus infection

Hepatitis C virus (HCV) exposure leads to persistent life‐long infections characterized by chronic inflammation often developing into cirrhosis and hepatocellular carcinoma. The mechanism by which HCV remains in the liver while inducing an inflammatory and antiviral response remains unclear. Though the innate immune response to HCV in patients seems to be quite active, HCV has been shown in cell culture to employ a diverse array of innate immune antagonists, which suggests that current model systems to study interactions between HCV and the innate immune system are not representative of what happens in vivo. We recently showed that hepatoma‐derived HepG2 cells support the entire HCV life cycle if the liver‐specific microRNA, miR‐122, is expressed along with the entry factor, CD81 (termed HepG2‐HFL cells). We found that there was a striking difference in these cells' ability to sustain HCV infection and spread when compared with Huh‐7 and Huh‐7.5 cells. Additionally, HepG2‐HFL cells exhibited a more robust antiviral response when challenged with other RNA viruses and viral mimetics than Huh‐7 and Huh‐7.5 cells. HCV infection elicited a potent interferon‐lambda (IFN‐λ), IFN‐stimulated gene, and cytokine response in HepG2‐HFL cells, but not in Huh‐7 cells, suggesting that HepG2‐HFL cells more faithfully recapitulate the innate immune response to HCV infection in vivo. Using this model, we found that blocking the retinoic acid‐inducible gene I (RIG‐I)‐like receptor pathway or the IFN‐λ‐signaling pathway promoted HCV infection and spread in HepG2‐HFL cells. Conclusion: HepG2‐HFL cells represent a new system to study the interaction between HCV and the innate immune system, solidifying the importance of IFN‐λ in hepatic response to HCV infection and revealing non‐redundant roles of RIG‐I and melanoma differentiation‐associated protein 5 in HCV recognition and repression of infection. (Hepatology 2014;60:1170–1179)
Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial

Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate‐stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double‐blind, placebo‐controlled, phase III study, 870 patients with TACE‐eligible HCC were planned to be randomly assigned (1:1) after the first TACE to receive either brivanib 800 mg or placebo orally once‐daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow‐up was approximately 16 months. Intention‐to‐treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 [95% confidence interval {CI}: 19.1 to not reached] vs. 26.1 months [19.0‐30.9]; hazard ratio [HR]: 0.90 [95% CI: 0.66‐1.23]; log‐rank P = 0.5280). Brivanib improved TTES/VI (HR, 0.64 [95% CI: 0.45‐0.90]), TTP (0.61 [0.48‐0.77]), and rate of TACE (0.72 [0.61‐0.86]), but not TTDP (0.94 [0.72‐1.22]) versus placebo. Most frequent grade 3‐4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%). Conclusions: In this study, brivanib as adjuvant therapy to TACE did not improve OS. (Hepatology 2014;60:1697–1707)
Dynamic Eco-Driving for Signalized Arterial Corridors and Its Indirect Network-Wide Energy/Emissions Benefits

There are various strategies being considered to reduce fuel consumption and emissions from the transportation sector. From the transportation operations perspective, one strategy that has gained interest worldwide is eco-driving. Eco-driving typically consists of changing a person's driving behavior based on providing general advice to the driver, such as accelerating slowly, driving smoothly, and reducing high speeds. More advanced dynamic eco-driving provides real-time advice to drivers based on changing traffic and infrastructure conditions for even greater fuel and emission savings. The concept of dynamic eco-driving takes advantage of real-time traffic sensing and infrastructure information, which can then be communicated to a vehicle with a goal of reducing fuel consumption and emissions. This article considers dynamic eco-driving in an arterial corridor with traffic control signals, where signal phase and timing (SPaT) information of traffic lights is provided to the vehicle as it drives down the corridor. The vehicle can then adjust its velocity while traveling through the corridor with the goal of minimizing fuel consumption and emissions. A dynamic eco-driving velocity planning methodology has been developed and is described herein. This algorithm has then been extensively tested in simulation, showing individual vehicle fuel consumption and CO2 reductions of around 10–15%, depending on corridor parameters including traffic volume, traffic speed, and other factors. This 10–15% improvement is realized directly by the vehicle that is equipped with this dynamic eco-driving technology and can be accomplished with very little time loss. We have also carried out an extensive analysis of the entire traffic stream under different traffic volumes and different penetration rates of the dynamic eco-driving technology. It is found that there are also significant indirect network-wide energy and emissions benefits on the overall traffic, even at low penetration rates of the technology-equipped vehicles. Based on the simulation results, the maximum fuel saving and emission reduction occur during medium traffic volumes (corresponding to traffic volume of 300 vehicles/hr/link) and with low penetration rates (5%, 10%, and 20%). Under these conditions, the total traffic energy/emissions savings typically triple what is saved from the technology-equipped vehicles alone (e.g., total 4% savings compared to 1.3% savings). This is due primarily to the eco-driving velocity planning affecting nonequipped vehicles that follow behind.
The endothelial-erectile dysfunction connection: an essential update.

INTRODUCTION The endothelial monolayer plays a crucial role in the vasodilation and hemodynamic events involved in erection physiology. Due to its relevant functions, a close link has been established between endothelial integrity and erectile dysfunction (ED). Endothelial dysfunction is induced by the detrimental actions of vascular risk factors (VRFs), identified as common correlates for the development of cardiovascular disease and ED. It is currently recognized that ED is the early harbinger of a more generalized vascular systemic disorder, and, therefore, an evaluation of endothelial health in ED patients should be of prime relevance. Several noninvasive methods for endothelial function assessment have been proposed, including the Penile Nitric Oxide Release Test (PNORT). AIM To highlight the most recent gathered knowledge on basic and clinical mechanisms underlying loss of cavernosal endothelial function promoted by VRFs and to discuss local and systemic methods for endothelial function assessment in ED individuals, focusing on the PNORT. MAIN OUTCOME MEASURES A complete revision on the novel basic and clinical links between endothelial and ED. METHODS A systematic review of the literature regarding the aforementioned issues. RESULTS Risk factor-associated cavernosal endothelial dysfunction is mostly induced by unifying mechanisms, including oxidative stress and impaired endothelial nitric oxide functional activities, which present clinically as ED. Several techniques to evaluate endothelial dysfunction were revised, with advantages and limitations debated, focusing on our detailed expertise using the PNORT method. CONCLUSIONS The established endothelial-erectile dysfunction connection was thoroughly revised, from basic mechanisms to the clinical importance of endothelial dysfunction assessment as diagnosis for generalized vascular disease. Further studies are required to disclose efficient approaches to repair disabled endothelium and both restore and prevent endothelial dysfunction.
Sexual, marital, and social impact of a man's perceived infertility diagnosis.

INTRODUCTION Male factor infertility is a relatively common problem. This diagnosis may increase sexual, marital, and relationship strain in male partners of infertile couples. AIM To measure the personal, social, sexual, and marital impacts of a male factor infertility diagnosis among men in couples evaluated for infertility. METHODS Cross-sectional analysis of 357 men in infertile couples from eight academic and community-based fertility clinics. Participants completed written surveys and face-to-face and telephone interviews at study enrollment. This interview queried each participant's perception of their infertility etiology to determine the primary study exposure (i.e., male factor only, male and female factors, female factor only, unknown). MAIN OUTCOME MEASURES Personal Impact, Social Impact, Marital Impact, and Sexual Impact scales. RESULTS Among the 357 men, no male factor was reported in 47%, isolated male factor was present in 12%, combined male and female factors were present in 16%, and unexplained infertility was present in 25% of couples. Male factor infertility was independently associated with worse Sexual (mean 39 vs. 30, standard deviation [SD] 2.7, P = 0.004) and Personal (mean 37 vs. 29, SD 3.8, P = 0.04) Impact scores relative to men in couples without male factor infertility. These differences remained statistically significant after controlling for male age, partner age, race, religion, educational level, employment status, prior pregnancy, duration of infertility, and prior paternity. CONCLUSIONS Male partners in couples who perceive isolated male factor infertility have a lower sexual and personal quality of life compared with male partners of couples without perceived male factor infertility. Social strain is highest among couples without a clear etiology for infertility. These findings highlight the clinically significant negative sexual, personal, and social strains of a perceived infertility diagnosis for men.
A self-regulation traffic-condition-based route guidance strategy with realistic considerations: Overlapping routes, stochastic traffic, and signalized intersections

ABSTRACT Variable message signs that provide various types of route guidance information have been widely deployed in large cities. To release proper information only using easily collected data, a simple traffic-condition-based (TCB) route guidance strategy was recently proposed. The strategy works based on the estimation of free-flow and congested traffic conditions and is capable of approximating user optimal equilibrium stably. Due to little consideration of the complexity of urban road networks, the TCB strategy is still away from field applications in urban areas. To further push the strategy toward field tests, this article improves the TCB strategy in the following aspects: supplementing the strategy with a self-regulation ability by considering existing traffic conditions; decomposing link capacity to solve the problem of overlapping routes by comparing link capacity on alternative routes; coping with stochastic traffic; and the impact of signalized intersections by utilizing aggregated data. A scenario for an urban road network in Beijing, China, is simulated to test the improved strategy, and the simulation results clearly indicate the effectiveness of the proposed improvements. The improvements extend the TCB strategy on moderately complicated urban road networks, and still have the advantages of simple diversion rules, easily obtained input data, and stable and effective diversion processes.
The Real–Time Stop–Skipping Problem

As a departure from previous studies on the stop–skipping control problem, this study investigates the possibility of implementing a stop–skipping policy for operations control in a real–time manner. Stop–skipping is investigated for a service disruption of varying length, occurring in the middle of a route, as a means of responding to the disruption more rapidly. Based on a preliminary analysis that shows that a basic stop–skipping policy may not be appropriate for real–time application, a policy alternative is constructed such that the control vehicle can still drop off passengers at stops in the skipping segment. The stop–skipping strategy is formulated separately for both policies as a nonlinear integer programming problem. The problem formulation includes assumptions of random distributions of passenger boardings and alightings, specifically with the binomial distribution and Poisson distribution representing the passenger alighting and boarding processes, respectively. The problem solution uses an exhaustive search method by taking advantage of the relatively small scale of the problem. A simulation study is conducted to examine how the performance of the two stop–skipping policies changes with the passenger distribution pattern, the service disruption location, the disruption length, as well as the vehicle travel time variability on the route. These simulation results suggest that both policies are not very sensitive to the travel time variability individually, when compared to other major factors. However, the travel time variability could contribute significantly to the difference in performance of the two policies because it affects the performance of the two policies in opposite ways. For both normal and downtown–oriented passenger distribution patterns, both policies perform similarly in term of total passenger waiting time reduction for a majority of cases. However, a significant difference in the performance of the two policies can still be seen for a large percentage of cases under varying circumstances. These results suggest that the downtown–oriented passenger distribution pattern may present the most desirable condition for the policy alternative. For the reverse–direction passenger distribution pattern, the policy alternative rarely outperforms the basic policy due to the inherent dynamics of the policy itself.
Risk assessment of clinical outcomes in Asian patients with chronic hepatitis B using enhanced liver fibrosis test

Serum fibrosis markers, such as the enhanced liver fibrosis (ELF) test, have been suggested as alternatives for liver biopsy (LB) in assessing liver fibrosis. We investigated the efficacy of the ELF test in predicting development of liver‐related events (LREs) in patients with chronic hepatitis B (CHB). A total of 170 patients (103 men; 60.6%) with CHB who underwent LB and serological tests for determining ELFs were enrolled. All patients were followed up to monitor LRE development, defined as hepatic decompensation, hepatocellular carcinoma, and/or liver‐related death. The mean age was 45.3 years. During the follow‐up period (median, 41 months), 39 (22.9%) patients experienced LREs. In patients with LREs, age, proportion of male gender, ELF test results, age–spleen–platelet ratio (ASPRI), liver stiffness (LS) value, and proportion of histological cirrhosis were significantly higher than those in patients without LREs (all P < 0.05). Areas under the receiver operating characteristic curves to predict LRE development were 0.808 for the ELF test, 0.732 for LS value, 0.713 for histological fibrosis stages using Batts and Ludwig's scoring system, and 0.687 for ASPRI. On multivariate analysis, along with age, the ELF test was an independent predictor of LRE development (adjusted hazard ratio [HR], 1.438; P < 0.001). When we applied a three‐tier stratification of our study population using cut‐off ELF values of 8.10 and 10.40, patients with low (P = 0.002; adjusted HR: 0.045; 95% confidence interval [CI]: 0.006‐0.330) and intermediate (P < 0.001; adjusted HR: 0.239; 95% CI: 0.122‐0.469) ELF range were found less likely to develop LREs, compared to those with high ELF range. Conclusion: ELF is useful in a noninvasive prediction of LRE development. Transient elastography showed a statistically similar prognostic performance for LREs as the ELF, but other noninvasive tests were inferior. (Hepatology 2014;60:1911‐1919)
Unrecognized chronic hepatitis C virus infection among baby boomers in the emergency department

The Centers for Disease Control and Prevention and U.S. Preventive Services Task Force have highlighted public screening as an essential strategy for increasing hepatitis C virus (HCV) detection in persons born between 1945 and 1965 (“baby boomers”). Because earlier HCV screening efforts have not targeted emergency department (ED) baby boomer patients, we describe early experience with integrated opt‐out HCV antibody (Ab) screening of medically stable baby boomers presenting to an urban academic ED. We performed HCV Ab testing 24 hours per day and confirmed positive test results using polymerase chain reaction (PCR). The primary outcome was prevalence of unrecognized HCV infection. Among 2,325 unique HCV‐unaware baby boomers, 289 (12.7%) opted out of HCV screening. We performed HCV Ab tests on 1,529 individuals, of which 170 (11.1%) were reactive. Among Ab reactive cases, follow‐up PCR was performed on 150 (88.2%), of which 102 (68.0%) were confirmed RNA positive. HCV Ab reactivity was more likely in males compared to females (14.7% vs. 7.4%; P < 0.001), African Americans compared to whites (13.3% vs. 8.8%; P = 0.010), and underinsured/ uninsured patients compared to insured patients (16.8%/16.9% vs. 5.0%; P = 0.001). Linkage‐to‐care service activities were recorded for 100 of the 102 confirmed cases. Overall, 54 (54%) RNA‐positive individuals were successfully contacted by phone within five call‐back attempts. We confirmed initial follow‐up appointments for 38 (70.4%) RNA‐positive individuals successfully contacted, and 21 (55.3%) individuals with confirmed appointments attended their initial visit with a liver specialist; 3 (7.9%) are awaiting an upcoming scheduled appointment. Conclusion: We observed high prevalence of unrecognized chronic HCV infection in this series of baby boomers presenting to the ED, highlighting the ED as an important venue for high‐impact HCV screening and linkage to care. (Hepatology 2015;61:776–782)