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In this study, we investigate the energy loss of highly charged ions interacting with various tungsten surfaces. The analysis primarily focuses on elucidating the impact of electron density distributions on energy loss of ions. Furthermore, we explore the correlation between surface azimuthal angles and energy loss under both uniform and inhomogeneous electron density distributions. Utilizing the classical over-the-barrier model (COBM), simulations involving trajectory calculations, energy loss, charge-exchange processes, and surface electron distributions, etc., were performed. Remarkably, the significant influence of axial channeling of surfaces on ion energy loss is observed. For the comparison of ion energy loss under uniform and inhomogeneous electron density distributions, the results reveal a more pronounced effect of electron density inhomogeneity on ion energy loss at higher energy-loss values. Additionally, the calculated energy-loss spectra of Ar16+ ions grazing on graphite surfaces show reasonable agreement with experimental data. These findings are crucial for understanding the surface structure of crystals. [ABSTRACT FROM AUTHOR]

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. Primary care providers play a critical role in the screening, diagnosis, and management of MASLD and/or metabolic dysfunction-associated steatohepatitis (MASH), though they can face challenges in this setting, particularly where healthcare resources are limited and barriers to care exist. To address these challenges, several guidelines have been developed to provide evidence-based recommendations for the clinical assessment and management of patients with MASLD/MASH. To provide a unified, simple-to-understand, practical guide for MASLD screening, diagnosis, and management based on current guideline recommendations, for use by primary care providers in daily practice. Evidence-based recommendations from several international guidelines were summarized, focusing on the similarities and differences between them. Recommendations are broadly aligned across the guidelines, but several key differences are evident. Practical guidance is provided on screening, identifying target populations for risk stratification, initial evaluation of individuals with suspected MASLD, surveillance, risk stratification and referral, as well as approaches to the management of MASLD and associated comorbidities, with specific considerations for the primary care setting. Primary care providers are ideally placed to identify at-risk individuals, implement evidence-based interventions to prevent the development of fibrosis and cirrhosis, and effectively manage comorbidities. Equipping primary care providers with the necessary knowledge and tools to effectively manage MASLD/MASH may help to improve patient outcomes and reduce the burden of liver disease. [ABSTRACT FROM AUTHOR]

A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C virus (HCV)-associated decompensated cirrhosis. However, large global studies, while confirming the effectiveness of SOF/VEL in a broad range of patients, often exclude these patients. This Phase 2, single-arm, open-label study in adult patients with HCV-associated decompensated cirrhosis in France and the USA aimed to provide further data on the safety and efficacy of SOF/VEL plus RBV for 12 weeks in this population. Patients were treated with a fixed-dose combination of SOF 400 mg/VEL 100 mg plus weight-based RBV once daily for 12 weeks. The inclusion criteria were chronic HCV infection (≥6 months), quantifiable HCV RNA at screening, Child–Turcotte–Pugh class B or C cirrhosis, and liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma. Among 32 patients who initiated treatment, 78.1% achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Failure to achieve SVR12 was due to non-virologic reasons (investigator discretion, n = 1; death, n = 6). All 25 patients in the per-protocol population achieved SVR12 and all but one achieved sustained virologic response 24 weeks after the end of treatment. Adverse events (AEs) were as expected for a patient population with advanced liver disease. All Grade 3–4 and serious AEs and deaths were deemed unrelated to treatment. In patients with HCV-associated decompensated cirrhosis, SOF/VEL plus RBV achieved high SVR12 rates and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic steatohepatitis (NASH) is the more severe, inflammatory type of nonalcoholic fatty liver disease (NAFLD). NASH, a leading indication for liver transplantation, is growing in prevalence. The extent of liver fibrosis, ranging from fibrosis stage (FS) of none (F0) to cirrhosis (F4), is a strong predictor of health outcomes. There is little information on patient demographics and clinical characteristics by fibrosis stage and NASH treatment outside of academic medical centers. Methods: We conducted a cross-sectional observational study using Ipsos' syndicated NASH Therapy Monitor database, consisting of medical chart audits provided by sampled NASH-treating physicians in the United States in 2016 (n = 174) and 2017 (n = 164). Data was collected online. Results: Of 2,366 patients reported on by participating physicians and included in the analysis, 68% had FS F0–F2, 21% had bridging fibrosis (F3), and 9% had cirrhosis (F4). Common comorbidities were type 2 diabetes (56%), hyperlipidemia (44%), hypertension (46%), and obesity (42%). Patients with more advanced fibrosis scores (F3-F4) had higher comorbidity rates than patients with F0-F2. Commonly used diagnostic tests included ultrasound (80%), liver biopsy (78%), AST/ALT ratio (43%), NAFLD fibrosis score (25%), transient elastography (23%), NAFLD liver fat score (22%), and Fatty Liver Index (19%). Most commonly prescribed medications were vitamin E (53%), statins (51%), metformin (47%), angiotensin converting enzyme inhibitors (28%), and beta blockers (22%). Medications were commonly prescribed for reasons other than their known effects. Conclusion: Physicians in this study, drawn from a spectrum of practice settings, relied on ultrasound and liver biopsy for diagnosis and vitamin E, statins, and metformin for pharmacological treatment of NASH. These findings imply poor adherence to guidelines in the diagnosis and management of NAFLD and NASH. Plain language summary: Nonalcoholic steatohepatitis (NASH) is a liver disease caused by excess fat in the liver which can lead to liver inflammation and scarring (fibrosis), ranging from stage F0 (no scarring) to F4 (advanced scarring). The stage of liver scarring can predict the likelihood of future health problems, including liver failure and liver cancer. However, we do not fully understand how patient characteristics may vary at different stages of liver scarring. We looked at medical information from physicians treating patients diagnosed with NASH to understand how patient characteristics might differ based on the severity of their liver scarring. The majority (68%) of patients were stage F0-F2, with 30% having advanced scarring (F3-F4). In addition to NASH, many patients also had type 2 diabetes, high cholesterol, high blood pressure, and obesity. Patients with more advanced scarring (F3-F4) were more likely to have these diseases than patients with less severe disease (F0-F2). Diagnosis of NASH by participating physicians was based on tests including imaging (ultrasound, CT scan, MRI), liver biopsy, blood tests, and whether patients had other conditions that would put them at risk for NASH. The medications that the doctors prescribed most often to their patients included vitamin E and drugs to treat high cholesterol, high blood pressure, or diabetes. Medications were frequently prescribed for reasons other than their known effects. By understanding how patient characteristics vary by stages of liver scarring and how NASH is currently managed may help guide the evaluation and treatment of NASH when NASH-specific therapies become available. [ABSTRACT FROM AUTHOR]

The ongoing emergence of SARS-CoV-2 virus variants remains a source of concern because it is accompanied by the potential for increased virulence as well as evasion of immunity. Here we show that, although having an almost identical spike gene sequence as another Omicron variant (BA.5.2.1), a BA.4 isolate lacked all the typical disease characteristics of other isolates seen in the Golden Syrian hamster model despite replicating almost as effectively. Animals infected with BA.4 had similar viral shedding profiles to those seen with BA.5.2.1 (up to day 6 post-infection), but they all failed to lose weight or present with any other significant clinical signs. We hypothesize that this lack of detectable signs of disease during infection with BA.4 was due to a small (nine nucleotide) deletion (∆686–694) in the viral genome (ORF1ab) responsible for the production of non-structural protein 1, which resulted in the loss of three amino acids (aa 141–143). [ABSTRACT FROM AUTHOR]

The golden Syrian hamster (Mesocricetus auratus) is now commonly used in preclinical research for the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the assessment of vaccines, drugs and therapeutics. Here, we show that hamsters inoculated via the intranasal route with the same infectious virus dose of prototypical SARS-CoV-2 administered in a different volume present with different clinical signs, weight loss and viral shedding, with a reduced volume resulting in reduced severity of disease similar to that obtained by a 500-fold reduction in the challenge dose. The tissue burden of the virus and the severity of pulmonary pathology were also significantly affected by different challenge inoculum volumes. These findings suggest that a direct comparison between the severity of SARS-CoV-2 variants or studies assessing the efficacy of treatments determined by hamster studies cannot be made unless both the challenge dose and inoculation volume are matched when using the intranasal route. Additionally, analysis of sub-genomic and total genomic RNA PCR data demonstrated no link between sub-genomic and live viral titres and that sub-genomic analyses do not provide any information beyond that provided by more sensitive total genomic PCR. [ABSTRACT FROM AUTHOR]

We previously created a mandatory, inpatient, hepatology resident curriculum that immediately improved comfort, knowledge, and career interest in chronic liver disease (CLD). The durability of these effects needs to be known to use this intervention to address the hepatologist shortage. Thus, we aimed to assess this curriculum's long‐term outcomes on internal medicine (IM) residents' CLD comfort, knowledge, and career interest. From 2015 to 2019 at a single institution, one IM resident was always assigned to the rotation. Similar anonymous assessments were administered to incoming postgraduate year (PGY)‐1 residents and graduating PGY‐3 residents, including a historic control cohort that graduated in June 2015. At residency completion, the intervention cohort (n = 61) had significantly higher comfort (1, not at all comfortable/strongly disagree; 5, very comfortable/strongly agree) with both hepatology (e.g., hepatitis C, 2.5 vs. 3.3, P < 0.001) and common IM topics (e.g., heart failure, 3.6 vs. 4.8, P < 0.001) but not specialty topics lacking curricula (e.g., inflammatory bowel disease, 2.8 vs. 2.7, P = 0.54). Compared to the historic cohort (n = 27), the intervention cohort was more comfortable in several CLD topics (e.g., cirrhosis, 3.2 vs. 3.8; P = 0.005) and answered more questions correctly (65% vs. 55%; P = 0.04), but career interest was unchanged (1.9 vs. 1.8; P = 0.45). Many residents (33%) would consider a hepatology career if training were separated from gastroenterology. Conclusion: With the completion of a mandatory hepatology curriculum, residents' CLD comfort and knowledge durably improved and exceeded that of historic counterparts. Initial career interest was not sustained, perhaps due to prerequisite gastroenterology training. These findings suggest IM educational initiatives may better address hepatology workforce needs by generating comanagers than by recruiting trainees. [ABSTRACT FROM AUTHOR]

TERN‐101 is a nonsteroidal farnesoid X‐receptor agonist being developed for the treatment of nonalcoholic steatohepatitis (NASH). We assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TERN‐101 capsule and tablet formulations in healthy volunteers. In a randomized, double‐blind, placebo‐controlled study, 38 participants were enrolled and randomized to receive placebo or 25‐, 75‐, or 150‐mg TERN‐101 capsules orally once daily for 7 days. In a separate open‐label PK and formulation‐bridging study, 16 participants received single doses of TERN‐101 tablets (5 and 25 mg) or capsules (25 mg). TERN‐101 was overall well‐tolerated in this healthy volunteer population; no pruritus was reported. TERN‐101 capsule administration over 7 days resulted in decreases in serum 7α‐hydroxy‐4‐cholesten‐3‐one that were sustained for 24 hours after the last dose (maximum suppression 91% from baseline), indicating target engagement in the liver. TERN‐101 capsules exhibited less than dose‐proportional PK. Relative to capsules, TERN‐101 tablets showed increased bioavailability, with 24‐hour plasma exposure of the 5‐mg tablet similar to that of the 25‐mg capsule. There was no significant effect of food on exposure. The overall safety, PK, and PD profiles of TERN‐101 support its further evaluation for the treatment of NASH. [ABSTRACT FROM AUTHOR]

We conducted a meta-analysis to investigate the effects of the Mediterranean Diet (Med-Diet) on hepatic steatosis and insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Six randomized controlled trials were selected for the meta-analysis (sample size: 250 participants). In the meta-analysis, there was no significant difference in body mass index and waist circumference between the Med-Diet and control groups. Med-Diet significantly reduced fatty liver index (FLI) compared with the control diet (standard mean difference [SMD]: –1.06; 95% CI: –1.95 to –0.17; p  = 0.02). Med-Diet significantly reduced homeostasis model assessment of insulin resistance (HOMA-IR) compared with the control diet (SMD: –0.34; 95% CI: –0.65 to –0.03; p  = 0.03). Similarly, a meta-regression analysis using age showed that Med-Diet significantly reduced FLI and HOMA-IR (95% CI: –0.956 to –0.237, p  = 0.001 and 95% CI: –0.713 to –0.003, p  = 0.048, respectively). This meta-analysis demonstrated that Med-Diet improved hepatic steatosis and insulin resistance in patients with NAFLD. Thus, Med-Diet is a beneficial pharmaconutritional therapy in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Hypogonadism affects hepatic lipid metabolism and is expected to promote nonalcoholic fatty liver disease (NAFLD). The aims of this study were to determine (1) the prevalence of NAFLD in hypogonadal males and (2) the impact of correction of hypogonadism by LPCN 1144 (Lipocine, Inc., Salt Lake City, UT), an oral testosterone prodrug, on NAFLD in this population. Data were derived from a multicenter open‐label single‐arm trial of LPCN 1144 for hypogonadal males, in which a subset (n = 36) had serial magnetic resonance imaging–proton density fat fraction measurements (National Clinical Trial 03868059). NAFLD prevalence, defined by magnetic resonance imaging–proton density fat fraction ≥5%, was 66%. Eighty‐one percent of those with baseline liver fat (BL) ≥5% had improvement in liver fat content, and NAFLD resolved in 33% of subjects at 8 weeks (mean relative reduction: 45%) and 48% (mean relative reduction: 55%) after 16 weeks of LPCN 1144 therapy. The reduction in liver fat was greater in those with higher BL (BL ≥5%: 71%; BL ≥8%: 80%; and BL ≥10%: 75%). Normalization rate of alanine aminotransferase and gamma‐glutamyltransferase greater than the upper limit of normal range were 100% and 50% of treated patients, respectively. LPCN 1144 was not associated with major adverse events. Conclusion: Treatment with LPCN 1144 (oral T prodrug) in hypogonadal males with NAFLD resolved NAFLD in approximately half of the affected patients without any safety signals. Further studies are needed to validate its use in hypogonadal males with nonalcoholic steatohepatitis. [ABSTRACT FROM AUTHOR]

Knockout of sulfatase 2 is associated with decreased steatohepatitis and fibrosis in a mouse model of nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 319: G333-G344, 2020. First published July 20, 2020; doi:10.1152/ajpgi.00150.2019.--Sulfatase 2 (SULF2) is a heparan sulfate editing enzyme that regulates the milieu of growth factors and cytokines involved in a variety of cellular processes. We used a murine model of diet-induced steatohepatitis to assess the effect of SULF2 downregulation on the development of nonalcoholic steatohepatitis (NASH) and liver fibrosis. Wild-type B6;129 mice (WT) and Sulf2-knockout B6; 129P2-SULF2Gt(PST111)Byg mice (Sulf2-KO) were fed a fast-food diet (FFD) rich in saturated fats, cholesterol, and fructose or a standard chow diet (SC) ad libitum for 9 mo. WT mice on FFD showed a threefold increase in hepatic Sulf2 mRNA expression, and a 2.2-fold increase in hepatic SULF2 protein expression compared with WT mice on SC. Knockout of Sulf2 led to a significant decrease in diet-mediated weight gain and dyslipidemia compared with WT mice on FFD. Knockout of Sulf2 also abrogated diet-induced steatohepatitis and hepatic fibrosis compared with WT mice on FFD. Furthermore, expression levels of the profibrogenic receptors TGFR2 and PDGFR were significantly decreased in Sulf2-KO mice compared with WT mice on FFD. Together, our data suggest that knockout of Sulf2 significantly downregulates dyslipidemia, steatohepatitis, and hepatic fibrosis in a diet-induced mouse model of NAFLD, suggesting that targeting of SULF2 signaling may be a potential therapeutic mechanism in NASH. [ABSTRACT FROM AUTHOR]

Asia has intermediate-to-high prevalence and high morbidity of hepatitis B virus (HBV) infection. The use of guideline-recommended nucleos(t)ide analogs with high barrier to resistance, such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), is one of the key interventions for curbing HBV infection and associated morbidity in Asia. However, there are some challenges to the use of ETV and TDF; while ETV is associated with high resistance in lamivudine (LAM)-exposed (especially LAM-refractory) patients; bone and renal safety issues are a major concern with TDF. Hence, a panel of twenty-eight expert hepatologists from Asia convened, reviewed the literature, and developed the current expert opinion-based review article for the use of TAF in the resource-constrained settings in Asia. This article provides a comprehensive review of two large, phase 3, double-blind, randomized controlled trials of TAF versus TDF in HBeAg-negative (study 0108) and HBeAg-positive (study 0110) chronic HBV patients (> 70% Asians). These studies revealed as follows: (1) non-inferiority for the proportion of patients who had HBV DNA < 29 IU/mL; (2) significantly high rate of normalization of alanine aminotransferase levels; (3) no incidence of resistance; and (4) significantly better bone and renal safety, with TAF vs. TDF up to 144 weeks. Considering the benefits of TAF, the expert panel proposed recommendations for optimizing the use of TAF in Asia, along with guidance on specific patient groups at risk of renal or bone disease suitable for TAF therapy. The guidance provided in this article may help clinicians optimize the use of TAF in Asia. [ABSTRACT FROM AUTHOR]

We present a patient with intractable and debilitating pain secondary to chronic pancreatitis who was effectively treated with total pancreatectomy with islet autotransplantation (TPIAT). Islets engrafted into his liver significantly contributed to improved blood glucose control and quality of life. Subsequently, the patient developed alcohol related acute liver failure and en bloc liver and pancreas transplantation was performed to replace the failing liver with engrafted islets. Pancreas transplantation was required to resolve his life-threatening severe hypoglycemic episodes. Herein, we detail an innovative and multidisciplinary management of this complex medical problem. [ABSTRACT FROM AUTHOR]

Background and Aims: NAFLD is the most prevalent liver disease globally, affecting 20% of the world population. Healthcare resource utilization (HRU) attributable to NAFLD has been difficult to define.Methods: We performed a case control study on NAFLD patients from 2005 to 2015 in a large integrated healthcare system with an affiliated insurance company that prospectively captures HRU information. Outcomes encompassed costs, liver transplantation and mortality rates.Results: There were 17,085 patients, of which 4512 were NAFLD cases and 12,573 were non-NAFLD controls. The cohorts were similar in age and gender distribution (p > 0.05). The NAFLD cohort had a younger mean age of death (60.9 vs. 63.3, p = 0.004) and had over twice the number of annual healthcare visits (14.6 vs. 7.1). The increased overall annual overall cost attributable to NAFLD (in 2015 $) was $449/year. Overall, NAFLD was independently associated with 17% higher annual attributable healthcare costs. More advanced NAFLD (FS 3-4) was associated with a 40% increase in median annual healthcare costs (vs. FS 0-2). The strongest predictors of HRU among patients with NAFLD were advanced fibrosis and medical co-morbidities. The rate of liver transplantation was 18 times greater (0.054%/year) in the NAFLD compared with the non-NAFLD cohort, while mortality rate was 1.7 times greater.Conclusions: Within a large, integrated healthcare system a diagnosis of NAFLD is independently associated with a 17% overall excess in HRU and a several-fold increase liver transplantation and mortality. Although the dollar amounts will change over time and between healthcare systems, the proportional need for HRU will have broad applicability and implications. [ABSTRACT FROM AUTHOR]

Asia has an intermediate‐to‐high prevalence of and high morbidity and mortality from hepatitis B virus (HBV) infection. Optimization of diagnosis and initiation of treatment is one of the crucial strategies for lowering disease burden in this region. Therefore, a panel of 24 experts from 10 Asian countries convened, and reviewed the literature, to develop consensus guidance on diagnosis and initiation of treatment of HBV infection in resource‐limited Asian settings. The panel proposed 11 recommendations related to diagnosis, pre‐treatment assessment, and indications of therapy of HBV infection, and management of HBV‐infected patients with co‐infections. In resource‐limited Asian settings, testing for hepatitis B surface antigen may be considered as the primary test for diagnosis of HBV infection. Pre‐treatment assessments should include tests for complete blood count, liver and renal function, hepatitis B e‐antigen (HBeAg), anti‐HBe, HBV DNA, co‐infection markers and assessment of severity of liver disease. Noninvasive tests such as AST‐to‐platelet ratio index, fibrosis score 4 or transient elastography may be used as alternatives to liver biopsy for assessing disease severity. Considering the high burden of HBV infection in Asia, the panel adopted an aggressive approach, and recommended initiation of antiviral therapy in all HBV‐infected, compensated or decompensated cirrhotic individuals with detectable HBV DNA levels, regardless of HBeAg status or alanine transaminase levels. The panel also developed a simple algorithm for guiding the initiation of treatment in noncirrhotic, HBV‐infected individuals. The recommendations proposed herein, may help guide clinicians, to optimize the diagnosis and improvise the treatment rates for HBV infection in Asia. [ABSTRACT FROM AUTHOR]

Identifying the optimal allocation policy with regard to hepatocellular carcinoma has been a persistent and evolving challenge. The current criteria for LT for HCC endorsed by the United Network of Organ Sharing (UNOS) are based on the Milan Criteria: a solitary tumor < 5 cm, or maximum of three tumors ≤ 3 cm each, without vascular invasion or evidence of extrahepatic spread. Contraindications to HCC exception points include: stage 1 HCC, ruptured HCC, extrahepatic HCC, and main portal or hepatic vein HCC invasion. Based upon projected waitlist dropout rates due to tumor growth, patients with HCC are assigned MELD standardized exception points. In addition to tumor size and number, AFP levels are an important predictor of recurrence of HCC following liver transplantation. Standardized exception points for HCC patients are not awarded to patients with AFP levels > 1000 ng/mL that do not decrease to < 500 ng/mL with treatment. Appeals for MELD exception points for patients with HCC vary widely between UNOS regions, with success of nonstandardized exception point appeals varying from 3.1 to 21% between regions. In an effort to make prioritization for HCC more consistent, a national liver review board (NLRB)is being convened that will focus on developing a national guidance for assessing common requests and addressing exception points, including for HCC. [ABSTRACT FROM AUTHOR]

Recent excavations of a Late to Post-Meroitic furnace workshop at Meroe, Sudan prompted questions concerning the use of some of its unusual design features and the nature of ironmaking practice. To begin addressing these questions, four iron smelting experiments were conducted in a purpose-built workshop modelled from the archaeological remains. Some of the goals of the campaign included identification and testing of potential ore and technical ceramic resources as well as the production of slag with characteristics that mirrored those of the archaeological deposits. The primary objective, however, was the further development of a model for Late to Post-Meroitic direct process iron production. Comparison of the microstructural and chemical characteristics of the archaeological and experimental ironmaking residues leads to a rejection of hypothesised ore sources adjacent to Meroe, support for hypothesised technical ceramic resource locations and a failure to replicate Late-Post-Meroitic smelting slag. However, the comparison also makes a strong contribution to the developing model of smelting practice at Meroe by emphasising the need to create more consistent redox conditions within the furnace, greater standardisation in preparing technical ceramics and the use of relatively lean ores (≈ 60 wt.% Fe). [ABSTRACT FROM AUTHOR]

Purpose of Review: The rising prevalence of obesity in general and non-alcoholic steatohepatitis (NASH) specifically as an indication for liver transplantation has occurred in parallel with an increase in the consideration and performance of bariatric surgery before and after liver transplantation. We review the impact and relative merits of bariatric surgery before, during, and after liver transplantation.Recent Findings: The sleeve gastrectomy approach has several practical advantages over other forms of weight loss surgery and has been shown to improve metabolic parameters. Bariatric surgical procedures inevitably affect immunosuppression pharmacokinetics, with the least impact being observed following sleeve gastrectomy. In the non-transplant setting, bariatric surgery has been shown to be an effective therapy for histological features of NASH.Summary: When compared to lifestyle changes alone, bariatric surgery performed during or after liver transplantation results in sustained weight loss and improved metabolic parameters associated with liver disease, cardiovascular risk, and overall mortality. Further studies are needed to confirm which surgical procedures, timing, and NASH patients will receive most benefit. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patient‐reported outcomes (PROs) represent patients’ perspective about their well‐being. Aim: To assess PRO changes in patients with non‐alcoholic steatohepatitis (NASH) after treatment with selonsertib (SEL) and to associate them with different biomarkers. Methods: Patients with NASH and stage 2‐3 fibrosis received SEL 6 mg or 18 mg orally QD alone or in combination with simtuzumab (SIM, 125 mg SC weekly) or SIM alone for 24 weeks. Biopsies were obtained at baseline and at treatment week 24. PROs were assessed using SF‐36, CLDQ and WPAI:SHP. Results: Seventy‐two patients with NASH were included (54 ± 10 years, 31% male, 65% stage 3, 71% diabetes). Baseline physical health‐related PRO scores were significantly lower than population norms (P < .05). During treatment, there were no consistent differences in treatment‐emergent PRO changes between different regimens (P > .05). However, NASH subjects who experienced ≥2 decrease in NAFLD Activity Score or ≥1‐stage reduction in fibrosis showed significant improvements in their PROs (up to +15.5% of a PRO range size, P < .05). Additionally, improvements in PROs (up to +21.5%, P < .05) were noted in patients with at least 50% relative reduction in collagen, while NASH subjects with >17% increase in their collagen experienced PRO worsening (up to −13.9%, P < .05). Baseline serum CK‐18, IL‐6 and CRP significantly correlated with PROs (rho from −0.24 to −0.38, P < .05). Conclusions: A decrease in hepatic collagen is the most prominently associated with improvement of PROs in NASH patients with F2‐F3 treated with SEL. Furthermore, serum cytokines are associated with baseline PROs and with treatment‐emergent changes in PROs in patients with NASH. [ABSTRACT FROM AUTHOR]

Recent achievements leading, amongst other things, to the observation of the two-photon 1S-2S transition in antihydrogen are reviewed. We summarise some of the technical advances that were necessary to facilitate this, and how these addressed the requirements posed by the underlying physical processes. Aspects of the latter have been elucidated by simulations aimed at describing as closely as possible the experimental situations, and we describe some recent insights from that work. We will close with a look to the future. Graphical abstract: [ABSTRACT FROM AUTHOR]

The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13-276 pmol·s-1·ml-1 per unit citrate synthase) than SC mice (17-394 pmol·s-1·ml-1 per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of NASH.NEW & NOTEWORTHY This study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include 1) hepatic lipid composition changes in a multiphasic fashion as NASH evolves; 2) insulin resistance precedes hepatic inflammation and fibrosis, answering a longstanding chicken-and-egg question regarding the relationship of insulin resistance to liver histology in NASH; and 3) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. [ABSTRACT FROM AUTHOR]

Background and Objectives: Biliary tract cancers (BTC) including, cholangiocarcinoma (CC) and gallbladder cancer (GBC), are rare and highly fatal malignancies. The etiology and inherited susceptibility of both malignancies are poorly understood. We quantified the risk of BTC in first-degree (FDR), second-degree (SDR), and first cousin (FC) relatives of individuals with BTC, stratified by tumor subsite.Methods: BTC diagnosed between 1980 and 2011 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and gender-matched BTC-free controls were selected to form the comparison group for determining BTC risk in relatives using Cox regression analysis.Results: Of the 1302 index patients diagnosed with BTC, 550 (42.2 %) were located in the gallbladder and 752 (57.8 %) were cholangiocarcinomas. There was no elevated risk of BTC (all subsites combined) in FDRs (HR 0.94, 95 % CI 0.29-3.0), SDRs (HR 0.25, 95 % CI 0.06-1.03), and FCs (HR 0.96, 95 % CI 0.61-1.51) of BTC cases compared to cancer-free controls. Similarly, no increased familial risk of GBC or CC was found in relatives of BTC patients stratified by tumor subsite compared to relatives of controls.Conclusions: Relatives of BTC patients are not at an increased risk of GBC or CC in a statewide population. This suggests that biliary tract cancer risk is not associated with a familial predisposition and may be mitigated more strongly by environmental modifiers. [ABSTRACT FROM AUTHOR]

Background: It is now widely recognized that there is an urgent need for new antibacterial drugs, with novel mechanisms of action, to combat the rise of multi-drug resistant bacteria. However, few new compounds are reaching the market. Antibacterial drug discovery projects often succeed in identifying potent molecules in biochemical assays but have been beset by difficulties in obtaining antibacterial activity. A commonly held view, based on analysis of marketed antibacterial compounds, is that antibacterial drugs possess very different physicochemical properties to other drugs, and that this profile is required for antibacterial activity. Results: We have re-examined this issue by performing a cheminformatics analysis of the literature data available in the ChEMBL database. The physicochemical properties of compounds with a recorded activity in an antibacterial assay were calculated and compared to two other datasets extracted from ChEMBL, marketed antibacterials and drugs marketed for other therapeutic indications. The chemical class of the compounds and Gram-negative/Gram-positive profile were also investigated. This analysis shows that compounds with antibacterial activity have physico-chemical property profiles very similar to other drug classes. Conclusions: The observation that many current antibacterial drugs lie in regions of physicochemical property space far from conventional small molecule therapeutics is correct. However, the inference that a compound must lie in one of these "outlier" regions in order to possess antibacterial activity is not supported by our analysis. [ABSTRACT FROM AUTHOR]

Background: Management guidelines from the American Association for the Study of Liver Diseases/American College of Gastroenterology/American Gastroenterology Association published in 2012 for nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) recommend weight loss, vitamin E and pioglitazone as effective therapies for the treatment of biopsy-confirmed NASH. However, little is known about how physicians in the US diagnose NASH or whether published guidelines are being followed. Methods: We assessed current diagnostic and treatment patterns of the management of NAFLD and NASH among academic gastroenterologists and hepatologists in the US using a standardized survey developed to collect information regarding respondents’ practice environments, diagnostic techniques, and medication usage in patients with NAFLD/NASH. Results: We invited 482 gastroenterologists and hepatologists, predominantly from academic centers, of whom 163 completed the survey. Only 24% of providers routinely perform liver biopsy, predominantly among patients with elevated serum aminotransferases. Vitamin E is prescribed regularly by 70% while only 14% routinely prescribe pioglitazone. Despite recommendations to the contrary, ~25% prescribe pioglitazone or vitamin E without biopsy confirmation of NASH. Metformin is used as frequently as pioglitazone despite its proven lack of efficacy in NASH. Overall, 40–73% adhere to published guidelines, depending on the specific question. There was no significant difference seen in adherence to guidelines between gastroenterologists and hepatologists. Conclusion: This survey suggests that clinical practice patterns among gastroenterologists and hepatologists for the management of NASH frequently diverge from published practice guidelines. Although liver biopsy remains the gold standard to diagnose NASH, less than 25% of respondents routinely require it to make the diagnosis of NASH. We conclude that NASH is underdiagnosed in gastroenterology and hepatology practices, highlighting the need to refine noninvasive diagnostic tools. [ABSTRACT FROM AUTHOR]