Search

Despite its considerable and growing burden, there are currently no Food and Drug Administration‐approved treatments for metabolic dysfunction‐associated steatotic liver disease or its progressive form, metabolic dysfunction‐associated steatohepatitis (MASH). Several glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and other agents are in various phases of clinical development for use in MASH; an ideal therapy should reduce liver fat content, improve chronic liver disease, help mitigate metabolic comorbidities and decrease all‐cause mortality. Because of interconnected disease mechanisms, metabolic dysfunction‐associated steatotic liver disease/MASH often coexists with type 2 diabetes (T2D), obesity and cardiovascular disease. Various GLP‐1RAs are Food and Drug Administration‐approved for use in T2D, and two, liraglutide and semaglutide, are approved for overweight and obesity. GLP‐1RAs decrease glucose levels and body weight and improve cardiovascular outcomes in people with T2D who are at high risk of cardiovascular disease. In addition, GLP‐1RAs have been reported to reduce liver fat content and liver enzymes, reduce oxidative stress and improve hepatic de novo lipogenesis and the histopathology of MASH. Weight loss may contribute to these effects; however, the exact mechanisms are unknown. Adverse events that are commonly associated with GLP‐1RAs include vomiting, nausea and diarrhoea. There is a lack of evidence from meta‐analyses regarding the increased risk of acute pancreatitis and various forms of cancer with GLP‐1RAs. Large‐scale, phase 3 trials, which will provide definitive data on GLP‐1RAs and other potential therapies in MASH, are ongoing. Given the spectrum of modalities under investigation, it is hoped that these trials will support the identification of pharmacotherapies that provide clinical benefit for patients with MASH. [ABSTRACT FROM AUTHOR]

Strategies to reduce liver biopsy (LB) screen failures through better patient selection are needed for clinical trials. Standard fibrosis biomarkers were not derived to detect "at-risk" metabolic dysfunction-associated steatohepatitis (MASH; MASH with metabolic dysfunction-associated steatotic liver disease score ≥4 and fibrosis stage ≥2). We compared the performance of screening pathways that incorporate NIS2+™, an optimized version of the blood-based NIS4® technology designed to identify at-risk MASH, with those incorporating fibrosis (FIB)-4 within the RESOLVE-IT clinical trial (NCT02704403), aiming for optimized selection of patients for LB. A retrospective simulation analysis was conducted in the RESOLVE-IT screening pathway (RSP) cohort. LB failure rate (LBFR), number of patients needed to screen, and overall cost estimations of different pathways were calculated for a range of NIS2+™ and FIB-4 cut-offs and compared with those of the RSP, which relied on investigators' local practices. An analysis of potential recruitment bias based on histology, sex, age, or comorbidities was performed. The analysis cohort included 1,929 patients, 765 (40%) with at-risk MASH. The NIS2+™ pathway resulted in a significantly lower LBFR (39%) compared with the FIB-4 pathway (58%) or the RSP (60%) when using cost-optimized cut-offs (NIS2+™, 0.53; FIB-4, 0.58). For every 1,000 inclusions, NIS2+™ significantly reduced unnecessary LBs (632 vs. 1,522; -58%) and screening costs (US$12.7 million vs. US$15.0 million) vs. the RSP, while the number of patients needed to screen increased moderately (3,220 to 4,033). NIS2+™ alone is better than FIB-4 alone or combined with FIB-4. This analysis demonstrated that patient selection for LB using NIS2+™ significantly reduced unnecessary biopsies and screening costs, which could greatly improve the feasibility of MASH clinical trials. Simple and accurate non-invasive strategies to optimize the selection of patients who should be referred for liver biopsy for inclusion in MASH clinical trials is critical to reduce the high liver biopsy failure rates. While the use of the Fibrosis-4 index alone did not lead to a significant improvement of the screening process, selecting patients using NIS2+™, a recently developed optimization of the NIS4® technology for the detection of at-risk MASH, showed improved performance by simultaneously reducing liver biopsy failure rates and the overall cost of the trial, while maintaining the number of patients needed to screen at a manageable level and not generating any bias in included patients' characteristics. This makes NIS2+™ an accurate and reliable screening tool that could improve the recruitment of patients in future MASH clinical trials, and would lead to increased patient comfort and security, ensuring timely and cost-efficient trial completion. [Display omitted] • The liver biopsy failure rate in MASH clinical trials is unacceptably high. • We used NIS2+™, a two-biomarker test, to refer patients with at-risk MASH for liver biopsy. • NIS2+™ reduced liver biopsy failure rates and screening costs. • NIS2+™ screening performance was superior to that of FIB-4. • The profile of patients included with NIS2+™ screening pathway was not impacted. [ABSTRACT FROM AUTHOR]

Summary: Background: Non‐alcoholic steatohepatitis (NASH) is a progressive form of non‐alcoholic fatty liver disease (NAFLD) associated with steatosis, hepatocellular injury, inflammation and fibrosis. In a Phase 2 trial in adults with NASH (NCT02912260), resmetirom, an orally administered, liver‐targeted thyroid hormone receptor‐β selective agonist, significantly reduced hepatic fat (via imaging) and resolved NASH without worsening fibrosis (via liver biopsy) in a significant number of patients compared with placebo. Aims: To present the design of the Phase 3 MAESTRO clinical programme evaluating resmetirom for treatment of NASH (MAESTRO‐NAFLD‐1 [NCT04197479], MAESTRO‐NAFLD‐OLE [NCT04951219], MAESTRO‐NASH [NCT03900429], MAESTRO‐NASH‐OUTCOMES [NCT05500222]). Methods: MAESTRO‐NASH is a pivotal serial biopsy trial in up to 2000 adults with biopsy‐confirmed at‐risk NASH. Patients are randomised to a once‐daily oral placebo, 80 mg resmetirom, or 100 mg resmetirom. Liver biopsies are conducted at screening, week 52 and month 54. MAESTRO‐NAFLD‐1 is a 52‐week safety trial in ~1400 adults with NAFLD/presumed NASH (based on non‐invasive testing); ~700 patients from MAESTRO‐NAFLD‐1 are enrolled in MAESTRO‐NAFLD‐OLE, a 52‐week active treatment extension to further evaluate safety. MAESTRO‐NASH‐OUTCOMES is enrolling 700 adults with well‐compensated NASH cirrhosis to evaluate the potential for resmetirom to slow progression to hepatic decompensation events. Non‐invasive tests (biomarkers, imaging) are assessed longitudinally throughout, in addition to validated patient‐reported outcomes. Conclusion: The MAESTRO clinical programme was designed in conjunction with regulatory authorities to support approval of resmetirom for treatment of NASH. The surrogate endpoints, based on week 52 liver biopsy, serum biomarkers and imaging, are confirmed by long‐term clinical liver‐related outcomes in MAESTRO‐NASH (month 54) and MAESTRO‐NASH‐OUTCOMES (time to event). [ABSTRACT FROM AUTHOR]

NIS4® is a blood-based non-invasive test designed to effectively rule in/rule out at-risk non-alcoholic steatohepatitis (NASH), defined as non-alcoholic fatty liver disease activity score ≥4 and significant fibrosis (stage ≥2), among patients with metabolic risk factors. Robustness of non-invasive test scores across characteristics of interest including age, type 2 diabetes mellitus, and sex, and optimised analytical aspects are critical for large-scale implementation in clinical practice. We developed and validated NIS2+™, an optimisation of NIS4®, specifically designed to improve score robustness. A well-balanced training cohort (n = 198) included patients from the GOLDEN-505 trial. The validation (n = 684) and test (n = 2,035) cohorts included patients from the RESOLVE-IT trial. Well-matched subgroups were created to avoid potential confounding effects during modelling and analysis of score robustness. Models were trained using logistic regressions for at-risk NASH detection and compared using Bayesian information criteria. Performance of NIS2+™ was compared with that of NIS4®, Fibrosis-4, and alanine aminotransferase using area under the receiver operating characteristic curve, and robustness was analysed through score distribution. Using the training cohort to compare all combinations of NIS4® biomarkers, NIS2 (miR-34a-5p, YKL-40) was identified as the best combination of parameters. To correct for the sex effect on miR-34a-5p (validation cohort), sex and sex ∗ miR-34a-5p parameters were added, creating NIS2+™. In the test cohort, NIS2+™ exhibited a statistically higher area under the receiver operating characteristic curve (0.813) vs. NIS4® (0.792; p = 0.0002), Fibrosis-4 (0.653; p <0.0001), and alanine aminotransferase (0.699; p <0.0001). NIS2+™ scores were not affected by age, sex, BMI, or type 2 diabetes mellitus status, providing robust clinical performances irrespective of patient characteristics. NIS2+™ constitutes a robust optimisation of NIS4® technology for the detection of at-risk NASH. The development of non-invasive tests for accurate, large-scale detection of patients with at-risk non-alcoholic steatohepatitis (NASH; defined as NASH with non-alcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2) – who are at higher risk for disease progression and for developing liver-related life-threatening outcomes – is critical for identifying this patient population in the clinical setting and improving the screening process of NASH clinical trials. We report the development and validation of NIS2+™, a diagnostic test designed as an optimisation of NIS4® technology, a blood-based panel currently used to detect at-risk NASH in patients with metabolic risk factors. NIS2+™ showed improved performance for the detection of at-risk NASH compared with NIS4® and other non-invasive liver tests that was not impacted by patients' characteristics of interest, such as age, sex, type 2 diabetes mellitus, BMI, dyslipidaemia, and hypertension. This makes NIS2+™ a robust and reliable tool for the diagnosis of at-risk NASH among patients with metabolic risk factors, and an effective candidate for large-scale implementation in clinical practice and clinical trials. [Display omitted] • Non-invasive tools for large-scale diagnosis of at-risk NASH are needed. • We developed NIS2+™, a two-biomarker test corrected for sex, to detect at-risk NASH. • NIS2+™ clinical performance was superior to that of NIS4®. • NIS2+™ showed a strong performance to rule in/out at-risk NASH at fixed cutoffs. • NIS2+™ was not impacted by patients' characteristics of interest for NAFLD. [ABSTRACT FROM AUTHOR]

Pioglitazone (Pio) is efficacious in NASH, but its utility is limited by PPARγ-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARγ activity but retains non-genomic activity. We tested the hypothesis that PXL065 would have similar efficacy but a better safety profile than Pio in patients with NASH. Patients (≥8% liver fat, NAFLD activity score [NAS] ≥4, F1–F3) received daily doses of PXL065 (7.5, 15, 22.5 mg) or placebo 1:1:1:1 for 36 weeks. The primary endpoint was relative % change in liver fat content (LFC) on MRI-proton density fat fraction; liver histology, non-invasive tests, safety-tolerability, and pharmacokinetics were also assessed. One hundred and seventeen patients were evaluated. All PXL065 groups met the primary endpoint (-21 to -25% LFC, p = 0.008–0.02 vs. placebo); 40% (22.5 mg) achieved a ≥30% LFC reduction. Favorable trends in non-invasive tests including reductions in PIIINP (p = 0.02, 22.5 mg) and NAFLD fibrosis score (p = 0.04, 22.5 mg) were observed. On histology (n = 92), a ≥1 stage fibrosis improvement occurred in 40% (7.5 mg), 50% (15 mg, p = 0.06), and 35% (22.5 mg) vs. 17% for placebo; up to 50% of PXL065-treated patients achieved a ≥2 point NAS improvement without fibrosis worsening vs. 30% with placebo. Metabolic improvements included: HbA1c (-0.41% p = 0.003) and insulin sensitivity (HOMA-IR, p = 0.04; Adipo-IR, p = 0.002). Adiponectin increased (+114%, 22.5 mg, p <0.0001) vs. placebo. There was no dose-dependent effect on body weight or PXL065-related peripheral oedema signal. Overall, PXL065 was safe and well tolerated. Pharmacokinetics confirmed dose-proportional and higher steady state R- vs. S-Pio exposure. Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile – these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease. PXL065 is a novel molecule which retains an efficacy profile in NASH similar to Pio with reduced potential for PPARγ-driven side effects. A pivotal clinical trial is warranted to confirm the histological benefits reported herein. Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile – these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease. [Display omitted] • Pioglitazone is used in NASH but has side effects. • PXL065 is a novel deuterium-stabilized R-pioglitazone enantiomer which lacks PPARγ activity. • PXL065 reduced liver fat and improved non-invasive tests, histology, and glycemia/insulin sensitivity. • PXL065 reduced potential PPARγ-driven side effects of weight gain and oedema. • PXL065 is a new oral approach to NASH which warrants further study in a pivotal trial. [ABSTRACT FROM AUTHOR]

Cultivars URS OLADA and URS POENTE, with superior agronomic performance were bred by the Oat Breeding Program of UFRGS. These cultivars were developed using germplasm from the Quaker Oat International Nursery, a long-term collaborative program of open exchange of oats superior germplasm among breeders in a global scale. [ABSTRACT FROM AUTHOR]

The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH). This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12. One hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively. In patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit. 2018-003119-22. NCT03812029. Non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease worldwide. Affected patients are also at higher risk of developing chronic kidney disease. There are no approved therapies and only few options to treat this population. The phase IIa LIVIFY trial results show that single daily administration of oral vonafexor, an FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials, with the aim of addressing the unmet medical need in NASH. [Display omitted] • Vonafexor is an FXR agonist in development for patients with NASH and at-risk liver fibrosis. • In this randomized trial, vonafexor was safe, induced liver fat reduction and weight loss, and improved liver enzymes and renal function. • As NASH increases the risk of kidney problems, these results support development of vonafexor for patients with liver and kidney disease. [ABSTRACT FROM AUTHOR]

The Mps1 and Aurora B kinases regulate and monitor kinetochore attachment to spindle microtubules during cell division, ultimately ensuring accurate chromosome segregation. In yeast, the critical spindle attachment components are the Ndc80 and Dam1 complexes (Ndc80c and DASH/Dam1c, respectively). Ndc80c is a 600-Å-long heterotetramer that binds microtubules through a globular "head" at one end and centromere-proximal kinetochore components through a globular knob at the other end. Dam1c is a heterodecamer that forms a ring of 16–17 protomers around the shaft of the single kinetochore microtubule in point-centromere yeast. The ring coordinates the approximately eight Ndc80c rods per kinetochore. In published work, we showed that a site on the globular "head" of Ndc80c, including residues from both Ndc80 and Nuf2, binds a bipartite segment in the long C-terminal extension of Dam1. Results reported here show, both by in vitro binding experiments and by crystal structure determination, that the same site binds a conserved segment in the long N-terminal extension of Mps1. It also binds, less tightly, a conserved segment in the N-terminal extension of Ipl1 (yeast Aurora B). Together with results from experiments in yeast cells and from biochemical assays reported in two accompanying papers, the structures and graded affinities identify a communication hub for ensuring uniform bipolar attachment and for signaling anaphase onset. • The kinase Mps1 binds the Ndc80 complex through a conserved motif • X-ray crystallography shows a common Ndc80c binding site for Mps1 and Dam1 • The Ipl1 N-terminal extension recognizes the Ndc80c site bound by Mps1 and Dam1 • Alphafold predictions suggest broad conservation of these shared interactions Zahm and Harrison combine binding studies and structure determinations to identify a common interaction site on the Ndc80 complex of yeast kinetochores for kinases Mps1 and Ipl1 and for the DASH subunit, Dam1. Sequences and alphafold predictions suggest a widely conserved regulatory hub on Ndc80c, consistent with data in accompanying articles. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Kim et al papers. To view these articles, visit https://doi.org/10.1111/apt.17726 and https://doi.org/10.1111/apt.17780 [ABSTRACT FROM AUTHOR]

INTRODUCTION: AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD. METHODS: In this multicenter, 16-week, placebo-controlled, single-blind, randomized clinical study in subjects with NAFLD stratified by type 2 diabetes, AXA1125 24 g, AXA1957 13.5 g or 20.3 g, or placebo was administered twice daily. Key metabolism (MRI-proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR]) and fibroinflammation markers (alanine aminotransferase [ALT], corrected T1 [cT1], keratin-18 [K-18] M65, and N-terminal type III collagen propeptide [Pro-C3]) were evaluated. Safety outcomes included adverse events and standard laboratory assessments. RESULTS: Baseline characteristics of the 102 enrolled subjects, including 40 with type 2 diabetes, were consistent with presumed nonalcoholic steatohepatitis. AXA1125 showed consistently greater biologic activity than AXA1957 or placebo. Week 16 changes from baseline with AXA1125 vs placebo: MRIPDFF 222.9% vs 25.7%, HOMA-IR 24.4 vs 10.7, ALT 221.9% vs 27.2%, K-18 M65 213.6% vs 120.1%, cT1269.6 vs118.3 ms (P < 0.05), and Pro-C3213.6% vs23.6%. Week 16 changes from baseline with AXA1957 20.3 g: MRI-PDFF 28.1%, HOMA-IR 18.4, ALT 220.7%, K-18 M65 6.6%, cT1234.7 ms, and Pro-C3 215.6%. A greater proportion of subjects treated with AXA1125 achieved clinically relevant thresholds: >30% MRI-PDFF, ≥17-IU/L ALT, and >80-ms cT1 reductions at week 16. Study products were safe and well tolerated with stable lipid and weight profiles. DISCUSSION: Both compositions showed multitargeted activity on relevant NAFLD pathways. AXA1125 demonstrated the greatest activity over 16 weeks, warranting continued clinical investigation in nonalcoholic steatohepatitis subjects. [ABSTRACT FROM AUTHOR]

Large prospective studies to establish the prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), are lacking. We prospectively assessed the prevalence and severity of NAFLD/NASH in a cohort of asymptomatic middle-aged Americans attending a colonoscopy class at a gastroenterology clinic. Screening for NAFLD was performed using magnetic resonance (MR)-based LiverMultiScan® proton density fat fraction (LMS-PDFF). MR exams also included corrected T1 and elastography for liver stiffness measurement (LSM). FibroScan® was also used to measure LSM. Participants with predetermined abnormal imaging parameters were offered a liver biopsy. Biopsies were read in a blinded fashion with results based on the consensus by 2 expert pathologists. The prevalence of NAFLD was determined by PDFF ≥5% or by histological diagnosis of NAFLD (if biopsy data were available). The prevalence of NASH was defined by biopsy. Of 835 participants, 664 met the inclusion and exclusion criteria. The mean age was 56 ± 6.4 years, 50% were male, the mean BMI was 30.48 ± 5.46 kg/m2, and 52% were obese. The prevalence of NAFLD was 38% (95% CI 34–41%) and the prevalence of NASH was 14% (95% CI 12–17%). While no patient had cirrhosis on biopsy, significant fibrosis (F ≥2) was present in 5.9% (95% CI 4–8%) and bridging fibrosis in 1.6% (95% CI 1-3%). In a multivariable analysis, factors associated with the presence of NASH were race, obesity, and diabetes. Using state-of-the-art liver imaging modalities and reference biopsy, this study establishes an overall prevalence of NAFLD of 38% and NASH by biopsy of 14% in this cohort of asymptomatic middle-aged US adults. There are no prospective studies to determine how common is nonalcoholic steatohepatitis (NASH), the severe form of non-alcoholic fatty liver disease (NAFLD). In a large number of asymptomatic middle-aged Americans, we used a combination of state-of-the-art liver imaging methods and liver biopsy to prospectively determine the prevalence of NAFLD and NASH. NAFLD was diagnosed in 38%, NASH in 14%, and significant liver fibrosis in 6% of asymptomatic middle-aged Americans. [Display omitted] • In a prospective large cohort of middle-aged Americans living in Texas, the prevalence of NAFLD was estimated to be 38%. • Based on liver histology data, NASH was diagnosed in 14% of the entire cohort and 37% of those with NAFLD. • NASH was more common in Hispanics and those with obesity or type 2 diabetes. [ABSTRACT FROM AUTHOR]

The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. In this 12-week, randomized, placebo-controlled study, we evaluated MET409 – a non-bile acid agonist with a unique chemical scaffold – in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (−25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of −23.4% for 80 mg and −20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. −1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced. [Display omitted] • The benefit of FXR agonism in patients with NASH has been clinically validated. • However, improvements in efficacy/tolerability for the therapeutic class have been elusive. • MET409, a novel non-bile acid agonist, resulted in a class-leading 12-week relative liver fat reduction of 38–55%. • MET409 resulted in differentiated pruritus and LDL-cholesterol profiles – issues that have hampered FXR development. • Data provide first evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. [ABSTRACT FROM AUTHOR]

Liver biopsies are a critical component of pivotal studies in non-alcoholic steatohepatitis (NASH), constituting inclusion criteria, risk stratification factors and endpoints. We evaluated the reliability of NASH Clinical Research Network scoring of liver biopsies in a NASH clinical trial. Digitized slides of 678 biopsies from 339 patients with paired biopsies randomized into the EMMINENCE study – examining a novel insulin sensitizer (MSDC-0602K) in NASH – were read independently by 3 hepatopathologists blinded to treatment code and scored using the NASH CRN histological scoring system. Various endpoints were computed from these scores. Inter-reader linearly weighted kappas were 0.609, 0.484, 0.328, and 0.517 for steatosis, fibrosis, lobular inflammation, and ballooning, respectively. Inter-reader unweighted kappas were 0.400 for the diagnosis of NASH, 0.396 for NASH resolution without worsening fibrosis, and 0.366 for fibrosis improvement without worsening NASH. In the current study, 46.3% of the patients included in the study based on 1 hepatopathologist's qualifying reading were deemed not to meet the study's histologic inclusion criteria by at least 1 of the 3 hepatopathologists. The MSDC-0602K treatment effect was lowest for those histologic features with lower inter-reader reliability. Simulations show that the lack of reliability of endpoints and inclusion criteria can drastically reduce study power – from >90% in a well-powered study to as low as 40%. The reliability of hepatopathologists' liver biopsy evaluation using currently accepted criteria is suboptimal. This lack of reliability may affect NASH pivotal studies by introducing patients who do not meet NASH study entry criteria, misclassifying fibrosis subgroups, and attenuating apparent treatment effects. Since liver biopsy analysis plays such an important role in clinical studies of non-alcoholic steatohepatitis, it is important to understand the reliability of hepato-pathologist readings. We examined both inter- and intra-reader variability in a large data set of paired liver biopsies from a clinical trial. We found very poor inter-reader and modest intra-reader variability. This result has important implications for entry criteria, fibrosis stratification, and the ability to measure a treatment effect in clinical trials. • Liver biopsy is a critical inclusion criteria and outcome measure in NASH studies. • Reader variability was tested in 678 biopsies from a NASH study of MSDC-0602K. • Kappas were poor for the diagnosis of NASH, its resolution and fibrosis improvement. • Almost half of the patients would have been excluded from entry by 1 of the readers. • Poor reliability allows improper entry, misclassification, and diminishes treatment effect. [ABSTRACT FROM AUTHOR]

Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH. We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events. Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups. Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH. Patients with non-alcoholic steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 weeks of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients. Clinicaltrials.gov numbers NCT03053050 and NCT03053063. • Selonsertib was safe and inhibited its target (ASK1) but did not lead to fibrosis regression or reduce disease progression in NASH. • Improvement in liver fibrosis on biopsy was associated with improvement only in other histologic features. • Improvements in ELF score and liver stiffness by transient elastography correlated with a variety of clinical parameters. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) is characterized by hepatocyte steatosis, ballooning, and lobular inflammation which may lead to fibrosis. Lipotoxicity activates caspases, which cause apoptosis and inflammatory cytokine (IL-1β and IL-18) production. Emricasan is a pan-caspase inhibitor that decreases serum aminotransferases and caspase activation in patients with NASH. This study postulated that 72 weeks of emricasan treatment would improve liver fibrosis without worsening of NASH. In this double-blind, placebo-controlled study 318 patients were randomized 1:1:1 to twice-daily treatment with emricasan (5 mg or 50 mg) or matching placebo for 72 weeks. Patients had definite NASH and NASH CRN fibrosis stage F1-F3, as determined by a central reader, on a liver biopsy obtained within 6 months of randomization. Emricasan treatment did not achieve the primary objective of fibrosis improvement without worsening of NASH (emricasan 5 mg: 11.2%; emricasan 50 mg: 12.3%; placebo: 19.0%; odds ratios vs. placebo 0.530 and 0.588, with p = 0.972 and 0.972, respectively) or the secondary objective of NASH resolution without worsening of fibrosis (emricasan 5 mg: 3.7%; emricasan 50 mg: 6.6%; placebo: 10.5%; odds ratios vs. placebo 0.334 and 0.613, with p = 0.070 and 0.335, respectively). In the small subset of patients with consistent normalization of serum alanine aminotransferase over 72 weeks, emricasan may have improved histologic outcomes. Emricasan treatment did not improve liver histology in patients with NASH fibrosis despite target engagement and may have worsened fibrosis and ballooning. Caspase inhibition lowered serum alanine aminotransferase in the short-term but may have directed cells to alternative mechanisms of cell death, resulting in more liver fibrosis and hepatocyte ballooning. Clinical Trials.gov # NCT02686762. Non-alcoholic steatohepatitis (NASH) is characterized by fat accumulation in liver cells, which leads to inflammation and fibrosis. Emricasan was previously shown to inhibit some of the liver enzymes which lead to liver inflammation and fibrosis. In this study, emricasan did not improve liver inflammation or fibrosis in patients with NASH and pre-existing liver fibrosis. • Pan-caspase inhibition with emricasan did not improve liver histology in NASH and may have worsened fibrosis and ballooning. • Caspase inhibition lowered average serum ALT values in the overall population but did not consistently normalize values in individual patients. • Emricasan was generally well-tolerated over 72 weeks of treatment. • While speculative, pan-caspase inhibition may have shifted cells from apoptotic to more inflammatory forms of cell death. [ABSTRACT FROM AUTHOR]

• A new insulin sensitizer can be dosed to full effect without dose-limiting side effects. • MSDC-0602K improved glucose metabolism and liver enzyme levels in patients with NASH, with or without T2D. • Dose-dependent improvements were seen for all categories of liver histology. • Aspartate aminotransferase and glycated hemoglobin cut-offs defined patients who benefitted most from treatment. MSDC-0602K is a novel insulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier while minimizing direct binding to the transcriptional factor PPARγ. Herein, we aimed to assess the efficacy and safety of MSDC-0602K in patients with non-alcoholic steatohepatitis. Patients with biopsy-confirmed NASH and fibrosis (F1-F3) were randomized to daily oral placebo, or 1 of 3 MSDC-0602K doses in a 52-week double-blind study. The primary efficacy endpoint was hepatic histological improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) with a ≥1-point reduction in either ballooning or lobular inflammation and no increase in fibrosis stage at 12 months. Secondary endpoints included NAS improvement without worsening fibrosis, NASH resolution, and fibrosis reduction. Exploratory endpoints included changes in insulin sensitivity, liver injury and liver fibrosis markers. Patients were randomly assigned to placebo (n = 94), or 62.5 mg (n = 99), 125 mg (n = 98), or 250 mg (n = 101) of MSDC-0602K. At baseline, glycated hemoglobin was 6.4 ± 1.0%, 61.5% of patients had fibrosis F2/F3 and the average NAS was 5.3. The primary endpoint was reached in 29.7%, 29.8%, 32.9% and 39.5% of patients in the placebo, 62.5 mg, 125 mg and 250 mg dose arms, respectively, with adjusted odds ratios relative to placebo of 0.89 (95% CI 0.44–1.81), 1.22 (95% CI 0.60–2.48), and 1.64 (95% CI 0.83–3.27). The 2 highest doses of MSDC-0602K led to significant reductions in glucose, glycated hemoglobin, insulin, liver enzymes and NAS compared to placebo. The incidence of hypoglycemia and PPARγ-agonist-associated events such as edema and fractures were similar in the placebo and MSDC-0602K groups. MSDC-0602K did not demonstrate statistically significant effects on primary and secondary liver histology endpoints. However, effects on non-invasive measures of liver cell injury and glucose metabolism support further exploration of MSDC-0602K's safety and potential efficacy in patients with type 2 diabetes and liver injury. [ClinicalTrials.gov Identifier: NCT02784444]. First-generation insulin sensitizers are used to treat type 2 diabetes, but are associated with side effects including edema, bone fractures, and hypoglycemia. MSDC-0602K is a second-generation insulin sensitizer designed to reduce these side effects. We hypothesized that insulin sensitization could improve non-alcoholic steatohepatitis. In the current study of patients with non-alcoholic steatohepatitis, MSDC-0602K did not demonstrate significant effects on liver histology with the biopsy techniques used. However, useful information was gained for the design of future studies and MSDC-0602K significantly decreased fasting glucose, insulin, glycated hemoglobin, and markers of liver injury without dose-limiting side effects. [ABSTRACT FROM AUTHOR]

• The proposed method controls the panel's temperature during the summer. • This method facilities snow removal process from a PV panel. • Using venting channel causes approximately 50% less energy loss. • Maximum energy loss due to the insulations is less than 5%. Photovoltaic solar systems in cold regions deal with energy loss due to snow accumulation on the system during the winter and panel temperature increase during the summer. In this paper, a method is proposed to control the surface temperature of a rooftop PV panel during all seasons via having a particular insulation mounted on the back of the PV panel. The main reason for such insulation is the need for snow removal from the panel during the winter. Using a heating snow removal system with the insulation can improve the panel performance significantly; however, during the summer, it can increase the panel temperature, reducing the energy production of the panel. Therefore, a modified insulation system has been proposed to reduce the adverse effect of having insulation during the summer. The insulation on the back of the panel produced an air channel of approximately 3 cm depth equipped with several vents. The insulation was also painted black on the side facing the panel to increase radiative heat transfer from the panel. In the summer, natural convection through the vents and radiation heat transfer between the panel and the insulation help to control the panel temperature. On the other hand, during the winter, closing the vents maximizes the effect of a snow removal system. Several experiments were conducted under natural conditions for a rooftop system equipped with the new insulation. The effect of solar radiation and vent configurations on the panel output were studied to find the optimum configuration for the vents. A numerical simulation was also conducted to investigate the effect of other parameters: wind speed, panel tilt angle and surface emissivity of the insulation. The proposed venting system can provide approximately 50% less energy loss as compared to the case that the insulation did not have any open vent, while still minimizing the energy required for snow removal in the winter period. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-β agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH.Methods: MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1-3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260.Findings: 348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (-32·9% resmetirom vs -10·4% placebo; least squares mean difference -22·5%, 95% CI -32·9 to -12·2; p<0·0001) and week 36 (-37·3% resmetirom [n=74] vs -8·5 placebo [n=34]; -28·8%, -42·0 to -15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom.Interpretation: Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging.Funding: Madrigal Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Highlights • Snow removal from PV/T panels by circulating hot fluid to the panel's back. • A Lagrangian method was used to calculate the average fluid heat flux to the panel • The absorber plate designcan affect the snow removal from the panel. • A non-dimensional number is defined to represent the snow removal method efficiency. Abstract Photovoltaic-thermal (PV/T) systems can generate thermal and electrical energy by using solar radiation. The production and implementation cost of PV/T systems has decreased continuously over the past decade. Consequently, the number of PV/T systems installed around the world has increased including regions with significant annual snowfall. However, a key challenge is to reduce the effects of snow accumulation on the panel surfaces. The aim of this study is to propose a method for removing snow from PV/T panels by circulating hot fluid through the back of the panel. To evaluate the method, two PV/T panels were installed adjacent to each other outdoor at a tilt angle of 45° to the horizontal. Therefore, to accurately measure the heat flux required for melting snow, one of the panels was insulated and heated by circulating hot fluid through its absorber plate bonded to the back surface. The reference panel remained uninsulated and empty, with no fluid circulation. The surface temperature of each panel was measured during the snow removal process as well as atmospheric temperature, solar irradiance and wind speed. Comparing the results for the insulated and uninsulated panels showed that this method can clean the panel in a short period of time. The results of this study were also compared with the results given by a numerical model presented in the literature for snow removal from PV modules by electrically heating the panel. In addition, an improved configuration for the back-absorber plate of a PV/T panel was proposed to enhance the snow removal process. Finally, a non-dimensional number was also defined to show the ratio of the energy used to remove snow from a panel to the energy generated by the panel after the snow removal based on the daily panel production. [ABSTRACT FROM AUTHOR]

Background: Given the worldwide prevalence of NAFLD and NASH, there is a need to develop treatments to slow or reverse disease progression. GR-MD-02 (galactoarabino-rhamnogalaturonate) has been shown to reduce hepatic fibrosis in animal studies, and lower serum biomarkers of NASH fibrogenesis in humans. The primary aim of this study was to determine the difference between four-months of treatment with GR-MD-02 or placebo in liver inflammation and fibrosis as measured by iron-corrected T1 (cT1) mapping, a non-invasive magnetic resonance imaging (MRI) biomarker that correlates with the extent of hepatic fibro-inflammatory disease. The secondary aims were to determine change in liver stiffness as measured by magnetic resonance elastography (MRE) and shear-wave ultrasonic elastography (LSM), and to explore test-retest repeatability of the three biomarkers. Materials and methods: Thirty subjects (13 females, 46–71 years) with NASH and advanced fibrosis were recruited. Subjects were randomized to receive 8 mg.kg-1 GR-MD-02 (via IV infusion) or placebo, administered biweekly over a 16-week period. Therapeutic efficacy was examined using cT1, MRE, and LSM. Statistical analyses on group differences in the biomarkers were performed using robust ANCOVA models adjusting for baseline measurement and additional covariates. Results: There was no significant difference in cT1 (p = 0.16) between GR-MD-02 and placebo groups following a 16-week intervention. There was also no significant difference in liver stiffness, measured by MRE (p = 0.80) or LSM (p = 0.63), between groups. Examination of repeatability of the cT1, MRE and LSM revealed coefficient of variations of 3.1%, 11% and 40% respectively. Conclusions: 8 mg.kg-1 of GR-MD-02 had no significant effect on non-invasive biomarkers of liver inflammation or fibrosis over a 4-month period. Histological confirmation was not available in this study. The high reproducibility of the primary outcome measure suggests that cT1 could be utilized for monitoring longitudinal change in patients with NASH. [ABSTRACT FROM AUTHOR]

Highlights • Imposing reverse current through PV cells with a modified frame can remove snow from PV panels. • Formation of snow bridge on the panel surface can cause local thermal stresses. • Using frameless PV panels is recommended for the PV systems in a region with annual snowfalls. • The freshly fallen snow covering a panel should only bemelted on the panel. Abstract A key challenge to the wide-scale implementation of photovoltaic solar panels (PV) in cold and remote areas is dealing with the effects of snow and ice buildup on the panel surfaces. In this study, a thermal method for snow removal from PV solar panels was experimentally tested. Nine PV panels were mounted at tilt angles of 30, 45 and 55° (three panels at each angle). One of the panels at each angle was insulated on the back with a heater embedded between the panel surface and a back layer of insulation. The other two panels remained unheated as reference cases. Outdoor tests were conducted under natural conditions including different snowfall conditions. Solar radiation, ambient temperature, relative humidity and wind speed were also measured during each test. Results showed that the frame at the bottom edge of the panels prevented the snow-cover from sliding off the panels. In addition, it was observed that the entire panel surface requires heat to remove snow, as the panel thermal conduction was not sufficient to conduct heat to unheated areas. To investigate these issues, the lower edge of the frame for one of the reference panels at tilt angle of 45° was removed, and the panel was heated using reversing electrical current flow through it. For most of the experiments with this panel, the snow-cover slid off the panel in less than 30 min. [ABSTRACT FROM AUTHOR]

NAFLD is the leading cause of chronic liver disease in the Western world with an estimated prevalence of 20-30 %. Lifestyle interventions targeted at weight loss through dietary interventions and exercise are the most effective treatment, but only a minority of patients are able to achieve and sustain the necessary intervention targets. Weight loss of 3-5 % has been associated with a reduction of hepatic steatosis while weight loss of ≥5-7 % has correlated with resolution of NASH in some studies. Greater reductions in weight loss (≥10 %) may improve hepatic fibrosis. In the absence of weight loss, no specific diet has demonstrated superiority. Physical activity can improve hepatic steatosis and metabolic indices even without weight loss. Diet coupled with exercise can produce significant weight loss and may improve histologic components of the NAFLD activity score. While formal guidelines for diet and exercise in NAFLD are lacking, adherence to diet and exercise recommendations similar to those from the American Diabetes Association for diabetic care seems reasonable. Dietary supplementation with vitamin E in non-diabetics with biopsy-proven NASH has been shown to improve NAFLD activity score. The role for other macronutrients, micronutrients, antioxidants, and probiotics in the treatment of NAFLD remains limited. [ABSTRACT FROM AUTHOR]

Kinetochores connect mitotic-spindle microtubules with chromosomes, allowing microtubule depolymerization to pull chromosomes apart during anaphase while resisting detachment as the microtubule shortens. The heterodecameric DASH/Dam1 complex (DASH/Dam1c), an essential component of yeast kinetochores, assembles into a microtubule-encircling ring. The ring associates with rodlike Ndc80 complexes to organize the kinetochore-microtubule interface. We report the cryo–electron microscopy structure (at ~4.5-angstrom resolution) of a DASH/Dam1c ring and a molecular model of its ordered components, validated by evolutionary direct-coupling analysis. Integrating this structure with that of the Ndc80 complex and with published interaction data yields a molecular picture of kinetochore-microtubule attachment, including how flexible, C-terminal extensions of DASH/Dam1c subunits project and contact widely separated sites on the Ndc80 complex rod and how phosphorylation at previously identified sites might regulate kinetochore assembly. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic steatohepatitis is a chronic liver disease characterised by the presence of hepatic steatosis, inflammation, and hepatocellular injury, for which no Food and Drug Administration (FDA)-approved treatment exists. FGF19 is a hormone that regulates bile acid synthesis and glucose homoeostasis. We aimed to assess the safety and efficacy of NGM282, an engineered FGF19 analogue, for the treatment of non-alcoholic steatohepatitis.Methods: In this randomised, double-blind, placebo-controlled, phase 2 study, we recruited patients aged 18-75 years with biopsy-confirmed non-alcoholic steatohepatitis as defined by the non-alcoholic steatohepatitis clinical research network histological scoring system, from hospitals and gastroenterology and liver clinics in Australia and the USA. Key eligibility criteria included a non-alcoholic fatty liver disease activity score of 4 or higher, stage 1-3 fibrosis, and at least 8% liver fat content. Patients were randomly assigned (1:1:1) via a web-based system and stratified by diabetic status to receive either 3 mg or 6 mg subcutaneous NGM282 or placebo. The primary endpoint was the absolute change from baseline to week 12 in liver fat content. Responders were patients who achieved a 5% or larger reduction in absolute liver fat content as measured by MRI-proton density fat fraction. Efficacy analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02443116.Findings: Between July 14, 2015, and Aug 30, 2016, 166 patients were screened across 18 sites in Australia and the USA. 82 patients were randomly assigned to receive 3 mg NGM282 (n=27), 6 mg NGM282 (n=28), or placebo (n=27). At 12 weeks, 20 (74%) patients in the 3 mg dose group and 22 (79%) in the 6 mg dose group achieved at least a 5% reduction in absolute liver fat content from baseline (relative risk 10·0 [95% CI 2·6-38·7] vs 11·4 [3·0-43·8], respectively; p<0·0001 for both comparisons) versus two (7%) in the placebo group. Overall, 76 (93%) of 82 patients experienced at least one adverse event, most of which were grade 1 (55 [67%]), and only five (6%) were grade 3 or worse. The most commonly (≥10%) reported adverse events were injection site reactions (28 [34%]), diarrhoea (27 [33%]), abdominal pain (15 [18%]), and nausea (14 [17%]). These adverse events were reported more frequently in the NGM282 groups compared with the placebo group. No life-threatening events or patient deaths occurred during the study.Interpretation: NGM282 produced rapid and significant reductions in liver fat content with an acceptable safety profile in patients with non-alcoholic steatohepatitis. Further study of NGM282 is warranted in this patient population.Funding: NGM Biopharmaceuticals. [ABSTRACT FROM AUTHOR]

During a single human lifetime, nearly one quintillion chromosomes separate from their sisters and transit to their destinations in daughter cells. Unlike DNA replication, chromosome segregation has no template, and, unlike transcription, errors frequently lead to a total loss of cell viability. Rapid progress in recent years has shown how kinetochores enable faithful execution of this process by connecting chromosomal DNA to microtubules. These findings have transformed our idea of kinetochores from cytological features to immense molecular machines and now allow molecular interpretation of many long-appreciated kinetochore functions. In this review we trace kinetochore protein connectivity from chromosomal DNA to microtubules, relating new findings to important points of regulation and function. [ABSTRACT FROM AUTHOR]

A flat-plate solar collector can reach “stagnation” temperatures exceeding 170 °C particularly during power failures or periods when there is minimal energy demand. Excessive pressures may occur in a solar collector during stagnation conditions – a potentially danger for residents. In this work the authors propose experimental and numerical investigations of natural cooling of flat plate solar collectors to control their overheating under stagnation conditions. Experimental and numerical investigations have been conducted on a commercially available Enerworks Heat Safe (EHS) residential flat plate solar collector integrated with a back mounted air channel. Numerical investigations have been performed employing a three-dimensional finite-volume numerical model validated against experiments carried out by the authors. The validated numerical tool was applied to explore the dissipation of heat from the collector through natural convection and its dependence on collector geometrical parameters, tilt angle and operational conditions. It was found that a solar collector integrated with a well designed back mounted air cooling channel and a control valve at the outlet opening would be able to provide suitable heat transfer rates and keeps the maximum temperature of the absorber plate over a practical range of stagnation conditions. From the conducted investigations it has been evidenced that an optimal size of back-mounted collector air-channel can be found with suitable tilt angle, corresponding to which the overheating of collectors can be controlled passively under stagnation conditions. [ABSTRACT FROM AUTHOR]

Membrane fusion is the critical step for infectious cell penetration by enveloped viruses. We have previously used single-virion measurements of fusion kinetics to study the molecular mechanism of influenza-virus envelope fusion. Published data on fusion inhibition by antibodies to the "stem" of influenza virus hemagglutinin (HA) now allow us to incorporate into simulations the provision that some HAs are inactive. We find that more than half of the HAs are unproductive even for virions with no bound antibodies, but that the overall mechanism is extremely robust. Determining the fraction of competent HAs allows us to determine their rates of target-membrane engagement. Comparison of simulations with data from H3N2 and H1N1 viruses reveals three independent functional variables of HA-mediated membrane fusion closely linked to neutralization susceptibility. Evidence for compensatory changes in the evolved mechanism sets the stage for studies aiming to define the molecular constraints on HA evolvability. [ABSTRACT FROM AUTHOR]

The article reports on the article "Morphologies of synaptic protein membrane fusion interfaces," published in a 2017 issue of "PNAS" by P. Gipson and team, which discusses the use of electron cryotomography to study lipid bilayer synaptic-vesicle fusion mediated by synaptobrevin or viral proteins.