Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Comparison of Seasonal foEs and fbEs Occurrence Rates Derived from Global Digisonde Measurements

A global climatology of sporadic-E occurrence rates (ORs) based on ionosonde measurements is presented for the peak blanketing frequency, fbEs, and the ordinary mode peak frequency of the layer, foEs. ORs are calculated for a variety of sporadic-E frequency thresholds: no lower limit, 3, 5, and 7 MHz. Seasonal rates are calculated from 64 Digisonde sites during the period 2006–2020 using ionograms either manually or automatically scaled with ARTIST-5. Both foEs and fbEs ORs peak in the Northern Hemisphere during the boreal summer, with a decrease by roughly a factor of 2–3 in fbEs rates relative to foEs rates without a lower threshold on the sporadic-E intensity. This ratio of foEs to fbEs OR increases with increasing sporadic-E intensity, up to a factor of 5 for the 7 MHz threshold. An asymmetry is observed with the Southern Hemisphere peaks during the austral summer, with slightly lower rates compared with the Northern Hemisphere during the boreal summer. A drastic decrease in ORs is observed for the higher intensity thresholds, such that the fbEs occurrence rates for 7 MHz are nearly zero during most locations and seasons. These updated occurrence rates can be used for future statistical comparisons with GPS radio occultation-based sporadic-E occurrence rates

Comparison of Seasonal foEs and fbEs Occurrence Rates Derived from Global Digisonde Measurements

A global climatology of sporadic-E occurrence rates (ORs) based on ionosonde measurements is presented for the peak blanketing frequency, fbEs, and the ordinary mode peak frequency of the layer, foEs. ORs are calculated for a variety of sporadic-E frequency thresholds: no lower limit, 3, 5, and 7 MHz. Seasonal rates are calculated from 64 Digisonde sites during the period 2006–2020 using ionograms either manually or automatically scaled with ARTIST-5. Both foEs and fbEs ORs peak in the Northern Hemisphere during the boreal summer, with a decrease by roughly a factor of 2–3 in fbEs rates relative to foEs rates without a lower threshold on the sporadic-E intensity. This ratio of foEs to fbEs OR increases with increasing sporadic-E intensity, up to a factor of 5 for the 7 MHz threshold. An asymmetry is observed with the Southern Hemisphere peaks during the austral summer, with slightly lower rates compared with the Northern Hemisphere during the boreal summer. A drastic decrease in ORs is observed for the higher intensity thresholds, such that the fbEs occurrence rates for 7 MHz are nearly zero during most locations and seasons. These updated occurrence rates can be used for future statistical comparisons with GPS radio occultation-based sporadic-E occurrence rates

Comparison of Seasonal foEs and fbEs Occurrence Rates Derived from Global Digisonde Measurements

A global climatology of sporadic-E occurrence rates (ORs) based on ionosonde measurements is presented for the peak blanketing frequency, fbEs, and the ordinary mode peak frequency of the layer, foEs. ORs are calculated for a variety of sporadic-E frequency thresholds: no lower limit, 3, 5, and 7 MHz. Seasonal rates are calculated from 64 Digisonde sites during the period 2006–2020 using ionograms either manually or automatically scaled with ARTIST-5. Both foEs and fbEs ORs peak in the Northern Hemisphere during the boreal summer, with a decrease by roughly a factor of 2–3 in fbEs rates relative to foEs rates without a lower threshold on the sporadic-E intensity. This ratio of foEs to fbEs OR increases with increasing sporadic-E intensity, up to a factor of 5 for the 7 MHz threshold. An asymmetry is observed with the Southern Hemisphere peaks during the austral summer, with slightly lower rates compared with the Northern Hemisphere during the boreal summer. A drastic decrease in ORs is observed for the higher intensity thresholds, such that the fbEs occurrence rates for 7 MHz are nearly zero during most locations and seasons. These updated occurrence rates can be used for future statistical comparisons with GPS radio occultation-based sporadic-E occurrence rates

Why are Hoogsteen base pairs energetically disfavored in A-RNA compared to B-DNA?

A(syn)-U/T and G(syn)-C+ Hoogsteen (HG) base pairs (bps) are energetically more disfavored relative to Watson–Crick (WC) bps in A-RNA as compared to B-DNA by >1 kcal/mol for reasons that are not fully understood. Here, we used NMR spectroscopy, optical melting experiments, molecular dynamics simulations and modified nucleotides to identify factors that contribute to this destabilization of HG bps in A-RNA. Removing the 2′-hydroxyl at single purine nucleotides in A-RNA duplexes did not stabilize HG bps relative to WC. In contrast, loosening the A-form geometry using a bulge in A-RNA reduced the energy cost of forming HG bps at the flanking sites to B-DNA levels. A structural and thermodynamic analysis of purine-purine HG mismatches reveals that compared to B-DNA, the A-form geometry disfavors syn purines by 1.5–4 kcal/mol due to sugar-backbone rearrangements needed to sterically accommodate the syn base. Based on MD simulations, an additional penalty of 3–4 kcal/mol applies for purine-pyrimidine HG bps due to the higher energetic cost associated with moving the bases to form hydrogen bonds in A-RNA versus B-DNA. These results provide insights into a fundamental difference between A-RNA and B-DNA duplexes with important implications for how they respond to damage and post-transcriptional modifications