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Annarosa Floreani1,2 1University of Padova, Padova, Italy; 2Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, ItalyCorrespondence: Annarosa FloreaniUniversity of Padova, Padova, ItalyTel +10393899418841Email annarosa.floreani@unipd.itAbstract: The standard therapy for primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA) which has shown to improve hepatic biochemistry, delay histological progression and improve transplant-free survival. Approximately 30– 40% of patients do not respond or are intolerant to UDCA. Obeticholic acid, a farnesoid X receptor (FXR) agonist is the only agent approved by the Food and Drug Administration for patients who do not respond to UDCA. Recently, combination therapy with UDCA and bezafibrate has been shown to improve biochemistry and both GLOBE and UK-PBC score in patients with an inadequate response to UDCA. More recently, new pharmacological agents have been included in Phase 2 and Phase 3 trials: PPAR agonists, non-bile acid FXR agonists, anti-NOX agents, immunomodulators and mesenchymal stem cells transplantation. This review gives an overview on the current experimental pharmacological agents employed in the treatment of PBC.Keywords: PBC, treatment, ursodeoxycholic acid, obeticholic acid, fibrates, FXR agonists, PPAR agonists

Background & Aims: Biochemical response to ursodeoxycholic acid (UDCA) therapy is associated with good prognosis in people living with primary biliary cholangitis (PBC). Biochemical response is typically assessed early in disease and it is not known what proportion of patients lose previously attained biochemical response, nor whether this impacts long-term liver transplant (LT)-free survival. Methods: We identified all UDCA-treated patients with PBC from the Canadian Network for Autoimmune Liver disease with biochemical measurements at 1 year, and evaluated their liver biochemistry over time. Inadequate biochemical response was defined as serum alkaline phosphatase ≥1.67x the upper limit of normal or abnormal serum total bilirubin at 1 year of UDCA therapy and all time points thereafter. Multistate Markov models were used to estimate transition rates between biochemical response states and from each state to LT or death. Results were validated in an external cohort (GLOBAL PBC registry). Results: A total of 823 patients from eight centers were included. Mean age at diagnosis was 53 years, 91% were female, 33% had inadequate biochemical response to UDCA at 1 year (n = 269). Patients who retained initial adequate response had lower rates of LT or death compared to patients who subsequently lost response (relative rate 0.102, 95% CI 0.047-0.223). Patients who regained adequate response had lower rates than patients who did not (0.016, 95% CI 0.001-0.568), and patients who lost response once more (0.010, 95% CI 0.001-0.340). Patients who regained adequate response for a third time also had lower rates than patients who did not (0.151, 95% CI 0.040-0.566). Analyses in the GLOBAL PBC registry (n = 2,237) validated these results. Conclusion: Loss of biochemical response at any time is associated with heightened risks of LT or death in people living with PBC. Achievement of biochemical response is an important goal throughout follow-up, regardless of biochemical response profile early in therapy. Impact and implications:: Early biochemical response to ursodeoxycholic acid is associated with good prognosis in patients with primary biliary cholangitis (PBC). Our work demonstrates that patients with PBC transition between biochemical response states over time, and that these transitions correspond with changes in risk of liver transplantation or death. Clinicians should re-evaluate risk and optimize treatment decisions for patients with PBC throughout follow-up, regardless of early biochemical response to therapy.

Abstract Previous studies have documented natural infections of SARS-CoV-2 in various domestic and wild animals. More recently, studies have been published noting the susceptibility of members of the Cervidae family, and infections in both wild and captive cervid populations. In this study, we investigated the presence of SARS-CoV-2 in mammalian wildlife within the state of Vermont. 739 nasal or throat samples were collected from wildlife throughout the state during the 2021 and 2022 harvest season. Data was collected from red and gray foxes (Vulpes vulples and Urocyon cineroargentus, respectively), fishers (Martes pennati), river otters (Lutra canadensis), coyotes (Canis lantrans), bobcats (Lynx rufus rufus), black bears (Ursus americanus), and white-tailed deer (Odocoileus virginianus). Samples were tested for the presence of SARS-CoV-2 via quantitative RT-qPCR using the CDC N1/N2 primer set and/or the WHO-E gene primer set. Surprisingly, we initially detected a number of N1 and/or N2 positive samples with high cycle threshold values, though after conducting environmental swabbing of the laboratory and verifying with a second independent primer set (WHO-E) and PCR without reverse transcriptase, we showed that these were false positives due to plasmid contamination from a construct expressing the N gene in the general laboratory environment. Our final results indicate that no sampled wildlife were positive for SARS-CoV-2 RNA, and highlight the importance of physically separate locations for the processing of samples for surveillance and experiments that require the use of plasmid DNA containing the target RNA sequence. These negative findings are surprising, given that most published North America studies have found SARS-CoV-2 within their deer populations. The absence of SARS-CoV-2 RNA in populations sampled here may provide insights in to the various environmental and anthropogenic factors that reduce spillover and spread in North American’s wildlife populations.

Abstract Long Interspersed Nuclear Elements-1s (L1s) are transposable elements that constitute most of the genome’s transcriptional output yet have still largely unknown functions. Here we show that L1s are required for proper mouse brain corticogenesis operating as regulatory long non-coding RNAs. They contribute to the regulation of the balance between neuronal progenitors and differentiation, the migration of post-mitotic neurons and the proportions of different cell types. In cortical cultured neurons, L1 RNAs are mainly associated to chromatin and interact with the Polycomb Repressive Complex 2 (PRC2) protein subunits enhancer of Zeste homolog 2 (Ezh2) and suppressor of zeste 12 (Suz12). L1 RNA silencing influences PRC2’s ability to bind a portion of its targets and the deposition of tri-methylated histone H3 (H3K27me3) marks. Our results position L1 RNAs as crucial signalling hubs for genome-wide chromatin remodelling, enabling the fine-tuning of gene expression during brain development and evolution.

Background/Objectives: A weekly combination of a high volume of moderate-intensity continuous training (MICT) with a low volume of high-intensity interval training (HIIT) provides important improvements in body composition and physical capacities in individuals with obesity. However, previous studies did not determine the weekly proportions of HIIT and MICT a priori. This study aimed to investigate changes in body composition, physical capacities and the fat oxidation rate in obese male adults by comparing a combination of MICT and HIIT, called combined training (COMB), with HIIT for a 12-week period. Methods: Thirty-four obese male adults (mean age: 39.4 ± 7.0 y; mean body mass index [BMI] 34.0 ± 4.2 kg·m−2) participated in this study (n = 18 for COMB, n = 16 HIIT), attending ∼ 36 training sessions. The COMB group performed 3 repetitions of 2 min at 95% of peak oxygen uptake (V’O2 peak) (e.g., HIIT ≤20%), followed by 30 min at 60% of VO2 peak (e.g., MICT ≥80%). The HIIT group performed 5–7 repetitions of 2 min at 95% of VO2 peak. At baseline (PRE) and at the end of the training period (POST), body composition, VO2 peak, and the fat oxidation rate were measured. The two training programs were equivalent in caloric expenditure. Results: At POST, body mass (BM) and fat mass (FM) decreased by a mean of 3.09 ± 3.21 kg and 3.90 ± 2.40 kg, respectively (P

Inter-row management in vineyards can influence the abundance of grapevine pests and their natural enemies. In 2013–2015, in a vineyard in northeastern Italy, the influence of two vineyard inter-row management strategies (i.e., alternate mowing, AM, and periodical tillage, PT) on the population dynamics of grapevine leafhoppers Hebata vitis and Zygina rhamni and their natural enemies, the mymarid Anagrus atomus and spiders (Araneae), and other hymenopteran parasitoids, were studied with different survey approaches. The infestations of both leafhoppers were lower in AM than PT due to the reduced leafhopper oviposition and higher nymph mortality in AM. This occurred although leafhopper egg parasitization by A. atomus was greater in PT than AM according to a density-dependent relationship with the leafhopper egg amount. Hymenopteran parasitoids other than A. atomus were the most abundant in AM, probably due to the higher availability of nectar and pollen than in PM. The significantly higher population densities of hunting spiders in AM than PT can be associated with the higher predation of leafhopper nymphs. Therefore, the study demonstrated that the alternate mowing of vineyard inter-rows enhances the abundance of natural enemies, such as spiders and hymenopteran parasitoids, and can contribute to grapevine leafhopper pest control.

Gender Medicine has had an enormous expansion over the last ten years. Autoimmune liver diseases include several conditions, i.e., autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and conditions involving the liver or biliary tree overlapping with AIH, as well as IgG4-related disease. However, little is known about the impact of sex in the pathogenesis and natural history of these conditions. The purpose of this review is to provide an update of the gender disparities among the autoimmune liver diseases by reviewing the data published from 1999 to 2023. The epidemiology of these diseases has been changing over the last years, due to the amelioration of knowledge in their diagnosis, pathogenesis, and treatment. The clinical data collected so far support the existence of sex differences in the natural history of autoimmune liver diseases. Notably, their history could be longer than that which is now known, with problems being initiated even at a pediatric age. Moreover, gender disparity has been observed during the onset of complications related to end-stage liver disease, including cancer incidence. However, there is still an important debate among researchers about the impact of sex and the pathogenesis of these conditions. With this review, we would like to emphasize the urgency of basic science and clinical research to increase our understanding of the sex differences in autoimmune liver diseases.

BackgroundSpinal muscular atrophy (SMA) is a progressive neuromuscular disorder that causes muscle weakness and is the leading genetic cause of infant mortality worldwide. While no definitive cure exists, the approval of 3 genetic-based therapies in Canada since 2018 has led to significant improvements in muscle function for children with SMA. With that, there are no evidence-based rehabilitation interventions and minimal evidence on the combined effects of genetic-based therapies and rehabilitation. ObjectiveThis protocol describes the methodology to assess the feasibility of a twice-weekly outpatient rehabilitation intervention focusing on gross and fine motor function to inform the methodology and sample size of a definitive clinical trial. MethodsWe will conduct a single-center nonrandomized pilot and feasibility trial to explore an outpatient rehabilitation intervention for children aged 6 months to 3 years with SMA treated with genetic-based therapies. Participation in the study will occur over a 25-week period, with a baseline assessment visit followed by a 12-week intervention period and a 12-week nonintervention period. The rehabilitation intervention comprises weekly physical and occupational therapy for 11 weeks. Assessments will occur at baseline (week 0), end of intervention or early withdrawal (week 12), and follow-up (week 24). Predetermined feasibility indicators will evaluate study feasibility across process (recruitment rates, eligibility criteria, adherence rates, retention rates, questionnaire suitability, and acceptability), resource (time, implementation, and execution), management (materials and data), and scientific (safety, tolerability, and preliminary efficacy) domains. ResultsThis project was funded in March 2022, and data will be collected between March 2023 and December 2023. Data analysis will occur between January 2024 and March 2024, with publication expected in the fall of 2024. The protocol for the feasibility trial will be considered successful if it meets the success criteria set out for the feasibility indicators. Indicators of specific interest include all process indicators, as well as time. Exploratory indicators will be reported. Pragmatically, the results of the feasibility trial will inform changes to the protocol and the start-up of a definitive multisite trial. ConclusionsThis novel twice-weekly outpatient rehabilitation intervention will be the first step toward filling the need for an evidence-based rehabilitation intervention for children with SMA treated with genetic-based therapies. It is expected that consistent and intensive rehabilitation therapy will augment functional gains being observed in this population. In the future, a definitive trial will measure the efficacy of the intervention. Trial RegistrationClinicalTrials.gov NCT05638750; https://clinicaltrials.gov/study/NCT05638750 International Registered Report Identifier (IRRID)DERR1-10.2196/46363

Background & aimsPrimary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC.MethodsAESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin

Background & aimsGut-homing lymphocytes that express the integrin α4β7 and CCR9 might contribute to development of primary sclerosing cholangitis (PSC). Vedolizumab, which blocks the integrin α4β7, is used to treat patients with inflammatory bowel diseases (IBD), but there are few data on its efficacy in patients with PSC. We investigated the effects of vedolizumab in a large international cohort of patients with PSC and IBD.MethodsWe collected data from European and North American centers participating in the International PSC Study Group from patients with PSC and IBD who received at least 3 doses of vedolizumab (n = 102; median vedolizumab treatment duration, 412 days). Demographic and clinical data were collected from baseline and during the follow-up period (until liver transplantation, death, or 56 days after the final vedolizumab infusion). We analyzed overall changes in biochemical features of liver and proportions of patients with reductions in serum levels of alkaline phosphatase (ALP) of 20% or more, from baseline through last follow-up evaluation. Other endpoints included response of IBD to treatment (improved, unchanged, or worsened, judged by the treating clinician, as well as endoscopic score) and liver-related outcomes.ResultsIn the entire cohort, the median serum level of ALP increased from 1.54-fold the upper limit of normal at baseline to 1.64-fold the upper limit of normal at the last follow-up examination (P = .018); serum levels of transaminases and bilirubin also increased by a small amount between baseline and the last follow-up examination. Serum levels of ALP decreased by 20% or more in 21 patients (20.6%); only the presence of cirrhosis (odds ratio, 4.48; P = .019) was independently associated with this outcome. Of patients with available endoscopic data, 56.8% had a response of IBD to treatment. Liver-related events occurred in 21 patients (20.6%), including bacterial cholangitis, cirrhosis decompensation, or transplantation.ConclusionsIn an analysis of patients with PSC and IBD in an international study group, we found no evidence for a biochemical response to vedolizumab, although serum level of ALP decreased by 20% or more in a subset of patients. Vedolizumab appears to be well tolerated and the overall response of IBD was the same as expected for patients without PSC.