GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Evaluation and Management of Skeletal Health in Celiac Disease: Position Statement

OBJECTIVE: To review the evaluation and management of skeletal health in patients with celiac disease (CD), and to make recommendations on screening, diagnosis, treatment and follow-up of low bone mineral density (BMD) in CD patients

Pilot Trial of Arginine Deprivation Plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) being much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aims at investigating the safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy, ADI-PEG 20. Nine patients were enrolled in this pilot study. The combination therapy was safe and tolerable with an absence of immune-related adverse events (irAE) of special interest, but with four of nine patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of the treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at the baseline in metastases

Moral Narratives Workshop Proceedings

The Moral Narratives Workshop (www. moralnarratives.org) was organized in 2022 to kickstart and develop an interdisciplinary, empirical study of stories told about people’s moral actions and characters. Across eight weeks, the workshop featured talks on topics such as the cognitive mechanisms of moral narrative construction (e.g., narrator’s goals, pragmatic inferences, the role of audiences, deception), the various functions of moral narratives (e.g., cultural/master narratives, narrative identity, understanding, legitimization and maintenance of power, persuasion, autobiographical memory, victimizing, redemption, moral development), featuring cases of moral narratives in various contexts (e.g., criminal justice, propaganda, politics, journalism, literature, science communication). Each talk was followed by an hour-long group discussion expanding on the themes of the talks. Participants came from diverse backgrounds, including psychology, philosophy, linguistics, communications, journalism, literature, political science, and anthropology. Here, we provide a record of the insights arising from the group discussions. Its contents faithfully reflect the diversity, complexity and messiness of human knowledge production. We intend for these workshop proceedings to serve as a rich and generative resource for future scholarship on moral narratives