GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort.

Background: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA) expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA) and (GAA) expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine.

Methods: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial.

Sex-dependent placental methylation quantitative trait loci provide insight into the prenatal origins of childhood onset traits and conditions.

Molecular quantitative trait loci (QTLs) allow us to understand the biology captured in genome-wide association studies (GWASs). The placenta regulates fetal development and shows sex differences in DNA methylation. We therefore hypothesized that placental methylation QTL (mQTL) explain variation in genetic risk for childhood onset traits, and that effects differ by sex.

Long-read genome sequencing reveals a novel intronic retroelement insertion in NR5A1 associated with 46,XY differences of sexual development.

Despite significant advancements in rare genetic disease diagnostics, many patients with rare genetic disease remain without a molecular diagnosis. Novel tools and methods are needed to improve the detection of disease-associated variants and understand the genetic basis of many rare diseases. Long-read genome sequencing provides improved sequencing in highly repetitive, homologous, and low-complexity regions, and improved assessment of structural variation and complex genomic rearrangements compared to short-read genome sequencing.

Challenges in diagnosis and treatment of multiple atypical parathyroid tumors in a patient with extrapyramidal symptoms: case report and literature review.

Background: Atypical parathyroid tumors (APTs) are rare entities. We report the case of a patient with multiple APT presenting with extrapyramidal symptoms and a delayed hypercalcemic crisis.

Case Description: A 72-year-old man presented to a tertiary referral center's emergency room (ER) following two episodes of temporary loss of consciousness.

Further decompensation in cirrhosis: Results of a large multicenter cohort study supporting Baveno VII statements.

Background And Aims: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis.

Approach And Results: Multicenter cohort study.

The application of epiphenotyping approaches to DNA methylation array studies of the human placenta.

: Genome-wide DNA methylation (DNAme) profiling of the placenta with Illumina Infinium Methylation bead arrays is often used to explore the connections between exposures, placental pathology, and fetal development. However, many technical and biological factors can lead to signals of DNAme variation between samples and between cohorts, and understanding and accounting for these factors is essential to ensure meaningful and replicable data analysis. Recently, "epiphenotyping" approaches have been developed whereby DNAme data can be used to impute information about phenotypic variables such as gestational age, sex, cell composition, and ancestry.

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

Background & Aims: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model.

Mistakes Are Common; Should We Worry about Them?

Mutations arising early in human development are surprisingly common, but most often are confined to the placenta. These mutations provide clues to the normal developmental processes leading to a healthy placenta, despite these features being shared in common with cancer.

Abdominal obesity phenotype is associated with COVID-19 chest X-ray severity score better than BMI-based obesity.

Purpose: Chest X-ray (CXR) severity score and BMI-based obesity are predictive risk factors for COVID-19 hospital admission. However, the relationship between abdominal obesity and CXR severity score has not yet been fully explored.

Methods: This retrospective cohort study analyzed the association of different adiposity indexes, including waist circumference and body mass index (BMI), with CXR severity score in 215 hospitalized patients with COVID-19.

Confined placental mosaicism involving multiple de novo copy number variants associated with fetal growth restriction: A case report.

The presence of multiple large (>1 Mb) copy number variants (CNVs) in non-malignant tissue is rare in human genetics. We present a liveborn male with a birth weight below the first percentile associated with placental mosaicism involving eight 2.4-3.

Genomic imbalances in the placenta are associated with poor fetal growth.

Background: Fetal growth restriction (FGR) is associated with increased risks for complications before, during, and after birth, in addition to risk of disease through to adulthood. Although placental insufficiency, failure to supply the fetus with adequate nutrients, underlies most cases of FGR, its causes are diverse and not fully understood. One of the few diagnosable causes of placental insufficiency in ongoing pregnancies is the presence of large chromosomal imbalances such as trisomy confined to the placenta; however, the impact of smaller copy number variants (CNVs) has not yet been adequately addressed.

A Monocentric Retrospective Observational Study of Comorbidities in Patients Affected by Autoimmune Bullous Diseases.

Background/aim: Autoimmune bullous diseases (AIBDs) of the skin and mucosae include a heterogeneous group of chronic diseases, which could be associated with various comorbidities. The purpose of this study was to evaluate the comorbidity profiles of patients affected by AIBDs, who referred to the Dermatological Clinic of Padua from December 2015 to June 2018.

Patients And Methods: A monocentric retrospective observational study was conducted on 157 patients with diagnosis of AIBDs.

The significance of the placental genome and methylome in fetal and maternal health.

The placenta is a crucial organ for supporting a healthy pregnancy, and defective development or function of the placenta is implicated in a number of complications of pregnancy that affect both maternal and fetal health, including maternal preeclampsia, fetal growth restriction, and spontaneous preterm birth. In this review, we highlight the role of the placental genome in mediating fetal and maternal health by discussing the impact of a variety of genetic alterations, from large whole-chromosome aneuploidies to single-nucleotide variants, on placental development and function. We also discuss the placental methylome in relation to its potential applications for refining diagnosis, predicting pathology, and identifying genetic variants with potential functional significance.

Accurate ethnicity prediction from placental DNA methylation data.

Background: The influence of genetics on variation in DNA methylation (DNAme) is well documented. Yet confounding from population stratification is often unaccounted for in DNAme association studies. Existing approaches to address confounding by population stratification using DNAme data may not generalize to populations or tissues outside those in which they were developed.

Association of a placental Interleukin-6 genetic variant (rs1800796) with DNA methylation, gene expression and risk of acute chorioamnionitis.

Background: Acute chorioamnionitis (aCA), inflammation of the placenta and fetal membranes, is a frequently reported lesion in preterm deliveries. Genetic variants in innate immune system genes such as Interleukin-6 (IL6) may contribute to the placenta's inflammatory response, thus predisposing some pregnancies to aCA. These genetic variants may modulate molecular processes such as DNA methylation and gene expression, and in turn might affect susceptibility to aCA.

Considerations when processing and interpreting genomics data of the placenta.

The application of genomic approaches to placental research has opened exciting new avenues to help us understand basic biological properties of the placenta, improve prenatal screening/diagnosis, and measure effects of in utero exposures on child health outcomes. In the last decade, such large-scale genomic data (including epigenomics and transcriptomics) have become more easily accessible to researchers from many disciplines due to the increasing ease of obtaining such data and the rapidly evolving computational tools available for analysis. While the potential of large-scale studies has been widely promoted, less attention has been given to some of the challenges associated with processing and interpreting such data.

No evidence for association of 677C>T and 1298A>C variants with placental DNA methylation.

Background: 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in one-carbon metabolism that ensures the availability of methyl groups for methylation reactions. Two single-nucleotide polymorphisms (SNPs) in the gene, 677C>T and 1298A>C, result in a thermolabile enzyme with reduced function. These variants, in both the maternal and/or fetal genes, have been associated with pregnancy complications including miscarriage, neural tube defects (NTDs), and preeclampsia (PE), perhaps due to altered capacity for DNA methylation (DNAm).

Review: placental biomarkers for assessing fetal health.

The placenta is a multifunctional organ that regulates key aspects of pregnancy maintenance and fetal development. As the placenta is in direct contact with maternal blood, cellular products (DNA, RNA, proteins, etc.) from the placenta can enter maternal circulation by a variety of ways.

The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome.

Background/aims: Some evidence suggests that the systemic inflammatory response syndrome (SIRS) contributes to the poor outcome of cirrhotic patients. We studied 141 cirrhotic patients consecutively admitted to a tertiary referral centre assessing prevalence of SIRS and its relationship with in-hospital outcome.

Methods: Presence of SIRS was assessed on admission and during hospital stay.