De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa.

The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent variants in the U4 RNA, transcribed from the gene, and in at least two other genes were discovered to cause neurodevelopmental disorder.

Identification of novel 3D-genome altering and complex structural variants underlying retinitis pigmentosa type 17 through a multistep and high-throughput approach.

Introduction: Autosomal dominant retinitis pigmentosa type 17 (adRP, type RP17) is caused by complex structural variants (SVs) affecting a locus on chromosome 17 (chr17q22). The SVs disrupt the 3D regulatory landscape by altering the topologically associating domain (TAD) structure of the locus, creating novel TAD structures (neo-TADs) and ectopic enhancer-gene contacts. Currently, screening for RP17-associated SVs is not included in routine diagnostics given the complexity of the variants and a lack of cost-effective detection methods.

A proteogenomic atlas of the human neural retina.

The human neural retina is a complex tissue with abundant alternative splicing and more than 10% of genetic variants linked to inherited retinal diseases (IRDs) alter splicing. Traditional short-read RNA-sequencing methods have been used for understanding retina-specific splicing but have limitations in detailing transcript isoforms. To address this, we generated a proteogenomic atlas that combines PacBio long-read RNA-sequencing data with mass spectrometry and whole genome sequencing data of three healthy human neural retina samples.

Next-generation sequencing to genetically diagnose a diverse range of inherited eye disorders in 15 consanguineous families from Pakistan.

Inherited retinal dystrophies (IRDs) are characterized by photoreceptor dysfunction or degeneration. Clinical and phenotypic overlap between IRDs makes the genetic diagnosis very challenging and comprehensive genomic approaches for accurate diagnosis are frequently required. While there are previous studies on IRDs in Pakistan, causative genes and variants are still unknown for a significant portion of patients.

Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.

The correlation of urea and creatinine concentrations in sweat and saliva with plasma during hemodialysis: an observational cohort study.

Objectives: Urea and creatinine concentrations in plasma are used to guide hemodialysis (HD) in patients with end-stage renal disease (ESRD). To support individualized HD treatment in a home situation, there is a clinical need for a non-invasive and continuous alternative to plasma for biomarker monitoring during and between cycles of HD. In this observational study, we therefore established the correlation of urea and creatinine concentrations between sweat, saliva and plasma in a cohort of ESRD patients on HD.

Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis.

Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability.

Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases.

Macular degenerations (MDs) are a subgroup of retinal disorders characterized by central vision loss. Knowledge is still lacking on the extent of genetic and nongenetic factors influencing inherited MD (iMD) and age-related MD (AMD) expression. Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the ABCA4 gene in patients with Stargardt disease to identify associated coding and noncoding variation, however many MD patients still remain genetically unexplained.

Acute kidney injury in critical COVID-19: a multicenter cohort analysis in seven large hospitals in Belgium.

Background: Acute kidney injury (AKI) has been reported as a frequent complication of critical COVID-19. We aimed to evaluate the occurrence of AKI and use of kidney replacement therapy (KRT) in critical COVID-19, to assess patient and kidney outcomes and risk factors for AKI and differences in outcome when the diagnosis of AKI is based on urine output (UO) or on serum creatinine (sCr).

Methods: Multicenter, retrospective cohort analysis of patients with critical COVID-19 in seven large hospitals in Belgium.

The effect of exposure to long working hours on alcohol consumption, risky drinking and alcohol use disorder: A systematic review and meta-analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing Joint Estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates), with contributions from a large network of experts. Evidence from mechanistic data suggests that exposure to long working hours may increase alcohol consumption and cause alcohol use disorder. In this paper, we present a systematic review and meta-analysis of parameters for estimating the number of deaths and disability-adjusted life years from alcohol consumption and alcohol use disorder that are attributable to exposure to long working hours, for the development of the WHO/ILO Joint Estimates.

WHO/ILO work-related burden of disease and injury: Protocol for systematic reviews of exposure to long working hours and of the effect of exposure to long working hours on alcohol consumption and alcohol use disorders.

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing a joint methodology for estimating the national and global work-related burden of disease and injury (WHO/ILO joint methodology), with contributions from a large network of experts. In this paper, we present the protocol for two systematic reviews of parameters for estimating the number of deaths and disability-adjusted life years from alcohol consumption and alcohol use disorder attributable to exposure to long working hours, to inform the development of the WHO/ILO joint methodology.

Objectives: We aim to systematically review studies on exposure to long working hours (Systematic Review 1) and systematically review and meta-analyse estimates of the effect of exposure to long working hours on alcohol consumption and alcohol use disorder (Systematic Review 2), applying the Navigation Guide systematic review methodology as an organizing framework.

Drug-induced HPA axis alterations during acute critical illness: a multivariable association study.

Objective: Critical illness is hallmarked by low plasma ACTH in the face of high plasma cortisol. We hypothesized that frequently used drugs could play a role by affecting the hypothalamic-pituitary-adrenal axis.

Design: Observational association study.

Heart rate time series characteristics for early detection of infections in critically ill patients.

It is difficult to make a distinction between inflammation and infection. Therefore, new strategies are required to allow accurate detection of infection. Here, we hypothesize that we can distinguish infected from non-infected ICU patients based on dynamic features of serum cytokine concentrations and heart rate time series.

MECHANISMS IN ENDOCRINOLOGY: New concepts to further unravel adrenal insufficiency during critical illness.

The concept of 'relative' adrenal insufficiency during critical illness remains a highly debated disease entity. Several studies have addressed how to diagnose or treat this condition but have often yielded conflicting results, which further fuelled the controversy. The main reason for the controversy is the fact that the pathophysiology is not completely understood.

Photocatalytic abatement results from a model street canyon.

During the European Life+ project PhotoPAQ (Demonstration of Photocatalytic remediation Processes on Air Quality), photocatalytic remediation of nitrogen oxides (NOx), ozone (O3), volatile organic compounds (VOCs), and airborne particles on photocatalytic cementitious coating materials was studied in an artificial street canyon setup by comparing with a colocated nonactive reference canyon of the same dimension (5 × 5 × 53 m). Although the photocatalytic material showed reasonably high activity in laboratory studies, no significant reduction of NOx, O3, and VOCs and no impact on particle mass, size distribution, and chemical composition were observed in the field campaign. When comparing nighttime and daytime correlation plots of the two canyons, an average upper limit NOx remediation of ≤2% was derived.

New insights into the controversy of adrenal function during critical illness.

Critical illness represents a life-threatening disorder necessitating recruitment of defence mechanisms for survival. Herein, the hypothalamic-pituitary-adrenal axis is essential. However, the relevance of a relative insufficiency of the hypothalamic-pituitary-adrenal axis in critical illness, which is diagnosed by a suppressed cortisol response to exogenous adrenocorticotropic hormone (ACTH) irrespective of the plasma cortisol concentration, is controversial.

Effect of Early Parenteral Nutrition on the HPA Axis and on Treatment With Corticosteroids in Intensive Care Patients.

Background: Nutrition can affect the hypothalamus-pituitary-adrenal axis. We hypothesized that early administration of parenteral nutrition (PN) during critical illness reduces plasma ACTH and cortisol concentrations and thereby increases the use of corticosteroids.

Methods: This is a preplanned substudy of a randomized controlled trial (EPaNIC) that compared early PN with late PN in 4640 critically ill patients.

Construction of a photocatalytic de-polluting field site in the Leopold II tunnel in Brussels.

Within the framework of the European Life+-funded project PhotoPAQ (Demonstration of Photocatalytic remediation Processes on Air Quality), which was aimed at demonstrating the effectiveness of photocatalytic coating materials on a realistic scale, a photocatalytic de-polluting field site was set up in the Leopold II tunnel in Brussels, Belgium. For that purpose, photocatalytic cementitious materials were applied on the side walls and ceiling of selected test sections inside a one-way tunnel tube. This article presents the configuration of the test sections used and the preparation and implementation of the measuring campaigns inside the Leopold II tunnel.

The HPA axis response to critical illness: New study results with diagnostic and therapeutic implications.

For decades, elevated plasma cortisol concentrations in critically ill patients were exclusively ascribed to a stimulated hypothalamus-pituitary-adrenal axis with increased circulating adrenocorticotropic hormone (ACTH) inferred to several-fold increase adrenal cortisol synthesis. However, 'ACTH-cortisol dissociation' has been reported during critical illness, referring to low circulating ACTH coinciding with elevated circulating cortisol. It was recently shown that metabolism of cortisol is significantly reduced in critically ill patients explained by a suppression of the activity and expression of cortisol metabolizing enzymes in kidney and liver.

Impact of duration of critical illness on the adrenal glands of human intensive care patients.

Context: Adrenal insufficiency is considered to be prevalent during critical illness, although the pathophysiology, diagnostic criteria, and optimal therapeutic strategy remain controversial. During critical illness, reduced cortisol breakdown contributes substantially to elevated plasma cortisol and low plasma ACTH concentrations.

Objective: Because ACTH has a trophic impact on the adrenal cortex, we hypothesized that with a longer duration of critical illness, subnormal ACTH adrenocortical stimulation predisposes to adrenal insufficiency.

Cortisol metabolism in critical illness: implications for clinical care.

Purpose Of Review: Critical illness is uniformly characterized by elevated plasma cortisol concentrations, traditionally attributed exclusively to increased cortisol production driven by an activated hypothalamic pituitary adrenal axis. However, as plasma adrenocorticotropic hormone (ACTH) concentrations are often not elevated or even low during critical illness, alternative mechanisms must contribute.

Recent Findings: Recent investigations revealed that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the main cortisol metabolizing enzymes in liver and kidney.

Reduced nocturnal ACTH-driven cortisol secretion during critical illness.

Recently, during critical illness, cortisol metabolism was found to be reduced. We hypothesize that such reduced cortisol breakdown may suppress pulsatile ACTH and cortisol secretion via feedback inhibition. To test this hypothesis, nocturnal ACTH and cortisol secretory profiles were constructed by deconvolution analysis from plasma concentration time series in 40 matched critically ill patients and eight healthy controls, excluding diseases or drugs that affect the hypothalamic-pituitary-adrenal axis.

Endocrine responses to critical illness: novel insights and therapeutic implications.

Context: Critical illness, an extreme form of severe physical stress, is characterized by important endocrine and metabolic changes. Due to critical care medicine, survival from previously lethal conditions has become possible, but many patients now enter a chronic phase of critical illness. The role of the endocrine and metabolic responses to acute and prolonged critical illness in mediating or hampering recovery remains highly debated.