A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries.

Advanced genomic technologies such as whole exome or whole genome sequencing have improved diagnoses and disease outcomes for individuals with genetic diseases. Yet, variants of unknown significance (VUS) require rigorous validation to establish disease causality or modification, or to exclude them from further analysis. Here, we describe a young individual of Polynesian ancestry who in the first 13 mo of life presented with SARS-CoV-2 pneumonia, severe enterovirus meningitis and adenovirus gastroenteritis, and severe adverse reaction to MMR vaccination. Genomic analysis identified a previously reported pathogenic homozygous variant in IFNAR1 (c.1156G > T, p.Glu386* LOF), which is common in Western Polynesia. Moreover, a new and putatively deleterious canonical splice site variant in DOCK8 was also found in homozygosity (c.3234 + 2T > C). This DOCK8 variant is common in Polynesians and other under-represented ancestries in large genomic databases. Despite in silico bioinformatic predictions, extensive in vitro and ex vivo analysis revealed the DOCK8 variant likely be neutral. Thus, our study reports a novel case of IFNAR1 deficiency, but also highlights the importance of functional validation of VUS, including those predicted to be deleterious, and the pressing need to expand our knowledge of the genomic architecture and landscape of under-represented populations and ancestries.

Safety and usability of proning pillows in intensive care: A scoping review.

OBJECTIVES: Proning is an established technique for the care of intubated patients with severe respiratory failure. Positioning devices used to support the head and body of patients placed in the prone position are often associated with the formation of pressure injuries. Despite robust literature on the prevention and monitoring of pressure injuries, little is described about the role of proning pillows on pressure injuries. The objective of this review is to understand the extent of evidence pertaining to the safety and usability of different types of proning pillows in the intensive care setting. REVIEW METHOD: A scoping review of the literature was completed using predefined search terms in three databases and identified 296 articles. An additional 26 were included from reference lists. Twenty studies are included in the analysis; most were published in the past 3 years, with >50% in surgical settings. DATA SOURCES: Three databases were searched: PubMed, Scopus, and EMBASE. REVIEW METHODS: The review followed the PRISMA Extension for Scoping Reviews, and data were reviewed using Covidence. RESULTS: The most prevalent proning pillow is a standard, noncontoured foam head positioner. It is responsible for the majority of facial pressure injuries in all settings of care. Memory foam pillows and helmet-based systems offer improved surface pressure distribution, although their usability in the intensive care setting remains poorly studied. Inflatable air-cell-based devices present an alternative, but the lack of supporting research and the costs may explain their poor uptake. Several articles proposed the use of pressure sensor systems to evaluate devices. We propose a set of ergonomic parametres to consider when choosing or designing a positioning device for proned patients. CONCLUSION: The evidence pertaining to the safety and usability of proning pillows in the intensive care setting is scarce, which provides opportunities for future research to improve the efficacy in the prevention of pressure injuries and the user experience.

Multimetallic complexes and functionalized gold nanoparticles based on a combination of d- and f-elements.

The new DO3A-derived dithiocarbamate ligand, DO3A-(t)Bu-CS2K, is formed by treatment of the ammonium salt [DO3A-(t)Bu]HBr with K2CO3 and carbon disulfide. DO3A-(t)Bu-CS2K reacts with the ruthenium complexes cis-[RuCl2(dppm)2] and [Ru(CH═CHC6H4Me-4)Cl(CO)(BTD)(PPh3)2] (BTD = 2,1,3-benzothiadiazole) to yield [Ru(S2C-DO3A-(t)Bu)(dppm)2](+) and [Ru(CH═CHC6H4Me-4)(S2C-DO3A-(t)Bu)(CO)(PPh3)2], respectively. Similarly, the group 10 metal complexes [Pd(C,N-C6H4CH2NMe2)Cl]2 and [PtCl2(PPh3)2] form the dithiocarbamate compounds, [Pd(C,N-C6H4CH2NMe2)(S2C-DO3A-(t)Bu)] and [Pt(S2C-DO3A-(t)Bu)(PPh3)2](+), under the same conditions. The linear gold complexes [Au(S2C-DO3A-(t)Bu)(PR3)] are formed by reaction of [AuCl(PR3)] (R = Ph, Cy) with DO3A-(t)Bu-CS2K. However, on reaction with [AuCl(tht)] (tht = tetrahydrothiophene), the homoleptic digold complex [Au(S2C-DO3A-(t)Bu)]2 is formed. Further homoleptic examples, [M(S2C-DO3A-(t)Bu)2] (M = Ni, Cu) and [Co(S2C-DO3A-(t)Bu)3], are formed from treatment of NiCl2·6H2O, Cu(OAc)2, or Co(OAc)2, respectively, with DO3A-(t)Bu-CS2K. The molecular structure of [Ni(S2C-DO3A-(t)Bu)2] was determined crystallographically. The tert-butyl ester protecting groups of [M(S2C-DO3A-(t)Bu)2] (M = Ni, Cu) and [Co(S2C-DO3A-(t)Bu)3] are cleaved by trifluoroacetic acid to afford the carboxylic acid products, [M(S2C-DO3A)2] (M = Ni, Cu) and [Co(S2C-DO3A)3]. Complexation with Gd(III) salts yields trimetallic [M(S2C-DO3A-Gd)2] (M = Ni, Cu) and tetrametallic [Co(S2C-DO3A-Gd)3], with r(1) values of 11.5 (Co) and 11.0 (Cu) mM(-1) s(-1) per Gd center. DO3A-(t)Bu-CS2K can also be used to prepare gold nanoparticles, Au@S2C-DO3A-(t)Bu, by displacement of the surface units from citrate-stabilized nanoparticles. This material can be transformed into the carboxylic acid derivative Au@S2C-DO3A by treatment with trifluoroacetic acid. Complexation with Gd(OTf)3 or GdCl3 affords Au@S2C-DO3A-Gd with an r(1) value of 4.7 mM(-1) s(-1) per chelate and 1500 mM(-1) s(-1) per object.

Looking at the fringes of MedTech innovation: a mapping review of horizon scanning and foresight methods.

OBJECTIVES: Horizon scanning (HS) is a method used to examine signs of change and may be used in foresight practice. HS methods used for the identification of innovative medicinal products cannot be applied in medical technologies (MedTech) due to differences in development and regulatory processes. The aim of this study is to identify HS and other methodologies used for MedTech foresight in support to healthcare decision-making. METHOD: A mapping review was performed. We searched bibliographical databases including MEDLINE, Embase, Scopus, Web of Science, IEEE Xplore and Compendex Engineering Village and grey literature sources such as Google, CORE database and the International HTA database. Our searches identified 8888 records. After de-duplication, and manual and automated title, abstracts and full-text screening, 49 papers met the inclusion criteria and were data extracted. RESULTS: Twenty-five single different methods were identified, often used in combination; of these, only three were novel (appearing only once in the literature). Text mining or artificial intelligence solutions appear as early as 2012, often practised in patent and social media sources. The time horizon used in scanning was not often justified. Some studies regarded experts both as a source and as a method. Literature searching remains one of the most used methods for innovation identification. HS methods were vaguely reported, but often involved consulting with experts and stakeholders. CONCLUSION: Heterogeneous methodologies, sources and time horizons are used for HS and foresight of MedTech innovation with little or no justification provided for their use. This review revealed an array of known methods being used in combination to overcome the limitations posed by single methods. The review also revealed inconsistency in methods reporting, with a lack of any consensus regarding best practice. Greater transparency in methods reporting and consistency in methods use would contribute to increased output quality to support informed timely decision-making.

CoQ10 Deficient Endothelial Cell Culture Model for the Investigation of CoQ10 Blood-Brain Barrier Transport.

Primary coenzyme Q10 (CoQ10) deficiency is unique among mitochondrial respiratory chain disorders in that it is potentially treatable if high-dose CoQ10 supplements are given in the early stages of the disease. While supplements improve peripheral abnormalities, neurological symptoms are only partially or temporarily ameliorated. The reasons for this refractory response to CoQ10 supplementation are unclear, however, a contributory factor may be the poor transfer of CoQ10 across the blood-brain barrier (BBB). The aim of this study was to investigate mechanisms of CoQ10 transport across the BBB, using normal and pathophysiological (CoQ10 deficient) cell culture models. The study identifies lipoprotein-associated CoQ10 transcytosis in both directions across the in vitro BBB. Uptake via SR-B1 (Scavenger Receptor) and RAGE (Receptor for Advanced Glycation Endproducts), is matched by efflux via LDLR (Low Density Lipoprotein Receptor) transporters, resulting in no "net" transport across the BBB. In the CoQ10 deficient model, BBB tight junctions were disrupted and CoQ10 "net" transport to the brain side increased. The addition of anti-oxidants did not improve CoQ10 uptake to the brain side. This study is the first to generate in vitro BBB endothelial cell models of CoQ10 deficiency, and the first to identify lipoprotein-associated uptake and efflux mechanisms regulating CoQ10 distribution across the BBB. The results imply that the uptake of exogenous CoQ10 into the brain might be improved by the administration of LDLR inhibitors, or by interventions to stimulate luminal activity of SR-B1 transporters.

Drug-Induced Mitochondrial Toxicity.

The mitochondrial respiratory chain (MRC) and ATP synthase (complex V) play an essential role in cellular energy production by the process of oxidative phosphorylation. In addition to inborn errors of metabolism, as well as secondary causes from disease pathophysiology, an impairment of oxidative phosphorylation can result from drug toxicity. These 'off-target' pharmacological effects can occur from a direct inhibition of MRC enzyme activity, an induction of mitochondrial oxidative stress, an uncoupling of oxidative phosphorylation, an impairment of mitochondrial membrane structure or a disruption in the replication of mitochondrial DNA. The purpose of this review is to focus on the off-target mitochondrial toxicity associated with both commonly used pharmacotherapies and a topical 'weight loss' agent. The mechanisms of drug-induced mitochondrial impairment will be discussed together with putative therapeutic strategies to counteract the adverse effects of the pharmacotherapy.

Coenzyme Q10 in the Treatment of Mitochondrial Disease

Abstract Currently, there is a paucity of available treatment strategies for oxidative phosphorylation disorders. Coenzyme Q10 (CoQ10) and related synthetic quinones are the only agents to date that have proven to be beneficial in the treatment of these heterogeneous disorders. The therapeutic efficacy of CoQ10 is not restricted to patients with an underlying CoQ10 deficiency and is thought to result from its ability to restore electron flow in the mitochondrial respiratory chain (MRC) as well as to increase the cellular antioxidant capacity. At present, however, there is no consensus on the appropriate dosage or therapeutic plasma level of CoQ10, and this information will be required before CoQ10 can be utilized effectively in the treatment of mitochondrial disease. The following review will outline our current knowledge on the use of CoQ10 in the treatment of MRC disorders and primary CoQ10 deficiencies.