Diagnostics and treatments of COVID-19: two-year update to a living systematic review of economic evaluations

Objectives: As the initial crisis of the COVID-19 pandemic recedes, healthcare decision makers are likely to want to make rational evidence-guided choices between the many interventions now available. We sought to update a systematic review to provide an up-to-date summary of the cost-effectiveness evidence regarding tests for SARS-CoV-2 and treatments for COVID-19.Methods: Key databases, including MEDLINE, EconLit and Embase, were searched on 3 July 2023, 2 years on from the first iteration of this review in July 2021. We also examined health technology assessment (HTA) reports and the citations of included studies and reviews. Peer-reviewed studies reporting full health economic evaluations of tests or treatments in English were included. Studies were quality assessed using an established checklist, and those with very serious limitations were excluded. Data from included studies were extracted into predefined tables.Results: The database search identified 8,287 unique records, of which 54 full texts were reviewed, 28 proceeded for quality assessment, and 15 were included. Three further studies were included through HTA sources and citation checking. Of the 18 studies ultimately included, 17 evaluated treatments including corticosteroids, antivirals and immunotherapies. In most studies, the comparator was standard care. Two studies in lower-income settings evaluated the cost effectiveness of rapid antigen tests and critical care provision. There were 17 modelling analyses and 1 trial-based evaluation.Conclusion: A large number of economic evaluations of interventions for COVID-19 have been published since July 2021. Their findings can help decision makers to prioritise between competing interventions, such as the repurposed antivirals and immunotherapies now available to treat COVID-19. However, some evidence gaps remain present, including head-to-head analyses, disease-specific utility values, and consideration of different disease variants.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021272219], identifier [PROSPERO 2021 CRD42021272219]

Identification of common genetic variation that modulates alternative splicing

Alternative splicing of genes is an efficient means of generating variation in protein function. Several disease states have been associated with rare genetic variants that affect splicing patterns. Conversely, splicing efficiency of some genes is known to vary between individuals without apparent ill effects. What is not clear is whether commonly observed phenotypic variation in splicing patterns, and hence potential variation in protein function, is to a significant extent determined by naturally occurring DNA sequence variation and in particular by single nucleotide polymorphisms (SNPs). In this study, we surveyed the splicing patterns of 250 exons in 22 individuals who had been previously genotyped by the International HapMap Project. We identified 70 simple cassette exon alternative splicing events in our experimental system; for six of these, we detected consistent differences in splicing pattern between individuals, with a highly significant association between splice phenotype and neighbouring SNPs. Remarkably, for five out of six of these events, the strongest correlation was found with the SNP closest to the intron-exon boundary, although the distance between these SNPs and the intron-exon boundary ranged from 2 bp to greater than 1,000 bp. Two of these SNPs were further investigated using a minigene splicing system, and in each case the SNPs were found to exert cis-acting effects on exon splicing efficiency in vitro. The functional consequences of these SNPs could not be predicted using bioinformatic algorithms. Our findings suggest that phenotypic variation in splicing patterns is determined by the presence of SNPs within flanking introns or exons. Effects on splicing may represent an important mechanism by which SNPs influence gene function

Lensing from small-scale travelling ionospheric disturbances observed using LOFAR

Observations made using the LOw-Frequency ARray (LOFAR) between 10:15 and 11:48 UT on the 15th of September 2018 over a bandwidth of approximately 25-65 MHz contain discrete pseudo-periodic features of ionospheric origin. These features occur within a period of approximately 10 min and collectively last roughly an hour. They are strongly frequency dependent, broadening significantly in time towards the lower frequencies, and show an overlaid pattern of diffraction fringes. By modelling the ionosphere as a thin phase screen containing a wave-like disturbance, we are able to replicate the observations, suggesting that they are associated with small-scale travelling ionospheric disturbances (TIDs). This modelling indicates that the features observed here require a compact radio source at a low elevation and that the TID or TIDs in question have a wavelength <~30 km. Several features suggest the presence of deviations from an idealised sinusoidal wave form. These results demonstrate LOFAR-s capability to identify and characterise small-scale ionospheric structures

Matrix-Assisted Laser Desorption/Ionisation, Time-of-Flight Mass Spectrometry in Genomics Research

The beginning of this millennium has seen dramatic advances in genomic research. Milestones such as the complete sequencing of the human genome and of many other species were achieved and complemented by the systematic discovery of variation at the single nucleotide (SNP) and whole segment (copy number polymorphism) level. Currently most genomics research efforts are concentrated on the production of whole genome functional annotations, as well as on mapping the epigenome by identifying the methylation status of CpGs, mainly in CpG islands, in different tissues. These recent advances have a major impact on the way genetic research is conducted and have accelerated the discovery of genetic factors contributing to disease. Technology was the critical driving force behind genomics projects: both the combination of Sanger sequencing with high-throughput capillary electrophoresis and the rapid advances in microarray technologies were keys to success. MALDI-TOF MS-based genome analysis represents a relative newcomer in this field. Can it establish itself as a long-term contributor to genetics research, or is it only suitable for niche areas and for laboratories with a passion for mass spectrometry? In this review, we will highlight the potential of MALDI-TOF MS-based tools for resequencing and for epigenetics research applications, as well as for classical complex genetic studies, allele quanti. cation, and quantitative gene expression analysis. We will also identify the current limitations of this approach and attempt to place it in the context of other genome analysis technologies

Mutational analysis of two positional candidate susceptibility genes for bipolar disorder on chromosome 12q23-q24: phenylalanine hydroxylase and human LIM-homeobox LHX5

Objectives: In the search for chromosome 12 genes potentially involved in the pathogenesis of bipolar disorder we will screen Phenylalanine hydroxylase and human LIM-homeobox LHX5 genes for sequence variants, both of which have been suggested as candidate genes. The genes lie on chromosome 12q23–24, near the Darier's disease gene, ATP2A2. We have previously reported two families in which the pattern of segregation of illness is consistent with genetic linkage between this chromosomal region and a putative highly penetrant autosomal dominant major affective disorder locus (pedigree 324, maximum LOD=2.1; pedigree 5501, maximum LOD=3.6). Methods: We screened the coding and intronic flanking regions of the phenylalanine hydroxylase and LHX5 genes for sequence variation by denaturing high-performance liquid chromatography in individuals from the pedigrees. Results: In total, nine single nucleotide polymorphisms and one 6 base pair deletion were identified. Conclusion: Our studies allowed us to conclude that none of these variants act as a highly penetrant autosomal dominant susceptibility locus for mood disorder in our families

Massively parallel sequencing of customised forensically informative SNP panels on the MiSeq

Forensic DNA-based intelligence, or forensic DNA phenotyping, utilises SNPs to infer the biogeographical ancestry and externally visible characteristics of the donor of evidential material. SNaPshot® is a commonly employed forensic SNP genotyping technique, which is limited to multiplexes of 30–40 SNPs in a single reaction and prone to PCR contamination. Massively parallel sequencing has the ability to genotype hundreds of SNPs in multiple samples simultaneously by employing an oligonucleotide sample barcoding strategy. This study of the Illumina MiSeq massively parallel sequencing platform analysed 136 unique SNPs in 48 samples from SNaPshot PCR amplicons generated by five established forensic DNA phenotyping assays comprising the SNPforID 52-plex, SNPforID 34-plex, Eurasiaplex, Pacifiplex and IrisPlex. Approximately 3 GB of sequence data were generated from two MiSeq flow cells and profiles were obtained from just 0.25 ng of DNA. Compared with SNaPshot, an average 98% genotyping concordance was achieved. Our customised approach was successful in attaining SNP profiles from extremely degraded, inhibited, and compromised casework samples. Heterozygote imbalance and sequence coverage in negative controls highlight the need to establish baseline sequence coverage thresholds and refine allele frequency thresholds. This study demonstrates the potential of the MiSeq for forensic SNP analysis