NMD3 regulates both mRNA and rRNA nuclear export in African trypanosomes via an XPOI-linked pathway

Trypanosomes mostly regulate gene expression through post-transcriptional mechanisms, particularly mRNA stability. However, much mRNA degradation is cytoplasmic such that mRNA nuclear export must represent an important level of regulation. Ribosomal RNAs must also be exported from the nucleus and the trypanosome orthologue of NMD3 has been confirmed to be involved in rRNA processing and export, matching its function in other organisms. Surprisingly, we found that TbNMD3 depletion also generates mRNA accumulation of procyclin-associated genes (PAGs), these being co-transcribed by RNA polymerase I with the procyclin surface antigen genes expressed on trypanosome insect forms. By whole transcriptome RNA-seq analysis of TbNMD3-depleted cells we confirm the regulation of the PAG transcripts by TbNMD3 and using reporter constructs reveal that PAG1 regulation is mediated by its 5′UTR. Dissection of the mechanism of regulation demonstrates that it is not dependent upon translational inhibition mediated by TbNMD3 depletion nor enhanced transcription. However, depletion of the nuclear export factors XPO1 or MEX67 recapitulates the effects of TbNMD3 depletion on PAG mRNAs and mRNAs accumulated in the nucleus of TbNMD3-depleted cells. These results invoke a novel RNA regulatory mechanism involving the NMD3-dependent nuclear export of mRNA cargos, suggesting a shared platform for mRNA and rRNA expor

Prospectus, January 20, 1987

https://spark.parkland.edu/prospectus_1987/1001/thumbnail.jp

Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS program

This study compared initiation of insulin and other AHAs with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs 16%), insulin (3% vs 9%;) or any non-insulin AHA (5% vs 12%; p<0.001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31,0.43; p<0.001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about two years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (p<0.001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes. Trial registration: ClinicalTrials.gov identifiers NCT01032629, NCT01989754. This article is protected by copyright. All rights reserved

Atypical scrapie in sheep from a UK research flock which is free from classical scrapie

Background: In the wake of the epidemic of bovine spongiform encephalopathy the British government established a flock of sheep from which scrapie-free animals are supplied to laboratories for research. Three breeds of sheep carrying a variety of different genotypes associated with scrapie susceptibility/resistance were imported in 1998 and 2001 from New Zealand, a country regarded as free from scrapie. They are kept in a purpose-built Sheep Unit under strict disease security and are monitored clinically and post mortem for evidence of scrapie. It is emphasised that atypical scrapie, as distinct from classical scrapie, has been recognised only relatively recently and differs from classical scrapie in its clinical, neuropathological and biochemical features. Most cases are detected in apparently healthy sheep by post mortem examination.Results: The occurrence of atypical scrapie in three sheep in (or derived from) the Sheep Unit is reported. Significant features of the affected sheep included their relatively high ages (6 y 1 mo, 7 y 9 mo, 9 y 7 mo respectively), their breed (all Cheviots) and their similar PRNP genotypes (AFRQ/AFRQ, AFRQ/ALRQ, and AFRQ/AFRQ, respectively). Two of the three sheep showed no clinical signs prior to death but all were confirmed as having atypical scrapie by immunohistochemistry and Western immunoblotting. Results of epidemiological investigations are presented and possible aetiologies of the cases are discussed.Conclusion: By process of exclusion, a likely explanation for the three cases of atypical scrapie is that they arose spontaneously and were not infected from an exterior source. If correct, this raises challenging issues for countries which are currently regarded as free from scrapie. It would mean that atypical scrapie is liable to occur in flocks worldwide, especially in older sheep of susceptible genotypes. To state confidently that both the classical and atypical forms of scrapie are absent from a population it is necessary for active surveillance to have taken place

The cost of primary care consultations associated with long COVID in non-hospitalised adults:a retrospective cohort study using UK primary care data

Abstract Background The economic impact of managing long COVID in primary care is unknown. We estimated the costs of primary care consultations associated with long COVID and explored the relationship between risk factors and costs. Methods Data were obtained on non-hospitalised adults from the Clinical Practice Research Datalink Aurum primary care database. We used propensity score matching with an incremental cost method to estimate additional primary care consultation costs associated with long COVID (12 weeks after COVID-19) at an individual and UK national level. We applied multivariable regression models to estimate the association between risk factors and consultations costs beyond 12 weeks from acute COVID-19. Results Based on an analysis of 472,173 patients with COVID-19 and 472,173 unexposed individuals, the annual incremental cost of primary care consultations associated with long COVID was £2.44 per patient and £23,382,452 at the national level. Among patients with COVID-19, a long COVID diagnosis and reporting of longer-term symptoms were associated with a 43% and 44% increase in primary care consultation costs respectively, compared to patients without long COVID symptoms. Older age, female sex, obesity, being from a white ethnic group, comorbidities and prior consultation frequency were all associated with increased primary care consultation costs. Conclusions The costs of primary care consultations associated with long COVID in non-hospitalised adults are substantial. Costs are significantly higher among those diagnosed with long COVID, those with long COVID symptoms, older adults, females, and those with obesity and comorbidities

Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort

BACKGROUND: The hepatitis C virus (HCV) infects nearly 3% of the World's population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B single nucleotide polymorphisms (SNPs), rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of HCV infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (more than 1%) haplotypes for IL28B, one tagged by the rs8099917 minor allele, four tagged by rs12979860. METHODS: We used massively parallel sequencing of the IL28B and IL28A gene regions generated by polymerase chain reaction (PCR) from pooled DNA samples from 100 responders and 99 non-responders to therapy, to identify common variants. Variants that had high odds ratios and were validated were then genotyped in a cohort of 905 responders and non-responders. Their predictive power was assessed, alone and in combination with HLA-C. RESULTS: Only SNPs in the IL28B linkage disequilibrium block predicted drug response. Eighteen SNPs were identified with evidence for association with drug response, and with a high degree of confidence in the sequence call. We found that two SNPs, rs4803221 (homozygote minor allele positive predictive value (PPV) of 77%) and rs7248668 (PPV 78%), predicted failure to respond better than the current best, rs8099917 (PPV 73%) and rs12979860 (PPV 68%) in this cross-sectional cohort. The best SNPs tagged a single common haplotype, haplotype 2. Genotypes predicted lack of response better than alleles. However, combination of IL28B haplotype 2 carrier status with the HLA-C C2C2 genotype, which has previously been reported to improve prediction in combination with IL28B, provides the highest PPV (80%). The haplotypes present alternative putative transcription factor binding and methylation sites. CONCLUSIONS: Massively parallel sequencing allowed identification and comparison of the best common SNPs for identifying treatment failure in therapy for HCV. SNPs tagging a single haplotype have the highest PPV, especially in combination with HLA-C. The functional basis for the association may be due to altered regulation of the gene. These approaches have utility in improving diagnostic testing and identifying causal haplotypes or SNPs

Identifying diagnostic criteria for upper- and lower-limb lymphoedema

BACKGROUND Bioimpedance spectroscopy (BIS) assesses resistance (impedance) to the flow of an electrical current. Through the measurement of impedance to currents at low (R0) and high (Rinf) frequencies, extracellular fluid (ECF) and total body fluid (TBF) can be measured, respectively, and intracellular fluid (Ri = ICF) subsequently extrapolated (TBW = ECF + ICF). Measuring bilateral upper-limb or lower-limb secondary lymphoedema following cancer is complicated by the unavailability of a comparable, unaffected limb. Availability of normative BIS data for all 4 limb segments would enable an extension of BIS in the diagnosis of bilateral upper-, as well as lower-limb lymphoedema. The purpose of this study was to describe normative arm to leg, arm to arm and leg to leg impedance ratios and to determine optimal cut-off thresholds for diagnosing lymphoedema by testing the accuracy of cut-offs based on normative means plus or minus 0.5 to 3 SDs to diagnose known cases of lymphoedema

RTT advanced practice and how it can change the future of radiotherapy

The radiation therapy (RT) landscape is continuously evolving, necessitating adaptation in roles and responsibilities of radiation therapists (RTTs). Advanced Practice Radiation Therapists (APRTs) have taken on a proactive role in expanding services and assuming responsibilities within multi-professional teams. A European Society for Radiotherapy and Oncology (ESTRO) brought geographically diverse and experienced RTTs together, to discuss how advanced practice (AP) in the RTT profession should be future-proofed and create a global platform for collaboration. Challenges in achieving consensus and standardisation of APRT was identified across jurisdictions, emphasising the importance of international collaboration. Whilst highlighting the pivotal role of APRTs in driving innovation, improving patient care, and navigating the complexities of modern RT practice, this position paper presents outcomes and recommendations from the workshop. Discussions highlighted the need for standardised role definitions, education frameworks, regulatory support, and career development pathways to enable the advancement of APRT effectively. Increasing networks and collaboration is recommended to ensure APRTs can shape the future of RT

RTT advanced practice and how it can change the future of radiotherapy

The radiation therapy (RT) landscape is continuously evolving, necessitating adaptation in roles and responsibilities of radiation therapists (RTTs). Advanced Practice Radiation Therapists (APRTs) have taken on a proactive role in expanding services and assuming responsibilities within multi-professional teams. A European Society for Radiotherapy and Oncology (ESTRO) brought geographically diverse and experienced RTTs together, to discuss how advanced practice (AP) in the RTT profession should be future-proofed and create a global platform for collaboration. Challenges in achieving consensus and standardisation of APRT was identified across jurisdictions, emphasising the importance of international collaboration. Whilst highlighting the pivotal role of APRTs in driving innovation, improving patient care, and navigating the complexities of modern RT practice, this position paper presents outcomes and recommendations from the workshop. Discussions highlighted the need for standardised role definitions, education frameworks, regulatory support, and career development pathways to enable the advancement of APRT effectively. Increasing networks and collaboration is recommended to ensure APRTs can shape the future of RT