Designing and Undertaking a Health Economics Study of Digital Health Interventions.

This paper introduces and discusses key issues in the economic evaluation of digital health interventions. The purpose is to stimulate debate so that existing economic techniques may be refined or new methods developed. The paper does not seek to provide definitive guidance on appropriate methods of economic analysis for digital health interventions. This paper describes existing guides and analytic frameworks that have been suggested for the economic evaluation of healthcare interventions. Using selected examples of digital health interventions, it assesses how well existing guides and frameworks align to digital health interventions. It shows that digital health interventions may be best characterized as complex interventions in complex systems. Key features of complexity relate to intervention complexity, outcome complexity, and causal pathway complexity, with much of this driven by iterative intervention development over time and uncertainty regarding likely reach of the interventions among the relevant population. These characteristics imply that more-complex methods of economic evaluation are likely to be better able to capture fully the impact of the intervention on costs and benefits over the appropriate time horizon. This complexity includes wider measurement of costs and benefits, and a modeling framework that is able to capture dynamic interactions among the intervention, the population of interest, and the environment. The authors recommend that future research should develop and apply more-flexible modeling techniques to allow better prediction of the interdependency between interventions and important environmental influences.This paper is one of the outputs of two workshops, one supported by the Medical Research Council (MRC)/National Institute for Health Research (NIHR) Methodology Research Programme (PI Susan Michie) and the Robert Wood Johnson Foundation (PI Kevin Patrick), and the other by the National Science Foundation (PI Donna Spruitj-Metz, proposal # 1539846). The Health Economics Research Unit is funded in part by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Elsevier

Impact of abiotic factors and husbandry on saprolegniosis in salmonid farms

Funding Information: This work was financially supported by the EU H2020 [ H2020-SFS-10a-2014 (ParaFishControl, grant agreement No. 634429) (PT, MS, RG, JD-U, PvW, BO & MF)], the BBSRC [ BB/P020224/1 (MS & PvW) & BB/M026566/1 (MS & PvW)] and the University of Aberdeen (MS & PvW). The authors would like to thank all the fish farmers/staff and colleagues who collaborated in the fieldwork and provided valuable information for the study. Publisher Copyright: © 2022 The AuthorsPeer reviewedPublisher PD

Co-transcriptional degradation of aberrant pre-mRNA by Xrn2

Eukaryotic protein-coding genes are transcribed as pre-mRNAs that are matured by capping, splicing and cleavage and polyadenylation. Although human pre-mRNAs can be long and complex, containing multiple introns and many alternative processing sites, they are usually processed co-transcriptionally. Mistakes during nuclear mRNA maturation could lead to potentially harmful transcripts that are important to eliminate. However, the processes of human pre-mRNA degradation are not well characterised in the human nucleus. We have studied how aberrantly processed pre-mRNAs are degraded and find a role for the 5′→3′ exonuclease, Xrn2. Xrn2 associates with and co-transcriptionally degrades nascent β-globin transcripts, mutated to inhibit splicing or 3′ end processing. Importantly, we provide evidence that many endogenous pre-mRNAs are also co-transcriptionally degraded by Xrn2 when their processing is inhibited by Spliceostatin A. Our data therefore establish a previously unknown function for Xrn2 and an important further aspect of pre-mRNA metabolism that occurs co-transcriptionally

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer.

BACKGROUND: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer. METHOD: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). RESULTS: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P \u3c .05), with borderline significances achieved in the other two (P \u3c .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours. CONCLUSION: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients

Socioeconomic Position and Adolescent Trajectories in Smoking, Drinking, and Psychiatric Distress

Purpose: Smoking, drinking, and psychiatric distress are inter-related and may also be associated with socioeconomic position (SEP). This paper investigates the role of SEP in adolescent development across all three of these outcomes. Methods: Data were self-reported by adolescents in the Twenty-07 Study (N = 1,515) at ages 15, 17, and 18 years. Latent class analysis was used to identify homogeneous subgroups of adolescents with distinct developmental patterns. Associations between developmental patterns and a range of socioeconomic indicators were then tested. Results: Five classes were identified. A Low Risk class had low levels for all outcomes. A High Distress class had persistently high levels of distress, but was otherwise similar to the Low Risk group. A High Drinking class drank alcohol earlier and more heavily but also had higher levels of distress than the Low Risk group. Smokers were grouped in two classes, Early Smokers and Late Smokers, and both also had raised levels of drinking and distress. Early Smokers tended to begin earlier and smoke more heavily than Late Smokers. Relative to the Low Risk class, adolescents in a disadvantaged SEP were more likely to be Early Smokers and somewhat less likely to be in the High Drinking class. SEP was not consistently associated with membership in the High Distress or Late Smokers classes. Conclusions: Associations with SEP are evident in opposing directions or absent depending on the combination and timing of outcomes, suggesting that a disadvantaged SEP is not a simple common cause for all three outcomes. © 2013 Society for Adolescent Health and Medicine. All rights reserved

Long-term adverse effects and healthcare burden of rectal cancer radiotherapy: systematic review and meta-analysis

BackgroundAs rectal cancer survival increases, more patients survive with potentially severe, long-term gastrointestinal and genitourinary complications from radiotherapy. The burden of these complications for patients and healthcare services is unclear, which this review aims to quantify.MethodsSystematic search of Medline and Embase for randomized-controlled trials (RCTs) and multicentre observational studies published since 2000, reporting hospitalization/procedural intervention for long-term (>6 months post-treatment) gastrointestinal or genitourinary complications after radiotherapy and surgery for rectal cancer. Prevalence values were pooled in a meta-analysis assuming random effects. Organ-preservation patients were excluded.Results4044 records screened; 24 reports from 23 studies included (15 RCTs, 8 Observational), encompassing 15 438 patients. Twenty-one studies (median follow-up 60 months) reported gastrointestinal complications post-radiotherapy: pooled prevalence 11% (95% confidence interval (95% CI) 8–14%). Thirteen reported small bowel obstruction: prevalence 9% (95% CI 6–12%), a 58% increased risk compared with surgery alone (RR 1.58, 95% CI 1.26–1.98, n = 5 studies). Seven reported fistulas: prevalence 1% (95% CI 1–2%). Thirteen reported genitourinary complications: prevalence 4% (95% CI 1–6%); RR 1.10 (95% CI 0.88–1.38, n = 3 studies) compared with surgery alone.ConclusionsOver 10% of patients are hospitalized for long-term complications following rectal cancer radiotherapy. Serious gastrointestinal complications are commonplace; late small bowel obstruction is more common in patients having radiotherapy and surgery compared with surgery alone. Patients and clinicians need to be aware of these risks

Phos-tag analysis of Rab10 phosphorylation by LRRK2:a powerful assay for assessing kinase function and inhibitors

Autosomal dominant mutations that activate the leucine-rich repeat kinase-2 (LRRK2) cause inherited Parkinson's disease. Recent work has revealed that LRRK2 directly phosphorylates a conserved Thr/Ser residue in the effector-binding switch-II motif of a number of Rab GTPase proteins, including Rab10. Here we describe a facile and robust method to assess phosphorylation of endogenous Rab10 in mouse embryonic fibroblasts (MEFs), lung and spleen derived B Cells, based on the ability of the Phos-tag reagent to retard the electrophoretic mobility of LRRK2 phosphorylated Rab10. We exploit this assay to show that phosphorylation of Rab10 is ablated in kinase inactive LRRK2[D2017A] knock-in MEFs and mouse lung, demonstrating that LRRK2 is the major Rab10 kinase in these cells/tissue. We also establish that the Phos-tag assay can be deployed to monitor the impact that activating LRRK2 pathogenic (G2019S and R1441G) knock-in mutations have on stimulating Rab10 phosphorylation. We show that upon addition of LRRK2 inhibitors, Rab10 is dephosphorylated within 1-2 min, markedly more rapidly than the Ser935 and Ser1292 biomarker sites that require 40-80 min. Furthermore, we find that phosphorylation of Rab10 is suppressed in LRRK2[S910A, S935A] knock-in MEFs indicating that phosphorylation of Ser910 and Ser935 and potentially 14-3-3 binding play a role in facilitating the phosphorylation of Rab10 by LRRK2 in vivo. The Rab Phos-tag assay has the potential to significantly aide with evaluating the effect that inhibitors, mutations and other factors have on the LRRK2 signalling pathway