E-learning for self-management support: Introducing blended learning for graduate students - A cohort study 13 Education 1303 Specialist Studies in Education 11 Medical and Health Sciences 1117 Public Health and Health Services

Background: E-learning allows delivery of education in many diverse settings and researchers have demonstrated it can be as effective as learning conducted in traditional face-to-face settings. However, there are particular practices and skills needed in the area of providing patient self-management support (SMS), that may not be achievable online. The aim of this study was to compare three approaches in the training of university students regarding the preparation of a Chronic Condition Self-Management Care Plan: 1) traditional face-to-face delivery of SMS training, 2) an e-learning approach and 3) a blended approach (combining e-learning and face-to-face teaching). Methods: Graduate entry physiotherapy students and medical students at Flinders University were recruited. Depending on the cohort, students were either exposed to traditional face-to-face training, e-learning or a blended model. Outcomes were compared between the three groups. We measured adherence to care plan processes in the preparation of an assessment piece using the Flinders Program Chronic Care Self Management tools. A total of 183 care plans were included (102 traditional, 52 blended, 29 e-learning,). All students submitted the Flinders Program Chronic Care Plan for university assessment and these were later assessed for quality by researchers. The submission was also assigned a consumer engagement score and a global competence score as these are integral to successful delivery of SMS and represent the patient perspective. Results: The blended group performed significantly better than the traditional group in quality use of the Flinders Program tools: Problem and Goals (P < 0.0001). They also performed significantly better in the total care plan score (P < 0.0001) and engagement score (P < 0.0001). There was no significant difference between the groups for the Partners in Health tool. Conclusions: In this pilot study, the blended learning model was a more effective method for teaching self-management skills than the traditional group, as assessed in the development of a chronic condition self-management care plan. We anticipate that future research with identical groups of students would yield similar results but in the meantime, academics can have confidence that blended learning is at least as effective as traditional learning methods

Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis-acting variants on transcription factor occupancy divergence. Transcription factor binding differences linked to cis-acting variants generally exhibit additive inheritance, while those linked to trans-acting variants are most often dominantly inherited. Cis-acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is also observed and may be modulated by long-range chromatin contacts. Our results reveal the regulatory mechanisms that interplay to drive transcription factor occupancy, chromatin state, and gene expression in complex mammalian cell states.We thank the CRUK—CI Genomics, BRU, and Bioinformatics Cores for technical assistance and the EMBL-EBI systems team for management of computational resources. This research was supported by the European Molecular Biology Laboratory (E.S.W., D.T., J.C.M., P.F.), Cancer Research UK (B.M.S., T.F.R., F.C., C.F., A.R., D.T.O.), the BOLD ITN (B.M.S.), Darwin Fellowship (A.K.), the Wellcome Trust (WT202878/B/16/Z, WT108749/Z/15/Z) (P.F.), (WT202878/A/16/Z) (D.T.O), (WT095606) (A.C.F.-S) and (WT098051) (P.F., D.T.O.), EMBO Long-term (ALTF1518-2012) and Advanced Fellowships (aALTF1672-2014) (E.S.W.), and by the European Research Council (award 615584) and EMBO Young Investigator Programme (D.T.O.)

Supporting patients to prepare for total knee replacement: evidence-, theory- and person-based development of a ‘Virtual Knee School’ digital intervention

Introduction Digital delivery of pre-operative total knee replacement (TKR) education and prehabilitation could improve patient outcomes pre- and post-operatively. Rigorously developing digital interventions is vital to help ensure they achieve their intended outcomes whilst mitigating their potential drawbacks. Objective To develop a pre-operative TKR education and prehabilitation digital intervention, the ‘Virtual Knee School’ (VKS). Methods The VKS was developed using an evidence-, theory- and person-based approach. This involved a mixed methods design with four phases. The first three focused on planning the VKS. The final phase involved creating a VKS prototype and iteratively refining it through concurrent think-aloud interviews with nine patients who were awaiting/had undergone TKR. Meta-inferences were generated by integrating findings from all the phases. Results Most participants found the VKS prototype acceptable overall and considered it a valuable resource. Conversely, a minority of participants felt the prototype’s digital format or content did not meet their individual needs. Participants’ feedback was used to refine the prototype’s information architecture, design, and content. Two meta-inferences were generated and recommend: 1.Comprehensive pre-operative TKR education and prehabilitation support should be rapidly accessible in digital and non-digital formats. 2.Pre-operative TKR digital interventions should employ computer- and self-tailoring to account for patients’ individual needs and preferences. Conclusions Integrating evidence, theory, and stakeholders’ perspectives enabled the development of a promising VKS digital intervention for patients awaiting TKR. The findings suggest future research evaluating the VKS is warranted and provide recommendations for optimising pre-operative TKR care. Patient or Public contribution Patient and Public Involvement (PPI) was central throughout the project. For example, PPI representatives contributed to the project planning, were valued members of the Project Advisory Group, had key roles in developing the VKS prototype, and helped disseminate the project findings

Content and delivery of pre-operative interventions for patients undergoing total knee replacement: A rapid review

Background: Total knee replacement (TKR) is a common operation typically performed for end-stage knee osteoarthritis. Patients awaiting TKR often have poor health-related quality of life. Approximately 20% of patients experience persistent pain post-TKR. Pre-operative TKR interventions could improve pre- and post-operative outcomes, but future research is required to inform their design. This review aimed to identify and synthesize recent literature on the content and delivery of pre-operative TKR interventions to help guide future research and clinical practice. Methods: This rapid review included randomized trials of pre-operative TKR interventions (‘outcomes studies’) and primary studies exploring patients’ and/or health professionals’ views of pre-operative TKR interventions (‘views studies’). Medline, Embase, PsycINFO, CINAHL and the Cochrane Central Register of Controlled Trials were searched for English language studies published between January 2009 and December 2020. Eligible studies’ reference lists were screened. Studies were appraised using the Mixed Methods Appraisal Tool. The findings were narratively synthesized using a convergent segregated approach. Results: From 3263 records identified, 52 studies were included (29 outcomes studies, 21 views studies, two outcomes/views studies). The studies’ methodological quality varied but was generally highest in qualitative studies. The outcomes studies investigated education (n=5), exercise (n=20), psychological (n=2), lifestyle (n=1) and/or other interventions (n=5). The views studies addressed education (n=20), exercise (n=3), psychological (n=1), lifestyle (n=4) and/or other interventions (n=1). Only three outcomes studies (two randomized controlled trials (RCTs) and a pilot study) compared the effectiveness of intervention components/delivery approaches. The two RCTs’ results suggest that pre-operative TKR exercise interventions are equally effective regardless of whether they include strength or strength plus balance training and whether they are hospital- or home-based. Personal tailoring and using more than one delivery format were associated with improved outcomes and/or perceived as beneficial for multiple intervention types. Conclusions: Definitive evidence on the optimal design of pre-operative TKR interventions is lacking. Personal tailoring and employing multiple delivery formats appear to be valuable design elements. Preliminary evidence suggests that including balance training and hospital versus home delivery may not be critical design elements for pre-operative TKR exercise interventions

Human papillomavirus and survival of patients with oropharyngeal cancer.

BACKGROUND: Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown. METHODS: We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer. RESULTS: The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P\u3c0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage. CONCLUSIONS: Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.

Worldwide trends in population-based survival for children, adolescents, and young adults diagnosed with leukaemia, by subtype, during 2000-14 (CONCORD-3): analysis of individual data from 258 cancer registries in 61 countries.

BACKGROUND Leukaemias comprise a heterogenous group of haematological malignancies. In CONCORD-3, we analysed data for children (aged 0-14 years) and adults (aged 15-99 years) diagnosed with a haematological malignancy during 2000-14 in 61 countries. Here, we aimed to examine worldwide trends in survival from leukaemia, by age and morphology, in young patients (aged 0-24 years). METHODS We analysed data from 258 population-based cancer registries in 61 countries participating in CONCORD-3 that submitted data on patients diagnosed with leukaemia. We grouped patients by age as children (0-14 years), adolescents (15-19 years), and young adults (20-24 years). We categorised leukaemia subtypes according to the International Classification of Childhood Cancer (ICCC-3), updated with International Classification of Diseases for Oncology, third edition (ICD-O-3) codes. We estimated 5-year net survival by age and morphology, with 95% CIs, using the non-parametric Pohar-Perme estimator. To control for background mortality, we used life tables by country or region, single year of age, single calendar year and sex, and, where possible, by race or ethnicity. All-age survival estimates were standardised to the marginal distribution of young people with leukaemia included in the analysis. FINDINGS 164 563 young people were included in this analysis: 121 328 (73·7%) children, 22 963 (14·0%) adolescents, and 20 272 (12·3%) young adults. In 2010-14, the most common subtypes were lymphoid leukaemia (28 205 [68·2%] patients) and acute myeloid leukaemia (7863 [19·0%] patients). Age-standardised 5-year net survival in children, adolescents, and young adults for all leukaemias combined during 2010-14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia. Individuals with lymphoid leukaemia had better age-standardised survival (from 43% in Ecuador to ≥80% in parts of Europe, North America, Oceania, and Asia) than those with acute myeloid leukaemia (from 32% in Peru to ≥70% in most high-income countries in Europe, North America, and Oceania). Throughout 2000-14, survival from all leukaemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries. INTERPRETATION This study offers the first worldwide picture of population-based survival from leukaemia in children, adolescents, and young adults. Adolescents and young adults diagnosed with leukaemia continue to have lower survival than children. Trends in survival from leukaemia for adolescents and young adults are important indicators of the quality of cancer management in this age group. FUNDING Children with Cancer UK, the Institut National du Cancer, La Ligue Contre le Cancer, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, Rossy Family Foundation, US National Cancer Institute, and the American Cancer Society

Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases

Pervasive lesion segregation shapes cancer genome evolution

Cancers arise through the acquisition of oncogenic mutations and grow through clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, quantification of oncogenic selection, and fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.This work was supported by: Cancer Research UK (20412, 22398), the European Research Council (615584, 682398), the Wellcome Trust (WT108749/Z/15/Z, WT106563/Z/14/A, WT202878/B/16/Z), the European Molecular Biology Laboratory, the MRC Human Genetics Unit core funding programme grants (MC_UU_00007/11, MC_UU_00007/16), and the ERDF/Spanish Ministry of Science, Innovation and Universities-Spanish State Research Agency/DamReMap Project (RTI2018-094095-B-I00)

Reconstruction of Family-Level Phylogenetic Relationships within Demospongiae (Porifera) Using Nuclear Encoded Housekeeping Genes

Background: Demosponges are challenging for phylogenetic systematics because of their plastic and relatively simple morphologies and many deep divergences between major clades. To improve understanding of the phylogenetic relationships within Demospongiae, we sequenced and analyzed seven nuclear housekeeping genes involved in a variety of cellular functions from a diverse group of sponges. Methodology/Principal Findings: We generated data from each of the four sponge classes (i.e., Calcarea, Demospongiae, Hexactinellida, and Homoscleromorpha), but focused on family-level relationships within demosponges. With data for 21 newly sampled families, our Maximum Likelihood and Bayesian-based approaches recovered previously phylogenetically defined taxa: Keratosap, Myxospongiaep, Spongillidap, Haploscleromorphap (the marine haplosclerids) and Democlaviap. We found conflicting results concerning the relationships of Keratosap and Myxospongiaep to the remaining demosponges, but our results strongly supported a clade of Haploscleromorphap+Spongillidap+Democlaviap. In contrast to hypotheses based on mitochondrial genome and ribosomal data, nuclear housekeeping gene data suggested that freshwater sponges (Spongillidap) are sister to Haploscleromorphap rather than part of Democlaviap. Within Keratosap, we found equivocal results as to the monophyly of Dictyoceratida. Within Myxospongiaep, Chondrosida and Verongida were monophyletic. A well supported clade within Democlaviap, Tetractinellidap, composed of all sampled members of Astrophorina and Spirophorina (including the only lithistid in our analysis), was consistently revealed as the sister group to all other members of Democlaviap. Within Tetractinellidap, we did not recover monophyletic Astrophorina or Spirophorina. Our results also reaffirmed the monophyly of order Poecilosclerida (excluding Desmacellidae and Raspailiidae), and polyphyly of Hadromerida and Halichondrida. Conclusions/Significance: These results, using an independent nuclear gene set, confirmed many hypotheses based on ribosomal and/or mitochondrial genes, and they also identified clades with low statistical support or clades that conflicted with traditional morphological classification. Our results will serve as a basis for future exploration of these outstanding questions using more taxon- and gene-rich datasets

A role for Caf1 in mRNA deadenylation and decay in trypanosomes and human cells

The eukaryotic Ccr4/Caf1/Not complex is involved in deadenylation of mRNAs. The Caf1 and Ccr4 subunits both potentially have deadenylating enzyme activity. We investigate here the roles of Ccr4 and Caf1 in deadenylation in two organisms that separated early in eukaryotic evolution: humans and trypanosomes. In Trypanosoma brucei, we found a complex containing CAF1, NOT1, NOT2 and NOT5, DHH1 and a possible homologue of Caf130; no homologue of Ccr4 was found. Trypanosome CAF1 has deadenylation activity, and is essential for cell survival. Depletion of trypanosome CAF1 delayed deadenylation and degradation of constitutively expressed mRNAs. Human cells have two isozymes of Caf1: simultaneous depletion of both inhibited degradation of an unstable reporter mRNA. In both species, depletion of Caf1 homologues inhibited deadenylation of bulk RNA and resulted in an increase in average poly(A) tail length