Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function.

Crosstalk between cancer and stellate cells is pivotal in pancreatic cancer, resulting in differentiation of stellate cells into myofibroblasts that drives tumour progression. To assess cooperative mechanisms in a 3D context, we generated chimeric spheroids using human and mouse cancer and stellate cells. Species-specific deconvolution of bulk-RNA sequencing data revealed cell type-specific transcriptomes underpinning invasion. This dataset highlighted stellate-specific expression of transcripts encoding the collagen-processing enzymes ADAMTS2 and ADAMTS14. Strikingly, loss of ADAMTS2 reduced, while loss of ADAMTS14 promoted, myofibroblast differentiation and invasion independently of their primary role in collagen-processing. Functional and proteomic analysis demonstrated that these two enzymes regulate myofibroblast differentiation through opposing roles in the regulation of transforming growth factor ß availability, acting on the protease-specific substrates, Serpin E2 and fibulin 2, for ADAMTS2 and ADAMTS14, respectively. Showcasing a broader complexity for these enzymes, we uncovered a novel regulatory axis governing malignant behaviour of the pancreatic cancer stroma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Integrin-αvß6 targeted peptide-toxin therapy in a novel αvß6-expressing immunocompetent model of pancreatic cancer.

Previously we reported that a novel αvß6-specific peptide-drug conjugate (SG3299) could eliminate established human pancreatic ductal adenocarcinoma (PDAC) xenografts. However the development of effective therapies for PDAC, which is an essential need, must show efficacy in relevant immunocompetent animals. Previously we reported that the KPC mouse transgenic PDAC model that closely recapitulates most stages of development of human PDAC, unlike in humans, failed to express αvß6 on their tumours or metastases. In this study we have taken the KPC-derived PDAC line TB32043 and engineered a variant line (TB32043mb6S2) that expresses mouse integrin αvß6. We report that orthotopic implantation of the αvß6 over-expressing TB32043mb6S2 cells promotes shorter overall survival and increase in metastases. Moreover, systemic treatment of mice with established TB32043mb6S2 tumours in the pancreas with SG2399 lived significantly longer (p < 0.001; mean OS 48d) compared with PBS or control SG3511 (mean OS 25.5d and 26d, respectively). Thus SG3299 is confirmed as a promising candidate therapeutic for the therapy of PDAC.

Insights from the first phylogenomic analysis of flat wasps (Hymenoptera, Bethylidae) reveal two new subfamilies.

Despite significant advances in alpha level taxonomy in the past few decades, the higher-level phylogeny of flat wasps (Hymenoptera, Bethylidae) remains poorly explored. Herein we provide the first phylogenomic assessment of the family based on data from ultraconserved elements for 96 species in 61 genera of the family, with material from 29 countries and all biogeographic regions. Dataset cutoffs including ultraconserved element loci recovered for 50 and 70% of terminals resulted in matrices with 1513 and 451 loci, which were analysed in both parsimony and maximum likelihood frameworks. We also provide the first analyses of divergence dating for the family based on the calibration of 12 nodes. All analyses recovered the Bethylidae as a monophyletic group and estimated the origin of the family at around 143 Ma. The results suggest that all extant subfamilies had already diversified by the Late Cretaceous. All topologies suggest that Glenosema and Chilepyris form a clade separate from other Scleroderminae; owing to the morphological distinctiveness of each genus, we propose that they are accommodated in two new subfamilies, Glenoseminae subf. nov. and Chilepyrinae subf. nov. The monotypic sclerodermine genus Galodoxa was consistently recovered within Epyrinae and is transferred to the latter subfamily.

The Chalcidoidea bush of life: evolutionary history of a massive radiation of minute wasps.

Chalcidoidea are mostly parasitoid wasps that include as many as 500 000 estimated species. Capturing phylogenetic signal from such a massive radiation can be daunting. Chalcidoidea is an excellent example of a hyperdiverse group that has remained recalcitrant to phylogenetic resolution. We combined 1007 exons obtained with Anchored Hybrid Enrichment with 1048 ultra-conserved elements (UCEs) for 433 taxa including all extant families, >95% of all subfamilies, and 356 genera chosen to represent the vast diversity of the superfamily. Going back and forth between the molecular results and our collective knowledge of morphology and biology, we detected bias in the analyses that was driven by the saturation of nucleotide data. Our final results are based on a concatenated analysis of the least saturated exons and UCE datasets (2054 loci, 284 106 sites). Our analyses support an expected sister relationship with Mymarommatoidea. Seven previously recognized families were not monophyletic, so support for a new classification is discussed. Natural history in some cases would appear to be more informative than morphology, as illustrated by the elucidation of a clade of plant gall associates and a clade of taxa with planidial first-instar larvae. The phylogeny suggests a transition from smaller soft-bodied wasps to larger and more heavily sclerotized wasps, with egg parasitism as potentially ancestral for the entire superfamily. Deep divergences in Chalcidoidea coincide with an increase in insect families in the fossil record, and an early shift to phytophagy corresponds with the beginning of the "Angiosperm Terrestrial Revolution". Our dating analyses suggest a middle Jurassic origin of 174 Ma (167.3-180.5 Ma) and a crown age of 162.2 Ma (153.9-169.8 Ma) for Chalcidoidea. During the Cretaceous, Chalcidoidea may have undergone a rapid radiation in southern Gondwana with subsequent dispersals to the Northern Hemisphere. This scenario is discussed with regard to knowledge about the host taxa of chalcid wasps, their fossil record and Earth's palaeogeographic history.

Conducting high-quality and reliable acoustic analysis: A tutorial focused on training research assistants.

Open science practices have led to an increase in available speech datasets for researchers interested in acoustic analysis. Accurate evaluation of these databases frequently requires manual or semi-automated analysis. The time-intensive nature of these analyses makes them ideally suited for research assistants in laboratories focused on speech and voice production. However, the completion of high-quality, consistent, and reliable analyses requires clear rules and guidelines for all research assistants to follow. This tutorial will provide information on training and mentoring research assistants to complete these analyses, covering areas including RA training, ongoing data analysis monitoring, and documentation needed for reliable and re-creatable findings.

Fostering Responsible Conduct of Research for Early-Stage Investigators: Challenges and Opportunities.

The rise of academic misconduct poses significant challenges to the integrity and credibility of scholarly research. Early-stage investigators (ESIs), particularly those representing marginalized groups, face unique pressures in navigating the "publish or perish" paradigm while establishing their careers. This commentary articulates strategies for cultivating research environments conducive to the responsible conduct of research (RCR) for ESIs. By establishing shared values, planning research meticulously, conducting research collaboratively, and reporting findings transparently, ESIs can foster a culture of prevention and accountability in research. Ultimately, navigating beyond traditional methodologies to support RCR necessitates a fundamental reimagining of academic culture, reconceptualizing productivity to prioritize quality over quantity, and to encompass "invisible" work often shouldered by investigators with marginalized identities. Addressing scientific misconduct challenges requires a whole-system approach, encompassing individual leadership, policy changes, and institutional accountability. By implementing concrete strategies and systemic reforms, academia can reaffirm its commitment to responsible research conduct and safeguard the integrity of scholarly endeavors.

Effectiveness of digital and remote provision of the Healthier You: NHS Diabetes Prevention Programme during the COVID-19 pandemic.

AIMS: To assess weight change in the Healthier You: NHS Diabetes Prevention Programme (NHS DPP) delivered via video conferencing (remote) sessions or delivered via specific digital interventions through apps or websites, during the COVID-19 pandemic compared to group-based face-to-face interventions, pre-pandemic. METHODS: Prospectively collected national service-level data relating to individuals with non-diabetic hyperglycaemia (HbA1c 42-47 mmol/mol (6.0%-6.4%) or fasting plasma glucose 5.5-6.9 mmol/L) referred to the NHS DPP from June 2016 to March 2022. RESULTS: Between March 2020 and March 2022, 335,961 people were referred to the programme and were offered a choice of remote or digital intervention. This was preceded by 556,793 people referred to the face-to-face programme between June 2016 and February 2022. Uptakes to intervention sessions were 47% for those offered a choice and 39% for face-to-face. Remote and digital participants were significantly younger (60 and 56 vs. 65 years) and heavier (86.1 kg and 91.0 kg vs. 84.1 kg) compared to face-to-face. Weight change was assessed for 42,407 remote, 7699 digital and 97,205 face-to-face participants with sufficient time to have finished the programme and no missing data. Mean weight losses for participants attending at least one intervention session were: 2.40 (2.36-2.44) kg, 2.59 (2.49-2.68) kg and 2.01 (1.98-2.04) kg for remote, digital and face-to-face participants respectively. Corresponding mean weight losses for those who completed the programme were: 3.24 (3.19-3.30) kg, 4.76 (4.60-4.92) kg and 3.04 (3.00-3.07) kg. There were no significant differences in weight change between interventions by ethnicity and deprivation. CONCLUSIONS: Weight losses achieved through remote and digital interventions were greater than those previously achieved through face-to-face interventions, without evidence of exacerbation of health inequalities.

Long-term clinical and cost-effectiveness of a therapist-supported online remote behavioural intervention for tics in children and adolescents: extended 12- and 18-month follow-up of a single-blind randomised controlled trial.

BACKGROUND: Little is known about the long-term effectiveness of behavioural therapy for tics. We aimed to assess the long-term clinical and cost-effectiveness of online therapist-supported exposure and response prevention (ERP) therapy for tics 12 and 18 months after treatment initiation. METHODS: ORBIT (online remote behavioural intervention for tics) was a two-arm (1:1 ratio), superiority, single-blind, multicentre randomised controlled trial comparing online ERP for tics with online psychoeducation. The trial was conducted across two Child and Adolescent Mental Health Services in England. Participants were recruited from these two sites, across other clinics in England, or by self-referral. This study was a naturalistic follow-up of participants at 12- and 18-month postrandomisation. Participants were permitted to use alternative treatments recommended by their clinician. The key outcome was the Yale Global Tic Severity Scale Total Tic Severity Score (YGTSS-TTSS). A full economic evaluation was conducted. Registrations are ISRCTN (ISRCTN70758207); ClinicalTrials.gov (NCT03483493). RESULTS: Two hundred and twenty-four participants were enrolled: 112 to ERP and 112 to psychoeducation. The sample was predominately male (177; 79%) and of white ethnicity (195; 87%). The ERP intervention reduced baseline YGTSS-TTSS by 2.64 points (95% CI: -4.48 to -0.79) with an effect size of -0.36 (95% CI: -0.61 to -0.11) after 12 months and by 2.01 points (95% CI: -3.86 to -0.15) with an effect size of -0.27 (95% CI -0.52 to -0.02) after 18 months, compared with psychoeducation. Very few participants (<10%) started new tic treatment during follow-up. The cost difference in ERP compared with psychoeducation was £304.94 (-139.41 to 749.29). At 18 months, the cost per QALY gained was £16,708 for ERP compared with psychoeducation. CONCLUSIONS: Remotely delivered online ERP is a clinical and cost-effective intervention with durable benefits extending for up to 18 months. This represents an efficient public mental health approach to increase access to behavioural therapy and improve outcomes for tics.

Dose frequency randomized controlled trial for Dynamic Temporal and Tactile Cueing (DTTC) treatment for childhood apraxia of speech: protocol paper.

BACKGROUND: Childhood apraxia of speech (CAS) is a pediatric motor-based speech sound disorder that requires a specialized approach to intervention. The extant literature on the treatment of CAS commonly recommends intensive treatment using a motor-based approach, with some of the best evidence supporting the use of Dynamic Temporal and Tactile Cueing (DTTC). To date, a rigorous and systematic comparison of high and low dose frequency (i.e., frequency of therapy sessions) has not been undertaken for DTTC, resulting in a lack of evidence to guide decisions about the optimal treatment schedule for this intervention. The current study aims to fill this gap in knowledge by comparing treatment outcomes when dose frequency is varied. METHODS: A randomized controlled trial will be conducted to examine the efficacy of low versus high dose frequency on DTTC treatment outcomes in children with CAS. A target of 60 children, 2;6-7;11 years of age, will be recruited to participate in this study. Treatment will be provided in the community setting by speech-language pathologists who have completed specialized training administering DTTC in a research reliable manner. True randomization with concealed allocation will be used to assign children to either the low or high dose frequency group. Treatment will be administered in 1-h sessions either 4 times per week over a 6-week period (high dose) or 2 times per week over a 12-week period (low dose). To measure treatment gains, probe data will be collected before treatment, during treatment, and 1 day, 1 week, 4 weeks, and 12 weeks post-treatment. Probe data will consist of customized treated words and a standard set of untreated words to assess generalization of treatment gains. The primary outcome variable will be whole word accuracy, encompassing segmental, phonotactic, and suprasegmental accuracy. DISCUSSION: This will be the first randomized controlled trial to evaluate dose frequency for DTTC treatment in children with CAS. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05675306, January 6, 2023.

The effectiveness of digital delivery versus group-based face-to-face delivery of the English National Health Service Type 2 Diabetes Prevention Programme: a non-inferiority retrospective cohort comparison study.

BACKGROUND: Face-to-face group-based diabetes prevention programmes have been shown to be effective in many settings. Digital delivery may suit some patients, but research comparing the effectiveness of digital with face-to-face delivery is scarce. The aim was to assess if digital delivery of the English National Health Service Diabetes Prevention Programme (NHS DPP) is non-inferior to group-based face-to-face delivery in terms of weight change, and evaluate factors associated with differential change. METHODS: The study included those recruited to the NHS DPP in 2017-2018. Individual-level data from a face-to-face cohort was compared to two cohorts on a digital pilot who (i) were offered no choice of delivery mode, or (ii) chose digital over face-to-face. Changes in weight at 6 and 12 months were analysed using mixed effects linear regression, having matched participants from the digital pilot to similar participants from face-to-face. RESULTS: Weight change on the digital pilot was non-inferior to face-to-face at both time points: it was similar in the comparison of those with no choice (difference in weight change: -0.284 kg [95% CI: -0.712, 0.144] at 6 months) and greater in digital when participants were offered a choice (-1.165 kg [95% CI: -1.841, -0.489]). Interactions between delivery mode and sex, ethnicity, age and deprivation were observed. CONCLUSIONS: Digital delivery of the NHS DPP achieved weight loss at least as good as face-to-face. Patients who were offered a choice and opted for digital experienced better weight loss, compared to patients offered face-to-face only.

Influences on Patient Uptake of and Engagement With the National Health Service Digital Diabetes Prevention Programme: Qualitative Interview Study.

BACKGROUND: Digital diabetes prevention programs (digital-DPPs) are being implemented as population-based approaches to type 2 diabetes mellitus prevention in several countries to address problems with the uptake of traditional face-to-face diabetes prevention programs. However, assessments of digital-DPPs have largely focused on clinical outcomes and usability among those who have taken them up, whereas crucial information on decision-making about uptake (eg, whether a user downloads and registers on an app) and engagement (eg, the extent of use of an app or its components over time) is limited. Greater understanding of factors that influence uptake and engagement decisions may support large-scale deployments of digital-DPPs in real-world settings. OBJECTIVE: This study aimed to explore the key influences on uptake and engagement decisions of individuals who were offered the National Health Service Healthier You: Digital Diabetes Prevention Programme (NHS-digital-DPP). METHODS: A qualitative interview study was conducted using semistructured interviews. Participants were adults, aged ≥18 years, diagnosed with nondiabetic hyperglycemia, and those who had been offered the NHS-digital-DPP. Recruitment was conducted via 4 providers of the NHS-digital-DPP and 3 primary care practices in England. Interviews were conducted remotely and were guided by a theoretically informed topic guide. Analysis of interviews was conducted using an inductive thematic analysis approach. RESULTS: Interviews were conducted with 32 participants who had either accepted or declined the NHS-digital-DPP. In total, 7 overarching themes were identified as important factors in both decisions to take up and to engage with the NHS-digital-DPP. These were knowledge and understanding, referral process, self-efficacy, self-identity, motivation and support, advantages of digital service, and reflexive monitoring. Perceptions of accessibility and convenience of the NHS-digital-DPP were particularly important for uptake, and barriers in terms of the referral process and health care professionals' engagement were reported. Specific digital features including health coaches and monitoring tools were important for engagement. CONCLUSIONS: This study adds to the literature on factors that influence the uptake of and engagement with digital-DPPs and suggests that digital-DPPs can overcome many barriers to the uptake of face-to-face diabetes prevention programs in supporting lifestyle changes aimed at diabetes prevention.

Design and Early Use of the Nationally Implemented Healthier You National Health Service Digital Diabetes Prevention Programme: Mixed Methods Study.

BACKGROUND: The Healthier You National Health Service Digital Diabetes Prevention Programme (NHS-digital-DPP) is a 9-month digital behavior change intervention delivered by 4 independent providers that is implemented nationally across England. No studies have explored the design features included by service providers of digital diabetes prevention programs to promote engagement, and little is known about how participants of nationally implemented digital diabetes prevention programs such as this one make use of them. OBJECTIVE: This study aimed to understand engagement with the NHS-digital-DPP. The specific objectives were to describe how engagement with the NHS-digital-DPP is promoted via design features and strategies and describe participants' early engagement with the NHS-digital-DPP apps. METHODS: Mixed methods were used. The qualitative study was a secondary analysis of documents detailing the NHS-digital-DPP intervention design and interviews with program developers (n=6). Data were deductively coded according to an established framework of engagement with digital health interventions. For the quantitative study, anonymous use data collected over 9 months for each provider representing participants' first 30 days of use of the apps were obtained for participants enrolled in the NHS-digital-DPP. Use data fields were categorized into 4 intervention features (Track, Learn, Coach Interactions, and Peer Support). The amount of engagement with the intervention features was calculated for the entire cohort, and the differences between providers were explored statistically. RESULTS: Data were available for 12,857 participants who enrolled in the NHS-digital-DPP during the data collection phase. Overall, 94.37% (12,133/12,857) of those enrolled engaged with the apps in the first 30 days. The median (IQR) number of days of use was 11 (2-25). Track features were engaged with the most (number of tracking events: median 46, IQR 3-22), and Peer Support features were the least engaged with, a median value of 0 (IQR 0-0). Differences in engagement with features were observed across providers. Qualitative findings offer explanations for the variations, including suggesting the importance of health coaches, reminders, and regular content updates to facilitate early engagement. CONCLUSIONS: Almost all participants in the NHS-digital-DPP started using the apps. Differences across providers identified by the mixed methods analysis provide the opportunity to identify features that are important for engagement with digital health interventions and could inform the design of other digital behavior change interventions.

Broadening Benefits and Anticipating Tradeoffs with a Proposed Ecosystem Service Analysis Framework for the US Army Corps of Engineers.

Would-be adopters of ecosystem service analysis frameworks might ask, 'Do such frameworks improve ecosystem service provision or social benefits sufficiently to compensate for any extra effort?' Here we explore that question by retrospectively applying an ecosystem goods and services (EGS) analysis framework to a large river restoration case study conducted by the US Army Corps of Engineers (USACE) and comparing potential time costs and outcomes of traditional versus EGS-informed planning. USACE analytic methods can have a large influence on which river and wetland restoration projects are implemented in the United States because they affect which projects or project elements are eligible for federal cost-share funding. A new framework is designed for the USACE and is primarily distinguished from current procedures by adding explicit steps to document and compare tradeoffs and complementarity among all affected EGS, rather than the subset that falls within project purposes. Further, it applies economic concepts to transform ecological performance indicators into social benefit indicators, even if changes cannot be valued. We conclude that, for large multi-partner restoration projects like our case study, using the framework provides novel information on social outcomes that could be used to enhance project design, without substantially increasing scoping costs. The primary benefits of using the framework in the case study appeared to stem from early comprehensive identification of stakeholder interests that might have prevented project delays late in the process, and improving the communication of social benefits and how tradeoffs among EGS benefits were weighed during planning.

Gene Tree Estimation Error with Ultraconserved Elements: An Empirical Study on Pseudapis Bees.

Summarizing individual gene trees to species phylogenies using two-step coalescent methods is now a standard strategy in the field of phylogenomics. However, practical implementations of summary methods suffer from gene tree estimation error, which is caused by various biological and analytical factors. Greatly understudied is the choice of gene tree inference method and downstream effects on species tree estimation for empirical data sets. To better understand the impact of this method choice on gene and species tree accuracy, we compare gene trees estimated through four widely used programs under different model-selection criteria: PhyloBayes, MrBayes, IQ-Tree, and RAxML. We study their performance in the phylogenomic framework of $>$800 ultraconserved elements from the bee subfamily Nomiinae (Halictidae). Our taxon sampling focuses on the genus Pseudapis, a distinct lineage with diverse morphological features, but contentious morphology-based taxonomic classifications and no molecular phylogenetic guidance. We approximate topological accuracy of gene trees by assessing their ability to recover two uncontroversial, monophyletic groups, and compare branch lengths of individual trees using the stemminess metric (the relative length of internal branches). We further examine different strategies of removing uninformative loci and the collapsing of weakly supported nodes into polytomies. We then summarize gene trees with ASTRAL and compare resulting species phylogenies, including comparisons to concatenation-based estimates. Gene trees obtained with the reversible jump model search in MrBayes were most concordant on average and all Bayesian methods yielded gene trees with better stemminess values. The only gene tree estimation approach whose ASTRAL summary trees consistently produced the most likely correct topology, however, was IQ-Tree with automated model designation (ModelFinder program). We discuss these findings and provide practical advice on gene tree estimation for summary methods. Lastly, we establish the first phylogeny-informed classification for Pseudapis s. l. and map the distribution of distinct morphological features of the group. [ASTRAL; Bees; concordance; gene tree estimation error; IQ-Tree; MrBayes, Nomiinae; PhyloBayes; RAxML; phylogenomics; stemminess].

Supportive care needs of men with prostate cancer: A systematic review update.

BACKGROUND: Prostate cancer is highly prevalent and impacts profoundly on patients' quality of life, leading to a range of supportive care needs. METHODS: An updated systematic review and thematic synthesis of qualitative data using the Preferred Reporting Items for Systematic Reviews (PRISMA) reporting guidelines, to explore prostate cancer patients' experience of, and need for, supportive care. Five databases (Medline, Embase, PsycInfo, Emcare and ASSIA) were searched; extracted data were synthesised using Corbin and Strauss's 'Three Lines of Work' framework. RESULTS: Searches identified 2091 citations, of which 105 were included. Overarching themes emerged under the headings of illness, everyday life and biographical work. Illness work needs include consistency and continuity of information, tailored to ethnicity, age and sexual orientation. Biographical work focused on a desire to preserve identity in the context of damaging sexual side effects. Everyday life needs centred around exercise and diet support and supportive relationships with partners and peers. Work-related issues were highlighted specifically by younger patients, whereas gay and bisexual men emphasised a lack of specialised support. CONCLUSION: While demonstrating some overarching needs common to most patients with prostate cancer, this review offers novel insight into the unique experiences and needs of men of different demographic backgrounds, which will enable clinicians to deliver individually tailored supportive care.

Pattern Separation and Source Memory Engage Distinct Hippocampal and Neocortical Regions during Retrieval.

Detailed representations of past events rely on the ability to form associations between items and their contextual features (i.e., source memory), as well as the ability to distinctly represent a new event from a similar one stored in memory (i.e., pattern separation). These processes are both known to engage the hippocampus, although whether they share similar mechanisms remains unclear. It is also unknown if, and in which region(s), activity related to these processes overlaps and/or interacts. Here, we used high-resolution fMRI to examine the contributions of hippocampal subfields and neocortical areas to pattern separation and source memory with an experimental paradigm that concurrently tested both. During encoding, male and female human subjects incidentally studied items in one of four quadrants on the screen. During test, they viewed repeated items (targets), similar items (lures), and new items (foils) and were asked to indicate whether each item was old, similar, or new. Following each item judgment, subjects were asked to indicate the quadrant in which the original stimulus was presented. Thus, each lure trial had a lure discrimination component (taxing pattern separation) and a location judgment (source memory). We found two main response profiles: (1) pattern separation-related signals in DG/CA3 and perirhinal cortex and (2) source memory signals in posterior CA1, parahippocampal cortex, and angular gyrus. Whole-brain voxelwise analysis revealed that activity related to lure discrimination and source memory was largely nonoverlapping. These findings suggest that distinct processes underlie the retrieval of pattern separated item representations and recollection of source information.SIGNIFICANCE STATEMENT Recalling past events with detail and accuracy depends on the ability to remember the contextual features of an event (i.e., source memory) as well as the ability to distinguish among similar events in memory (i.e., pattern separation). Previous work has shown that these processes are behaviorally dissociable (e.g., people can have clear memory for context but misidentify people or items). However, both processes engage the hippocampus, and it is unclear whether they rely on shared or distinct neural mechanisms. Here, we used high-resolution fMRI to concurrently assess hippocampal and neocortical activity related to source memory and pattern separation. We found that activity related to these processes was largely nonoverlapping, shedding light on two complementary but distinct mechanisms supporting episodic memory.

Inherent DNA-binding specificities of the HIF-1α and HIF-2α transcription factors in chromatin.

Hypoxia-inducible factor (HIF) is the major transcriptional regulator of cellular responses to hypoxia. The two principal HIF-α isoforms, HIF-1α and HIF-2α, are progressively stabilized in response to hypoxia and form heterodimers with HIF-1ß to activate a broad range of transcriptional responses. Here, we report on the pan-genomic distribution of isoform-specific HIF binding in response to hypoxia of varying severity and duration, and in response to genetic ablation of each HIF-α isoform. Our findings reveal that, despite an identical consensus recognition sequence in DNA, each HIF heterodimer loads progressively at a distinct repertoire of cell-type-specific sites across the genome, with little evidence of redistribution under any of the conditions examined. Marked biases towards promoter-proximal binding of HIF-1 and promoter-distant binding of HIF-2 were observed under all conditions and were consistent in multiple cell type. The findings imply that each HIF isoform has an inherent property that determines its binding distribution across the genome, which might be exploited to therapeutically target the specific transcriptional output of each isoform independently.

An Evaluation Service for Digital Public Health Interventions: User-Centered Design Approach.

BACKGROUND: Digital health interventions (DHIs) have the potential to improve public health by combining effective interventions and population reach. However, what biomedical researchers and digital developers consider an effective intervention differs, thereby creating an ongoing challenge to integrating their respective approaches when evaluating DHIs. OBJECTIVE: This study aims to report on the Public Health England (PHE) initiative set out to operationalize an evaluation framework that combines biomedical and digital approaches and demonstrates the impact, cost-effectiveness, and benefit of DHIs on public health. METHODS: We comprised a multidisciplinary project team including service designers, academics, and public health professionals and used user-centered design methods, such as qualitative research, engagement with end users and stakeholders, and iterative learning. The iterative approach enabled the team to sequentially define the problem, understand user needs, identify opportunity areas, develop concepts, test prototypes, and plan service implementation. Stakeholders, senior leaders from PHE, and a working group critiqued the outputs. RESULTS: We identified 26 themes and 82 user needs from semistructured interviews (N=15), expressed as 46 Jobs To Be Done, which were then validated across the journey of evaluation design for a DHI. We identified seven essential concepts for evaluating DHIs: evaluation thinking, evaluation canvas, contract assistant, testing toolkit, development history, data hub, and publish health outcomes. Of these, three concepts were prioritized for further testing and development, and subsequently refined into the proposed PHE Evaluation Service for public health DHIs. Testing with PHE's Couch-to-5K app digital team confirmed the viability, desirability, and feasibility of both the evaluation approach and the Evaluation Service. CONCLUSIONS: An iterative, user-centered design approach enabled PHE to combine the strengths of academic and biomedical disciplines with the expertise of nonacademic and digital developers for evaluating DHIs. Design-led methodologies can add value to public health settings. The subsequent service, now known as Evaluating Digital Health Products, is currently in use by health bodies in the United Kingdom and is available to others for tackling the problem of evaluating DHIs pragmatically and responsively.

Fidelity of Delivery and Contextual Factors Influencing Children's Level of Engagement: Process Evaluation of the Online Remote Behavioral Intervention for Tics Trial.

BACKGROUND: The Online Remote Behavioral Intervention for Tics (ORBIT) study was a multicenter randomized controlled trial of a complex intervention that consisted of a web-based behavioral intervention for children and young people with tic disorders. In the first part of a two-stage process evaluation, we conducted a mixed methods study exploring the reach, dose, and fidelity of the intervention and contextual factors influencing engagement. OBJECTIVE: This study aims to explore the fidelity of delivery and contextual factors underpinning the ORBIT trial. METHODS: Baseline study data and intervention usage metrics from participants in the intervention arm were used as quantitative implementation data (N=112). The experiences of being in the intervention were explored through semistructured interviews with children (n=20) and parent participants (n=20), therapists (n=4), and referring clinicians (n=6). A principal component analysis was used to create a comprehensive, composite measure of children and young people's engagement with the intervention. Engagement factor scores reflected relative uptake as assessed by a range of usage indices, including chapters accessed, number of pages visited, and number of log-ins. The engagement factor score was used as the dependent variable in a multiple linear regression analysis with various contextual variables as independent variables to assess if there were any significant predictors of engagement. RESULTS: The intervention was implemented with high fidelity, and participants deemed the intervention acceptable and satisfactory. The engagement was high, with child participants completing an average of 7.5 of 10 (SD 2.7) chapters, and 88.4% (99/112) of participants completed the minimum of the first four chapters-the predefined threshold effective dose. Compared with the total population of children with tic disorders, participants in the sample tended to have more educated parents and lived in more economically advantaged areas; however, socioeconomic factors were not related to engagement factor scores. Factors associated with higher engagement factor scores included participants enrolled at the London site versus the Nottingham site (P=.01), self-referred versus clinic referred (P=.04), higher parental engagement as evidenced by the number of parental chapters completed (n=111; ρ=0.73; P<.001), and more therapist time for parents (n=111; ρ=0.46; P<.001). A multiple linear regression indicated that parents' chapter completion (ß=.69; t110=10.18; P<.001) and therapist time for parents (ß=.19; t110=2.95; P=.004) were the only significant independent predictors of child engagement factor scores. CONCLUSIONS: Overall, the intervention had high fidelity of delivery and was evaluated positively by participants, although reach may have been constrained by the nature of the randomized controlled trial. Parental engagement and therapist time for parents were strong predictors of intervention implementation, which has important implications for designing and implementing digital therapeutic interventions in child and adolescent mental health services. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-019-3974-3.

The Supportive Care Needs of Cancer Patients: a Systematic Review.

Cancer, and the complex nature of treatment, has a profound impact on lives of patients and their families. Subsequently, cancer patients have a wide range of needs. This study aims to identify and synthesise cancer patients' views about areas where they need support throughout their care. A systematic  search of the literature from PsycInfo, Embase and Medline databases was conducted, and a narrative. Synthesis of results was carried out using the Corbin & Strauss "3 lines of work" framework. For each line of work, a group of key common needs were identified. For illness-work, the key needs idenitified were; understanding their illness and treatment options, knowing what to expect, communication with healthcare professionals, and staying well. In regards to everyday work, patients wanted to maintain a sense of normalcy and look after their loved ones. For biographical work, patients commonly struggled with the emotion impact of illness and a lack of control over their lives. Spiritual, sexual and financial problems were less universal. For some types of support, demographic factors influenced the level of need reported. While all patients are unique, there are a clear set of issues that are common to a majority of cancer journeys. To improve care, these needs should be prioritised by healthcare practitioners.