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Basin inversion is commonly attributed to the reverse reactivation of basin-bounding normal faults. This association implies that basin uplift and inversion-related structures are mainly controlled by the frictional behaviour of pre-existing faults and associated damage zones. In this study, we use lithospheric-scale analogue experiments of orthogonal extension followed by shortening to explore how the flow behaviour of ductile layers underneath rift basins promote or suppress basin inversion. Our experiments show that the rheology of the ductile lower crust and lithospheric mantle, modulated by the imposed bulk strain rate, determine (1) basin distribution in a wide rift setting and (2) strain accommodation by fault reactivation and basin uplift during subsequent shortening. When the ductile layers deform uniformly during extension (i.e. stretching) and shortening (i.e. thickening), all of the basins are inverted. When deformation in the ductile layers is localised during extension (i.e. necking) and shortening (i.e. folding), only some basins – which are evenly spaced apart – are inverted. We interpret the latter as selective basin inversion, which may be related to the superposition of crustal-scale and lithospheric-scale boudinage during the previous basin-forming extensional phase and/or folding of the ductile layers during shortening.

Introduction Bipolar Disorder (BD) is a complex psychiatric condition that typically manifests during late adolescence and early adulthood. Over the past two decades, international studies have reported that BD often goes unrecognized and untreated for several years, which can lead to negative clinical and functional outcomes. However, the components of delay in the diagnosis and treatment of BD in adolescents and young adults and various factors influencing those components have not been systematically explored. Objectives To determine the known factors that contribute to delays in the treatment of BD in adolescents and young adults and identify current knowledge gaps. Methods A conceptual framework based on the Model of Pathways to Treatment by Scott and colleagues was used as a foundation for our search and extraction strategy to ensure all components of delay and potential factors influencing each component are explored. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline (PRISMA-ScR) to systematically search the electronic databases of MEDLINE (OVID), EMBASE, PsycINFO and CINAHL for peer-reviewed original research articles published from January 01, 2000 through March 29, 2023. Inclusion was restricted to studies with quantitative or qualitative data on individuals diagnosed with bipolar spectrum disorders with symptomatic onset or study participation between the ages of 13-24. Grey literature and studies not published in English were excluded due to resource limitations. Two independent reviewers screened the references retrieved by the literature search based on our inclusion criteria. The findings of included studies were summarized in a narrative and tabular form according to component of delay. Results Our search yielded 5180 unique citations, of which 44 articles met our inclusion criteria. We present findings on the patient, illness, and healthcare provider/mental health system factors contributing to the delays in illness appraisal, help-seeking, diagnosis, and treatment. Conclusions To the best of our knowledge, this is the first systematic scoping review to explore the potential factors that influence delays in the treatment of BD in adolescents and young adults. Findings from this review will inform clinical practice and policy. We also demonstrate the utility of a systematic approach to identifying the components of delay, from symptom recognition through treatment, as a methodology to help identify knowledge gaps to inform future research. Disclosure of Interest None Declared

Neurodivergent youth, such as those with diagnoses of autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD), are frequently victimized by their peers. This bullying victimization may occur in unique ways that are not captured by existing questionnaires. The "Assessment of Bullying Experiences" ("ABE") is a questionnaire specific to neurodivergent youth with acceptable psychometric properties in autistic and non-autistic samples. This study sought to establish scoring criteria and clinical cutoffs for the "ABE." Participants were 335 parents of youth (ages 6-17) characterized as autistic, having ADHD, or from a community comparison sample. Receiver operating characteristic (ROC) analyses were used to (1) compare accuracy of the "ABE" total score in predicting bullying victimization experiences and (2) identify optimal questionnaire cutoffs. Clinical utility of these cutoffs was confirmed using ANCOVA analyses. The "ABE" had good-to-excellent discrimination for bullying victimization across groups. Bullied youth had greater symptoms of anxiety/depression compared to youth who were not bullied; this relationship was partially explained by autism characteristics. "ABE" clinical cutoffs generated bullying victimization prevalence rates consistent with existing literature (50% autism, 28% non-autism). The "ABE" is a useful measure to streamline bullying victimization assessment in neurodivergent youth and inform group-specific intervention.

In health care and child welfare, clinical records and case notes serve multiple functions. When records are aggregated and processed to create administrative data, they can be analyzed and used to inform policy development and decision-making. To be useful, such data should be complete, accurate, and recorded in a standardized way. However, sources of bias and error can impact the quality of administrative data. During the development of national child welfare data in Canada, child welfare sector partners expressed concerns about the accuracy and completeness of data about children and families. This protocol describes a study that seeks to answer two questions: 1) What individual and institutional factors influence how client data is recorded by child welfare workers in Canada? 2) What data quality issues are created through documentation and case recording practices that may impact the use of clinical case management system data for public health statistics? In this protocol, we describe an exploratory mixed methods study that involves an online survey, interviews with a purposive sample of child welfare workers, and a document review of case recording guidelines. To be eligible for the study, participants must have worked at a child welfare agency or department with clinical documentation responsibilities as a part of their job. We will use descriptive statistics to analyze the survey data and thematic analysis to analyze the qualitative data. This study will help uncover strengths, limitations, and possible sources of bias created through case recording and documentation practices in child welfare. Study results will be shared through presentations to interest holders and will inform the further development of national child welfare data in Canada.

On March 11th 2020, the World Health Organization characterised COVID-19 as a pandemic. Responses to containing the spread of the virus have relied heavily on policies involving restricting contact between people. Evolving policies regarding shielding and individual choices about restricting social contact will rely heavily on perceived risk of poor outcomes from COVID-19. In order to make informed decisions, both individual and collective, good predictive models are required. For outcomes related to an infectious disease, the performance of any risk prediction model will depend heavily on the underlying prevalence of infection in the population of interest. Incorporating measures of how this changes over time may result in important improvements in prediction model performance. This protocol reports details of a planned study to explore the extent to which incorporating time-varying measures of infection burden over time improves the quality of risk prediction models for COVID-19 death in a large population of adult patients in England. To achieve this aim, we will compare the performance of different modelling approaches to risk prediction, including static cohort approaches typically used in chronic disease settings and landmarking approaches incorporating time-varying measures of infection prevalence and policy change, using COVID-19 related deaths data linked to longitudinal primary care electronic health records data within the OpenSAFELY secure analytics platform.

Neurodivergent youth (i.e., autistic, attention-deficit hyperactivity disorder) are at increased risk for school refusal and subsequent disengagement. Factors associated with school refusal in this population remain unclear. Latent profile analysis was conducted to identify profiles of school and demographic variables associated with parent-reported school refusal for 508 neurodivergent and community youth (ages 6-17 years). Five profiles were identified, including three groups characterized by frequent school refusal, high levels of neurodivergent traits, and frequent peer victimization. Differentiation was noted via educational placement, support needs, mental health, and bullying. Implications concern identification and intervention for subgroups of neurodivergent youth.

The growing body of literature on bullying in autism spectrum disorder (ASD) suggests individuals with ASD are bullied more frequently than their non-ASD peers. However, there is no gold standard assessment tool for bullying in ASD, and the use of differing methodologies generates varying prevalence estimates. This systematic review evaluates the assessment methods for bullying in ASD and summarizes the participant characteristics in this literature. None of the identified measures meet literature recommendations for bullying assessment in ASD. Additionally, there is a need for increased sample diversity regarding the gender, race, and cognitive ability of ASD participants. Recommendations for researchers and practitioners are discussed, including the need for a gold standard assessment tool and consistency in the operationalization of bullying.

Abstract Background Thromboembolism has been reported as a consequence of severe COVID-19. Although warfarin is a commonly used anticoagulant, it acts by antagonising vitamin K, which is low in patients with severe COVID-19. To date, the clinical evidence on the impact of regular use of warfarin on COVID-19-related thromboembolism is lacking. Methods On behalf of NHS England, we conducted a population-based cohort study investigating the association between warfarin and COVID-19 outcomes compared with direct oral anticoagulants (DOACs). We used the OpenSAFELY platform to analyse primary care data and pseudonymously linked SARS-CoV-2 antigen testing data, hospital admissions and death records from England. We used Cox regression to estimate hazard ratios (HRs) for COVID-19-related outcomes comparing warfarin with DOACs in people with non-valvular atrial fibrillation. We also conducted negative control outcome analyses (being tested for SARS-CoV-2 and non-COVID-19 death) to assess the potential impact of confounding. Results A total of 92,339 warfarin users and 280,407 DOAC users were included. We observed a lower risk of all outcomes associated with warfarin versus DOACs [testing positive for SARS-CoV-2, HR 0.73 (95% CI 0.68–0.79); COVID-19-related hospital admission, HR 0.75 (95% CI 0.68–0.83); COVID-19-related deaths, HR 0.74 (95% CI 0.66–0.83)]. A lower risk of negative control outcomes associated with warfarin versus DOACs was also observed [being tested for SARS-CoV-2, HR 0.80 (95% CI 0.79–0.81); non-COVID-19 deaths, HR 0.79 (95% CI 0.76–0.83)]. Conclusions Overall, this study shows no evidence of harmful effects of warfarin on severe COVID-19 disease.

Cholesteryl ester transfer protein (CETP) facilitates the net transfer of cholesteryl esters (CEs) and TGs between lipoproteins, impacting the metabolic fate of these lipoproteins. Previous studies have shown that a CETP antibody can alter CETP's preference for CE versus TG as transfer substrate, suggesting that CETP substrate preference can be manipulated in vivo. Hamster and human CETPs have very different preferences for CE and TG. To assess the effect of altering CETP's substrate preference on lipoproteins in vivo, here, we expressed human CETP in hamsters. Chow-fed hamsters received adenoviruses expressing no CETP, hamster CETP, or human CETP. Plasma CETP mass increased 2-fold in both the hamster and human CETP groups. Although the animals expressing human CETP still had low levels of hamster CETP, the CE versus TG preference of their plasma CETP was similar to that of the human ortholog. Hamster CETP overexpression had little impact on lipoproteins. However, expression of human CETP reduced HDL up to 50% and increased VLDL cholesterol 2.5-fold. LDL contained 20% more CE, whereas HDL CE was reduced 40%, and TG increased 6-fold. The HDL3:HDL2 ratio increased from 0.32 to 0.60. Hepatic expression of three cholesterol-related genes (LDLR, SCARB1, and CYP7A1) was reduced up to 40%. However, HDL-associated CE excretion into feces was unchanged. We conclude that expression of human CETP in hamsters humanizes their lipoprotein profile with respect to the relative concentrations of VLDL, LDL, HDL, and the HDL3:HDL2 ratio. Altering the lipid substrate preference of CETP provides a novel approach for modifying plasma lipoproteins.

Cholesteryl ester transfer protein (CETP) exists as full-length (FL) and exon 9 (E9)-deleted isoforms. The function of E9-deleted CETP is poorly understood. Here, we investigated the role of E9-deleted CETP in regulating the secretion of FL-CETP by cells and explored its possible role in intracellular lipid metabolism. CETP overexpression in cells that naturally express CETP confirmed that E9-deleted CETP is not secreted, and showed that cellular FL- and E9-deleted CETP form an isolatable complex. Coexpression of CETP isoforms lowered cellular levels of both proteins and impaired FL-CETP secretion. These effects were due to reduced synthesis of both isoforms; however, the predominate consequence of FL- and E9-deleted CETP coexpression is impaired FL-CETP synthesis. We reported previously that reducing both CETP isoforms or overexpressing FL-CETP impairs cellular triglyceride (TG) storage. To investigate this further, E9-deleted CETP was expressed in SW872 cells that naturally synthesize CETP and in mouse 3T3-L1 cells that do not. E9-deleted CETP overexpression stimulated SW872 triglyceride synthesis and increased stored TG 2-fold. Expression of E9-deleted CETP in mouse 3T3-L1 cells produced a similar lipid phenotype. In vitro, FL-CETP promotes the transfer of TG from ER-enriched membranes to lipid droplets. E9-deleted CETP also promoted this transfer, although less effectively, and it inhibited the transfer driven by FL-CETP. We conclude that FL- and E9-deleted CETP isoforms interact to mutually decrease their intracellular levels and impair FL-CETP secretion by reducing CETP biosynthesis. E9-deleted CETP, like FL-CETP, alters cellular TG metabolism and storage but in a contrary manner.

Summary: Background: Residents in care homes have been severely impacted by COVID-19. We describe trends in the mortality risk among residents of care homes compared to private homes. Methods: On behalf of NHS England we used OpenSAFELY-TPP to calculate monthly age-standardised risks of death due to all causes and COVID-19 among adults aged >=65 years between 1/2/2019 and 31/03/2021. Care home residents were identified using linkage to Care and Quality Commission data. Findings: We included 4,340,648 people aged 65 years or older on the 1st of February 2019, 2.2% of whom were classified as residing in a care or nursing home. Age-standardised mortality risks were approximately 10 times higher among care home residents compared to those in private housing in February 2019: comparative mortality figure (CMF) = 10.59 (95%CI = 9.51, 11.81) among women, and 10.87 (9.93, 11.90) among men. By April 2020 these relative differences had increased to more than 17 times with CMFs of 17.57 (16.43, 18.79) among women and 18.17 (17.22, 19.17) among men. CMFs did not increase during the second wave, despite a rise in the absolute age-standardised COVID-19 mortality risks. Interpretation: COVID-19 has had a disproportionate impact on the mortality of care home residents in England compared to older residents of private homes, but only in the first wave. This may be explained by a degree of acquired immunity, improved protective measures or changes in the underlying frailty of the populations. The care home population should be prioritised for measures aimed at controlling COVID-19. Funding: Medical Research Council MR/V015737/1

Apolipoprotein F (ApoF) modulates lipoprotein metabolism by selectively inhibiting cholesteryl ester transfer protein activity on LDL. This ApoF activity requires that it is bound to LDL. How hyperlipidemia alters total plasma ApoF and its binding to LDL are poorly understood. In this study, total plasma ApoF and LDL-bound ApoF were quantified by ELISA (n = 200). Plasma ApoF was increased 31% in hypercholesterolemic plasma but decreased 20% in hypertriglyceridemia. However, in donors with combined hypercholesterolemia and hypertriglyceridemia, the elevated triglyceride ameliorated the rise in ApoF caused by hypercholesterolemia alone. Compared with normolipidemic LDL, hypercholesterolemic LDL contained ∼2-fold more ApoF per LDL particle, whereas ApoF bound to LDL in hypertriglyceridemia plasma was

Abstract Background Measurement of what knowledge is taken-up and how that information is used to inform practice and policies can provide an understanding about the effectiveness of knowledge uptake and utilization processes. In 2007, the Knowledge Uptake and Utilization Tool (KUUT) was developed to evaluate the implementation of knowledge into practice. The KUUT has been used by numerous large health organizations despite limited validity evidence and a narrow understanding about how the tool is used in practice and interpreted by users. As such, the overall purpose of this protocol is to redevelop the KUUT and gather validity evidence to examine and support its use in various health-related organizations. This protocol paper outlines a validation and redevelopment procedure for the KUUT using the unitary view of validity. Methods The protocol outlined in this article proceeds through four phases, starting with redeveloping the tool, then evaluating validity evidence based on: test content, response processes and internal structure. The initial phase gathers information to redevelop the tool, and evaluates item content and response format. The second phase evaluates response process validity evidence by examining how a variety of users interact with the tool. In the third phase, the tool will be pilot tested with knowledge users and, in the final phase, psychometric properties of the tool will be examined and a final scoring structure will be determined. A knowledge translation plan described herein outlines where the final tool will be housed and how the information about the tool will be disseminated. Discussion This protocol outlines a procedure to gather different sources of validity evidence for the KUUT. By addressing limitations in the original KUUT, such as complexities with scoring, a redeveloped KUUT supporting validity evidence will enhance the ability of health-related organizations to effectively use this tool for its intended purpose.

Cholesteryl ester transfer protein (CETP) regulates intravascular lipoprotein metabolism. In vitro studies indicate that ApoF alters CETP function by inhibiting its activity with LDL. To explore in vivo the complexities driving ApoF's effects on CETP, we developed a siRNA-based hamster model of ApoF knockdown. In both male and female hamsters on chow- or fat-fed diets, we measured lipoprotein levels and composition, determined CETP-mediated transfer of cholesteryl esters (CEs) between lipoproteins, and quantified reverse cholesterol transport (RCT). We found that apoF knockdown in chow-fed hamsters had no effect on lipoprotein levels or composition, but these ApoF-deficient lipoproteins supported 50–100% higher LDL CETP activity in vitro. ApoF knockdown in fat-fed male hamsters created a phenotype in which endogenous CETP-mediated CE transfer from HDL to LDL increased up to 2-fold, LDL cholesterol increased 40%, HDL declined 25%, LDL and HDL lipid compositions were altered, and hepatic LDLR gene expression was decreased. Diet-induced hypercholesterolemia obscured this phenotype on occasion. In fat-fed female hamsters, ApoF knockdown caused similar but smaller changes in plasma CETP activity and LDL cholesterol. Notably, ApoF knockdown impaired HDL RCT in fat-fed hamsters but increased sterol excretion in chow-fed animals. These in vivo data validate in vitro findings that ApoF regulates lipid transfer to LDL. The consequences of ApoF knockdown on lipoproteins and sterol excretion depend on the underlying lipid status. By minimizing the transfer of HDL-derived CE to LDL, ApoF helps control LDL cholesterol levels when LDL clearance mechanisms are limiting.

Background: Care home residents have been severely affected by the COVID-19 pandemic. Electronic Health Records (EHR) hold significant potential for studying the healthcare needs of this vulnerable population; however, identifying care home residents in EHR is not straightforward. We describe and compare three different methods for identifying care home residents in the newly created OpenSAFELY-TPP data analytics platform. Methods: Working on behalf of NHS England, we identified individuals aged 65 years or older potentially living in a care home on the 1st of February 2020 using (1) a complex address linkage, in which cleaned GP registered addresses were matched to old age care home addresses using data from the Care and Quality Commission (CQC); (2) coded events in the EHR; (3) household identifiers, age and household size to identify households with more than 3 individuals aged 65 years or older as potential care home residents. Raw addresses were not available to the investigators. Results: Of 4,437,286 individuals aged 65 years or older, 2.27% were identified as potential care home residents using the complex address linkage, 1.96% using coded events, 3.13% using household size and age and 3.74% using either of these methods. 53,210 individuals (32.0% of all potential care home residents) were classified as care home residents using all three methods. Address linkage had the largest overlap with the other methods; 93.3% of individuals identified as care home residents using the address linkage were also identified as such using either coded events or household age and size. Conclusion: We have described the partial overlap between three methods for identifying care home residents in EHR, and provide detailed instructions for how to implement these in OpenSAFELY-TPP to support research into the impact of the COVID-19 pandemic on care home residents.

Abstract: Cholesteryl ester transfer protein (CETP) modulates lipoprotein metabolism by transferring cholesteryl ester (CE) and triglyceride (TG) between lipoproteins. However, differences in the way CETP functions exist across species. Unlike human CETP, hamster CETP prefers TG over CE as a substrate, raising questions regarding how substrate preference may impact lipoprotein metabolism. To understand how altering the CE versus TG substrate specificity of CETP might impact lipoprotein metabolism in humans, we modified CETP expression in fat/cholesterol-fed hamsters, which have a human-like lipoprotein profile. Hamsters received adenoviruses expressing no CETP, hamster CETP, or human CETP. Total plasma CETP mass increased up to 70% in the hamster and human CETP groups. Hamsters expressing human CETP exhibited decreased endogenous hamster CETP, resulting in an overall CE:TG preference of plasma CETP that was similar to that in humans. Hamster CETP overexpression had little impact on lipoproteins, whereas human CETP expression reduced HDL by 60% without affecting LDL. HDLs were TG enriched and CE depleted and much smaller, causing the HDL3:HDL2 ratio to increase threefold. HDL from hamsters expressing human CETP supported higher LCAT activity and greater cholesterol efflux. The fecal excretion of HDL-associated CE in human CETP animals was unchanged. However, much of this cholesterol accumulated in the liver and was associated with a 1.8-fold increase in hepatic cholesterol mass. Overall, these data show in a human-like lipoprotein model that modification of CETP's lipid substrate preference selectively alters HDL concentration and function. This provides a powerful tool for modulating HDL metabolism and impacting sterol balance in vivo.

Abstract Background Effective knowledge translation (KT) is critical to implementing program and policy changes that require shared understandings of knowledge systems, assumptions, and practices. Within mainstream research institutions and funding agencies, systemic and insidious inequities, privileges, and power relationships inhibit Indigenous peoples’ control, input, and benefits over research. This systematic review will examine literature on KT initiatives in Indigenous health research to help identify wise and promising Indigenous KT practices and language in Canada and abroad. Methods Indexed databases including Aboriginal Health Abstract Database, Bibliography of Native North Americans, CINAHL, Circumpolar Health Bibliographic Database, Dissertation Abstracts, First Nations Periodical Index, Medline, National Indigenous Studies Portal, ProQuest Conference Papers Index, PsycInfo, Social Services Abstracts, Social Work Abstracts, and Web of Science will be searched. A comprehensive list of non-indexed and grey literature sources will also be searched. For inclusion, documents must be published in English; linked to Indigenous health and wellbeing; focused on Indigenous people; document KT goals, activities, and rationale; and include an evaluation of their KT strategy. Identified quantitative, qualitative, and mixed methods’ studies that meet the inclusion criteria will then be appraised using a quality appraisal tool for research with Indigenous people. Studies that score 6 or higher on the quality appraisal tool will be included for analysis. Discussion This unique systematic review involves robust Indigenous community engagement strategies throughout the life of the project, starting with the development of the review protocol. The review is being guided by senior Indigenous researchers who will purposefully include literature sources characterized by Indigenous authorship, community engagement, and representation; screen and appraise sources that meet Indigenous health research principles; and discuss the project with the Indigenous Elders to further explore the hazards, wisdom, and processes of sharing knowledge in research contexts. The overall aim of this review is to provide the evidence and basis for recommendations on wise practices for KT terminology and research that improves Indigenous health and wellbeing and/or access to services, programs, or policies that will lead to improved health and wellbeing. Systematic review registration PROSPERO CRD42016049787 .