Characterising illness stages and recovery trajectories of eating disorders in young people via remote measurement technology (STORY): a multi-centre prospective cohort study protocol.

BACKGROUND: Eating disorders (EDs) are serious, often chronic, conditions associated with pronounced morbidity, mortality, and dysfunction increasingly affecting young people worldwide. Illness progression, stages and recovery trajectories of EDs are still poorly characterised. The STORY study dynamically and longitudinally assesses young people with different EDs (restricting; bingeing/bulimic presentations) and illness durations (earlier; later stages) compared to healthy controls. Remote measurement technology (RMT) with active and passive sensing is used to advance understanding of the heterogeneity of earlier and more progressed clinical presentations and predictors of recovery or relapse. METHODS: STORY follows 720 young people aged 16-25 with EDs and 120 healthy controls for 12 months. Online self-report questionnaires regularly assess ED symptoms, psychiatric comorbidities, quality of life, and socioeconomic environment. Additional ongoing monitoring using multi-parametric RMT via smartphones and wearable smart rings ('Oura ring') unobtrusively measures individuals' daily behaviour and physiology (e.g., Bluetooth connections, sleep, autonomic arousal). A subgroup of participants completes additional in-person cognitive and neuroimaging assessments at study-baseline and after 12 months. DISCUSSION: By leveraging these large-scale longitudinal data from participants across ED diagnoses and illness durations, the STORY study seeks to elucidate potential biopsychosocial predictors of outcome, their interplay with developmental and socioemotional changes, and barriers and facilitators of recovery. STORY holds the promise of providing actionable findings that can be translated into clinical practice by informing the development of both early intervention and personalised treatment that is tailored to illness stage and individual circumstances, ultimately disrupting the long-term burden of EDs on individuals and their families.

Autopsy of a failed trial part 2: Outcomes, challenges, and lessons learnt from the DAISIES trial.

OBJECTIVE: The relative merits of inpatient or day-treatment for adults with anorexia nervosa (AN) are unknown. The DAISIES trial aimed to establish the non-inferiority of a stepped-care day patient treatment (DPT) approach versus inpatient treatment as usual (IP-TAU) for improving body mass index (BMI) at 12 months in adults with AN. The trial was terminated due to poor recruitment. This paper presents outcomes and investigates the reasons behind the trial's failure. METHOD: Fifteen patients with AN (of 53 approached) participated and were followed-up to 6 or 12 months. Summary statistics were calculated due to low sample size, and qualitative data concerning treatment experiences were analysed using thematic analysis. RESULTS: At baseline, participants in both trial arms rated stepped-care DPT as more acceptable. At 12 months, participants' BMIs had increased in both trial arms. Qualitative analysis highlighted valued and challenging aspects of care across settings. Only 6/12 sites opened for recruitment. Among patients approached, the most common reason for declining participation was their treatment preference (n = 12/38). CONCLUSIONS: No conclusions can be drawn concerning the effectiveness of IP-TAU and stepped-care DPT, but the latter was perceived more positively. Patient-related, service-related and systemic factors (COVID-19) contributed to the trial's failure. Lessons learnt can inform future studies.

Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice.

In a previous transcriptomic study of human bone marrow stromal cells (BMSCs, also known as bone marrow-derived "mesenchymal stem cells"), SFRP2 was highly over-represented in a subset of multipotent BMSCs (skeletal stem cells, SSCs), which recreate a bone/marrow organ in an in vivo ectopic bone formation assay. SFRPs modulate WNT signaling, which is essential to maintain skeletal homeostasis, but the specific role of SFRP2 in BMSCs/SSCs is unclear. Here, we evaluated Sfrp2 deficiency on BMSC/SSC function in models of skeletal organogenesis and regeneration. The skeleton of Sfrp2-deficient (KO) mice is overtly normal; but their BMSCs/SSCs exhibit reduced colony-forming efficiency, reflecting low SSC self-renewal/abundancy. Sfrp2 KO BMSCs/SSCs formed less trabecular bone than those from WT littermates in the ectopic bone formation assay. Moreover, regeneration of a cortical drilled hole defect was dramatically impaired in Sfrp2 KO mice. Sfrp2-deficient BMSCs/SSCs exhibited poor in vitro osteogenic differentiation as measured by Runx2 and Osterix expression and calcium accumulation. Interestingly, activation of the Wnt co-receptor, Lrp6, and expression of Wnt target genes, Axin2, C-myc and Cyclin D1, were reduced in Sfrp2-deficient BMSCs/SSCs. Addition of recombinant Sfrp2 restored most of these activities, suggesting that Sfrp2 acts as a Wnt agonist. We demonstrate that Sfrp2 plays a role in self-renewal of SSCs and in the recruitment and differentiation of adult SSCs during bone healing. SFRP2 is also a useful marker of BMSC/SSC multipotency, and a factor to potentially improve the quality of ex vivo expanded BMSC/SSC products.

A Factor Analytic Model of Drug-Related Behavior in Adolescence and Its Impact on Arrests at Multiple Stages of the Life Course.

OBJECTIVES: Recognizing the inherent variability of drug-related behaviors, this study develops an empirically-driven and holistic model of drug-related behavior during adolescence using factor analysis to simultaneously model multiple drug behaviors. METHODS: The factor analytic model uncovers latent dimensions of drug-related behaviors, rather than patterns of individuals. These latent dimensions are treated as empirical typologies which are then used to predict an individual's number of arrests accrued at multiple phases of the life course. The data are robust enough to simultaneously capture drug behavior measures typically considered in isolation in the literature, and to allow for behavior to change and evolve over the period of adolescence. RESULTS: Results show that factor analysis is capable of developing highly descriptive patterns of drug offending, and that these patterns have great utility in predicting arrests. Results further demonstrate that while drug behavior patterns are predictive of arrests at the end of adolescence for both males and females, the impacts on arrests are longer lasting for females. CONCLUSIONS: The various facets of drug behaviors have been a long-time concern of criminological research. However, the ability to model multiple behaviors simultaneously is often constrained by data that do not measure the constructs fully. Factor analysis is shown to be a useful technique for modeling adolescent drug involvement patterns in a way that accounts for the multitude and variability of possible behaviors, and in predicting future negative life outcomes, such as arrests.

Narratives of HIV: measuring understanding of HIV and the law in HIV-positive patients.

OBJECTIVE: This study aimed to identify the understanding of people living with HIV and AIDS (PLWHA) regarding the application of the law around transmission of HIV in England and Wales. DESIGN: A questionnaire was designed to prompt participants attending a large HIV department to discuss their understanding of the law with reference to HIV transmission. The design focused on qualitative analysis as there were insufficient data available to inform a metric reflecting quantitative data on PLWHA's understanding of the legal implications of transmission. METHODS: The data were collected from PLWHA attending their HIV outpatient appointment to ensure relevance of population to the analysis. The answers were analysed using grounded theory and thematic analysis to identify key themes and theories for further testing. RESULTS: Analysis demonstrated that understanding of legal obligations and outcomes of prosecutions was poor and patchy, with behavioural restrictions often overstated. There was a strong theme of ownership of responsibility amongst PLWHA, and of reference to principles of morality beyond legal restrictions. CONCLUSIONS: PLWHA remain at risk of prosecution through poor understanding of the law. Clinical services and advocacy agencies should strive to increase understanding in order to enable PLWHA to comprehend the law and negotiate it successfully. This information should be shared as a process, not an isolated event.

On the Association Between Repeat Bully Victimizations and Carrying a Firearm: Evidence in a National Sample.

Bullying is a significant public concern. The purpose of the present study is to investigate whether being repeatedly victimized by a bully during childhood and adolescence is associated with gun carrying in adolescence and adulthood. Using data from the National Longitudinal Survey of Youth 1997, we found that just over one fourth of the respondents reported carrying a gun at some point in their lifetime. Respondents experiencing repeat bully victimizations reported higher rates of gun carrying during the last 12 months and the last 30 days. No support was found for the association of repeat bully victimizations and carrying a gun to school. Individuals victimized during childhood (before the age of 12) and during adolescence were found to be at risk of carrying a gun later in the life course. Repeat bully victimizations should be considered a marker for gun-carrying behaviors in adolescence and adulthood.

Like Parent Like Child? The Role of Delayed Childrearing in Breaking the Link Between Parent's Offending and Their Children's Antisocial Behavior.

This paper investigates the impact of parents' history of violent offending, their age at first birth, and the interaction of the two on their adolescent children's violent behavior. We employ intergenerational longitudinal data from the Rochester Youth Development Study to estimate parental trajectories of offending from their early adolescence through early adulthood. We show that the particular shape of the parents' propensity of offending over time can interact with their age at first birth to protect their children from delinquency. We investigate these relationships for children at 6 and 10 years of age. We find that for some groups delaying childrearing can insulate children from their parents' offending.

Directed differentiation of human induced pluripotent stem cells toward bone and cartilage: in vitro versus in vivo assays.

The ability to differentiate induced pluripotent stem cells (iPSCs) into committed skeletal progenitors could allow for an unlimited autologous supply of such cells for therapeutic uses; therefore, we attempted to create novel bone-forming cells from human iPSCs using lines from two distinct tissue sources and methods of differentiation that we previously devised for osteogenic differentiation of human embryonic stem cells, and as suggested by other publications. The resulting cells were assayed using in vitro methods, and the results were compared with those obtained from in vivo transplantation assays. Our results show that true bone was formed in vivo by derivatives of several iPSC lines, but that the successful cell lines and differentiation methodologies were not predicted by the results of the in vitro assays. In addition, bone was formed equally well from iPSCs originating from skin or bone marrow stromal cells (also known as bone marrow-derived mesenchymal stem cells), suggesting that the iPSCs did not retain a "memory" of their previous life. Furthermore, one of the iPSC-derived cell lines formed verifiable cartilage in vivo, which likewise was not predicted by in vitro assays.

Are Risky Youth Less Protectable As They Age? The Dynamics of Protection During Adolescence and Young Adulthood.

Research on recidivism in criminal justice and desistance in criminology are not integrated. Yet, both fields seem to be moving towards models that look at how positive elements in a person's environment can impact a person's behavior, conditional on different levels of risk. This study builds on this observation by applying interactional theory and the concept of Risk-Needs-Responsivity to theorize that both Needs and Responsivity will change over time in predictable ways. We then use a novel empirical approach with the Rochester Youth Development Study to show that even in late adolescence, individuals who are at risk for violence can be protected from future violence and risky behavior like gun carrying with positive events in their environment and personal life. In young adulthood, fewer people are still at risk for violence, and those who are at risk are harder to protect from future violence and gun carrying.

Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP.

Families with nonsyndromic dentinogenesis imperfecta (DGI) and the milder, dentin dysplasia (DD), have mutations in one allele of the dentin sialophosphoprotein (DSPP) gene. Because loss of a single Dspp allele in mice (and likely, humans) causes no dental phenotype, the mechanism(s) underling the dominant negative effects were investigated. DSPP mutations occur in three classes. (The first class, the mid-leader missense mutation, Y6D, was not investigated in this report.) All other 5' mutations of DSPP result in changes/loss in the first three amino acids (isoleucine-proline-valine [IPV]) of mature DSPP or, for the A15V missense mutation, some retention of the hydrophobic leader sequence. All of this second class of mutations caused mutant DSPP to be retained in the rough endoplasmic reticulum (rER) of transfected HEK293 cells. Trafficking out of the rER by coexpressed normal DSPP was reduced in a dose-responsive manner, probably due to formation of Ca2+-dependent complexes with the retained mutant DSPP. IPV-like sequences begin many secreted Ca2+-binding proteins, and changing the third amino acid to the charged aspartate (D) in three other acidic proteins also caused increased rER accumulation. Both the leader-retaining A15V and the long string of hydrophobic amino acids resulting from all known frameshift mutations within the 3'-encoded Ca2+-binding repeat domain (third class of mutations) caused retention by association of the mutant proteins with rER membranes. More 5' frameshift mutations result in longer mutant hydrophobic domains, but the milder phenotype, DD, probably due to lower effectiveness of the remaining, shorter Ca2+-binding domain in capturing normal DSPP protein within the rER. This study presents evidence of a shared underlying mechanism of capturing of normal DSPP by two different classes of DSPP mutations and offers an explanation for the mild (DD-II) versus severe (DGI-II and III) nonsyndromic dentin phenotypes. Evidence is also presented that many acidic, Ca2+-binding proteins may use the same IPV-like receptor/pathway for exiting the rER.

Assessing the Impact of Drug Use and Drug Selling on Violent Offending in a Panel of Delinquent Youth.

Despite a vast number of empirical studies arguing for or against a causal relationship between illegal drug use and selling and violent behavior, the debate continues. In part this is due to methodological weaknesses of previous research. Using data from the Rochester Youth Development Study, the current study seeks to improve on prior research designs to allow for a more precise examination of the mechanisms that lead from an individual's drug use (chiefly, marijuana use in the current sample) and drug selling to violent action. Results will allow for greater confidence in making causal inference regarding a long-standing concern in the discipline.

Dkk1 and Dkk2 regulate epicardial specification during mouse heart development.

BACKGROUND: Dkk1 and Dkk2 interact with LRP5 and LRP6 to modulate canonical Wnt signaling during development, and are known to be expressed in the developing heart. However, a loss-of-function mutation in either gene by itself produces no discernable heart phenotype. METHODS: Using standard husbandry techniques, Dkk1 null and Dkk2 null mouse lines were crossed to create double null embryos, which we examined using histological and immunohistochemical methods. RESULTS: Double null embryos die perinatally, with a gross head phenotype reminiscent of Dkk1 null embryos. Upon examination of late stage hearts, we observe myocardial defects including ventricular septal defects. At earlier stages, double mutant hearts show myocardial and epicardial hyperplasia. Myocardial hypertrophy is associated with a moderate increase in cell proliferation, but epicardial hypercellularity is not. Rather, the field of proepicardial precursor cells near the liver shows a broadening of expression for the cardiac-specific gap junction protein Connexin 43. CONCLUSIONS: Dkk1 and Dkk2 both inhibit Wnt signaling to regulate early myocardial proliferation and each can compensate for the loss of the other in that role. Wnt signaling regulates myocardial proliferation in both heart fields at early stages. Additionally, Wnt signaling is sufficient to increase proepicardial specification as measured by Connexin 43 expression, resulting in a hypercellular epicardium and perhaps contributing to later defects.

Brush border spectrin is required for early endosome recycling in Drosophila.

An apical brush border is a characteristic of many mature epithelia. This dynamic structure consists of dense microvilli supported by F-actin bundles that protrude into the apical cytoplasm, where they are crosslinked by spectrin and myosin II to form the terminal web. Little is known about the terminal web, through which vesicles transit to and from the apical membrane. Analysis of mutations in beta(Heavy)-spectrin, the Drosophila brush border spectrin, reveals that this protein is necessary for the maintenance of Rab5 endosomes in the midgut. As a consequence, an apical H+ V-ATPase that is probably responsible for lumenal acidification is lost both from the brush border and Rab5 endosomes. Epistasis tests indicate that beta(Heavy)-spectrin is required during endocytosis after Dynamin and before Rab5-mediated endosome activities. These data are consistent with the location of spectrin in the terminal web, and suggest that this molecule is required for correct sorting decisions at the early endosome.