StandUPTV: Preparation and optimization phases of a mHealth intervention to reduce sedentary screen time in adults.

Recreational sedentary screen time (rSST) is the most prevalent sedentary behavior for adults outside of work, school, and sleep, and is strongly linked to poor health. StandUPTV is a mHealth trial that uses the Multiphase Optimization Strategy (MOST) framework to develop and evaluate the efficacy of three theory-based strategies for reducing rSST among adults. This paper describes the preparation and optimization phases of StandUPTV within the MOST framework. We identified three candidate components based on previous literature: (a) rSST electronic lockout (LOCKOUT), which restricts rSST through electronic means; (b) adaptive prompts (TEXT), which provides adaptive prompts based on rSST behaviors; and (c) earning rSST through increased moderate-vigorous physical activity (MVPA) participation (EARN). We also describe the mHealth iterative design process and the selection of an optimization objective. Finally, we describe the protocol of the optimization randomized controlled trial using a 23 factorial experimental design. We will enroll 240 individuals aged 23-64 y who engage in >3 h/day of rSST. All participants will receive a target to reduce rSST by 50% and be randomized to one of 8 combinations representing all components and component levels: LOCKOUT (yes vs. no), TEXT (yes vs. no), and EARN (yes vs. no). Results will support the selection of the components for the intervention package that meet the optimization objective and are acceptable to participants. The optimized intervention will be tested in a future evaluation randomized trial to examine reductions in rSST on health outcomes among adults.

Sexual and gender identity and note-leaving among adult suicide decedents in the USA.

BACKGROUND: Suicide is one of the leading causes of preventable death in the USA, representing a critical public health threat. Suicide risks differ for different populations. In particular, the sexual and gender minority (SGM) population remains at increased risk for suicide. One of the circumstances that may differ for SGM and non-SGM individuals is the propensity to leave a suicide note. Information regarding note-leaving may be helpful in informing suicide prevention and intervention. AIMS: This study documents the differences in note-leaving in SGM individuals compared with non-SGM individuals, using recent data from the National Violent Death Reporting System (N = 98 515) and accounting for important covariates. METHOD: We fit a logistic regression model with SGM status and covariates predicting note-leaving in suicide. RESULTS: SGM decedents were 1.508 times more likely to leave a note than their non-SGM counterparts, controlling for demographic, mental health and substance use covariates. CONCLUSIONS: These findings highlight the importance of tailoring suicide prevention and intervention efforts to meet the needs of SGM populations.

Functional humanization of immunoglobulin heavy constant gamma 1 Fc domain human FCGRT transgenic mice.

A major asset of many monoclonal antibody (mAb)-based biologics is their persistence in circulation. The MHC class I family Fc receptor, FCGRT, is primarily responsible for this extended pharmacokinetic behavior. Engagement of FCGRT with the crystallizable fragment (Fc) domain protects IgG from catabolic elimination, thereby extending the persistence and bioavailability of IgG and related Fc-based biologics. There is a need for reliable in vivo models to facilitate the preclinical development of novel IgG-based biologics. FcRn-humanized mice have been widely accepted as translationally relevant surrogates for IgG-based biologics evaluations. Although such FCGRT-humanized mice, especially the mouse strain, B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr (abbreviated Tg32), have been substantially validated for modeling humanized IgG-based biologics, there is a recognized caveat - they lack an endogenous source of human IgG that typifies the human competitive condition. Here, we used CRISPR/Cas9-mediated homology-directed repair to equip the hFCGRT Tg32 strain with a human IGHG1 Fc domain. This replacement now results in mice that produce human IgG1 Fc-mouse IgG Fab2 chimeric antibodies at physiologically relevant levels, which can be further heightened by immunization. This endogenous chimeric IgG1 significantly dampens the serum half-life of administered humanized mAbs in an hFCGRT-dependent manner. Thus, such IgG1-Fc humanized mice may provide a more physiologically relevant competitive hFCGRT-humanized mouse model for the preclinical development of human IgG-based biologics.

Selection of Candida albicans trisomy during oropharyngeal infection results in a commensal-like phenotype.

When the fungus Candida albicans proliferates in the oropharyngeal cavity during experimental oropharyngeal candidiasis (OPC), it undergoes large-scale genome changes at a much higher frequency than when it grows in vitro. Previously, we identified a specific whole chromosome amplification, trisomy of Chr6 (Chr6x3), that was highly overrepresented among strains recovered from the tongues of mice with OPC. To determine the functional significance of this trisomy, we assessed the virulence of two Chr6 trisomic strains and a Chr5 trisomic strain in the mouse model of OPC. We also analyzed the expression of virulence-associated traits in vitro. All three trisomic strains exhibited characteristics of a commensal during OPC in mice. They achieved the same oral fungal burden as the diploid progenitor strain but caused significantly less weight loss and elicited a significantly lower inflammatory host response. In vitro, all three trisomic strains had reduced capacity to adhere to and invade oral epithelial cells and increased susceptibility to neutrophil killing. Whole genome sequencing of pre- and post-infection isolates found that the trisomies were usually maintained. Most post-infection isolates also contained de novo point mutations, but these were not conserved. While in vitro growth assays did not reveal phenotypes specific to de novo point mutations, they did reveal novel phenotypes specific to each lineage. These data reveal that during OPC, clones that are trisomic for Chr5 or Chr6 are selected and they facilitate a commensal-like phenotype.

Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development.

Improved mouse models for type 1 diabetes (T1D) therapy development are needed. T1D susceptibility is restored to normally resistant NOD.ß2m-/- mice transgenically expressing human disease-associated HLA-A*02:01 or HLA-B*39:06 class I molecules in place of their murine counterparts. T1D is dependent on pathogenic CD8+ T-cell responses mediated by these human class I variants. NOD.ß2m-/--A2.1 mice were previously used to identify ß-cell autoantigens presented by this human class I variant to pathogenic CD8+ T cells and for testing therapies to attenuate such effectors. However, NOD.ß2m-/- mice also lack nonclassical MHC I family members, including FcRn, required for antigen presentation, and maintenance of serum IgG and albumin, precluding therapies dependent on these molecules. Hence, we used CRISPR/Cas9 to directly ablate the NOD H2-Kd and H2-Db classical class I variants either individually or in tandem (cMHCI-/-). Ablation of the H2-Ag7 class II variant in the latter stock created NOD mice totally lacking in classical murine MHC expression (cMHCI/II-/-). NOD-cMHCI-/- mice retained nonclassical MHC I molecule expression and FcRn activity. Transgenic expression of HLA-A2 or -B39 restored pathogenic CD8+ T-cell development and T1D susceptibility to NOD-cMHCI-/- mice. These next-generation HLA-humanized NOD models may provide improved platforms for T1D therapy development.