Daily sleepiness magnifies the relation between same-day passive and active suicide ideation.

Disrupted sleep has been linked to suicidal thoughts and behavior. Less is known, however, about the underlying mechanisms of this relationship. A more nuanced understanding of the link between sleep and suicide may help inform treatment decisions and the development of prevention and intervention strategies. The present study examined daily average sleepiness as a moderator to the relation between same-day passive and active suicide ideation (SI). Fifty-nine young adults (mean age = 21.04; SD = 2.22) endorsing SI at least twice in the two weeks prior to baseline completed 3-5 daily surveys of sleepiness and SI over 2 weeks as part of a broader study. Across several indicators of sleepiness (desire to stay awake, desire to fall asleep), passive SI (desire to die, desire to live), and active SI (occurrence, intensity, duration, and controllability), the overall findings demonstrated that daily average sleepiness magnified the relation between same-day passive SI and active SI severity. These findings indicate that being sleepier than usual may increase the likelihood that passive SI transitions to active SI. Future research is needed to test the causal influence of sleepiness on this transition.

Pharmacogene expression during progression of metabolic dysfunction-associated steatotic liver disease: Studies on mRNA and protein levels and their relevance to drug treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common worldwide. Genes and proteins contributing to drug disposition may show altered expression as MASLD progresses. To assess this further, we undertook transcriptomic and proteomic analysis of 137 pharmacogenes in liver biopsies from a large MASLD cohort. We performed sequencing on RNA from 216 liver biopsies (206 MASLD and 10 controls). Untargeted mass spectrometry proteomics was performed on a 103 biopsy subgroup. Selected RNA sequencing signals were replicated with an additional 187 biopsies. Comparison of advanced MASLD (fibrosis score 3/4) with milder disease (fibrosis score 0-2) by RNA sequencing showed significant alterations in expression of certain phase I, phase II and ABC transporters. For cytochromes P450, CYP2C19 showed the most significant decreased expression (30 % of that in mild disease) but significant decreased expression of other CYPs (including CYP2C8 and CYP2E1) also occurred. CYP2C19 also showed a significant decrease comparing the inflammatory form of MASLD (MASH) with non-MASH biopsies. Findings for CYP2C19 were confirmed in the replication cohort. Proteomics on the original discovery cohort confirmed decreased levels of several CYPs as MASLD advanced but this decrease was greatest for CYP2C19 where levels fell to 40 % control. This decrease may result in decreased CYP2C19 activity that could be problematic for prescription of drugs activated or metabolized by CYP2C19 as MASLD advances. More limited decreases for other P450s suggest fewer issues with non-CYP2C19 drug substrates. Negative correlations at RNA level between CYP2C19 and several cytokine genes provided initial insights into the mechanism underlying decreased expression.

Lead-Free Semiconductors: Phase-Evolution and Superior Stability of Multinary Tin Chalcohalides.

Tin-based semiconductors are highly desirable materials for energy applications due to their low toxicity and biocompatibility relative to analogous lead-based semiconductors. In particular, tin-based chalcohalides possess optoelectronic properties that are ideal for photovoltaic and photocatalytic applications. In addition, they are believed to benefit from increased stability compared with halide perovskites. However, to fully realize their potential, it is first necessary to better understand and predict the synthesis and phase evolution of these complex materials. Here, we describe a versatile solution-phase method for the preparation of the multinary tin chalcohalide semiconductors Sn2SbS2I3, Sn2BiS2I3, Sn2BiSI5, and Sn2SI2. We demonstrate how certain thiocyanate precursors are selective toward the synthesis of chalcohalides, thus preventing the formation of binary and other lower order impurities rather than the preferred multinary compositions. Critically, we utilized 119Sn ssNMR spectroscopy to further assess the phase purity of these materials. Further, we validate that the tin chalcohalides exhibit excellent water stability under ambient conditions, as well as remarkable resistance to heat over time compared to halide perovskites. Together, this work enables the isolation of lead-free, stable, direct band gap chalcohalide compositions that will help engineer more stable and biocompatible semiconductors and devices.

Bone Proteomics Method Optimization for Forensic Investigations.

The application of proteomic analysis to forensic skeletal remains has gained significant interest in improving biological and chronological estimations in medico-legal investigations. To enhance the applicability of these analyses to forensic casework, it is crucial to maximize throughput and proteome recovery while minimizing interoperator variability and laboratory-induced post-translational protein modifications (PTMs). This work compared different workflows for extracting, purifying, and analyzing bone proteins using liquid chromatography with tandem mass spectrometry (LC-MS)/MS including an in-StageTip protocol previously optimized for forensic applications and two protocols using novel suspension-trap technology (S-Trap) and different lysis solutions. This study also compared data-dependent acquisition (DDA) with data-independent acquisition (DIA). By testing all of the workflows on 30 human cortical tibiae samples, S-Trap workflows resulted in increased proteome recovery with both lysis solutions tested and in decreased levels of induced deamidations, and the DIA mode resulted in greater sensitivity and window of identification for the identification of lower-abundance proteins, especially when open-source software was utilized for data processing in both modes. The newly developed S-Trap protocol is, therefore, suitable for forensic bone proteomic workflows and, particularly when paired with DIA mode, can offer improved proteomic outcomes and increased reproducibility, showcasing its potential in forensic proteomics and contributing to achieving standardization in bone proteomic analyses for forensic applications.

Differences in the relation of binge drinking and prescription drug misuse to suicide ideation and attempts between college-aged adults and adults above the age of 25: Findings from the 2015-2019 National Survey on Drug Use and Health (NSDUH).

OBJECTIVE: To clarify the role of age in risk associated with drug misuse and binge drinking, this study examines the differential relations of binge drinking and prescription drug misuse to risk of suicidal ideation and attempts in young adults of college age (18-24) compared to those above the age of 25. METHODS: We used data from the National Survey on Drug Use and Health (NSDUH) for the years 2015 through 2019 (N = 269,078). RESULTS: The study found that, for adults above college age, the presence of any past-month binge drinking was associated with a higher likelihood of past-year suicide ideation (b = 0.427, OR = 1.532, 95%CI [1.388, 1.692]) and attempts (b = 0.637, OR = 1.891, 95%CI [1.271, 2.813]) compared to college-aged adults. Similarly, past-month prescription drug misuse showed stronger associations with past-year suicide ideation (b = 0.831, OR = 2.297, 95%CI [1.952, 2.701]) and attempts (b = 0.539, OR = 1.715, 95%CI [1.264, 2.327]) in adults above college age. CONCLUSION: These findings highlight that binge drinking and prescription drug misuse appears to become more strongly associated with suicide ideation and attempts after adults age beyond young adulthood.

Improving Emergency Medicine Clinician Awareness of Prehospital-Administered Medications.

Background/problem: Information transfer between emergency medical services (EMS) and emergency medicine (EM) is at high risk for omissions and errors. EM awareness of prehospital medication administration affects patient management and medication error. In April 2020, we surveyed emergency physicians and emergency department nurse practitioners (NPs) and physician assistants (PAs) regarding the EMS handoff process. Emergency physicians and NPs/PAs endorsed knowing what medications were given, or having received direct verbal handoff from EMS "Often" or "Always" only 20% of the time (n = 71), identifying a need to improve the written handoff process. To assess rates of medication error due to lack of awareness of prehospital administered medications, we measured glucocorticoid redosing in the emergency department (ED) following prehospital dexamethasone administration. In 2020, glucocorticoids were redosed 30% of the time, and our aim was to reduce glucocorticoid redosing to 10% by June 2022. Intervention: We developed and implemented a system innovation where prehospital-administered medications documented in a nursing flowsheet during verbal handoff are pulled directly into the triage note where they are more likely to be reviewed by receiving EM clinicians. Results: Shewhart p-charts were used to evaluate for statistical process change in the process measure of triage note documentation of prehospital medication administration and the outcome measure of glucocorticoid redosing. While the frequency of prehospital dexamethasone administration in the triage note increased, no statistical process change outcome measure of glucocorticoid redosing was observed. However, on repeat survey of EM clinicians in July 2022, 50% now indicated they were aware of prehospital medication administration "Often" or "Always" (n = 61, p = 0.003), 87% maintained they use the triage note as the main source of information regarding prehospital medication administration, and 81% "Always" review the triage note. Conclusions: Innovations that improve accessibility of written documentation of prehospital medication administration were associated with improved subjective assessment of EM clinician awareness of prehospital medications, but not the outcome measure of medication error. Effective error reduction likely requires better system integration between prehospital and EM records.

Development of a cationic polyethyleneimine-poly(lactic-co-glycolic acid) nanoparticle system for enhanced intracellular delivery of biologics.

Intracellular delivery of proteins, peptides and biologics is an emerging field which has the potential to provide novel opportunities to target intracellular proteins, previously deemed 'undruggable'. However, the delivery of proteins intracellularly remains a challenge. Here, we present a cationic nanoparticle delivery system for enhanced cellular delivery of proteins through use of a polyethyleneimine and poly-(lactic-co-glycolic acid) polymer blend. Cationic nanoparticles were shown to provide increased cellular uptake compared to anionic and neutral nanoparticles, successfully delivering Variable New Antigen Receptors (vNARs), entrapped within the nanoparticle core, to the cell interior. vNARs were identified as ideal candidates for nanoparticle entrapment due to their remarkable stability. The optimised 10% PEI-PLGA nanoparticle formulation displayed low toxicity, was uniform in size and possessed appropriate cationic charge to limit cellular toxicity, whilst being capable of escaping the endo/lysosomal system and delivering their cargo to the cytosol. This work demonstrates the ability of cationic nanoparticles to facilitate intracellular delivery of vNARs, novel biologic agents with potential utility towards intracellular targets.

Use of Ultrasound-Guided Tendon Fenestration and Injection Procedures for Treatment of Tendinosis.

Introduction: Overuse injuries such as tendinosis are a common complaint at sports medicine clinics. When conservative management for tendinosis has failed, ultrasound-guided tendon fenestration and injection procedures, such as dry needling, needling tenotomy, autologous whole blood injections, and prolotherapy, can be utilized for treatment. This study examined the effectiveness of these procedures for pain improvement and ability to return to activity for patients with tendinosis. Methods: This study involved a chart review of patients 15 years or older who underwent at least one treatment for tendinosis at a sports medicine clinic between January 1, 2014 and April 17, 2019. Eligible patients had at least one of the following procedures: 1) percutaneous dry needling, 2) percutaneous needle tenotomy, 3) autologous whole blood injection, and/or 4) prolotherapy. A Current Procedural Terminology (CPT) code query was used to screen patient charts for study inclusion. Results: In total, 680 patients' data were reviewed, and 343 patients met inclusion criteria. Patients underwent a total of 598 unique procedures. Dry needling represented most procedures (62.8%, n = 375). Most patients reported diminished pain at follow up (73.0%, n = 268). Prolotherapy had the highest percentage among the follow up patients reporting diminished pain (81.0%, n = 17). Most patients were able to return to activity at follow-up (47.4%, n = 172). A greater proportion of patients with autologous whole blood injection were able to return to activity (60.7%, n = 85). Conclusions: Most patients with tendinosis who underwent tendon fenestration or injection procedures reported diminished pain at follow-up. Autologous whole blood injection may be more likely to diminish patient pain and allow return to activity than other procedure types. More research is needed across all anatomical sites to compare the generalized effectiveness of these procedures.

Exploring human papillomavirus vaccination decision making through mother and adolescent dyad interviews.

INTRODUCTION: The purpose of our research was to explore how parents and their adolescent children make decisions about the human papillomavirus (HPV) vaccine, and to inform future interventions that aim to facilitate inclusive decision-making processes. METHOD: Purposive and snowball sampling strategies targeted parents and their adolescent children (ages = 11-13) in a large city in Australia. We conducted separate and joint semistructured interviews in 2013 with six mother-adolescent dyads (50% female adolescents and 50% male). Interviews were analyzed using a grounded theory approach. RESULTS: Factors that both facilitate and impede decision making emerged, including: background knowledge, values, historical experiences, parenting style, and opinion weights. DISCUSSION: New interventions, strategies, and tools that are informed by these decision-making factors can be used to aid productive, mutual decision making between parents and adolescents and support adolescent autonomy and self-sufficiency in health decision making. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Unlearning and relearning sexuality: a qualitative exploration of The Sex Wrap, a sex education podcast.

BACKGROUND: Traditional school-based sexuality education has a myriad of problems with its successful delivery, including access to comprehensive sexuality curricula, access to trained facilitators, and community and parental fears. As an alternative form of sexuality education, The Sex Wrap podcast is released in weekly episodes of about 20-45min, providing listeners with diverse, evidence-based sexual health information. METHODS: Participants in a larger mixed-methods study evaluating The Sex Wrap were invited to participate in qualitative in-depth interviews to explore their experiences with sexuality education, including The Sex Wrap , and how they relate to information received through the podcast. Seventeen interviews were conducted with listeners of The Sex Wrap , aged 20-25years old. RESULTS: One core category and three axial codes were identified in the interview data. The core category is: sexuality education is an ongoing process that includes learning and unlearning. The three temporally related axial codes are: (1) experiences with formal and informal sexuality education (mostly negative) drove participants to seek more information about sex, (2) participants use The Sex Wrap as a way of exploring and personalising information about sexuality, and (3) participants equipped with comprehensive sexuality education are empowered to educate their peers. CONCLUSIONS: This study suggests that podcast-based interventions, such as The Sex Wrap , can play a key role in young people's process of sexuality education and should be considered for incorporation into other forms of sex education.

Utility of Blood-Based Tau Biomarkers for Mild Cognitive Impairment and Alzheimer's Disease: Systematic Review and Meta-Analysis.

OBJECTIVES: With the development of new technologies capable of detecting low concentrations of Alzheimer's disease (AD) relevant biomarkers, the idea of a blood-based diagnosis of AD is nearing reality. This study aims to consider the evidence of total and phosphorylated tau as blood-based biomarkers for mild cognitive impairment (MCI) and AD when compared to healthy controls. METHODS: Studies published between 1 January 2012 and 1 May 2021 (Embase and MEDLINE databases) measuring plasma/serum levels of tau in AD, MCI, and control cohorts were screened for eligibility, including quality and bias assessment via a modified QUADAS. The meta-analyses comprised 48 studies assessing total tau (t-tau), tau phosphorylated at threonine 181 (p-tau181), and tau phosphorylated at threonine 217 (p-tau217), comparing the ratio of biomarker concentrations in MCI, AD, and cognitively unimpaired (CU) controls. RESULTS: Plasma/serum p-tau181 (mean effect size, 95% CI, 2.02 (1.76-2.27)) and t-tau (mean effect size, 95% CI, 1.77 (1.49-2.04)) were elevated in AD study participants compared to controls. Plasma/serum p-tau181 (mean effect size, 95% CI, 1.34 (1.20-1.49)) and t-tau (mean effect size, 95% CI, 1.47 (1.26-1.67)) were also elevated with moderate effect size in MCI study participants compared to controls. p-tau217 was also assessed, albeit in a small number of eligible studies, for AD vs. CU (mean effect size, 95% CI, 1.89 (1.86-1.92)) and for MCI vs. CU groups (mean effect size, 95% CI, 4.16 (3.61-4.71)). CONCLUSIONS: This paper highlights the growing evidence that blood-based tau biomarkers have early diagnostic utility for Alzheimer's disease. REGISTRATION: PROSPERO No. CRD42020209482.

Functionalization of polymeric nanoparticles with targeting VNAR ligands using vinyl sulfone conjugation.

Actively targeted drug loaded nanoparticles represent an exciting new form of therapeutics for cancer and other diseases. These formulations are complex and in order to realize their ultimate potential, optimization of their preparation is required. In this current study, we have examined the conjugation of a model targeting ligand, conjugated in a site-specific manner using a vinyl sulfone coupling approach. A disulfide-functionalized poly(L-lactide)-b-poly(oligo(ethylene glycol) methacrylate)-stat-(bis(2-methacryloyl)oxyethyl disulfide) (PLA-b-P(OEGMA-stat-DSDMA)) diblock copolymer was synthesized by simultaneous ring opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. Subsequently, the disulfide bonds of the polymer were reduced to thiols and divinyl sulfone was attached to the polymer using thiol-ene chemistry to produce the vinyl sulfone (VS)-functionalized PLA-b-P(OEGMA-stat-VSTEMA) amphiphilic block copolymer. Single emulsion - solvent evaporation was employed using a blend of this polymer with poly(D,L-lactide-co-glycolide) (PLGA) to produce VS-functionalized polymeric nanoparticles. The ability of these novel nanoparticles to attach ligands was then exemplified using a single domain variable new antigen receptor (VNAR) with a free carboxyl terminal cysteine residue. The resulting VNAR-functionalized nanoparticles were found to maintain specific affinity to their cognate antigen (DLL4) for at least 72 h at 4 °C. The simplicity of the degradable amphiphilic block copolymer synthesis and the efficiency of VNAR conjugation to the VS-functionalized nanoparticles show the potential of this platform for therapeutic development.

Tracheostomy in children is associated with neutrophilic airway inflammation.

BACKGROUND: Tracheostomies in children are associated with significant morbidity, poor quality of life, excess healthcare costs and excess mortality. The underlying mechanisms facilitating adverse respiratory outcomes in tracheostomised children are poorly understood. We aimed to characterise airway host defence in tracheostomised children using serial molecular analyses. METHODS: Tracheal aspirates, tracheal cytology brushings and nasal swabs were prospectively collected from children with a tracheostomy and controls. Transcriptomic, proteomic and metabolomic methods were applied to characterise the impact of tracheostomy on host immune response and the airway microbiome. RESULTS: Children followed up serially from the time of tracheostomy up to 3 months postprocedure (n=9) were studied. A further cohort of children with a long-term tracheostomy were also enrolled (n=24). Controls (n=13) comprised children without a tracheostomy undergoing bronchoscopy. Long-term tracheostomy was associated with airway neutrophilic inflammation, superoxide production and evidence of proteolysis when compared with controls. Reduced airway microbial diversity was established pre-tracheostomy and sustained thereafter. CONCLUSIONS: Long-term childhood tracheostomy is associated with a inflammatory tracheal phenotype characterised by neutrophilic inflammation and the ongoing presence of potential respiratory pathogens. These findings suggest neutrophil recruitment and activation as potential exploratory targets in seeking to prevent recurrent airway complications in this vulnerable group of patients.

Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina.

Age-related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the retinal pigment epithelium (RPE) and photoreceptors atrophy and/or retinal and choroidal angiogenesis. Here we use AMD patient-specific RPE cells with the Complement Factor H Y402H high-risk polymorphism to perform a comprehensive analysis of extracellular vesicles (EVs), their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced polarised EV secretion. Multi-omics analyses demonstrate that AMD RPE EVs carry RNA, proteins and lipids, which mediate key AMD features including oxidative stress, cytoskeletal dysfunction, angiogenesis and drusen accumulation. Moreover, AMD RPE EVs induce amyloid fibril formation, revealing their role in drusen formation. We demonstrate that exposure of control RPE to AMD RPE apical EVs leads to the acquisition of AMD features such as stress vacuoles, cytoskeletal destabilization and abnormalities in the morphology of the nucleus. Retinal organoid treatment with apical AMD RPE EVs leads to disrupted neuroepithelium and the appearance of cytoprotective alpha B crystallin immunopositive cells, with some co-expressing retinal progenitor cell markers Pax6/Vsx2, suggesting injury-induced regenerative pathways activation. These findings indicate that AMD RPE EVs are potent inducers of AMD phenotype in the neighbouring RPE and retinal cells.

Low levels of discriminant validity between self-report measures of self-esteem, shame, and self-criticism: Implications for the measurement of self-evaluation and creation of the Negative Self-Evaluation Scale.

This article examined the discriminant and convergent validity of commonly used self-report measures of self-criticism, self-esteem, and shame. A confirmatory factor analysis (CFA) using multiple self-report measures of each construct showed low levels of discriminant validity between self-reported self-esteem, shame, and self-criticism and instead demonstrated correspondingly high levels of shared variance. However, bifactor analyses on the items across each measure suggested that self-report measures of self-esteem, shame, and self-criticism may contain distinct characteristics that are underrepresented in current measures of each construct. Based on the factor loadings in item-level bifactor analyses, a new measure, the Negative Self-Evaluation Scale (NSES), was constructed to improve the assessment of the unique characteristics of shame, self-esteem, and self-criticism. Implications for current and future practices concerning the measurement of each construct are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Nuclear alpha-synuclein is present in the human brain and is modified in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is pathologically defined by the cytoplasmic accumulation of alpha-synuclein (aSyn) within neurons in the brain. Predominately pre-synaptic, aSyn has been reported in various subcellular compartments in experimental models. Indeed, nuclear alpha-synuclein (aSynNuc) is evident in many models, the dysregulation of which is associated with altered DNA integrity, transcription and nuclear homeostasis. However, the presence of aSynNuc in human brain cells remains controversial, yet the determination of human brain aSynNuc and its pathological modification is essential for understanding synucleinopathies. Here, using a multi-disciplinary approach employing immunohistochemistry, immunoblot, and mass-spectrometry (MS), we confirm aSynNuc in post-mortem brain tissue obtained from DLB and control cases. Highly dependent on antigen retrieval methods, in optimal conditions, intra-nuclear pan and phospho-S129 positive aSyn puncta were observed in cortical neurons and non-neuronal cells in fixed brain sections and in isolated nuclear preparations in all cases examined. Furthermore, an increase in nuclear phospho-S129 positive aSyn immunoreactivity was apparent in DLB cases compared to controls, in both neuronal and non-neuronal cell types. Our initial histological investigations identified that aSynNuc is affected by epitope unmasking methods but present under optimal conditions, and this presence was confirmed by isolation of nuclei and a combined approach of immunoblotting and mass spectrometry, where aSynNuc was approximately tenfold less abundant in the nucleus than cytoplasm. Notably, direct comparison of DLB cases to aged controls identified increased pS129 and higher molecular weight species in the nuclei of DLB cases, suggesting putative pathogenic modifications to aSynNuc in DLB. In summary, using multiple approaches we provide several lines of evidence supporting the presence of aSynNuc in autoptic human brain tissue and, notably, that it is subject to putative pathogenic modifications in DLB that may contribute to the disease phenotype.

Semiconducting silicon-phosphorus frameworks for caging exotic polycations.

A series of novel semiconductors AAe6Si12P20X (A = Na, K, Rb, Cs; Ae = Sr, Ba; X = Cl, Br, I) is reported. Their crystal structures feature a tetrahedral Si-P framework with large zeolite-like pores hosting two types of cations, monoatomic A+ and unprecedented octahedral X@Ae611+. Mixing of the A and Ba cations was detected by single crystal X-ray diffraction and confirmed by multinuclear solid state NMR. The reported compounds are highly stable semiconductors with a bandgap range from 1.4 to 2.0 eV.

Pilot randomized controlled trial using the theory of planned behavior to promote sexual consent of undergraduates in Greek-letter organizations.

OBJECTIVE: Sexual assault is prevalent among undergraduates in Greek-letter organizations (GLO). Prevention efforts promote sexual consent, though few explicitly employ theoretical constructs known to positively influence behavior. This study evaluated theory-informed educational posters promoting sexual consent seeking. PARTICIPANTS: Forty undergraduate GLO students (20 female, 20 male) were recruited through in-person, email, and social media solicitation. Data collection was completed March-November 2019 during the spring and fall semesters. METHODS: A double-blind randomized controlled trial was conducted. Intervention participants viewed theory-informed educational posters promoting sexual consent. RESULTS: The intervention group demonstrated more favorable consent intention (p = .024; η2 = 0.131) and consent subjective norms (p = .040; η2 = 0.109). Intervention group males showed a greater improvement in one of four consent attitudes (p = .045; η2 = 0.211). CONCLUSIONS: Brief exposures to theory-informed messaging may help to improve subjective norms and behavioral intent to seek sexual consent among undergraduate GLO members.