Conduct problems, hyperactivity, and screen time among community youth: can mindfulness help? an exploratory study.

Background: The influence of mindfulness-based intervention (MBI) programs on behavioural problems among community youth is largely understudied. While technology continues to evolve and the prevalence of screen-based activities is rising, limited studies have accounted for screen time when examining the efficacy of an MBI. Accordingly, this study investigated the impact of MBI on conduct problems and hyperactivity among community youth, accounting for sociodemographic characteristics and four types of screen time. Method: Linear regression models were used to investigate 1) the association between four types of screen time and behavioural problems (i.e., conduct problems and hyperactivity) and 2) the efficacy of online mindfulness programs in reducing behavioural problems among community youth. The data were collected at baseline, intervention completion and 1-month follow-up (Spring 2021 to Spring 2022) in Ontario, Canada (n=117, mean age=16.82, male=22%, non-White=21%). Results: The average score for conduct problems was within the normal range, while the average score for hyperactivity was considered borderline at baseline. Accounting for other types of screen time, time spent playing video games was significantly associated with increased conduct problems (ß= 1.75, p=.03), albeit rendering non-significant after correcting for multiple comparisons. The online mindfulness program was significantly associated with reduced hyperactivity, controlling for baseline mental health, age, sex and screen time. Conclusion: The current findings suggest a 12-week online mindfulness program may play a positive role in reducing hyperactivity even when accounting for screen time. Our findings advocate the evidence base on the efficacy of MBI in managing hyperactivity.

Triphenylphosphonium-functionalized dimeric BODIPY-based nanoparticles for mitochondria-targeting photodynamic therapy.

The dimerization of boron dipyrromethene (BODIPY) moieties is an appealing molecular design approach for developing heavy-atom-free triplet photosensitizers (PSs). However, BODIPY dimer-based PSs generally lack target specificity, which limits their clinical use for photodynamic therapy. This study reports the synthesis of two mitochondria-targeting triphenylphosphonium (TPP)-functionalized meso-ß directly linked BODIPY dimers (BTPP and BeTPP). Both BODIPY dimers exhibited solvent-polarity-dependent singlet oxygen (1O2) quantum yields, with maximum values of 0.84 and 0.55 for BTPP and BeTPP, respectively, in tetrahydrofuran. The compact orthogonal geometry of the BODIPY dimers facilitated the generation of triplet excited states via photoinduced charge separation (CS) and subsequent spin-orbit charge-transfer intersystem crossing (SOCT-ISC) processes and their rates were dependent on the energetic configuration between the frontier molecular orbitals of the two BODIPY subunits. The as-synthesized compounds were amphiphilic and hence formed stable nanoparticles (∼36 nm in diameter) in aqueous solutions, with a zeta potential of ∼33 mV beneficial for mitochondrial targeting. In vitro experiments with MCF-7 and HeLa cancer cells indicated the effective localization of BTPP and BeTPP within cancer-cell mitochondria. Under light irradiation, BTPP and BeTPP exhibited robust photo-induced therapeutic effects in both cell lines, with half-maximal inhibitory concentration (IC50) values of ∼30 and ∼55 nM, respectively.

High-Dose Isoniazid Lacks EARLY Bactericidal Activity Against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized, Phase 2 Clinical Trial.

RATIONALE: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis (MDR-TB). However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically confer high-level resistance) is not established. OBJECTIVE: To characterize early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb. METHODS: A5312 was a Phase 2A randomized, open-label trial. Participants with tuberculosis caused by katG-mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive PK sampling was performed on day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA-mutated, and katG-mutated M.tb). EBA was determined using nonlinear mixed-effects modelling. RESULTS: Of 80 treated participants, 21 had katG-mutated M.tb. Isoniazid PK was best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived Cmax and AUC in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg∙h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal Emax relationship. Isoniazid potency against katG-mutated M.tb was approximately 10-fold lower than against inhA-mutated M.tb. The highest dose (20 mg/kg) did not demonstrate measurable EBA, except in a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. CONCLUSIONS: This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT01936831.

Particulate matter (PM10) exacerbates on MK-801-induced schizophrenia-like behaviors through the inhibition of ERK-CREB-BDNF signaling pathway.

Particulate matter (PM), released into the air by a variety of natural and human activities, is a key indicator of air pollution. Although PM is known as the extensive health hazard to affect a variety of illness, few studies have specifically investigated the effects of PM10 exposure on schizophrenic development. In the present study, we aimed to investigate the impact of PM10 on MK-801, N-methyl-D-aspartate (NMDA) receptor antagonist, induced schizophrenia-like behaviors in C57BL/6 mouse. Preadolescent mice were exposed PM10 to 3.2 mg/m3 concentration for 4 h/day for 2 weeks through a compartmentalized whole-body inhalation chamber. After PM10 exposure, we conducted behavioral tests during adolescence and adulthood to investigate longitudinal development of schizophrenia. We found that PM10 exacerbated schizophrenia-like behavior, such as psychomotor agitation, social interaction deficits and cognitive deficits at adulthood in MK-801-induced schizophrenia animal model. Furthermore, the reduced expression levels of brain-derived neurotrophic factor (BDNF) and the phosphorylation of BDNF related signaling molecules, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were exacerbated by PM10 exposure in the adult hippocampus of MK-801-treated mice. Thus, our present study demonstrates that exposure to PM10 in preadolescence exacerbates the cognitive impairment in animal model of schizophrenia, which are considered to be facilitated by the decreased level of BDNF through reduced ERK-CREB expression.

Whitening Efficacy of Toothpastes on Coffee-Stained Teeth: An Enamel Surface Analysis.

AIM: This study aimed to identify the optimal toothpaste for removing coffee-induced stains while also evaluating its impact on tooth enamel through roughness and abraded depth parameters, providing a comprehensive understanding of their effects. MATERIALS AND METHODS: Three whitening toothpastes and 2 conventional toothpastes were prepared for a simulated brushing procedure on coffee-stained bovine enamel tooth specimens. Using a toothbrushing machine, up to 10,000 brushstrokes were completed, while spectrophotometric readings were taken at designated intervals. A mixed-effects model for statistical analysis determined the effects of toothpaste and brushing on colour change, roughness, and abraded depth. RESULTS: Whitening toothpastes significantly deviated from the control (P < .001, P < .001, and P < .003, respectively), whereas the conventional toothpaste did not exhibit a significant contrast (P < .081). Regarding colour restoration following coffee staining, whitening toothpastes showed higher restoration than conventional toothpastes. Surface roughness and abraded depth parameters increased with accumulated brushing. CONCLUSIONS: Sodium hexametaphosphate-containing toothpaste demonstrated the highest efficacy in removing coffee-induced stains and restoring tooth colour. Nevertheless, this stronger whitening effect was associated with increased abrasion. While conventional toothpastes exhibited some whitening effects, the most substantial improvement in lightness was consistently observed with whitening toothpastes. CLINICAL RELEVANCE: Understanding how whitening toothpaste affects enamel integrity is crucial for refining formulations and advancing dental care. This knowledge lays the groundwork for more effective oral care products and improved whitening procedures, ultimately enhancing the overall quality of dental treatments.

The impact of the COVID-19 pandemic on the use of restraint and seclusion interventions in Ontario emergency departments: A population-based study.

While COVID-19 impacted all aspects of health care and patient treatment, particularly for patients with mental health/substance use (MH/SU) concerns, research has suggested a concerning increase in the use of restraint and seclusion (R/S) interventions, although results vary depending on facility type and patient population. Thus, the present study sought to explore COVID-related changes in the use of R/S interventions among patients presenting to Ontario emergency departments (EDs) with MH/SU complaints. To determine whether temporal and clinical factors were associated with changes in R/S use during COVID, binary logistic regression models were computed using data from the National Ambulatory Care Reporting System database. We then compared both prevalence rates and probability of an R/S event occurring during an ED visit in Ontario before and after the onset of COVID. The number of ED visits during which an R/S event occurred for patients presenting with MH/SU concerns increased by 9.5%, while their odds of an R/S event occurring during an ED visit increased by 23% in Ontario after COVID onset. Similarly, R/S event probability increased for patients presenting with MH/SU concerns after COVID onset (0.7% - 21.3% increase), particularly during the first wave, with the greatest increases observed for concerns associated with increased restraint risk pre-COVID. R/S intervention use increased substantially for patients presenting to Ontario EDs with MH/SU concerns during the first wave of COVID when the strain on healthcare system and uncertainty about the virus was arguably greatest. Patients with concerns already associated with increased R/S risk also showed the largest increases in R/S probability, suggesting increased behavioural issues during treatment among this population after COVID onset. These results have the potential to inform existing policies to mitigate risks associated with R/S intervention use during future public health emergencies and in general practice.

Artificial Synapse Based on a δ-FAPbI3/Atomic-Layer-Deposited SnO2 Bilayer Memristor.

Halide perovskite-based resistive switching memory (memristor) has potential in an artificial synapse. However, an abrupt switch behavior observed for a formamidinium lead triiodide (FAPbI3)-based memristor is undesirable for an artificial synapse. Here, we report on the δ-FAPbI3/atomic-layer-deposited (ALD)-SnO2 bilayer memristor for gradual analogue resistive switching. In comparison to a single-layer δ-FAPbI3 memristor, the heterojunction δ-FAPbI3/ALD-SnO2 bilayer effectively reduces the current level in the high-resistance state. The analog resistive switching characteristics of δ-FAPbI3/ALD-SnO2 demonstrate exceptional linearity and potentiation/depression performance, resembling an artificial synapse for neuromorphic computing. The nonlinearity of long-term potentiation and long-term depression is notably decreased from 12.26 to 0.60 and from -8.79 to -3.47, respectively. Moreover, the δ-FAPbI3/ALD-SnO2 bilayer achieves a recognition rate of ≤94.04% based on the modified National Institute of Standards and Technology database (MNIST), establishing its potential in an efficient artificial synapse.

Coffee-stained tooth enamel color restoration and surface abrasion with whitening and regular toothpaste.

PURPOSE: To evaluate the effectiveness of whitening toothpaste in restoring tooth color after coffee staining and its potential impact on enamel surfaces compared with regular toothpaste. METHODS: Bovine tooth enamel specimens were prepared and stained with coffee solutions before undergoing brushing simulation with different toothpaste slurries (whitening, regular, reference). For precise evaluation, spectrophotometric measurements were taken at intervals to assess color changes using the CIELAB (Commission Internationale de l'Éclairage Lab*) color space. Additionally, profilometric measurements were taken to determine the impact of toothpaste type on the roughness and abraded depth of the enamel surface. To understand the effects of toothpaste and brushing on color change, surface roughness, and abraded depth, while also considering correlations between these factors, the findings were analyzed using mixed-effects models. RESULTS: The whitening toothpaste group demonstrated the highest recovery rate (71%) after 10,000 brushstrokes, followed by the regular toothpaste group (48%) and the reference slurry group (43%). The mixed-effects model analysis revealed that the reference group had a smaller change in lightness (ΔL) than those in the regular toothpaste group. The whitening toothpaste group showed a greater change in lightness on average than those in the regular toothpaste group, with an increase in lightness as the number of brushstrokes increased. According to the roughness and abraded depth data, the whitening toothpaste group was least affected by brushing, while the reference and regular toothpaste groups showed higher levels of roughness and abraded depth at all intervals. CLINICAL SIGNIFICANCE: Gaining a thorough understanding of the effectiveness of whitening toothpaste and its impact on the enamel surface plays a crucial role in refining toothpaste formulations and advancing tooth whitening techniques in dental care.

The Association between High-Caffeine Drink Consumption and Anxiety in Korean Adolescents.

BACKGROUND: As excessive caffeine intake may be associated with anxiety disorders, one of the most prevalent mental illnesses among adolescents globally, this study investigated the association between high caffeine consumption and anxiety in a nationally representative sample of South Korean adolescents. METHODS: 46,873 participants from the Korea Youth Risk Behavior Web-based Survey (KYRBS) 2022 were included. The Generalized Anxiety Disorder-7 (GAD-7) questionnaire was used to evaluate anxiety symptoms. Survey questions determined the number of times each participant consumed high-caffeine drinks per week. The chi-square test was used to investigate and compare the general characteristics of the study population, and a modified Poisson regression was used to analyze the relationship. RESULTS: Both male and female participants reporting excessive high-caffeine drink consumption exhibited higher anxiety levels (adjusted prevalence ratio [aPR]: 1.19, 95% confidence interval [CI]: 1.08-1.31 in males; aPR: 1.14, CI: 1.05-1.23 in females). This association remained statistically significant in subgroup analyses, particularly among high school students and those with a shorter sleep duration. The relationship between high-caffeine drink consumption and anxiety strengthened with increasing anxiety levels. Additionally, there was a dose-dependent relationship between the prevalence of anxiety and high-caffeine drinks. CONCLUSION: High caffeine consumption increases anxiety in South Korean adolescents. This association proved consistent regardless of sex or other socioeconomic factors.

Comparison of computed tomography perfusion and magnetic resonance dynamic susceptibility contrast perfusion-weighted imaging in canine brain.

Brain perfusion allows for the evaluation of cerebral hemodynamics, particularly in brain infarcts and tumors. Computed tomography (CT) perfusion (CTP) provides reliable data; however, it has a limited scan field of view and radiation exposure. Magnetic resonance (MR) perfusion provides detailed imaging of small structures and a wide scan field of view. However, no study has compared CTP and MR perfusion and assessed the correlation between the perfusion parameters measured using CTP and MR perfusion. The aim of the present study was to assess the correlation and agreement of the cerebral perfusion derived from dynamic susceptibility contrast (DSC)-MRI and CTP in dogs. In this crossover design study, the cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time, and time to peak were measured in the temporal cerebral cortex, caudate nucleus, thalamus, piriform lobe, and hippocampus using CTP and DSC-MRI in six healthy beagle dogs and a dog with a pituitary tumor. On the color map of healthy beagles, blood vessels and the perivascular brain parenchyma appeared as red-green, indicating high perfusion, and the areas distant from the vessels appeared as green-blue, indicating low perfusion levels in CTP and DSC-MRI. CTP parameters were highest in the piriform lobe (CBF = 121.11 ± 12.78 mL/100 g/min and CBV = 8.70 ± 2.04 mL/100 g) and lowest in the thalamus (CBF = 63.75 ± 25.24 mL/100 g/min and CBV = 4.02 ± 0.55 mL/100 g). DSC-MRI parameters were also highest in the piriform lobe (CBF = 102.31 ± 14.73 mL/100 g/min and CBV = 3.17 ± 1.23 mL/100 g) and lowest in the thalamus (CBF = 37.73 ± 25.11 mL/100 g/min and CBV = 0.81 ± 0.44 mL/100 g) although there was no statistical correlation in the quantitative perfusion parameters between CTP and DSC-MRI. In a dog with a pituitary tumor, the color map of the tumor appeared as a red scale, indicating high perfusion and higher CBF and CBV on CTP (149 mL/100 g and 20 mL/100 g/min) and on DSC-MRI (116.3 mL/100 g and 15.32 mL/100 g/min) compared to those measured in healthy dogs. These findings indicate that DSC-MRI and CTP maps exhibit comparability and interchangeability in the assessment of canine brain perfusion.

Bioaccumulation and in vivo tracking of radiolabeled 4-nonylphenol in mice.

4-Nonylphenol (4NP) is concerning due to its growing presence and endocrine-disrupting nature, raising concerns about its impact on health. In this study 124I-labeled 4NP was synthesized for in vivo tracing. Positron emission tomography imaging and biodistribution studies showed significant accumulation in various tissues after oral or intraperitoneal administration, emphasizing its intricate distribution and potential long-term effects, crucial for future risk assessments.

64Cu-Labeled Boron-Containing Cyclic RGD Peptides for BNCT and PET Imaging.

The burgeoning interest in developing boron neutron capture therapy (BNCT) tracers and their accompanying diagnostics for the treatment of recalcitrant tumors has prompted this investigation. Our study aims to devise a tumor treatment strategy utilizing BNCT to target the αvß3 integrin. To this end, we propose a pioneering boron-infused cyclic Arg-Gly-Asp (RGD) peptide, cRGD(d-BPA)K, designed as an efficacious BNCT tracer. Additionally, we introduce its diagnostic complement, DOTA-cRGD(d-BPA)K, tailored for positron emission tomography (PET) to visualize αvß3 expressed tumors. Radiolabeling [64Cu]Cu-DOTA-cRGD(d-BPA)K (64Cu-1) resulted in a high radiochemical yield and purity. The radiotracer exhibited exceptional in vitro stability and demonstrated significant uptake in U87MG tumors via PET imaging. Biodistribution analysis using compound 2 showed a 7.0 ppm accumulation of boron in the U87MG tumor 1 h post-intravenous injection. Furthermore, compound 2 displayed superior tumor/blood (2.41) and tumor/muscle (2.46) ratios compared to the clinically approved l-BPA-fructose. Both compound 2 and its diagnostic counterpart 64Cu-1 hold potential for BNCT and cancer diagnosis, respectively, via molecular imaging.

Oral subacute polypropylene microplastics administration effect on potential immunotoxicity in ICR mice.

Exposure to microplastics may be associated with damage of immune system. Polypropylene microplastics (PP-MPs) with a wide range of beneficial applications have not been extensively studied with respect to the immune system. The aim of this investigation is to examine the influence of two different sizes of PP-MPs (5.2 and 23.9 µm diameter) on immune system components in ICR mice. PP-MPs were administered orally to female and male mice at 0 (corn oil vehicle), 500, 1000, or 2000 mg/kg/d for single and daily for 4-week repeated toxicity test, respectively. No significant differences were observed in number of thymic CD4+, CD8+, CD4+CD8+ T lymphocytes, splenic helper T cells, cytotoxic T cells, and B cells. The ratio of interferon-γ to interleukin-4 in culture supernatants from activated splenocytes ex vivo (48 hr) was lower in females which were repeatedly administered with PP-MPs compared to vehicle irrespective of PP-MPs size and dose. In contrast, the opposite trend was observed in males. Production of tumor necrosis factor-α was upregulated in females that were repeatedly exposed to PP-MPs. The serum IgG2a/IgG1 ratio was lowered in female receiving large-size PP-MPs. Data suggest that immune disturbances resulting in predominant type-2 helper T cell reactivity may occur in mice, especially in females, when repeatedly exposed to PP-MPs. Further investigations with longer exposure periods are necessary to determine the immunotoxicities attributed to PP-MPs.

LC3B drives transcription-associated homologous recombination via direct interaction with R-loops.

Exploring the connection between ubiquitin-like modifiers (ULMs) and the DNA damage response (DDR), we employed several advanced DNA damage and repair assay techniques and identified a crucial role for LC3B. Notably, its RNA recognition motif (RRM) plays a pivotal role in the context of transcription-associated homologous recombination (HR) repair (TA-HRR), a particular subset of HRR pathways. Surprisingly, independent of autophagy flux, LC3B interacts directly with R-loops at DNA lesions within transcriptionally active sites via its RRM, promoting TA-HRR. Using native RNA immunoprecipitation (nRIP) coupled with high-throughput sequencing (nRIP-seq), we discovered that LC3B also directly interacts with the 3'UTR AU-rich elements (AREs) of BRCA1 via its RRM, influencing its stability. This suggests that LC3B regulates TA-HRR both proximal to and distal from DNA lesions. Data from our LC3B depletion experiments showed that LC3B knockdown disrupts end-resection for TA-HRR, redirecting it towards the non-homologous end joining (NHEJ) pathway and leading to chromosomal instability, as evidenced by alterations in sister chromatid exchange (SCE) and interchromosomal fusion (ICF). Thus, our findings unveil autophagy-independent functions of LC3B in DNA damage and repair pathways, highlighting its importance. This could reshape our understanding of TA-HRR and the interaction between autophagy and DDR.

Genome-wide association analyses using machine learning-based phenotyping reveal genetic architecture of occupational creativity and overlap with psychiatric disorders.

Creativity is known to be heritable and exhibits familial aggregation with psychiatric disorders; however, the complex nature of their relationship has not been well-established. In the present study, we demonstrate that using an expanded and validated machine learning (ML)-based phenotyping of occupational creativity (OC) can allow us to further understand the trait of creativity, which was previously difficult to define and study. We conducted the largest genome-wide association study (GWAS) on OC with 241,736 participants from the UK Biobank and identified 25 lead variants that have not yet been reported and three candidate causal genes that were previously associated with educational attainment and psychiatric disorders. We found extensive genetic overlap between OC and psychiatric disorders with mixed effect direction through various post-GWAS analyses, including the bivariate causal mixture model. In addition, we discovered a strongly genetic correlation between our original GWAS and the GWAS adjusted for education years (rg = 0.95). Our GWAS analysis via ML-based phenotyping contributes to the understanding of the genetic architecture of creativity, which may inform genetic discovery and genetic prediction in human cognition and psychiatric disorders.

Shared genetic architectures of educational attainment in East Asian and European populations.

Educational attainment (EduYears), a heritable trait often used as a proxy for cognitive ability, is associated with various health and social outcomes. Previous genome-wide association studies (GWASs) on EduYears have been focused on samples of European (EUR) genetic ancestries. Here we present the first large-scale GWAS of EduYears in people of East Asian (EAS) ancestry (n = 176,400) and conduct a cross-ancestry meta-analysis with EduYears GWAS in people of EUR ancestry (n = 766,345). EduYears showed a high genetic correlation and power-adjusted transferability ratio between EAS and EUR. We also found similar functional enrichment, gene expression enrichment and cross-trait genetic correlations between two populations. Cross-ancestry fine-mapping identified refined credible sets with a higher posterior inclusion probability than single population fine-mapping. Polygenic prediction analysis in four independent EAS and EUR cohorts demonstrated transferability between populations. Our study supports the need for further research on diverse ancestries to increase our understanding of the genetic basis of educational attainment.

Piezoelectrically and Topographically Engineered Scaffolds for Accelerating Bone Regeneration.

Bone regeneration remains a critical concern across diverse medical disciplines, because it is a complex process that requires a combinatorial approach involving the integration of mechanical, electrical, and biological stimuli to emulate the native cellular microenvironment. In this context, piezoelectric scaffolds have attracted considerable interest owing to their remarkable ability to generate electric fields in response to dynamic forces. Nonetheless, the application of such scaffolds in bone tissue engineering has been limited by the lack of a scaffold that can simultaneously provide both the intricate electromechanical environment and the biocompatibility of the native bone tissue. Here, we present a pioneering biomimetic scaffold that combines the unique properties of piezoelectric and topographical enhancement with the inherent osteogenic abilities of hydroxyapatite (HAp). Notably, the novelty of this work lies in the incorporation of HAp into polyvinylidene fluoride-co-trifluoro ethylene in a freestanding form, leveraging its natural osteogenic potential within a piezoelectric framework. Through comprehensive in vitro and in vivo investigations, we demonstrate the remarkable potential of these scaffolds to accelerate bone regeneration. Moreover, we demonstrate and propose three pivotal mechanisms─(i) electrical, (ii) topographical, and (iii) paracrine─that collectively contribute to the facilitated bone healing process. Our findings present a synergistically derived biomimetic scaffold design with wide-ranging prospects for bone regeneration as well as various regenerative medicine applications.

Evaluating the agreement between different substance use recall periods in multiple HIV cohorts.

BACKGROUND: This study aims to evaluate the agreement in substance use on both binary and ordinal scales between 3-month and 6-month recall periods with samples from different communities, demographic backgrounds, and HIV status. METHODS: We administered the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) to 799 participants from three different North American cohorts focused on substance use and HIV. We conducted a within-person agreement analysis by calculating the agreement levels and Kappa statistic between data collected using the 3-month recall ASSIST and 6-month custom substance use surveys as well as different terminology for each substance in multiple cohorts. RESULTS: For all drugs studied, the agreement on the binary use or ordinal frequency of use metrics showed a high agreement level between 80.4% and 97.9% and an adequate adjusted kappa value between 0.61 and 0.96, suggesting substantial agreement. According to the agreement criteria we proposed, substance use data collected using different recall periods and with variation in drug names can be harmonized across cohorts. CONCLUSIONS: This study is the first to evaluate the feasibility of data harmonization of substance use by demonstrating high level of agreement between different recall periods in different cohorts. The results can inform data harmonization efforts in consortia where data are collected from cohorts using different questions and recall periods.

Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy.

Activation of hypoxia-inducible factor 1α (HIF1α) contributes to blood-retinal barrier (BRB) breakdown and pathological neovascularization responsible for vision loss in ischemic retinal diseases. During disease progression, mitochondrial biology is altered to adapt to the ischemic environment created by initial vascular dysfunction, but the mitochondrial adaptive mechanisms, which ultimately contribute to the pathogenesis of ischemic retinopathy, remain incompletely understood. In the present study, it is identified that expression of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) is essential for BRB breakdown and pathologic retinal neovascularization in mouse models mimicking ischemic retinopathies. Genetic Trap1 ablation or treatment with small molecule TRAP1 inhibitors, such as mitoquinone (MitoQ) and SB-U015, alleviate retinal pathologies via proteolytic HIF1α degradation, which is mediated by opening of the mitochondrial permeability transition pore and activation of calcium-dependent protease calpain-1. These findings suggest that TRAP1 can be a promising target for the development of new treatments against ischemic retinopathy, such as retinopathy of prematurity and proliferative diabetic retinopathy.