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Objective: To highlight the detection of xylazine and nitrazolam in conjunction with benzimidazole opioids (nitazenes) and other novel benzodiazepines in a cluster of patients after putative heroin use., Methods: Deidentified clinical and analytical data were gathered from patients enrolled in the Emerging Drugs Network of Australia system., Results: In December 2023, three adults presented to the ED with sedation following putative use of heroin. Toxicological analysis of blood samples identified xylazine, protonitazene, metonitazene, bromazolam and nitrazolam. Local health authorities subsequently issued an alert., Conclusion: This is the first signal of xylazine and nitrazolam use in Australia. These results demonstrate toxico-surveillance programmes with analytical confirmation of drugs are invaluable in monitoring illicit drug use., (© 2024 Australasian College for Emergency Medicine.)

Introduction: Nitazenes are a group of potent synthetic opioids that have had increasing prominence as novel psychoactive drugs in the last 5 years. We describe emergency department nitazene-related presentations., Methods: This is a prospective series of patients with analytically confirmed nitazene presentations identified by the Emerging Drugs Network of Australia and Emerging Drugs Network of Australia Victoria. Both studies' databases were searched between July 2020 and February 2024 with clinical data and blood nitazene concentrations abstracted., Results: There were 32 presentations, 23 (72%) males, with a median age of 31 years (range 18-63 years). Only five (16%) intentionally ingested a nitazene, with most (12, 38%) believing they had taken alternative opioids. Co-exposures occurred in 31 (97%), mostly metamfetamine. Naloxone was administered in 23 (72%) presentations, with a median total dose of intravenous naloxone within 1 h post hospital presentation of 400 μg (interquartile range [IQR] 160-450 μg). Four (13%) received a naloxone infusion. Thirteen (41%) were admitted to the intensive care unit. The median length of stay was 17 h (IQR 7-39 h). Protonitazene was the commonest nitazene detected in 23 (72%) presentations with a median concentration of 2.0 mg/L (range 0.7-15 mg/L). The lowest concentration of protonitazene in a patient that received naloxone was 0.7 mg/L., Discussion and Conclusions: Most patients were unaware they were using nitazenes. Given their potency, this has important implications for harm, particularly in those not intentionally using opioids. Nitazene exposure was mostly unintentional. Naloxone use was common and standard dosing regimens appeared effective in most cases., (© 2025 Australasian Professional Society on Alcohol and other Drugs.)

Retinal pigmented epithelial (RPE) cells have critical functions in the retina. These cells rely heavily on their mitochondria to generate energy, offer metabolites for biosynthesis through the TCA cycle, regulate apoptosis, and process lipids from photoreceptors. Therefore, mitochondrial damage has significant consequences for the RPE and, by proxy, photoreceptors. Researchers have identified damaged mitochondrial DNA (mtDNA) accumulation in patient samples from aged and diseased individuals. These damages include point mutations and complete deletions of mtDNA segments. The most significant observation in these studies is a positive correlation between the accumulation of damaged mtDNA with the stage of AMD rather than aging. This chapter will discuss how mitochondrial dysfunction in the RPE can drive disease pathobiology by altering their physiological functions., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Since the Voyager mission flybys in 1979, we have known the moon Io to be both volcanically active and the main source of plasma in the vast magnetosphere of Jupiter. Material lost from Io forms neutral clouds, the Io plasma torus and ultimately the extended plasma sheet. This material is supplied from Io's upper atmosphere and atmospheric loss is likely driven by plasma-interaction effects with possible contributions from thermal escape and photochemistry-driven escape. Direct volcanic escape is negligible. The supply of material to maintain the plasma torus has been estimated from various methods at roughly one ton per second. Most of the time the magnetospheric plasma environment of Io is stable on timescales from days to months. Similarly, Io's atmosphere was found to have a stable average density on the dayside, although it exhibits lateral (longitudinal and latitudinal) and temporal (both diurnal and seasonal) variations. There is a potential positive feedback in the Io torus supply: collisions of torus plasma with atmospheric neutrals are probably a significant loss process, which increases with torus density. The stability of the torus environment may be maintained by limiting mechanisms of either torus supply from Io or the loss from the torus by centrifugal interchange in the middle magnetosphere. Various observations suggest that occasionally (roughly 1 to 2 detections per decade) the plasma torus undergoes major transient changes over a period of several weeks, apparently overcoming possible stabilizing mechanisms. Such events (as well as more frequent minor changes) are commonly explained by some kind of change in volcanic activity that triggers a chain of reactions which modify the plasma torus state via a net change in supply of new mass. However, it remains unknown what kind of volcanic event (if any) can trigger events in torus and magnetosphere, whether Io's atmosphere undergoes a general change before or during such events, and what processes could enable such a change in the otherwise stable torus. Alternative explanations, which are not invoking volcanic activity, have not been put forward. We review the current knowledge on Io's volcanic activity, atmosphere, and the magnetospheric neutral and plasma environment and their roles in mass transfer from Io to the plasma torus and magnetosphere. We provide an overview of the recorded events of transient changes in the torus, address several contradictions and inconsistencies, and point out gaps in our current understanding. Lastly, we provide a list of relevant terms and their definitions., Competing Interests: Competing InterestsThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s) 2025.)

The present research examined the effects of an Early Advancement in Social-Emotional Health and Positivity (EASP) multicomponent positive psychological intervention on parents' well-being in Hong Kong. Participants were parents of young children (N = 120; M age  = 37.19 years, SD = 4.71, range = 24-53; female = 95.00%) who participated in the one-month randomized control trial. Participants were randomly assigned into the intervention (n = 50) and waitlist control groups (n = 70). Parents in the intervention group received two online workshops and an evidence-based smartphone application that targeted four positive psychological skills: (1) mindful parenting, (2) hope, (3) positive reappraisal, and (4) growth mindset. The results of the multivariate regression analysis revealed that the intervention significantly improved various dimensions of participants' positive psychological skills, subjective well-being, and psychological well-being immediately at the conclusion of the program. The findings of this study underscore the importance of the well-being payoffs linked to cultivating positive psychological skills among parents of young children., (© 2024 The Authors. Family Process published by Wiley Periodicals LLC on behalf of Family Process Institute.)

Intravenous midazolam is frequently used for procedural sedation. Use of ritonavir containing antivirals in patients requiring procedural sedation with intravenous midazolam is postulated to increase the risk or prolong the consequences of exposure related adverse events. The primary objective of this study was to characterize interaction of ritonavir with IV midazolam. The secondary objective was to define the time course over with the interaction of ritonavir with IV midazolam resolves following cessation of ritonavir. Physiologically based pharmacokinetic modeling was used to conduct clinical trials with a parallel group design defining exposure to a single 5 mg IV dose of midazolam in the presence and absence of nirmatrelvir/ritonavir dosed twice daily for 5 days. Simulations comprised 50 virtual healthy subjects aged 20 to 50 years (50% female). Based on FDA criteria, a moderate/strong interaction between nirmatrelvir/ritonavir and intravenous midazolam (area under the curve [AUC] ratio >2) was observed when intravenous midazolam was administered up to 72 h following cessation of nirmatrelvir/ritonavir. The geometric mean (90% CI) midazolam AUC ratio was 9.21 (5.44 to 16.43) when coadministered on the final day of nirmatrelvir/ritonavir dosing. Importantly, there was no change in peak exposure; the geometric mean (90% CI) midazolam maximum concentration ratio was 0.99 (0.99 to 1.00). Use of ritonavir containing antivirals is unlikely to increase a patient's risk of experiencing an exposure related adverse event following administration of intravenous midazolam but may prolong complications in patients who experience an event. A meaningful interaction persists for 72 h following cessation of nirmatrelvir/ritonavir., (© 2024, The American College of Clinical Pharmacology.)

The present study investigated the effectiveness of the Early Advancement in Social-Emotional Health and Positivity (EASP) program, a positive psychological intervention promoting preschool teachers' well-being and the motivational aspect of professional competence. Participants were 273 in-service preschool teachers (M age  = 34.56 years, SD = 9.52, range = 22-58; female = 98.90%) who participated in a 2-month randomized controlled trial. Participants were randomly assigned to the intervention group (n = 143) receiving 1) four online workshops, 2) a smartphone app, and 3) an online activity, or to the wait-list control group (n = 130), which received the intervention materials after all the data collection. Participants reported their well-being dimensions, teaching self-efficacy, and autonomous motivation for teaching before and after the intervention. Results from a path analytic model exhibited excellent fit with the data, χ2 = 37.62, df = 33, CFI = .99, TLI = .98, RMSEA = .02 [90% CI = 0.00, 0.05], SRMR = .02. The intervention had direct effects on changes in well-being dimensions, including positivity, outcome, strength, engagement, and resilience (β = .14 to .26, ps = .00 to .04), and indirect intervention effects on changes in teaching self-efficacy and autonomous motivation for teaching (β = .14 to .15, ps = .00 to .01). These findings highlighted the potential value of implementing positive psychological interventions in educational settings to promote the well-being and professional competence among preschool teachers., (© 2024 The Authors. Applied Psychology: Health and Well‐Being published by John Wiley & Sons Ltd on behalf of International Association of Applied Psychology.)

In response to the need to introduce nursing knowledge into the curriculum of nursing training institutes, the university nursing department of the Faculty of Angers has chosen a model of clinical judgment matched to nursing theories. This article describes the implementation of this project, which was carried out as part of an experiment to create a "nursing sciences" course for a health degree., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: The germline human leukocyte antigen (HLA) status has been found to be associated with immunotherapy outcomes in patients with NSCLC, but its correlation to immunotherapy-induced pneumonitis and prognostic impact in the Asian population remains largely unknown., Methods: We evaluated the HLA genotype of the germline and available tumor samples in 42 patients with programmed death-ligand 1 expression of 50% or higher undergoing pembrolizumab immunotherapy. The HLA allele expression was correlated with tumor response, disease survival, and the occurrence of pneumonitis., Results: It was observed that the germline HLA-C homozygosity and HLA-DRB1∗13 expression were related to a worse progression-free survival and treatment response. Importantly, all patients (7/7 patients) who developed pneumonitis in our cohort expressed the HLA-DPB1∗02 allele, and the incidence of pneumonitis was 31.8% (7/22 patients) in patients expressing this allele compared with 0% (0/20 patients) in those without this allele ( p  = 0.009). Investigation of the tumor samples from 15 patients revealed some degree of HLA loss in the HLA class I loci in 40% (6/15) of patients, and no significant difference in tumor mutation burden was found among patients with different treatment responses., Conclusion: Taken together, this study evaluated the impact of HLA status in both germline and tumor samples in patients with NSCLC with high programmed death-ligand 1 expression, and the high incidence of immunotherapy-induced pneumonitis in patients expressing the HLA-DPB1∗02 allele may suggest a routine HLA typing and closer monitoring in this patient subset., Competing Interests: Dr. Mok reports receiving fees for serving on advisory boards and consulting, and speakers fees and institutional grants and research support from 10.13039/100008021Bristol Myers Squibb, 10.13039/100009947Merck Sharp & Dohme, 10.13039/100004336Novartis, 10.13039/100004319Pfizer; has received fees for serving on advisory boards and consulting and speakers fees from ACEA Pharma, Amgen, Boehringer lngelheim Pharmaceuticals, Inc., Daiichi Sankyo, Inc., Fishawack Facilitate, Ltd., Lilly, OrigiMed Co. Ltd., Sanofi-Aventis; owns stock and has received fees for serving on advisory boards and board of directors and leadership roles from HutchMed; institutional grants and research support and fees for serving on advisory boards and consulting from Merck Serono and SFJ Pharmaceutical Ltd.; has received fees for serving on advisory boards, board of directors and leadership roles and consulting from Lunit, Inc. fees for serving on advisory boards and for consulting from AbbVie Inc., BerryOncology, Blueprint Medicines Corporation, C4 Therapeutics, Inc, CStone Pharmaceuticals, Curio Science, Eisai, Gilead Sciences, Inc., Gritstone Oncology,Inc., Guardant Health, Hengrui Therapeutics Inc., IQVIA, Janssen, lgnyta, Inc., lncyte Corporation, lnivata, Loxo Oncology Inc., Mirati Therapeutics Inc., Puma Biotechnology Inc., Vertex Pharmaceuticals, Yuhan Corporation; has received speakers fees and fees for consulting from Alpha Biopharma Co., Ltd., Amoy Diagnostics Co., Ltd., AstraZeneca (before January 1, 2019), BeiGene; has received fees for serving on advisory boards and institutional grants and research support from 10.13039/100004325AstraZeneca, Gl Therapeutics, Inc., Takeda; institutional grants and research support from 10.13039/100004337Roche, XCovery; has received speakers fees from Daz Group, InMed Medical Communication, Janssen Pharmaceutica NV, Liangyihui Network Technology Co., Ltd., Lucence Health Inc., MD Health Brazil, Medscape LLC, Merck Pharmaceuticals HK Ltd., P. Permanyer SL, PeerVoice, Physicians’ Education Resource, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostic/Foundation One, Shanghai BeBirds Translation and Consulting Co., Ltd., Taiho, Takeda Oncology, touchIME; has received fees for consulting from Elevation Oncology, MoreHealth, Qiming Development (HK) Ltd., Roche Pharmaceuticals, Takeda Pharmaceuticals HK Ltd.; has received fees for serving on advisory boards for Roche/Genentech and Virtus Medical Group; has received fees for a board of directors/leadership role with AstraZeneca PLC; discloses serving on advisory boards (uncompensated) for geneDecode Co., Ltd.; owns stock from Act Genomics-Sanomics Group and Aurora Tele-Oncology Ltd.; declares uncompensated board of directors/leadership roles with the American Society of Clinical Oncology, Asian Thoracic Oncology Research Group, Chinese Lung Cancer Research Foundation Limited, Chinese Society of Clinical Oncology, Hong Kong Cancer Fund, Hong Kong Cancer Therapy Society, International Association for the Study of Lung Cancer (ending April 30, 2019). Dr. Cheng reported serving as an advisory committee member for Merck Sharp & Dohme, AstraZeneca, Eisai, and Ipsen. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Objectives: Antivenoms are important emergency medications to be held within Australia, particularly in regional and remote locations. We audited current antivenom holdings in hospitals and health services across South Australia (SA) and compared to recommendations in the 'Snakebite and Spiderbite Management Guidelines' from the State's Toxinology service. The process also assessed the feasibility of 'real-time' remote stock monitoring., Methods: Fifty-three sites listed in the guideline were recommended to hold antivenom, though only 49 are currently operational. Interrogation of antivenom stock for 29 sites was possible using electronic reports generated from the State Pharmacy database. The 20 remaining centres had their stock levels confirmed by calling the centres directly. Data obtained were then compared to recommended levels of antivenom holdings in the guideline with discrepancies and associated costs documented. A separate report verification process was used to determine 'real-time' accuracy of the electronic reports., Results: Thirty-seven sites (75%) held more than the recommended number of antivenom vials, totalling 129 vials in excess with an approximate total cost of $110 000. Twelve sites (24%) held inadequate stock to deliver a treatment dose for 19 envenoming events. The report verification revealed variances in the electronic reports., Conclusions: This audit has demonstrated a significant disparity between recommended and actual antivenom holdings across most sites in SA and has also revealed that 'real-time' remote monitoring of state antivenom holdings is not currently feasible. Correction of stock levels to that recommended may result in financial benefit for State Health while also addressing inequity in regional and remote healthcare provision., (© 2024 Australasian College for Emergency Medicine.)

This study explores the efficacy of the Early Advancement in Social-Emotional Health and Positivity (EASP) programme, designed to enhance personal resources, namely self-compassion and positivity among preschool social workers, to reduce stress and bolster work engagement. A total of 84 preschool social workers (M age  = 32.47 years, SD = 6.86, range = 22-55; female = 90.48%) participated in a 5-week randomized control trial. Participants were randomly allocated to either the intervention group (n = 38), which received four online workshops and an online activity, or the wait-list control group (n = 46), which received the intervention post-data collection. Self-compassion, positivity, work engagement, and work stress were measured before and after the intervention. Results from a path analytic model indicated excellent fit with the data, χ2 = 2.08, df = 3, Comparative Fit Index = 1.00, Tucker-Lewis Index = 1.00, Root Mean Square Error of Approximation = 0.00 (90% CI = 0.00-0.16), SRMR = 0.03. The intervention demonstrated direct effects on changes in self-compassion (β = 0.21, p = 0.04) and positivity (β = 0.28, p = 0.03), with indirect effects on work engagement (β = 0.13, p = 0.02), while no significant impact was observed on work stress (β = -0.09, p = 0.06). These findings underscore the efficacy of positive psychological interventions in fostering work engagement among social workers. Incorporating the EASP programme into ongoing professional development activities is recommended to enhance the job engagement and psychological well-being of social workers in early childhood education and care sectors., (© 2024 The Author(s). Stress and Health published by John Wiley & Sons Ltd.)

The purpose of this study was to determine the effect of hydration status on the change in sweat sodium (Na + ), chloride (Cl - ), and potassium (K + ) concentrations during exercise-heat stress. Fifteen subjects (Six female, nine male; 29 ± 9 y; 71 ± 14 kg) completed 90 min of cycling (81% HR max ) in the heat (~33°C, 42% rh) with fluid replacement to maintain euhydration (EUH) or without fluid to dehydrate to 2.4 ± 0.4% body mass loss (DEH). Sweat was collected from the forehead (FH), right scapula (SCAP), and left (LVFA) and right (RVFA) ventral forearms using the absorbent pad technique at the beginning (0-30 min) and end of exercise (60-90 min). Sweat was analyzed for Na + , Cl - , and K + concentrations using ion chromatography. Data are reported as mean ± SD or median ± IQR. There were no differences (Paired t-tests or Wilcoxon signed-rank tests) between EUH and DEH in the change in sweat Na + (FH: 24.3 ± 21.5 vs. 30.8 ± 22.4 mmol/L; SCAP: 9.7 ± 6.2 vs. 9.6 ± 8.2 mmol/L; LVFA: 7.5 ± 6.0 vs. 5.6 ± 5.9 mmol/L; RVFA: 8.2 ± 8.6 vs. 7.8 ± 5.2 mmol/L), sweat Cl - , or sweat K + at any site (p = 0.07-0.99). The change in sweat electrolyte concentrations during 90 min of exercise in the heat was not significantly influenced by mild dehydration in recreational to moderately-trained male and female athletes., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The epidemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has had a significant global impact, especially on immunosuppressed populations such as heart transplant recipients. While SARS-CoV-2 initially infects the respiratory system, cardiovascular complications induced by coronavirus disease 2019 (COVID-19) include cardiac arrest, myocardial infarction, heart failure, myocarditis, arrhythmia, acute myocyte injury, thrombotic events, and cardiogenic shock. Here, we present a case of a 45-year-old African American male who tested positive for COVID-19 infection six months after receiving a heart transplant. The patient was asymptomatic initially, but two weeks later he developed dyspnea, early satiety, and abdominal bloating. The patient was admitted to the hospital for acute renal failure and subsequently diagnosed with moderate acute T cell-mediated allograft rejection (Grade 2R) by endomyocardial biopsy. Three months after testing positive for COVID-19, the patient suffered a sudden cardiac death. At autopsy, the epicardium was diffusely edematous and showed vascular congestion. The coronary arteries showed a striking concentric narrowing of lumens and diffusely thickened arterial walls of all major extramural arteries deemed consistent with a rapidly progressive form of cardiac allograft vasculopathy (CAV). SARS-CoV-2 nucleocapsid protein was localized by immunohistochemistry (IHC) in endothelial cells of venules and capillaries within the epicardium. Our localization of SARS-CoV-2 in coronary vessel endothelial cells by IHC suggests that endothelial cell infection, endotheliitis, and immune-related inflammation may be a primary mechanism of vascular injury. The present case represents an early onset rapidly progressive form of CAV. This case may be the first case of post-transplant arteriopathy occurring in such a short time that includes corresponding autopsy, surgical pathology, and IHC data., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Several blinding diseases affecting the retina and optic nerve are exacerbated by or caused by dysregulated inflammation and oxidative stress. These diseases include uveitis, age related macular degeneration, diabetic retinopathy and glaucoma. Consequently, despite their divergent symptoms, treatments that reduce oxidative stress and suppress inflammation may be therapeutic. The production of inflammatory cytokines and their activities are regulated by a class of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS1 and SOCS3 are known to dampen signaling via pathways employing Janus kinases and signal transducer and activator of transcription proteins (JAK/STAT), Toll-like Receptors (TLR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen activated kinase (MAPK) and NLR family pyrin domain containing 3 (NLRP3). We have developed cell-penetrating peptides from the kinase inhibitory region of the SOCS1 and SOCS3 (denoted as R9-SOCS1-KIR and R9-SOCS3-KIR) and tested them in retinal pigment epithelium (RPE) cells and in macrophage cell lines. SOCS-KIR peptides exhibited anti-inflammatory, anti-oxidant and anti-angiogenic properties. In cell culture, both Th1 and Th17 cells were suppressed together with the inhibition of other inflammatory markers. We also observed a decrease in oxidants and a simultaneous rise in neuroprotective and anti-oxidant effectors. In addition, treatment prevented the loss of gap junction proteins and the ensuing drop in transepithelial electrical resistance in RPE cells. When tested in mouse models by eye drop instillation, they showed protection against autoimmune uveitis, as a prophylactic as well as a therapeutic. Mice with endotoxin-induced uveitis were protected by eye drop administration as well. R9-SOCS3-KIR was particularly effective against the pathways acting through STAT3, e.g. IL-6 and VEGF-A mediated responses that lead to macular degeneration. Eye drop administration of R9-SOCS3-KIR stimulated production of antioxidant effectors and reduced clinical symptoms in mouse model of oxidative stress that replicates the RPE injury occurring in AMD. Because these peptides suppress multiple pathogenic stimuli and because they can be delivered topically to the cornea, they are attractive candidates for therapeutics for uveitis, macular degeneration, diabetic retinopathy and glaucoma., Competing Interests: CA and HJ are listed as inventors in a patent held by the University of Florida for the technology involving R9-SOCS3-KIR peptide. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ahmed, Johnson and Lewin.)

MYCN oncogene amplification is frequently observed in aggressive childhood neuroblastoma. Using an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice, we identify a single germline point mutation in the transcriptional corepressor Runx1t1, which abolishes MYCN-driven tumorigenesis. This loss-of-function mutation disrupts a highly conserved zinc finger domain within Runx1t1. Deletion of one Runx1t1 allele in an independent Runx1t1 knockout mouse model is also sufficient to prevent MYCN-driven neuroblastoma development, and reverse ganglia hyperplasia, a known pre-requisite for tumorigenesis. Silencing RUNX1T1 in human neuroblastoma cells decreases colony formation in vitro, and inhibits tumor growth in vivo. Moreover, RUNX1T1 knockdown inhibits the viability of PAX3-FOXO1 fusion-driven rhabdomyosarcoma and MYC-driven small cell lung cancer cells. Despite the role of Runx1t1 in MYCN-driven tumorigenesis neither gene directly regulates the other. We show RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex recruited by HAND2 to enhancer regions to regulate chromatin accessibility and cell-fate pathway genes., (© 2024. The Author(s).)

Seismic observations of impacts on Mars indicate a higher impact flux than previously measured. Using six confirmed seismic impact detections near the NASA InSight lander and two distant large impacts, we calculate appropriate scalings to compare these rates with lunar-based chronology models. We also update the impact rate from orbital observations using the most recent catalog of new craters on Mars. The snapshot of the current impact rate at Mars recorded seismically is higher than that found using orbital detections alone. The measured rates differ between a factor of 2 and 10, depending on the diameter, although the sample size of seismically detected impacts is small. The close timing of the two largest new impacts found on Mars in the past few decades indicates either a heightened impact rate or a low-probability temporal coincidence, perhaps representing recent fragmentation of a parent body. We conclude that seismic methods of detecting current impacts offer a more complete dataset than orbital imaging.

The present study aims to (1) identify the profiles of subjective well-being (SWB) and psychological well-being (PWB) in a sample of pre-service teachers during the second wave of the COVID-19 pandemic in Hong Kong, and (2) explore how different profiles are linked with teachers' self-efficacy. Participants were 291 pre-service teachers ( M age = 21.295, SD = 2.812, female = 89.903%) who were invited to complete self-report measures of SWB, PWB, and teachers' self-efficacy. Latent profile analysis with maximum likelihood estimation was conducted to identify well-being profiles that emerged in this sample. The results suggested a 3-class model with a high, moderate, and low well-being group. The findings also revealed that the pre-service teachers' well-being profiles as reflected by SWB and PWB indicators were consistent. Moreover, the pre-service teachers in the higher well-being group reported higher teaching self-efficacy than those in the lower well-being group. Findings highlighted the benefits of supporting pre-service teachers' well-being (i.e., SWB and PWB) to maintain their teachers' self-efficacy during the COVID-19 pandemic when teacher education and practicum are significantly disrupted. Interventions targeting various positive psychological skills (e.g., mindfulness, self-compassion, and positive reappraisal) are warranted. Future investigation is needed to examine the longitudinal relationship between pre-service teachers' well-being and self-efficacy., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This study aimed to develop and validate a new measurement tool, the Rehabilitation Adherence Inventory (RAI), to measure patients' rehabilitation adherence. We recruited 236 patients with anterior cruciate ligament (ACL) ruptures from the United Kingdom (Mage = 33.58 ± 10.03, range = 18 to 59; female = 46.2%). Participants completed a survey, that measured their rehabilitation adherence, rehabilitation volume, psychological needs support, autonomous motivation, and intention at baseline, and at the 2nd and 4th month. Factorial, convergent, discriminant, concurrent, predictive, ecological validity and test-retest reliability of the RAI were tested via exploratory factor analysis (EFA), confirmatory factor analysis (CFA), and structural equation modelling (SEM). All the EFAs, CFAs, and SEMs yielded acceptable to excellent goodness-of-fit, χ2 = 10.51 to 224.12, df = 9 to 161, CFI > 0.95, TLI > 0.95, RMSEA <0.09 [90%C I < 0.06 to 0.12], SRMR <0.04. Results fully supported the RAI's factorial, convergent, discriminant, and ecological validity, and test-retest reliability. The concurrent and predictive validity of the RAI was only partially supported because the RAI scores at baseline was positively associated with rehabilitation frequency at all time points ( r  = 0.34 to 0.38, p  < 0.001), but its corresponding associations with rehabilitation duration were not statistically significant ( p  = 0.07 to 0.93). Overall, our findings suggest that this six-item RAI is a reliable and valid tool for evaluating patients' rehabilitation adherence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lee, Xu, Yung, Ong, Chan, Chung and Chan.)

Dysbiosis of the human oral microbiota has been reported to be associated with oral cavity squamous cell carcinoma (OSCC) while the host-microbiota interactions with respect to the potential impact of pathogenic bacteria on host genomic and epigenomic abnormalities remain poorly studied. In this study, the mucosal bacterial community, host genome-wide transcriptome and DNA CpG methylation were simultaneously profiled in tumors and their adjacent normal tissues of OSCC patients. Significant enrichment in the relative abundance of seven bacteria species (Fusobacterium nucleatum, Treponema medium, Peptostreptococcus stomatis, Gemella morbillorum, Catonella morbi, Peptoanaerobacter yurli and Peptococcus simiae) were observed in OSCC tumor microenvironment. These tumor-enriched bacteria formed 254 positive correlations with 206 up-regulated host genes, mainly involving signaling pathways related to cell adhesion, migration and proliferation. Integrative analysis of bacteria-transcriptome and bacteria-methylation correlations identified at least 20 dysregulated host genes with inverted CpG methylation in their promoter regions associated with enrichment of bacterial pathogens, implying a potential of pathogenic bacteria to regulate gene expression, in part, through epigenetic alterations. An in vitro model further confirmed that Fusobacterium nucleatum might contribute to cellular invasion via crosstalk with E-cadherin/β-catenin signaling, TNFα/NF-κB pathway and extracellular matrix remodeling by up-regulating SNAI2 gene, a key transcription factor of epithelial-mesenchymal transition (EMT). Our work using multi-omics approaches explored complex host-microbiota interactions and provided important insights into genetic and functional basis in OSCC tumorigenesis, which may serve as a precursor for hypothesis-driven study to better understand the causational relationship of pathogenic bacteria in this deadly cancer., (© 2024. The Author(s).)

Competing Interests: There are no conflicts of interest.

This study investigated the cross-sectional relationships between reading-related affective and cognitive factors and reading skills among adolescents with and without dyslexia. Participants were 120 Chinese-speaking eighth graders, including 60 adolescents with dyslexia and 60 typically developing adolescents from Hong Kong, China. Adolescents completed questionnaires on general anxiety, reading anxiety, and reading self-concept. They were also assessed on measures of rapid digit naming, verbal working memory, word reading, reading fluency, and reading comprehension. The results showed that readers with dyslexia reported higher levels of general anxiety and reading anxiety and lower levels of reading self-concept than typical readers. They also showed difficulties in rapid digit naming and verbal working memory. Importantly, controlling for rapid digit naming and verbal working memory, reading self-concept was uniquely associated with word reading and reading fluency for readers with and without dyslexia. Furthermore, reading anxiety and reading self-concept were uniquely associated with reading comprehension for the two groups of readers. The findings point to the importance of considering affective factors when examining the reading skills of Chinese readers and the utility of targeting these factors when supporting the learning of adolescents with and without dyslexia., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Inflammation and oxidative stress contribute to age-related macular degeneration (AMD) and other retinal diseases. We tested a cell-penetrating peptide from the kinase inhibitory region of an intracellular checkpoint inhibitor suppressor of cytokine signaling 3 (R9-SOCS3-KIR) peptide for its ability to blunt the inflammatory or oxidative pathways leading to AMD., Methods: We used anaphylatoxin C5a to mimic the effect of activated complement, lipopolysaccharide (LPS), and tumor necrosis factor alpha (TNFα) to stimulate inflammation and paraquat to induce mitochondrial oxidative stress. We used a human retinal pigment epithelium (RPE) cell line (ARPE-19) as proliferating cells and a mouse macrophage cell line (J774A.1) to follow cell propagation using microscopy or cell titer assays. We evaluated inflammatory pathways by monitoring the nuclear translocation of NF-κB p65 and mitogen-activated protein kinase p38. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used to evaluate the induction of inflammatory markers. In differentiated ARPE-19 monolayers, we evaluated the integrity of tight junction proteins through microscopy and the measurement of transepithelial electrical resistance (TEER). We used intraperitoneal injection of sodium iodate in mice to test the ability of R9-SOC3-KIR to prevent RPE and retinal injury, as assessed by fundoscopy, optical coherence tomography, and histology., Results: R9-SOCS3-KIR treatment suppressed C5a-induced nuclear translocation of the NF-kB activation domain p65 in undifferentiated ARPE-19 cells. TNF-mediated damage to tight junction proteins in RPE, and the loss of TEER was prevented in the presence of R9-SOCS3-KIR. Treatment with the R9-SOCS3-KIR peptide blocked the C5a-induced expression of inflammatory genes. The R9-SOCS3-KIR treatment also blocked the LPS-induced expression of interleukin-6, MCP1, cyclooxygenase 2, and interleukin-1 beta. R9-SOCS3-KIR prevented paraquat-mediated cell death and enhanced the levels of antioxidant effectors. Daily eye drop treatment with R9-SOCS3-KIR protected against retinal injury caused by i.p. administration of sodium iodate., Conclusions: R9-SOCS3-KIR blocks the induction of inflammatory signaling in cell culture and reduces retinal damage in a widely used RPE/retinal oxidative injury model. As this peptide can be administered through corneal instillation, this treatment may offer a convenient way to slow down the progression of ocular diseases arising from inflammation and chronic oxidative stress., (Copyright © 2023 Molecular Vision.)

Chronic oxidative stress impairs the normal functioning of the retinal pigment epithelium (RPE), leading to atrophy of this cell layer in cases of advance age-related macular degeneration (AMD). The purpose of our study was to determine if buspirone, a partial serotonin 1A (5-HT1A) receptor agonist, protected against oxidative stress-induced changes in the RPE. We exposed differentiated human ARPE-19 cells to paraquat to induce oxidative damage in culture, and utilized a mouse model with sodium iodate (NaIO 3 )-induced oxidative injury to evaluate the effect of buspirone. To investigate buspirone's effect on protective gene expression, we performed RT-PCR. Cellular toxicities and junctional abnormalities due to paraquat induction in ARPE-19 cells and buspirone's impact were assessed via WST-1 assays and ZO-1 immunostaining. We used spectral-domain optical coherence tomography (SD-OCT) and ZO-1 immunostaining of RPE/choroid for structural analysis. WST-1 assays showed dose-dependent protection of viability in buspirone-treated ARPE-19 cells in culture and preservation of RPE junctional integrity under oxidative stress conditions. In the NaIO 3 model, daily intraperitoneal injection (i.p.) of buspirone (30 mg/kg) for 12 days improved the survival of photoreceptors compared to those of vehicle-treated eyes. ZO-1-stained RPE flat-mounts revealed the structural preservation of RPE from oxidative damage in buspirone-treated mice, as well as in buspirone-induced Nqo1 , Cat , Sqstm1 , Gstm1 , and Sod2 genes in the RPE/choroid compared to untreated eyes. Since oxidative stress is implicated in the pathogenesis AMD, repurposing buspirone, which is currently approved for the treatment of anxiety, might be useful in treating or preventing dry AMD.

Background: Cancer-associated fibroblasts (CAFs), integral to the tumour microenvironment, are pivotal in cancer progression, exhibiting either pro-tumourigenic or anti-tumourigenic functions. Their inherent phenotypic and functional diversity allows for the subdivision of CAFs into various subpopulations. While several classification systems have been suggested for different cancer types, a unified molecular classification of CAFs on a single-cell pan-cancer scale has yet to be established., Methods: We employed a comprehensive single-cell transcriptomic atlas encompassing 12 solid tumour types. Our objective was to establish a novel molecular classification and to elucidate the evolutionary trajectories of CAFs. We investigated the functional profiles of each CAF subtype using Single-Cell Regulatory Network Inference and Clustering and single-cell gene set enrichment analysis. The clinical relevance of these subtypes was assessed through survival curve analysis. Concurrently, we employed multiplex immunofluorescence staining on tumour tissues to determine the dynamic changes of CAF subtypes across different tumour stages. Additionally, we identified the small molecule procyanidin C1 (PCC1) as a target for matrix-producing CAF (matCAF) using molecular docking techniques and further validated these findings through in vitro and in vivo experiments., Results: In our investigation of solid tumours, we identified four molecular clusters of CAFs: progenitor CAF (proCAF), inflammatory CAF (iCAF), myofibroblastic CAF (myCAF) and matCAF, each characterised by distinct molecular traits. This classification was consistently applicable across all nine studied solid tumour types. These CAF subtypes displayed unique evolutionary pathways, functional roles and clinical relevance in various solid tumours. Notably, the matCAF subtype was associated with poorer prognoses in several cancer types. The targeting of matCAF using the identified small molecule, PCC1, demonstrated promising antitumour activity., Conclusions: Collectively, the various subtypes of CAFs, particularly matCAF, are crucial in the initiation and progression of cancer. Focusing therapeutic strategies on targeting matCAF in solid tumours holds significant potential for cancer treatment., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Objective: Aluminum phosphide (ALP) and zinc phosphide (ZnP) are toxic agrochemical pesticides, which are commonly used as an agent of self-harm in developing countries. Because of high toxicity of phosphides, we evaluated toxico-epidemiology ALP and ZnP poisoning in with respect to outcome., Methods: We performed a cross-sectional study with retrospective chart review including the records for patients admitted due to phosphide poisoning (ALP, ZnP) in a poisoning referral center in Khorshid Hospital, affiliated with Isfahan University of Medial Sciences, Isfahan, Iran. Demographic characteristics, clinical manifestations, outcome (survived or death), and length of hospital stay for the patients were recorded in a data collecting form. Binary backward stepwise logistic regression was used for outcome prediction., Findings: Sixty patients were evaluated in the study. The mean age of patients was 27.61. Thirty-nine patients were men. 96.7% of the patients ingested it intentionally. Most of the patients on admission were conscious (66.7%). Abnormality of EKG was noted in 8.3%. The mortality in ALP and ZnP poisoning was 39.2% and 22.2%, respectively. Serum bicarbonate and base excess in the venous blood gas analysis, systolic blood pressure, and serum sodium level were significantly different between patients with ALP and ZnP poisoning on admission time ( P < 0.05). On admission, systolic blood pressure was an important predictive factor for mortality (odds ratio 4.87; 95% confidence interval: 1.5-15.45; P = 0.007)., Conclusion: The rate of mortality in phosphide poisoning is high. Knowing predictive factors for mortality help physicians for selecting patients in intensive care unit admission and aggressive treatment., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Research in Pharmacy Practice.)

Effective teacher training programs entail cultivating not only professional teaching competencies but also promoting psychological strengths. However, there is a lack of investigation into how different modes of delivering psychological interventions influence well-being outcomes in the teaching profession, such as preschool educators. This study examines the effects of different technologically driven modes of implementing a PROSPER-based psychological intervention on positivity, relationship, outcome, strengths, purpose, engagement, and resilience. One hundred twenty-eight pre-service preschool teachers were randomly assigned to (1) the full intervention (i.e., online workshop and smartphone app); (2) the online workshop; (3) the smartphone app; and (4) the wait-list control group. The results demonstrated that the online workshop mode yielded the strongest intervention effects on well-being outcomes: positivity, purpose, engagement, and resilience. Although the smartphone app mode did not significantly improve psychological outcomes, combining this approach with the online workshop format appeared to have positive retention effects on positivity at the Time 3 follow-up. The findings suggest that the traditional mode of implementing positive psychological interventions could be more effective than the smartphone app-based mode in bolstering pre-service teachers' well-being., (© 2023 International Association of Applied Psychology.)

Rationale: Patients with anterior cruciate ligament (ACL) reconstruction often have poor adherence to post-surgery rehabilitation., Objective: This study applied the integrated model of self-determination theory and the theory of planned behavior to examine the effects of a smartphone-delivered intervention on the recovery outcomes of patients with an ACL rupture during post-surgery rehabilitation period. Additionally, we explored the effects of the intervention on participants with different beliefs toward rehabilitation at baseline., Methods: The randomized control trial recruited 96 eligible participants (M age = 27.82 years, SD = 8.73; female = 39%) who underwent ACL reconstruction surgery. Participants were randomly assigned to an intervention group (n = 41), which received standard post-surgical treatment (usual-care) and smartphone application ("ACL-Well"), or a usual-care control group (n = 55). The primary outcomes were recovery outcomes from ACL surgery measured by knee muscle strength and laxity, and subjective knee evaluation completed 4-month post-intervention. Secondary outcomes were the psychological and behavioral outcomes measured at baseline, at 2- and 4-month post-intervention., Results: ANCOVA indicated no significant between-group differences in primary outcomes: knee muscle strength, knee laxity and subjective knee evaluation, Fs(1, 27 to 55) = 0.01 to 1.36, p = .25 to .99, η2 = 0.01 to 0.03. For the secondary outcomes, growth mixture modelling revealed self-determined treatment motivation declined significantly over the intervention period in the control group (M slope = -0.39 to -0.12, p = .01 to .04), but not in the intervention group (M slope = -0.19 to -0.08, p = .06 to .38)., Conclusions: The smartphone application fell short in promoting orthopedic outpatients' recovery outcomes. Yet, it shows some promises as a mean to maintain patients' motivation and adherence to treatment., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: The epidemiology of invasive non-typhoidal Salmonella (iNTS) in the Philippines is not well elaborated. The present study describes the serotype distribution and antimicrobial susceptibility patterns of iNTS in the Philippines from 2014 to 2018., Methods: Invasive NTS isolates were collected through the Department of Health's Antimicrobial Resistance Surveillance Program (ARSP). The identification of the isolates was confirmed using automated (Vitek®, bioMérieux, Marcy l'Étoile, France) and conventional methods. The isolates were serotyped using the slide agglutination method, and susceptibility testing was performed using Clinical and Laboratory Standards Institute guidelines. Demographic data were collected from the ARSP database., Results: There were 138 isolates collected from human invasive specimens with 97.8% from blood samples. The most common serotypes were Salmonella Enteritidis ( n  = 84, 60.9%) and Salmonella Typhimurium ( n  = 18, 13.0%). Most of the isolates were from males ( n  = 88, 63.8%) and from the 0-5-year age group ( n  = 61, 44.2%). The proportions of iNTS isolates resistant to first-line antibiotics were as follows: ampicillin (23.2%), chloramphenicol (9.6%), ciprofloxacin (8.7%), ceftriaxone (2.2%) and trimethoprim-sulfamethoxazole (8.8%). The proportion of isolates with multidrug resistance was 13.0% (18/138) with the most common resistance profile being resistance to ampicillin-chloramphenicol-ciprofloxacin from Salmonella Enteritidis isolates ( n  = 5)., Discussion: Resistance to first-line antibiotics limits the therapeutic choices for Salmonella infection. Relevant local antimicrobial resistance data on iNTS may support appropriate empiric therapy among vulnerable populations., Competing Interests: The authors have no conflicts of interest to declare., ((c) 2023 The authors; licensee World Health Organization.)

For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed in vitro screening of 125 patient-derived samples against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in NTRK, BRAF, and ALK and responses to matching targeted drugs. The in vitro results were further validated in patient-derived xenograft models in vivo and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers., Significance: Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers., (©2023 The Authors; Published by the American Association for Cancer Research.)

Rehydration is important for athlete performance and recovery. However, it can be challenging to follow appropriate fluid replacement practices due in part to difficulties in tracking fluid intake in real time. The purpose of this study was to determine the accuracy of a smart bottle in measuring fluid intake during exercise. Thirty male American football athletes drank from bottles equipped with a smart cap during outdoor pre-season practices (110 ± 30 min; 29.3 ± 3.0 °C; 75 ± 11% rh). The cap technology included optical sensors, microprocessors, batteries, and wireless connectivity that transmitted fluid volume data to a smartphone application in real-time. Reference measurements of fluid intake from the smart bottle were determined by gravimetry followed by conversion to volume using the density of the fluid consumed. There was no significant mean difference in fluid intake between the smart bottle and reference method (1220 ± 371 ml vs. 1236 ± 389 ml, p = 0.39 paired t test). Bland-Altman 95% limits of agreement between methods was - 212 to 180 ml. The smart bottle provided accurate measurements of fluid intake during exercise in real-world field conditions on a group level and within limits of agreement of - 212 to 180 ml (or approximately ± 15% of overall fluid intake) on an individual level., (© 2023. The Author(s).)

This two-wave prospective study applied the Social Influence in Sport Model to investigate whether the social influences of parents, physical education (PE) teachers, and peers were predictive of students' intention to engage in leisure-time physical activity (PA). Participants were 2,484 secondary school students (11-18 years old) who completed a questionnaire assessing positive influence, punishment, and dysfunction from the three social agents (parents, PE teachers, and peers) at baseline, and PA intention at a 1-month follow-up. Structural equation modelling (SEM) yielded excellent goodness-of-fit and consistent pathways between the three social agents. Students' leisure-time PA intention (R 2  = .103 to 0.112) was positively associated with positive influence (β = .223 to 0.236, p < .001) and punishment (β = .214 to 0.256, p < .01), and negatively associated with dysfunction (β = - 0.281 to -.335, p < .001). Multi-group SEM showed that the predictions were invariant between parents, PE teachers, and peers. Furthermore, no significant differences in students' gender were found between perceived social influence and PA intention. The findings supported the application of the Social Influence in Sport Model in explaining the role of significant others on students' intention to take part in leisure-time PA., (© 2023 The Society of Chinese Scholars on Exercise Physiology and Fitness. Published by Elsevier (Singapore) Pte Ltd.)

Adipose browning has demonstrated therapeutic potentials in several diseases. Here, by conducting transcriptomic profiling at the single-cell and single-nucleus resolution, we reconstituted the cellular atlas in mouse inguinal subcutaneous white adipose tissue (iWAT) at thermoneutrality or chronic cold condition. All major nonimmune cells within the iWAT, including adipose stem and progenitor cells (ASPCs), mature adipocytes, endothelial cells, Schwann cells, and smooth muscle cells, were recovered, allowing us to uncover an overall and detailed blueprint for transcriptomes and intercellular cross-talks and the dynamics during white adipose tissue brown remodeling. Our findings also unravel the existence of subpopulations in mature adipocytes, ASPCs, and endothelial cells, as well as new insights on their interconversion and reprogramming in response to cold. The adipocyte subpopulation competent of major histocompatibility complex class II (MHCII) antigen presentation is potentiated. Furthermore, a subcluster of ASPC with CD74 expression was identified as the precursor of this MHCII + adipocyte. Beige adipocytes are transdifferented from preexisting lipid generating adipocytes, which exhibit developmental trajectory from de novo differentiation of amphiregulin cells (Aregs). Two distinct immune-like endothelial subpopulations are present in iWAT and are responsive to cold. Our data reveal fundamental changes during cold-evoked adipose browning., (Copyright © 2023 Qing Liu et al.)

Autosomal dominant retinitis pigmentosa (adRP) is frequently caused by mutations in RHO, the gene for rhodopsin. In previous experiments in dogs with the T4R mutation in RHO, an AAV2/5 vector expressing an shRNA directed to human and dog RHO mRNA and an shRNA-resistant human RHO cDNA (AAV-RHO820-shRNA820) prevented retinal degeneration for more than eight months following injection. It is crucial, however, to determine if this RNA replacement vector acts in a mutation-independent and species-independent manner. We, therefore, injected mice transgenic for human P23H RHO with this vector unilaterally at postnatal day 30. We monitored their retinal structure by using spectral-domain optical coherence tomography (SD-OCT) and retinal function using electroretinography (ERG) for nine months. We compared these to P23H RHO transgenic mice injected unilaterally with a control vector. Though retinas continued to thin over time, compared to control injected eyes, treatment with AAV-RHO820-shRNA820 slowed the loss of photoreceptor cells and the decrease in ERG amplitudes during the nine-month study period. Unexpectedly, we also observed the preservation of retinal structure and function in the untreated contralateral eyes of AAV-RHO820-shRNA820 treated mice. PCR analysis and western blots showed that a low amount of vector from injected eyes was present in uninjected eyes. In addition, protective neurotrophic factors bFGF and GDNF were elevated in both eyes of treated mice. Our finding suggests that using this or similar RNA replacement vectors in human gene therapy may provide clinical benefit to both eyes of patients with adRP., Competing Interests: Declaration of Competing Interest The University of Florida holds patents covering the AAV vector used in these experiments, and ASL and MTM may earn royalties due to these patents., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

PTEN hamartoma tumour syndrome is characterised by mutations in the human PTEN gene. We performed transcriptomic and proteomic analyses of neural tissues and primary cultures from heterozygous and homozygous Pten-knockout mice. The somatosensory cortex of heterozygous Pten-knockout mice was enriched in immune response and oligodendrocyte development Gene Ontology (GO) terms. Parallel proteomic analysis revealed differentially expressed proteins (DEPs) related to dendritic spine development, keratinisation and hamartoma signatures. However, primary astrocytes (ASTs) from heterozygous Pten-knockout mice were enriched in the extracellular matrix GO term, while primary cortical neurons (PCNs) were enriched in immediate-early genes. In ASTs from homozygous Pten-knockout mice, cilium-related activity was enriched, while PCNs exhibited downregulation of forebrain neuron generation and differentiation, implying an altered excitatory/inhibitory balance. By integrating DEPs with pre-filtered differentially expressed genes, we identified the enrichment of traits of intelligence, cognitive function and schizophrenia, while DEPs in ASTs were significantly associated with intelligence and depression., (© 2023. The Author(s).)

Background: Gamma-hydroxybutyrate is a potent central nervous system depressant with a narrow recreational dose window and analytical detection time. We describe data relating to intoxicated patients presenting to emergency departments across metropolitan Adelaide who tested positive for gamma-hydroxybutyrate. This work was part of the Emergency Department Admission Blood Psychoactive Testing study., Methods: Over a 15-month period, patients presenting to four metropolitan emergency departments with symptoms of drug intoxication were enrolled in the study. The methodology involved the collection of demographic and clinical data and a de-identified blood sample which underwent comprehensive toxicological analysis. Gamma-hydroxybutyrate was determined using an acid-catalysed cyclisation followed by liquid-liquid extraction and gas chromatography-mass spectrometry. Data relating to samples positive for gamma-hydroxybutyrate were examined., Results and Discussion: A total of 1120 patients were enrolled between March 2019 and May 2020, 309 of whom were positive for gamma-hydroxybutyrate (27.6%). Of these, 256 (83%) were also positive for metamfetamine (methamphetamine). The most common clinical observation in gamma-hydroxybutyrate-positive patients was central nervous system depression (89%). There was a significant relationship between gamma-hydroxybutyrate status and sex; although males outnumbered females in absolute terms, a higher proportion of females (32%) tested positive for gamma-hydroxybutyrate than males (25%, P  = 0.0155). Blood gamma-hydroxybutyrate concentrations ranged from 10 to 651 mg/L (0.096-6.2 mmol/L) and increasing gamma-hydroxybutyrate concentration correlated with severe toxicity. The presence of gamma-hydroxybutyrate had a significant impact on the patient discharge destination: the majority (69.2%) of gamma-hydroxybutyrate-positive patients were managed and discharged from the emergency department or their attached short stay wards. A significantly higher proportion of gamma-hydroxybutyrate-positive patients were admitted to the intensive care unit (28.2%) compared with gamma-hydroxybutyrate-negative patients (12.7%, chi-squared = 36.85, P  <0 .001). Gamma-hydroxybutyrate positive cases accounted for 45.8% of all study-related intensive care unit admissions., Conclusions: Gamma-hydroxybutyrate is commonly detected in illicit drug-related emergency department presentations and is detected disproportionately in the patient cohort who require intensive care unit level care.

Understanding survivorship experiences at different stages postliver transplantation (poat-LT) is essential to improving care. Patient-reported concepts including coping, resilience, post-traumatic growth (PTG), and anxiety/depression, have been implicated as important predictors of quality of life and health behaviors after LT. We aimed to descriptively characterize these concepts at different post-LT survivorship stages. This cross-sectional study featured self-reported surveys measuring sociodemographic, clinical characteristics, and patient-reported concepts including coping, resilience, PTG, anxiety, and depression. Survivorship periods were categorized as early (1 y or below), mid (1-5 y), late (5-10 y), and advanced (10 y or above). Univariable and multivariable logistic and linear regression modeling examined factors associated with patient-reported concepts. Among 191 adult LT survivors, the median survivorship stage was 7.7 years (interquartile range: 3.1-14.4) and median age was 63 years (range: 28-83); most were male (64.2%) and Caucasian (84.0%). High PTG was more prevalent in the early survivorship period (85.0%) than late survivorship (15.2%). High trait resilience was only reported by 33% of survivors and associated with higher income. Lower resilience was seen among patients with longer LT hospitalization stays and late survivorship stages. About 25% of survivors had clinically significant anxiety and depression, which was more frequent among early survivors and females with pre-LT mental health disorders. In multivariable analysis, factors associated with lower active coping included survivors ≥65 years, non-Caucasian race, lower levels of education, and nonviral liver disease. In a heterogeneous cohort including early and late LT survivors, there was variation in levels of PTG, resilience, anxiety, and depression at different survivorship stages. Factors associated with positive psychological traits were identified. Understanding determinants of LT survivorship has important implications for how we should monitor and support LT survivors., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2) 1 , could represent a new chemoprophylactic approach for COVID-19 that complements vaccination 2,3 . However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials., (© 2022. The Author(s).)

Background: Adipose tissue plays a pivotal role in the pathology of metabolic disorders. In the past decade, brown and brown-like adipose tissues were detected in adult humans and show therapeutic potential in ageing-related metabolic diseases., Objective: This study investigated expressions of major brown adipose markers in white adipose tissue (WAT) of different ages. Their associations with metabolic parameters and key adipokines were interrogated., Design: Cross-sectional study, 2019-2021., Methods: We recruited 21 young, 67 middle-aged, and 34 older patients. Omental adipose tissues were collected, and expressions of key brown markers and adipokines and the adipocyte size were evaluated. The fat depot distribution was evaluated by computed tomography., Results: UCP1 and PRDM16 mRNA expressions declined with ageing in WAT and were more associated with age, than with the body mass index (BMI). The increased visceral adipose tissue (VAT) amount, as well as the VAT to subcutaneous adipose tissue (SAT) ratio, was decreased in the highest tertile of UCP1 expression, while individuals in different PRDM16 mRNA tertiles exhibited similar fat distribution. UCP1 mRNA was positively correlated with ADIPOQ and the strength of the correlation declined with ageing. In contrast, the association between UCP1 and LEP was insignificant in young and middle-aged groups but became significantly correlated in the older-people group. We also found a positive correlation between UCP1 and PRDM16., Conclusions: PRDM16 and UCP1, despite their key functions in adipose browning, exhibit differential clinical correlations with metabolic features in human WAT in an age-dependent manner. These two genes may participate in the pathogenesis of ageing-related metabolic diseases, but with distinct mechanisms., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The advanced form of AMD, geographic atrophy, is associated with increased RPE oxidative stress and chronic inflammation. Here we evaluated the effects of delivering an anti-inflammatory viral gene by an AAV-vector in a mouse model of geographic atrophy. We measured changes in retinal function, structure, and morphology over nine months with electroretinography, optical coherence tomography, and fundoscopy, respectively. In addition, we used retinal tissue to quantify changes in markers of inflammation by multiplex ELISA, RT-qPCR, and immunofluorescence staining. Our AAV significantly delayed the loss of retinal function and structure and decreased retinal inflammation compared to the control AAV treatment. Our results suggest that modulating retinal inflammation could significantly slow the progression of geographic atrophy.

The habitability of Europa is a property within a system, which is driven by a multitude of physical and chemical processes and is defined by many interdependent parameters, so that its full characterization requires collaborative investigation. To explore Europa as an integrated system to yield a complete picture of its habitability, the Europa Clipper mission has three primary science objectives: (1) characterize the ice shell and ocean including their heterogeneity, properties, and the nature of surface-ice-ocean exchange; (2) characterize Europa's composition including any non-ice materials on the surface and in the atmosphere, and any carbon-containing compounds; and (3) characterize Europa's geology including surface features and localities of high science interest. The mission will also address several cross-cutting science topics including the search for any current or recent activity in the form of thermal anomalies and plumes, performing geodetic and radiation measurements, and assessing high-resolution, co-located observations at select sites to provide reconnaissance for a potential future landed mission. Synthesizing the mission's science measurements, as well as incorporating remote observations by Earth-based observatories, the James Webb Space Telescope, and other space-based resources, to constrain Europa's habitability, is a complex task and is guided by the mission's Habitability Assessment Board (HAB)., Competing Interests: Competing InterestsThe authors have no competing interests to declare that are relevant to the content of this article., (© The Author(s) 2023.)

Parents are often regarded as one of the significant social agents who are important to the participation of physical activity (PA) among children and adolescents. However, within the literature, the relationships between parental influences and child and adolescent PA have been inconclusive and discordant. The purpose of this meta-analysis was to quantify and synthesize the associations between parental social influences (positive parental influence, punishment, and discouragement) and the PA level of children and adolescents. Through a systematic literature search using PsycINFO, Web of Science, PubMed, ProQuest, and SPORTDiscus databases, we identified 112 eligible studies and subsequently extracted 741 effect sizes for our analysis. Multilevel meta-analysis showed that the corrected zero-order correlation of positive parental influence was positive and statistically significant, r = 0.202, SE = 0.014, t = 14.975, p < 0.001, 95% confidence interval (CI) = [0.176, 0.228]. Further moderation analysis also found that this was significantly moderated by parental gender (maternal vs. paternal), respondent of influence measure (parent-reported vs. child-reported), and type of PA measure (subjective vs. objective). The corrected zero-order correlations of negative parental influences (i.e., punishment and discouragement) were not statistically significant, and no significant moderation effects were observed. The findings of our meta-analysis showed that children and adolescents had higher PA levels when their parents supported PA participation by exerting positive social influence. Punishment and discouragement against PA by parents did not appear to be significantly associated with the PA level of children and adolescents. The findings of negative parental social influence were mixed and required further investigations.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a bridging therapy for refractory cardiogenic shock, and limb ischemia is a concern with femoral cannulation. Because of the rich collateral pelvic circulatory supply, buttock ischemia is not common and is usually a complication after aneurysmal aortic repair or internal iliac artery embolization after pelvic trauma. Gluteal necrosis occurring as an extracorporeal membrane oxygenation complication has not been reported in the literature. In this case series, we report three patients with ischemic buttock after initiating VA-ECMO and discuss the risk factors and the clinical and radiological features supportive of the diagnosis. We review the gluteal and pelvic vascular anatomy, postulate how cannula size, ethnicity, catecholamines, and reversal of gluteal arterial flow contributed to this rare entity in our patients and explain how these findings have changed our institution's practice., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

Introduction: Substance use is a common contributing factor to emergency department (ED) presentations. While screening, brief intervention, and referral to treatment for alcohol and tobacco is common in ED settings, it is not routinely conducted for illicit substances. This study aimed to deploy the ASSIST-Lite to screen for risky use of alcohol and other drugs in the ED, to identify differences in risk based on between demographic characteristics., Method: All ED attenders, aged 18 years or older, deemed well enough to participate were approached. Recruitment occurred at the Royal Adelaide Hospital ED between May and June 2017. Participants were asked to self-complete the ASSIST-Lite in the ED waiting room. Overall, 632 people were approached, of which 479 (75.8%) agreed to participate., Results: Alcohol (72.2%), tobacco (27.1%) and cannabis (15.2%) were most commonly reported. Eighty-nine participants reported moderate- or high-risk use of two substances, and a further 49 individuals reported moderate- or high-risk use of three or more substances. Across most substances, age, gender and employment status was associated with risky substance use, with higher likelihood of risk reported by males, unemployed and younger participants. Unemployment was also significantly associated with increased risk severity for both moderate and high-risk illicit use., Discussions and Conclusions: The rate of risky illicit and polysubstance use found here highlight the need more focused research in ED settings. The findings also provide support for more routine screening, and early intervention approaches; and suggest the need for active referral pathways through an alcohol and other drug consultation liaison service., (© 2022 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Background: Current ways to diagnose citrate accumulation (CA) in patients receiving regional citrate anticoagulation (RCA) continuous renal replacement therapy (CRRT) are confounded by various clinical factors. Serum citrate measurement emerges as a more direct way to diagnose CA, but its clinical utility and optimal cut-off values remain undefined. This study examined serum citrate kinetics and its diagnostic performance for CA in patients receiving RCA CRRT., Methods: A multicentre prospective study was carried out in two tertiary referral centre intensive care units in Hong Kong with serum citrate levels measured at baseline and 2, 6, 12, 24, 36, 48 and 72 h after initiation of RCA CRRT and their relationships with the development of CA., Results: Among the 133 patients analysed, 18 patients (13.5%) developed CA. The serum citrate levels at baseline and 2, 6 and 12 h after initiation of RCA CRRT in patients who had CA were significantly higher than the non-CA group ( P  < .001 for all). The CA group also had higher serum citrate levels than the non-CA group {median 0.93 mmol/L [interquartile range (IQR) 0.81-1.16) versus 0.37 mmol/L (IQR 0.26-0.57), P  < .001}. Using a cut-off of 0.85 mmol/L, the serum citrate level had a sensitivity of 0.77 and a specificity 0.96 for the diagnosis of CA [area under the receiver operating characteristics curve (AUROC) 0.90, P  < .001]. The 2-h and 6-h serum citrate levels had good discriminatory abilities for predicting subsequent development of CA (AUROC 0.86 and 0.83 for 2-h and 6-h citrate levels using cut-off values of 0.34 and 0.63 mmol/L, respectively; P  < .001)., Conclusion: Serum citrate levels were significantly higher in patients with CA compared with patients without CA. Serum citrate levels showed good performance in diagnosing and predicting the development of CA., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

The growing concerns regarding the risks of transmitting the COVID-19 virus have intensified the job-related stressors commonly encountered by teachers in various cultural contexts. Evidence shows how the COVID-19 crisis has negatively impacted teachers' mental health outcomes such as stress, depression, and quality of life, which highlights the significance of designing psychological programs to boost teachers' well-being. This study examined the effects of a well-being intervention based on the Positivity, Relationship, Outcomes, Strength, Purpose, Engagement, and Resilience (PROSPER) framework on well-being outcomes among 76 in-service teachers (M age  = 26.05 years, SD = 4.71, range = 20-45; female = 93.4%) in Hong Kong. Participants completed survey measures associated with the seven PROSPER outcomes at baseline and 2-month follow-up. Multivariate regression analysis indicated that there were statistically significant multivariate effects for intervention conditions, Wilks' Lambda F(7, 58) = 4.50, p = .01. Results demonstrated that teachers who were assigned to the intervention condition (n = 36) had significantly higher scores than those in the control condition (n = 40) on positivity (b = 0.41, 95% CI [0.16, 0.65], p = .01), strength (b = 0.62, 95% CI [0.23, 1.01], p = .01), purpose (b = 0.61, 95% CI [0.18, 1.04], p = .01), and resilience (b = 0.57, 95% CI [0.07, 1.07], p = .04). Our findings provide evidence on the mental health benefits of the PROSPER-based psychological intervention program for preschool teachers., (Copyright © 2022 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.)

Background: Soumbala is a highly loved alkaline traditional fermented food condiment in Burkina Faso. It harbors various microbiota dominated by fermentative Bacillus spp. as functional microorganism with little confirmed health-promoting properties., Methods: The present study aimed to evaluate six Bacillus strains previously isolated and identified from soumbala. These strains were selected as presumptively safe bacteria for probiotic and technological characteristics. These strains were assessed for in vitro probiotic criteria (tolerance to acidic pH, gastric juice, 0.3% (m/v) bile salts, intestinal juice and 0.4% (w/v) phenol, cell surface hydrophobicity, auto-aggregation capacity, antimicrobial activity against foodborne pathogens, antibiotic susceptibility and biofilm production) and technological properties, including protease, amylase, lipase, and tannase activity, as well as poly-γ-glutamic acid (PGA) production and thermo-tolerance., Results: All tested Bacillus strains (B54, F20, F24, F21, F26 and F44) presented variable relevant probiotic properties (good tolerance to pH 2 and pH 4, gastric juice, bile salts, intestinal juice and phenol), with marked differences in hydrophobicity and auto-aggregation capacity ranging from 73.62-94.71% and 49.35-92.30%, respectively. They exhibited a broad spectrum of activity against foodborne pathogens depending on target pathogen, with the highest activity exhibited by strain F20 (29.52 mm) against B. cereus 39 (p <  0.001). They also showed good biofilm production as well as variable hydrolytic enzyme activities, including protease (43.00-60.67 mm), amylase (22.59-49.55 mm), lipase (20.02-24.57 mm), and tannase (0-10.67 mm). All tested Bacillus strains tolerated temperature up to 50 °C, while only strains F26 and F44 showed the best PGA production., Conclusion: Overall, the tested cultures exhibiting potential probiotic and technological characteristics; particularly B. cereus F20, B. benzoevorans F21, B. cabrialessi F26, and B. tequilensis F44 could be a source of probiotic-starters of commercial interest in the production of high-quality soumbala., (© 2022. The Author(s).)

Background: Paraquat (PQ) poisoning is a serious public health concern, especially in developing countries, due to its easy access and lack of awareness of potential harms. No effective treatment has been reported yet. Conventional hemodialysis (HD) is still used in many centers for excreting PQ or reducing acute kidney injury, but there is no consensus on its efficacy. Therefore, we aimed to review the HD efficacy in PQ poisoning mortality., Materials and Methods: We searched Web of Science, PubMed, Excerpta Medical Database, Google Scholar, Scopus, Cochrane, Web of Knowledge, Pro-Quest, ScienceDirect, Springer, Clinical Key, Scientific Information Database, Magiran, and Iran-doc, in publications before January 1, 2020. We compared patients who underwent HD (Group 1) with those who did not (Group 2). The outcome was considered mortality/survival. The data were analyzed by Comprehensive Meta-analysis Software., Results: This systematic review and meta-analysis included five studies with a combined total of 203 patients. The patients in the Group 1 had higher mortality than Group 2 (odds ratio, 2.84; 95% confidence interval: 1.22-6.64; P = 0.02). There was no evidence of publication bias ( P value for Egger's test = 0.833)., Conclusion: Although HD did not affect the survival of patients, other variables such as the amount of ingested PQ, poisoning severity, the time between PQ ingestion and the start of HD, duration, and times of HD sessions may influence the results regarding mortality., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Research in Medical Sciences.)

Rationale: Hyperactivation of Hippo-Yes-associated protein (YAP) signaling pathway governs tumorigenesis of gastric cancer (GC). Here we reveal that minichromosome maintenance complex component 6 (MCM6) is a critical transcriptional target of YAP in GC. We aim to investigate the function, mechanism of action, and clinical implication of MCM6 in GC. Methods: The downstream targets of YAP were screened by RNA sequencing (RNA-seq) and microarray, and further validated by chromatin immunoprecipitation PCR and luciferase reporter assays. The clinical implication of MCM6 was assessed in multiple GC cohorts. Biological function of MCM6 was evaluated in vitro , in patient-derived organoids, and in vivo . RNA-seq was performed to unravel downstream signaling of MCM6. Potential MCM6 inhibitor was identified and the effect of MCM6 inhibition on GC growth was evaluated. Results: Integrative RNA sequencing and microarray analyses revealed MCM6 as a potential YAP downstream target in GC. The YAP-TEAD complex bound to the promoter of MCM6 to induce its transcription. Increased MCM6 expression was commonly observed in human GC tissues and predicted poor patients survival. MCM6 knockdown suppressed proliferation and migration of GC cells and patient-derived organoids, and attenuated xenograft growth and peritoneal metastasis in mice. Mechanistically, MCM6 activated PI3K/Akt/GSK3β signaling to support YAP-potentiated gastric tumorigenicity and metastasis. Furthermore, MCM6 deficiency sensitized GC cells to chemo- or radiotherapy by causing DNA breaks and blocking ATR/Chk1-mediated DNA damage response (DDR), leading to exacerbated cell death and tumor regression. As there are no available MCM6 inhibitors, we performed high-throughput virtual screening and identified purpureaside C as a novel MCM6 inhibitor. Purpureaside C not only suppressed GC growth but also synergized with 5-fluorouracil to induce cell death. Conclusions: Hyperactivated YAP in GC induces MCM6 transcription via binding to its promoter. YAP-MCM6 axis facilitates GC progression by inducing PI3K/Akt signaling. Targeting MCM6 suppresses GC growth and sensitizes GC cells to genotoxic agents by modulating ATR/Chk1-dependent DDR, providing a promising strategy for GC treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Microdebris ingestion in fish is widespread and has adverse effects on marine life. This study assessed the occurrence and type of microdebris found in three commercially important fish species from different landing sites along Guyana's coast. Visual examination of fish gut content was initially carried out using the naked eye and a hand lens. Microscopic examinations were subsequently carried out to determine the number and type of debris present. Forty percent of the fishes examined had microdebris present in their bodies. A total of 112 microdebris particles were collected from 90 specimens of three species (Bagre bagre, Nebris microps, Macrodon ancyclodon). The microdebris particles observed included pellets, microbeads, fragments, fiber (wool), films, and foams. White-colored materials were the most frequently ingested. Most of the collected materials were large microdebris (>1 to 5 mm) that resembled pellets and microbeads. This study displayed the prevalence of microdebris ingestion by commercial fish in Guyana., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)